Evaluation of Secondary Amenorrhea

Shana L. Birnbaum

Secondary amenorrhea is defined as cessation of menses for 3 or more months in a woman with previously normal cycles. The incidence of secondary amenorrhea is about 3% in unselected populations. The primary physician is frequently consulted by women who have missed one or more menstrual periods. Concerns about pregnancy and menopause are prominent. Knowing how to initiate an efficient workup for functional or structural abnormalities of the hypothalamic-pituitary-ovarian axis and knowing when to refer are important components of the primary care of women with this problem.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18)

Amenorrhea reflects an interruption in the mechanisms of normal menstruation and may result from a disturbance at the level of the hypothalamus, pituitary, ovaries, or uterus. Polycystic ovarian syndrome, one of the most common causes of amenorrhea, involves abnormalities throughout the hypothalamic-pituitary-ovarian access.

Hypothalamic Amenorrhea

Functional Hypothalamic Amenorrhea

Hypothalamic amenorrhea most often results from a functional impairment of pulsatile gonadotropin-releasing hormone (GnRH) secretion causing loss of a luteinizing hormone (LH) surge and failure to ovulate. The most profound disturbances of GnRH release may occur in the context of marked weight loss (<70% ideal, as in anorexia nervosa and other eating disorders; see Chapter 234), severe emotional upset, or excessive exercise (competitive athletes). Hypothalamic response to such stressors is variable, with evidence suggesting a genetic basis for some of the variability.

Athletes in sports requiring low body weight or subjective judging (figure skating, gymnastics, ballet) are more prone to exercise-induced hypothalamic amenorrhea. A relative caloric deficiency seems to be necessary for this type of amenorrhea because some weight-stable nonathletic women with functional hypothalamic amenorrhea exhibit evidence of subclinical eating disorders characterized by severe restriction of dietary fat.

Leptin, a hormone secreted by fat cells in proportion to body fat stores, may be involved in mediating this relationship; leptin levels are lower in women with hypothalamic amenorrhea, and athletes with amenorrhea appear to lose the diurnal variation in leptin secretion. In one small study of women with hypothalamic amenorrhea, leptin administration resulted in improvement of GnRH pulsatility and reversal of the amenorrhea.

In patients with severe functional impairment of GnRH release, estrogen levels can fall so far below normal that the patient is at risk for osteopenia; osteoporosis may ensue if the condition goes untreated for a prolonged period of time. This has resulted in recognition of the so-called female athlete triad of amenorrhea, disordered eating, and osteopenia or osteoporosis. In the setting of significant hypoestrogenism, there is little or no endometrial proliferation, so withdrawal bleeding does not occur on uterine exposure to progesterone. Although women with severe functional hypothalamic amenorrhea can achieve a return of pulsatile GnRH release and restoration of normal periods and estrogen status with correction of the underlying problem, the bone loss may be permanent.

More commonly seen are milder functional forms of impaired GnRH release in the settings of situational stress, excessive exercise, concurrent illness, or mild weight loss. In mild functional hypothalamic disease, follicle-stimulating hormone (FSH) secretion continues at a low-normal level, allowing estrogen production, which results in endometrial proliferation. Withdrawal bleeding occurs on exposure to progesterone, whether endogenous or exogenous.

Endocrinopathy- and Drug-Related Causes

A host of endocrinopathies may interfere with normal GnRH release and result in amenorrhea. Conditions causing excess production of cortisol, androgens, or prolactin have been linked to impairment of GnRH release. Hypothyroidism with its associated elevated thyrotropin-releasing hormone (TRH) levels may present as amenorrhea because of the ability of TRH to trigger prolactin secretion.

Drugs are sometimes responsible, including oral contraceptives and dopaminergic agents (e.g., phenothiazines, risperidone, metoclopramide). Menses usually return within 2 months of stopping oral contraceptives, although “postpill amenorrhea” can last up to 6 months. More prolonged amenorrhea suggests underlying pathology unrelated to oral contraceptive use.

Pituitary Pathology

Disruption of normal pituitary function may lead to secondary amenorrhea. Tumors, infiltrative disease, and postpartum injury are among the potential causes. While amenorrhea is not a frequent consequence of most pituitary neoplasms, it does develop in up to a quarter of women with prolactinoma.

