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84. Francis WJA, Jeffcoate TNA. Dyspareunia following vaginal operations. J Opt Soc Am 1961;68:1–10.

85. Cundiff GW, Weidner AC, Visco AG, et al. An anatomic and functional assessment of the discrete defect rectocele repair. Am J Obstet Gynecol 1998;179:1451–1457.

86. Porter WE, Steele A, Walsh P, et al. The anatomic and functional outcomes of defect–

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87. Kenton K, Shott S, Brubaker ll. Outcome after rectovaginal fascia reattachment for rectocele repair. Am J Obstet Gynecol 1999;181:1360–1364.

88. Glavind K, Madsen H. A prospective study of the discrete fascial defect rectocele repair.

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89. Singh K, Cortes E, Reid WMN. Evaluation of the fascial technique for surgical repair of isolated posterior vaginal wall prolapse. Obstet Gynecol 2003;101:320–324.

90. Kohli N, Miklos JR. Dermal graft augmented rectocele repair. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:146–149.

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92. Watson SJ, Loder PB, Halligan S, et al. Transperineal repair of symptomatic rectocele with Marlex mesh: a clinical, physiological and radiologic assessment of treatment. J Am Coll Surg 1996;183:257–261.

93. Goh JTW, Dwyer PL. Effectiveness and safety of polypropylene mesh in vaginal prolapse surgery. Int Urogynecol J 2001;12:S90.

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95. Cundiff GW, Harris RL, Coates K, et al. Abdominal sacral colpoperineopexy: a new approach for correction of posterior compartment defects and perineal descent associates with vaginal vault prolapse. Am J Obstet Gynecol 1997;177:1345–1355.

96. Visco AG, Weidner AC, Barber MD, et al. Vaginal mesh erosion after abdominal sacral colpopexy. Am J Obstet Gyencol 2001;184:297–302.

97. Sullivan ES, Longaker CJ, Lee PY. Total pelvic mesh repair; a ten–year experience. Dis Colon Rectum 2001;44:857–863.

98. Lyons TL, Winer WK. Laparoscopic rectocele repair using polyglactin mesh. J Am Assoc Gynecol Laparosc 1997;4:381–384.

99. Seracchioli R, Hourcubie JA, Vianello F, et al. Laparoscopic treatment of pelvic floor defects in women of reproductive age. J Am Assoc Gynecol Laparosc 2004;11:332–335.

100. Kahn MA, Kumar D, Stanton SL. Posterior colporrhaphy vs. transanal repair of the rectocele: an initial follow up of a prospective randomized trial. Br J Obstet Gynaecol 1998;105:57.

101. Nieminen K, Hiltunen KM, Laitinen J, et al. Transanal or vaginal approach to rectocele repair: a prospective randomized pilot study. Dis Colon Rectum 2004;47:1636–1642.

102. Janssen LWM, van Dijke CF. Selection criteria for anterior rectal wall repair in symptomatic rectocele and anterior rectal wall prolapse. Dis Colon Rectum 1994;37:1100–1107.

103. Van Dam JH, Huisman WM, Hop WCJ, et al. Fecal continence after rectocele repair: a prospective study. Int J Colorectal Dis 2000;15:54–57.

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115. Sharp TR. Sacrospinous suspension made easy. Obstet Gynecol 1993;82:873–875.

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Editors: Berek, Jonathan S.

Title: Berek & Novak's Gynecology, 14th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > Section VI - Urogynecology and Pelvic Reconstructive Surgery > 25 - Anorectal Dysfunction 25

Anorectal Dysfunction

Robert E. Gutman

Geoffrey W. Cundiff

Defecatory dysfunction and fecal incontinence are common conditions that have tremendous psychosocial and economic implications.

The differential diagnosis for anorectal dysfunction is broad and can be classified into systemic factors, anatomic and structural abnormalities, and functional disorders.

A thorough history and physical examination is critical for the evaluation of fecal incontinence and defecatory dysfunction, as well as appropriate ancillary testing.

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Treatment of anorectal dysfunction should focus on treatment of the underlying condition with nonsurgical management attempted before surgery.

Overlapping sphincteroplasty is the procedure of choice for fecal

incontinence caused by a disrupted anal sphincter.

Anorectal dysfunction encompasses a variety of conditions that disrupt normal anorectal function. Such conditions can be subdivided as those that cause defecatory dysfunction and fecal incontinence. Although anorectal dysfunction transcends any individual medical specialty, the pathophysiology, evaluation, and management of conditions relevant to obstetrician–gynecologists are presented in this chapter.

Normal Colorectal Function

Anal continence and defecation are complex physiologic processes that require intact and coordinated neurologic and anatomic function, including colonic absorption and motility, rectal compliance, anorectal sensation, and the multifaceted continence mechanism. An understanding of normal physiology and pathophysiology is essential to the treatment of women with anorectal dysfunction.

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Stool Formation and Colonic Transit

The colon plays an important role in absorption and regulation of water and electrolytes. As much as 5 liters of water and associated electrolytes can be absorbed in 1

day. Parasympathetic–mediated peristaltic contraction of colonic smooth muscle transfers fecal material to the rectum. A delay in stool transit at the rectosigmoid region of the colon allows for maximal absorption of water and sodium.

Storage

As stool accumulates in the rectosigmoid, rectal distention triggers a transient decrease in the internal anal sphincter (IAS) tone and an increase in the external anal sphincter (EAS) tone known as the rectoanal inhibitory reflex. Exposure of the anal canal to fecal matter facilitates sampling, whereby the anal canal and its abundant sensory nerves determine stool consistency (i.e., solid, liquid, or gas). Accommodation occurs as the normally compliant rectal vault relaxes in response to increased volume. This cycle, combined with increased rectal distention, stimulates an urge to defecate. This urge can be voluntarily suppressed through cortical control, resulting in further accommodation and activation of the continence mechanism.

Continence Mechanism

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Muscles

The key muscles of the continence mechanism are the puborectalis, IAS, and EAS.

The puborectalis muscle originates from the pubic rami at the level of the arcus tendineus levator ani and passes laterally to the vagina and rectum in a U–shaped configuration, creating a sling around the genital hiatus. Contraction of the puborectalis muscle narrows the genital hiatus, developing the near 90–degree anorectal angle. The resting tone of the puborectalis muscle serves as the primary continence mechanism for solid stool. The IAS and EAS are essential for continence of flatus and liquid stool. The internal sphincter maintains most of the resting tone for the sphincter complex through autonomic reflex arcs and is essential for passive continence. Although the external sphincter also maintains constant resting tone, it is ultimately responsible for preventing fecal urgency and stress incontinence associated with sudden increases in intra–abdominal pressure. This function is under both voluntary and involuntary control. The anal cushions act as the final anatomic barrier. They fill with blood, causing occlusion of the anal canal.

Nerves

Many pathologic states disrupt normal function through denervation. The IAS receives its sympathetic supply from L5, which passes through the pelvic plexus via the hypogastric plexus. The parasympathetic supply from S2–4 synapses at the pelvic plexus, where it joins the sympathetic nerves. The IAS acts through reflex arcs at the spinal cord without voluntary control. The puborectalis (levator ani) is innervated by branches of the S2–

4 sacral roots and does not receive direct innervation from the pudendal nerve (1). The EAS

is innervated bilaterally by the pudendal nerve (S2–4) via Alcock's canal. The pudendal nerve fibers cross over at the level of the spinal cord, allowing preservation of EAS function in the event of unilateral damage. The rich sensory supply from the anal canal travels along the inferior rectal branch of the pudendal nerve.

Evacuation

Initiation of defecation is normally under cortical control. As previously discussed, delivery of stool to the rectum stimulates the rectoanal inhibitory reflex, permitting sampling followed by accommodation. Further rectal distention results in an urge to defecate. Evacuation occurs with voluntary relaxation of the pelvic floor muscles (puborectalis muscle and EAS) in conjunction with increased intra–abdominal and intrarectal pressure

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from Valsalva. This results in widening of the anorectal angle and shortening of the anal canal, which facilitates emptying. Coordinated peristaltic activity of the rectosigmoid assists evacuation. After this process is complete, the closing reflex is initiated, resulting in contraction of the pelvic floor muscles and activation of the continence mechanism.

Epidemiology

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The epidemiology of anorectal dysfunction has been best defined in terms of the incidence and prevalence of fecal incontinence. Few studies have been done to assess the incidence and prevalence of defecatory dysfunction.

Defecatory Dysfunction

The term defecatory dysfunction often is used synonymously with the symptom of constipation. Constipation is an imprecise term used by patients to report a variety of symptoms, including infrequent stools, dyschezia, straining, variation in stool consistency and caliber, incomplete emptying, bloating, and abdominal pain.

The most common symptoms associated with constipation are straining and hard stools (2,3). Defecatory dysfunction is defined by many physicians as infrequent stools, typically fewer than three bowel movements per week. This definition is based on stool frequency studies in which 95% of women have more than three bowel movements per week. Using this definition, the prevalence of constipation should be 5% (4). However, the prevalence of constipation has been estimated to range from 2% to 28%, depending on the definition applied (5,6,7).

There is an increased prevalence of constipation among women and elderly individuals, nonwhite individuals, and those with low income and low education levels (5,6,7). Based on an estimated 2.5 million visits to U.S. physicians per year for constipation (8), with an average cost of $2,752 per patient (9), the annual cost for evaluation of constipation would be approximately $6.9 billion. An estimated 85% of physician visits results in a prescription; thus, drug costs would increase this amount substantially (8). Constipation does have a detrimental effect on health–related quality of life (3,10). Constipation contributed to decreased mental and physical scores for quality of life on the SF–36 Health Survey in a Canadian–based population (10).

Fecal Incontinence

The reported prevalence of fecal incontinence varies between 2% and 3% for community–dwelling individuals, 3% to 17% for those of increased age, and 46% to 54% for nursing home residents (11). A prevalence of 28% has been reported among patients seeking benign gynecologic care (12). Epidemiological studies of fecal incontinence are compromised by social stigmata and the lack of a uniform definition. Definitions of fecal incontinence vary with respect to the type of material passed (solid, liquid, or gas), the frequency and duration of events (once in a lifetime to twice a week), and the impact on quality of life. Most authors agree that the true prevalence of this condition is underestimated in the current scientific literature. A large health survey in the United States found age, female sex, physical limitations, and poor general health to be independent risk factors associated with fecal incontinence (13).

Fecal incontinence has tremendous psychosocial and economic implications for individuals and society as a whole. The loss of such a basic function can be emotionally devastating, leading to poor self–esteem, depression, social isolation, Ovid: Berek & Novak's Gynecology

and decreased quality of life ( 12,14). Fecal incontinence is the second leading reason for nursing home placement in the United States, even though fewer than one third of individuals with this condition seek medical attention (12,14). The overall annual cost to treat

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fecal incontinence is difficult to pinpoint, but accounts for more than $400,000,000 per year in the cost of adult diapers alone (14).

Symptom–Based Approach to Colorectal Disorders

Several medical conditions cause defecatory dysfunction, fecal incontinence, or combined symptoms. Following is the differential diagnosis—a proposed classification system based on systemic factors, anatomic and structural abnormalities, and functional disorders.

Differential Diagnosis

Disordered Defecation

Causes of defecatory dysfunction have traditionally been divided into systemic disorders and idiopathic constipation (all nonsystemic causes). Idiopathic constipation can be subdivided into anatomic and structural abnormalities and functional disorders (Table 25.1).

Diabetes, hypothyroidism, and pregnancy are the most common endocrinologic systemic factors that cause constipation, and all have a component of decreased gastrointestinal motility and intestinal transit. In one study, gastrointestinal symptoms were present in 76% of patients with diabetes, including constipation, which occurred in 60% (15). In patients with diabetes, constipation is believed to be secondary to intestinal autonomic neuropathy, resulting in delayed or absent gastrocolic reflex and decreased bowel motility. This enteric neuropathy may also cause gastroparesis and diarrhea. Although diabetes has been classified with the endocrinologic causes, it should also be grouped with the enteric neuropathies. Pregnancy is not considered a disease state; however, there is an 11% to 38% prevalence of constipation that is believed to be due primarily to the effect of progesterone on smooth muscle (16). The neurologic systemic factors can be divided into central and peripheral processes. Spinal cord lesions, multiple sclerosis, and Parkinson disease affect the autonomic nervous system. Trauma to the sacral nerves often leads to severe constipation from decreased left–sided colonic motility, decreased rectal tone and sensation, and increased distention. These findings are also seen in patients with meningomyelocele, damage to the lumbosacral spine, and pelvic floor trauma (17,18).

Higher spinal cord lesions result in delayed sigmoid transit and decreased rectal compliance. In these upper motor neuron lesions, colonic reflexes are intact, and defecation can be initiated by digital stimulation of the anal canal (19,20). Individuals with multiple sclerosis can have no gastrocolic reflex, decreased colonic motility, decreased rectal compliance, and even rectosphincteric dyssynergia (21,22). Constipation worsens with the duration of illness and may be compounded by the side effects of medical therapy. Similar findings of Ovid: Berek & Novak's Gynecology

rectosphincteric dyssynergia and medication side effects are present with Parkinson disease.

Among the peripheral neurogenic disorders, dysfunction occurs at the level of the enteric nerves. The ultimate example of this finding is congenital aganglionosis (Hirschsprung disease).

The absence of intramural ganglion cells in the submucosal and myenteric plexuses of the rectum causes loss of the rectosphincteric inhibitory reflex. Patients with this illness usually present with functional obstruction and proximal colonic dilation. In most patients, the condition is diagnosed within 6 months of age, although milder cases can be seen later in life.

Other systemic factors to consider are collagen vascular and muscle disorders. Importantly, some of the most commonly used prescription and over–the–counter medications, including aluminum antacids, beta–blockers, calcium channel blockers, anticholinergics, antidepressants, and opiates, cause defecatory dysfunction (Table 25.2). Lifestyle issues, such as P.939

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inadequate fiber intake and insufficient fluid intake, can exert similar effects independently or in conjunction with other disorders.

Table 25.1 Causes of Defecatory Dysfunction and Fecal Incontinence

Fecal Incontinence

Defecatory Dysfunction

Systemic Factors

Metabolic/Endocrine

Diabetes mellitus

Thyroid disease

Hypercalcemia

Hypokalemia

Neurological

Central Nervous System

Multiple sclerosis, Parkinson disease, stroke, tumor, dementia

Peripheral Nervous System

Hirschsprung disease, spina bifida, autonomic neuropathy, pudendal neuropathy Infectious

Bacterial, viral, parasitic diarrhea

Collagen Vascular/Muscle Disorder

Systemic sclerosis, amyloidosis, myotonic dystrophy, dermatomyositis

Idiopathic/Autoimmune

Inflammatory bowel disease

Food allergy

Medications

Prescription, over the counter

Anatomical/Structural Abnormalities

Pelvic Outlet Obstruction

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Pelvic organ prolapse

Descending perineum syndrome

Anismus/rectosphincteric dyssynergia

Intussusception, rectal prolapse

Volvulus

Neoplasia

Benign strictures

Hemorrhoids

Anal Sphincter Disruption/Fistula

Obstetrical trauma

Surgical trauma

Anal intercourse

Injury (trauma, radiation proctitis)

Functional

Motility Disorders

Global motility disorder

Colonic inertia/slow–transit constipation

Irritable bowel syndrome

Functional constipation

Functional diarrhea

Functional Limitations

Decreased mobility

Decreased cognition

Table 25.2 Drugs Associated with Constipation

Over–the-Counter Medications

Antidiarrheals (loperamide, Kaopectate)

Antacids (with aluminum or calcium)

Iron supplements

Prescription Medications

Anticholinergics

Others

Antidepressants

Iron

Antipsychotics

Barium sulfate

Antispasmodics

Metallic intoxication (arsenic, lead, mercury)

Antiparkinsonian drugs

Opiates

Antihypertensives

Nonsteroidal anti-inflammatory agents

Calcium channel blockers

Anticonvulsants

Beta-blockers

Vinca alkaloids

Diuretics

5-HT3 antagonists ( ondansetron, granisetron)

Ganglionic blockers

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Structural abnormalities refer to the obstructive disorders, such as pelvic organ prolapse, perineal descent, intussusception, rectal prolapse, and tumors.

Functional disorders are those that do not have an identifiable anatomic or systemic etiology. Most functional disorders are motility disorders, such as slow–

transit constipation/colonic inertia, irritable bowel syndrome (constipation predominant), and functional constipation. Patients also may have functional limitations, such as decreased mobility and cognition. It is important to understand that this classification system is somewhat arbitrary, and several of these conditions are interrelated.

Fecal Incontinence

Anal continence depends on a complex interaction of cognitive, anatomic, neurologic, and physiologic mechanisms. The continence mechanism can often compensate for a deficiency in one of these processes, but it can be overwhelmed with increased severity or decreased function over time. Systemic etiologies of fecal incontinence often are due to disease states that cause diarrhea. The rapid transport of large volumes of liquid stool to the rectum can produce urgency and incontinence even in healthy individuals (23). Fecal incontinence frequently results from infectious diarrhea caused by bacteria (e.g., Clostridium, E.

coli, Salmonella, Shigella, Yersinia, Campylobacter), viruses (e.g., Rotavirus, Norwalk, human immunodeficiency virus [HIV]), and parasites (e.g., Entamoeba, Giardia, Cryptosporidium, Ascaris). Numerous medications and dietary items cause diarrhea and fecal incontinence (Table 25.3). Endocrine factors that can lead to fecal incontinence include diabetes mellitus and hyperthyroidism. With diabetes, diarrhea can develop from autonomic dysfunction, bacterial overgrowth, osmotic diarrhea with sugar substitutes, and pancreatic insufficiency. Inflammatory bowel disease is considered an idiopathic/

autoimmune systemic factor. Ulcerative colitis and Crohn disease cause fecal incontinence during exacerbations with bouts of bloody diarrhea. Inflammatory bowel disease can also result in structural abnormalities, such as anal fissures, fistulas, abscesses, and operative complications that lead to fecal incontinence.

Table 25.3 Drugs and Dietary Items Associated with Diarrhea

Over–the-Counter Medications

Laxatives

Antacids (with magnesium)

Prescription Medications

Laxatives

Chemotherapy

Diuretics

Colchicine

Thyroid preparations

Cholestyramine

Cholinergics

Neomycin

Prostaglandins

Para–aminosalicylic acid

Dietary Items

Dietetic foods, candy or chewing gum, and elixirs with sorbitol, mannitol, or xylitol Ovid: Berek & Novak's Gynecology

Olestra

Caffeine

Ethanol

Monosodium glutamate

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As with defecatory dysfunction, neurologic causes of fecal incontinence can be divided into central and peripheral disorders. Among the central nervous system disorders, upper motor neuron lesions above the level of the defecation center (located in the sacral cord) cause spastic bowel dysfunction. Cortical communication is disrupted, resulting in impaired cognitive control and sensory deficit. The anal sphincter is under spastic contraction, but digital stimulation can be performed to initiate reflex evacuation. Head trauma, neoplasms, and cerebral vascular accidents that damage portions of the frontal lobe result in loss of control of both micturition and defecation. Greater loss of inhibition is present when the lesion is located more anteriorly in the frontal lobe. Spinal cord trauma and lower motor neuron lesions above the defecation center tend to cause permanent loss of cortical control. For 2 to 4 weeks following spinal cord injury, “spinal shock” occurs, resulting in a temporary loss of reflexes below the level of the lesion, flaccid bowel function, constipation, and fecal impaction. After the initial shock, spastic paralysis ensues with hyperactive bowel function. The gastrocolic reflex, along with digital stimulation, initiates reflex evacuation in the absence of cortical inhibition. Fortunately, IAS tone is maintained despite the loss of EAS control for stress and urge situations.

Both constipation and fecal incontinence can occur in these patients.

The demyelination that is seen in multiple sclerosis is randomly distributed and can occur at any level in the central nervous system. In addition to the somatic disruption that is similar to spinal cord injury, autonomic dysfunction frequently is present. People with dementia and other degenerative disorders that cause cognitive impairment frequently have fecal incontinence caused by overflow incontinence. Although sensory nerves are functioning properly, these individuals lack the cognitive awareness necessary to inhibit defecation until a socially acceptable time, and they develop overflow incontinence.

Lower motor neuron lesions occurring at or below the level of the defecation center in the sacral cord cause flaccid bowel dysfunction. Cortical communication is disrupted, resulting in impaired cognitive control and sensory deficit. The bowel reflexes, including the bulbocavernosus and anal reflexes, are interrupted. The anal sphincter is flaccid, and fecal retention with overflow incontinence usually occurs. Digital disimpaction and Valsalva often are required for evacuation. Digital stimulation has no effect, and medications tend to work P.942

poorly. Examples of motor neuron lesions include tumor or trauma to the cauda equina, tabes dorsalis, spina bifida, and peripheral neuropathy.

The classic example of peripheral neuropathy is congenital aganglionosis (Hirschsprung disease), which was discussed earlier. The most common peripheral neuropathy occurs with diabetes. Approximately 20% of individuals with diabetes have fecal incontinence Ovid: Berek & Novak's Gynecology

(24). The cause tends to be multifactorial with the exact mechanism uncertain. Fecal incontinence can occur with diabetic diarrhea or years later from progressive disease.

Individuals with diabetes frequently experience intestinal autonomic neuropathy, an abnormal gastrocolic reflex, and chronic constipation. The subsequent pelvic floor denervation causes fecal incontinence by sensory neuropathy, failure of the rectoanal inhibitory reflex, and sphincter dysfunction (25). Consequently, fecal incontinence from peripheral neuropathy can be the result of defective sampling, a disrupted rectoanal inhibitory reflex, or pudendal neuropathy with sphincter dysfunction. Patients may experience stress or urge incontinence as well as overflow incontinence.

Anatomic and structural causes of fecal incontinence are usually due to obstetric or surgical trauma. Damage or dysfunction of the IAS, EAS, and puborectalis can result in varying degrees of fecal incontinence. Those with impaired resting tone from a defective IAS

will have passive incontinence (incontinence at rest), which is worse during sleep because of decreased EAS activity (26). An inability to respond to sudden distention and to suppress defecation is often seen with external sphincter dysfunction. External and internal sphincter dysfunction often result in incontinence of liquid stool. Incontinence of solid stool is usually seen with widening of the anorectal angle from damage to the puborectalis muscles.

Damage to the anal cushions usually causes minor soiling. Other anatomic and structural abnormalities associated with fecal incontinence include obstructive disorders such as pelvic organ prolapse, descending perineum syndrome, anismus, and intussusception; fistulas from diverticulitis, inflammatory bowel disease, cancer, or surgical trauma; and decreased rectal compliance from inflammatory bowel disease, cancer, and radiation.

Decreased compliance results in higher intraluminal pressures with smaller volumes of stool, poor storage capacity, urgency, and incontinence (27).

Functional disorders associated with fecal incontinence include irritable bowel syndrome (diarrhea variant), functional diarrhea, decreased mobility, and decreased cognition.

Combined Disorders of Defecation and Fecal Incontinence

Several conditions have the potential to cause both defecatory dysfunction and fecal incontinence (see Table 25.1). Most of these disorders cause combined symptoms through the development of fecal impaction followed by overflow incontinence. This situation can be seen with many of the neurological conditions, pelvic outlet obstructive disorders, functional disorders of irritable bowel syndrome, decreased mobility, and decreased cognition.

The cause of these symptoms often is multifactorial.

Structural versus Functional Disorders

Disordered Defecation

Disordered defecation can result from outlet obstruction or functional motility disorders.

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Outlet Obstruction

Anismus/Rectosphincteric Dyssynergia

Anismus is otherwise known as rectosphincteric dyssynergia, pelvic floor dyssynergia, spastic floor syndrome, and paradoxical puborectalis syndrome. The anorectal angle narrows as a result of paradoxical contraction of the puborectalis and external anal sphincter during defecation. Frequent symptoms

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include dyschezia, straining, hard stools, incomplete emptying, and tenesmus. A recent prospective study of 120 consecutive patients with dyssynergic defecation found a higher prevalence in women (77%) (28,29). The need for digital assistance (digital disimpaction or splinting) to evacuate the rectum occurs in up to 58% of patients. Psychosocial factors, such as a history of sexual abuse, depression, eating disorder, obsessive–

compulsive disorder, and stress, may play an important role in this disease. In this study, 22% reported a history of sexual abuse, and 31% reported a history of physical abuse.

One third believed the problem began during childhood, and 24% reported a precipitating illness or surgery was related to a particular event. Five percent of women claimed that pregnancy or childbirth was a precipitating factor. This condition also is seen in young children with constipation and dyschezia. The response to biofeedback and pelvic floor physical therapy, as well as the aforementioned patient characteristics, indicate a learned response mechanism is involved (28,29).

Pelvic Organ Prolapse

Pelvic organ prolapse bears special mention because it is often seen by gynecologists but inconsistently associated with defecatory dysfunction. Prolapse is very common, although many women with this condition are asymptomatic. Those with symptoms may report incomplete evacuation and the need to apply digital pressure to the posterior vaginal wall or perineum to aid in evacuation of stool (digitation or splinting). It is important to rule out other causes of constipation, because these symptoms are nonspecific, and rectocele can result from chronic straining and increased intra–abdominal pressure. Defecatory dysfunction related to pelvic organ prolapse can result from rectocele, enterocele, or perineal descent, either individually or in combination.

