Pure Gonadal Dysgenesis

Pure gonadal dysgenesis refers to phenotypically female individuals with streak gonads and normal female external genitalia and normal müllerian structures whose karyotype can be either 46,XY (Swyer syndrome) or 46,XX. This heterogeneous condition results from a structural abnormality on the Y chromosome, a mutation in the SRY gene, or a mutation in an autosomal gene.

Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis refers to individuals with defective gonadal development secondary to a chromosomal mosaic variant. Their karyotypes show partial sex chromosome monosomy with an absence or abnormality of the second sex chromosome, with 45,XO/46,XY being the most common. Their phenotypes range from phenotypic female to pseudohermaphrodite to phenotypic male, depending on the ratio of 45,XO cells to those with normal (46,XX or 46,XY) karyotypes in each gonad. These patients present with abnormal sex differentiation. There can be a streak gonad on one side and a dysgenetic gonad or normal testicle on the other and with concurrent ipsilateral Wolffian or müllerian development. Most of these individuals have short stature, and one third will show characteristics of Turner’s syndrome.

The majority of patients with gonadal dysgenesis will never have menses. This group of patients make up 40% of cases of primary amenorrhea, and 40% will have an abnormal karyotype. This abnormal karyotype will be Turner’s syndrome (46,XO) 50% of the time and a mosaicism such as XO/XY 25% of the time.

Patients who present with gonadal dysgenesis and a normal karyotype need to be assessed for a variety of other conditions, such as neurosensory deafness and fragile X syndrome. These clinical associations are particularly true when familial premature ovarian failure is identified.⁹

Turner’s Syndrome

It is known that specific genes in the X chromosome are essential for normal functioning of the ovaries.¹¹ It appears that both X chromosomes with normally functioning genes need to be present in the oocytes to prevent the formation of a streak gonad.

Turner’s syndrome (45,XO) is the most common cause of gonadal dysgenesis. It is usually caused by nondisjunction of the sex chromosomes and occurs in approximately 1 out of 2500 live births. In some cases, Turner’s syndrome occurs in patients with normal karyotypes (46,XX) when a genetic abnormality results in one of the X chromosomes not being fully functional.

The characteristic physical features common to females with Turner’s syndrome include short stature, somatic abnormalities (webbed neck, shield chest, increased angle at the elbow known as cubitus valgus, cardiovascular abnormalities), and prepubertal status associated with elevated gonadotropins.¹² Patients with Turner’s syndrome require special attention to the autoimmune disorders and renal anomalies that are frequently found with the condition. All patients with Turner’s syndrome should seek expert cardiology consultation and screening, including chest X-ray and echocardiography, at the time of diagnosis. Annual cardiac examinations, including evaluation of blood pressure, and repeated screening at 3- to 5-year intervals if the initial screening reveals no abnormalities. When the cardiac echo is abnormal or the ascending aorta cannot be visualized, magnetic resonance imaging (MRI) of the chest should be performed in all patients.¹²

Due to the absence of one of the X chromosomes, these patients have streak gonads with complete lack of ovarian follicle development. The absence of sex hormone production from the ovary in early adolescence results in the absence of puberty and primary amenorrhea.

Patients with variations of the syndrome can present with some clinical features but not all of the characteristic physical findings. For this reason, Turner’s syndrome should be suspected in every adolescent with primary amenorrhea, sexual infantilism, and poor growth during the teenage years. If the serum FSH is elevated in such a patient, a karyotype should be obtained. Even if the FSH is normal, a karyotype should be obtained to rule out mosaicism in adolescents with poor growth after puberty (i.e., <5 feet tall).

Gonadal Dysgenesis 46,XY: Swyer Syndrome

This condition is associated with normal female phenotype and an 46,XY karyotype. These patients have normal external genitalia and normal müllerian structures with normal female testosterone levels and lack of secondary sexual development. Because the gonad is dysgenetic, antimüllerian hormone is deficient, explaining the presence of a uterus. Testosterone is low and therefore there is regression of the Wolffian ducts.

About 10% to 15% of patients with Swyer syndrome possess mutations of the SRY (sex-determining region on the Y chromosome) gene located on the distal portion of Yp.^13,14 Due to the significant increased risk for tumor development in patients with a Y chromosome and streak gonads, gonadectomy is recommended at an early age.

Noonan’s Syndrome

A disorder that can be confused with Turner’s syndrome is Noonan’s syndrome. In this autosomal dominant syndrome there is no chromosomal defect, but the affected individuals (both males and females) have a Turner phenotype, with webbed neck, short stature, lowset ears, and cardiac and skeletal deformities.

Management of Gonadal Dysgenesis

Adolescents with gonadal dysgenesis will require hormone therapy to induce puberty and stimulate increased growth. Low-dose estrogen (0.25 to 0.3 mg/day) is used for the first year to reproduce normal pubertal development and to minimize the effect on epiphysis closure and therefore try to achieve a more acceptable final height. In some cases growth hormone is used as well to increase final adult height. After about 1 year of estrogen therapy, progesterone (medroxyprogesterone acetate, 5 mg/day, or other forms of progesterone) can be added during the last half of the month. The dose of estrogen is increased gradually so as to complete pubertal development over 2 or 3 years.

The final maintenance dose is usually 2 mg of estradiol valerate or 1.25 mg conjugated estrogens daily. The estrogen can be started earlier if growth hormone is used. If not, estrogen initiation can be delayed for a short time but no later than age 14 or 15. The use of ethinyl estradiol has been shown to increase hypertensive risk in Turner’s syndrome patients. Patients with Y chromosomes will require gonadectomy to avoid the risk of developing a malignancy.

Oocyte donation offers women with Turner’s syndrome the opportunity to achieve pregnancy. However, the increased cardiovascular demands of pregnancy also may pose unique and serious risk given their high rate of cardiovascular malformations (25% to 50% prevalence). A recent Practice Committee position from the American Society for Reproductive Medicine (ASRM) has stated that because the risk for aortic dissection or rupture during pregnancy may be 2% or higher, the risk of death during pregnancy is increased as much as 100-fold.¹² Any significant cardiac abnormality should be regarded as a contraindication to oocyte donation. Even those having a normal evaluation should be thoroughly counseled regarding the high risk of cardiac complications during pregnancy because aortic dissection may still occur.¹²

Müllerian Agenesis

Mullerian agenesis, also referred to as Mayer-Rokitansky-Küster-Hauser syndrome, is a condition in which all or part of the uterus and vagina are absent in the presence of otherwise normal female sexual characteristics. This diagnosis accounts for approximately 10% of cases associated with primary amenorrhea.¹⁵ In Finland, the incidence was calculated to be approximately 1 of every 5000 newborn girls.¹⁶ In müllerian agenesis, the ovaries are not affected and thus ovarian function is normal. Secondary sexual development and height are in a normal range.

