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Ovulatory Dysfunction

By

Robert W. Rebar

, MD, Western Michigan University Homer Stryker M.D. School of Medicine

Reviewed/Revised Feb 2024
View PATIENT EDUCATION

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 by measurement of hormone levels or serial pelvic ultrasonography. Treatment is usually induction of ovulation with clomiphene or other medications.

Etiology of Ovulatory Dysfunction

Chronic ovulatory dysfunction in premenopausal women is most commonly caused by

But it has many other causes, including

  • Hyperprolactinemia

  • Hypothalamic-pituitary dysfunction (most commonly, functional hypothalamic amenorrhea)

  • Other conditions that can cause anovulation (eg, diabetes, hypo- or hyperthyroidism, depression, certain antidepressants, obesity, excessive exercise, excessive weight loss, use of medications that contain estrogens or progestins)

Symptoms and Signs of Ovulatory Dysfunction

Diagnosis of Ovulatory Dysfunction

  • Menstrual history

  • Home ovulation testing kits

  • Sometimes basal body temperature monitoring

  • Measurement of urinary or serum hormones or ultrasonography

Anovulation is often apparent based on the menstrual history.

Measuring daily morning body temperature Overview of Infertility 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 or 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).

Treatment of Ovulatory Dysfunction

  • Treatment of the underlying disorder

  • Letrozole or clomiphene

  • Possibly metformin if body mass index is 35 kg/m2

  • Gonadotropins if clomiphene is ineffective

Ovulation is induced with hormonal or metabolic medications. Treatments have been most extensively studied in patients with PCOS, a common etiology of ovulatory dysfunction (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 ).

Letrozole

Letrozole, an aromatase inhibitor, rather than clomiphene is preferred by many clinicians. Letrozole has a much shorter half-life in plasma than clomiphene. Evidence indicates that in women with obesity and PCOS, letrozole is more likely to induce ovulation than clomiphene, and that this effect may also occur in women with PCOS without obesity (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 ). No evidence indicates that letrozole is more effective than clomiphene for causes of anovulation other than PCOS, but it appears to be at least as effective.

Letrozole is started between the third and fifth 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.

Clomiphene

Chronic anovulation that is not due to hyperprolactinemia may also be treated with the antiestrogen clomiphene citrate.

Clomiphene is most effective when the cause is polycystic ovary syndrome Polycystic Ovary Syndrome (PCOS) Polycystic ovary syndrome is a clinical syndrome typically characterized by anovulation or oligo-ovulation, signs of androgen excess (eg, hirsutism, acne), and multiple ovarian cysts in the... read more Polycystic Ovary Syndrome (PCOS) (PCOS). Clomiphene 50 mg orally once a day is started between the third and fifth 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% (3 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 ).

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 approximately 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.

Metformin

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 (4 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.

Exogenous gonadotropins

For all women with ovulatory dysfunction that does not respond to letrozole or clomiphene, 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 third to fifth 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

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

Treatment of the underlying disorder

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 United States, either letrozole or clomiphene is the first medication used to treat functional hypothalamic amenorrhea, followed by exogenous gonadotropins, if ovulation induction with either oral agent is unsuccessful.

Treatment references

  • 1. Teede HJ, Tay CT, Laven JJE, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447-2469. doi:10.1210/clinem/dgad463

  • 2. 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. doi:10.1056/NEJMoa1313517

  • 3. Gysler M, March CM, Mishell DR Jr, Bailey EJ: A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 37(2):161-167, 1982. doi:10.1016/s0015-0282(16)46033-4

  • 4. 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

  • 5. White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81(11):3821-3824. doi:10.1210/jcem.81.11.8923819

  • 6. Schirmer DA 3rd, Kulkarni AD, Zhang Y, Kawwass JF, Boulet SL, Kissin DM. Ovarian hyperstimulation syndrome after assisted reproductive technologies: trends, predictors, and pregnancy outcomes. Fertil Steril. 2020;114(3):567-578. doi:10.1016/j.fertnstert.2020.04.004

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 in most women, usually with letrozole or clomiphene.

Drugs Mentioned In This Article

Drug Name Select Trade
Clomid, Serophene
Femara
Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet, RIOMET ER
Novarel, Ovidrel, Pregnyl
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NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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