2014 Update on Fertility

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.