Prolactinoma

The excess prolactin production inhibits normal GnRH release and impairs gonadotropin production. The characteristic clinical picture is one of galactorrhea, infertility, and amenorrhea (see Chapter 100). As prolactin levels rise, plasma concentrations of gonadotropins and estradiol begin to fall, resulting in amenorrhea or oligomenorrhea. Because prolactin is primarily controlled by negative inhibition from hypothalamic dopamine, an alternative mechanism for hyperprolactinemia is disruption of the pituitary stalk, as by a tumor.

Most prolactinomas are small (<10 mm in diameter) and are designated as microadenomas. Patients with microadenomas usually have otherwise normal pituitary function, whereas those with macroadenomas (>10 mm) may experience reduced secretion of anterior pituitary hormones. If large enough, the tumor can displace pain-sensitive neurologic structures and cause headache; impingement on the optic chiasm may result in a visual field defect. Over time, most patients with microadenomas experience a decrease in prolactin production and a return of ovulation, even without treatment.

Many patients with both micro- and macroadenomas are able to safely discontinue treatment with time. Among women who become pregnant, there is only a 1% chance that a microadenoma will undergo symptomatic enlargement, but there is a 10% to 35% risk of a macroadenoma enlarging; such women need close monitoring with visual field testing and consideration of surgical debulking before pregnancy.

Other Pituitary Causes

Less common pituitary lesions include sellar tumors, postpartum pituitary necrosis (Sheehan syndrome), empty sella, hemochromatosis, and granulomatous disease (e.g., sarcoidosis). These destructive lesions can impair functioning pituitary tissue. Growth hormone production is generally the first to suffer but does not cause symptoms. Subsequently, reduced FSH and LH synthesis may lead to amenorrhea, often the presenting complaint. Headache and visual field defects may follow later, along with manifestations of panhypopituitarism. In empty sella syndrome, there appears to be herniation of the arachnoid down into the sella, compressing its contents and producing a ballooning of the bony sella on x-ray. The typical patient is a woman, obese and multiparous, who complains of headache. In this syndrome, amenorrhea is caused by mild hyperprolactinemia resulting from loss of normal inhibition of prolactin secretion rather than true hypopituitarism.

Ovarian Dysfunction

Ovarian dysfunction leading to amenorrhea is characterized by marked elevations in LH and FSH and low levels of estrogen and progesterone. In all types of ovarian failure, estrogen deficiency is marked, and osteoporosis may ensue. Normal menopause results from depletion of ovarian follicles and typically occurs between 45 and 55 years of age. As estrogen production declines, gonadotropins increase, reaching extreme levels as the serum estradiol concentration drops to less than 5% of normal (about 5 pg/mL). Manifestations of the loss of normal cyclic hormone production include hot flashes, anovulatory bleeding, and missed periods, followed by total cessation of periods (see Chapter 118).

Primary Ovarian Insufficiency

Primary ovarian insufficiency (previously termed “premature menopause” or “premature ovarian failure”) presents in a similar fashion, except that the patient is younger than the age of 40 years. There are no associated endocrinopathies or systemic illnesses in the idiopathic form of primary ovarian insufficiency, which is responsible for 90% of cases, although a positive family history of the disorder is not uncommon.

About 4% of women presenting with primary ovarian insufficiency will have an autoimmune oophoritis, often in combination with adrenal insufficiency and sometimes as a component of autoimmune polyglandular syndrome. This hereditary syndrome may present as adrenal insufficiency or ovarian, thyroid, and pancreatic endocrine dysfunction and can be accompanied by myasthenia gravis, vitiligo, or pernicious anemia. Women who experience apparent primary ovarian insufficiency before the age of 30 years may have mosaic Turner syndrome or a partial × chromosome deletion. A premutation in the fragile X syndrome gene (FMR1) is recognized as a relatively common finding among women with primary ovarian insufficiency, although the mechanism is unknown; the prevalence of the premutation is as high as 14% in those women with a family history of primary ovarian insufficiency and up to 3% in those with sporadic primary ovarian insufficiency. Other rare genetic mutations causing early ovarian insufficiency, such as ovarian resistance to FSH in which a somatic mutation inactivates the FSH receptor, are subjects of active investigation.

