(See also Overview of Infertility.)
Etiology of Ovulatory Dysfunction
Chronic ovulatory dysfunction in premenopausal women is most commonly caused by
Polycystic ovary syndrome (PCOS)
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
Women with ovulatory dysfunction may have amenorrhea or abnormal uterine bleeding.
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 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
≥ 35 kg/m2
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).
Letrozole
Letrozoleletrozole2clomiphene for causes of anovulation other than PCOS, but it appears to be at least as effective.
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
Clomiphene is most effective when the cause is polycystic ovary syndrome (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).
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 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
insulin-resistant, as many patients with PCOS are. However, clomiphene alone is more effective than metformin4). 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.
> 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 approximately 50% (5).
After gonadotropin therapy, 10 to 30% of successful pregnancies are multiple.
Ovarian hyperstimulation syndrome occurs in 10 to 20% of patients (6); ovaries can become massively enlarged, and intravascular fluid volume shifts into the peritoneal space, causing potentially life-threatening ascites and hypovolemia. (See also American Society for Reproductive Medicine: Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: A guideline (2016).)
Treatment of the underlying disorder
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.
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.
