Aromatase inhibitors, a new option for inducing ovulation

Early evidence confirms efficacy of AIs

After our pioneering reports of successful ovulation induction^3-9 and improved ovarian response to stimulation by gonadotropins^5-7 using AIs in small, nonrandomized, controlled trials, several larger and better designed clinical trials followed and supported our findings.^10-19

Clinical trials comparing AIs with clomiphene citrate have consistently reported a universal “trend” toward superiority of AIs in achieving pregnancy despite comparable levels of success in achieving ovulation.^{10,11,14,16-19} However, these published clinical trials lacked adequate sample size to definitively confirm the superiority of AIs in achieving clinical pregnancy. We believe AIs are superior because, in our experience, they have helped women achieve pregnancy even after failure of several cycles of clomiphene treatment.^4,15

Should an AI follow a trial of clomiphene?

U.Y., the patient described at the opening of this article, has two main options now that she has completed six cycles of clomiphene citrate without conceiving. The usual strategy would be a shift to more sophisticated treatment using gonadotropin injection. However, exogenous gonadotropins have several disadvantages:

• the drugs must be injected (orally inactive)
• they are more expensive than clomiphene citrate and AIs
• they require close monitoring by an infertility specialist with expensive and sophisticated technology
• they carry a risk of severe ovarian hyperstimulation, which is unlikely with clomiphene citrate and unreported with AIs
• multiple pregnancy is likely, particularly in conjunction with intrauterine insemination
• the risk of ovarian hyperstimulation with gonadotropin injection is much higher in women with PCOS, such as U.Y., as is the likelihood of multiple pregnancy.

The reason U.Y. has not conceived after six cycles of clomiphene citrate is likely related to the drug’s antiestrogenic effects on the endometrium, which appeared to be very thin (4–6 mm) on US imaging around the day of ovulation. If she fails to conceive with AIs, she will probably not become pregnant after a switch to gonadotropin injection unless more advanced treatment is included, such as in vitro fertilization (IVF) and embryo transfer. Other causes of her infertility—besides ovulatory dysfunction—may explain the failure to conceive.

Comparable pregnancy rates have been observed for AIs and gonadotropin injection, although further study is needed—specifically, clinical trials comparing gonadotropin and AIs in conjunction with timed intercourse or intrauterine insemination, or both.

CASE 2 No response to clomiphene citrate

G.A., 28 years old, has been trying to conceive for 3 years. She reports having irregular menstrual periods indicative of anovulation, and body temperature charts and progesterone levels support that diagnosis. She undergoes three cycles of clomiphene citrate at dosages ranging from 50 to 150 mg/day for 5 days starting on day 3 of the menstrual cycle. Despite treatment, she fails to ovulate.

Would an AI increase her chance of ovulating and conceiving?

Failure to ovulate after treatment with clomiphene citrate may have any of several causes, including inappropriate patient selection and resistance to the drug.

An example of inappropriate patient selection would be a woman with hypothalamic/hypopituitary anovulation; this type of patient often has insufficient levels of endogenous gonadotropins (luteinizing hormone and FSH). Another example would be a woman with reduced ovarian reserve; this type of patient is often unresponsive to clomiphene citrate and may have substantially elevated gonadotropin levels, most notably high FSH on day 3 of the menstrual cycle.

AIs are unlikely to induce ovulation in either of these patients. For the first type of patient, exogenous gonadotropin injection would be appropriate, as would be a gonadotropin-releasing hormone (GnRH) pump. For a woman with reduced ovarian reserve, an oocyte donor and IVF are the best treatment option.

Success with an AI is unlikely when there is no appropriate indication for clomiphene citrate. For example, a woman with severe insulin resistance who fails to ovulate in response to clomiphene citrate is unlikely to ovulate in response to an AI. In that case, an insulin sensitizer—alone or in combination with clomiphene citrate or an AI—would be the appropriate option. Other measures to reduce insulin resistance, such as weight loss, exercise, and dietary modification, may also be helpful.

CASE 3 Ovulatory patient with endometriosis fails to conceive on clomiphene

R.C., 34 years old, has been trying to conceive for 2 years. Her basic infertility workup, which included a hysterosalpingogram and semen analysis, did not reveal any abnormalities. She has regular menstrual cycles suggestive of ovulation. In addition, luteal-phase progesterone levels and biphasic body temperature charts both indicate regular ovulation.

After six cycles of clomiphene citrate, her gynecologist performs diagnostic laparoscopy. Other than minimal, stage 1 endometriosis, confirmed by pathologic examination of peritoneal biopsies, there are no remarkable findings. Methylene blue tubal perfusion confirms patent fallopian tubes during the operation. The gynecologist fulgurates the minimal endometriotic implants using carbon dioxide laser. Two months after the procedure, the patient undergoes three more cycles of clomiphene citrate, without success.