Other Causes

Cancer treatment may cause direct irreversible ovarian injury when radiation therapy is used (see Chapter 89) and potentially reversible suppression in the setting of alkylating agent chemotherapy (see Chapter 88). Extensive endometriosis may compromise ovarian function, as might mumps-related oophoritis. Ovarian tumors rarely destroy enough ovarian tissue to cause amenorrhea, but granulosa cell tumors, which produce excess estrogen, and arrhenoblastomas, which synthesize excess androgen, may be responsible for amenorrhea.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), originally described as the Stein-Leventhal syndrome in 1935, is a well-recognized cause of amenorrhea, characterized clinically by androgen excess and oligomenorrhea or amenorrhea. It is present in approximately 6% to 8% of women of reproductive age and has significance beyond gynecologic repercussions. Many but not all patients are obese with insulin resistance, sharing characteristics with metabolic syndrome, with potentially increased longterm cardiovascular risk. Similarly, many but not all patients have the bilaterally enlarged polycystic ovaries that give the syndrome its name (conversely, not all women with polycystic ovaries have the syndrome, although there is increasing evidence that women with polycystic ovarian morphology may have mild biochemical abnormalities along the PCOS spectrum). The pathophysiology of PCOS is an area of intense investigation, with abnormalities recognized at multiple levels in a complex interaction of gonadotropins, estrogens, androgens, and insulin.

Biochemical features include androgen elevation, reduced sex hormone-binding globulins, elevated LH levels (without a midcycle surge), low normal FSH levels, and hyperinsulinemia. Insulin resistance is common and may play an important role in perpetuating the disease; hyperinsulinemia appears to trigger excessive ovarian production of testosterone and also inhibits hepatic synthesis of sex hormone-binding globulins. Treatment to correct hyperinsulinemia, either through insulin-sensitizing medications or with weight loss, causes many of the biochemical features of the disease to revert toward normal.

Diagnosis of PCOS had been primarily clinical, based on a 1990 National Institutes of Health consensus conference that established chronic anovulation and androgen excess (commonly manifested as hirsutism or acne) as the primary diagnostic criteria, but these were revised in a 2003 Rotterdam consensus conference to include polycystic ovaries on ultrasound. Two out of the three criteria (oligo- and/or anovulation, clinical and or biochemical signs of hyperandrogenism, and polycystic ovaries) must be present, and other causes of androgen excess, including hyperprolactinemia, late-onset congenital adrenal hyperplasia (CAH), and androgen-secreting tumor, need to be ruled out. An early-morning 17-hydroxyprogesterone drawn during the follicular phase that is less than 2 ng/mL excludes CAH.

Uterine Pathology

Endometrial scarring may occur as a consequence of radiation therapy, septic abortion, or overly vigorous curettage. Adhesions can obliterate the uterine cavity (Asherman syndrome). Similarly, cervical trauma can result in scarring.

DIFFERENTIAL DIAGNOSIS (19)

Table 112-1 lists the causes of secondary amenorrhea, distinguishing among hypothalamic, pituitary, ovarian, and uterine etiologies. In one representative series of patients with secondary amenorrhea, hypothalamic dysfunction accounted for 30% of cases, PCOS for 30%, pituitary disease (mostly prolactinomas) for 15%, ovarian failure for 12%, and uterine problems for about 5%.

TABLE 112-1 Important Causes of Amenorrhea

Hypothalamic Dysfunction
	Mild
		Situational stress
		Dieting, particularly dietary fat restriction
		Concurrent illness
		Celiac disease
		Increased exercise
		Drugs (phenothiazines, oral contraceptives)
		Idiopathic
	Marked
		Anorexia nervosa with severe weight loss
		Serious emotional stress or psychopathology
		Serious concurrent illness
		Competitive excessive exercise
		Excess androgen, prolactin, or cortisol
		Idiopathic
Pituitary Disease
	Prolactinoma
	Other pituitary neoplasm
	Empty sella syndrome
	Pituitary infarction (Sheehan syndrome)
	Granulomatous disease (sarcoidosis)
	Hemochromatosis
Ovarian
	Menopause
	Polycystic ovary syndrome (may have hypothalamic etiology)
	Primary ovarian insufficiency (idiopathic, autoimmune disease, radiation therapy, chemotherapy, endometriosis, oophoritis, FMR1 premutation)
	FSH resistance or other genetic mutation
Uterine
	Obliteration of uterine cavity by intrauterine scarring and synechiae formation—Asherman syndrome (overly vigorous curettage, septic abortion, radiation)
	Cervical scarring with resultant os closure
Endocrinopathies
	Thyroid disease
	Cushing syndrome
	Hyperandrogenism
Pregnancy