Letrozole vs. Clomiphene: the OG Study

Letrozole vs. Clomiphene: the OG Study

Your Fertility Pharmacist
ovulation induction, PCOS

This landmark trial demonstrated higher rates of live birth and ovulation with letrozole vs. clomiphene in women with polycystic ovary syndrome (PCOS).

Study Background

WHAT

  • comparison of live births using letrozole or clomiphene citrate (CC) for ovulation induction in infertile women with PCOS

WHY

  • CC has low-modest efficacy for live births and undesirable side effects

  • letrozole inhibits estrogen’s impact on the hypothalamic-pituitary access through a different mechanism and has a shorter half-life than CC, which may improve the side-effect profile and pregnancy rates

WHERE/WHEN

  • eleven academic health centers in the US; data control center at Yale

  • 2009-2013

WHO

Female Inclusion Criteria:

  • ages 18-40

  • PCOS as per modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries)

  • current infertility (20% previously had given birth)

  • normal uterine cavity + at least one patent fallopian tube

  • commitment (with partner) to have regular intercourse with the intent to conceive

Female Exclusion Criteria:

  • alternate endocrine disorders (prolactin excess, thyroid disease)

  • taking confounding medicines (i.e. other fertility drugs, sex steroids, and/or insulin sensitizers)

Male Partner Inclusion Criteria:

  • sperm concentration at least 14 million per mL

  • documented motility in at least one ejaculate within the past year

HOW

  • received investigational new drug approval for the use of letrozole as an infertility agent

  • randomized females 1:1 to letrozole 2.5 mg daily or CC 50 mg daily x five days after menstruating spontaneously or via medroxyprogesterone acetate induction of withdrawal bleeding; in subsequent cycles, increased to max dose of 7.5 mg (letrozole) and 150 mg (clomiphene), with a max of five cycles permitted

  • investigators could induce menstrual bleeding after anovulatory cycle (utilized in 24.6% of cycles)

  • Both medications over-encapsulated to appear identical

  • Females who conceived were followed until fetal hearbeat detected via ultrasound, tracked through medical records

  • Optional participation in registry following infants from birth until three years of age

Statistics (Briefly)

  • designed for 81% power, 10% points in proportion of cumulative live births between groups

  • all data analyzed per intention to treat (ITT); intended to enroll 375 patients per arm in case of 20% dropout rate (# needed for analysis = 300 per arm)

Results

  • Characteristics

    • 3457 screened —> 1054 consented —> 750 randomized into the two groups

    • dropouts/ excluded from further analyses: letrozole had 73 (19.5%) vs. CC had 85 (22.6%); p = 0.3 with no differences between groups for dropout reasons

    • baseline demographics largely similar

  • Efficacy

    • letrozole group had more live births vs. CC (27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth with letrozole, 1.44; 95% confidence interval, 1.10 to 1.87

    • No group differences in live birth based on treatment cycle number

    • BMI assessed at all tertiles showed superiority of letrozole for live birth

    • Progestin-induced bleeding after an anovulatory cycle showed no significant differences in live-birth rates vs. no progestin use

  • Safety

    • CC was associated with significantly higher incidence of hot flushes vs. letrozole (33% vs. 20%); letrozole associated with significantly higher incidences of fatigue (21.7% vs. 14.9%) and dizziness (12.3% and 7.6%)

    • Four congenital anomalies with letrozole and one with CC but the between-group difference was not significant (p=0.65)

    • No significant differences between groups for neonatal complications

    • Two serious adverse events related to ovarian cyst formation occurred on treatment with letrozole and one with CC

Study Authors’ Thoughts

  • Study underpowered to rule out potential difference in congenital anomalies or in twins (though twin rate higher with CC)

  • BMI of population higher than many parts of world but reflective of US; improvements on letrozole in this trial show that BMI and metabolic parameters do not necessarily need to be modified in order to improve PCOS infertility; noted lack of lifestyle intervention requirement in this trial

  • High dropout rate (~20%) similar to similar infertility trial

This Pharmacist’s Thoughts

  • Sterling study design for women trying to conceive

    • protocol designed by NICHD Reproductive Medicine Network and approved by two groups, an NIH-appointed ad board and a data & safety monitoring committee

    • Double-blind with overencapsulated medications

    • Registry to follow pregnancy and infant outcomes

  • Would have been helpful to track ages of male partners for possible influence of age on male fertility

    Conclusions

This rigorously designed trial strongly influenced recommendations to shift letrozole to become the first-line pharmacologic agent used for ovulation induction in women with PCOS.

Resources

Bronson R. and Kruljac I, Butorac D, Vrkljan M. Letters to the Editor: Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(15):1463-1464. doi:10.1056/NEJMc1409550

Centers for Disease Control and Prevention. PCOS (Polycystic Ovary Syndrome) and Diabetes. https://www.cdc.gov/diabetes/basics/pcos.html. Accessed April 21, 2024.

Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014;(2):CD010287. Published 2014 Feb 24. doi:10.1002/14651858.CD010287.pub2

Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2022;9(9):CD010287. Published 2022 Sep 27. doi:10.1002/14651858.CD010287.pub4

Kar S. Current evidence supporting "letrozole" for ovulation induction. J Hum Reprod Sci. 2013;6(2):93-98. doi:10.4103/0974-1208.117166

Kruljac I, Butorac D, Vrkljan M. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(15):1462-1463. doi:10.1056/NEJMc1409550

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517

Legro RS, Diamond MP, Coutifaris C, et al. Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins. Fertil Steril. 2020;113(5):1005-1013. doi:10.1016/j.fertnstert.2019.12.023

Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75(2):305-309. doi:10.1016/s0015-0282(00)01705-2

Palomba S, Santagni S, Falbo A, La Sala GB. Complications and challenges associated with polycystic ovary syndrome: current perspectives. Int J Womens Health. 2015;7:745-763
https://doi.org/10.2147/IJWH.S70314

World Health Organization. Polycystic Ovary Syndrome. World Health Organization; 2023. Accessed April 21, 2024. https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome

Zhang H. Pregnancy in Polycystic Ovary Syndrome II (PPCOSII). ClinicalTrials.gov identifier: NCT00719186 . Updated June 14, 2018. Accessed April 20, 2020. https://classic.clinicaltrials.gov/ct2/show/NCT00719186

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