ABSTRACT & COMMENTARY
Use of Letrozole vs Clomiphene Citrate for Ovulation Induction in Women with PCOS
By Michael A. Thomas, MD
Professor, Reproductive Endocrinology and Infertility; Director, Division of Reproductive Endocrinology and Infertility, University of Cincinnati College of Medicine
Dr. Thomas reports no financial relationships relevant to this field of study.
Synopsis: Polycystic ovarian syndrome patients with normospermic partners undergoing ovulation induction with letrozole had a higher live birth rate and no increase in adverse outcomes than women who received clomiphene citrate.
Source: Legro RS, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women and is the most common cause of anovulatory infertility. The current first-line treatment options for this patient population include the oral agents clomiphene citrate (CC), which is approved by the FDA for this purpose, and letrozole (LE), an aromatase inhibitor increasingly used for ovulation induction but only approved for use in breast cancer treatment. Because smaller studies have shown no clear difference between these two medications, the National Institutes of Health’s Reproductive Medicine Network (RMN), which is comprised of a consortium of university-based infertility practices, decided to perform a prospective, double-blind, multicenter trial of 750 infertile women with PCOS diagnosed using the Rotterdam criteria.1 These women were randomly assigned in a 1:1 ratio to use either LE or CC for up to five treatment cycles. Starting doses were LE 2.5 mg and CC 50 mg. These medications were increased in subsequent cycles if no evidence of ovulation was documented (progesterone concentration > 3 ng/mL). Maximum LE dose was 7.5 mg and maximum CC dose was 150 mg. Enrolled participants had to be younger than 40 years of age, have at least one patent fallopian tube and have a normal uterine cavity, a male partner with a sperm concentration of at least 14 million/mL, and have intravaginal intercourse on a regular basis. The primary outcome of this study was live birth. Secondary outcomes included ovulation, pregnancy loss, singleton birth, and congenital anomalies.
Compared to CC, women who received LE had higher cumulative live births rates (27.5% [103/374] vs 19.1% [72/376], P = 0.007)] and ovulation rates (61.7% [834/1352] vs 48.3% [688/1425], P = < 0.001) per total treatment cycles. There were no overall differences between the two treatment groups in terms of demographic data, congenital anomalies, multiple gestation, ovarian torsion, ruptured corpus luteal cyst, ectopic pregnancy, heterotopic pregnancy, pregnancy of unknown location, hospitalization, premature labor, postpartum anemia requiring transfusion, fetal death, or neonatal death. Of those patients who ovulated, PCOS patients using LE had a higher rate of singleton birth (34.1% vs 26%, P = 0.03). When actively using the medications, patients taking LE noted an increase in fatigue and dizziness while those using CC had a higher incidence of hot flashes.
General gynecologists and some primary care providers routinely use oral agents for ovulation induction in PCOS patients in outpatient settings. Clomiphene citrate is a selective estrogen receptor modulator that antagonizes the negative feedback of estrogen at the level of the hypothalamus, which results in an increase in endogenous gonadotropins to stimulate the ovaries. Therefore, it works centrally to affect ovulation. Letrozole is an aromatase inhibitor that induces follicle development by blocking the conversion of androgens to estrogens, which secondarily increases gonadotropin production to stimulate the ovaries, as the hypothalamus perceives a lower ovarian production of estradiol. Both medications are easy to use with few side effects.
Over the last 50 years, CC has served as the first-line option in the treatment of infertility in women with PCOS with or without knowledge of semen parameters or tubal status. Usually the dose is titrated from 50 mg up to 250 mg until an ovulatory response is achieved, as determined by either the use of a urine test for the luteinizing hormone (LH) surge or visualization of a mature preovulatory follicle on ultrasound. However, CC can have some drawbacks that may make it undesirable for patients. These concerns include poor efficacy (22% rate of live birth rate over six cycles), higher than normal incidence of multiple births (3-8%), as well as mood changes and hot flashes.2
Clomiphene resistance (inability to develop a follicle at any dose) has been noted in up to 25% of PCOS patients.2 Glucocorticoids, particularly dexamethasone (Dex), and metformin, an insulin receptor sensitizing agent, have been used to overcome CC resistance. Two large trials evaluated CC alone vs CC with Dex 0.5 mg (given cycle days 3-12).3,4 The addition of Dex increased the ovulation and conception rates from 15-20% and 5% (CC only) to 75-88% and 40%, respectively. Despite these positive results, Dex and other glucocorticoids are associated with bloating, weight gain, mood changes, osteoporosis, and other adverse conditions.
Although metformin has been used alone as a medication to induce ovulation in PCOS patients, it has not been shown to be consistently effective for this indication. Metformin is a biguanide that works by suppressing hepatic gluconeogenesis and increasing peripheral insulin sensitivity.5 Its administration in this patient population results in a reduction in all of the following: LH pulse amplitude, androstenedione levels, testosterone levels, ovarian volume, and Ferriman-Gallwey scores (numbered system in which a "score" of 0-4 is assigned to determine the extent of hair growth over nine sites from the upper lip to the inner thigh).6 When used in combination with CC, metformin (up to 500 mg three times per day) has been shown to decrease CC resistance.7 Despite this potential beneficial effect, the RMN had previously demonstrated that the use of CC with (26.8%) or without (22.5%) metformin conferred similar pregnancy rates.8 Therefore, the addition of metformin offered no enhanced benefit to CC users.
Generally, LE therapy is initiated at a dose of 2.5 mg for 5 days, and the dose is increased stepwise up to 10 mg until ovulation is noted. Although a meta-analysis of six peer-reviewed papers involving 841 infertile PCOS patients treated with either LE or CC demonstrated no difference in pregnancy rate, abortion rate, and multiple gestations,9 methodological limitations prompted the RMN to perform a randomized, controlled trial to settle the question.
The primary goal of this study was to determine which oral ovulation induction (OI) agent offers the best possibility of pregnancy in a group of patients who need to "reboot" their hypothalamic-pituitary-ovarian axis to ovulate. LE was shown to result in higher rates of ovulation and live birth and a lower risk of multiple gestation (if ovulation is confirmed). These highly favorable findings would indicate that the use of CC for OI in patients with PCOS is dead. But will this study change prescribing habits? It is not likely, given that the majority of CC prescribers are generalists who either have never heard of LE and/or have never been instructed to use this medication during residency or a postgraduate course. Finally, LE is not FDA-approved for OI use. Although this last point has not stopped most fertility providers from making LE their favorite "go-to" wonder drug, generalists may be more hesitant to jump on the bandwagon until more long-term data eliminate any safety issues. The biggest concern is the potential risk of accidentally prescribing LE while a patient is pregnant with a female fetus, which theoretically could result in masculinizing a female fetus due to interference with the aromatization of maternal androgens to estrogen. Our center and others have LE users sign a waiver that explains these potential risks if fetal exposure takes place.
This study opens the door for LE to become an additional fertility treatment modality for PCOS anovulation. Demonstration of superiority over CC should make LE the prime ovulation induction option for this patient population.
- Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19-25.
- Legro RS, et al. N Engl J Med 2007;356:551-566.
- Parsanezhad ME, et al. Fertil Steril 2002;78:1001-1004.
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- Legro RS, et al. N Engl J Med 2007;356:551-566.
- He D, Jiang F. Reprod Biomed Online 2011;23:91-96.