Rectocele is a herniation of the rectal mucosa through a defect in the rectovaginal septum. These site–specific defects can be transverse or longitudinal through the inferior, middle, or superior regions of the rectovaginal septum (30). Enterocele is a herniation of a peritoneal sac and bowel through the pelvic floor, typically between the uterus or vaginal cuff and rectum. It is more common following hysterectomy and retropubic urethropexy. There are two theories surrounding the formation of an enterocele.

The first theory implicates a defect in the fibromuscular endopelvic fascia of the vagina, allowing peritoneum and bowel to herniate. The second theory attributes its formation to a support defect with full thickness protrusion, including endopelvic fascia (31). Ultimately, Ovid: Berek & Novak's Gynecology

the mechanism might be attributed to a combination of the two theories because some support defects are secondary to superior breaks in the rectovaginal and pubocervical fascia. Patients with rectocele and enterocele may have similar symptoms, including pelvic pain, pressure, vaginal protrusion, obstipation, fecal incontinence and sexual dysfunction. Although associations have been made between defecatory dysfunction and advanced stages of pelvic organ prolapse, a causal relationship remains to be established. Controversy remains as to whether anatomic herniation is the cause of these symptoms or the effect of underlying colonic dysfunction, chronic constipation, and straining.

Descending perineum syndrome is defined as descent of the perineum (at the level of the anal verge) beyond the ischial tuberosities during Valsalva. Excessive perineal descent was first described in the colorectal literature by Parks et al. in 1966 (32,33). It occurs as a result of inferior detachment of the rectovaginal septum from the perineal body. As the condition progresses, the patient can develop pudendal neuropathy from stretch injury.

Perineal descent has been associated with a variety of defecatory disorders, including constipation, fecal incontinence, rectal pain, solitary rectal ulcer syndrome, rectocele, and enterocele (34).

Rectal Intussusception

Rectal intussusception or intrarectal prolapse is the circumferential prolapse of the upper rectal wall into the rectal ampulla but not through the anal verge. It occurs most often in women in the fourth and fifth decade. The most common symptoms are obstructive, including incomplete emptying, manual disimpaction,

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splinting, pain with defecation, and bleeding. Other symptoms include fecal incontinence, decreased urge to defecate, inability to distinguish between gas and feces, and mucus discharge with pruritus ani. Bleeding often originates from a solitary rectal ulcer or localized proctitis of the involved bowel segment (35). Intussusception is frequently seen in as many as one third of women with defecatory dysfunction and other symptoms, such as constipation, rectal pain, and fecal incontinence (36). It has also been seen in 29%

of asymptomatic patients (37). The intussusception rarely develops into total rectal prolapse (38).

Functional Motility Disorders

Colonic Inertia/Slow–Transit Constipation

Severe constipation, defined as fewer than three stools per week and refractory to therapy, is relatively rare; however, these patients frequently suffer from motility disorders such as global motility disorder and colonic inertia. Women are more likely to be affected than men. Colonic inertia or slow–transit constipation is defined as the delayed passage of radiopaque markers through the proximal colon without retropulsion of markers from the left colon and in the absence of systemic or obstructive disorders. The cause remains unclear. Patients with this disorder have impaired phasic colonic motor activity Ovid: Berek & Novak's Gynecology

and diminished gastrocolic reflexes (39,40). Studies on the role of laxatives, absorption, hormones, psychological abnormalities, and endogenous opioids have been inconclusive.

Current literature suggests a possible neurologic or smooth muscle disorder (40,41).

Functional Bowel Disorders

Functional bowel disorders, as defined by the Rome II Criteria (42), consist of irritable bowel syndrome, functional abdominal bloating, functional constipation, functional diarrhea, and unspecified functional bowel disorders. In this section we will focus primarily on IBS.

Irritable bowel syndrome (IBS) has been estimated to have a prevalence of 10% to 20% and is more common in women and younger individuals. It accounts for 25% to 50% of all referrals to gastrointestinal clinics. Irritable bowel syndrome has distinct diagnostic criteria, including the exclusion of structural or metabolic abnormalities. These patients often have other gastrointestinal, genitourinary, and psychological illness, including gastroesophageal reflux disease, fibromyalgia, headache, backache, chronic pelvic pain, sexual dysfunction, lower urinary tract dysfunction, depression, and anxiety. Stressful life events seem to correlate with the onset and exacerbation of symptoms. A detailed history frequently reveals past physical or sexual abuse (42). Currently, specific criteria allow for classification of IBS into diarrhea–, constipation–, and pain–predominant categories (Table 25.4). The constipation variant is most commonly associated with defecatory dysfunction, whereas the diarrhea variant causes fecal incontinence. The pain or spastic variant causes predominantly abdominal discomfort but can also be associated with both defecatory dysfunction and fecal incontinence. After excluding organic disease, the criteria listed in Table 25.4 have a sensitivity of 65%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 76% (43).

Functional constipation is a term created by the Rome II criteria as a unifying definition of constipation (Table 25.5). The rationale for the criteria listed in Table 25.5 stems from the variability in patient definitions of constipation (42).

Fecal Incontinence

Sphincter Disruption

In young women, obstetric injury is the most common cause of fecal incontinence.

The mechanism of injury can be from anatomic disruption of the anal sphincter complex, pelvic floor denervation, or a combination of the two conditions. The risk factors for anal P.945

sphincter laceration are primiparity, high birth weight, forceps delivery, and episiotomy (44,45,46). Although there are limited long–term prospective studies demonstrating the natural history of anal sphincter injury, pelvic floor neuropathy, and the progression of these conditions to fecal incontinence, current literature supports the relationship of early–

onset symptoms to sphincter damage and delayed–onset symptoms to neuropathy (47).

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This relationship would account for the large discrepancy in the prevalence of fecal incontinence between younger men and women that decreases as the population ages (48).

Table 25.4 Diagnostic Criteria of Irritable Bowel Syndromea

At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two of three features:

1. Relieved with defecation and/or

2. Onset associated with a change in frequency of stool and/or

3. Onset associated with a change in form (appearance) of stool

Supporting symptoms of IBS

1. Fewer than three bowel movements a week

2. More than three bowel movements a day

3. Hard or lumpy stools

4. Loose (mushy) or watery stools

5. Straining during a bowel movement

6. Urgency (having to rush to have a bowel movement)

7. Feeling of incomplete bowel movement

8. Abdominal fullness, bloating, or swelling

Diarrhea–predominant 1 or more of 2, 4, or 6 and none of 1, 3, or 5; or 2 or more of 2, 4, or 6 and one of 1 or 5.

Constipation–predominant 1 or more of 1, 3, or 5 and none of 2, 4, or 6; or 2 or more of 1, 3, or 5 and one of 2, 4, or 6.

IBS, irritable bowel syndrome.

a From Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. In: Drossman DA, Corazziari E, Talley NJ, et al. eds.

Rome II: the functional gastrointestinal disorders. 2nd ed. McLean, VA: Degnon Associates, 2000:351–432.

Table 25.5 Diagnostic Criteria of Functional Constipationa

At least 12 weeks, which need not be consecutive, in the preceding 12 months of two or more of:

1. Straining >1/4 of defecations

2. Lumpy or hard stools >1/4 of defecations

3. Sensation of incomplete evacuation >1/4 of defecations

4. Sensation of anorectal obstruction/blockage >1/4 of defecations

5. Manual maneuvers to facilitate >1/4 of defecations (e.g., digital evacuation, support of the pelvic floor)

6. <3 defecations per week

If loose stools are not present, and there are insufficient criteria for IBS.

IBS, irritable bowel syndrome.

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a From Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. In: Drossman DA, Corazziari E, Talley NJ, et al. eds.

Rome II: the functional gastrointestinal disorders. 2nd ed. McLean, VA: Degnon Associates, 2000:351–432.

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Obstetric Trauma

Third– and fourth–degree lacerations at delivery are associated with an increased risk of fecal incontinence (odds ratio [OR] 3.09) (47). Whereas the incidence of clinically documented third– and fourth–degree anal sphincter tears is between 0.5% and 5.9% (44,46,49), occult third– and fourth–degree defects are present in 28% to 35% of primiparous women and 44% of multiparous women, and approximately one third of these patients have symptoms of anal incontinence. Patients with occult anal sphincter tears are 8.8 times more likely to have fecal incontinence (46,50). Forceps–assisted vaginal delivery significantly increases this risk, but the data on vacuum–assisted delivery are less conclusive (45,51,52). Elective cesarean delivery, in contrast with emergency cesarean delivery, was believed to prevent anal incontinence, but recent studies argue against any protective effect with cesarean delivery, irrespective of timing (46,51,53). Midline episiotomy is strongly linked to sphincter damage and fecal incontinence (45,54). One study of a large population found conflicting results, with an overall protective effect seen with episiotomy (OR 0.89). The likelihood of fourth–degree laceration was increased (OR 1.12) and of third–

degree laceration was decreased (OR 0.81) (44). A Cochrane review supports the restrictive use of both midline and mediolateral episiotomy (55). In another study, an important finding was that one half of patients who underwent immediate repair of a third–degree laceration had symptoms of anal incontinence, and 85% had persistent sphincter defects on endoanal ultrasonography (56).

Surgical Trauma

Iatrogenic injury follows obstetric trauma as the second most common cause of direct sphincter damage. Surgical procedures that have been associated with fecal incontinence include anal fistula repair, anal sphincterotomy, hemorrhoidectomy, and anal dilation. Fistulotomy is the most common procedure that results in fecal incontinence.

Rectovaginal or anovaginal fistulas can develop after obstetric injury, operative complications during pelvic surgery, and inflammatory bowel disease exacerbations. Fistulas cause fecal incontinence, and the degree of postoperative dysfunction depends on the location of the fistula and the amount of sphincter that is disrupted during the surgical repair. It also depends on the preoperative level of sphincter function and pudendal nerve function. Anal sphincterotomy to treat painful anal fissures can lead to incontinence by disruption of rectal sensory innervation and anal cushions and transection of the anal sphincter (57,58). Hemorrhoidectomy often results in minor soiling as a result of resection of the anal cushions, which act as the final mucosal barrier. Similar to sphincterotomy, rectal sensory innervation can be disrupted, and injury to Ovid: Berek & Novak's Gynecology

the internal sphincter can occur during sharp dissection (58,59).

Sphincter Denervation

Idiopathic (primary neurogenic) fecal incontinence results from denervation of both the anal sphincter and pelvic floor muscles. Denervation injury related to obstetric trauma accounts for approximately three out of every four cases of idiopathic fecal incontinence and is the most common overall cause of fecal incontinence (60,61).

Obstetric Trauma

The two proposed mechanisms of pudendal neuropathy are stretch injury during the second stage of labor and compression of the nerve as it exits Alcock's canal (60). Established risk factors for pelvic floor neuropathy include multiparity, high birth weight, forceps delivery, prolonged active second stage, and third–degree laceration (62,63).

Several studies have shown increased pudendal nerve terminal motor latencies following vaginal delivery, especially after sphincter laceration (46,61,64). Most women will recover function within a few months postpartum. Others will have evidence of injury several years later, which may represent the cumulative effects of subsequent deliveries (61,65). However, fecal incontinence will develop in only a fraction of patients with neuropathy (63).

Descending Perineum Syndrome

As noted previously, prolonged straining for any reason can cause descending perineum syndrome. This syndrome is defined as descent of the perineum beyond the ischial tuberosities during Valsalva (32,33). Pudendal

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neuropathy results from stretching and entrapment of the pudendal nerve. This diagnosis is supported by findings of elongation of the pudendal nerve, prolonged pudendal nerve motor terminal latency, and decreased anal sensation in women with perineal descent (66,67,68). As pudendal neuropathy progresses, it ultimately leads to fecal incontinence (34,69).

Table 25.6 Diagnostic Criteria of Functional Diarrheaa

At least 12 weeks, which need not be consecutive, in the preceding 12 months of: 1. Loose (mushy) or watery stools

2. Present more than 3/4 of the time; and

3. No abdominal pain

From Thompson WG, Longstreth GF, Drossman DA, et al. Functional Bowel disorders and functional abdominal pain. In: Drossman DA, Corazziari E, Talley NJ, et al. eds.

Rome II: The Functional Gastrointestinal Disorders. 2nd ed. McLean, VA: Degnon Associates, 2000:351–432.

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Functional Bowel Disorders

Irritable Bowel Syndrome

The diarrhea variant of irritable bowel syndrome is often associated with fecal incontinence as well as disordered defecation. The criteria for diagnosis are in Table 25.4.

Functional Diarrhea

The Rome II criteria create a unifying definition of diarrhea called functional diarrhea (Table 25.6). The rationale for the criteria listed in Table 25.6 stems from the variability in patients' descriptions of diarrhea (42).

Pitfalls for the Pelvic Floor Surgeon

It sometimes is easy to overlook or misinterpret signs and symptoms of constipation and defecatory dysfunction. Any acute change in bowel habits must be evaluated thoroughly, and malignancy must be considered in the differential diagnosis. Even in the presence of chronic disease, malignancy must still be excluded. Persistent symptoms after an empiric trial of medical therapy should prompt further evaluation, such as a colonoscopy or flexible sigmoidoscopy. It is also possible to mistakenly attribute symptoms of defecatory dysfunction and constipation to pelvic organ prolapse when prolapse is actually the result of an underlying bowel disorder. In this case, surgical treatment of prolapse will have little lasting benefit if the underlying bowel disorder remains untreated.

History and Physical Examination

History

A thorough history and physical examination are critical to the evaluation of fecal incontinence and defecatory dysfunction. The history of present illness should focus on the bowel habits, including frequency and consistency of bowel movements (hard versus soft, formed versus unformed, diarrhea versus constipation). The duration and severity of symptoms as well as exacerbating factors are important to understanding the impact on quality of life. Patients should be questioned about straining with bowel movements, symptoms of incomplete emptying, and splinting of the perianal region, perineal body, or posterior vaginal wall to assist with evacuation. They should also be asked about the need to perform digital disimpaction because they are unlikely to volunteer this information. With respect to fecal incontinence, information should be obtained about leakage with solids, liquid, and flatus and the ability to discriminate between these different types of stool (sampling). Similar to urinary incontinence, fecal incontinence can Ovid: Berek & Novak's Gynecology

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be stress related, urge related, or unconscious. Questions about alternating diarrhea and constipation, mucus or blood in the stools, constitutional symptoms, and changes in stool caliber can help the investigator uncover systemic and functional etiologies. Finally, it is important to ask about adaptive behaviors, pad or diaper use, and past and present treatments including surgery, physical therapy, and medications.

A large amount of information can be obtained efficiently through questionnaires.

Validated questionnaires quantify symptoms, which are subjective in nature, to objectively measure response to treatment. A valuable survey to assess defecatory dysfunction is the Colorectal–Anal Distress Inventory (CRADI), which has been incorporated into the Pelvic Floor Distress Inventory (PFDI) (70). The latter is a useful tool for evaluating symptoms of prolapse, urinary incontinence, fecal incontinence, voiding dysfunction, and defecatory dysfunction. Other useful symptom scales and bother scores for fecal incontinence include the Wexner Score (71), Fecal Incontinence Severity Index (72), and Fecal Incontinence Quality of Life Scale (73).

The medical history, surgical history, family history, and review of systems should focus on uncovering potential systemic and obstructive disorders shown in Table 25.1. A complete obstetric history should include the number of vaginal deliveries, operative vaginal deliveries, or presence of a third– or fourth–degree laceration, which is critical for patients with fecal incontinence. Length of the second stage of labor, birth weight, and the use of episiotomy should be ascertained because they may pose risk factors for sphincter damage and denervation. The sexual history should include questions about prior rape, anal intercourse, and dyspareunia. Use of over–the–counter, prescription, and illegal drugs should be recorded as well as food allergies.

Physical Examination

The evaluation of anorectal dysfunction requires a basic general examination as well as a focused abdominal and pelvic examination. The general physical survey should include a global assessment of mobility and cognitive function. Routine examination of the abdomen involves inspection, palpation, and auscultation to rule out the presence of masses, organomegaly, and areas of peritoneal irritation. This examination should be followed by a detailed evaluation of the vagina, perineum, and anorectum. The goals of the pelvic examination are to define objectively the degree of prolapse and determine the integrity of the connective tissue, neurologic function, and muscular support of the pelvic organs.

Neurologic Examination

Important elements of the neurologic examination are assessment of cranial nerve function, sensation and strength of the lower extremities, and reflexes for the lower extremities, bulbocavernosus, and anal wink. These examinations evaluate the function of the lower lumbar and sacral nerve roots, recognizing the importance of the second through fourth sacral nerve roots in pelvic floor dysfunction. The perineal reflexes can Ovid: Berek & Novak's Gynecology

be elicited by stroking the labia majora and perianal skin or tapping the clitoris with a cotton–

tipped swab. The anal wink, bulbocavernosus, and cough reflexes all test the integrity of motor innervation to the external anal sphincter (S2–4). Sensation over the inner thigh, vulva, and perirectal areas should be tested for symmetry to light touch and pinprick.

Muscle Strength

The integrity of the pelvic floor muscles should be assessed at rest and with voluntary contraction to determine strength, duration, and anterior lift. The ability to relax these muscles and tenderness on palpation should also be evaluated.

Several standardized systems have been described to objectively measure muscle strength, but none has been accepted as a standard. The puborectalis muscle should be readily palpable posteriorly as it creates a 90–degree angle between the anal and rectal canals.

Voluntary contraction of this muscle “lifts” the examining finger anteriorly toward the pubic rami.

An intact

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external anal sphincter muscle that has decreased tone and contractility often indicates pudendal neuropathy. Similarly, neuropathy affecting the puborectalis can be recognized by an obtuse anorectal angle and weak voluntary contraction. Similar to the urethral axis, the anorectal angle can also be tested using a cotton–tipped swab, although this text is rarely performed. Deflection is measured in the supine position at rest, with strain, and with squeeze.

Vaginal Support

The salient points of pelvic organ prolapse (see Chapter 24) for patients with defecatory dysfunction are the support of the vaginal apex, posterior wall, and perineal body, although some experts believe anterior wall defects can also affect defecatory dysfunction. The posterior wall is assessed while supporting the vaginal apex and anterior wall with a Sims' speculum. This permits the examiner to focus on identifying specific locations of rectovaginal fascial defects. A rectovaginal examination aids in identification of defects in the rectovaginal fascia or perineal body. Loss of vaginal rugation has also been reported overlying the site of a rectovaginal fascial tear (74). This technique is especially useful for enteroceles, which have a smooth, thin epithelium over the enterocele sac or peritoneum.

Normally, the perineum should be located at the level of the ischial tuberosities, or within 2 cm of this landmark. A perineum below this level, either at rest or with straining, represents perineal descent. Subjective findings of perineal descent include widening of the genital hiatus and perineal body, as well as flattening of the intergluteal sulcus. Women with perineal descent also tend to have less severe stages of pelvic organ prolapse based on the Pelvic Organ Prolapse Quantification (POP–Q) staging system (75) because it measures descent from the hymenal ring. Consequently, an increase in the length of the perineal body and genital hiatus with straining suggests perineal descent. The degree of perineal descent can also be measured objectively with a St. Mark's perineometer, although a thin ruler placed in the posterior introitus at the level of the ischial tuberosities also can be used. Descent is measured Ovid: Berek & Novak's Gynecology

as the distance the perineal body moves when the patient strains. Although pelvic floor fluoroscopy is the standard technique for measuring perineal descent, this technique is most useful in patients with symptoms of severe defecatory dysfunction and evidence of perineal descent on pelvic examination.

Anorectal Examination

Visual and digital inspection of the vagina and anus will help to identify structural abnormalities such as prolapse, fistulas, fissures, hemorrhoids, or prior trauma. As previously mentioned, a rectovaginal examination provides useful information regarding the integrity of the rectovaginal septum and can demonstrate laxity in the support of the perineal body. The rectovaginal examination also is helpful in the diagnosis of enteroceles, which can be felt as protrusion of bowel between the vaginal and rectal fingers with straining.

Digital rectal examination should be performed at rest, with squeeze, and while straining.

The presence of fecal material in the anal canal may suggest fecal impaction or neuromuscular weakness of the anal continence mechanism. Circumferential protrusion of the upper rectum around the examining finger during straining suggests intussusception, which often occurs in combination with laxity of the posterior rectal support along the sacrum.

The integrity of the external anal sphincter and puborectalis muscle can be evaluated by observation and palpation of these structures during voluntary contraction. Evidence of dovetailing of the perianal skin folds and the presence of a perineal scar with an asymmetric contraction often indicates a sphincter defect. When a patient is asked to contract her pelvic floor muscles, two motions should be present: The external anal sphincter should contract concentrically, and the anal verge should be pulled inward. These actions should also be apparent on digital rectal examination. As mentioned previously, the 90–degree angle created by the puborectalis should be readily palpable posteriorly and, with voluntary contraction, the examining finger should be lifted anteriorly toward the pubic rami.

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Both the puborectalis and external anal sphincter should relax during Valsalva effort. Patients with anismus may experience a paradoxical contraction of these muscles during straining.

Finally, defects in the anterior aspects of the external anal sphincter may be detected by digital examination.

Testing

Sophisticated diagnostic testing is currently being used in clinical research and in anorectal physiology laboratories to quantify the function of the colon and anorectum. Following is a description of these techniques as they relate to the management of fecal incontinence and disordered defecation.

Fecal Incontinence

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Endoanal Ultrasonography

Endoanal ultrasonography permits accurate imaging of both the internal and external anal sphincters. It can assess the continuity and thickness of the muscle and currently is considered the single best method for detecting anal sphincter defects.

Endoanal ultrasonography is performed using a Bruel–Kjaer (Copenhagen, Denmark) ultrasound scanner with a 360–degree rectal endoprobe (type 1850) with a 7.0 MHz transducer (focal length, 2–5 cm) housed within a plastic cone (Fig. 25.1). The normal IAS is a continuous hypoechoic band of smooth muscle surrounded by the thick echogenic layer of the striated EAS. A sphincter defect occurs when there is disruption in these muscle bands.

Location and severity of the defect can be described by circumferential distance in degrees, percent thickness, and distance from the anal verge (Fig. 25.2). Measurements are usually taken in the proximal, middle, and distal anal canal. It is important to recognize the physiologic split in the proximal EAS as it merges with the puborectalis muscle of the levator ani. Misinterpretation of this finding as a sphincter defect can result in an increased prevalence of reported defects.

The puborectalis muscle appears as a U–shaped or V–shaped thick echogenic layer outside the IAS in the proximal anal canal. Magnetic resonance imaging (MRI) may be equally as effective or better at diagnosing sphincter defects, especially with the use of a vaginal or rectal coil. For this purpose, MRI is more expensive, and currently its use is largely investigational. It may be beneficial in cases in which endoanal ultrasonography results are inconclusive or the quality of the study is poor.

Electromyography

Electromyography (EMG) is used to evaluate neuromuscular integrity of the EAS

following a traumatic injury such as childbirth, as well as to document the presence

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of pelvic floor neuropathy (76). This technique measures the electrical activity arising in muscle fibers during contraction and at rest. Different types of electrodes may be employed, including surface electrodes, concentric needle electrodes, and single–fiber electrodes. Surface electrodes are less invasive because they are applied near or within the anal canal, but they are capable only of recording basic anal sphincter activity. This technique often is used in conjunction with biofeedback therapy. Concentric needle electrodes are most commonly used in anorectal physiology laboratories to selectively survey an individual muscle's activity. Insertion of the thin needlelike cannulas containing steel wire electrodes can be painful. Even smaller single–fiber EMG electrodes are used to record the activity of single muscle fibers, which can be quantified to calculate fiber density. Following denervation injury, increased muscle fiber density occurs during reinnervation. Thus, single–fiber EMG

can provide indirect evidence of neurologic injury by mapping the EAS and identifying injured areas. This technique rarely is used in clinical practice. Endoanal ultrasonography offers increased patient comfort and more reliable results than EMG and has replaced this technique for the detection of EAS disruption because of increased patient comfort and more reliable results.

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Figure 25.1 Bruel–Kjaer (Copenhagen, Denmark) ultrasound probe (type 1850) with a 7.0

MHz transducer (focal length, 2 to 5 cm) housed with a plastic cone.

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Figure 25.2 A: Endoanal ultrasound image from the distal anal canal demonstrating defects in the internal sphincter from 10 to 3 o'clock and the external sphincter from 10 to 2

o'clock. B: Endoanal ultrasound image from the middle anal canal demonstrating defects in the internal sphincter from 12 to 2 o'clock and the external sphincter from 10 to 1 o'clock.

C: Endoanal ultrasound image from the proximal anal canal demonstrating an intact IAS and a normal physiologic split in the external sphincter.

Motor nerve conduction studies provide another means of measuring pelvic floor neuropathy. The axon of a nerve is stimulated, and the time it takes the action potential to reach the muscle supplied by the nerve is recorded. The delay between stimulation and the muscle response is called the nerve latency. Pudendal nerve terminal motor latency (PNTML) can be determined by transrectal stimulation of the pudendal nerve using a St. Mark's electrode (77). A nerve stimulator is mounted on an examination glove at the fingertip (Fig.

25.3) and positioned transrectally over each ischial spine. A stimulus of up to 50 mV over a duration of 0.1 milliseconds is applied, and the latency of the EAS muscle contraction is measured.

