Aromatase inhibitors, a new option for inducing ovulation
This class of drugs may boost the pregnancy rate in selected populations
IN THIS ARTICLE
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.
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).
Aromatase inhibitors work best in these applications
Induction of ovulation, particularly in women with polycystic ovary syndrome:
Ovarian stimulation (superovulation) in ovulatory women with unexplained or endometriosis-related infertility
Strong evidence from several clinical trials
Use in conjunction with controlled ovarian hyperstimulation by gonadotropins with intrauterine insemination and assisted reproduction
Accumulating evidence of several advantages when used with gonadotropins:
Avoid AIs in these situations
When clomiphene citrate fails to induce ovulation in a woman with insulin resistance
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 likely
Pregnancy is unlikely
When the patient has hypothalamic/hypopituitary anovulation or ovarian failure
Ovarian 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.
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
Third-generation AIs that are commercially available in North America, Europe, and other parts of the world include:
- two nonsteroidal preparations: anastrozole (Arimidex) and letrozole (Femara)
- one steroidal agent: exemestane (Aromasin).
Letrozole and anastrozole are reversible, competitive agents with considerably greater potency (more than 1,000 times greater) than the first-generation AI aminoglutethimide. At a dosage of 1 to 5 mg/day, they reduce estrogen levels by 97% to more than 99%.
AIs are completely absorbed after oral administration, with a mean terminal half-life of approximately 45 hours (range: 30–60 hours). Exemestane has a shorter circulating half-life of approximately 9 hours, but may have a longer effect because it is irreversible.21
Mild gastrointestinal (GI) disturbances account for most of the adverse events, and rarely limit therapy.
How AIs work
Although we continue to accrue data on the use of AIs to induce ovulation, the underlying mechanism of action has not been studied. However, we believe that AIs work both centrally (at the level of the hypothalamus and pituitary) and peripherally (at the level of the ovaries).22-28
At the central level, AIs suppress estrogen production by directly, specifically, and potently inhibiting the aromatase enzyme (i.e., estrogen synthase, the enzyme responsible for the synthesis of estrogen). Because the aromatase enzyme is expressed in various tissues and organs—most notably, the ovaries, brain, and fat29—AIs suppress estrogen production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels are thought to release the hypothalamus and pituitary gland from their negative-feedback mechanism, thereby increasing production of endogenous gonadotropins from the pituitary gland and stimulating ovarian follicular development and ovulation (FIGURE).
At the peripheral level, the aromatase enzyme catalyzes the terminal step in the steroidogenesis cascade that converts androgens into estrogen. When that enzyme is inhibited, enzyme substrate (androgens) is thought to accumulate. Contrary to the general belief that androgens are deleterious to ovarian follicles, studies in primates have demonstrated that androgens actually up-regulate the expression of gonadotropin receptors, particularly follicle-stimulating hormone (FSH) receptors.30 This renders the ovaries more sensitive to gonadotropin stimulation—whether the gonadotropins are endogenous or exogenous.22-28
FIGURE Aromatase inhibitors promote follicle development, then fade from the scene in time to prevent hyperovulation
Administration of an aromatase inhibitor (AI) on cycle days 3 to 7 suppresses ovarian estradiol (E2) secretion, as shown in A, which reduces estrogen-negative feedback at the hypothalamus and pituitary. As a result, follicle-stimulating hormone (FSH) secretion increases, fostering growth of multiple ovarian follicles. The growing follicles, shown in B, cause estrogen levels to rise again, depressing FSH, and leading to monofollicular ovulation in most cases.
Clomiphene citrate is a selective estrogen receptor modulator (SERM) that is believed to induce ovulation through its antiestrogenic properties at the level of the hypothalamus or pituitary gland, or both. Clomiphene down-regulates estrogen receptors at this level, and the hypothalamus and pituitary gland react as though the estrogen level is very low. This reverses the suppression of endogenous gonadotropins by estrogen, and gonadotropin levels rise, stimulating ovarian follicular development.
The down-regulation of estrogen receptors with clomiphene administration is not limited to the hypothalamus and pituitary gland, but also occurs peripherally at the endometrium and cervix, where it is not so desirable. When the cervix is affected, it becomes an unfavorable environment for sperm to penetrate, and when the endometrium is affected, its hypoestrogenic status may reduce the likelihood of embryo implantation—or may increase the risk of pregnancy loss if implantation occurs.
These peripheral antiestrogenic prop erties of clomiphene citrate may account for the discrepancy between high ovulation and low pregnancy rates.22-28 Several strategies to overcome this problem—e.g., adding estrogen, starting clomiphene citrate earlier in the menstrual period, or using another SERM, such as tamoxifen—have been largely unsuccessful. With clomiphene citrate, depletion of estrogen receptors has long-term effects because of the drug’s relatively long half-life (several days).31
In contrast, AIs do not appear to affect the expression of estrogen receptors in different body tissues, such as the endometrium and cervix. AIs have a shorter half-life (8 hours to 2 days), and nonsteroidal third-generation agents have a reversible inhibitory effect on the aromatase enzyme. Moreover, the rise in endogenous gonadotropins stimulates the production of more aromatase enzyme. This newly formed aromatase enzyme, and the return of a normal aromatase level after a short half-life of AI, leads the maturing ovarian follicles to secrete estrogen, which reaches a physiologic level soon after the last administration of AI. The rising estrogen level allows development of a more hospitable uterine environment (endometrium and cervical mucus).22-28
Early evidence confirms efficacy of AIs
After our pioneering reports of successful ovulation induction3-9 and improved ovarian response to stimulation by gonadotropins5-7 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.
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.