Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting reproductive-aged women and is the leading cause of infertility due to chronic lack of ovulation. For individuals with PCOS trying to conceive, the primary goal of fertility treatment is to induce the regular release of a mature egg. Letrozole, known commercially as Femara, has emerged as the first-line oral medication for ovulation induction in this population, offering an effective pathway to restoring ovulatory cycles and achieving pregnancy.
The Role of Letrozole in PCOS Fertility
Letrozole, initially developed for breast cancer treatment, functions as an aromatase inhibitor, temporarily blocking the enzyme responsible for converting androgens into estrogen. This temporary reduction in circulating estrogen levels is key to its action in fertility.
The brain senses this transient drop in estrogen and signals the pituitary gland to release more Follicle-Stimulating Hormone (FSH). FSH stimulates the growth and maturation of ovarian follicles. This increased FSH surge encourages the development of a dominant follicle, leading to a higher likelihood of ovulation. Letrozole is favored over older treatments like Clomiphene Citrate because it does not have the anti-estrogenic effect on the uterine lining or cervical mucus, which can hinder conception.
Standard Treatment Protocol and Monitoring
Letrozole administration typically follows a standardized protocol. The medication is usually started on cycle days three through five and taken daily for five consecutive days. The starting dose is often 2.5 milligrams (mg), though specialists may begin at 5 mg if a patient has not responded to the lower dose previously.
Monitoring is essential to ensure the medication is working safely. Several days after the last pill, patients undergo transvaginal ultrasounds to track the size and number of developing follicles. Blood tests measure hormone levels, such as estradiol and luteinizing hormone (LH), to pinpoint the timing of ovulation. If a patient fails to ovulate at the initial dose, the dosage is increased in 2.5 mg increments, up to a maximum of 7.5 mg or 10 mg, in subsequent cycles until an ovulatory response is achieved.
Cycle-by-Cycle Success Rates and Cumulative Probability
The number of cycles needed to conceive with Letrozole is determined by examining both cycle-specific and cumulative success rates. Letrozole is highly effective at inducing ovulation in women with PCOS, with rates ranging from 60% to over 80% per cycle. However, this high ovulation rate does not translate directly into an equally high pregnancy rate, as conception requires more than just egg release.
The cycle-specific pregnancy rate—the chance of becoming pregnant in a single ovulatory cycle—is estimated to be around 15% to 20%. The probability of pregnancy increases over time, which is why specialists recommend a limited number of treatment cycles. Most successful pregnancies occur within the first three to four ovulatory cycles.
By the end of six ovulatory cycles, the cumulative live birth rate for women using Letrozole can be around 27.5%, with cumulative pregnancy rates reported up to 45%. Factors such as higher Body Mass Index (BMI), older age, and elevated Anti-Müllerian Hormone (AMH) levels negatively affect success. Conversely, a lower BMI and having previously achieved pregnancy are associated with better outcomes.
When to Adjust Treatment or Consider Alternatives
A patient is considered to have experienced a “Letrozole failure” if conception has not occurred after completing three to six cycles of confirmed ovulation. For those who ovulate but do not conceive, further testing may be warranted to investigate other factors, such as sperm quality or tubal function.
One common next step is combining Letrozole with an insulin-sensitizing medication like Metformin, which can improve ovulatory response and pregnancy rates. Another option is moving to injectable gonadotropins, which directly stimulate the ovaries but require intense monitoring due to the risk of multiple births and ovarian hyperstimulation syndrome. If these less invasive approaches fail, the next tier of treatment involves advanced reproductive technologies (ART), such as intrauterine insemination (IUI) or in vitro fertilization (IVF).