Ovulatory Dysfunction

Commonly, chronic anovulation that is not due to hyperprolactinemia is initially treated with the antiestrogen clomiphene citrate.

Clomiphene is most effective when the cause is polycystic ovary syndrome (PCOS). Clomiphene 50 mg orally once a day is started between the 3rd and 5th day after bleeding begins; bleeding may have occurred spontaneously or have been induced (eg, by progestin withdrawal). Clomiphene is continued for 5 days. Ovulation usually occurs 5 to 10 days (mean 7 days) after the last day of clomiphene; if ovulation occurs, menses follows within 35 days of the induced bleeding episode.

If menses does not occur, a pregnancy test is done. If the woman is not pregnant, the treatment cycle is repeated. The daily dose can be increased by up to 50 mg every cycle to a maximum of 200 mg/dose as needed to induce ovulation. Treatment is continued as needed for up to 4 ovulatory cycles. Most women who become pregnant do so by the fourth cycle in which ovulation occurs. Ovulation occurs in 75 to 80% of women treated with clomiphene, but the pregnancy rate is at most 40 to 50%.

Adverse effects of clomiphene include vasomotor flushes (10%), abdominal distention (6%), breast tenderness (2%), nausea (3%), visual symptoms (1 to 2%), and headaches (1 to 2%). Multifetal pregnancy Multifetal Pregnancy Multifetal pregnancy is presence of > 1 fetus in the uterus. Multifetal (multiple) pregnancy occurs in up to 1 of 30 deliveries. Risk factors for multiple pregnancy include Ovarian stimulation... read more (primarily twins) occurs in about 5%, and ovarian hyperstimulation syndrome occurs in ≤ 1%. Ovarian cysts are common. A previously suggested association between clomiphene taken for > 12 cycles and ovarian cancer has not been confirmed.

Clomiphene should not be given to women who are pregnant because, theoretically, it may cause genital birth defects.

Letrozole is an aromatase inhibitor that may be used instead of clomiphene. Letrozole has a much shorter half-life in plasma than clomiphene. Evidence indicates that in obese women with PCOS, letrozole (an aromatase inhibitor) is more likely to induce ovulation than clomiphene (1 Treatment references Ovulatory dysfunction is abnormal, irregular (with ≤ 9 menses/year), or absent ovulation. Menses are often irregular or absent. Diagnosis is often possible by menstrual history or can be confirmed... read more ). Data indicate that this effect may also occur in thin women with PCOS. No evidence indicates that letrozole is more effective than clomiphene for causes of anovulation other than PCOS.

Letrozole, like clomiphene, is started between the 3rd and 5th day after menstrual bleeding begins. Initially, women are given 2.5 mg orally once a day for 5 days. If ovulation does not occur, the dose can be increased by 2.5 mg every cycle to a maximum of 7.5 mg/dose.

The most common adverse effects of letrozole are fatigue and dizziness.

Letrozole should not be given to women who are pregnant because theoretically, it may cause genital birth defects.

For women with PCOS, metformin (750 to 1000 mg orally twice a day) may be a useful adjunct in inducing ovulation, particularly if the patient is insulin-resistant, as many patients with PCOS are. However, clomiphene alone is more effective than metformin alone and is just as effective as metformin and clomiphene together (2 Treatment references Ovulatory dysfunction is abnormal, irregular (with ≤ 9 menses/year), or absent ovulation. Menses are often irregular or absent. Diagnosis is often possible by menstrual history or can be confirmed... read more ). Metformin is not first-line therapy for women who have PCOS and want to become pregnant.

Metformin may be useful for women with a body mass index > 35 kg/m2 and should be considered for women with PCOS and glucose intolerance.

For all women with ovulatory dysfunction that does not respond to clomiphene (or letrozole, when used), human gonadotropins (ie, preparations that contain purified or recombinant follicle-stimulating hormone [FSH] and variable amounts of luteinizing hormone [LH]) can be used. Several IM and subcutaneous preparations with similar efficacy are available; they typically contain 75 IU of FSH activity with or without LH activity. They are usually given once a day, beginning on the 3rd to 5th day after induced or spontaneous bleeding; ideally, they stimulate maturation of 1 to 3 follicles, determined ultrasonographically, within 7 to 14 days.

Ovulation is typically triggered with human chorionic gonadotropin (hCG) 5,000 to 10,000 IU IM after follicle maturation; criteria for using hCG may vary, but typically, at least one follicle should be > 16 mm in diameter. Alternatively, a gonadotropin-releasing hormone (GnRH) agonist can be used to trigger ovulation, especially in women at high risk of ovarian hyperstimulation syndrome.

Although risk of ovarian hyperstimulation syndrome in women at high risk is lower when a GnRH agonist is used to trigger ovulation, it is safer to not trigger ovulation if women are at high risk of ovarian hyperstimulation syndrome or multifetal pregnancy. Risk factors for these problems include

When exogenous gonadotropins are used appropriately, > 95% of women treated with them ovulate, but the pregnancy rate is only 50 to 75%.

After gonadotropin therapy, 10 to 30% of successful pregnancies are multiple.

Ovarian hyperstimulation syndrome occurs in 10 to 20% of patients; ovaries can become massively enlarged, and intravascular fluid volume shifts into the peritoneal space, causing potentially life-threatening ascites and hypovolemia. (See also the American Society for Reproductive Medicine guideline Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: A guideline.)

Underlying disorders (eg, hyperprolactinemia Treatment Prolactinomas are noncancerous tumors made up from lactotrophs in the pituitary gland. The most common symptom of a prolactinoma is galactorrhea. Diagnosis is by measurement of prolactin levels... read more ) are treated.

If the cause is functional hypothalamic amenorrhea, gonadorelin acetate, a synthetic GnRH agonist given as a pulsatile IV infusion, can induce ovulation. Doses of 2.5- to 5.0-mcg boluses (pulse doses) regularly every 60 to 90 minutes are most effective. Gonadorelin acetate is unlikely to cause multifetal pregnancy.

Because gonadorelin is no longer available in the US, clomiphene citrate is the first drug used to treat functional hypothalamic amenorrhea, followed by exogenous gonadotropins, if ovulation induction with clomiphene is unsuccessful.