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Ovulatory Dysfunction

By Robert W. Rebar, MD, Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine

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Ovulatory dysfunction is abnormal, irregular (with ≤ 9 menses/yr), or absent ovulation. Menses are often irregular or absent. Diagnosis is often possible by history or can be confirmed by measurement of hormone levels or serial pelvic ultrasonography. Treatment is usually induction of ovulation with clomiphene or other drugs.

Etiology

Chronic ovulatory dysfunction in premenopausal women is most commonly caused by

But it has many other causes, including

Symptoms and Signs

Ovulatory dysfunction is suspected if menses are absent, irregular, or not preceded by symptoms, such as breast tenderness, lower abdominal bloating, or moodiness (collectively termed molimina).

Diagnosis

  • Menstrual history

  • Sometimes basal body temperature monitoring

  • Measurement of urinary or serum hormones or ultrasonography

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 h 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 ovarian follicle diameter and rupture (and should also 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 wk 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 (eg, PCOS).

Treatment

  • Clomiphene or letrozole

  • Possibly metformin if body mass index is 35

  • Gonadotropins if clomiphene is ineffective

Ovulation can usually be induced with drugs.

Clomiphene

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 PCOS. Clomiphene 50 mg po once/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.

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. 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.

Letrozole

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 po once/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.

Metformin

For women with PCOS, metformin (750 to 1000 mg po bid) 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. 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.

Exogenous gonadotropins

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 FSH and variable amounts of LH) can be used. Several IM and sc preparations with similar efficacy are available; they typically contain 75 IU of FSH activity with or without LH activity. They are usually given once/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

  • Presence of > 3 follicles > 16 mm in diameter

  • Preovulatory serum estradiol levels > 1500 pg/mL (or possibly > 1000 pg/mL) in women with several small ovarian follicles

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 Ovarian hyperstimulation syndrome.)

Treatment of the underlying disorder

Underlying disorders (eg, hyperprolactinemia) are treated.

If the cause is 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 q 60 to 90 min 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 hypothalamic amenorrhea, followed by exogenous gonadotropins, if ovulation induction with clomiphene is unsuccessful.

Treatment reference

Key Points

  • 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 for most women, usually with clomiphene citrate or letrozole.