The differential diagnosis of patients who present with primary amenorrhea and have a genital tract anomaly is summarized in Table 16-4. Partial development of the müllerian structures can lead to obstructed menses and painful distention of a hematocolpos, hematometra, or hematoperitoneum. It is important to separate müllerian agenesis from complete androgen insensitivity syndrome, because the vagina may be absent or short in both disorders.¹⁷

It is currently unknown why müllerian agenesis occurs, but likely causes are mutations of genes that are responsible for müllerian tract maintenance. Thus far, no mutations have been reported.¹⁸ It appears that the mode of inheritance is not autosomal dominant.¹⁹

Approximately 30% of patients will have urinary tract anomalies, such as pelvic kidney, horseshoe kidney, unilateral renal agenesis, hydronephrosis, and ureteral duplication. Another 10% to 12% will have skeletal anomalies mostly associated with the spine. There are also reports of absent digits and webbing or fusion of fingers or toes (syndactyly).

Although ultrasound could be an important aid in confirming the presence or absence of uterine structures, MRI is usually more definitive. Occasionally laparoscopic visualization is needed, because there is disagreement between MRI and laparoscopic findings.²⁰ If persistent chronic pelvic pain and symptoms associated with endometriosis are present, laparoscopy can usually aid in determining the location and potential removal of incompletely formed müllerian structures.

Outflow Obstructions

Imperforate hymen is the most frequent obstructive female genital tract anomaly, with an estimated frequency of approximately 0.1%. Imperforate hymen usually occurs sporadically, but familial cases have been reported.²¹ Although this entity can present in infants or children of any age as a mucocolpos, a bulging intact hymen with hematocolpos presenting at the time of menarche is not unusual. Hymenectomy effectively alleviates this problem.

A transverse vaginal septum is somewhat less common than an imperforate hymen, occurring in fewer than 1 in 20,000 females. The presentation and surgical treatment is similar to an imperforate hymen if the transverse vaginal septa is located in the lower third of the vagina. However, more than 80% are located in the middle and upper vagina. Diagnosis is usually made by ultrasound or MRI. When located in these areas, septa tend to be thicker, and surgery is more difficult. Surgical management is described in detail in Chapter 51.

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (formerly known as testicular feminization), is an X-linked recessive condition in which genotypic males (46,XY) develop into apparently phenotypic females who have no müllerian structures and intra-abdominal testes. The underlying cause is an abnormally functioning androgen receptor, which prevents normal masculinization. This syndrome will be identified in as many as 5% of all patients presenting with primary amenorrhea.¹⁷

In the case of complete androgen insensitivity syndrome, normal female external genitalia develop. Complete androgen insensitivity is uncommon, with a reported incidence as low as 1 in 60,000 live births. In cases of incomplete androgen insensitivity syndrome, the external genitalia can demonstrate a range of intersex abnormalities from mildly virilized female external genitalia to mildly undervirilized male external genitalia.

Evaluation of Androgen Insensitivity Syndrome

These patients usually present with a family history of scant pubic hair and the presence of inguinal masses. Other female family members should be evaluated for the same diagnosis.

Patients with the condition may have a eunuchoid habitus with long arms and large hands and feet. Although the breasts develop for the most part normally, they lack glandular tissue and the nipples are small with a pale areola.

On pelvic examination, the patients will have scant or absent pubic hair and a blind vagina that is no more than a few centimeters long. More than 50% of patients have inguinal hernias and underdeveloped labia minora. Laboratory evaluation will demonstrate a 46,XY karyotype and elevated total testosterone (in the normal male range).²² This distinguishes patients with androgen insensitivity syndrome from those with müllerian agenesis, who will have an XX karyotype and total testosterone in the normal female range.

Gonadal malignancies have been reported in the 20% range, but are rarely seen before age 20. Therefore, a typical plan of action for these patients is to wait, allowing them to reach their normal adult stature and full breast development, then perform bilateral laparoscopic gonadectomy after puberty has been reached.

Patients with lack of 17β-hydroxysteroid dehydrogenase activity also have impaired testosterone production and present clinically as incomplete androgen insensitivity. The treatment for both conditions is essentially the same.

Isolated Gonadotropin Deficiency

This disorder is characterized by a decrease or absence in endogenous gonadotropin-releasing hormone (GnRH) secretion, which results in very low to undetectable luteinizing hormone (LH) and FSH levels. Individuals with the disorder have incomplete development of secondary sexual characteristics, primary amenorrhea, eunuchoid features, and in some cases a decreased sense of smell or anosmia (Kallmann syndrome). Male patients with Kallmann syndrome have X-linked recessive idiopathic hypogonadotropic hypogonadism accompanied by anosmia caused by mutations in the KAL1 gene, localized to the pseudoautosomal region of Xp.^23,24

The protein product of KAL1, anosmin, possesses neural cell adhesion molecule properties. Anosmin provides a guide for GnRH neurons and olfactory nerves to migrate from the olfactory placode across to the olfactory bulb. When anosmin is absent or defective, GnRH and olfactory neurons fail to synapse normally. The KAL1 gene escapes X inactivation and an inactive pseudogene is present on Yq. For individuals with anosmia or hyposmia, there is evidence of hypoplasia of the olfactory bulbs on MRI. No KAL1 gene mutations have been identified in females with idiopathic hypogonadotropic hypogonadism and anosmia, suggesting that other autosomal genes may be involved.²⁵

LH Receptor Abnormalities

Abnormalities of the LH receptor in 46,XX females will result in normal female sexual development and primary amenorrhea.²⁶ Serum LH may be normal to increased, FSH is normal, follicular phase estradiol levels are normal, and progesterone is low. The uterus is small and the ovaries are consistent with anovulation.

Gonadotropin-Releasing Hormone Receptor Abnormalities

Abnormalities of GnRH receptors have also been identified. The phenotype of GnRH resistance ranges from complete idiopathic hypogonadotropic hypogonadism to oligo-ovulation. Baseline levels of LH and FSH may be in the prepubertal or normal range. However, levels of other pituitary hormones, such as thyrotropin, growth hormone, prolactin, and corticotropin, are normal. Due to the failure to increase gonadal sex steroid secretion during puberty, secondary sex characteristics fail to develop and closure of the epiphyseal plates of the long bones is delayed, resulting in a eunuchoid habitus in which the arm span is greater than the height. Even in patients with complete forms, pulsatile GnRH administration may increase pituitary gonadotropin response; pregnancies have been reported.²⁷

Treatment

Treatment of isolated gonadotropin deficiency and receptor abnormalities will require low-dose estrogen (0.25 to 0.3 mg/day) to induce progressive pubertal maturation in a manner similar to Turner’s syndrome. Patients should be monitored at 2- or 3-month intervals to determine the rate of skeletal growth and development. After the first year, the addition of a progestin (medroxyprogesterone acetate, 5 mg/day) can be added for the last half of the month to induce menses and protect the endometrium from cancer. Once sexual maturation is completed, patients can be maintained on cyclic hormones or oral contraceptives.

What Age?

An evaluation of primary amenorrhea is indicated when an adolescent fails to menstruate by age 15 in the presence of normal secondary sexual development (two standard deviations above the mean of 13 years), or within 5 years after breast development, if that occurred before age 10.² This age has recently been adjusted to a younger age, because girls are menstruating at a younger age. If there is a failure to initiate breast development by age 13 (two standard deviations above the mean of 10 years), an investigation should also be initiated.² These criteria are not absolute, and complete evaluation should be initiated if the patient presents with amenorrhea and obvious associated pathology such as cyclic pain or a blind vaginal pouch.