A value of 2.2 milliseconds or less is considered normal. A recent study evaluating normative values for pudendal and perineal nerve latencies observed increased latencies with increased age (78). Prolongation of the PNTML is indicative of damage to that nerve or the presence of a demyelinating condition. Pudendal nerve function has prognostic value in the surgical repair of traumatic sphincter injuries (79) and is useful in preoperative counseling.

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Figure 25.3 St. Mark's electrode used for measuring pudendal nerve motor terminal latency. The stimulating electrode is on the fingertip, and the receiving electrode is on the proximal finger near the knuckle.

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Anal Manometry

Anal manometry is used to quantify function of the anal sphincter mechanism.

Water–perfused manometry catheters or water–filled balloons are most often used to measure anal canal pressures. Resting anal canal pressures reflect IAS function, and pressures in the lower anal canal during maximal voluntary contraction reflect EAS function. Vector analysis can be used to detect asymmetry within the anal sphincter. Anal manometry provides indirect evidence of sphincter injury; low resting tone indicates IAS injury, and decreased maximum squeeze pressures indicates EAS injury. Anal pressures are influenced by a variety of factors, including tissue compliance and muscular tone. Consequently, anal manometry results are difficult to interpret and correlate poorly with the specific anatomic defect. Interpretation is further complicated by the wide variation of normal pressure values that change with age and parity. Significant overlaps occur between manometric values for incontinent patients and those without incontinence. Thus, anal manometry may be of limited value in the eval uation and treatment of anal sphincter defects and fecal incontinence.

Proctoscopy and Flat Tire Test

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Proctoscopy has an important role in the evaluation of fecal incontinence. It can be performed independently or during colonoscopy, flexible sigmoidoscopy, and flat tire test. Proctoscopy can detect anorectal pathology, such as prolapsing hemorrhoids, intussusception, ulcerative or radiation proctitis, or a solitary rectal ulcer. The flat tire test is added when a rectovaginal or colovaginal fistula is suspected but cannot be visualized on routine office evaluation. This test usually is performed under anesthesia but can also be done in the office setting. Saline or water is placed in the vagina with the patient Trendelenberg's position. Using a proctoscope or rigid sigmoidoscope, air is instilled into the rectum. Vaginal retractors provide visualization of the posterior vaginal epithelium and vaginal apex. Observation of bubbling into the vaginal fluid confirms the diagnosis of a rectovaginal or colovaginal fistula. The rectal site of the fistula usually is identifiable, depending on the size and location of the fistula as well as the quality of the bowel preparation.

Disordered Defecation

Sitzmark Study

Colonic transit studies are performed using ingested radiopaque markers followed by serial abdominal radiography. Patients are asked to follow a high–fiber diet over the test period and avoid the use of laxatives, suppositories, or enemas. A capsule containing 20 to 24 markers is ingested initially, and abdominal radiography is performed either daily or on the fourth day, the seventh day, and every 3 days thereafter until all the markers are gone.

Segmental transit times are then calculated using a mathematical formula. Colonic transit study results are used to classify patients with constipation into delayed transit, normal transit, and outlet obstruction. After day 6, there should be fewer than five markers remaining in the colon. With slow transit, more than five markers are scattered throughout the colon. With outlet obstruction, more than five markers are in the rectosigmoid region, and transit is normal throughout the rest of the colon.

Pelvic Floor Fluoroscopy and Magnetic Resonance Imaging

Pelvic fluoroscopy permits radiological evaluation of pelvic floor and anorectal anatomy and physiology. It is particularly useful in obstructive defecation disorders, such as intussusception, rectocele, enterocele, anismus, and perineal descent. The patient is placed on a radiolucent commode, and contrast material is instilled into the rectum.

The addition of vaginal, bladder, and oral contrast material is helpful diagnostically when multicompartmental prolapse is suspected. A series of lateral still images or continuous imaging using videography are made with fluoroscopy while the patient is at rest, during defecation, and with contraction of the anal sphincter. Similar films can be obtained for evacuation of the bladder. Pelvic fluoroscopy has many names, including defecography, P.954

defecating proctography, defecating cystoproctography, and colpocystoproctography, depending on the technique used. The measurements obtained include size of the rectal ampulla, length of the anal canal, anorectal angle, puborectalis motion, and pelvic floor descent. Severity of Ovid: Berek & Novak's Gynecology

prolapse and pelvic floor descent is quantified in relation to the pubococcygeal line.

Pelvic fluoroscopy is superior to physical examination for diagnosing enterocele (80), and this technique has the advantage of being able to distinguish enteroceles from sigmoidoceles. Rectosphincteric dyssynergia may be present when the patient experiences incomplete relaxation of the puborectalis muscle during rectal evacuation, the anorectal angle is preserved, and there is incomplete emptying. Pelvic fluoroscopy is considered the definitive test for diagnosing intussusception (81), and it is the preferred technique for quantifying perineal descent.

Dynamic MRI with luminal contrast is an imaging modality similar to pelvic fluoroscopy. Its ability to detect prolapse is similar to that of fluoroscopy, but MRI can visualize pelvic floor musculature and soft tissue, thus giving it the advantage of detecting ballooning of the levator muscles and levator ani hernias. The supine position of the testing is a drawback; however, there are isolated reports of upright dynamic MRI using open scanners that show results comparable to fluoroscopy for detection of anorectal pathology (82).

Fluoroscopy and dynamic MRI can be used in situations involving severe multicompartmental prolapse or in which the severity of the symptoms is disproportionate to examination findings.

Anal Manometry

Anal manometry is used to determine maximum resting pressure, maximum squeeze pressure, rectal sensation and compliance, as well as the presence of an intact rectoanal inhibitory reflex. With disordered defecation, it can be used to diagnose Hirschprung disease and anismus. The addition of surface EMG to document relaxation helps exclude anismus as a cause of obstructed defecation. Failure of the anal sphincter to relax with defecation and increased electrical activity of the EAS and puborectalis are seen in patients with anismus. In contrast, there should be no increase in the electrical activity measured by surface electrodes for patients with Hirschprung disease.

Colonoscopy and Proctoscopy

Standard gastrointestinal evaluation for patients with symptoms of disordered defecation should include a barium enema or colonoscopy to eliminate the possibility of colorectal malignancy. Proctoscopy should be included as part of the routine examination because it may reveal anorectal pathology. .

Therapeutic Approach to Fecal Incontinence

Treatment of fecal incontinence should first focus on nonsurgical options, including dietary modification, medical therapy, and biofeedback. Any underlying systemic conditions or gastrointestinal disorders should be treated before initiating an extensive evaluation for other causes of fecal incontinence. If symptoms persist, further investigation should be undertaken. If the evaluation discloses an underlying EAS defect and conservative therapy has been unsuccessful, it is reasonable to proceed with surgical treatment.

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Following is an overview of treatment options and the efficacy of each approach. The lack of a consistent outcome measures makes it difficult to compare efficacy among treatments.

Some studies base success on strict conformity with criteria for continence, but the results vary for continence of flatus, liquid, or solid stool. Other studies base success on more subjective criteria, such as improvement following treatment. Daily diaries can be maintained, but the results may be unreliable. Even if a validated symptom survey and quality–of–life scale are employed, few studies use the same outcome measure.

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Nonsurgical Treatment

Nonsurgical management focuses on maximizing the continence mechanism through alteration of stool characteristics or behavioral modification. Stool consistency and volume can be manipulated by dietary and pharmacologic means to achieve passage of one to two well–formed stools per day. The rationale for this approach is that formed stool is easier to control than liquid stool. Additionally, behavior modification can be employed using bowel regimens that focus on the predictable elimination of feces. Physical therapy and biofeedback can also be useful for strengthening the continence mechanism.

Pharmacologic Approaches

Dietary Modification and Fiber

Dietary modification for treatment of fecal incontinence frequently involves avoidance of foods that precipitate loose stools and diarrhea. Common dietary irritants include spicy foods, coffee and other caffeinated beverages, beer and alcohol, and citrus fruits. Avoidance of dairy products or the addition of lactase dietary supplements is essential for those with lactose intolerance. The addition of fiber may improve fecal incontinence by functioning as a stool bulking agent to increase volume and density. The average individual in the United States consumes less than one half of the recommended daily fiber intake (25–35 g). Various fiber sources are listed in Table 25.7, with the highest content found in fiber cereals. It is difficult to consume the recommended daily amount from diet alone, and fiber supplements often are required. Although the increased stool volume and density helps many individuals maintain continence, excessive fiber with inadequate fluid intake may predispose elderly patients to fecal impaction.

Constipating Agents

Constipating agents have the most value in patients with chronic loose stools or diarrhea. They can also help improve symptoms in patients with fecal frequency and urgency. Loperamide (Imodium) and diphenoxylate hydrochloride with atropine (Lomotil) are the most commonly used agents. Loperamide has been shown to prolong transit time and stimulate anal sphincter function. With either of these agents, careful titration is recommended Ovid: Berek & Novak's Gynecology

to prevent the primary side effect of constipation. It is generally preferable P.956

to begin using 2 to 4 mg of loperamide daily and then titrate up to 4 mg three to four times per day. A 4–mg dose before meals has been shown to increase anal tone and improve continence (83). Lomotil is started at a dose of 1 to 2 tablets every day or every other day and titrated up to 1 to 2 tablets three to four times a day as needed. Caution should be exercised for patients taking other anticholinergic medications. Anticholinergic side effects include dry mouth, drowsiness, lightheadedness, and tachycardia. Codeine can also be used as a constipating agent.

It should be used judiciously in those with chronic disorders and in elderly patients because of side effects common to narcotics, including addiction with prolonged usage and central nervous system and respiratory depression. A study of 82 geriatric patients documented the efficacy of pharmacologic treatment for fecal incontinence (84). Patients were treated based on the underlying cause. Those with fecal impaction received lactulose and enemas, whereas those with neurogenic fecal incontinence received codeine phosphate as a constipating agent and enemas. The rate of cure for fecal incontinence was 60% in the treatment group versus 32%

for controls ( P <0.001).

Table 25.7 Fiber Sources

Cereals

Fiber Supplements

All–Bran Extra Fiber (1/2 c)

15 g

Konsyl (1tsp)

6.0 g

Fiber One (1/2 c)

14 g

Perdiem (1tsp)

4.0 g

Raisin Bran (1/2 c)

7 g

Metamucil (1tsp)

3.4 g

All Bran (1/2 c)

6 g

Maalox w/fiber (1 tbs)

3.4 g

Fruit & Fiber (2/3 c)

5 g

Mylanta w/fiber (1tsp)

3.4 g

Frosted Mini Wheats (1/2 c)

3 g

Citrucel (1tbs)

2.0 g

Breads

Vegetables

Whole wheat (1 slice)

2.0 g

Lettuce (1 c)

1.4 g

White (1 slice)

0.5 g

Celery (1)

0.5 g

Bagel (1)

1.0 g

Tomato, raw (1)

1.0 g

Modified from Ellerkmann MR, Kaufman H. Defecatory dysfunction. In: Bent AE, Ostergard DR, Cundiff GW, et al, eds. Ostergard's urogynecology . 5th ed.

Philadelphia, PA: Lippincott Williams & Wilkins, 2002:362, with permission.

Medications for Irritable Bowel Syndrome

Dietary treatment of IBS consists of avoiding foods that are associated with symptoms, including alcohol, caffeine, sorbitol, and foods that increase gas production. Although increased dietary fiber or fiber supplementation has been shown to improve the constipation–predominant form of this illness, fiber supplementation has little effect on the diarrhea variant associated with fecal incontinence. Pharmacologic therapy is directed toward the predominant symptom. Loperamide and Lomotil tend to be useful first–line agents for treating diarrhea. Tricyclic antidepressants improve abdominal discomfort and are also Ovid: Berek & Novak's Gynecology

valuable in diarrhea–predominant patients because of their constipating effect. The serotonin type 3 (5HT3) antagonist alosetron (Lotronex) has been approved by the U.S. Food and Drug Administration for the treatment of severe diarrhea–predominant IBS refractory to treatment. It has shown improvement in global assessment measures, but its use is limited because of multiple isolated case reports of ischemic colitis. The recommended dose is 1 mg once or twice daily. It does not appear to be effective for the spastic–pain variant of IBS.

Anticholinergics ( dicyclomine, hyoscyamine) and antispasmotics ( mebeverine, pinaverine) are targeted at the pain and bloating symptoms but may also be useful for the diarrhea variant because of their constipating side effects. Studies comparing anticholinergic medications to placebo show inconclusive results with only modest benefits. Antispasmotic agents may also be of value and are available in many countries but are not approved for use in the United States. Currently, additional 5HT3 antagonists and 5HT4 antagonists are under development.

Most studies are poorly designed and difficult to interpret because of a high placebo response rate that often exceeds 30% (85,86).

Behavioral Approaches

Biofeedback

Biofeedback can be an effective therapeutic modality provided patients are motivated and comprehend instructions. The two proposed mechanisms through which biofeedback improves fecal continence are afferent and efferent training. Afferent training focuses on improving sensation in the anorectal canal through recruitment of adjacent neurons to decrease the sensory threshold of volume stimulation. The goal of this training is to enhance and restore anal sensation and the rectoanal inhibitory reflex. Efferent training enhances and restores voluntary contraction of the EAS, which permits additional recruitment of motor units and stimulates muscle hypertrophy. These two methods of training can be performed independently, but are often combined for additional therapeutic benefit. The most common training method uses an intrarectal balloon. The balloon acts to stimulate rectal distention and provide pressure feedback from coordinated or synchronized contraction of the P.957

pelvic floor muscles. Other techniques focus on strength training of the EAS alone using anal pressure feedback or EMG or afferent training alone using an intrarectal balloon without pelvic floor muscle contraction in response to the stimulus.

More than 35 studies have been done to evaluate the efficacy of biofeedback for treatment of fecal incontinence, and several excellent review articles and meta–analyses have determined the effects of individual treatments and predictors of patient response to treatment (87,88,89).

The results of all of these studies uniformly agree that biofeedback and pelvic floor exercises improve fecal incontinence and have a role in clinical practice. They also agree that the existing literature is fraught with methodologic problems and lacks validated outcomes and controls. Thus it is difficult to compare directly the study results.

Biofeedback is an ideal first–line therapy because it offers an effective, minimally invasive treatment without any reported adverse events. Biofeedback also appears Ovid: Berek & Novak's Gynecology

to provide a higher probability of successful outcome than standard medical care for treating functional fecal incontinence (67% versus 36%, respectively, P <0.001) (87).

A Cochrane review of biofeedback and exercises for treatment of fecal incontinence found only five randomized or quasirandomized control trials that qualified for inclusion (90).

The authors concluded that there is insufficient evidence to evaluate the efficacy of exercises and biofeedback for treatment of fecal incontinence. Specifically, they were not able to determine which patients are suitable for treatment, nor which method of treatment is optimal. A meta–analysis of biofeedback techniques included a review of 13 studies using strength training alone, 4 studies with sensory training alone, and 18 with coordinated sensory and strength training (89). The authors found no advantages between coordinated training (67% improved) and strength training (70% improved). However, strength training using EMG appeared to be better than strength training with anal canal pressure biofeedback (74%

versus 64% improved, respectively, P <0.04). The limitations of this study and the literature were acknowledged.

A large randomized control trial of biofeedback for fecal incontinence in 171

patients, divided into four treatment groups, showed no significant benefit when comparing standard care to similar care with the addition of biofeedback (54% versus 53% improvement, respectively) (91). In all groups, there was a high median rating of change of symptoms and median satisfaction with benefits relatively maintained at 1–year follow–up. All groups also displayed improvement in the validated symptom surveys and quality–

of–life measures as well as in anal sphincter function. The authors concluded that interactions with the therapist, patient education, and development of better coping strategies seem to be the most important factors for improvement rather than pelvic muscle exercises or biofeedback. Additional benefit may be derived with augmented biofeedback using electrical stimulation (92).

There are no clear indicators to predict which patients will benefit from biofeedback. Potential factors include age, duration and severity of incontinence, prior treatments or surgery, and severity of neurologic or physical damage. Controversy exists as to whether response to biofeedback is dependent on the presence of a structurally intact anal sphincter or normal pudendal nerve function (93,94,95,96). There is an obvious need for well–designed control trials using validated symptom surveys and quality–of–life instruments.

More objective measures are desirable, and studies should carefully document duration of treatment and length of follow–up.

Bowel Regimens

The goal of bowel regimens is to achieve predictable elimination of feces. This can be accomplished by using the gastrocolic reflex as well as by dietary and pharmacologic means. Defecation immediately following meals involves the physiologic response of the P.958

gastrocolic reflex to facilitate predictable emptying. The strength of the gastrocolic reflex varies among individuals and may be hypoactive or hyperactive with certain systemic Ovid: Berek & Novak's Gynecology

disorders, such as diabetes and multiple sclerosis. This technique can be especially useful in the morning to give the individual freedom from fecal incontinence throughout the day. The use of suppositories or enemas in the morning or at night in conjunction with the gastrocolic reflex may provide further relief of daytime symptoms. The goal is to leave the rectum empty between evacuations. Enema use, typically once or twice daily, should be titrated to the patient's baseline colonic activity. Regular toileting in elderly patients in nursing homes can improve fecal incontinence caused by overflow incontinence from fecal impaction.

The use of cone–tip colostomy–irrigation catheters is reserved for patients in whom other therapeutic modalities have failed. These catheters avoid the risk of rectal perforation and provide a dam to prevent efflux of the irrigating solutions (97).

Surgical Treatment

In general, surgical treatment should be employed after conservative measures have failed. Although there may be exceptions to this principle, most surgeons follow this recommendation because of the poor long–term outcomes and high complication rates with surgery for fecal incontinence.

Overlapping Sphincteroplasty

Overlapping sphincteroplasty is the procedure of choice for fecal incontinence caused by a disrupted anal sphincter. Most authorities believe that an overlapping technique is superior to an end–to–end repair, although there are few direct comparisons in the literature. The rationale for the overlapping technique is that a more secure repair can be accomplished by placing sutures through the scarred connective tissue rather than the sphincter muscle.

Sutures should be less likely to tear through or pull out of connective tissue than muscle.

Therefore, the key component of the overlapping technique is preservation of the scarred ends of the ruptured EAS for suture placement.

Technique

The initial step involves wide mobilization of the ruptured EAS without excision of the scarred ends of the sphincter. This is accomplished through an inverted semilunar perineal incision or a transverse incision near the posterior vaginal fourchette with inferiolateral extension. The latter incision facilitates repair in patients with damage to the rectovaginal septum attachment to the perineal body. Patients with EAS defects have either a band of intervening fibrous scar tissue between the viable muscular ends of sphincter or a complete separation with scar tissue present only on the ruptured ends of the sphincter. In the presence of complete separation of scar tissue, perineal body reconstruction usually is indicated at the time of repair to restore normal anatomy. A Peña muscle stimulator aids in identification of the distal ends of the EAS and differentiates viable muscle tissue from scar tissue. The stimulator can be used to outline the sphincter before incision as well as during the dissection. It is important to apprise the anesthesiologist of the stimulator usage so that paralytic agents are avoided.

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Excessive lateral dissection of the EAS past the 3 and 9 o'clock positions should be avoided as this is where the inferior rectal branches of the pudendal nerve innervate the EAS. Moderate bleeding often is encountered during this dissection, and the use of needlepoint electrocautery can maximize hemostasis. Controversy exists regarding the need to separate the EAS and IAS before repair. Identification of the intersphincteric groove facilitates dissection of the EAS. Dissection in this plane is relatively simple and avoids damage to either sphincter. Defects in the IAS can be more difficult to visualize because this muscle is intimately associated with the rectal mucosa. Examination with a finger in the anal canal is often helpful.

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The reconstruction begins with repair of an existing IAS defect using a 3–0 delayed absorbable monofilament suture. Next, the EAS defect is repaired with the primary goal of overlapping at least 2 to 3 cm to ensure adequate bulk of sphincter muscle encircling the anal canal. The EAS is overlapped using three to four mattress sutures of 2–0 delayed absorbable monofilament suture through the distal scar tissue. Once the sutures are tied, there should be resistance palpable with placement of a finger in the anal canal. Copious irrigation is performed throughout the procedure. Following sphincter repair, a perineal body reconstruction and rectocele repair should be undertaken, if indicated, to maximize the normal continence mechanism. Finally, the perineal skin is closed with interrupted absorbable monofilament sutures. Closure frequently requires modification of the initial incision because of changes in the perineal architecture that result from the repair. The most common approach is an inverted Y–shaped closure of the incision (Fig. 25.4).

Some surgeons recommend the overlapping repair regardless of whether it is performed immediately postpartum, delayed postpartum, or several years after obstetric injury. Performance of the overlapping technique is difficult immediately postpartum and requires

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adequate anesthesia, exposure, and equipment. Many surgeons believe that this can only be accomplished in the operating room. This repair lacks the theoretical advantage of using scar tissue to improve suture holding; however, it maximizes surface area for scarification of the sphincter ends. For a delayed postpartum repair, it is recommended to wait 3 to 6 months to permit complete resolution of inflammation and reinnervation. Two randomized control trials compared end–to–end approximation to overlapping sphincteroplasty P.961

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(98,99). One study randomized 112 primiparous women undergoing immediate repair of a third–

or fourth–degree sphincter tear (99). The authors did not detect any significant differences in objective or subjective outcomes between either of the two repairs at 3 months follow–

up. Approximately one half of the women had minor alteration in fecal continence, whereas 7

(6%) had daily soiling. Despite good symptomatic results, 74 (66%) had full–thickness EAS

defects on endoanal ultrasonography. The other randomized trial involved a delayed repair in

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23 patients more than 1 year following delivery (99). The scar was preserved for each repair, and a puborectalis plication was performed. At a median follow–up of 18 months, there were no detectable differences in continence scores; however, the study was clearly underpowered.

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Figure 25.4 Overlapping sphincteroplasty procedure. A: Inverted semilunar perineal incision with the distal ends of the external sphincter outlined using the Peña muscle stimulator. B: The external sphincter has been dissected, the scar divided in the midline, and the internal sphincter repaired. C: The external sphincter is overlapped using three mattress sutures of 2–0

delayed absorbable monofilament suture through the distal scar tissue. D: The sutures are tied. E: The skin is closed.

Efficacy

Despite the many large series reporting the outcomes of overlapping sphincteroplasty, almost all are retrospective in nature and lack validated measures of symptom severity and quality–of–

life considerations. Several overlapping sphincteroplasty series with a total of 891 patients were evaluated from 1984 to 2001. Although the length of follow–up was variable, the results showed excellent and good outcomes in approximately two thirds of patients (median 67%, range 52%–83%) (100). None of these studies had long–term outcomes.

More recent studies suggest poor long–term outcomes for the

overlapping sphincteroplasty. In a series of 55 women who underwent overlapping sphincteroplasty for fecal incontinence secondary to obstetric trauma (101), researchers contacted 47 (86%) patients by postal questionnaire and telephone interview with a median time since surgery of 77 months (range 60–96 months). The investigators observed less symptomatic improvement when compared with the results at 15 months postoperative evaluation. After excluding one patient because of Crohn disease, eight (17%) failed because they required additional surgery, such as colostomy, postanal repair, and artificial bowel sphincter. Among the remaining 38 patients, 27 (71%) reported improved bowel control, 5 (13%) were unimproved, and 6 (16%) were worse. No patient was fully continent to solid and liquid stool and flatus. Only 23 (50%) patients had “good” outcomes defined as not requiring further continence surgery and fecal incontinence less than once per month.

In another study, investigators contacted 49 (69%) of 71 patients by telephone interview (102).

All underwent overlapping sphincteroplasty with a median follow–up of 62.5 months (range 47–

141 months). Only 6 (12%) patients were totally continent, and another 18 (37%) were continent to liquid and solid stool. In other words, more than half of the patients had incontinence to liquid or solid stool. The largest series with long–term follow–up involved contact of 130 (71%) of Ovid: Berek & Novak's Gynecology

191 patients using a postal or telephone questionnaire (103). The median time from surgery for respondents was 10 years (range 7–16 years). Of those who responded, 6% had no incontinence, 16% were incontinent of flatus only, 19% had soiling only, and 57%

were incontinent of solid stool. These outcomes were significantly worse than the previously reported 3–year assessment (104). Despite the fact that 61% had a poor outcome defined as having fecal incontinence or requiring additional surgery for incontinence, 62% still considered their bowel control to be better than before surgery, and 74% were satisfied with the results of their surgery. Thus, although control may be improved when compared with preoperative status, continence outcomes do not seem to be maintained at long–term follow–up.

The cause of this deterioration in long–term outcomes is unknown. Possible explanations include weakening of the muscles with normal aging, repair breakdown, and underlying nerve damage from either obstetric injury or the repair itself. A problem with most studies is the lack of a follow–up ultrasonography to determine if the repair is intact. The effect of P.963

pudendal nerve function on overlapping sphincteroplasty is somewhat controversial.

Significantly lower success rates have been show in a comparison of those with normal pudendal nerve terminal motor latencies to those with abnormal latencies (63% versus 17%, P <0.01) (105). Other studies have confirmed this finding (79,106,107), but the more recent studies fail to show a difference based on preoperative neurophysiologic testing (101,103).

Other controversial factors that may affect outcome include age, duration of fecal incontinence, size of the defect, and anal manometry results.

