Pφ

Amenorrhea caused by hypothalamic dysfunction probably represents a spectrum of related disorders including functional hypothalamic amenorrhea (FHA), amenorrhea in the female athlete, and amenorrhea associated with eating disorders. The precise mechanism of these disorders is not known, but all share a reduction in hypothalamic gonadotropin-releasing hormone (GnRH) production. FHA accounts for about 15% to 35% of cases of amenorrhea, making it one of the most common causes. The blunted GnRH release pattern leads to decreased FSH and LH but an increased FSH/LH ratio similar to that seen before puberty. Estradiol levels are also decreased, and patients are usually anovulatory. Leptin, an adipocyte hormone that acts as a satiety factor and a cofactor in the maturation of the reproductive system, has been implicated in the development of HA. Leptin can stimulate GnRH pulsatility and gonadotropin secretion and is decreased in patients across the spectrum of HA.

TP

Amenorrhea in the female athlete is part of the “female athlete triad,” which also includes disordered eating and osteoporosis. Elite athletes in sports such as gymnastics, diving, and marathon running, as well as ballet dancers, are particularly vulnerable to this triad. In these patients, body fat often is below the 10th percentile.

Patients with anorexia nervosa also have severely reduced body fat, and often their body weight is <85% of normal for age and height. These patients have a distorted body image, fear weight gain, and exist in a self-imposed starvation state. In addition to low body weight and wasting, they may also have bradycardia, hypothermia, constipation, and dry skin. Patients with bulimia may have normal weight and physical exam findings but can still have neuroendocrine abnormalities leading to irregular menses.

Dx

FHA can be related to strenuous exercise or poor nutrition without falling into either of the previous two categories but can also result from psychological stress. Often, these patients are high achievers with an impaired ability to cope with the stress of daily life and/or acutely stressful situations.

GnRH pulsatility cannot be measured, so LH pulsatility is used as a surrogate, and in clinical practice the FSH/LH ratio is used to assess problems with hypothalamic function. In HA, the FSH/LH ratio is >1 in the setting of hypoestrogenemia, although the absolute concentrations of both gonadotropins are decreased. In patients with FHA who have mild perturbations in the HPO axis, these lab data may be normal. In that case HA can be diagnosed when other causes of anovulation are ruled out and the history of amenorrhea coincides with increased physical or psychological stress.

Pφ

Hyperprolactinemia accounts for 15% to 30% of amenorrhea. About 50% of patients with elevated prolactin levels have evidence of a pituitary mass on MRI, and about 40% to 50% of these masses are prolactinomas. Under normal circumstances, prolactin release is under tonic inhibition by dopamine, but these tumors are able to function autonomously. They can be classified as microadenomas when <10 mm in diameter and as macroadenomas when >10 mm in diameter. The serum prolactin level can help physicians predict tumor size; microprolactinomas are more likely with prolactin levels <100 ng/mL, while higher values raise suspicion for a macroprolactinoma. This cutoff is not definitive, however. The precise mechanism of prolactin’s action on the menstrual cycle is not known.

TP

In addition to experiencing amenorrhea, patients with a prolactinoma often present with galactorrhea. This milky discharge can sometimes be expressed by the physician on breast exam. If the prolactinoma is large, it may cause headache, visual disturbances by compression on the optic chiasm, or other CNS perturbations. If the patient has a microprolactinoma, she will probably have normal visual fields and may have no CNS disturbances.

Dx

A serum prolactin level should be checked as a screening test for all women presenting with amenorrhea. Certain medications, including estrogen-containing OCPs, neuroleptics, tricyclic antidepressants, metoclopromide, methyldopa, and verapamil, can cause elevations in prolactin level. Prolactin can also be transiently elevated in response to stress, exercise, breast stimulation, or eating, and is elevated normally in pregnancy and during lactation. Prolactin is most reliably measured in the midmorning and in a fasting state. The test should be repeated under these ideal circumstances if the initial prolactin level is mildly or moderately elevated without an obvious cause. All patients with a confirmed elevation in prolactin level should have a dedicated pituitary MRI. If a macroprolactinoma is present, the patient’s other pituitary axes should be checked with FSH, LH, TSH, insulin-like growth factor 1 (IGF-1, a surrogate for growth hormone), and an 8:00 AM ACTH with cortisol.