History and Physical Examination

A careful history is a key component to the evaluation and planning for the treatment of amenorrhea (Fig. 16-1). Special emphasis should be focused on physical or emotional stress, nutritional status, and history of genetic inherited disorders. The family should be questioned about familial disorders such as diabetes mellitus, previous medical disorders that may have been treated with gonadotoxic agents, and surgical disorders that involve the genital tract, including abnormal sexual differentiation. The functional inquiry should include secondary sexual development, galactorrhea, and the presence of hyperandrogenic symptoms.

Figure 16-1 Flow diagram in the evaluation of adolescents with primary amenorrhea, showing major decision points.

A detailed physical examination includes gynecologic examination, body mass index, pubertal status, signs of hyperandrogenism or other skin manifestations of endocrine disorders, and genital tract evaluation. Milestones of sexual development and growth should be documented. The most important single feature on history and physical examination is the presence or absence of breast development, which is a clear indication of the initiation of puberty.

The presence of galactorrhea either described by the patient or observed by a careful breast examination is of great clinical significance. Specific clinical features of the galactorrhea, such as whether it is unilateral or bilateral, constant or intermittent, will determine the potential endocrine nature of the symptom. Galactorrhea of hormonal origin comes from multiple duct openings on the breast. This is in contrast to secretions occurring from a single duct, which are usually related to a local problem.

Gynecologic examination will usually reveal the presence of any genital abnormities, including obstructive processes.

Imaging

In patients with primary amenorrhea, physical examination will often detect genital tract anomalies. However, the characterization of the specific anomaly often requires imaging studies. In some cases, abdominal ultrasonography is adequate to determine the presence or absence of a uterus. Probably the most effective imaging method for characterizing congenital anomalies is MRI of the pelvis. Congenital anomalies are considered in depth in Chapters 12 and 51.

In patients without secondary sexual development, radiographic determination of bone age should be obtained. In patients with elevated prolactin, an MRI of the pituitary is required.

Laboratory Evaluation

Patients with primary amenorrhea should have an initial set of laboratory studies, which will often determine the next series of diagnostic or therapeutic management steps. Patients with normal secondary sexual development should have a pregnancy test in most cases. For patients without signs of secondary sexual development, a karyotype should be performed. For all patients regardless of sexual development, the investigation starts with measurement of serum FSH, thyrotropin, and prolactin. The estimation of thyrotropin is still indicated to evaluate for subclinical hypothyroidism, even in the absence of overt thyroid disease. However, only severe forms of hypothyroidism lead to amenorrhea, and an evaluation of the thyroid would probably be performed before amenorrhea occurs.

If hirsutism is present or if androgen insensitivity syndrome is suspected, androgens should be evaluated. Total testosterone will be elevated in this syndrome as well as in cases of ovarian tumors. Dehydroepiandrosterone sulfate (DHEAS) will be elevated in patients with adrenal tumors and Cushing’s disease. Borderline elevation of these androgens is often seen with polycycstic ovary syndrome. 17-hydroxyprogesterone is often elevated in patients with adult onset congenital adrenal hyperplasia, although a provocative test is often necessary in subtle cases.

Regulation of GnRH Secretion

The secretion of LH and FSH from the pituitary is regulated by pulsatile secretion of GnRH from the hypothalamus. Small alterations in GnRH pulsatile frequency and/or amplitude can result in a range from subtle luteal phase defects to anovulation and amenorrhea.

The neurohormone GnRH is produced in specific neurons localized in the preoptic area of the hypothalamus. GnRH is secreted in a pulsatile manner into the portal bloodstream at the level of the median eminence. It travels to the anterior pituitary, where it stimulates gonadotrophs to secrete LH and FSH via membrane receptors. GnRH is degradated by proteolysis within a few minutes.

It is not possible to directly assess GnRH secretion, because this decapeptide is rapidly metabolized within 2 to 4 minutes in the peripheral circulation. Clinical investigation relies on measurement of LH concentrations as the surrogate marker for hypothalamic GnRH secretion. In women with regular menstrual cycles, clinical studies have demonstrated a characteristic pulsatile secretion of LH at a frequency of 90 to 120 minutes during the follicular phase and a frequency of 180 to 240 minutes during the luteal phase.

Gonadotropin-releasing hormone secretion is modulated by many other endocrine and neuronal systems. Some of the most important neurotransmitter agents that regulate GnRH secretion are dopamine, norepinephrine, and serotonin. Activation of the noradrenergic system is associated with increased GnRH release, whereas dopaminergic or serotonergic activation inhibit GnRH release. These observations explain the disruption of normal menstrual cycles in patients who take dopamine receptor antagonists (e.g., phenothiazine), stimulants, antidepressants, and sedatives.

Two amino acids, glutamate and aspartate, have been implicated in a regulatory role for GnRH secretion, primarily during pubertal maturation. These two amino acids have been shown to be localized to the arcuate nucleus in the media basal hypothalamus adjacent to GnRH neurons and appear to activate GnRH secretion during puberty in monkeys.

Endogenous opiate peptides (e.g., endorphins, enkephalin, and dynorphin) appear to play an inhibitory role in GnRH secretion. In patients with hypothalamic amenorrhea, blockade of opiate receptors with antagonists (e.g., naloxone or naltrexone) induces an increase in pulsatile release of GnRH and LH. Long-term treatment of hypothalamic amenorrhea patients with naltrexone can result in return of normal menstrual cycles in some individuals.

Hypothalamic Dysfunction and Amenorrhea

The basic defect in women with hypothalamic amenorrhea is the failure of the hypothalamus to increase GnRH output in the presence of severe hypoestrogenism. Most investigators believe that there is a slowing of the GnRH pulse generator, as reflected by a decrease in peripheral pulsatile LH secretion in these women. The pattern of LH secretion may vary. During the early onset, LH pulse frequency and amplitude may be normal. In more severe cases, regression to a pubertal pattern with sleep-associated increases may be observed.

The pituitary gland is fully capable of synthesis and release of LH and FSH. However, responses to exogenous GnRH in these individuals may vary depending on the endogenous GnRH priming of the pituitary gland. LH and FSH responses to exogenous GnRH may be absent, normal, or supranormal. In these patients, after a period of priming with intravenous pulsatile GnRH (1 to 2 mg/90 minutes), normal levels of LH and FSH can be restored and responses to exogenous GnRH become normal. Taken together, these observations suggest that endogenous GnRH secretion is deficient and gonadotropin secretion and ovarian function can be normalized with physiologic replacement of exogenous, pulsatile GnRH.

Primary Hypothalamic Amenorrhea

Primary hypothalamic amenorrhea is a diagnosis of exclusion when no specific cause of amenorrhea has been found. Patients with hypothalamic amenorrhea unrelated to stress will usually have normal prolactin and thyrotropin levels with a low or normal serum FSH level. Patients with hypothalamic amenorrhea also have decreased pulsatile frequency and amplitude for LH, which is believed to be a direct reflection of changes in GnRH pulses.

