Clinical Review

Aromatase inhibitors, a new option for inducing ovulation

OBG Manag. 2008 January;20(1):57-74

Mohamed F.M. Mitwally, MD

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

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IN THIS ARTICLE

Avoid aromatase inhibitors in these situations
Why aromatase inhibitors are superior to clomiphene
Five pearls for inducing ovulation

References

1. Dickey RP, Taylor SN, Lu PY, Sartor BM, Rye PH, Pyrzak R. Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate-intrauterine insemination. Fertil Steril. 2002;78:1088-1095.

2. Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligomenorrheic infertility. J Clin Endocrinol Metab. 1999;84:1617-1622.

3. Mitwally MFM, Casper RF. Aromatase inhibition: a novel method of ovulation induction in women with polycystic ovarian syndrome. Reprod Technol. 2000;10:244-247.

4. Mitwally MFM, Casper RF. Use of an AI for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75:305-309.

5. Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril. 2002;77:776-780.

6. Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotropin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod. 2003;188:1588-1597.

7. Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investig. 2004;11:406-415.

8. Mitwally MFM, Casper RF. Single dose administration of the aromatase inhibitor, letrozole: a simple and convenient effective method of ovulation induction. Fertil Steril. 2005;83:229-231.

9. Mitwally MFM, Casper RF. Pregnancy outcome after the use of an AI for induction of ovulation. Am J Obstet Gynecol. 2005;192:381-386.

10. Fatemi HM, Kolibianakis E, Tournaye H, et al. Clomiphene citrate versus letrozole for ovarian stimulation: a pilot study. Reprod Biomed Online. 2003;75:543-546.

11. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril. 2004;82:1561-1563.

12. Goswami SK, Das T, Chattopadhyay R, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod. 2004;19:2031-2035.

13. Garcia-Velasco JA, Moreno L, Pacheco A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril. 2005;84:82-87.

14. Bayar U, Tanrierdi HA, Barut A, et al. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85:1045-1048.

15. Elnashar A, Fouad H, Eldosoky M, et al. Letrozole induction of ovulation in women with clomiphene citrate-resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle stimulating hormone ratio. Fertil Steril. 2006;85:161-164.

16. Atay V, Cam C, Muhcu M, et al. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation. J Int Med Res. 2006;34:73-76.

17. Sohrabvand F, Ansari S, Bagheri M. Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Hum Reprod. 2006;21:1432-1435.

18. Sipe CS, Davis WA, Maifeld M, Van Voorhis BJ. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins. Fertil Steril. 2006;86:1676-1681.

19. Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial. Fertil Steril. 2006;86:1447-1451.

20. Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. Clin Cancer Res. 2001;7:2620-2635.

21. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology Technology Assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol. 2002;2015:3317-3327.

22. Mitwally MF, Casper RF. Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women. Drugs. 2006;66:2149-2160.

23. Mitwally MFM, Casper RF. Letrozole for ovulation induction. Exp Rev Obstet Gynecol. 2006;1:15-27.

24. Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab. 2006;91:760-771.

25. Mitwally MF, Casper RF, Diamond MP. The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment. Reprod Biol Endocrinol. 2005;3:54.-

26. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med. 2004;22:61-78.

27. Mitwally MF, Casper RF. Aromatase inhibitors for the treatment of infertility. Expert Opin Investig Drugs. 2003;12:353-371.

28. Mitwally MF, Casper RF. Aromatase inhibition for ovarian stimulation: future avenues for infertility management. Curr Opin Obstet Gynecol. 2002;14:255-263.

29. Cole PA, Robinson CH. Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem. 1990;33:2933-2944.

30. Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999;848:2951-2956.

31. Mikkelson TJ, Kroboth PD, Cameron WJ. Single dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986;46:392-396.

32. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2000;(2):CD000057.-

33. Mitwally MF, Albuarki H, Ashraf M, Diamond MP, Abuzeid M. Clomiphene reduces chance of pregnancy in infertile women with endometriosis following laparoscopic surgery. J Soc Gynecol Investig. 2006;13(2) (suppl):abstract 646.-

34. Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update. 2006;12:49-56.

35. Goss PE. Risks versus benefits in the clinical application of aromatase inhibitors. Endocr Relat Cancer. 1999;6:325-332.

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Fast Track

Aromatase inhibitors suppress estrogen production in the ovaries, brain, and adipose tissue

Aromatase inhibitors do not appear to affect expression of estrogen receptors in the endometrium and cervix

Success with an aromatase inhibitor is unlikely when there is no appropriate indication for clomiphene citrate

Because the aromatase enzyme is expressed in endometriotic lesions, aromatase inhibitors may have the added benefit of suppressing endometriosis

In a recent study, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate

A large study found a similar incidence of cardiac anomaly among women treated with letrozole and the general population

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

APPLICATION	EVIDENCE
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 reproduction	Accumulating 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

SITUATION	JUSTIFICATION
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 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.

We have reported^3-9 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