Fertility and Letrozole: Emerging Roles in Polycystic Ovary Syndrome (PCOS)
Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine
disorders affecting women of reproductive age, with a global prevalence
estimated at 6–12%. Characterized by anovulation, hyperandrogenism, and
polycystic ovarian morphology, PCOS is a leading cause of female infertility. Over
over the years, treatment strategies have evolved to improve ovulation rates, with
Letrozole—a third-generation aromatase inhibitor—emerging as a first-line agent
Letrozole: Mechanism of Action
Letrozole works by inhibiting the enzyme aromatase, which converts androgens
to estrogens in the ovary and peripheral tissues. This reduction in estrogen leads to
to decreased negative feedback on the hypothalamus and pituitary gland, thereby
increasing the release of gonadotropins—follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). The increased FSH stimulates ovarian follicular
Unlike clomiphene citrate (CC), which acts as a selective estrogen receptor
modulator (SERM), Letrozole does not have anti-estrogenic effects on the
endometrium or cervical mucus, making it a more physiologic and targeted
approach to ovulation induction.
Letrozole vs. Clomiphene Citrate
For decades, Clomiphene citrate was the first-line treatment for ovulation
induction in women with PCOS. However, a growing body of evidence now
supports Letrozole as a superior alternative:
Higher Ovulation Rates: Studies, including the landmark PPCOS II trial,
demonstrated that Letrozole is associated with higher ovulation and live birth
rates compared to Clomiphene.
Monofollicular Development: Letrozole tends to induce the development of a
single dominant follicle, thereby reducing the risk of multiple gestations.
Improved Endometrial Thickness: Because Letrozole does not deplete estrogen
receptors, it supports better endometrial receptivity than Clomiphene.
Clinical Evidence
In the PPCOS II trial (2014), a multicenter, randomized, double-blind study
involving 750 women with PCOS, Letrozole led to significantly higher live birth
rates (27.5%) compared to Clomiphene (19.1%). Ovulation occurred more
Consistently across cycles, and the incidence of multiple pregnancies was low and
comparable between groups.
Dosing and Protocols
Letrozole is typically administered at a dose of 2.5–7.5 mg orally for 5 days,
starting on day 3 or 5 of the menstrual cycle. Ovulation is usually monitored using
mid-cycle ultrasound, LH surge detection, or serum progesterone levels in the
luteal phase.
Common Dosing Regimen
Starting Dose: 2.5 mg daily for 5 days
Titration: Increase to 5 or 7.5 mg in subsequent cycles if ovulation does not occur
Ovulation Monitoring: Transvaginal ultrasound or ovulation predictor kits
Advantages of Letrozole in PCOS
Improved ovulation and pregnancy rates
Lower risk of multiple pregnancy
Better endometrial receptivity
Minimal side effects
Shorter half-life compared to Clomiphene
Limitations and Considerations
Off-label Use: Letrozole is not FDA-approved for ovulation induction, though it is
widely used and endorsed by professional societies such as the American College
of Obstetricians and Gynecologists (ACOG).
Side Effects: While generally well tolerated, side effects may include fatigue,
dizziness, headaches, and hot flashes.
Contraindications: Should not be used in women with liver dysfunction or during
pregnancy.
Future Directions
Ongoing research is examining Letrozole in combination with other therapies,
such as Metformin or lifestyle interventions, for enhanced fertility outcomes.
Personalized dosing protocols based on ovarian reserve and hormonal profile may
Further refine treatment.
Additionally, studies are exploring the role of Letrozole in intrauterine
insemination (IUI) and in vitro fertilization (IVF) settings, particularly in women
with poor ovarian response or estrogen-sensitive conditions.
