Abnormal secretion of GnRH accounts for one-third of patients with amenorrhea (113). Chronic disease, malnutrition, stress, psychiatric disorders, eating disorders, and exercise inhibit GnRH pulses, thus altering the menstrual cycle (Table 30.5). Other hormonal systems that produce excess or insufficient hormones can cause abnormal feedback and adversely affect GnRH secretion. In hyperprolactinemia, Cushing disease (excess ACTH), and acromegaly (excess GH), excess pituitary hormones are secreted that inhibit GnRH secretion. It is uncommon to have functional hypothalamic amenorrhea without a secondary cause. Prognosis for recovery is better if the precipitating cause of the amenorrhea can be reversed (114).
When the decrease in GnRH pulsatility is severe, amenorrhea results. With less severe alterations in GnRH pulsatility, anovulation and oligomenorrhea can occur. The pulsatile secretion of GnRH is modulated by interactions with neurotransmitters and peripheral gonadal steroids. Endogenous opioids, corticotropin-releasing hormones (CRH), melatonin, and α-aminobutyric acid (GABA) inhibit the release of GnRH, whereas catecholamines, acetylcholine, and vasoactive intestinal peptide stimulate GnRH pulses. Dopamine and serotonin have variable effects (115).
Decreased leptin levels are associated with hypothalamic amenorrhea, regardless of whether it is caused by exercise, eating disorders, or idiopathic factors (116,117). Leptin is a hormone secreted by adipocytes that is involved in energy hemostasis. Receptors are found in the hypothalamus and bone, making it an excellent candidate for a modulator of menstrual function and bone mass. Levels correlate with nutritional changes and body mass index. Administration of leptin to women with hypothalamic amenorrhea increased levels of LH, estradiol, insulinlike growth factor-1 (IGF-1), and thyroid hormone. Ovulation and increased bone mass occurred in these patients (117). Weight loss occurring with leptin administration limits the utility of using leptin as a therapeutic agent.
Table 30.5 Abnormalities Affecting Release of Gonadotropin-Releasing Hormone a Severity of the condition determines estrogen status—the more severe, the more likely to manifest as hypoestrogenism.
amenorrhea. Patients attempt to maintain their low body weight by food restriction, laxative abuse, and intense exercise. This is a life-threatening disorder with a mortality rate as high as 9%. Amenorrhea may precede, coincide, or follow the weight loss. Multiple hormonal patterns are altered. The 24-hour patterns of FSH and LH may show constantly low levels as seen in childhood or increased LH pulsatility during sleep consistent with the pattern seen in early puberty. Hypercortisolism is present despite normal ACTH levels, and the ACTH response to CRH administration is blunted. Circulating triiodothyronine (T3) is low, yet circulating inactive reverse T3 concentrations are high (118). Patients may develop cold and heat intolerance, lanugo hair, hypotension, bradycardia, and diabetes insipidus. They may have yellowish discoloration of the skin resulting from elevated levels of serum carotene caused by altered vitamin A metabolism.
Binge eating is associated with bulimia consisting of vomiting, laxative abuse, and diuretics to control weight. Signs of bulimia include tooth decay, parotid gland hypertrophy (chipmunk jowls), hypokalemia, and metabolic alkalosis (119).