Women with chronic anovulation who have low or absent estrogen production and do not experience withdrawal bleeding after progestogen treatment usually have hypogonadotropic hypogonadism due to disease of either the pituitary or the central nervous system.

Isolated hypogonadotropic hypogonadism associated with defects of smell (olfactory bulb defects) is known as the Kallmann syndrome, which is due to a single gene defect in the X-linked KAL gene. Affected women are sexually infantile and have a defect in the synthesis and/or release of GnRH.

Hypothalamic lesions that impair GnRH production and cause hypogonadotropic hypogonadism include craniopharyngioma, germinoma (pinealoma), glioma, Hand-Schu"ller-Christian disease, teratomas, endodermal-sinus tumors, tuberculosis, sarcoidosis, and metastatic tumors that cause suppression or destruction of the hypothalamus. Central nervous system trauma and irradiation can also cause hypothalamic amenorrhea and deficiencies in secretion of growth hormone, adrenocorticotropic hormone (ACTH), vasopressin, and thyroid hormone. Rare, autosomal recessive defects in the GnRH receptor have also been described.

More commonly, gonadotropin deficiency leading to chronic anovulation is believed to arise from functional disorders of the hypothalamus or higher centers. A history of a stressful event in a young woman is frequent. Gonadotropin and estrogen levels are in the low to low-normal range as compared with normal women in the early follicular phase of the cycle. In addition, rigorous exercise, such as jogging or ballet, and diets that result in excessive weight loss may lead to chronic anovulation, particularly in girls with a history of prior menstrual irregularity. The amenorrhea in these women does not appear to be a result of weight loss alone but a combination of a decrease in body fat and chronic stress. An extreme form of weight loss with chronic anovulation occurs in anorexia nervosa. In anorexia nervosa amenorrhea can precede, follow, or coincide with weight loss.

In addition, chronic debilitating diseases such as end-stage kidney disease, malignancy, inflammatory bowel disease, and malabsorption can lead to hypogonadotropic hypogonadism via a hypothalamic mechanism.

Treatment of chronic anovulation due to hypothalamic disorders includes ameliorating the stressful situation, decreasing exercise, and correcting weight loss, as appropriate. These women are susceptibleto the development of osteoporosis; estrogen replacement therapy is recommended to induce and maintain normal secondary sexual characteristics and prevent bone loss in those who do not desire pregnancy, and gonadotropin or gonadorelin therapy is indicated when pregnancy is desired. When appropriate, therapy is directed at the primary disease of the hypothalamus.

Disorders of the pituitary can lead to the estrogen-deficient form of chronic anovulation by at least two mechanisms - direct interference with gonadotropin secretion by lesions that either obliterate or interfere with the gonadotrope cells (chromophobe adenomas, Sheehan’s syndrome) or inhibition of gonadotropin secretion in association with excess prolactin (prolactinoma). Pituitary tumors may secrete no hormone, one hormone, or more than one hormone. Prolactin levels are elevated in 50 to 70% of patients with pituitary tumors, either because of prolactin secretion by the tumor itself (in the case of prolactinomas) or because the tumor mass interferes with the normal hypothalamic inhibition of prolactin secretion.

Prolactin excess associated with low levels of LH and FSH constitutes a specific subtype of hypogonadotropic hypogonadism. One-tenth or more of amenorrheic women have increased levels of prolactin, and more than half of women with both galactorrhea and amenorrhea have elevated prolactin levels. The amenorrhea is most often associated with decreased or absent estrogen production, but prolactin-secreting tumors on occasion are associated with normal ovulatory menses or chronic anovulation with estrogen present. In the latter half of pregnancy, prolactin-secreting pituitary tumors may expand, leading to headaches, compression of the optic chiasm, bitemporal hemianopia, and blindness. Therefore, before inducing ovulation for the purposes of achieving pregnancy, it is mandatory to exclude the presence of a pituitary tumor.