Stress-Related Amenorrhea

Exposure to chronic stress often disrupts reproductive function. Chronic environmental stressors lead to long-term activation of the hypothalamic-pituitary-adrenal (HPA) axis, which in turn induces ovulatory dysfunction at either the hypothalamic or the pituitary level. An acute stress response is much less likely to alter ovulatory function.

The stress response associated with chronic stress involves activation of the HPA axis and increased secretion of a “stress response complex” of hormones such as corticotropin-releasing hormone (CRH), corticotropin, cortisol, prolactin, oxytocin, vasopressin, norepinephrine, and epinephrine (Table 16-7). These hormonal effects impact on reproductive function at several levels. For example, CRH has been shown to directly inhibit GnRH secretion in rats, monkeys, and humans at the hypothalamic level in vitro and in vivo. This inhibition can be negated by administration of a CRH receptor antagonist or by naloxone.

Table 16-7 Associated Neuroendocrine Abnormalities in Hypothalamic Amenorrhea

Taken together, these observations suggest that the inhibitory effect of CRH is mediated in part by increased secretion of endogenous opioids. The increased secretion of corticotropin at the pituitary level may also suppress pituitary response to GnRH. In addition, increased cortisol levels may also dampen pituitary response to GnRH.

Exercise-Induced Hypothalamic Amenorrhea

Menstrual cycle disturbances are common among competitive athletes, including ballet dancers, marathon runners, gymnasts, and figure skaters.²⁸ Depending on the type of activity and competition level, the incidence of amenorrhea varies from 5% to 25%. The incidence of menstrual irregularities appears to be greatest in activities that favor a low body weight, such as ballet (6% to 43%) and middle and long distance running (24% to 26%). The incidence appears to be less frequent in bicycling (12%) and swimming (12%).

In athletes with menstrual irregularities, LH pulsatility is altered and can range from a decreased frequency to a transitional pattern. It is well known that acute exercise leads to hyperactivation of the HPA axis. However, LH pulsatility is not disrupted by the stress of exercise but rather because of reduced energy availability. The role of leptin in these circumstances is similar to its role in other energy deprivation states.

Many of these athletes have the “female athlete triad” of amenorrhea, osteoporosis, and eating disorders.

Bulimia and Anorexia Nervosa

Severe eating disorders such as bulimia and anorexia nervosa disrupt menstrual function. Bulimia is characterized by alternating episodes of consumption of large amounts of food over a short time (binge eating) followed by periods of self-induced vomiting, excessive use of laxatives or diuretics, and food restriction. The incidence of bulimia is estimated to be 4.5% to 18% percent among high school and college students. Bulimia usually begins between ages 17 and 25. Anorexia nervosa is a severe eating disorder characterized by extreme weight loss (>25% of ideal body weight), body image disturbances, and an intense fear of becoming overweight and refusal to take action to increase the weight. The overall incidence of anorexia ranges from 0.64 per 100,000 to 1.12 per 100,000.

It is extremely important for the clinician to recognize early signs of these disorders so that appropriate intervention and treatment can be obtained. The mortality associated with anorexia is as high as 9%, usually secondary to cardiac arrhythmia precipitated by electrolyte abnormalities and diminished heart muscle mass. Suicide is also more common. The clinical features of bulimia and anorexia are listed in Tables 16-8 and 16-9.

Table 16-8 Common Features of Bulimia

Table 16-9 Common Features of Anorexia Nervosa

Anorexia nervosa is associated with multiple neuroendocrine abnormalities (Table 16-10). As a result of decreased caloric intake, thyroxine (T₄) conversion to triiodothyronine (T₃) is decreased, resulting in lowered basal metabolism. As a result, thyroxine is converted to an inactive isoform, reverse triiodothyronine (reverse T₃). Profound hypothalamic dysfunction is manifest by hypothermia and impaired secretion of vasopressin that can result in partial diabetes insipidus with the inability to concentrate urine. Hyperactivation of the HPA axis results in hypersecretion of cortisol, but manifestations of hypercortisolism are rarely present due to number of decreased cellular glucocorticoid receptors. These patients also have increased central opioid activity.

Table 16-10 Neuroendocrine Abnormalities Associated with Anorexia Nervosa

Bulimia and anorexia result in a prepubertal pattern of LH similar to patients with functional hypothalamic amenorrhea secretion, presumably due to a marked decrease in GnRH secretion. With weight gain, patients with anorexia will resume normal patterns of LH secretion and may have normal or supranormal responses to GnRH. Despite return to normal body weight, up to 50% remain anovulatory.

As in all energy deprivation states, leptin plays a critical role in the disruption of the hypothalamic function that results in amenorrhea. Leptin is a protein hormone secreted by adipose tissue and has an important role in adaptation to starvation. Leptin-deficient ob/ob mice and leptin-resistant db/db mice show obesity and hypogonadotropic hypogonadism. However, the principal role of leptin is in caloric deprivation; it acts as the signal from the periphery to the brain about energy deficit. This energy deficit is signaled to the hypothalamic-pituitary axis through decreased leptin levels. Leptin may have a role in the other neuroendocrine abnormalities such as thyroid and insulin-like growth factor-I (IGF-I) seen in anorexics and in other energy-deficient states such as excessive exercise.²⁹

Evaluation of Hypothalamic Amenorrhea

Because this is a diagnosis of exclusion, significant organic diseases must be excluded (see Table 16-2). A detailed interview may identify a stressful event or emotional crisis (divorce, relationship breakup, death of a friend or relative) preceding the amenorrhea. Other interpersonal and environmental stressors may also be present, such as academic pressures, job stresses, or psychosexual problems. A careful review of the patient’s current lifestyle, including exercise intensity, dietary choices, and the use of sedatives or hypnotics, may be helpful in characterizing the psychogenic stress components.³⁰

Patients with hypothalamic amenorrhea will have a history of normal menarche and regular menstrual cycles between 26 and 35 days in length. These women typically are intelligent, high-achievers who are usually thin or of normal body weight. The physical examination should focus on identifying galactorrhea, thyroid dysfunction, and evidence of hyperandrogenemia (i.e., acne, hirsutism). Oral examination may identify the peculiar dentition or enlarged salivary glands of a bulimic patient. The pelvic examination should be normal except for a thinned vaginal mucosa or absent cervical mucus, which are characteristics of hypoestrogenism. Despite these findings, these patients do not usually experience hot flushes.

Laboratory evaluation should include measurement of serum LH, FSH, prolactin, thyrotropin, and estradiol. LH and FSH can be either low or normal, and estradiol levels will be either low or within the lower limits of normal. Most of the other pituitary hormones should be in the normal range.

In many patients, the progestin challenge test (medroxyprogesterone acetate 10 mg for 7 days) will not result in uterine bleeding. This test is a bioassay for the absence of estrogen priming of the endometrium and reflects the low circulating levels of estradiol.

Clinical Management of Hypothalamic Amenorrhea

The first step in clinical management is to identify and treat environmental stressors. Appropriate support and counseling often helps patients develop coping mechanisms that allow them to live healthier lifestyles. In patients with eating disorders and in many athletes, dietary consultation is extremely helpful. After lifestyle modification, spontaneous recovery of menstrual function will occur in 70% to 80% of patients. For patients who continue to have oligomenorrhea, periodic evaluation of menstrual status every 4 to 6 months is prudent. The primary medical concerns for these patients are infertility and bone loss.

