Central nervous system – hypothalamus

Stress is a common cause of menstrual dysfunction, and may lead to amenorrhea if the stress is severe. The exact mechanism of how stress diminishes GnRH release is not clear. It has been observed that the increase in both catechol estrogens and β-endorphins associated with stress appears to inhibit LH (and probably FSH) release, most likely by altering the function of the neurotransmitters responsible for the normal episodic release of GnRH. Amenorrhea results when the low gonadotropin levels fail to stimulate sufficient estradiol production to cause endometrial proliferation.

Strenuous exercise also causes an increase in β-endorphins and catechol estrogens. However, exercise amenorrhea appears to be to limited to runners. Swimming, even when strenuous, is much less likely to cause amenorrhea, suggesting that weightbearing plays a role in limiting gonadotropin secretion. Menstruation resumes when the stress ceases.

Weight loss can cause amenorrhea in some women. This is presumably by the same “stress” response mechanism as noted above. When the total bodyweight diminishes, amenorrhea persists, even if the weight remains constant. The hypothalamus is responsive to fluctuations of weight as well as the total bodyweight and controls reproductive function. The pituitary and the remainder of the reproductive tract remain normal.

A special case of weight loss is anorexia nervosa. In this condition, both stress and weight loss combine to stop normal hypothalamic GnRH release. Amenorrhea may also occur in bulimia nervosa in which the BMI may remain normal, supporting the idea that weight loss is not the sole cause. If severe weight loss occurs and the patient weighs less than 25% of ideal bodyweight, an abnormal gonadotropin response to GnRH has been observed. This finding suggests that pituitary dysfunction also occurs in persons with anorexia nervosa when the weight loss becomes severe. Because anorexia nervosa is a psychiatric disorder, women with this disease should receive appropriate psychiatric treatment. Individuals with anorexia nervosa, as well as those with dietary weight loss, usually resume ovulatory menstrual cycles when they gain weight and reach a normal BMI.

Anatomic lesions in the brainstem or hypothalamus are an infrequent cause of secondary amenorrhea. Hypothalamic lesions include craniopharyngiomas, granulomatosis disease (tuberculosis and sarcoidosis), and sequelae of encephalitis. When these lesions are present, circulating gonadotropin and estradiol levels remain very low.

Phenothiazine derivatives, antihypertensive agents, and certain other drugs can produce amenorrhea without hyperprolactinemia, although usually prolactin levels are elevated with the use of these agents. Oral and injectable contraceptive steroids inhibit ovulation by acting on the hypothalamus to suppress GnRH as well as acting directly on the pituitary to suppress FSH and LH. In some individuals, this hypothalamic-pituitary suppression persists for several months after the discontinuation of steroid contraceptives, producing the syndrome termed “postpill amenorrhea.” Prolonged gonadotropin suppression is uncommon following discontinuation of the low doses of steroids present in currently used oral contraceptive formulations and does not last more than 6 months. The etiology of amenorrhea persisting more than 6 months after discontinuation of oral contraceptives is unrelated to their use. Amenorrhea after injection of depomedroxyprogesterone acetate (DMPA) may persist for a year or more after the last injection.

Functional hypothalamic amenorrhea

The general term functional hypothalamic amenorrhea (FHA) has been used to characterize secondary amenorrhea in women who do not ingest drugs, do not engage in strenuous exercise, are not undergoing environmental stress, have not lost weight, and do not have pituitary, ovarian or uterine abnormalities.

When sufficient gonadotropins are produced to maintain circulating estradiol levels above 40 pg/mL, the term hypothalamic-pituitary dysfunction has been used to characterize this disorder. When the estradiol levels fall below 40 pg/mL, the term hypothalamic-pituitary failure is used, indicating a more serious disorder. Serum estradiol levels above 40 pg/mL are usually sufficient to stimulate endometrial growth and sloughing of the endometrial tissue usually occurs when progesterone levels fall several days after exogenous progestins are last administered. The presence or absence of the withdrawal bleeding response to progesterone administration has also been used to differentiate between the two diagnostic categories of FHA instead of measurement of estradiol.

Piuitary lesions

Although most pituitary tumors secrete prolactin, some do not. However, they may impede the action of prolactininhibitory substance (dopamine) on the lactotrophs and thus result in mild elevations of prolactin. These tumors may cause secondary amenorrhea to occur without hyperprolactinemia. Chromophobe adenomas are the most common nonprolactin-secreting pituitary tumors. In addition, both basophilic (ACTH secreting) and acidophilic (growth hormone (GH) secreting) adenomas may not secrete prolactin.

Pituitary cells can become damaged or necrotic as a result of anoxia, thrombosis or hemorrhage. When pituitary cell destruction results from a hypotensive episode during pregnancy, the disorder is called Sheehan’s syndrome. When the disorder is unrelated to pregnancy, it is called Simmond’s disease. Diagnosing this cause of secondary amenorrhea is important because pituitary damage (unlike hypothalamic dysfunction) can be associated with decreased secretion of other pituitary hormones. Thus, individuals with pituitary lesions may have secondary hypothyroidism or adrenal insufficiency that seriously impairs their health, in addition to their decreased estrogen levels.

Ovarian factors

The ovaries may fail to secrete sufficient estrogen to produce endometrial growth if the follicles are damaged as a result of infection, interference with blood supply, chemotherapy, radiation or surgical depletion (e.g. bilateral cystectomies). Even without these etiologies, the ovaries may spontaneously stop producing sufficient estrogen to stimulate endometrial growth several years before the age of the physiologic menopause. When this condition occurs before the age of 40, the term premature ovarian failure (POF) is best used to describe the clinical entity. About 1% of women under the age of 40 years develop POF, and the incidence steadily increases from ages 15 to 39.