Although there are many controversial aspects to overlapping sphincteroplasty, the literature is in agreement that diverting colostomy is not necessary (99,108,109); bowel confinement does not improve outcomes (99,108,110); clinical improvement correlates with postoperative endoanal ultrasonography results (101,111,112); and prior sphincteroplasty does not affect outcomes (105,111,113).

Subsequent Deliveries

Multiple studies confirm the impact of anal sphincter laceration during the first delivery on the risk of a sphincter laceration in a second delivery (114,115,116). These studies have calculated odds ratios ranging between 2.5 and 5.3 for a second sphincter disruption.

Two recent population–based studies revealed adjusted odds ratios of 4.2 (95% CI, 3.9–4.6) and 4.3 (95% CI, 3.8–4.8) (115,116). These odds ratios probably represent underestimates because they do not take into account higher cesarean delivery rates in subsequent births for women with a history of sphincter laceration. Both of these studies observed significantly increased risk of recurrent sphincter laceration associated with increased birth weight. The studies estimated that approximately 25 cesarean deliveries have to be performed to prevent one recurrent sphincter laceration. In fact, only 10% of women with anal sphincter lacerations at second delivery had a history of prior sphincter laceration.

Therefore, although a history of prior sphincter laceration increases the risk of recurrent sphincter laceration, the risk remains relatively small. Nevertheless, it is important to accurately counsel expectant mothers about their risk of sphincter laceration. Using Ovid: Berek & Novak's Gynecology

this information, they can decide whether the risk of recurrent laceration outweighs the risk of elective cesarean birth. The risk of subsequent vaginal delivery on symptoms of fecal incontinence is unknown for women with a repaired anal sphincter. The presence or absence of pre–existing fecal incontinence, as well as the estimated fetal weight, should be considered in counseling for a subsequent pregnancy.

Graciloplasty

Surgical reconstruction with a muscle flap should be considered in cases in which there is insufficient muscle to repair the EAS and all conservative measures have failed. Insufficient muscle can be caused by trauma or severe atrophy that results from denervation injury and congenital disease. Most patients considering this procedure have already undergone an overlapping sphincteroplasty that failed. Graciloplasty, first described by Pickrell et al. in 1952 (117), is a skeletal muscle transposition procedure that uses the gracilis to create a new anal sphincter. There are three suitable muscles for this type of procedure: the gracilis, sartorius, and gluteus maximus. Ideally, the muscle should be easily mobilized and transposed but not essential for locomotion or posture. The sartorius and gluteus maximus are suboptimal because the sartorius receives segmental vascularization, which restricts rotation, and the gluteus maximus is important in daily activities such as running, climbing stairs, and rising from a sitting position. The gracilis is a better choice because it can easily be mobilized without damage. As the most superficial adductor, it receives neurovascular supply proximally and has no important independent function.

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Technique

Either one long incision or three small incisions are made in the medial thigh. The gracilis muscle is identified and mobilized toward its insertion onto the medial aspect of the tibia where the tendon is divided. Anterior and posterior perianal incisions are made approximately 1.5 cm from the anal verge. Tunnels are developed in the extrasphincteric space and from the proximal thigh to the anterior perianal incision. The gracilis muscle is then gently delivered to the anterior perianal incision, guided around the anus to the posterior perianal incision, and returned to the anterior incision encircling the anal canal. The distal tendon of the gracilis is passed behind the muscle and anchored to the contralateral periosteum of the ischium. In cases when there is inadequate length, it can be sutured to the ipsilateral ischium. This procedure can also be performed bilaterally. In patients with a large rectovaginal fistula or cloaca, a myocutaneous flap can be mobilized and used to help close the defect. Improvement of fecal incontinence is caused by passive increase of the resistance of the anal canal by the bulk of the encircling muscle (Fig. 25.5).

Experimental efforts to improve the efficacy of this procedure have focused on developing resting tone in the transposed muscle through the use of an implanted neurostimulator. The intent of the stimulated graciloplasty is to convert the fast–twitch muscle fibers into slow–

twitch muscle fibers, which are more fatigue resistant. Initially, implantation of the pacemaker was performed at 6 weeks after the graciloplasty, but now most are performed Ovid: Berek & Novak's Gynecology

concomitantly. Stimulation can be applied directly to the obturator nerve or intramuscularly to the nerve branches inside the muscle. The muscle is stimulated at a cyclic frequency, with gradual increases every 2 weeks. After 2 months, continuous stimulation is performed. Stimulation is adjusted to maintain tonic contraction around the anus, and it is interrupted or turned off to defecate.

Efficacy

An exhaustive review of the published literature identified 37 articles of patients undergoing dynamic graciloplasty (118). Most of these articles were case series, and there were no randomized trials or cohort studies evaluating safety and efficacy. Mortality rate was 1% (range 0%–13%, 95% CI, 1%–3%) after excluding cancer deaths. There was a high rate of morbidity (1.12 events per patient). Thus, most patients will have at least one adverse event, and several will have multiple complications. There is also a very high reoperation rate. The most common complications were infections (28%), stimulator and lead faults (15%), and leg pain (13%). Satisfactory continence was achieved 42% to 85% of the time, although satisfaction was not defined consistently across studies. The authors concluded that dynamic graciloplasty appeared to have equal or better efficacy than colostomy but carried a higher morbidity rate. Another review of the three largest case series (119,120,121) found success rates ranging from 55% to 78%. Major infections were found in 13% to 29%, pain in 27% to 28%, and device or lead problems in 12% to 18%. More recent series containing large numbers of patients found similar results for efficacy, morbidity, and reoperation rate (122,123). High rates of disturbed evacuation also were reported.

Artificial Sphincter

The artificial anal sphincter is an alternative to a graciloplasty. This is a modification of the device originally designed to treat urinary incontinence. The current device is the Acticon® Neosphincter (American Medical Systems, Minnetonka, Minnesota, USA) (Fig. 25.6).

The indications for its use are similar to those for the graciloplasty.

Technique

Implantation of the artificial anal sphincter is performed, similar to the graciloplasty, through perianal tunnels. A Silastic inflatable cuff is placed around the native sphincter P.965

to occlude the anal canal. A pressure–regulating balloon containing radio–opaque solution is situated in the retropubic space, and a control pump is positioned in the labia majora. Activation of the control pump deflates the cuff, permitting defecation (see Fig. 25.6).

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Figure 25.5 Graciloplasty. A: The gracilis muscle is identified and mobilized toward its insertion onto the medial aspect of the tibia where the tendon is divided. B: Anterior and posterior perianal incision are made approximately 1.5 cm from the anal verge. The muscle is then tunneled around the extrasphincteric space circumferentially. The distal tendon is passed behind the muscle and anchored to the contralateral periosteum of the ischium.

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Efficacy

A recent extensive review of the literature summarized 13 case series and one case report from 1996 to 2003. There were no randomized trials or cohort studies (124). The largest series consisted of 112 patients (125). There was one series with 53 patients, and all others had fewer than 28 patients apiece (126). Explantation was required in 17% to 41% of patients. Reasons for explantation included infection, erosion, device malfunction, pain, incontinence, and dissatisfaction, with infection being the most common. Surgical revision was necessary in 13% to 50% of the reports. Almost everyone had at least one adverse event, and more than one third of these events required surgical intervention. Reasons for surgical revision were similar to those for explantation. Rates of fecal impaction ranged from 6% to 83%.

All studies recorded statistically and clinically significant improvement in continence scores for patients with a functional artificial sphincter; however, most did not report the continence status for those in whom the device was explanted. The proportion of patients with a functional device ranged from 49% to 85%. The authors concluded that there is insufficient evidence on the safety and effectiveness of the artificial sphincter for fecal incontinence.

One randomized control trial of 14 patients compared artificial sphincter with a program of supportive care (127). Supportive care included all aspects of conservative management, P.967

such as physiotherapy, dietary advice, pharmacotherapy, and advice regarding skin care, odor management, anxiety reduction, and use of incontinence aids or appliances.

Significant improvements in continence scores and quality–of–life measures were seen in the artificial sphincter group but not in the control group at 6 months follow–up. Explantation rate was 14% (1 of 7 patients). Two other patients had complications, including severe fecal impaction and perineal wound erosion requiring reoperation. The authors conclude that the artificial sphincter is safe and effective compared with supportive care alone.

They anticipate perioperative and late complications, which may require explantation in up to one third of patients. It is also remarkable that only one patient (14%) whose condition was managed conservatively had significant improvement based on continence scores, whereas the status of all others was relatively unchanged.

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Figure 25.6 Acticon® Neosphincter. This device includes an inflatable cuff placed around the anal canal, a balloon reservoir stored behind the pubic bone, and a pump located in the labia. (Courtesy

of American Medical Systems, Inc. Minnetonka, Minnesota, http://www.AmericanMedicalSystems.

com. ).

Another study compared the effectiveness of artificial sphincter with dynamic graciloplasty (128). Two surgeons each performed four consecutive operations with each technique to minimize the learning curve of a new operation. Each started with a different procedure to avoid discrepancies in the time of follow–up. This prospective cohort study involved eight patients in each group who had similar demographic variables. Length of follow–up was 44 months in the artificial sphincter group and 39 months in the dynamic graciloplasty group. Early postoperative complications were similar in each group at 50%, as were late complications, with both groups reporting a high reoperation rate of 63%. There were six (75%) late Ovid: Berek & Novak's Gynecology

complications in the artificial sphincter group, of which three (38%) were nonreversible and required explantation. Postoperative continence scores were significantly lower with the artificial sphincter than with graciloplasty. The authors conclude that artificial sphincter has better efficacy and similar morbidity compared with dynamic graciloplasty. The rate of late complications for the artificial sphincter exceeded that reported in the literature, which may indicate poor long–term durability. Postoperative continence scores reflect those reported for artificial sphincter but are far worse than those for dynamic graciloplasty. The authors feel that the learning curve with the artificial sphincter is less important than that with graciloplasty.

Sacral Nerve Root Stimulator

Sacral neuromodulation (InterStim®, Medtronic, Minneapolis, Minnesota, USA) was approved by the U.S. Food and Drug Administration for treatment of urinary urge incontinence in 1997 and for nonobstructive urinary retention and urgency in 1999. It has been employed experimentally for the treatment of fecal incontinence.

The exact mechanism of action has not been fully elucidated. The goal of sacral nerve stimulation is to recruit residual function of the continence mechanism through electrical stimulation of its peripheral nerve supply. Initially, indications were confined to patients with deficient EAS

and levator ani function without gross morphologic defects and intact neuromuscular connections. More recently, the acceptable indications have expanded to include deficiency of the IAS, limited structural defects, and functional deficits of the internal and external anal sphincter.

Technique

The device is instilled exactly the same way as for treatment of urinary incontinence.

Current application is performed as a two–stage outpatient surgical procedure. The first stage involves instillation of the electrodes. The electrode is placed through the S2–4 foramen using minimally invasive surgical technique. During the test phase, multiple electrodes can be employed either bilaterally or at different levels to determine the site with the best response. Proper location is confirmed intraoperatively using fluoroscopy as well as visualization of an appropriate pelvic floor muscle response (bellows) with minimal plantar flexion of the first and second toes, which usually corresponds to S3 stimulation. An interval testing phase utilizes an external pulse generator that typically lasts 1 to 2 weeks. Those with a good response (decrease in fecal incontinence episodes

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of at least 50% documented by bowel–habit diary) will proceed to the second stage, implantation of the permanent pulse generator (IPG). Typically only one electrode is left in place at the end of the second stage. Once the permanent pulse generator is implanted, all adjustments are made using telemetry. The patient has a basic remote control that enables her to turn the device on or off and adjust the amplitude of the stimulation.

Efficacy

By the end of 2003, sacral nerve stimulation had been used to treat more than 1,300 patients Ovid: Berek & Novak's Gynecology

with fecal incontinence (129). Despite this large number, the analysis of the results is limited to several small case series. In all studies, significant improvements in continence scores lasting up to 99 months occurred. Most patients experienced at least a 75% improvement in continence scores, and improvement also occurred in the frequency of incontinence episodes, the ability to postpone defecation, and bowel emptying. Intent–to–treat analysis revealed 80%

to 100% therapeutic success. There also were significant improvements in quality–of–life measures using validated measurement scales. Complications occurred in 0% to 50% of patients, with the most common complications consisting of pain at the electrode or IPG

site, electrode migration, infection, or worsening of bowel symptoms. No permanent sequelae occurred, however. Effects of anorectal physiology varied among the published studies, highlighting the fact that the precise mechanism of action remains unclear.

A review of both fecal incontinence and constipation found that 149 (56%) of the 266 patients went on to permanent implantation (130). The rate of permanent implantation was higher for most studies, approximating 80%. Among implanted patients, 41% to 75% were completely continent to solid and liquid stool, and 75% to 100% had at least a 50% improvement in the number of incontinent episodes. One double–blind crossover trial with two patients had the stimulators set below the sensory threshold and turned on or off for 2–week intervals (131).

The number of fecal incontinence episodes per week improved from two to zero for one patient and from ten to one for the other patient. In another review, 19 (13%) adverse events occurred in 149 patients, findings that were similar to those mentioned previously (130). Thus, sacral nerve stimulation appears to be a promising new treatment for fecal incontinence with relatively limited complications.

Therapeutic Approach to Constipation

As with fecal incontinence, it is imperative to attempt conservative management of constipation and defecatory dysfunction before performing surgery. Initial evaluation should focus on identifying any underlying systemic conditions (see Table 25.1) associated with disordered defecation and optimizing treatment for these conditions. In the absence of systemic etiologies, it is reasonable to proceed with empiric, nonsurgical management, such as diet, fiber supplementation, and toileting behavior.

Biofeedback and laxatives can be used in more severe cases. Initially, disimpaction with regular enemas or laxatives is essential if the patient has fecal impaction. Symptoms that persist despite a trial of conservative management indicate the need for further evaluation of colonic and anorectal function. A diagnostic algorithm for idiopathic (nonsystemic) constipation is given in Figure 25.7. Treatment should then be tailored to the underlying cause. Some conditions associated with disordered defecation are best treated using nonsurgical techniques, whereas others may benefit from surgery once conservative management has failed. As with fecal incontinence, the lack of consistent outcome measures in the published literature makes it difficult to compare efficacy among treatments.

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Figure 25.7 Diagnostic Algorithm for Idiopathic Constipation. (From Ellerkmann MR, Kaufman H. Defecatory dysfunction. In: Bent AE, Ostergard DR, Cundiff GW, et al. , eds.

Ostergard's urogynecology and pelvic floor dysfunction. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2002:358, with permission.).

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Nonsurgical Treatment

Nonsurgical management focuses on maximizing anorectal function through alteration of stool characteristics or behavioral modification. Stool consistency and volume can be manipulated by dietary and pharmacologic means to achieve passage of one stool every day or every other day. Additionally, behavior modification can be employed using regular toileting to prevent fecal impaction. Physical therapy and biofeedback can also be useful for coordinating pelvic floor and anal sphincter relaxation with defecation.

Pharmacologic Approaches

Dietary Modification and Fiber

The role of increased fluid and fiber intake for the treatment of constipation is controversial. For years, it has been a commonly accepted belief that constipation is caused by low fluid intake and can be improved by increasing consumption. Several studies showed no association between fluid intake and constipation (132,133,134). However, one large study Ovid: Berek & Novak's Gynecology

of 21,012 nursing home residents found a weak association between decreased fluid intake and constipation with an odds ratio of 1.49 (135). In one interventional study, increased fluid intake failed to improve stool frequency, consistency, or defecatory dysfunction in children (136). Another interventional study using fiber and mineral water displayed an increase in stool frequency and a decrease in laxative use in adults with constipation (137). This study lacked baseline data collection resulting in recall bias, and the use of mineral water containing magnesium may confound the results because of its mild laxative effect. Overall, the existing data do not support increased fluid intake to treat constipation unless there is evidence of dehydration (132).

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The addition of fiber may improve constipation through several mechanisms. Fiber acts as a stool bulking agent and improves stool consistency through water absorption. It can also act as a substrate for bacterial proliferation and gas production. These mechanisms of action are believed to result in increased colonic motility, decreased transit time, and increased stool frequency.

Fiber therapy appears to have a beneficial effect in the treatment of diverticular disease (138), constipation of pregnancy (139), and possibly IBS (140). Its efficacy for idiopathic (nonsystemic) constipation remains uncertain. Dietary fiber intake for patients with constipation was similar to that of controls in several studies (133,134). A meta–analysis of 36 randomized trials using laxatives or fiber therapy for the treatment of constipation showed that the use of fiber or laxatives resulted in increased stool frequency and improved symptoms without the presence of severe side effects (141). Conversely, another meta–

analysis showed an inability to restore transit time and stool weight in constipated patients using dietary fiber (140). Approximately one half of the patients in another study responded to fiber treatment, but a much better response occurred in patients without an identifiable structural or motility disorder (142). Consequently, a low–fiber diet may be a contributing factor in chronic constipation, and an empiric trial of fiber therapy can be expected to help some patients. Side effects of increased gas production may limit compliance with treatment, so doses should be slowly titrated. Fiber therapy should be avoided in patients with impaction, megacolon or megarectum, or obstructive gastrointestinal lesions. Fiber therapy should also be used with caution in patients with cognitive dysfunction (dementia), difficulty with ambulation, and underlying neurogenic disease for fear of worsening the condition. There is no evidence to substantiate the recommendation for extra water intake with fiber supplements (143).

Laxatives

Laxatives are commonly used to treat constipation and disordered defecation. Many classes of laxatives are available over the counter.

Bulk–forming Laxatives

These come in natural forms ( psyllium) as well as synthetic form, ( Metamucil, Konsyl, Citrucel), and are felt to be the safest laxatives. They have mechanisms of action and side effects similar to that of fiber (144).

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Hyperosmolar Laxatives

These consist of poorly absorbed substances that increase intraluminal osmolarity and water absorption. This action results in greater stool volume with decreased consistency.

Examples include nonabsorbable sugars ( lactulose and sorbitol), glycerin, and polyethylene glycol ( GoLytely). Polyethylene glycol is a common preoperative bowel preparation. Side effects are diarrhea, increased flatus, and abdominal cramping (144).

Emollient Laxatives

These agents are divided into two subsets: docusate salts and mineral oil. The docusate salts have hydrophilic and hydrophobic properties similar to detergents. They soften stool and decrease surface tension by increasing stool water and lipid content. Examples include docusate calcium ( Surfak), docusate potassium ( Dialose, Kasof), and docusate sodium ( Colace, Comfolax). They also improve the absorption of other laxatives and are combined in preparations with stimulant laxatives such as Correctol, Peri-Colace, and Feen–a–Mint. The limited absorption of mineral oill allows it to penetrate and soften the stool. It can be used orally or rectally. Prolonged daily use can lead to decreased absorption of the fat–soluble vitamins A, D, E, and K. Use of mineral oill should be avoided in elderly and debilitated patients, as well as in those with esophageal motility disorders because of the potential for aspiration pneumonia.

Side effects include diarrhea, anal leakage, and pruritis ani (144,145,146).

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Saline Laxatives

These usually contain magnesium cations and phosphate anions that are relatively nonabsorbable and produce an osmotic gradient with increased water absorption. They also stimulate intestinal motility by increasing cholecystokinin release. Fast–acting effects can be seen with both oral (2–6 hours) and rectal (15 minutes) preparations. Examples include magnesium citrate, magnesium hydroxide ( Milk of Magnesia), magnesium sulfate, sodium phosphate, and biphosphate ( Phospho–soda, Fleet enema). Although generally well tolerated, electrolyte abnormalities can occur. These side effects should be avoided in patients with renal insufficiency because of the potential for magnesium toxicity (144,145,146).

Stimulant Laxatives

These are found in three basic types: castor oil, anthraquinones, and diphenylmethanes.

A metabolite of castor oil, ricinoleic acid, increases intestinal motility and secretion.

Anthraquinones (cascara sagrada, senna [Senekot], casanthranol [aloe], and danthron) are absorbed by the small intestine and stimulate motility by increasing intraluminal fluid and electrolyte content. Diphenylmethanes (phenolphthaleins [Feen–a–Mint, Correctol]

and bisacodyl [Dulcolax]) have a mechanism of action similar to anthraquinones. These agents are potent and are intended for short–term use in cases refractory to bulk or osmotic laxatives.

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It has been a long–standing belief that prolonged use can lead to a dilated atonic colon known as cathartic colon syndrome, melanosis coli, or neuronal degeneration. A recent article refutes the theory that stimulant laxatives damage the autonomic nervous system when used at recommended doses ( 132 ). Other side effects include cramping, nausea, and abdominal pain ( 144 , 145 , 146 ).

Prokinetic Agents

Medications that stimulate gastrointestinal motility primarily through neuromodulation of acetocholine levels include metoclopramide, cisapride, cholinergic agonists ( bethanechol), cholinesterase inhibitors (neostigmine), and serotonin agonists. Their efficacy in the treatment of chronic idiopathic constipation is uncertain. Metoclopramide is better for upper gastrointestinal motility disorders, whereas cisapride appears to exert its effect at the level of the colon (144,145,146).

Behavioral Approaches

Behavioral techniques such as biofeedback and bowel regimens may have a role in certain conditions associated with constipation and defecatory dysfunction. Overall, these approaches have far less application to disordered defecation than to fecal incontinence. Biofeedback is important in the treatment of anismus. Relaxation techniques and behavioral modification may be helpful for IBS. Bowel regimens in conjunction with laxatives, suppositories, and enemas can facilitate emptying by optimizing the gastrocolic reflex and increased peristaltic activity.

Efficacy of Nonsurgical Treatment

Irritable Bowel Syndrome

The most commonly used first–line treatment for the constipation variant of IBS is fiber supplementation and osmotic laxatives. The efficacy of bulking agents for this condition is controversial, and many studies, including meta–analyses, exhibit an effect similar to placebo. There may be benefit to the use of fiber because of the high placebo effect with IBS treatment and lack of serious adverse events associated with its use. However, patients may experience exacerbation of bloating and abdominal discomfort with fiber therapy. There are limited data (no randomized control trials) to determine the efficacy of osmotic laxatives.

They can be useful as adjunctive treatment options, but can also exacerbate abdominal pain and discomfort. A newer class of drugs, serotonin 5HT4 agonist

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tegaserod ( Zelnorm), stimulates peristalsis, increases colonic motility, decreases intestinal transit times, and reduces visceral hypersensitivity. The recommended dose is 6 mg twice daily. Randomized trials have consistently shown an approximately 10% greater improvement in global IBS symptoms when compared with placebo. Improvement in the bloating and pain symptoms also occurred. No episodes of ischemic colitis or cardiac toxicity have been Ovid: Berek & Novak's Gynecology

reported with the use of this medication, and the most common side effects are diarrhea and headache. Cisapride, a 5HT4 agonist with partial 5HT3 antagonist actions, has been withdrawn from use secondary to rare cardiac toxicity. Additional 5HT4 agonists, 5HT3 agonists, and cholecystokinin antagonists are in development (85,86).

Colonic Inertia and Slow–Transit Constipation

Patients with slow–transit constipation tend to respond poorly to fiber supplementation, although most have already tried an empiric trial of fiber before testing to confirm the diagnosis (142). Some patients may benefit from regular toileting, either in the morning or after meals when there is increased colonic motor activity. Biofeedback may have modest short–term benefits, but the long–term effect is questionable (147). Enemas and suppositories can be used in conjunction with bowel regimens. It is also reasonable to attempt a trial of any of the laxatives listed in Table 25.8. Stimulant laxatives commonly are used, but questions remain about the development of neuronal degeneration with prolonged usage. It is imperative that patients adhere to and not exceed the recommended dosages. Data regarding laxative use for this condition have failed to show a significantly better response than placebo. Prokinetic agents are intuitively the ideal choice to stimulate colonic motility.

Currently there is only one available prokinetic agent, tegaserod, approved for the treatment of constipation that improves colonic transit. Its data are almost entirely based on treatment of IBS, and there is a lack of information for its use in slow–transit constipation. Other prokinetic agents in various stages of testing include bethanechol, neostigmine, cholecystokinin antagonists, misoprostol, colchicine, neurotrophin–3, and other 5HT4 agonists such as prucalopride and mosapride (40).

Anismus

As with slow–transit constipation, initial management using bowel regimens, laxatives, enemas, suppositories, and fiber supplementation is appropriate for patients with anismus, yet many will have already tried conservative management before undergoing testing to confirm the diagnosis. These treatments are relatively well tolerated with few serious side effects. They have not been shown to have greater efficacy when compared with placebo, and their role in the treatment of anismus remains uncertain.

Specific treatment for this condition tends to focus on biofeedback because of studies indicating that this is an acquired behavioral disorder of defecation. Modalities such as diaphragmatic muscle training, simulated defecation, and manometric or electromyography–guided anal sphincter and pelvic muscle relaxation have been employed independently or combined with other techniques. These techniques have yielded symptomatic improvement in approximately 60% to 80% of patients. Many patients with dyssynergic defecation also have abnormal rectal sensation, so rectal sensory conditioning may provide additional benefit (28,40,148,149). Others have tried botulinum toxin injections to paralyze the puborectalis and anal sphincter muscle. Small case series have shown modest early improvement but the results do not appear to be long lasting (150,151).