Athletes have been characterized as having the “female athlete triad” of amenorrhea, osteoporosis, and eating disorders. Management of these patients should emphasize measurement of bone density, dietary and psychological counseling, weight change, and calcium intake. One goal of therapy may be to decrease the level of exercise, improve the diet, and achieve weight gain. For others, exercise may not induce amenorrhea but may be associated with longer menstrual cycles, luteal phase defects, and intermenstrual spotting. These reproductive defects may be reversible with a decrease in exercise level or intensity.

Postcontraception Amenorrhea

Amenorrhea after long-term contraception use remains a concern, but the issues of concern have changed. In the past, use of high-dose (>50 μg ethinyl estradiol) oral contraceptives was associated with prolonged amenorrhea after discontinuation. With modern low-dose oral contraceptives, amenorrhea is uncommon, but reversible cycle disturbances after discontinuing oral contraceptives can last up to 9 months or longer.³³ Fortunately, oral contraceptives do not affect fertility in the long term. Amenorrhea that continues more than 2 months after discontinuation of an oral contraceptive should trigger an investigation for other causes of amenorrhea.

A more common problem has become amenorrhea after the intramuscular use of medroxyprogesterone acetate (Depo-Provera) for contraception. Amenorrhea is common after discontinuation of this type of contraception, and the return to baseline fertility takes an average 10 months.³⁴ For this reason, investigation for amenorrhea after discontinuation of depot medroxyprogesterone should be limited until 12 months after the last injection.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common causes of ovulation dysfunction (see Chapter 19). Although this complex syndrome has a wide range of clinical manifestations, amenorrhea was one of the primary manifestations first described by Stein and Leventhal in 1935 along with infertility and enlarged ovaries.³⁵ Contemporary series suggest that only about 25% of patients with PCOS will have amenorrhea.³⁶ The pathology, diagnosis, and treatment of PCOS is discussed in depth in Chapter 15.

Other Hyperandrogenic States

Other hypoandrogenic states that mimic PCOS can also result in amenorrhea. Probably the most serious of these conditions are ovarian and adrenal tumors. Likewise, Cushing’s syndrome can cause amenorrhea secondary to increased androgens. Another cause is adult-onset congenital adrenal hyperplasia.

The basis of the workup to exclude these conditions includes measurement of serum androgens, including total testosterone, DHEAS, and 17-hydroxyprogesterone. Imaging of the ovaries and, in some cases, adrenal glands is also important. This details of this evaluation are given in Chapter 18.

Prolactin-Secreting Adenomas

Prolactin-secreting adenomas are the most common pituitary tumors, accounting for half of all pituitary adenomas found at autopsy. Classification has been attempted by a variety of different histologic findings; however, the most useful form of classification is according to function. Hyperprolactinemia is associated with decreased estradiol concentrations as well as amenorrhea or oligomenorrhea.

In women with hyperprolactinemia, the prevalence of pituitary tumor is 50% to 60%,³⁷ and the likelihood of a pituitary tumor is unrelated to the level of prolactin found.³⁷ The poor correlation between tumor size and serum prolactin indicates that MRI or computed tomography (CT) scanning of the pituitary should be performed whenever serum prolactin levels are consistently elevated.³⁸ Although the exact incidence of these tumors is unknown, autopsy series have shown the presence of microadenomas to range from 9% to 27%.^39,40 The distribution of these types of tumors appears equal among gender.

Empty Sella Syndrome

This syndrome refers to a congenital incompleteness of the diaphragm of the sella turcica, allowing for extension of the subarachnoid space into the pituitary fossa. This can also occur secondary to surgery, radiation therapy, or infarction of a pituitary tumor. This anatomic abnormality is found in approximately 5% of autopsies, with a high predominance in women. Empty sella is found in 4% to 16% of patients with amenorrhea-galactorrhea.⁴¹ Galactorrhea and elevated serum prolactin levels can be seen. Annual surveillance with serum prolactin levels is sufficient since they rarely develop prolactinomas. The purpose of treatment is alleviation of symptoms.

Postpartum Pituitary Necrosis (Sheehan’s Syndrome)

Postpartum pituitary necrosis is usually preceded by a history of severe obstetrical hemorrhage with hypotension, circulatory collapse, and shock.⁴² After fluid resuscitation of the patient, this condition may be manifested by clinical evidence of partial or panhypopituitarism. Simmonds was the first to describe this clinical syndrome although the most complete description has been attributed to Sheehan. This condition constitutes an endocrine emergency that can be life-threatening.

The pathophysiology of this process is not entirely clear. With pregnancy, there is an increase in blood supply to the pituitary bed and the pituitary gland enlarges. During the period of profound hypotension, Sheehan postulated that occlusive spasm of the arteries that supply the pituitary and stalk occurs. This leads to venous stasis and thrombosis of the pituitary portal vessels, causing a variable degree of pituitary ischemia and cell death. Many patients initially present with a failure to have breast engorgement and lactation due to a deficiency in prolactin secretion. These women may also have other anterior pituitary deficiencies.

The posterior pituitary is usually spared because it is less dependent on the portal blood supply. In some patients, the absence of corticotropin secretion leads to inadequate cortisol secretion, resulting in postural hypotension, nausea, vomiting, and lethargy. Hypothyroidism may be noted later in this syndrome. Recovery of pituitary function has been reported in a few cases.

Post-traumatic Hypopituitarism

This condition can arise after severe head trauma as a result of a sudden deceleration of the head and occult damage to the pituitary stalk or hypothalamus during a motor vehicle accident. Trauma may also be associated with a basal skull fracture or an episode of unconsciousness. These individuals will often manifest a delay from injury to presentation and may display evidence of partial hypopituitarism or panhypopituitarism. These symptoms can include amenorrhea, galactorrhea, hypogonadism, loss of axillary and pubic hair, anorexia, and weight loss.

In these patients, evaluation of adrenal function is most critical because adrenal failure is life-threatening. The diagnostic evaluation and management is similar to that described for Sheehan’s syndrome.

Pituitary Apoplexy

This medical emergency is characterized by an acute infarction of the pituitary gland. Patients will complain of a sudden onset of a severe retro-orbital headache and visual disturbances that may be accompanied by lethargy or loss of consciousness. These symptoms may mimic other neurologic emergencies such as hypertensive encephalopathy, cavernous sinus thrombosis, ruptured aneurysm, or basilar artery occlusion. CT or MRI may indicate hemorrhagic changes in the pituitary sella region.

Patients with pituitary tumors are at higher risk for this complication. For some patients, neurosurgical consultation and emergency decompression may become necessary. Provocative testing as described for Sheehan’s syndrome should be performed to evaluate for multiple pituitary deficits. Appropriate replacement of target tissue hormones should be instituted based on testing.

Postirradiation Hypopituitarism

Exposure to therapeutic radiation sources for treatment of midline tumors of the central nervous system can place patients at increased risk for delayed development of hypopituitarism. In general, sensitivity to radiation is greatest for gonadotrophs, followed by corticotrophs and thyrotrophs. The onset of pituitary deficiencies may be insidious but can occur within 1 year of radiotherapy. Periodic assessment of hypothalamic-pituitary function should be performed for an indefinite period of time, and appropriate replacement hormone therapy should be instituted as these deficiencies develop.

