Pregnancy is direct evidence of ovulation. Patients who do not ovulate cannot conceive without assistance. Ovulatory function requires the integration of many normally functioning systems. Normal thyroid function, normal insulin action, normal adrenal function and normal hypothalamic-pituitary function are all required for ovulation. When these systems are disrupted, follicular function is altered and ovulation becomes disrupted.
Normal, regular menstrual cycles usually reflect ovulatory cycles. Indeed, 95% of regular menstrual cycles are ovulatory (34). If cycles are irregular, the patient is most likely not ovulating, obviously a cause of infertility. Patients who do not ovulate and have polycystic ovarian syndrome may also have other associated findings of the disorder including insulin resistance, androgen excess, acanthosis nigricans and obesity. A thorough discussion of the pathophysiology, diagnosis and treatment of anovulation associated with the polycystic ovarian syndrome is the subject of chapter 6 in this volume and will only be mentioned in a cursory discussion herein.
Anovulation alone is not associated with any physical findings. Patients will have abundant, thin cervical mucus most of the time. This is the result of continuous, unopposed estrogen. In those whose have elevated androgens, hirsutism may be present. Acanthosis nigricans may also be found in the neck, in the axilla, and underneath the breasts.
Anovulation is diagnosed by a serum progesterone measurement less than 3 ng/ml drawn at least 4 days prior to a menstrual bleed. Proliferative endometrium on an endometrial biopsy performed during the week prior to a menstrual cycle is also diagnostic of anovulation. Finally, a basal body temperature chart revealing no biphasic increase in temperature is diagnostic of anovulation in 80% of cases; 20% of women with a monophasic basal body temperature will actually ovulate (35,36).
Ovulation may be stimulated in many women by administering clomiphene citrate. Clomiphene citrate is a serum estrogen receptor modulator which increases pituitary secretion of LH and FSH. When given to anovulatory women, the gonadotropins stimulate follicular development. The follicle continues to develop normally and feeds back to signal the pituitary that the oocyte is mature and an LH surge is needed. The so-called "ovarian clock" is restored and ovulation may be timed by monitoring urinary LH concentrations. Clomiphene successfully induces ovulation in 85% of women, although pregnancy rates are lower than 65% (37,38). When clomiphene is unsuccessful, gonadotropins may directly stimulate the ovarian follicle to develop and chorionic gonadotropin may be administered to simulate the LH surge and result in ovulation.
More recently, patients with polycystic ovarian disease have been treated with insulin sensitizing agents, particularly metformin (39,40). Although the precise mechanism whereby these agents result in ovulation is unknown, approximately 34% of women ovulated while on metformin versus 4% with placebo (even though insulin resistance could not be documented in all patients) (41).
Because women with ovarian failure also fail to ovulate, it is important to determine the cause of anovulation before beginning therapy.