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Pessary for Treatment of Pelvic Organ Prolapse

Pessaries of various shapes and sizes have been used for centuries to treat pelvic organ prolapse (152). They are a safe alternative to surgery, with the most common complications being increased vaginal discharge and erosion or ulceration of the vaginal wall. Although pessaries represent a common therapeutic modality, there are limited data regarding fitting and management (153). Even less is known about which type P.973

of pessary is better for enteroceles and rectoceles, although the site of prolapse does not appear to affect the ability to retain a pessary (154). Pessaries can be divided into subtypes of supportive and space occupying (155). Some of the space–occupying pessaries, such as the Gellhorn and cube, use a suction mechanism to maintain vaginal retention, whereas others, like the donut, do not. In theory, space–occupying pessaries and those that exert forces against the posterior wall and vaginal apex (donut, inverted Gehrung) should aid in treatment of rectoceles and enteroceles. However, there is a lack of data regarding the efficacy of pessaries for relieving symptoms of disordered defecation. One prospective study P.974

found that stage III–IV posterior vaginal wall prolapse was an independent predictor for discontinuation of pessary use in favor of surgical repair (156). More research is needed to determine the role of pessaries for treatment of rectoceles and enteroceles as well as symptoms that are likely to be improved using a pessary.

Table 25.8 Laxatives for the Treatment of Disordered Defecation

Type of Laxative

Adult Dose

Onset of Action

Side Effects

Bulk–Forming Laxatives

Natural ( psyllium)

7 g PO

12–72 h

Impaction above strictures

Synthetic ( methylcellulose)

4–6 g PO

12–72 h

Fluid overload

Emollient Laxatives

Docusate salts

50–500 mg PO

24–72 h

Skin rashes

Mineral oil

15–45 mll PO

6–8 h

Decreased vitamin absorption

Lipid pneumonia

Hyperosmolar Laxatives

Polyethylene glycol

3–22 ll PO

1 h

Abdominal bloating

Lactulose

15–60 mll PO

24–48 h

Abdominal bloating

Sorbitol

120 mll 25% solution PO

24–48 h

Abdominal bloating

Glycerine

3 g suppository

15–60 min

Rectal irritation

5–15 mll enema

15–30 min

Rectal irritation

Saline Laxatives

Magnesium sulfate

15 g PO

0.5–3 h

Magnesium toxicity

Magnesium phosphate

10 g PO

0.5–3 h

Magnesium citrate

200 mll PO

0.5–3 h

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Stimulant Laxatives

Castor oil

15–60 mll PO

2–6 h

Nutrient malabsorption

Diphenylmethanes

Phenolphthalein

60–100 mg PO

6–8 h

Skin rashes

Bisacodyl

30 mg PO

6–10 h

Gastric irritation

10 mg PR

0.25–1 h

Rectal stimulation

Anthraquinones

Cascara sagrada

1 mll PO

6–12 h

Melanosis coli

Senna

2 mll PO

6–12 h

Degeneration of Meissner and Auerbach plexuses

Aloe (Casanthrol)

250 mg PO

6–12 h

Danthron

75–150 mg PO

6–12 h

Hepatotoxicity ( w/docusate)

PO, by mouth; PR, per rectum.

From Wald A. Approach to the patient with constipation. In: Yamada T, ed. Textbook of gastroenterology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1999:921, with permission.

Surgical Treatment

Following is a review of the efficacy of various surgical treatments for specific conditions associated with constipation and disordered defecation.

Slow Transit/Colonic Inertia

Subtotal colectomy with ileosigmoid or ileorectal anastomosis is considered by many to be the surgical treatment of choice for slow–transit constipation refractory to medical management. Most surgeons restrict the use of this surgical procedure to the most extreme cases and typically operate on fewer than 10% of patients. Strict criteria for surgery include the following: chronic, severe, disabling symptoms unresponsive to medical therapy; slow transit in the proximal colon; no evidence of pseudo–obstruction; and normal anorectal function (144). Success rates are variable and depend on several factors.

An extensive review of colectomy for slow–transit constipation analyzed 32 studies from 1981

to 1988 and found satisfaction rates ranged from 39% to 100% (157). Higher success rates occurred in studies in the United States (n = 11, median 94%, range 75%–100%) and prospective studies (n = 16, median 90%, range 50%–100%). Superior outcomes occurred in those who had a complete physiologic evaluation and proven slow–transit constipation.

Patients with anismus had higher rates of recurrent symptoms and lower satisfaction levels (158). Poorer outcomes occurred with ileosigmoid and cecorectal anastomosis than with ileorectal anastomosis. Those with segmental resection (hemicolectomy) had the worst outcome. None of the studies had a comparison group, and outcomes were variable and lacking validated measures. Morbidity associated with the operation included small bowel obstruction (median 18%, range 2%–71%), need for reoperation (median 14%, range 0%–

50%), diarrhea (median 14%, range 0%–46%), fecal incontinence (median 14%, range 0%–

52%), recurrent constipation (median 9%, range 0%–33%), persistent abdominal pain Ovid: Berek & Novak's Gynecology

(median 41%, range 0%–90%), and permanent ileostomy (median 5%, range 0%–28%).

Mortality ranged from 0%–6% (159). A quality–of–life study revealed that the score correlated poorly with frequency of bowel movements. However, a lower score was seen in those patients who had persistent abdominal pain, diarrhea, fecal incontinence, and permanent ileostomies. Overall satisfaction with the procedure was very high and correlated with the quality–of–life score (160).

Surgical alternatives to subtotal colectomy include ileostomy, cecostomy with antegrade continence enemas, and sacral nerve stimulation. Subtotal colectomy has never been directly compared with ileostomy, but those who had a permanent diversion after subtotal colectomy had lower quality–of–life scores. Patients undergoing cecostomy with antegrade continence enemas can expect to have satisfactory function approximately one half of the time, with most requiring additional revision procedures secondary to stomal complications (161). Although sacral nerve stimulation has primarily been used for fecal incontinence, the results of a few small studies evoke optimism for its use in chronic constipation and slow–transit constipation (130,162,163).

Pelvic Organ Prolapse

The variety of surgical treatment techniques for the repair of rectocele include posterior colporrhaphy, defect–directed repair, posterior fascial replacement, transanal repair, and abdominal repair with sacral colpopexy. When an enterocele is present, a culdoplasty usually is performed. In cases of perineal descent, abdominal sacral colpoperineopexy is the procedure of choice. Suture rectopexy can be performed in

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conjunction with sacral colpoperineopexy if rectal prolapse is present. Despite the routine use of these procedures, data are limited regarding symptomatic improvement of disordered defecation. Greater detail regarding the specific techniques for many of these procedures will be provided in Chapter 24. This section will focus on surgical outcomes, including anatomic cure of prolapse, improvement of defecatory dysfunction symptoms, and morbidity associated with the procedure.

Posterior Colporrhaphy

Posterior colporrhaphy has been the surgical procedure for rectocele repair preferred by gynecologic surgeons for more than 100 years. Traditional posterior colporrhaphy narrows the vaginal caliber through plication of the rectovaginal septum and usually includes a perineorrhaphy, which narrows the introitus. Despite it broad use, there is a paucity of data regarding long–term anatomic success, symptomatic improvement, and sexual function following the procedure. The outcomes of several studies are summarized in Table

25.9

(164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182).

Anatomic cure and relief of vaginal bulge occurred in 76% to 96% of patients. In these studies, Ovid: Berek & Novak's Gynecology

the procedure was ineffective at treating constipation, vaginal digitations (splinting), and fecal incontinence. Dyspareunia developed in 8% to 26% of patients with and without levator plication (164,165,166,167,168,183). As early as 1961, high rates of dyspareunia have been reported with this procedure in as many as 50% of patients (184).

Many feel that the successful anatomic support obtained with this procedure is offset by the modest relief of functional symptoms and high rate of de novo dyspareunia. However, a recent prospective case series of 38 women undergoing posterior colporrhaphy along with concomitant procedures for rectocele and obstructed defecation revealed markedly different results (185). Fascial plication was performed without levator plication, and perineal body reconstruction rather than routine perineorrhaphy was employed when indicated.

Anatomic cure rate was 87% at 12 months and 79% at 24 months. Subjective cure rate was 97%

at 12 months and 89% at 24 months. There was significant improvement in preoperative and postoperative symptoms for constipation (76% versus 24%), digitations (100% versus 16%), awareness of prolapse (100% versus 5%), obstructed defecation (100% versus 13%), and dyspareunia (37% versus 5%). There was no difference in fecal incontinence and only 1 case of de novo dyspareunia. The authors attribute their improved anatomic and functional outcomes and combined improvement in dyspareunia to exclusion of levator plication, perineorrhaphy, and excision of vaginal epithelium. An additional benefit may be derived during mobilization of the vaginal epithelium, when scar tissue from prior episiotomy or surgery is divided. They also found that preoperative defecating proctography was of limited value and have stopped its routine use as part of the preoperative evaluation for women with symptomatic rectoceles and obstructive defecation.

Defect–Directed Repair

The goal of a defect–directed repair or site–specific repair is to restore normal anatomy (30).

This procedure can be combined with a perineal body reconstruction, if necessary, but usually does not routinely involve perineorrhaphy. Table 25.9 lists the anatomic and functional outcomes for this type of repair. Anatomic cure rates range from 82% to 100%, which are similar to those for posterior colporrhaphy. This procedure also resulted in modest improvement for symptoms of difficult evacuation, vaginal bulge, and vaginal digitations, which appear to be slightly better than for posterior

colporrhaphy (169,170,171,172,173,183). Constipation symptoms significantly decreased in only one study (169). All studies reported low rates of de novo dyspareunia with good functional and anatomic outcomes, but the long–term durability of the procedure is unknown. All but one of these studies included concomitant prolapse and urinary incontinence procedures.

There are no randomized trials comparing posterior colporrhaphy with defect–

directed repair. A retrospective (historical) cohort study of 307 patients with at least 1 year P.976

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of post operative follow–up evaluated 124 women who underwent site–specific repair and 183

who underwent posterior colporrhaphy (186). The decision regarding the type of surgical repair Ovid: Berek & Novak's Gynecology

was made intraoperatively by the surgeon. If a discrete defect was identified, a site–specific repair was performed. Otherwise, posterior colporrhaphy was performed for cases with diffuse attenuation of the rectovaginal septum. Approximately 75% of patients in each group underwent perineorrhaphy for separation of the perineal muscles. The recurrence rates for defect–directed repairs were more than double those for posterior colporrhaphy (33% versus 14% for second degree, 11% versus 4% for third degree or greater respectively based on the Baden–Walker halfway system). Mean postoperative point Bp was -2.2 ± 0.3 vs. -

2.7 ± 0.4, respectively, based on the POP–Q system. There were no detectable differences in postoperative constipation and fecal incontinence between the two procedures. When comparing preoperative and postoperative outcomes, neither procedure improved symptoms of constipation (31% versus 35%), abdominal pain (11% versus 10%), or fecal incontinence (17% versus 19%). Dyspareunia was higher postoperatively (17% versus 8%, p = 0.001) with no difference between surgical techniques (16% versus 17%). The high rate of dyspareunia in the absence of levator plication is most likely attributed to the perineorrhaphy, which was commonly used in both groups. Their outcomes must be interpreted with caution because of the large selection bias and lack of validated measures. Differences in postoperative blood pressure measurements may be statistically significant but not necessarily clinically significant. The results are intriguing, but future randomized control trials are necessary to ultimately determine which procedure is optimal.

Table 25.9 Rectocele Repairs

Posterior Colporrhaphy

Arnold (164)

Mellgren (165)a

Kahn (166)

Weber (167)a

Sand (168)a

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

N

29

25

25

231

171

53

53

70

67

Follow–up

12

42

12

12

(mean) months

Levator plication

Yes

Yes

Yes

No

No

Anatomical cure

80

96

76

90

(%)

Constipation (%)

75

54

100

88

22

33

Protrusion (%)

21

4

64

31

Splinting/

20

50

0

33

digitations (%)

Fecal

36

8

8

4

11

incontinence

De novo

23

8

16

26

dyspareuniab (%)

Defect–Directed Repair

Cundiff (169)

Porter (170)

Kenton (171)

Glavind (172)

Singh (173)a

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

N

69

61

125

72

66

46

67

67

42

33

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Follow–up

12

6

12

3

18

(mean) months

Anatomic cure

82

82

90

100

92

Constipation (%)

46

13

60

50

41

57

Difficult

32

15

61

44

53

46

40

4

57

27

defecation

Protrusion (%)

100

18

38

14

86

9

78

7

Splinting/

   

39

25

24

14

30

15

digitations (%)

Fecal

13

8

24

21

30

9

5

incontinence (%)

Dyspareunia (%)

29

19

67

46

28

8

12

3

31

15

De novo

2

4

7

3

0

dyspareuniab (%)

Repairs with Grafts

Oster (174)

Sand (168)a

Goh (175)a

Kohli (176)

Mercer–Jones (177)a

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

Autologous

Polygalactin mesh

Polypropylene

Porcine dermis

Polypropylene

Graft route

Transvaginal

Transvaginal

Transvaginal

Transvaginal

Transperineal

N

15

15

73

65

43

43

43

30

22

22

Follow–up

30

12

12

12

12

(mean) months

Anatomic cure

100

92

100

93

95

Constipation (%)

33

50

14

Difficult

47

0

95

32

defecation

Protrusion (%)

80

0

100

0

86

23

Splinting/

100

12

64

23

digitations (%)

Fecal

5

incontinence (%)

Dyspareunia (%)

20

Transanal Repair

Sullivan (178)

Sehapavak (179)

Jenssen (180))a

Van Dam (181)a,c

Ayabaca (182)a

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

N

137

117

355

204

64

64

89

89

49

34

Follow–up

18

12

52

48

(mean) months

Anatomic cure

96

98

70

72

90

Constipation (%)

82

15

63

33

83

32

Ovid: Berek & Novak's Gynecology

Difficult

58

2

72

16

92

27

defecation

Protrusion (%)

27

38

3

40

28

Splinting/

26

26

4

23

0

38

digitations (%)

Fecal

39

3

40

9

10

16

71

27

incontinence (%)

Dyspareunia (%)

0

20

28

44

a Prospective.

b In sexually active patients.

c Combined Transanal and Transvaginal Repair

Transanal Repair

Transanal repair involves repair of the rectocele through a transanal incision with excision of redundant rectal mucosa and plication of the rectovaginal septum and rectal wall. The procedure was developed and is primarily used by colorectal surgeons to treat constipation or obstructed defecation associated with “low” or distal rectoceles. The advantages of this approach include excision of redundant rectal mucosa and the ability to treat other anorectal pathology, such as hemorrhoids or anterior rectal wall prolapse (187). Disadvantages include the inability to repair higher rectoceles, enteroceles, cystoceles, uterine prolapse, and defects in the perineal P.978

body or anal sphincter (188). Major complications of infection (6%) and rectovaginal fistula (3%) are relatively rare (179). Most studies did not require vaginal bulging or protrusion symptoms as a prerequisite for surgery. The results of several studies are summarized in Table 25.8.

The anatomic cure rate was 70% to 98%, and symptoms of constipation, difficult evacuation, and vaginal digitations appear to improve (178,179,180,181,182,183).

Recent reviews have compared transanal with transvaginal rectocele repair using the results of two small, randomized control trials (189,190,191,192). Women with compromised sphincter function and other symptomatic prolapse were excluded. The results for transvaginal repair were superior to those for transanal repair with respect to subjective failure rate (relative risk [RR] 0.36, 95% CI 0.13 -1) and objective failure rate (RR 0.24, 95% CI 0.09–0.64) (189). In one study, a significant decrease occurred in the depth of rectocele on postoperative defecography for the transvaginal group compared with the transanal group (2.73 cm versus 4.13 cm, respectively) (192). The transvaginal group had fewer problems with bowel evacuation, but this finding was not statistically significant. In one study, researchers discovered that 38% of patients developed fecal incontinence following transanal repair (164). In the two randomized trials, no significant differences were seen in the rate of fecal incontinence or dyspareunia, but the studies were underpowered to detect a difference (191,192). Although a vaginal approach has been considered superior to a transanal approach for rectocele repair, studies are retrospective and impossible Ovid: Berek & Novak's Gynecology

to compare because the indications for transanal repairs are generally different from those for transvaginal repairs. A prospective, randomized trial with adequate power to evaluate symptomatic outcomes of bowel and sexual function along with anatomic cure is warranted.

Posterior Fascial Replacement

Rectocele repair with graft augmentation is becoming more common despite a paucity of supporting evidence indicating its benefits over standard procedures. The reason for its emergence is the theory that vaginal hernia repairs behave similar to abdominal hernia repairs, which have a documented decrease in recurrence when augmented with grafts. A variety of graft materials have been employed with posterior colporrhaphy and defect–directed repairs including autograft, allograft, xenograft, and synthetic mesh. There are no comparison data to aid in selecting the optimal graft. The purpose of the graft is debatable. It can either be intended to replace existing fascia as a permanent barrier or to provide an absorbable scaffold for collagen deposition, scar formation, and remodeling. The ideal material should have a low erosion rate, be relatively inexpensive, and decrease recurrence rates without causing bowel or sexual dysfunction. The outcomes for rectocele repair using graft materials placed either vaginally or abdominally appear in Table 25.9 (34,168,174,175,176,177,183,193,194), High anatomic cure rates of 89% to 100% occurred, and symptoms of constipation, difficult evacuation, and vaginal bulge also appeared to improve.

The largest prospective study and only randomized trial used absorbable vaginal mesh for rectocele repair (168). Patients were randomly assigned to fascial replacement with polyglactin 910 mesh at the time of anterior and posterior colporrhaphy. There were no differences in recurrence rates when comparing 70 women with a traditional colpoperineorrhaphy with 73 women having a traditional repair plus mesh: 10% versus 8% respectively. This study did not describe changes in bowel or sexual function, and there were no mesh–related adverse events. The risks of vaginal mesh erosion and severe complications may be relatively low but carry significant morbidity, including rectovaginal fistula, persistent vaginal bleeding and discharge, dyspareunia, and the need for additional surgery (175,183). Nonsynthetic grafts appear to be safer, with fewer erosions compared with synthetic grafts.

Future prospective, randomized trials are under way to assess the effect of fascial replacement on symptoms of bowel and sexual function as well as long–term anatomic cure.

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Abdominal Rectocele Repair

The abdominal approach to rectocele repair may be of value when a superior defect in the rectovaginal fascia occurs in a patient with accompanying enterocele, uterine prolapse, or vault prolapse. If a patient is undergoing an abdominal or laparoscopic procedure such as a sacral colpopexy, the graft can be extended along the posterior vaginal wall to correct proximal defects in the rectovaginal septum (195). There are limited data regarding the efficacy of abdominal rectocele repair. The indication for this procedure, as well as the need for additional vaginal repair of distal defects, often is Ovid: Berek & Novak's Gynecology

determined intraoperatively.

Sacral Colpoperineopexy for Perineal Descent

Sacral colpoperineopexy is a modification of sacral colpopexy aimed at correction of apical prolapse combined with rectocele and perineal descent (34). A continuous graft is placed from the anterior longitudinal ligament of the sacrum down to the perineal body.

This procedure can be accomplished either through a total abdominal approach or a combined abdominal and vaginal procedure. If performing a total abdominal approach, the rectovaginal space is opened, and the rectum is dissected off the posterior vaginal wall and rectovaginal septum toward the perineal body. The graft is then sutured to the perineal body or as close to it as possible. A rectovaginal examination with the surgeon's nondominant hand facilitates this attachment by supporting the perineal body.

The graft is secured to additional points along the posterior vaginal wall and apex, and sacral colpopexy is completed in the usual fashion.

If performing a combined abdominal and vaginal approach, the graft is secured to the perineal body vaginally. The posterior vaginal wall is opened, and a defect–directed rectocele repair is performed. Sacral colpopexy is accomplished in the usual fashion except that the vaginal dissection is opened superiorly, creating a window to the abdominal dissection. The graft can then be passed down from the abdominal field to the vaginal field and anchored inferiorly to the perineal body and laterally to the arcus tendineus fascia rectovaginalis.

Alternatively, perineal body stitches can be placed vaginally and then retrieved abdominally once the rectovaginal space is entered from above. The sutures are then incorporated into the caudal portion of the graft. The idea behind the latter technique is to minimize graft exposure to the vagina, which theoretically will decrease vaginal erosion rates (Fig 25.8).

Short–term outcomes for 19 patients who underwent sacral colpoperineopexy indicated good anatomic results for apical and posterior support as well as for perineal descent (34).

Complete cessation of defecatory dysfunction symptoms was accomplished in 66% of patients. In a report of outcomes for a slightly different variation of the sacral colpoperineopexy, the authors' technique involved attachment of Marlex mesh to the perineal body using a needle carrier (194). The failure rate was 25% and mesh erosion rate was 5% for 205 patients with up to 10–year follow–up. A study of Mersilene mesh erosion rates related to sacral colpopexy and sacral colpoperineopexy (196). They noted similar erosion rates between sacral colpopexy and colpoperineopexy when the vagina was not opened, 3.2% versus 4.5%, respectively.

However, the erosion rate was 16% with vaginal suture placement and 40% when the mesh was placed vaginally. The use of nonsynthetic grafts such as dermal allograft and xenograft may help prevent high erosion rates. In a case series of 11 patients, researchers performed sigmoid resection (if indicated) and suture rectopexy in conjunction with sacral colpoperineopexy using Alloderm for women with coexistent rectal prolapse, perineal descent, and defecatory dysfunction. Early follow–up (12.5 ± 7.7 months) revealed excellent improvement of defecatory dysfunction symptoms and quality–of–life considerations, with an 82% cure of perineal descent (197). Sacral colpoperineopexy appears to have value for a select group of patients, but larger prospective series with long–term anatomic and symptomatic outcomes are necessary to evaluate the durability of this procedure.

Ovid: Berek & Novak's Gynecology

Figure 25.8 Abdominal sacral colpoperineopexy with sigmoid resection and suture rectopexy. This sagittal view shows the posterior graft sutured to the rectovaginal fascia and perineal body after defect–directed rectocele repair. The anterior graft is sutured to the pubocervical fascia. Both sheets will be secured to the sacral periosteum to the right of the rectum.

Rectopexy sutures ( left) have not yet been tied and secured. (Courtesy of Geoffrey W. Cundiff, M.

D.).

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Rectal Prolapse

Numerous surgical procedures have been described for the treatment of rectal prolapse and are broadly categorized into perineal or abdominal approaches. Most surgeons prefer an Ovid: Berek & Novak's Gynecology

abdominal procedure because of lower recurrence rates, reserving perineal procedures for more debilitated patients.

Abdominal Procedures

Abdominal procedures vary with respect to the extent of rectal mobilization, method of rectal fixation, and inclusion or exclusion of bowel resection. During abdominal rectopexy, the mesorectal plane is developed and the rectum mobilized down to the pelvic floor posteriorly, with care taken to identify and preserve the hypogastric nerves. Division of the lateral ligaments may or may not be performed. The concern is that division of the lateral ligaments will lead to rectal denervation and increased postoperative constipation.

If performing a suture rectopexy, the fascia propria of the rectum is secured to the sacral periosteum from S–1 to S–3 (198). If performing a sigmoid resection with the rectopexy (Frykman–Goldberg resection rectopexy), the bowel resection is performed after mobilization and before suturing (199). The theoretical advantages of a rectosigmoid resection are creation of

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a dense area of fibrosis between the anastomotic suture line and the sacrum; removal of abundant rectosigmoid, avoiding torsion or volvulus; additional fixation through straightening of the left colon and decreased mobility from the phrenocolic ligament; and relief of constipation in select patients. It is typically reserved for patients with a long redundant sigmoid colon, although specific criteria have not been proposed. Mesh rectopexies are usually avoided because of concern for increased complications and infections associated with placement of a foreign body at the time of bowel resection. There are two basic types of mesh rectopexy: posterior mesh rectopexy and anterior sling rectopexy (Ripstein procedure) (200,201). A variety of materials have been used for this procedure, including absorbable and permanent mesh.

The assumption is that placement of this material will provide increased support through increased fibrous tissue formation. During the Ripstein procedure, an anterior sling of fascia lata or synthetic mesh is placed in front of the rectum and sutured to the sacrum. Most surgeons avoid this procedure because of fear of obstructed defecation. Modifications using a posterolateral wrap have been developed to resolve this problem.

In a series of greater than 10 patients, there were five open series and five laparoscopic reports for suture rectopexy (202). The recurrence rates ranged between 0% and 9%. Most reports showed an improvement in fecal incontinence symptoms, but the results for constipation were variable. There were no mortalities noted and no difference between laparoscopic and open results. For posterior mesh rectopexy, there were 14 open series and five laparoscopic reports. The recurrence rates ranged between 0% and 6%. As with suture rectopexy, there was general improvement in fecal incontinence, mixed results for constipation, and no differences between laparoscopic and open outcomes. The mortality rate was between 0% and 3%, with increased rates of infection if resection rectopexy was performed. For anterior sling rectopexy (Ripstein procedure), there were eight studies with a recurrence rate between 0% and 12%. Again, there was a trend toward improvement of fecal incontinence and mixed response for constipation. Mortality ranged from 0% to 3%. For resection rectopexy (Frykman–Goldberg procedure), there were nine open series and three Ovid: Berek & Novak's Gynecology

laparoscopic reports. Recurrence ranged between 0% and 5%. There was general improvement in continence as well as an overall reduction in constipation observed in most studies. Mortality rate was 0% for all studies but one, in which it was 6.7% (203). This study was a small, randomized trial comparing 15 patients undergoing resection rectopexy to 15 patients undergoing absorbable mesh rectopexy. The patient who died was in the resection group and had a myocardial infarction. The authors concluded that sigmoid resection did not seem to increase operative morbidity but tended to diminish postoperative constipation, possibly by causing less outlet obstruction. The study was underpowered to detect a difference in morbidity or mortality.