Evaluation of Pituitary Adenomas

The clinical manifestations of these adenomas are usually more obvious in women, due to the disruption of menses. The most common symptoms of a prolactin-secreting adenoma in women are galactorrhea, irregular periods, headaches, and infertility. Men can experience hypogonadism due to these tumors, but the tumors are usually large and produce high serum prolactin levels. Approximately one third of women with amenorrhea will have elevated prolactin levels; one third of women with galactorrhea and elevated prolactin levels will have normal menses and one third of women will have a high prolactin level without galactorrhea.⁴³ As many as a third of patients with secondary amenorrhea will have a prolactinoma and when associated with galactorrhea, half of the patients will have normal findings on imaging of the sella turcica.^43,44

The apparent clinical difficulty in associating clinical symptoms, laboratory values, and sella turcica imaging is the fact that there is tremendous variability in the detection of prolactin in clinical assays. The immunoreactivity of clinical assays usually detects the small form of prolactin, which also has more biologic activity. Big forms of prolactin can also be secreted by pituitary adenomas and, since this prolactin type cannot usually be detected by the immunoassays, the diagnosis of a pituitary adenoma may be missed. Therefore, whenever the clinical scenario of galactorrhea is present, particularly in a patient with irregular menstruation, imaging of the pituitary gland must be considered and clinical intervention should be instituted.^45,46

Some patients with high serum prolactin levels can also have what is referred to as a “high-dose hook effect” where large amounts of prolactin prevent accurate assessment by the immunoassay. Dilutions of serum samples are able to detect the abnormality.⁴⁷ The mechanism by which prolactin causes oligomenorrhea and amenorrhea is due to the inhibition of pulsatile secretion of GnRH by elevated prolactin.^48,49

The measurement of thyrotropin should be included as part of the evaluation. Although prolactin levels associated with hypothyroidism are generally less than 100 ng/mL, these levels can induce galactorrhea. Hyperprolactinemia in hypothyroidism is the result of increased thyrotropin-releasing hormone (TRH) stimulation of the pituitary gland. TRH is a potent stimulant of prolactin-secreting cells. The extent of pituitary deficiencies can be characterized by provocative testing with combined intravenous injection of the hypothalamic releasing factors GnRH, TRH, growth hormone releasing hormone, and CRH.⁵⁰

Management of Pituitary Adenomas

The use of dopamine agonists such as bromocriptine lowers the circulating levels of prolactin and restores the normal response of the ovary to gonadotropins and restores normal menstrual function. The treatment with bromocriptine, a dopamine agonist, inhibits pituitary prolactin secretion. This medication is associated with many side effects; 10% of patients cannot tolerate the medication and will discontinue it. Most patients complain of nausea, headache, and faintness, usually due to orthostatic hypotension. Other side effects include dizziness, fatigue, nasal congestion, vomiting, and abdominal cramps, which can be diminshed by starting the patient on a low dose of the medication and slowly increasing it. Some patients can benefit from vaginal administration of bromocriptine to avoid the gastrointestinal side effects.⁵¹ Vaginal administration is effective largely by avoiding the first pass through the liver.

There is no evidence that bromocriptine harms the fetus. However, most clinicians recommend discontinuing the medication during pregnancy.⁵² More than 80% of patients with amenorrhea and galactorrhea in association with hyperprolactinemia will have their menses restored 5 to 7 weeks after therapy is started.⁵³ The cessation of galactorrhea is much slower than the restoration of menses, and complete cessation of galactorrhea occurs in half of patients after 4 months of use. Up to 75% of patients who stop the treatment will develop symptoms again.⁵⁴

It is possible for macroadenomas to regress with bromocriptine treatment, but it requires higher doses and a longer period of use. Most patients have a rapid shrinkage in the first 3 months of therapy followed by a slower reduction.⁵⁵ Patients who initially present with serum prolactin levels over 1000 ng/mL have tumors that invade into their cavernous sinuses. These individuals usually have inoperable tumors and require long-term suppression with dopamine agonists. Bromocriptine can also be used for patients who have failed surgery and radiation therapy.

Cabergoline is an alternative to bromocriptine. Side effects seem to develop less frequently and the medication is taken once or twice weekly. Due to a limited experience on fetal safety, this agent should be used with caution in patients who are trying to conceive.^56–58

Transsphenoidal surgery has also been used to treat pituitary adenomas. Symptom resolution is achieved in 30% of patients with macroadenomas and 70% of patients with microadenomas; this is highly dependent on the experience of the neurosurgeon.⁵⁹ Tumor recurrence is high, especially after surgery for macroadenoma. Potential postoperative complications include panhypopituitarism, meningitis, cerebrospinal fluid leaks, and diabetes insipidus. The high success rate of medical therapy, recurrence of disease, and potential complications of surgery have limited the use of surgical intervention to patients who have failed medical therapy. Radiation therapy is less satisfactory than surgery for the treatment of pituitary adenomas, and the response is very slow. Under specific circumstances radiation can be delivered with a gamma knife procedure.

Patients who respond to treatment of hyperprolactinemia can breast-feed if desired and usually can experience normal lactation without fear of tumor growth. There is only a small chance of growth of most pituitary tumors during pregnancy. Up to 5% of patients will have tumor enlargement, which is usually asymptomatic; less than 2% will develop symptoms.⁶⁰ Most symptomatic patients present with headaches, which usually precede any visual abnormalities. During pregnancy there is normal pituitary growth, typically due to the increased size of the prolactin-secreting cells. Insufficient blood supply to the adenoma may cause this infarct. Occasionally patients may have restoration of normal menses from tumor infarction in pregnancy or postpartum.

Surveillance during pregnancy with monthly visual field examinations or serum prolactin measurements has not been clinically useful. Patients who become symptomatic should be assessed and treated. Most patients will respond to bromocriptine, and it is very uncommon to require termination of pregnancy or neurosurgery.⁶¹ Dopamine agonists used during pregnancy do not affect decidual secretion of prolactin, which is under control of estrogen and progesterone rather than dopamine.

Cushing’s Disease and Acromegaly

Although amenorrhea and/or galactorrhea are usually encountered with pituitary prolactinomas, these symptoms may also precede corticotropin- or growth hormone-secreting tumors. If the patient presents clinical symptoms of glucocorticoid excess suggestive of Cushing’s disease, a corticotropin serum level and a 24-hour urine collection for free cortisol should be ordered.

Excessive production of growth hormone can rarely occur in children and is referred to as gigantism. In adults excessive production of growth hormone from a pituitary tumor is called acromegaly. After the final height is achieved, the excessive growth of this syndrome is restricted to the acral areas, such as hands, feet, and facial features. Excessive sweating and fatigue are common. If the patient presents with signs and symptoms of acromegaly, a serum IGF-I level is the most appropriate test. This evaluation can be performed on a random blood test. On the contrary, growth hormone levels are only of value if obtained during an oral glucose tolerance test. The expected suppression of growth hormone with a glucose load is not seen. Glucose intolerance and hypertension are commonly found with both acromegaly and Cushing’s disease. Because the initial presentation of acromegaly can be amenorrhea, an elevated serum prolactin level, and a macroadenoma (>10 mm in diameter) on MRI, a serum IGF-I should be obtained in all patients who present with these findings.

