At least 80% or more of gynecologic endocrine disorders result from chronic anovulation. Women with chronic anovulation fail to ovulate spontaneously but may ovulate with appropriate therapy. The ovaries of such women do not secrete estrogen in a normal cyclic pattern. It is clinically useful to differentiate those women who produce enough estrogen to have withdrawal bleeding after progestogen therapy from those who do not; the latter often have hypothalamic-pituitary dysfunction.

Chronic Anovulation with Estrogen Present

This disorder is most commonly caused by polycystic ovarian syndrome, which is characterized by infertility, hirsutism, obesity, insulin resistance, and amenorrhea or oligomenorrhea. When spontaneous uterine bleeding occurs in women with PCOS, it is unpredictable as to time of onset, duration, and amount; on occasion the bleeding can be severe.

PCOS (polycystic ovarian syndrome), as originally described by Stein and Leventhal, was characterized by enlarged, polycystic ovaries, but it is now known to be associated with a variety of pathologic findings in the ovaries, only some of which result in enlargement and none of which are pathognomonic. The most common finding is a white, smooth, sclerotic ovary with a thickened capsule, multiple follicular cysts in various stages of atresia, a hyperplastic theca and stroma, and rare or absent corpora albicans. Other ovaries have hyperthecosis in which the ovarian stroma is hyperplastic and may contain lipid-laden luteal cells. Thus, the diagnosis of PCOS is a clinical one, based on the coexistence of chronic anovulation and varying degrees of androgen excess. The fundamental defect that causes PCOS is unknown, and it is likely to have several distinct causes.

In most women with PCOS, menarche occurs at the expected time, but oligomenorrhea ensues after a variable period. Signs of androgen excess (hirsutism) usually become evident soon after menarche. One scenario suggests that this disorder originates as an exaggerated adrenarche in obese girls. The combination of elevated levels of adrenal androgens and obesity leads to increased formation of extraglandular estrogen. This estrogen exerts a positive feedback on LH secretion and negative feedback on FSH secretion, resulting in a ratio of LH to FSH levels in plasma that is characteristically greater than 2. The increased LH levels can then lead to hyperplasia of the ovarian stroma and theca cells and increased androgen production, which in turn provides more substrate for peripheral aromatization and perpetuates the chronic anovulation. In the advanced stage of the disorder, the ovary is the major site of androgen production, but the adrenal may continue to secrete excess androgen as well. Ovarian follicles from women with PCOS have low aromatase activity, but normal aromatase can be induced by treatment with FSH. An association exists between PCOS/hyperthecosis, virilization, acanthosis nigricans, and insulin resistance; in the ovary, insulin may interact via the insulin-like growth factor receptors to enhance androgen synthesis in insulin-resistant states. Women with PCOS have an increased incidence of impaired glucose tolerance and type 2 diabetes mellitus.

Treatment

Treatment of PCOS is directed toward interrupting the self-perpetuating cycle and can be accomplished in several ways, such as by decreasing ovarian androgen secretion (by wedge resection or the use of oral contraceptive agents), decreasing peripheral estrogen formation (by weight reduction), or enhancing FSH secretion [by administration of clomiphene, human menopausal gonadotropin (hMG), GnRH (gonadorelin) by portable infusion pump, or purified FSH (urofollitropin )]. The choice of therapy depends on the clinical findings and the needs of the patient. An attempt at weight reduction is appropriate in all who are obese. If the woman is not hirsute and does not desire pregnancy, periodic withdrawal menses can be induced with medroxyprogesterone acetate 10 days per month; such treatment prevents the development of endometrial hyperplasia. If the woman is hirsute and does not desire pregnancy, the ovarian (and possibly the adrenal) component of androgen production can be suppressed with combined estrogen-progestogen oral contraceptive agents. Combined oral contraceptives are also indicated if prolonged or excessive menstrual bleeding is present. Once androgen excess is controlled, treatment of previously existing hair growth by shaving, depilatories, or electrolysis may be indicated. If pregnancy is desired, ovulation must be induced. Insulin-sensitizing drugs, such as metformin and the thiazolidinediones, improve fertility in women with PCOS. Clomiphene promotes ovulation in three-fourths of cases, or ovulation can be induced with hMG, urofollitropin, or gonadorelin. Pretreatment with GnRH analogues prior to use of hMG, urofollitropin, or gonadorelin may improve the rates of ovulation and pregnancy. Women with PCOS are at increased risk of ovarian hyperstimulation after treatment with gonadotropins. They also experience increased rates of spontaneous abortion. An alternative therapy is ovarian drilling by laser or cautery performed at laparoscopy when hormonal therapy is not effective; however, the procedure is associated with a high incidence of ovarian adhesions.

Chronic anovulation with estrogen present may also occur with tumors of the ovary. These include granulosa-theca cell tumors, Brenner tumors, cystic teratomas, mucous cystadenomas, and Krukenberg tumors. Such tumors can either secrete excess estrogen themselves or produce androgens that are aromatized in extraglandular sites. Chronic anovulation and the clinical features of PCOS result. Occasionally, areas of the ovary not involved with tumors show the characteristic histologic changes of PCOS. Other causes of chronic anovulation with estrogen present include adrenal production of excess androgen (usually adult-onset adrenal hyperplasia due to partial 21-hydroxylase deficiency) and hypothyroidism.