Aromatase inhibitors, a new option for inducing ovulation
This class of drugs may boost the pregnancy rate in selected populations
IN THIS ARTICLE
Would an AI help her conceive?
Most of the data on successful treatment with clomiphene citrate come from anovulatory women with PCOS in whom anovulation is the main cause of infertility. Evidence is weaker when the patient is ovulatory and has unexplained or endometriosis-associated infertility.32
A recent nonrandomized, controlled study that included women with a medical history comparable to R.C.’s found treatment with clomiphene citrate to significantly reduce the chance of pregnancy, compared with timed intercourse without clomiphene or other forms of ovarian stimulation, following conservative laparoscopic surgery for their endometriosis.33 We believe that clomiphene citrate is in-appropriate in women with endometriosis-related infertility—and may activate underlying endometriotic lesions.
For R.C., treatment with an AI is a viable option, particularly in light of recent data showing that the aromatase enzyme is expressed in endometriotic lesions.34 An AI could also enhance conception by further suppressing endometriosis through its effects on circulating estrogen levels and local estrogen production. This is an unproven extrapolation that seems scientifically appropriate to us, but needs confirmation by randomized clinical trials.
CASE 4 Woman with unexplained—and uninvestigated—infertility
E.D., 31 years old, has been trying to conceive for 1 year. Neither she nor her husband has undergone any study of their infertility problem.
Would empiric treatment with an AI be appropriate?
No treatment should begin until the patient and her partner have undergone the basic workup (TABLE 3). If a specific cause of infertility is determined, the patient should be treated accordingly. If no explanation for the infertility can be found, or anovulation is the likely cause, empirical ovarian stimulation with timed intercourse or intrauterine insemination is reasonable, provided:
- semen analysis is within normal limits
- ovarian function is present—i.e., the patient is expected to ovulate in response to ovarian stimulation
- at least one tube is patent and functional
- uterus has no serious abnormalities.
If ovarian stimulation fails to trigger ovulation or pregnancy, consider the options listed in TABLE 4
TABLE 3
Basic infertility workup
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TABLE 4
When ovarian stimulation fails, next step depends on several variables
| LEVEL OF FAILURE | CLOMIPHENE CITRATE | AROMATASE INHIBITORS |
|---|---|---|
| 1–No ovulation | Is indication appropriate? Neither clomiphene citrate nor AIs are appropriate for hypothalamic/hypopituitary anovulation or ovarian failure Is severe insulin resistance present? If so, consider insulin sensitizers and encourage exercise, dietary changes, and weight loss | |
| Other options: Change to AI or retry clomiphene citrate in conjunction with an insulin sensitizer. If treatment fails after 3 to 6 additional cycles, consider an injectable gonadotropin | Other options: Try adding an insulin sensitizer. If treatment fails after 3 to 6 additional cycles, consider an injectable gonadotropin | |
| 2–Ovulation but no pregnancy | Was another cause of infertility (besides ovulatory dysfunction) overlooked? Investigate further, if necessary Options: Consider AIs before injectable gonadotropins, especially when there is evidence, with clomiphene citrate, of a persistent antiestrogenic effect, such as thin endometrium around the time of ovulation; endometriosis; or unexplained infertility. Move to gonadotropins if AIs fail | |
Minimal adverse effects
AIs are generally well tolerated. The most common adverse effects are hot flushes, GI disturbances (nausea and vomiting), and leg cramps. In clinical trials involving postmenopausal women with breast cancer who were taking an AI, very few withdrew because of drug-related adverse effects.35 Those women took an AI on a daily basis over several months. Fewer adverse effects would be expected among usually healthy younger women administered a short course (a few days) for ovarian stimulation. In addition, our clinical experience has been that fewer women experience side effects such as mild hot flushes and symptoms similar to premenstrual syndrome when taking an AI, compared with clomiphene citrate.3-9
When any medication is given during pregnancy, there are concerns about its effects. Drugs used to induce ovulation are no exception. In fact, clomiphene citrate is classified as pregnancy category X—a fact frequently overlooked by treating physicians. As for AIs, recent studies found no evidence of teratogenicity or clastogenicity in animal embryos when anastrozole was given. The picture is murkier for letrozole.
