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drome in males (see Chapter 37). Patients do not progress through normal puberty and have low and nonpulsatile LH and FSH levels. However, they can have normal stature, female karyotype, and anosmia. The disorder is caused by a failure of olfactory lobe development and GnRH deficiency. Primary amenorrhea can also be caused by a congenital malformation of reproductive tract structures originating from the mullerian duct, including the absence or obstruction of the uterus, cervix, or upper vagina.

Secondary amenorrhea is the cessation of menstruation for longer than 6 months. Pregnancy, lactation, and menopause are common physiological causes of secondary amenorrhea. Other causes are premature ovarian failure, polycystic ovarian syndrome, hyperprolactinemia, and hypopituitarism.

Premature ovarian failure is characterized by amenorrhea, low estrogen levels, and high gonadotropin (LH and FSH) levels before age 40. The symptoms are similar to those of menopause, including hot flashes and an increased risk of osteoporosis. The etiology is variable, including chromosomal abnormalities,- lesions resulting from irradiation, chemotherapy, or viral infections,- and autoimmune conditions.

Polycystic ovarian syndrome, also called Stein-Leventhal syndrome, is a heterogeneous group of disorders characterized by amenorrhea or anovulatory bleeding, an elevated LH/FSH ratio, high androgen levels, hirsutism, and obesity. Although the etiology is unknown, the syndrome may be initiated by excessive adrenal androgen production, during puberty or following stress, that deranges the hypo-thalamic-pituitary axis secretion of LH. Androgens are converted peripherally to estrogens and stimulate LH release. Excess LH, in turn, increases ovarian stromal and thecal androgen production, resulting in impaired follicular maturation. The LH-stimulated ovaries are enlarged and contain many small follicles and hyperplastic and luteinized theca cells (the site of LH receptors). The elevated plasma androgen levels cause hirsutism, increased activity of sebaceous glands, and clitoral hypertrophy, which are signs of virilization in females.

Hyperprolactinemia is also a cause of secondary amenorrhea. Galactorrhea, a persistent milk-like discharge from the nipple in nonlactating individuals, is a frequent symptom and is due to the excess prolactin (PRL). The etiology of hyperprolactinemia is variable. Pituitary prolactinomas account for about 50% of cases. Other causes are hypo-thalamic disorders, trauma to the pituitary stalk, and psy-chotropic medications, all of which are associated with a reduction in dopamine release, resulting in an increased PRL secretion. Hypothyroidism, chronic renal failure, and hepatic cirrhosis are additional causes of hyperprolactine-mia. In some forms of hypothyroidism, increased hypothalamic thyrotropin-releasing hormone (TRH) is thought to contribute to excess PRL secretion, as experimental stud ies reveal that exogenous TRH increases the secretion of PRL. The mechanism by which elevated PRL levels suppress ovulation is not entirely clear. It has been postulated that PRL may inhibit GnRH release, reduce LH secretion in response to GnRH stimulation, and act directly at the level of the ovary by inhibiting the action of LH and FSH on follicle development.

Oligomenorrhea can be caused by excessive exercise and by nutritional, psychological, and social factors. Anorexia nervosa, a severe behavioral disorder associated with the lack of food intake, is characterized by extreme malnutrition and endocrine changes secondary to psychological and nutritional disturbances. About 30% of patients develop amenorrhea that is not alleviated by weight gain. Strenuous exercise, especially by competitive athletes and dancers, frequently causes menstrual irregularities. Two main factors are thought to be responsible: a low level of body fat, and the effect of stress itself through endorphins that are known to inhibit the secretion of LH. Other types of stress, such as relocation, college examinations, general illness, and job-related pressures, have been known to induce some forms of oligomenorrhea.

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