Clinical Review

Aromatase inhibitors, a new option for inducing ovulation

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This class of drugs may boost the pregnancy rate in selected populations


 

References

Dr. Mitwally holds patents licensed to Serono for use of aromatase inhibitors for infertility treatment.

Dr. Casper has a licensing agreement with Ares-Serono for use of aromatase inhibitors in assisted reproduction.

CASE 1 Ovulation begins, but pregnancy does not follow

U.Y. is a 32-year-old woman who has been trying to conceive for 3 years. Her infertility is caused by anovulation associated with polycystic ovary syndrome (PCOS). All other variables are within physiologic limits—she has patent tubes and an unremarkable uterus, and her partner has a normal semen analysis.

She has undergone six cycles of treatment with clomiphene citrate, with ovulation documented each time by ultrasonography (US) and measurement of luteal-phase progesterone levels. Her endometrial thickness is 4 to 6 mm around the day of ovulation.

Would an aromatase inhibitor increase her chances of conceiving?

This patient is an excellent candidate for ovulation induction using an aromatase inhibitor (AI).

The primary reason? She is unlikely to benefit from an increased dosage of clomiphene citrate because the dosage that triggers ovulation is believed to be most appropriate—an increase above that level is not expected to improve the chance of pregnancy. Moreover, conception is less likely after more than six cycles of clomiphene citrate.1,2

In this article, we describe the induction of ovulation using AIs—a relatively new, and off-label, application (TABLES 1 and 2). The strategies presented here are suitable for general ObGyns and do not require sophisticated technology such as rapid hormonal assays or transvaginal US.

Because this application is so new, with limited data published so far, much of the information presented here is based on our personal experience rather than level-1 evidence, which is sorely needed.

Of course, induction of ovulation is appropriate only after other specific causes of anovulation or ovulatory dysfunction are excluded, such as thyroid disorders, hyperprolactinemia, severe insulin resistance, and ovarian failure.

Concerns about teratogenicity of AIs appear to be largely unfounded (see below).

TABLE 1

Aromatase inhibitors work best in these applications

APPLICATIONEVIDENCE
Induction of ovulation, particularly in women with polycystic ovary syndrome:
  • first-line agent
  • after failure of clomiphene citrate

See case 1 and case 2
  • Strong evidence from several clinical trials
  • Accumulating evidence of consistent trend toward higher pregnancy rate, compared with clomiphene citrate
  • Evidence of successful ovarian stimulation and conception after failure of clomiphene citrate
Ovarian stimulation (superovulation) in ovulatory women with unexplained or endometriosis-related infertility
See case 3
Strong evidence from several clinical trials
Use in conjunction with controlled ovarian hyperstimulation by gonadotropins with intrauterine insemination and assisted reproductionAccumulating evidence of several advantages when used with gonadotropins:
  • Reduces the dosage of gonadotropins required
  • Improves ovarian response to gonadotropins
  • Theoretical benefit of reducing the risk of severe ovarian hyperstimulation syndrome

TABLE 2

Avoid AIs in these situations

SITUATIONJUSTIFICATION
When clomiphene citrate fails to induce ovulation in a woman with insulin resistance
See case 2
First try insulin sensitizers and other measures to improve insulin action (weight loss, exercise, and dietary modifications)
When other causes of infertility (besides ovulatory dysfunction) are likelyPregnancy is unlikely
When the patient has hypothalamic/hypopituitary anovulation or ovarian failureOvarian stimulation is dependent on capacity to produce endogenous gonadotropins and presence of responding ovarian follicles

Ovulation is good, but pregnancy is better

In women undergoing induction of ovulation, there are two levels of success: ovulation and pregnancy.

Clearly, the presence of other, nonovulatory infertility factors—e.g., male infertility and tubal-uterine problems—can prevent successful ovulation induction from translating into pregnancy.

We have reported3-9 on the successful use of AIs to stimulate the ovary and achieve pregnancy—even in women who fail to conceive after several treatment trials with clomiphene citrate.4

Other authors have conducted further investigations that have confirmed our findings and have recommended use of these agents for other aspects of infertility treatment, such as assisted reproduction.10-19

Latest generation of AIs is more benign

Many AIs have been developed over the past 30 years. The most recent are third-generation agents that were approved mainly to suppress estrogen production in postmenopausal women with breast cancer. Clinical failure of earlier generations of AIs for their approved indication was mainly due to significant adverse effects, lack of satisfactory potency, or lack of specificity in inhibiting the aromatase enzyme without inhibiting other enzymes of steroidogenesis.20

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