(See also Overview of Infertility.)
Chronic ovulatory dysfunction in premenopausal women is most commonly caused by
Polycystic ovary syndrome (PCOS)
But it has many other causes, including
Hypothalamic-pituitary dysfunction (most commonly, functional hypothalamic amenorrhea)
Other conditions that can cause anovulation (eg, diabetes, depression, certain antidepressants, excessive exercise, use of drugs that contain estrogens or progestins)
Anovulation is often apparent based on the menstrual history.
Measuring morning body temperature daily can help determine whether and when ovulation is occurring. However, this method is often inaccurate.
More accurate methods include
Home testing kits, which detect an increase in urinary luteinizing hormone (LH) excretion 24 to 36 hours before ovulation (requiring daily testing for several days around midcycle, usually beginning about or after cycle day 9)
Pelvic ultrasonography, which is used to monitor increases in ovarian follicle diameter and collapse of the follicle (monitoring should begin in the late follicular phase)
Measurement of serum progesterone and urinary pregnanediol glucuronide (a urinary metabolite of progesterone)
Serum progesterone levels of ≥ 3 ng/mL (≥ 9.75 nmol/L) or elevated levels of pregnanediol glucuronide in urine (measured, if possible, 1 week before onset of the next menstrual period) indicate that ovulation has occurred.
Intermittent or absent ovulation should prompt evaluation for disorders of the pituitary, hypothalamus, or ovaries (especially PCOS).
Ovulation can usually be induced with drugs.
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 (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.
Evidence indicates that in obese women with PCOS, letrozole (an aromatase inhibitor) is more likely to induce ovulation than clomiphene (1). Recent 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 has a much shorter half-life than clomiphene.
Letrozole, like clomiphene, is started between the 3rd and 5th day after 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). 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 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) 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.
1. Legro RS, Brzyski RG, Diamond MP, et al: Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 371:119-129, 2014.
2. Legro RS, Barnhart HX, Schlaff WD, et al: Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 356 (6):551–566, 2007. doi: 10.1056/NEJMoa063971.
The most common cause of ovulatory dysfunction in premenopausal women is PCOS; other causes include hypothalamic and pituitary dysfunction.
Diagnose ovulatory dysfunction based on menstrual history, results of pelvic ultrasonography, and/or measurement of serum progesterone and urinary pregnanediol glucuronide.
Induce ovulation in most women, usually with clomiphene citrate or letrozole.