Pφ

Pituitary adenomas, which are not prolactin-secreting, can also impact the menstrual cycle. Since prolactin release is under tonic inhibition by dopamine, anything that interrupts this inhibition can cause elevated prolactin and lead to abnormal menses. Most commonly, dopamine inhibition is blocked when a pituitary mass expands in such a way as to apply pressure to the infundibulum (the pituitary stalk). The dopaminergic neurons that inhibit prolactin release travel through this stalk, so their function is impaired when the stalk is compressed. Pituitary adenomas can also cause abnormal menses by compressing gonadotropin-releasing cells in the anterior pituitary.

TP

If an adenoma is impacting the menses by direct effects on the gonadotrophs, galactorrhea would not be expected. If the mass is a macroadenoma, the patient can have symptoms including headaches and visual changes. A macroadenoma may cause growth hormone deficiency, central hypothyroidism, and, rarely, central adrenal insufficiency. Because the adrenal axis is the most crucial for survival, this is the last axis to manifest dysfunction due to pituitary compression by a mass.

Dx

Serum prolactin level may be elevated in the setting of a pituitary adenoma that is not a prolactinoma, although the elevation is often not as pronounced; pituitary MRI should follow. If the patient has a macroadenoma with only mildly elevated prolactin levels and evidence that the adenoma is causing compression of the pituitary stalk and/or the pituitary itself, this is most likely a non-prolactin-producing macroadenoma. If the patient has a microadenoma with mildly elevated prolactin levels, further investigation may be necessary to determine the type of adenoma present. In either case, the patient requires evaluation of the other pituitary hormones, with measurement of FSH, LH, IGF-1, and TSH as well as a 24-hour urine free cortisol to assess the adrenal axis. In addition, the α-subunits of FSH and LH should be measured, because these are typically elevated in a “nonfunctioning” pituitary adenoma.

Pφ

Primary hypothyroidism is caused by decreased production of thyroid hormone by the thyroid gland, most often secondary to autoimmune destruction of the thyroid cells. Low circulating thyroid hormone levels lead to increased thyrotropin-releasing hormone (TRH) production by the hypothalamus and increased TSH release by the pituitary, but also act on lactotrophs to increase prolactin secretion. If the primary hypothyroidism persists, prolactin levels can rise significantly enough to cause menstrual irregularities.

TP

Patients may present with galactorrhea, as well as menstrual irregularities, if the prolactin level is high enough. Symptoms typical of hypothyroidism including weight gain, fatigue, constipation, cold intolerance, brittle nails, coarse and dry hair, and dry skin may also be experienced.

Dx

Because thyroid dysfunction is common in women, TSH is part of the routine testing done at initial screening for causes of amenorrhea. Patients with an elevated prolactin level should be tested for TSH level, if not already done, to determine whether hypothyroidism could be the cause for the prolactin elevation. The TSH will be elevated in hypothyroidism, with a low thyroid hormone (free T4) level.

Pφ

Primary hyperthyroidism results from overproduction of thyroid hormone by the thyroid gland. Most commonly this is due to Graves disease, an autoimmune process mediated by antibodies that bind to the TSH receptor and stimulate thyroid hormone release. The mechanism(s) causing irregular menses in hyperthyroid patients is not known.

TP

Patients with hyperthyroidism can present with weight loss, fatigue, irritability, impaired concentration, tachycardia, palpitations, diarrhea, heat intolerance, diaphoresis, hair loss, and warm, moist skin, and addition to amenorrhea.