The laparoscopic series demonstrated similar safety and efficacy to the open techniques, and the effect on continence and constipation tended to mirror the type of rectopexy performed. In a small, randomized trial, there were significant short–term benefits with laparoscopic rectopexy compared with open rectopexy, including earlier ambulation, more rapid return to normal diet, shorter hospital stay, and lower morbidity (204).

Most surgeons believe that there are no differences in recurrence rates between suture and mesh rectopexy. Consequently, the role of mesh in these procedures is suspect. The role of division of the lateral ligaments is somewhat controversial. A Cochrane Review performed in 2000 concluded that division of the lateral ligaments was associated with less recurrent prolapse but more postoperative constipation (205). The authors acknowledged the limitations of their review, which consisted of very few trials with small sample sizes and methodological weakness. A review of seven open and four laparoscopic series involving division of the lateral ligaments revealed a general improvement in fecal incontinence and either no change or worsening of constipation (202). Conversely, there were 15 open and four laparoscopic series with preservation of the ligaments that displayed improved continence and a trend toward reduced constipation. This study suggests that preservation of the lateral ligaments is associated with an improvement in fecal incontinence and constipation symptoms.

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Perineal Procedures

Perineal procedures are more easily tolerated because they avoid laparotomy. Thus, they are ideal for patients at high–risk for perioperative and postoperative morbidity and mortality. There are basically two perineal procedures: the Delorme procedure and perineal rectosigmoidectomy (Altemeier operation). Perianal encirclement procedures such as the Thiersch procedure are not recommended because of poor success rates, high recurrence rates, and fecal impaction.

The Delorme procedure was first described in 1900 and involves separation of the rectal mucosa from the sphincter and muscularis propria, followed by resection of the rectal mucosa, and plication of the distal rectal wall (muscularis propria) (206) (Fig. 25.9). A review of 10

series found a recurrence rate ranging between 4% and 38% and mortality rates of 0% to 4%

(202).The low mortality rates are impressive considering a higher–risk population; however, the recurrence rates make it a less desirable procedure among healthy patients. There was a general improvement in fecal incontinence and constipation. Fecal incontinence

Ovid: Berek & Novak's Gynecology

(presumably indicating anal sphincter disruption or denervation), chronic diarrhea, and severe perineal descent are associated with failure of this procedure (207). The Delorme operation may be preferred in cases when the prolapsing segment is shorter than 3 to 4 cm or there is no circumferential full–thickness prolapse, making perineal rectosigmoidectomy difficult to perform (202,208).

Perineal rectosigmoidectomy (Altemeier operation) has become the perineal procedure of choice (209). Among 12 studies, performance of full thickness excision of the rectosigmoid was associated with recurrence rates from 0% to 16% and mortality rates of 0% to 5%.

Patients generally have minimal pain and a relatively uneventful postoperative course.

Recurrent prolapse probably reflects inadequate resection. Incontinence results are modest at best but seem to improve substantially with the addition of levatorplasty. The addition of levatorplasty also appears to decrease the short–term recurrence rate (210), but there is no significant change in constipation with this procedure. Most agree that perineal rectosigmoidectomy with levatorplasty is the best procedure for very elderly patients and those with profound comorbidity. This is the preferred approach for patients with incarcerated, strangulated, or even gangrenous prolapsed rectal segment who are not candidates for abdominal rectopexy. Although there is a general consensus that abdominal rectopexy is better than perineal rectosigmoidectomy, there is

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only one small, prospective, randomized control trial comparing these procedures. This study did not have the power to detect a difference in recurrence rates but found that patients undergoing abdominal resection rectopexy had less fecal incontinence and better physiological results than patients who had perineal rectosigmoidectomy (205,211).

Ovid: Berek & Novak's Gynecology

Figure 25.9 Delorme's procedure. After mucosal stripping to the full extent of the prolapse, the circular smooth muscle or the rectum is plicated. A mucosa–to–mucosa anastomosis is then performed.

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3. Glia A, Lindberg G. Quality of life in patients with different types of functional constipation. Scand J Gastroenterol 1997;32:1083–1089.

4. Cundiff GW, Nygaard I, Bland DR, et al. Proceedings of the American Urogynecologic Society Multidisciplinary Symposium on Defecatory Disorders. Am J Obstet Gynecol 2000;182:S1–10.

5. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99:750–759.

6. Sonnenberg A, Koch TR. Epidemiology of constipation in the U.S. Dis Colon Rectum 1989;32:1–8.

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174. Oster S, Astrup A. A new vaginal operation for recurrent and large rectocele using dermis transplant. Acta Obstet Gynecol Scand 1981;60:493–495.

175. Goh JT, Dwyer PL. Effectiveness and safety of polypropylene mesh in vaginal prolapse surgery. Int Urogynecol J 2001;12:S90.

176. Kohli N, Miklos JR. Dermal graft–augmented rectocele repair. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:146–149.

177. MercerJones MA, Sprowson A, Varma JS. Outcome after transperineal mesh repair Ovid: Berek & Novak's Gynecology

of rectocele: a case series. Dis Colon Rectum 2004;47:864–868.

178. Sullivan ES, Leaverton GH, Hardwick CE. Transrectal perineal repair: an adjunct to improved function after anorectal surgery. Dis Colon Rectum 1968;11:106–114.

179. Sehapayak S. Transrectal repair of rectocele: an extended armamentarium of colorectal surgeons. A report of 355 cases. Dis Colon Rectum 1985;28:422–433.

180. Janssen LW, van Dijke CF. Selection criteria for anterior rectal wall repair in symptomatic rectocele and anterior rectal wall prolapse. Dis Colon Rectum 1994;37:1100–1107.

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181. van Dam JH, Huisman WM, Hop WC, et al. Fecal continence after rectocele repair: a prospective study. Int J Colorectal Dis 2000;15:54–57.

182. Ayabaca SM, Zbar AP, Pescatori M. Anal continence after rectocele repair. Dis Colon Rectum 2002;45:63–69.

183. Cundiff GW, Fenner D. Evaluation and treatment of women with rectocele: focus on associated defecatory and sexual dysfunction. Obstet Gynecol 2004;104:1403–1421.

184. Francis WJ, Jeffcoate TN. Dyspareunia following vaginal operations. J Opt Soc Am 1961;68:1–10.

185. Maher CF, Qatawneh AM, Baessler K, et al. Midline rectovaginal fascial plication for repair of rectocele and obstructed defecation. Obstet Gynecol 2004;104:685–689.

186. Abramov Y, Gandhi S, Goldberg RP, et al. Site–specific rectocele repair compared with standard posterior colporrhaphy. Obstet Gynecol 2005;105:314–318.

187. Zbar AP, Leinemann A, Fritsch H, et al. Rectocele: pathogenesis and surgical management. Int J Colorectal Dis 2003;18:369–384.

188. Goh JT, Tjandra JJ, Carey MP. How could management of rectoceles be optimized? ANZ

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191. Kahn MA, Stanton SL, Kumar D, et al. Posterior colporrhaphy is superior to the transanal repair for treatment of posterior vaginal wall prolapse. Neurourol Urodyn 1999;18:70–71.

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203. Luukkonen P, Mikkonen U, Jarvinen H. Abdominal rectopexy with sigmoidectomy vs rectopexy alone for rectal prolapse: a prospective, randomized study. Int J Colorectal Dis 1992;7:219–222.

204. Solomon MJ, Young CJ, Eyers AA, et al. Randomized clinical trial of laparoscopic versus open abdominal rectopexy for rectal prolapse. Br J Surg 2002;89:35–39.

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208. Takesue Y, Yokoyama T, Murakami Y, et al. The effectiveness of perineal rectosigmoidectomy for the treatment of rectal prolapse. Surg Today 1999;29:290–293.

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Editors: Berek, Jonathan S.

Title: Berek & Novak's Gynecology, 14th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > Section VII - Reproductive Endocrinology > 26 - Puberty 26

Puberty

Robert W. Rebar

Normal pubertal development occurs in a predictable orderly sequence over a definite time frame. .

The major causes of delayed puberty include anatomic genital tract

abnormalities and hypo– and hypergonadotropic amenorrhea. .

When pubertal development occurs asynchronously, with development of breasts in the absence of significant pubic and axillary hair, the diagnosis is usually androgen insensitivity. .

The most common cause of precocious puberty is constitutional (idiopathic), but more serious causes must be ruled out and therapy geared toward optimizing adult height. .

The most common cause of heterosexual development at the expected age of puberty is polycystic ovary syndrome (PCOS). .

Puberty is the period during which secondary sexual characteristics develop Ovid: Berek & Novak's Gynecology

and the capability of sexual reproduction is attained. The physical changes accompanying pubertal development result directly or indirectly from maturation of the hypothalamus, stimulation of the sex organs, and secretion of sex steroids. Hormonally, puberty in humans is characterized by the resetting of the classic negative gonadal steroid feedback loop, alterations in circadian and ultradian (frequent) gonadotropin rhythms, and the acquisition in the woman of a positive estrogen feedback loop, which controls the monthly rhythm as an interdependent expression of gonadotropins and ovarian steroids.

The ability to evaluate and treat aberrations of pubertal development requires an understanding of the normal hormonal and physical changes that occur at puberty.

An understanding of these changes is also important in evaluating young women with amenorrhea.

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Normal Pubertal Development

Factors Affecting Time of Onset

The major determinant of the timing of the onset of puberty is no doubt genetic, but a number of other factors appear to influence both the age at onset and the progression of pubertal development. Among these influences are nutritional state, general health, geographic location, exposure to light, and psychological state (1). The concordance of the age of menarche in mother–daughter pairs and between sisters and in ethnic populations illustrates the importance of genetic factors (1). Typically, the age of menarche is earlier than average in children with moderate obesity (up to 30% above normal weight for age), whereas delayed menarche is common in those with severe malnutrition. Children who live in urban settings, closer to the equator, and at lower altitudes typically begin puberty earlier than those who live in rural areas, farther from the equator, and at higher elevations. Blind girls apparently undergo menarche earlier than sighted girls, suggesting some influence of light (2).

In Western Europe, the age of menarche declined 4 months each decade between 1850 and 1960 (1). Recent data suggest that the trend toward earlier pubertal development may be continuing among girls (but not boys) who live in the United States (3). It has been presumed that these changes represent improved nutritional status and healthier living conditions.

One of the more controversial hypotheses has centered on the role of total body weight and body composition on the age of menarche. It has been argued that a girl must reach a critical body weight (47.8 kg) before menarche can occur (4). More importantly, body fat must increase to 23.5% from the typical 16% of the prepubertal state, which presumably is influenced by nutritional status (5). This hypothesis is supported by observations that menarche occurs earliest in obese girls, followed by normal–weight girls, then underweight girls, and lastly anorectic girls (Fig. 26.1). The importance of other factors is indicated by observations that menarche is often delayed in morbidly obese girls, those with diabetes, and those who exercise intensely but are of normal body weight and body fat percentage. Moreover, girls with precocious puberty may undergo menarche even if they have a low body fat percentage, and other girls show no pubertal development with a body fat percentage of 27%

(6). The hypothesis linking menarche to body weight and composition does not always seem valid because menarche is a late event in pubertal development.

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Physical Changes during Puberty

The changes associated with puberty occur in an orderly sequence over a definite time frame. Any deviation from this sequence or time frame should be regarded as abnormal. Moreover, the pubertal changes, their relationships to each other, and the ages at which they occur are distinctly different in girls and in boys. Although this chapter focuses on girls, changes in boys are considered briefly as well.

Tanner Stage

In girls, pubertal development typically takes place over 4.5 years (Fig. 26.2).

Although generally the first sign of puberty is accelerated growth, breast budding is usually the first recognized pubertal change, followed by the appearance of pubic hair, peak growth velocity, and menarche. The stages initially described by Marshall and Tanner are often used to describe breast and pubic hair development (7).

With regard to breast development (Fig. 26.3), Tanner stage 1 refers to the prepubertal state and includes no palpable breast tissue, with the areolae generally less than 2 cm in diameter.

The nipples may be inverted, flat, or raised. In Tanner stage 2, breast budding occurs, with a visible and palpable mound of breast tissue. The areolae begin to enlarge,

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the skin of the areolae thins, and the nipple develops to varying degrees. Tanner stage 3

is reflected by further growth and elevation of the entire breast. When the individual is seated and viewed from the side, the nipple is generally at or above the midplane of breast tissue. In most girls, Tanner stage 4 is defined by projection of the areola and papilla above the general breast contour in a secondary mound. Breast development is incomplete until Tanner stage 5, in which the breast is mature in contour and proportion. In most women, the nipple is more pigmented at this stage than earlier in development, and Montgomery's glands are visible around the circumference of the areola. The nipple is generally below the midplane of breast tissue when the woman is seated and viewed from the side. Full breast development usually occurs over 3 to 3.5 years, but it may occur in as little as 2

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years or not progress beyond stage 4 until the first pregnancy. Breast size is no indication of breast maturity.

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Figure 26.1 Normal twins at 12 years of age. The heavier twin (weighing 143 lb) is clearly more advanced in puberty than the lighter twin (weighing 87 lb). Anecdotal photographs and data such as these served to provide the basis for the theory that body fat, body mass, and menarche are linked.

(From Wilkins ll. The diagnosis and treatment of endocrine disorders in childhood and adolescence.

3rd ed. Springfield, IL: Charles C Thomas, 1965, with permission).

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Figure 26.2 Schematic sequence of events at puberty. An idealized average girl and an idealized average boy are represented. (From Rebar RW. Practical evaluation of hormonal status. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology: physiology, pathophysiology and clinical management. 3rd ed. Philadelphia, PA: WB

Saunders, 1991:830, with permission; based on data from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303, and Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–

23, with permission.).

Pubic hair staging is related both to quantity and distribution (Fig. 26.4). In Tanner stage 1, there is no sexually stimulated pubic hair present, but some nonsexual hair may be present in the genital area. Tanner stage 2 is characterized by the first appearance of coarse, long, crinkly pubic hair along the labia majora. In Tanner stage 3, coarse, curly hair extends onto the mons pubis. Tanner stage 4 is characterized by adult hair in thickness and texture, but the hair is not distributed as widely as in adults and typically does not extend onto the inner aspects of the thighs. Except in certain ethnic groups, including Asians and American Indians, pubic hair extends onto the thighs in Tanner stage 5.

The staging of male pubertal sexual maturation is based on genital size and pubic hair development. Tanner stage 1 is prepubertal. Tanner stage 2 of genital growth begins when testicular enlargement is first evident. Testis length along the longitudinal axis ranges from 2.5 to 3.2 cm. The size of the penis increases as well. Pigmented, curly pubic hair is first

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visible around the base of the penis. In Tanner stage 3, there is further growth of the penis in both length and diameter, the scrotum develops further, and testis length increases to 3.3 to 4 cm. Thicker, curly hair extends above the penis. Tanner stage 4 involves further growth of the genitalia, with testis length ranging from 4 to 4.5 cm. Extension of pubic hair over the genital area continues, but the volume is less than in the adult. At this stage, the prostate gland is palpable by rectal examination. In Tanner stage 5, the genitalia are within the adult range in size. Stretched penile length measured along the dorsum averages 15.7 cm in adult men. Pubic hair spreads laterally onto the medial thighs. Hair may or may not extend from the pubic area toward the umbilicus and anus.

Figure 26.3 Diagrammatic depiction of Tanner breast stages in adolescent women. (From Ross GT, Van de Wiele RL, Frantz AG. The ovaries and the breasts. In: Williams RH, ed.

Textbook of endocrinology. 6th edition. Philadelphia, PA: WB Saunders, 1981:355, with permission; adapted from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303).

Pigmented pubic hair is often the first recognized sign of male puberty even though it typically occurs 6 months after genital growth begins. Tanner stage 3 puberty often is accompanied by symmetric or asymmetric gynecomastia, and mature sperm first can be identified with microscopic urinalysis.

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Figure 26.4 Diagrammatic depiction of Tanner pubic hair staging in adolescent women.

(From Ross GT, VandeWiele RL, Frantz AG. The ovaries and the breasts. In: Williams RH, ed. Textbook of endocrinology. 6th ed. Philadelphia, PA: WB Saunders, 1981:355, with permission; adapted from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303.).

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Height and Growth Rate

Plotting height increments (i.e., growth velocity) against the phases of puberty allows one to see relationships during puberty (see Fig. 26.2). Girls reach peak height velocity early in puberty before menarche. As a consequence, they have limited growth potential after menarche. In contrast, boys reach peak height velocity about 2 years later than girls. Boys grow an average of 28 cm during the growth spurt, in comparison to a mean of 25 cm for girls. Adult men eventually are an average of 13 cm taller than adult women largely because they are taller at the onset of the growth spurt. Hormonal control of the pubertal growth spurt is complex.

Growth hormone (GH), insulinlike growth factor 1 (IGF–1), and gonadal steroids play major roles. Adrenal androgens appear to be less important. Mutations limiting conversion of androgens to estrogens in males have confirmed that estrogen is the major stimulus to the pubertal growth spurt in both boys and girls (8).

During the growth spurt associated with puberty, the long bones in the body lengthen, and the epiphyses ultimately close. The bone or skeletal age of any individual can be estimated closely by comparing x–rays documenting the development of bones in the nondominant hand (most commonly), knee, or elbow to standards of maturation for the normal population. The Greulich and Pyle atlas is used most often for this purpose (9). Skeletal age is more closely correlated with pubertal stage than with chronologic age during puberty.

With height and chronologic age, an individual's bone age can be used to predict final adult height using the Bayley–Pinneau tables (10).

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Another practical clinical approach to predicting adult height uses midparental height. The adjusted midparental height is calculated by adding 13 cm to the mother's height (for boys) or subtracting 13 cm from the father's height (for girls) and then determining the mean of the heights of the parents, including the adjusted height of the opposite–sex parent. Adding and subtracting 8.5 cm to the calculated predicted height approximates the target range of the third to the ninety–seventh percentile for the anticipated adult height of the child. This quick calculation can be of assistance in evaluating individuals with delayed or precocious pubertal development and those with short stature.

Several changes in body composition also occur during pubertal development. Although lean body mass, skeletal mass, and body fat are equal in prepubertal boys and girls, by maturity, men have 1.5 times the lean body mass and almost 1.5 times the skeletal mass of women, whereas women have twice as much body fat as men (1).

The changes in body contour in girls, with accumulation of fat at the thighs, hips, and buttocks, occur during the pubertal growth spurt. In this regard, testosterone is a potent anabolic steroid and is responsible for the major changes in boys, whereas estrogen increases total body fat in a characteristic distribution at the thighs, buttocks, and abdomen in girls.

Other physical changes show sexual dimorphism at puberty. In boys both the membranous and cartilaginous portions of the vocal cords lengthen much more than they do in girls, accounting for deepening of the voice. Comedones, acne, and seborrhea of the scalp begin because of increased secretion of adrenal and gonadal steroids at puberty. In general, early–

onset acne correlates with the development of severe acne later in puberty. The appearance of comedones in the nasal creases and behind the pinna may be the first indications of impending pubertal development. .

Hormonal Changes

By 10 weeks of gestation, gonadotropin–releasing hormone (GnRH) is present in the hypothalamus, and luteinizing hormone (LH) and follicle–stimulating hormone (FSH) are present in the pituitary gland (11). Gonadotropin levels are elevated in both female and male fetuses before birth; the levels of FSH are higher in females. At birth, gonadotropin and sex steroid concentrations are still high, but the levels decline during the first several weeks of life and remain low during the prepubertal years. The hypothalamic–pituitary unit appears to be suppressed by the extremely low levels of gonadal steroids present in childhood.

Gonadal suppression of gonadotropin secretion is demonstrated by higher gonadotropin levels in children with gonadal dysgenesis and those who undergo gonadectomy before puberty (12).

Several of the hormonal changes associated with pubertal development begin before any of the physical changes are obvious. Early in puberty, there is increased sensitivity of LH

to GnRH. Sleep–entrained increases in both LH and FSH can be documented early in puberty (13).

In boys, the nocturnal increases in gonadotropin levels are accompanied by simultaneous increases in circulating testosterone levels (14). In contrast, in girls, the nighttime increases in circulating gonadotropin levels are followed by increased secretion of estradiol the next day (15) (Fig. 26.5). This delay in estradiol secretion is believed to be due to the additional synthetic steps required in the aromatization of estrogens from androgens. Basal levels of both FSH and LH increase through puberty. The patterns differ in boys and girls, with LH levels (measured in mIU/mL) eventually becoming greater than FSH levels (16) (Fig. 26.6). Although it now appears that gonadotropins are always secreted in an episodic or pulsatile fashion, even before puberty, the pulsatile secretion of gonadotropins is more easily documented as puberty progresses and basal levels increase (17).

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Figure 26.5 Patterns of circulating luteinizing hormone (LH), follicle–stimulating hormone (FSH), and estradiol in a stage 3 pubertal girl over a 24–hour period with the encephalographic stage of sleep indicated. (From Boyar RM, Wu RHK, Roffwarg H, et al. Human puberty: 24–hour estradiol patterns in pubertal girls. J Clin Endocrinol Metab 1976;43:1418–1421, with permission.).

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Increased adrenal androgen secretion is important in stimulating adrenarche, the appearance of pubic and axillary hair, in both boys and girls. Pubarche specifically refers to the appearance of pubic hair. Progressive increases in circulating levels of the major adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), begin as early as 2 years of age, accelerate at 7 to 8 years of age, and continue until 13 to 15 years of age (18,19,20). The accelerated increases in adrenal androgens begin about 2 years before the increases in gonadotropin and gonadal sex steroid secretion when the hypothalamic–

pituitary–gonadal unit is still functioning at a low prepubertal level.

In girls, estradiol, secreted predominantly by the ovaries, increases steadily during puberty (16). Although, as noted, increases in estradiol first appear during the daytime hours, basal levels eventually increase during both the day and night. Estrone, which is secreted in part by the ovaries and arises in part from extraglandular conversion of estradiol and androstenedione, also increases early in puberty but plateaus by midpuberty. Thus, the ratio of estrone to estradiol decreases throughout puberty, indicating that ovarian production of estradiol becomes increasingly important and peripheral conversion

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of androgens to estrone becomes less important during maturation. .

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Figure 26.6 Increases (± standard error) in circulating levels of gonadotropins and adrenal and gonadal steroids through puberty in girls. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. (From Emans SJH, Goldstein DP. The physiology of puberty. In: Emans SJH, Goldstein DP, eds. Pediatric and adolescent gynecology. 3rd ed.

Boston, MA: Little, Brown, 1990:95, with permission.).

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In boys, most of the testosterone in the circulation arises from direct secretion by the Leydig cells of the testis. Testosterone induces development of a male body habitus and voice change, whereas dihydrotestosterone (DHT), produced following 5α reduction within target cells, induces enlargement of the penis and prostate gland, beard growth, and temporal hair recession during puberty. Mean plasma testosterone levels rise progressively during puberty, with the greatest increase occurring during Tanner stage 2 (21).

Growth hormone secretion increases along with increased gonadotropin secretion at the onset of puberty. It is believed that the increase in GH is mediated by estrogen, which in boys is dependent on aromatization of testosterone to estradiol and reflects increasing sex steroid production at puberty. Nonetheless, there are profound sex differences in GH

secretion during puberty. Girls have higher basal levels of GH throughout puberty, reaching maximal levels around the time of menarche and decreasing thereafter. In contrast, basal concentrations of GH remain constant throughout puberty in boys. Growth hormone secretion is highly pulsatile, with most pulses occurring during sleep and with sex steroids increasing pulse amplitude rather than altering pulse frequency.

Growth hormone stimulates production of insulinlike growth factor 1 (IGF–1) in all tissues, with concentrations found in the circulation spilling over from the liver. During puberty the negative feedback effect of IGF–1 on GH secretion must be reduced because both IGF–1 and GH levels are high. Growth hormone and IGF–1 no doubt play significant roles in the changes in body composition that occur at puberty because both hormones are potent anabolic agents.

In the final stages of puberty in both boys and girls, GH secretion begins to diminish, returning to prepubertal levels in adult life, despite continued exposure to high levels of gonadal steroids.

Mechanisms Underlying Puberty

The mechanisms responsible for the numerous hormonal changes that occur during puberty are poorly understood, although it is recognized that a “central nervous system program” must be responsible for initiating puberty. It appears that the hypothalamic–pituitary–gonadal axis in girls develops in two distinct stages during puberty.

First, sensitivity to the negative or inhibitory effects of the low levels of circulating sex steroids present in childhood decreases early in puberty. Second, late in puberty, there is maturation of the positive or stimulatory feedback response to estrogen, which is responsible for the ovulatory midcycle surge of LH.

