2014 Update on Fertility

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients.

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.