Dx

As is the case with hypothyroidism, TSH level should be used as a screening tool for all women presenting with amenorrhea. Primary hyperthyroidism is diagnosed with an elevated free T4 and a low or undetectable TSH.

Pφ

Androgen excess accounts for over 30% of amenorrhea and up to 75% of anovulation and is most often caused by PCOS. In 1990 the National Institutes of Health (NIH) developed criteria for the diagnosis of PCOS that included chronic anovulation and clinical and/or biochemical signs of hyperandrogenism with exclusion of other etiologies. In 2003 the Rotterdam consensus conference amended the criteria to require two out of three of the following: oligo-ovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries with exclusion of other etiologies (i.e., CAH, androgen-secreting tumors, Cushing syndrome). Hyperinsulinemia does seem to play a major role in the pathogenesis of PCOS, with a prevalence of 50% to 60% in this population, compared with 10% to 25% in the general population. Also, increasing evidence points to a strong genetic component to disease development.

TP

In addition to experiencing amenorrhea, patients with PCOS may have physical signs of androgen excess such as acne and/or hirsutism. Patients with PCOS can have normal pubertal development and menarche but often experience irregular menses thereafter. Patients may be placed on OCPs for cycle regulation without further investigation into the cause of their irregular menses, since irregular cycles are not necessarily abnormal in the years following menarche. In some cases PCOS is not diagnosed until patients present for evaluation of amenorrhea or oligomenorrhea when they stop OCPs and are trying to conceive.

Dx

PCOS often can be diagnosed on clinical grounds in the setting of amenorrhea or oligomenorrhea, acne, and hirsutism. Additional information can be obtained through pelvic ultrasonography, which may demonstrate polycystic ovaries, although this is not required to make the diagnosis. Biochemical abnormalities associated with PCOS include elevated total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), insulin, and LH/FSH ratio. These are not present in all women with the syndrome, however, and some can be present in the absence of PCOS. Patients should be evaluated for other causes of anovulation. If these can be ruled out, and the clinical setting and additional tests suggest PCOS, the diagnosis can then be established.

Pφ

POI is the preferred term for a condition previously called premature menopause or premature ovarian failure. This condition is considered to be present when a woman under 40 years of age has had amenorrhea for ≥4 months and two FSH level measurements at least 1 month apart that are in the menopausal range. In 90% of cases, the cause for POI is unknown, but 46,XX POI occasionally occurs as part of a syndrome such as Fragile X or autoimmune polyendocrine syndrome. Spontaneous 46,XX POI affects approximately 1 in 100 women by 40 years of age. Two major mechanisms resulting in POI are follicle dysfunction and follicle depletion. The latter may be the result of inadequate primordial follicles in utero, accelerated use of available follicles, or autoimmune or toxic (i.e., chemotherapy, radiation, ovarian torsion) effects leading to destruction of follicles.

TP

The condition usually develops after normal puberty, menarche, and a period of regular menses. Most commonly, women progress to amenorrhea gradually with a prodrome of irregular menses, but the condition occasionally presents with an abrupt cessation of menses. In some women, POI presents when menses fail to resume after pregnancy or cessation of OCPs. Women may experience symptoms of estrogen deficiency such as hot flashes, night sweats, sleep disturbance, and dyspareunia. Not all patients have severe estrogen deficiency, however, so some women have no symptoms other than amenorrhea.

Dx

After pregnancy has been ruled out, FSH, TSH, and prolactin levels should be checked. If the FSH is elevated into the postmenopausal range, levels should be checked again in 1 month with an estradiol level measurement. Patients with POI that is not associated with a known syndrome should have a karyotype analysis, testing for gene mutations associated with Fragile X syndrome, and adrenal antibodies. Pelvic ultrasonography is also recommended. About 10% to 15% of patients will have a positive family history with a first-degree relative affected. These patients should be queried about a personal or family history of other components of the autoimmune polyglandular syndrome, including hypothyroidism, adrenal insufficiency, and hypoparathyroidism.