Current evidence suggests that the central nervous system inhibits the onset of puberty until the appropriate time (22). Based on this theory, the neuroendocrine control of puberty is mediated by GnRH–secreting neurons in the medial basal hypothalamus, which together act as an endogenous pulse generator. At puberty, the GnRH pulse generator is reactivated (i.e., disinhibited), leading to increased amplitude and frequency of GnRH pulses.

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steroid secretion. What causes this “disinhibition” of GnRH release is unknown.

The relationship between body mass and the onset of puberty has focused attention on leptin, produced by adipocytes, as a candidate for the factor initiating puberty. In the infertile leptin–deficient mouse, leptin therapy can induce sexual maturation and maintain fertility. Observations of two patients with leptin receptor mutations who failed to enter puberty suggest that leptin may have a similar role in humans.

Longitudinal studies of leptin secretion have noted that there is increased leptin secretion around the time of pubertal onset. Leptin levels are increased throughout puberty in girls but not in boys. Thus, it is not clear how important leptin is to pubertal development.

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Aberrations of Pubertal Development

Classification

Several aberrations of pubertal development, as detailed in Table 26.1, can occur in girls.

Pubertal aberrations can be classified in four broad categories:.

Delayed or interrupted puberty exists in girls who fail to develop any secondary sex characteristics by age 13, have not had menarche by age 16, or have not attained menarche 5 or more years since the onset of pubertal development. .

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Asynchronous pubertal development is characterized by pubertal development that deviates from the normal pattern of puberty. .

Precocious puberty has been defined as pubertal development beginning before the age of 7 years in white girls and before the age of 6 years in African American girls (3). This new definition is controversial and has been challenged because some feel that evaluation for breast or pubic hair development before 9 or 8 years of age in white or African American girls, respectively, may be warranted (23). It is clear that, in most cases, development nearer to the mean age of puberty is less likely to have a pathologic basis. Precocious pubertal development is characterized in several ways. In isosexual precocious puberty, the early changes are common to the phenotypic sex of the individual. In heterosexual precocious puberty, the development is characteristic of the opposite sex. Precocious puberty is sometimes termed “true” when it is of central origin with activation of the hypothalamic–pituitary unit. In precocious pseudopuberty, also known as precocious puberty of peripheral origin, secretion of hormones in the periphery (commonly by neoplasms) stimulates pubertal development.

Heterosexual puberty is characterized by a pattern of development that is typical of the opposite sex occurring at the expected age of normal puberty. .

Table 26.1 Aberrations of Pubertal Development

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I. Delayed or interrupted puberty

A. Anatomic abnormalities of the genital outflow tract

1. Müllerian dysgenesis (Rokitansky–Küster–Hauser syndrome)

2. Distal genital tract obstruction

a. Imperforate hymen

b. Transverse vaginal septum

B. Hypergonadotropic (follicle–stimulating hormone >30 mIU/mL)

hypogonadism (gonadal “failure”)

1. Gonadal dysgenesis with stigmata of Turner syndrome

2. Pure gonadal dysgenesis

a. 46,XX

b. 46,XY

3. Early gonadal “failure” with apparent normal ovarian development C. Hypogonadotropic (luteinizing hormone and follicle–stimulating

hormone <10 mIU/mL) hypogonadism

1. Constitutional delay

2. Isolated gonadotropin deficiency

a. Associated with midline defects (Kallmann syndrome)

b. Independent of associated disorders

c. Prader–Labhart–Willi syndrome

d. Laurence–Moon–Bardet–Biedl syndrome

e. Many other rare syndromes

3. Associated with multiple hormone deficiencies

4. Neoplasms of the hypothalamic–pituitary area

a. Craniopharyngiomas

b. Pituitary adenomas

c. Other

5. Infiltrative processes (Langerhans cell–type histiocytosis) 6. After irradiation of the central nervous system

7. Severe chronic illnesses with malnutrition

8. Anorexia nervosa and related disorders

9. Severe hypothalamic amenorrhea (rare)

10. Antidopaminergic and gonadotropin–releasing hormone–inhibiting drugs (especially psychotropic agents, opiates)

11. Primary hypothyroidism

12. Cushing syndrome

13. Use of chemotherapeutic (especially alkylating) agents

II. Asynchronous pubertal development

A. Complete androgen insensitivity syndrome (testicular feminization)

B. Incomplete androgen insensitivity syndrome

III. Precocious puberty

A. Central (true) precocious puberty

1. Constitutional (idiopathic) precocious puberty

2. Hypothalamic neoplasms (most commonly hamartomas)

3. Congenital malformations

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5. After irradiation

6. Trauma

7. Infection

B. Precocious puberty of peripheral origin (precocious pseudopuberty)

1. Gonadotropin–secreting neoplasms

a. Human chorionic gonadotropin secreting

i. Ectopic germinomas (pinealomas)

ii. Choriocarcinomas

iii. Teratomas

iv. Hepatoblastomas

b. Luteinizing hormone–secreting (pituitary adenomas)

2. Gonadal neoplasms

a. Estrogen–secreting

i. Granulosa–theca cell tumors

ii. Gonadal sex–cord tumors

b. Androgen–secreting

i. Arrhenoblastomas

ii. Teratomas

3. Congenital adrenal hyperplasia

a. 21–Hydroxylase (P450c21) deficiency

b. 11β–Hydroxylase (P450c11) deficiency

c. 3β–Hydroxysteroid dehydrogenase deficiency

4. Adrenal neoplasms

a. Adenomas

b. Carcinomas

5. Autonomous gonadal hypersecretion

a. Cysts

b. McCune–Albright syndrome

6. Iatrogenic ingestion/absorption of estrogens or androgens

IV. Heterosexual puberty

A. Polycystic ovarian syndrome

B. Nonclassic forms of congenital adrenal hyperplasia

C. Idiopathic hirsutism

D. Mixed gonadal dysgenesis

E. Rare forms of male pseudohermaphroditism (Reifenstein syndrome,

5a–reductase deficiency)

F. Cushing syndrome (rare)

G. Androgen–secreting neoplasms (rare)

Disorders of sexual development and amenorrhea may be considered in relation to this classification of the aberrations of puberty. It is very helpful to document the growth of the individual and to plot the individual's height and weight on one of several commonly available growth charts (Fig. 26.7).

Delayed or Interrupted Puberty

The history and physical examination, with particular attention to growth, are most important in the evaluation of individuals with delayed puberty. Pubertal delay is

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much more common in boys than in girls. It is important to remember that puberty may be delayed in any child suffering from any severe chronic disease, including celiac disease, Crohn disease, sickle cell anemia, and cystic fibrosis. Thus, chronic illness should be excluded during the history and physical examination. One possible approach to evaluation is depicted in Figure 26.8.

Figure 26.7 Growth chart showing stature by age percentiles for girls aged 2 to 18 years.

Weight can be plotted in a similar fashion. Several excellent growth charts are available to clinicians, including those from Ross Laboratories (Columbus, OH), Serono Laboratories (Randolph, MA), and Genentech, Inc. (South San Francisco, CA). (From Hamill PVV, Drizd TA, Johnson CL, et al.

Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607–629, with permission; based on data from the National Center for Health Statistics.).

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Anatomic Abnormalities of the Genital Outflow Tract

Those girls who have mature secondary sex characteristics and any of a number of disorders of the outflow tract and uterus, often termed müllerian agenesis and dysgenesis, are most often identified on examination (Fig. 26.9). One of the most logical classification schemes that has been proposed is shown in Table 26.2 (24). The incidence of these anomalies was estimated to be 0.02% of the female population several years ago (25), but the incidence may have increased as a result of the maternal ingestion of diethylstilbestrol (DES) and the resultant increase in anomalies of the lumen of the uterus (class VI) (26). Of

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the disorders unrelated to drug use, the septate uterus (class V) is most common.

Disorders of the outflow tract and uterus often occur as a part of a syndrome of malformations that include abnormalities of the skeletal and renal systems ( Rokitansky–Küster–Hauser syndrome). Familial aggregates of the most common disorders of müllerian differentiation in girls

—müllerian aplasia and incomplete müllerian fusion—are best explained on the basis of polygenic and multifactorial inheritance (27). It is clear that the HOX genes, a family of regulatory genes that encode for transcription factors, are essential for proper development of the müllerian tract in the embryonic period (28), and HOXA 13 has been found to be altered in hand–foot–genital syndrome.

Figure 26.8 Flow diagram for the evaluation of delayed or interrupted pubertal development, including primary amenorrhea, in phenotypic girls. Girls with asynchronous development often present because of failure to menstruate. FSH, follicle–stimulating hormone; PRL, prolactin; T4, thyroxine; TSH, thyroid–stimulating hormone; CNS, central nervous system; MRI, magnetic resonance imaging; CT, computed tomography. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al, eds. Gynecology and obstetrics: a longitudinal approach. New York, NY: Churchill Livingstone, 1993:97–133.).

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The most common single anatomic disorder of puberty is the imperforate hymen, which prevents the passage of endometrial tissue and blood. These products can accumulate in the vagina ( hydrocolpos) or uterus ( hydrometrocolpos) and result in a bulging hymen that is often bluish in color. The affected individual often has a history of vague abdominal pain with approximately monthly exacerbations. It is sometimes difficult to distinguish an imperforate hymen from a transverse vaginal septum, and in most situations, examination under anesthesia is required.

Figure 26.9 Hysterosalpingograms of normal and abnormal female genital tracts.

The radiographic photographs have been reversed to accentuate the uterine cavities. A: Normal study with bilateral spill. B: Bicornuate uterus. C: Uterus didelphis. D: Uterus didelphis with double vagina. (Courtesy of Dr. A. Gerbie; from Spitzer IB, Rebar RW. Counselling for women with medical problems: ovary and reproductive organs. In: Hollingsworth D, Resnik R, eds. Medical counselling before pregnancy. New York, NY: Churchill Livingstone, 1988:213–

248, with permission.).

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Regardless of the cause, uterine anomalies not involving segmental müllerian agenesis or hypoplasia (class I) are compatible with normal pregnancy. However, increased fetal wastage has been reported in the presence of these anomalies (29). Uterine malformations have been associated with spontaneous abortion, preterm labor, abnormal presentations, and complications of labor (i.e., retained placenta). Many of these uterine anomalies can be identified with hysterosalpingography (see Fig.

26.9). Hysterosalpingography, laparoscopy, and hysteroscopy have been used to differentiate a septate uterus (class V) from a bicornuate uterus (class IV). It is now clear that magnetic resonance imaging (MRI) and endovaginal ultrasonography (sometimes with sonohysterography) are as accurate as these invasive techniques in identifying the Ovid: Berek & Novak's Gynecology

abnormality (30).

Obstruction or malformation of the distal genital tract must be distinguished from androgen insensitivity. Individuals with androgen insensitivity have breast development in the absence of significant pubic and axillary hair development; the vagina may be absent or foreshortened in these women.

Hypergonadotropic and Hypogonadotropic Hypogonadism

Basal levels of FSH and prolactin should be determined in individuals in whom secondary sex characteristics have not developed to maturity (see Fig. 26.8). Bone age should be estimated from x–rays of the nondominant hand. If prolactin levels are elevated, thyroid function should be assessed to determine whether the individual has primary hypothyroidism. Paradoxically, primary hypothyroidism can result in precocious puberty P.1007

as well. If thyroid function is normal, a hypothalamic or pituitary neoplasm is possible, and careful evaluation of the hypothalamic and pituitary area by MRI or computed tomography (CT) is indicated.

Table 26.2 Classification of Müllerian Anomalies

Class I. Segmented müllerian agenesis or hypoplasia

A. Vaginal

B. Cervical

C. Fundal

D. Tubal

E. Combined

Class II. Unicornuate uterus

A. With a rudimentary horn

1. With a communicating endometrial cavity

2. With a noncommunicating cavity

3. With no cavity

B. Without any rudimentary horn

Class III. Uterus didelphys

Class IV. Bicornuate uterus

A. Complete to the internal os

B. Partial

C. Arcuate

Class V. Septate uterus

A. With a complete septum

B. With an incomplete septum

Class VI. Uterus with internal luminal changes

Adapted from Buttrarm VC Jr, Gibbons WE. Müllerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril 1979;32:40, with permission.

The karyotype should be determined in any individual with delayed puberty and increased basal FSH concentrations. Regardless of the karyotype, the individual with hypergonadotropic hypogonadism has some form of ovarian “failure,” (i.e., primary hypogonadism).

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Forms of Gonadal Failure

Turner Syndrome

Most affected individuals have a 45,X karyotype and Turner syndrome; still others have mosaic karyotypes (i.e., 45,X/46,XX; 45,X/46,XY) and may present with the Turner phenotype as well. Intrauterine growth restriction is common in infants with a 45, X karyotype. After birth, these patients generally grow slowly, beginning in the second or third year of life. They typically have many of the associated stigmata, including lymphedema and sometimes large cystic hygromas of the neck at birth; a webbed neck; multiple pigmented nevi; disorders of the heart, kidneys (most commonly horseshoe), and great vessels (most commonly coarctation of the aorta); and small hyperconvex fingernails (31) (Fig.

26.10). Diabetes mellitus, thyroid disorders, essential hypertension, and other autoimmune disorders are often present in individuals

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with 45,X karyotypes. Most 45,X patients have normal intelligence, but many affected individuals have an unusual cognitive defect characterized by an inability to appreciate the shapes and relations of objects with respect to one another (i.e., space–form blindness). As they grow older, affected children typically are shorter than normal. Although they do not develop breasts at puberty, some pubic or axillary hair may develop because appropriate adrenarche can occur with failure of thelarche (i.e., breast development). Although less severe short stature and some adolescent development may occur with chromosomal mosaicism, it is reasonable to assume that any short, slowly growing, sexually infantile girl has Turner syndrome until proved otherwise because this disorder is so prevalent (about 1 in 2,500 newborn phenotypic females). In fact, the 45,X karyotype is the single most frequent chromosomal disorder in humans, but most affected fetuses are aborted spontaneously early in pregnancy. However, trisomy is the most common chromosomal type or category of abnormality in first–trimester losses.

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Figure 26.10 Typical appearance of two individuals with 45,X gonadal dysgenesis. A: This 16–year–old individual has obvious short stature, a webbed neck, shortened fourth metatarsals, and a thoracotomy scar from the repair of the coarctation of the aorta that was performed at 13 years of age. B: This 11–year–old individual also has obvious short stature and stigmata of Turner syndrome.

Note that these two individuals look more like each other than they might look like any genetic siblings.

The short stature commonly associated with the Turner phenotype appears largely to be due to the loss of a homeobox–containing gene (which encodes for an osteogenic gene) P.1009

located on the pseudoautosomal region (PAR 1) of the short arms of the X (Xp22) and Y

(Yp11.3) chromosomes (32). This gene, which is called either SHOX (short stature homeobox–containing gene) or PHOG (pseudoautosomal homeobox osteogenic gene), escapes X inactivation because of its pseudoautosomal location. The gene appears to account for about two thirds of the height deficit commonly associated with Turner syndrome.

Even in the presence of typical Turner stigmata, a karyotype is indicated to eliminate the possibility of the presence of any portion of a Y chromosome. If a Y chromosome is identified, surgical extirpation of the gonads is warranted to eliminate any possibility of a germ Ovid: Berek & Novak's Gynecology

cell neoplasm (estimated 20%–30% prevalence) (33,34). In individuals in whom there is no evidence of neoplastic dissemination, the uterus may be left in situ for donor in vitro fertilization and embryo transfer. Individuals with Turner syndrome are at increased risk of sudden death from aortic rupture or dissection resulting from cystic medial necrosis during pregnancy, and the risk may be as great as 2% or more (35). Echocardiography and counseling about this risk is warranted before pregnancy is contemplated. The evaluation of other commonly involved organ systems should include a careful physical examination, with special attention to the cardiovascular system, and thyroid function tests (including antibody assessment), fasting blood glucose, renal function tests, and intravenous pyelography or a renal ultrasonography.

Treatment of Turner Syndrome

To increase final adult height, commonly accepted treatment strategies include use of exogenous GH (36,37,38). With recombinant human GH use, the average height gain has varied from 4 to 16 cm. It appears that early initiation of therapy (between 2–8 years of age), gradually increasing the dose, and continuing treatment for a mean of 7 years can lead to achievement of a final height greater than 150 cm in most patients (37). Weekly doses of GH of 0.375 mg/

kg divided into seven daily doses are typical. It is not clear if an anabolic steroid such as oxandrolone will provide additional growth.

The gonadal steroid treatment of patients with Turner syndrome is as follows:.

To promote sexual maturation, therapy with exogenous estrogen should be initiated when the patient is psychologically ready, at about 12 to 13 years of age, and after

GH therapy has been administered for several years. Low–dose estrogen can be introduced at this time without compromising final adult height (39). .

Because the intent is to mimic normal pubertal development, therapy with low–

dose estrogen alone (such as 0.025 mg/day transdermal estradiol or 0.3–0.625 mg conjugated estrogens orally each day) should be initiated.

Progestins (5–10 mg medroxyprogesterone acetate or 200 mg micronized progesterone orally for 12–14 days every 1–2 months) can be added to prevent endometrial hyperplasia after the patient first experiences vaginal bleeding or after 6 months of unopposed

estrogen use if the patient has not yet had any bleeding.

The dose of estrogen is increased slowly over 1 to 2 years until the patient is taking about twice as much estrogen as the amount administered to postmenopausal women. .

Girls with gonadal dysgenesis must be monitored carefully for the development of hypertension with estrogen therapy.

The patients and their parents should be counseled regarding the emotional and physical changes that will occur with therapy.

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Mosaic Forms of Gonadal Dysgenesis

Individuals with rare mosaic forms of gonadal dysgenesis may develop normally at puberty. The decision to initiate therapy with exogenous estrogen should be based mainly on circulating FSH levels. Levels in the normal range for the patient's age imply the presence of functional gonads.

These individuals can become pregnant, with success rates of more than 50% using donor oocytes (40). The increased risk of sudden death during pregnancy resulting from aortic rupture should be assumed to be similar to that of other women with the Turner phenotype (35).

Pure Gonadal Dysgenesis

The term pure gonadal dysgenesis refers to 46,XX or 46,XY phenotypic females who have streak gonads. This condition may occur sporadically or may be inherited as an autosomal recessive trait or as an X–linked trait in XY gonadal dysgenesis (Fig.

26.11). Affected girls typically are of average height and have none of the stigmata of Turner syndrome, but they have elevated levels of FSH because the streak gonads produce neither steroid hormones nor inhibin. When gonadal dysgenesis occurs in 46,XY individuals, it is sometimes termed Swyer syndrome. Surgical extirpation is warranted in individuals with a 46, XY karyotype to prevent development of germ cell neoplasms. Both 46,XX and 46,XY forms of gonadal dysgenesis benefit from exogenous estrogen and are potential candidates for donor oocytes.

In early gonadal failure, the ovaries apparently develop normally but contain no oocytes by the expected age of puberty. These disorders are considered further in the discussion delineating the evaluation of amenorrhea (see Chapter 27).

Hypogonadotropic Hypogonadism

Hypothalamic–pituitary disturbances are usually associated with low levels of circulating gonadotropins (with both LH and FSH levels less than or equal to 10 mIU/mL) (41).

There are both sporadic and familial causes of hypogonadotropic hypogonadism, and the differential diagnosis is extensive. Mutations in several genes have been shown to cause hypogonadotropic hypogonadism in humans (42). This condition can arise from abnormalities in hypothalamic GnRH secretion, impaired release of gonadotropins from the pituitary gland, or both. At least six separate genes have been identified as causes of hypogonadotropic hypogonadism: (i) KAL1, (ii) FGFR1/KAL2, (iii) DAX 1 (the gene for X–

linked congenital adrenal hypoplasia), (iv) GNRHR (the gene for the GnRH receptor), (v) PC1

(the gene for prohormone convertase 1), and (vi) GPR54 (encoding a G–protein coupled receptor) (43,44,45). Because defects in these genes account for less than 20% of all cases of isolated hypogonadotropic hypogonadism, additional mutations probably exist but have yet to be identified. It is important to remember, however, that low levels of LH and FSH are normally present in the prepubertal years; thus, girls with constitutionally delayed puberty may mistakenly be presumed to have hypogonadotropic hypogonadism. In fact, constitutional delay is the most common cause of delayed puberty. In a normal population, 2% to 3% of normal children will be classified as having pubertal delay, and this finding may be considered a normal variant. Constitutional delayed growth and adolescence can be diagnosed only after careful evaluation excludes other causes of delayed puberty and normal sexual development is documented by longitudinal follow–up. The farther below the third percentile for height that the young girl is, the less likely it is that the cause is constitutional. Because some children are severely handicapped socially by constitutional pubertal delay, some physicians occasionally provide exogenous estrogen in Ovid: Berek & Novak's Gynecology

low doses for 3 to 4 months to stimulate some pubertal development. However, the benefits of treatment are not well documented, and there is little evidence to support the idea that treatment improves psychosocial function.

Kallmann Syndrome

As originally described in 1944 (46), Kallmann syndrome consisted of the triad of anosmia, hypogonadism, and color blindness in men. Women may be affected as well, and other associated defects may include cleft lip and palate,

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cerebellar ataxia, nerve deafness, and abnormalities of thirst and vasopressin release.

The frequency approximates 1 in 10,000 men and 1 in 50,000 women. Because autopsy studies have shown partial or complete agenesis of the olfactory bulb, the term olfactogenital dysplasia has also been used to describe the disorder. These anatomic findings coincide with embryologic studies documenting that GnRH neurons originally develop in the epithelium of the olfactory placode and normally migrate into the hypothalamus (47). In some affected individuals, gene defects have been found in one protein, anosmin, that facilitates this neuronal migration, thus leading to an absence of GnRH neurons in the hypothalamus and olfactory bulbs and consequent hypogonadotropic hypogonadism and anosmia (Kallmann syndrome) (48). The gene defect resulting in loss of this facilitory P.1012

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adhesion protein has been localized to the Xp22.3 locus in an X–linked form of the syndrome, and this locus has been designated KAL1. Because confirmed mutations in the coding sequence of the KAL gene occur only in a minority of individuals with Kallmann syndrome (49), other mutations no doubt will be identified in the future. Moreover, the disorder is so heterogeneous that it appears likely that it forms a structural continuum with other midline defects. Septo–optic dysplasia represents the most severe form of the disorder.

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Figure 26.11 A: A 16–year–old individual with 46,XX gonadal dysgenesis and primary amenorrhea. Circulating follicle–stimulating hormone (FSH) levels were markedly elevated. The small amount of breast development (Tanner stage 2) is unusual, but some pubertal development may occur in such patients. B: A 16–year–old individual with 46,XY gonadal dysgenesis who presented with primary amenorrhea and markedly elevated FSH levels. Most affected individuals do not present with as much pubic and axillary hair development. The right gonad contained a dysgerminoma, but there was no evidence of metastases. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al, eds. Gynecology and obstetrics: a longitudinal approach. New York, NY: Churchill Livingstone, 1993:97–133, with permission.) C: Clitoromegaly noted in the girl with 46,XY

gonadal dysgenesis depicted in Figure 26.11B. D: The same individual as depicted in Figure 26.11B and D with 46,XY gonadal dysgenesis 1 year after gonadectomy and replacement with exogenous estrogen.

Clinically, affected individuals typically present with sexual infantilism and an eunuchoid habitus, but some degree of breast development may occur (Fig. 26.12).

Primary amenorrhea is the rule. The ovaries are usually small, with follicles seldom developing beyond the primordial stage. Circulating gonadotropin levels are usually very low but almost invariably measurable. Affected individuals respond readily to pulsatile administration of exogenous GnRH, and clearly this is the most physiologic approach to ovulation induction (40). For women not seeking pregnancy, therapy with exogenous estrogen and progestin is indicated.

Isolated gonadotropin deficiency can also occur in association with the Prader–

Labhart–Willi syndrome, which is characterized by obesity, short stature, hypogonadism, small hands and feet (acromicria), mental retardation, and infantile hypotonia. When the syndrome occurs in association with the Laurence–

Moon–Bardet–Biedl syndrome, retinitis pigmentosa, postaxial polydactyly, obesity, and hypogonadism also may be present. Prader–Labhart–Willi syndrome apparently results from rearrangements of chromosome 15q11 to q13, an imprinted region of the human genome (50). Laurence–Moon–Bardet–Biedl syndrome, inherited in an autosomal recessive manner, is apparently heterogeneous, with at least four involved gene loci having been mapped to date (51).

Multiple pituitary hormone deficiencies, which are usually hypothalamic in origin, may be congenital and either part of an inherited constellation of findings or sporadic. If GH

or thyroid–stimulating hormone (TSH) concentrations are subnormal, growth and pubertal development will be affected. Thus, the condition should be diagnosed before the age of puberty. Because individuals with hypopituitarism have a high mortality rate, predominantly caused by vascular and respiratory disease (52), it is important to identify affected individuals. Later age at diagnosis, female sex, and above all craniopharyngioma have been identified as significant independent risk factors. Untreated gonadotropin deficiency also is an important risk factor for early mortality.