Gonadal Dysgenesis

Rare patients with gonadal dysgenesis may go through normal puberty and present with secondary amenorrhea, almost always before age 30. Women with secondary amenorrhea as a result of gonadal dysgenesis will usually have a normal 46,XX karyotype, although some will be found to have deletions, 47,XXX, or 46,XO.

Patients who present with gonadal dysgenesis and a normal karyotype need to be assessed for a variety of other conditions, such as neurosensory deafness (Perrault’s syndrome), as well as fragile X syndrome, the most common genetic cause of developmental disorders. About 16% of women who are carriers of the premutation allele for fragile X syndrome experience premature ovarian failure, particularly when familial premature ovarian failure or mental retardation is identified.⁹ When women with sporadic premature ovarian failure are screened, approximately 3% will be premutation carriers. Some females with premutation alleles may be affected with mild degrees of mental deficiency or learning disability.

There is also an association of premature ovarian failure with autosomal-dominant eyelid abnormalities. This is known as blepharophimosis-ptosis-epicanthus inversus syndrome. This syndrome is caused by a mutation in FOXL2, which is a transcription gene factor found on chromosome 3.^65,66 Several other autosomal disorders have been associated with ovarian failure; these will produce elevations of FSH without necessarily having oocyte depletion. Some of these include mutations of the phosphomannomutase 2 (PMM2) genes, the galactose-1-phosphate uridyltransferase (GALT) gene, the FSH receptor gene, and the autoimmune regulator gene (ARE), which is responsible for polyendocrinopathy-candidiasis-ectodermal dystrophy.⁶⁷

Autoimmune Causes

A common form of premature ovarian failure is due to autoimmune disease. Up to 40% of women with premature ovarian failure may have autoimmune abnormalities, most commonly autoimmune thyroiditis resulting in hypothyroidism.^68,69 Premature ovarian failure is also more common in women with insulin-dependent diabetes, myasthenia gravis, and parathyroid disease than in healthy women.⁷⁰ In 10% to 60% of cases of Addison’s disease, autoimmune ovarian failure may also be present.

Because these individuals are at increased risk for endocrine autoimmune conditions, patients should be evaluated every other year for occurrence of these abnormalities so early intervention can be achieved. Patients with unexplained premature ovarian failure should have a complete evaluation to exclude other autoimmune disorders; tests to perform include tests for calcium, phosphorus, fasting glucose, adrenal antibodies to 21-hydroxylase enzyme, free T₄, thyrotropin, and thyroid antibodies. This evaluation should be repeated on a yearly or every other year basis.⁷¹ Screening for antiovarian antibodies is not warranted because the assays have poor sensitivity and specificity.

Patients should be screened for adrenal disease with an evaluation for antiadrenal antibodies. If that test is positive, more sophisticated testing such as a corticotropin stimulation test is necessary. A fasting morning serum cortisol is not sufficiently sensitive.

Premature Ovarian Failure: Other Causes

Although elevated serum FSH levels are virtually synonymous with ovarian disorders, there are uncommon conditions that can raise FSH but are associated not with a primary ovarian problem but a central problem. These include pituitary adenomas that secrete FSH or specific enzyme defects such as 17-hydroxylase deficiency (P450c17) or galactose-1-phosphate uridyl transferase deficiency (galactosemia).

There have been a few reports of single gonadotropin deficiency; the measurement of both LH and FSH together will uncover these unusual disorders. In premature ovarian failure you will always find elevations of both hormones; a single elevation is suspicious.⁷² Most of these abnormalities are due to single-gene or amino acid substitutions. In these cases, an MRI of the pituitary will also uncover a pituitary adenoma that secretes these hormones, particularly if associated with an elevated α-subunit. However, these tumors are generally not associated with amenorrhea.

There can also be mutations of the receptors for gonadotropins; these patients are diagnosed with resistant or insensitive ovary syndrome. These patients generally have secondary amenorrhea with normal secondary sexual characteristics and do not respond to gonadotropins and have small antral follicles on ultrasound.⁷³

Mutations for the human FSH receptor gene have also been identified, both in females⁷⁴ and males. Females display hypergonadotropic hypogonadism from FSH resistance. The phenotype ranges from absent to normal breast development and primary or secondary amenorrhea. This is a relatively uncommon finding, but is found predominantly in certain populations such as Finland (1% of females are heterozygotes).

Mutations of the LH receptor in 46,XX females consist of normal sexual development and amenorrhea.²⁶ Serum LH may be normal to increased, FSH is normal, follicular phase estradiol levels are normal, and progesterone is low. The uterus is small and the ovaries are consistent with anovulation.

Diagnosis of Premature Ovarian Failure

The initial screen, as in all cases of amenorrhea, is with serum thyrotropin, prolactin, and FSH levels. The diagnosis of premature ovarian failure is made in the presence of elevated serum FSH, normal serum prolactin, and normal serum thyrotropin. Estradiol will also be decreased, and thus progesterone challenge will not result in withdrawal bleeding.

Ovarian biopsies are usually not necessary in patients with premature ovarian failure. The costs and risks of surgical intervention are substantial, and they do not change patient management. A transvaginal ultrasound to assess antral follicle count and ovarian volume may be useful.

Management of Premature Ovarian Failure

Patients with ovarian failure should be offered estrogen and progesterone replacement to maintain their secondary sexual characteristics and reduce the risk of osteoporosis. This can be easily achieved with combined oral contraceptives until the age of natural menopause as long as no contraindications to combined oral contraceptives are met. Some women who take low-dose exogenous estrogen therapy with a progestin, who have some ovarian follicles left with premature ovarian failure, can have spontaneous ovulation and conception is possible in rare cases.⁷⁵

Asherman’s Syndrome

Asherman’s syndrome is commonly used to describe the presence of intrauterine adhesions (or synechiae), most commonly secondary to uterine surgery. Patients are found to have Asherman’s syndrome after undergoing aggressive curettage for postpartum bleeding, after removal of multiple submucosal fibroids, or after metroplasty.⁷⁶ Recently uterine artery embolization has also been associated with the development of Asherman’s syndrome; although its mechanism is not well understood, it is believed to be secondary to ischemia associated with the embolization procedure.⁷⁷ Although the syndrome was first described as amenorrhea secondary to intrauterine synechiae, the presence of hypomenorrhea or amenorrhea is not considered a requirement for making this diagnosis today.^76,78

Typically, the diagnosis is made when synechiae are seen at the time of a hysterosalpingogram. Adhesions can be isolated or diffuse dense scarring. Amenorrhea is most commonly seen with diffuse scarring. Regardless of bleeding pattern, patients typically have normal ovarian function and normal changes in their basal body temperature.