Tumors of the Hypothalamus and Pituitary

Several different tumors of the hypothalamic and pituitary regions also may lead to hypogonadotropic hypogonadism (53) (Fig. 26.13A). Except for craniopharyngiomas, these tumors are relatively uncommon in

children. Craniopharyngiomas are usually suprasellar in location and may be asymptomatic well into the second decade of life. Such tumors may present as headache, visual disturbances, short stature or growth failure, delayed puberty, or diabetes insipidus. Visual field defects (including bilateral temporal hemianopsia), optic atrophy, or papilledema may be seen on physical examination. Laboratory evaluation should

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document hypogonadotropism and may also reveal hyperprolactinemia as a result of interruption of hypothalamic dopamine inhibition of prolactin release. Radiographically, the tumor may be either cystic or solid and may show areas of calcification. Appropriate therapy for hypothalamic–pituitary tumors may involve surgical excision or radiotherapy (with adequate pituitary hormone replacement therapy) and is best managed by a team of physicians that includes an endocrinologist, a neurosurgeon, and a radiotherapist.

Other Central Nervous System Disorders

Other central nervous system disorders that may lead to delayed puberty include infiltrative diseases, such as Langerhans cell–type

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histiocytosis, particularly the form known previously as Hand–Schüller-Christian disease (Figs. 26.13B and 26.13C). Diabetes insipidus is the most common endocrinopathy (because of infiltration of the supraoptic nucleus in the hypothalamus), but short stature resulting from GH deficiency and delayed puberty caused by gonadotropin deficiency are not uncommon in this disorder (54).

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Figure 26.12 Left A 21½–year–old woman with Kallmann syndrome. Note that the patient has some pubic and axillary hair. Bone age was 16 years. It is rare to see affected individuals today who were not given oral contraceptive agents to induce menses (with some consequent breast development). (From Wilkins ll. The diagnosis and treatment of endocrine disorders in childhood and adolescence. 3rd ed. Springfield, IL: Charles C Thomas, 1965, with permission.).

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Figure 26.13 Right A: A 16–year–old girl with delayed puberty. Breast budding began at 11 years of age, but there was no further development. During the year before presentation, her scholastic performance in school deteriorated, she gained 25 lb, she became increasingly lethargic, and nocturia and polydypsia were noted. Initial evaluation documented low follicle–stimulating hormone, elevated prolactin, and a bone age of 10.5 years.

Computed tomography scanning documented a large hypothalamic neoplasm that proved to be an ectopic germinoma. The patient was also documented to be hypothyroid and hypoadrenal and to have diabetes insipidus. Despite the elevated prolactin, she had no galactorrhea because of the minimal breast development. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al, eds. Gynecology and obstetrics: a longitudinal approach. New York, NY: Churchill Livingstone, 1993:97–133, with permission.). B: A 16–year–old girl (frontal view) with primary amenorrhea who progressed in puberty until about 12 years of age. Breast budding occurred at about 10 years of age.

The patient's short stature is obvious. She proved to have hypopituitarism. Classic radiographic findings established the diagnosis of Langerhans cell–type histiocytosis (Hand–Schüller-Christian disease). C: Side view of girl shown in Figure 26.13B.

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Irradiation of the central nervous system for treatment of any neoplasm or leukemia may result in hypothalamic dysfunction. Although GH deficiency is the most frequent finding, partial or complete gonadotropin deficiency may develop in some patients.

Severe chronic illnesses, often accompanied by malnutrition, also may lead to slowed growth in childhood and delayed adolescence. Regardless of the cause, weight loss to less than 80% to 85% of ideal body weight often results in hypothalamic GnRH deficiency. If adequate body weight and nutrition are maintained in chronic illnesses such as Crohn disease or chronic pulmonary or renal disease, sufficient gonadotropin secretion usually is present to initiate and maintain pubertal development.

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Anorexia Nervosa and Bulimia

Significant weight loss and psychological dysfunction occur simultaneously with anorexia nervosa (55,56). Although many anorectic girls experience amenorrhea after pubertal development has begun, if the disorder begins sufficiently early, pubertal development may be delayed or interrupted (Fig. 26.14). The following constellation of associated findings confirms anorexia nervosa in most individuals:.

Relentless pursuit of thinness.

Amenorrhea, sometimes preceding the weight loss.

Extreme inanition.

Obsessive–compulsive personality often characterized by overachievement.

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Distorted and bizarre attitude toward eating, food, or weight.

Distorted body image.

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Figure 26.14 A: A 20–year–old college woman with anorexia nervosa. B: A 16–year–old student with anorexia nervosa. In both cases, as is true of most such patients, pubertal development had been completed and menses initiated before anorexia led to marked weight loss.

Because normal body weight is commonly maintained in bulimia, it is unusual for bulimic patients to experience either delayed development or amenorrhea. Girls with anorexia nervosa may have, in addition to hypogonadotropic hypogonadism, partial diabetes insipidus, abnormal temperature regulation, chemical hypothyroidism with low serum triiodothyronine (T3) and high reverse T3 levels, and elevated circulating cortisol levels in the absence of evidence of hypercortisolism (57).

Fear of obesity, a syndrome of self–induced malnutrition common among teenage gymnasts and ballet dancers, also may slow growth and delay pubertal development (58). These children voluntarily reduce their caloric intake as much as 40%, leading to nutritional growth retardation. An additive role for endurance training in the delayed development is possible, but the mechanisms are unclear at this point. These conditions are essentially severe forms of hypothalamic amenorrhea. It is clear, however, that delayed puberty will occur inevitably unless adequate caloric intake is provided.

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Hyperprolactinemia

Low levels of LH and FSH may be associated with hyperprolactinemia. As noted, galactorrhea cannot occur in the absence of complete breast development. Pituitary prolactinomas are rare during adolescence but must be considered when certain signs and symptoms are present. Many individuals with prolactinomas have a history of delayed menarche. The association between the ingestion of certain drugs (most often psychotropic agents and opiates in this age group) is well established. Primary hypothyroidism also is associated with hyperprolactinemia because increased levels of thyrotropin–releasing hormone (TRH) stimulate secretion of prolactin. The empty sella syndrome, in which the sella turcica is enlarged but has been replaced by cerebrospinal fluid, may also be associated with hyperprolactinemia.

Use of Chemotherapeutic Agents

As survival rates following treatment for childhood malignancy improve, the effects of cancer therapy become ever more important. Both radiation therapy to the abdomen and systemic chemotherapeutic agents, particularly alkylating agents, have toxic effects on germ cells. Although prepubertal gonads appear less vulnerable than those of adults, ovarian failure is common. An argument can be made for endocrine assessment as early as 1 year following completion of therapy to identify children who will suffer from hypogonadism. Spontaneous ovarian activity can resume even years after therapy.

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Asynchronous Puberty

Asynchronous pubertal development is characteristic of androgen insensitivity (i.e., testicular feminization). Affected individuals typically present with breast development (usually only to Tanner stage 3) out of proportion with the amount of pubic and axillary hair present (Fig. 26.15). In this disorder, 46,XY individuals have bilateral testes, female external genitalia, a blindly ending vagina (often foreshortened and sometimes absent), and no müllerian derivatives (i.e., uterus and fallopian tubes) (59). Infrequently, patients may have clitoral enlargement and labioscrotal fusion at puberty, which is referred to as incomplete androgen insensitivity. .

Asynchronous puberty is heterogeneous but is always related to some abnormality of the androgen receptor or of androgen action (60). In perhaps 60% to 70% of cases, androgen receptors cannot be detected (i.e., the patient is receptor negative). In the remaining cases, androgen receptors are present (i.e., receptor positive), but mutations in the androgen receptor have been detected or there is a defect at a more distal step in androgen action (i.e., a postreceptor defect). Receptor–positive individuals are indistinguishable clinically from receptor–negative individuals. Several different mutations in the androgen receptor gene, most of which occur within the androgen–binding domain of the receptor, have been identified in affected individuals who are receptor positive. Severe X–

linked androgen receptor gene mutations cause complete androgen insensitivity, whereas mild mutations impair virilization with or without infertility, and moderate mutations result in a wide phenotypic spectrum of expression among siblings (61).

Because the Sertoli cells of the testes make antimüllerian hormone (AMH), müllerian derivatives are absent in this disorder; thus, müllerian regression occurs normally. The testes are often normal in size and may be located anywhere along the path of embryonic testicular descent—in the abdomen, inguinal canal, or labia. Half of all individuals with androgen insensitivity develop inguinal hernias. Recognizing that most such girls will be 46,XX, it is important to determine the karyotype in prepubertal girls with inguinal hernias, especially if a uterus cannot be detected with certainty by ultrasound.

The frequency of gonadal neoplasia is increased with this condition, but the extent is uncertain (33). Most clinicians believe the risk for neoplasia is low before 25 years of age; P.1018

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thus, the testes should be left in place until after pubertal feminization, especially because the risk of neoplasia appears to increase with age. Exogenous estrogen should be provided after gonadectomy.

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Figure 26.15 A: This 17–year–old individual presented with primary amenorrhea and was found to have a blind–ending vagina and bilateral inguinal masses. Circulating levels of testosterone were at the upper limits of the normal range for men, and the karyotype was 46,XY, confirming androgen insensitivity. B: Two inguinal testes were found at surgery. (From Simpson JL, Rebar RW. Normal and abnormal sexual differentiation and development. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, PA: JB

Lippincott, 1995:788–822, with permission.).

The diagnosis is often suspected by the typical physical findings and strongly suggested by normal (or even somewhat elevated) male levels of testosterone, normal or somewhat elevated levels of LH, and normal levels of FSH. The diagnosis is confirmed by a 46,XY karyotype.

Interacting with the patient and family requires sensitivity and care. It may be inadvisable to begin by informing the patient of the karyotype; the psychological implications may be devastating because the patient has been reared as a girl. Family members should be informed initially that müllerian aplasia occurred and that the risk for neoplasia mandates gonadectomy after puberty. Because the disorder can be inherited in an X–linked recessive fashion, families should undergo appropriate genetic counseling and screening to identify the possible existence of other affected family members.

Precocious Puberty

Although precocious pubertal development may be classified in several ways, it is perhaps simplest to think of the development as gonadotropin dependent (in which case it is almost invariably of central origin) or gonadotropin independent (of peripheral origin). Precocious puberty is 20 times more common in girls than in boys.

In fully 90% of girls, the precocious development is idiopathic, whereas this appears to be true for only 10% of boys. Family history, the rapidity with which secondary sexual characteristics are developing, the rate of growth, and the presence or absence of central nervous system disease should all be considered in deciding whether to pursue evaluation of a girl for precocious puberty. The evaluation of precocious puberty is as follows:.

Measurement of basal gonadotropin levels is the first step in the evaluation of a child with sexual precocity (Fig. 26.16).

Thyroid function should also be evaluated to rule out primary hypothyroidism as the cause of precocious development.

High levels of LH (which really may be human chorionic gonadotropin detected because of cross–reactivity with LH in immunoassays) suggest a gonadotropin–

producing neoplasm, most often a pinealoma (ectopic germinoma) or choriocarcinoma or, less often, a hepatoblastoma. (Gonadotropin–producing neoplasms are the only causes of precocious puberty in which the gonadotropin dependence does not equate with central precocious puberty.).

Low or pubertal levels of gonadotropins indicate the need to determine circulating estradiol concentrations in girls with isosexual development and to assess androgen levels, specifically testosterone, DHEAS, and 17α–hydroxyprogesterone in girls

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with heterosexual development.

Increased estradiol levels suggest an estrogen–secreting neoplasm, probably of ovarian origin.

Increased testosterone levels suggest an androgen–producing neoplasm of the ovary or the adrenal gland. Such neoplasms may be palpable on abdominal or rectal examination. Increased 17α–hydroxyprogesterone levels are diagnostic

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of 21–hydroxylase deficiency (ie, congenital adrenal hyperplasia [CAH]). Levels of DHEAS

are elevated in various forms of CAH as well.

If the estradiol levels are compatible with the degree of pubertal development observed, evaluation of the central nervous system by MRI or CT scanning is warranted.

Bone age should always be assessed in evaluating an individual with sexual precocity.

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Figure 26.16 Flow diagram for the evaluation of precocious puberty in phenotypic females. LH, luteinizing hormone; FSH, follicle–stimulating hormone; TSH, thyroid–stimulating hormone; T4, thyroxine; T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP, 17–

hydroxyprogesterone; CNS, central nervous system. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al. , eds. Gynecology and obstetrics: a longitudinal approach. New York, NY: Churchill Livingstone, 1993:97–133, with permission.).

Perhaps the most difficult decision for the gynecologist is determining how much evaluation is warranted for the young girl brought in by her mother for precocious breast budding only ( precocious thelarche) or the appearance of pubic or axillary hair alone ( precocious pubarche or adrenarche) (Fig. 26.17). In such cases, it is acceptable to many clinicians to follow the patient at frequent intervals and to proceed with evaluation if there is evidence of pubertal progression.

The feasibility of this approach may depend on the concerns of the parents. Premature thelarche may be caused by

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increased sensitivity of the breasts to low levels of estrogen or to increased estradiol secretion by follicular cysts. Premature adrenarche or pubarche may be due to increased sensitivity to low levels of androgens and must be distinguished from late–onset (nonclassic) CAH. If there is no evidence of breast development and the appearance of sexually stimulated hair (i.e., precocious puberty) or of progression, these conditions are virtually always benign.

Some girls with premature adrenarche are at risk of developing polycystic ovarian syndrome (PCOS) (62). Although mean androgen levels are within the normal range, a significant minority have an exaggerated response to corticotropin stimulation. Moreover, the magnitude of this response is inversely related to insulin sensitivity. Thus, premature adrenarche may be the first sign of insulin resistance or PCOS in some individuals. Treatment of coexisting obesity and long–term follow–up are indicated to address potential complications of PCOS and insulin resistance.

Constitutional (idiopathic) sexual precocity is the most common cause of precocious puberty. It is often familial and represents the so–called “tail” of the gaussian curve (i.e., the early 2.5% for the age distribution for the onset of puberty). In many of these girls, puberty is slowly progressive, but in a few, development progresses rapidly. The major complication of sexual precocity is limitation of height. Thus, therapy, may be warranted to prevent this consequence.

Central (True) Precocious Puberty

In central precocious puberty, GnRH prematurely stimulates increased gonadotropin secretion. Central precocious puberty may occur in children in whom there is no structural abnormality, in which case it is termed constitutional or idiopathic.

Alternatively, central precocious puberty may result from a tumor, infection, congenital abnormality, or traumatic injury affecting the hypothalamus. Tumors of the hypothalamus include hamartomas and, less frequently, neurogliomas and pinealomas. It appears that hamartomas produce GnRH in a pulsatile manner and thus stimulate gonadotropin secretion (63) (Fig. 26.18). A number of congenital malformations, including hydrocephalus, craniostenosis, arachnoid cysts, and septo–optic dysplasia, also can be associated with precocious puberty (as well as with sexual infantilism).

Precocious Puberty of Peripheral Origin

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In gonadotropin–independent precocious puberty, production of estrogens or androgens from the ovaries, adrenals, or rare steroid–secreting neoplasms leads to early pubertal development. Small functional ovarian cysts, typically asymptomatic, are common in children and may cause transient sexual precocity (64). Simple cysts (with a benign ultrasonographic appearance) can be observed and usually resolve over time. Of the various ovarian neoplasms that can secrete estrogens, granulosa–theca cell tumors occur most frequently but are still rare (65). Although such tumors may grow rapidly, more than two thirds are benign.

The McCune–Albright syndrome is characterized by polyostotic fibrous dysplasia of bone, irregular cafè–au–lait spots on the skin, and hyperfunctioning endocrinopathies.

Girls develop sexual precocity as a result of functioning ovarian cysts. Other endocrinopathies may include hyperthyroidism, hypercortisolism, hyperprolactinemia, and acromegaly. It is now known that mutations of the GSα subunit of the G protein, which couples extracellular hormonal signals to the activation of adenylate cyclase, are responsible for the autonomous hyperfunction of the endocrine glands and, presumably, for the other defects present in this disorder (66). Exposure to exogenous estrogens can mimic gonadotropin–

independent precocious puberty. Ingestion of oral contraceptives, other estrogen–

containing pharmaceutical agents, and estrogen–contaminated foods, as well as the topical use of estrogens, have been implicated in cases of precocious development in infants and children. Severe primary

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hypothyroidism has also been associated with sexual precocity; associated hyperprolactinemia may result in galactorrhea in affected individuals.

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Figure 26.17 Five–year–old girl with development of pubic hair (A) as shown more closely in (B) (precocious adrenarche). Gonadotropin levels were prepubertal, and bone age was appropriate for age. No further development occurred until breast budding at approximately age 9.

Congenital Adrenal Hyperplasia

Heterosexual precocious puberty is always of peripheral origin and is most often caused by CAH. Three adrenal enzyme defects—21–hydroxylase deficiency, 11β–

hydroxylase deficiency, and 3β–hydroxysteroid dehydrogenase deficiency—can lead not only to heterosexual precocity but also to virilization of the external genitalia because of increased androgen production beginning in utero (67). The clinical presentation of the various forms of CAH depends on the following factors: (i) the affected enzyme, (ii) the extent of residual enzymatic activity, and (iii) the physiologic consequences of deficiencies in the end products and excesses of precursor steroids.

21–Hydroxylase Deficiency

Most patients with classic CAH have 21–hydroxylase deficiency (Fig. 26.19). All forms of 21–hydroxylase deficiency are caused by homozygous or compound heterozygous mutations in the human CYP21A2 gene, which encodes the 21–hydroxylase enzyme; in the carrier, heterozygote state, only one allele is mutated (68). Two CYP21A2 genes, a 3′ CYP21A2B

gene encoding the functional enzyme and a pseudogene termed CYP21A2A, are situated very close to each other within the major histocompatibility locus on the short arm of chromosome 6.

At least one fourth of cases of 21–hydroxylase deficiency are due to unequal crossover and Ovid: Berek & Novak's Gynecology

genetic recombination between the two genes during meiosis. However, severe mutations do not correlate with severe phenotype, and phenotypic variability likely depends on the activity of other interacting genes.

Neonatal screening suggests an incidence of about 1 in 15,000 births. Because of the location of the gene within the major histocompatibility locus, siblings with 21–hydroxylase deficiency usually have identical human leukocyte antigen (HLA) types. There are various forms of 21–hydroxylase deficiency, including simple virilizing or classic (typically identified at birth because of genital ambiguity), salt–wasting (in which there is impairment of mineralocorticoid as well as glucocorticoid secretion), and late–onset or nonclassic (in which heterosexual development occurs at the expected age of puberty). The nonclassic form is discussed in the following section on heterosexual pubertal development.

Deficiency of 21–hydroxylase results in the impairment of the conversion of 17α–hydroxyprogesterone to 11–deoxycortisol and of progesterone to deoxycorticosterone (Fig. 26.20). As a consequence, precursors accumulate, and there is increased conversion to adrenal androgens. Because the development of the external genitalia is controlled by androgens, in the classic form of this disorder, girls are born with ambiguous genitalia, including an enlarged clitoris and fusion of the labioscrotal folds and the urogenital sinus. The internal female organs (including the uterus, fallopian tubes, and ovaries) develop normally because they are not affected by the increased androgen levels. Almost two thirds of affected newborns rapidly develop salt–wasting 21–hydroxylase deficiency, hyponatremia, hyperkalemia, and hypotension. During childhood, untreated girls with either the classic or salt–wasting form grow rapidly but have advanced bone ages, enter puberty early, experience early closure of their epiphyses, and ultimately are short in stature as adults. CAH, with appropriate therapy, is the only inherited disorder of sexual differentiation in which normal pregnancy and childbearing are possible. The classic and salt–wasting forms of 21–hydroxylase deficiency are easily diagnosed based on the presence of genital ambiguity and markedly elevated levels of 17α–hydroxyprogesterone. Some states have initiated neonatal screening programs to detect 21–hydroxylase deficiency at birth.

3β–Hydroxysteroid Dehydrogenase

Deficiency of 3β–hydroxysteroid dehydrogenase (3β–HSD), caused by mutations in the HSD3B2 gene encoding the 3β–HSDII enzyme,

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affects the synthesis of glucocorticoids, mineralocorticoids, and sex steroids. Typically, levels of 17–hydroxypregnenolone and DHEA are elevated (see Fig. 26.20). The classic form of the disorder, detectable at birth, is quite rare, and affected girls may be masculinized only slightly.

In severe cases, salt wasting may also be present.

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Figure 26.18 Left: A 7½–year–old girl with Tanner stage 4 pubertal development who began menstruating 1 month earlier. She was 57 inches tall (above the ninety–fifth percentile). Luteinizing hormone and follicle–stimulating hormone levels were consistent with her development. A large neoplasm that proved to be a hypothalamic hamartoma was present on computed tomography scan. Pubertal development began at about 5 years of age.

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Figure 26.19 Right: A: A 10½–year–old girl with 21–hydroxylase deficiency before treatment. 17–Ketosteroid (KS) excretion was 34 mg/day. B: The same patient after 9 months of therapy with cortisone (17–KS excretion: 4.6 mg/day). (From Wilkins ll. The diagnosis and treatment of endocrine disorders in childhood and adolescence. 3rd ed. Springfield, IL: Charles C Thomas, 1965:439, with permission.).

A nonclassic form of this disorder may be associated with heterosexual precocious pubertal development (as is the classic form if untreated), but postpubertal hyperandrogenism occurs more often. The androgen excess in individuals with nonclassic 3β–HSD deficiency appears to result from androgens derived from the peripheral conversion of increased serum concentrations of DHEA. This disorder is inherited in autosomal recessive fashion, with allelism at the 3β–HSD gene on chromosome 1 believed to be responsible for the varying degrees of enzyme deficiency.

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Figure 26.20 Gonadal and adrenal steroid pathways and the enzymes required for steroid conversion. DOC = deoxycorticosterone; 17α–OH Preg = 17α–hydroxypregnenolone; 17α–OH

Prog = 17α–hydroxyprogesterone; DHEA = dehydroepiandrosterone sulfate. (From Rebar RW, Kenigsberg D, Hodgen GD. The normal menstrual cycle and the control of ovulation. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, A: JB

Lippincott, 1995:868–880, with permission.).

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11–Hydroxylase Deficiency

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The classic form of 11–hydroxylase deficiency is believed to constitute 5% to 8% of all cases of CAH. Deficiency in 11–hydroxylase, caused by mutations in the CYP11B1 gene, results in the inability to convert 11–deoxycortisol to cortisol and the consequent accumulation of androgen precursors (see Fig. 26.20). Markedly elevated levels of 11–deoxycortisol and deoxycorticosterone are present in the disorder. Because deoxycorticosterone acts as a mineralocorticoid, many individuals with this disorder become hypertensive. A mild nonclassic form of 11–hydroxylase deficiency has been reported but apparently is very uncommon.

Treatment of Congenital Adrenal Hyperplasia

The treatment of CAH involves providing replacement doses of the deficient steroid hormones. Hydrocortisone (10–20 mg/m2 body surface area) or its equivalent is given daily in divided doses to suppress the elevated levels of pituitary corticotropin present and thus suppress the elevated androgen levels. With such treatment, signs of androgen excess should regress. In children, growth velocity and bone age should be monitored carefully because both overreplacement and underreplacement can result in premature closure of the epiphyses and short stature. Data now indicate that early diagnosis and compliance with therapy lead to adult height within 1 standard deviation of the anticipated target height in girls with 21–hydroxylase deficiency (69).

Mineralocorticoid replacement is generally required in individuals with 21–

hydroxylase deficiency whether or not they are salt losing. The intent of glucocorticoid therapy should be to suppress morning 17α–hydroxyprogesterone levels to between 300 and 900 ng/dL. Sufficient fluorocortisone should be given daily to suppress plasma renin activity to less than 5 mg/mll per hour.

Girls with ambiguous genitalia may require reconstructive surgery, including clitoral recession and vaginoplasty. Timing of such surgery is debated, but the girl must be of appropriate size to permit the surgery to be as simple as possible.

Heterosexual Pubertal Development

The most common cause of heterosexual development at the expected age of puberty is PCOS

(Fig. 26.21). Because the syndrome is heterogeneous and poorly defined, clinical difficulties result in diagnosis and management (70). For the sake of simplicity, PCOS may be defined as LH–dependent hyperandrogenism (71). Most clinical manifestations arise as a consequence of the hyperandrogenism and often include hirsutism beginning at or near puberty and irregular menses from the age of menarche because of oligo–ovulation or anovulation. Clinical manifestations are as follows:.

Affected girls may be but are not necessarily somewhat overweight.

In rare instances, menarche may be delayed, and primary amenorrhea also may occur.

Basal levels of LH tend to be elevated in most affected individuals, and androgen production is invariably increased, even though circulating levels of androgens may be near the upper limits of the normal range in many affected women.

In anovulatory women, estrone levels are typically greater than estradiol levels.

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Because circulating levels of estrogens are not diminished in PCOS and androgen levels are only mildly elevated, affected girls become both feminized and masculinized at puberty. This is an important feature because girls with classic forms of CAH who do not experience precocious puberty (and even those who do) only become masculinized at puberty (i.e., they do not develop breasts).

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Some degree of insulin resistance may be present, even in the absence of overt glucose intolerance (72).

Polycystic ovaries are frequently, but not always present in ultrasound examination.

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Figure 26.21 Typical facial hirsutism in 3 women with polycystic ovarian syndrome. A: 25

year–old. B: 21 year–old C: 17 year–old.

Differential Diagnosis and Evaluation

Distinguishing PCOS from the nonclassic forms of CAH is problematic and controversial (73,74). The evaluation is as follows:.


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