Management of Asherman’s Syndrome

Asherman’s syndrome is treated with hysteroscopy, by lysing the synechiae with scissors, cautery, or laser. To prevent the reformation of adhesions, patients in the past have had an intrauterine device or a pediatric Foley catheter placed inside the uterine cavity in the postoperative period. More recently, a balloon uterine stent that mimics the normal shape of the uterus has been developed. The balloon is typically kept inside the uterus for 7 to 10 days. Oral antibiotics are administered for variable lengths of time, typically for the length of treatment or a few days more. For patients who complain of cramping, nonsteroidal anti-inflammatory drugs are usually helpful. Although little prospective data are available, most clinicians give the patient 4 to 6 weeks of oral therapy with conjugated estrogens (2.5 mg) to regenerate the endometrium. This is followed by progestin to induce withdrawal bleed.

If the initial therapy is unsuccessful, patients sometimes have to undergo multiple surgeries until menstruation is restored. Some authors report a subsequent pregnancy rate of 70% to 80% if menses can be restored, although this is sometimes difficult in severe cases. Patients who become pregnant may be at increased risk for complications, including premature labor, placenta accreta, placental previa, and postpartum hemorrhage.

History

Basic to every history for women with amenorrhea is the menstrual history, sexual activity, and means of contraception. Years of irregular menses suggest PCOS but do not exclude pregnancy. Several modern means of contraception are prone to iatrogenic amenorrhea.

In young women, eating and exercise habits must be explored. Although hypothalamic amenorrhea is common in underweight young women, so is unintended pregnancy. Young women are also at greater risk for premature ovarian failure related to abnormal karyotype.

Genital tract disorders will almost always be accompanied by a history of gynecologic surgery, especially after a pregnancy. However, postpartum hemorrhage necessitating uterine curettage also brings up the possibility of Sheehan’s syndrome.

The history should identify subtle symptoms of endocrinologic or systemic disorders, such as vaginal dryness associated with premature ovarian failure, galactorrhea often associated with hyperprolactinemia, and the increased hair growth often seem in women with PCOS. Systemic diseases often have associated symptoms, such as the weight gain associated with both hypothyroidism and Cushing’s syndrome. Acne and increased midline hair are often signs of hyperandrogenic conditions such as PCOS or adult-onset congenital adrenal hyperplasia.

Clearly, many of these symptoms overlap and it is often tempting to prematurely jump to the diagnosis in a patient with classic symptoms of a common disorder. For this reason, it is important to let the history guide the additional tests, while not omitting parts of the basic workup.

Physical Examination

The physical examination will often give obvious or subtle hints of the underlying cause of secondary amenorrhea. Patients with PCOS will often be overweight with increased hair on the upper lip, chin, chest, and inner thighs. These signs tend to occur at the time of menarche and are more pronounced in adolescents with adult-onset congenital adrenal hyperplasia. Sudden and dramatic hirsutism suggests an ovarian or adrenal tumor. Short stature and Turner’s syndrome can suggest premature ovarian failure with a genetic basis.

Endocrinologic and systemic diseases often, but not always, have classic signs. Galactorrhea on breast examination suggests hyperprolactinemia, although only one third of women with elevated prolactin level will have this finding. Cushing’s syndrome is often associated with central obesity, moon face, abdominal striae, and “buffalo hump.”

Gynecologic examination is occasionally illustrative in women with secondary amenorrhea. During speculum examination, significant stenosis of the external cervix or vaginal atrophy associated with hypoestrogenemia can be obvious. Bimanual examination will often detect the enlarged uterus of pregnancy, but less commonly the bilaterally enlarged ovaries seen in PCOS.

As with the history, the physical examination should be used to guide the accessory tests. However, because many causes of secondary amenorrhea will not be obvious on physical examination, a comprehensive, stepwise approach to the basic workup is important.

Laboratory Evaluation

All patients presenting with secondary amenorrhea should have an initial set of laboratory studies, including a pregnancy test and thyrotropin, prolactin, and FSH levels. A positive pregnancy test will initiate a workup for pregnancy to determine location and viability. Elevated thyrotropin or prolactin levels indicate a need to evaluate the patient further for hypothyroidism or pituitary adenoma, respectively.

The results of the FSH measurement must be determined in relationship to other test results. An elevated FSH is an indication for further evaluation for premature ovarian failure. A normal or low FSH can be normal in patients with PCOS, and these patients will normally have withdrawal bleeding after a progestin challenge. In the presence of hypoestrogenemia as evidenced by low serum estradiol and failure to bleed after progestin challenge, either a low or normal FSH are abnormal and require an evaluation for hypothalamic disorders.

Evaluation of androgens is indicated in women with amenorrhea and any sign of androgen excess such as hirsutism or acne. Although many women with PCOS will have modestly elevated androgens (see Chapter 15), the most important objective of measuring androgens in women with apparent PCOS is exclusion of other causes of hyperandrogenic amenorrhea, most notably androgen-producing tumors of the ovary and adrenal glands, Cushing’s syndrome, and adult-onset adrenal hyperplasia.

Some women with elevated androgens will have minimal signs. This uncommon situation should be considered in women who do not appear to be hypoestrogenemic but do not bleed after progestin challenge. Evaluating both estradiol and androgen levels in these patients can sometimes help make the diagnosis.

Progestin Challenge Test

A traditional step early in the evaluation of secondary amenorrhea is the progestin challenge test. With a normal outflow tract and the presence of normal levels of circulating estrogen, menses will usually be induced by administering synthetic or natural progesterone. This can be in the form or medroxyprogesterone 10 mg a day for 7 days, intramuscular progesterone in oil 200 mg, or micronized progesterone 200 mg once a day for 7 days. Any amount of bleeding or spotting that occurs up to 7 days after the last progestin pill is considered to be a normal progestin challenge.

Lack of withdrawal bleeding after a progestin challenge requires further evaluation. If not already evaluated, determination of serum FSH and estradiol is important to exclude premature ovarian failure or occult hypothalamic amenorrhea. Even in women with no clinical signs of androgen excess, serum total testosterone and DHEAS should be measured, because high levels of androgens can result in endometrial atrophy, thus preventing withdrawal bleeding.

Failure to bleed after a progestin challenge is usually the result of estrogen deficiency or Asherman’s syndrome. To differentiate between these two, the patient should be pretreated with estrogen (e.g., conjugated estrogens 1.25 mg daily for 6 to 8 weeks) and the progestin challenge should be repeated. Patients who do not bleed after administration of both estrogen and progestin are likely to have an anatomic problem that is preventing menses.

Imaging

Transvaginal ultrasound is perhaps the most common modality used to image the pelvic organs. In patients with secondary amenorrhea, this approach will rarely be helpful. Polycystic ovaries can often be seen in patients with PCOS. However, their absence does not exclude this diagnosis. Most anatomic abnormalities that cause amenorrhea, such as intrauterine adhesions, are difficult to see by ultrasound. Saline infusion sonohysterogram is more accurate. Hysterosalpingogram is typically used to visualize intrauterine adhesions. However, it should be performed in the evaluation of secondary amenorrhea only in patients who have a history of a predisposing factor.

Surgical Evaluation

The etiology of secondary amenorrhea can usually be determined without surgical evaluation. In some cases, diagnostic hysteroscopy may be necessary to assess the endometrial cavity when imaging modalities give ambiguous results.