Polycystic Ovary Syndrome and Letrozole Treatment

Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder and is the most common cause of anovulatory infertility in women of reproductive age. Letrozole (LE), a specific aromatase inhibitor, was administered to women with PCOS who were resistant to clomiphene citrate (CC). LE could prevent the hypothalamic–pituitary axis from receiving estrogen negative feedback by inhibiting estrogen biosynthesis, thus increasing follicle-stimulating hormone (FSH) production and promoting follicle growth. Recently, LE gradually has replaced CC as the first-line ovulation induction agent administered to women with PCOS owing to the high rates of live birth and pregnancy.

LE Regimen for Ovulation Induction

The commonly used LE regimen for ovulation induction in women with PCOS is 2.5 mg daily for 5 days. If the initial dose fails to initiate follicular development, it often is increased to 5 mg in the next cycle after a progesterone-induced withdrawal period, and a maximum daily dose of 7.5 mg will be used in the subsequent cycle if still anovulatory.

In accordance with the theory that the "FSH window" is as important as the "FSH threshold" during the selection of dominant follicles, we hypothesized that longer treatment with LE could extend the "FSH window", thereby inducing follicle growth in patients who initially do not respond to routine treatment.

Study by Xiuxian Zhu and Yonglun Fu

In Xiuxian Zhu and Yonglun Fu's study, considering the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies, the FSH window was widened in a stepwise manner by extending the LE treatment duration step by step. They defined LE resistance as failure of ovulation after a 5-day regimen of 5 mg of LE per day for at least 1 cycle. For women with PCOS and LE resistance, a 7-day regimen of 5 mg LE daily was prescribed in the first ovulation induction cycle, and if ovulation did not occur, a 10-day regimen was prescribed in the subsequent cycle. Such a method of extending LE treatment duration was named as a "2-step extended LE regimen" in the present study. Herein, they reported the ovulation rates and clinical pregnancy outcomes in women with PCOS and LE resistance who underwent ovulation induction using the 2-step extended LE regimen.

Study Details and Results

This retrospective study was conducted at Shanghai First Maternity and Infant Hospital. Records of women with PCOS and LE resistance who underwent ovulation induction using the 2-step extended LE regimen between October 2019 and December 2021 were screened. A total of 69 women with PCOS and LE resistance were included. Ovulation rate was the primary outcome. Clinical pregnancy rate, live birth rate, spontaneous ovulation rate, and ovarian hyperstimulation syndrome rate were the secondary outcomes. Study results demonstrated that extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance.

• Of the 69 patients, 48 ovulated after the 7-day and 16 after the 10-day regimen.
• Overall, the cumulative ovulation rate reached 92.75% (64/69) after the 2-step extended LE regimen, with a cumulative clinical pregnancy rate of 31.88% (22/69) and a cumulative live birth rate of 24.63% (17/69).
• All patients ovulated spontaneously without exogenous trigger agents and none experienced ovarian hyperstimulation syndrome.

Of the 69 women with PCOS and LE resistance, 48 achieved ovulation after LE treatment duration was increased to 7 days, among whom 17 became pregnant and 14 achieved a live birth. For the other 21 women, LE treatment duration was increased to 10 days; among whom 16 achieved adequate follicular growth, 5 became pregnant, and 3 achieved a live birth. Overall, the cumulative ovulation rate reached 92.75%, the cumulative CPR was 31.88%, and the cumulative live birth rate was 24.64%. Study results demonstrated that extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance.

Management of Ovulatory Dysfunction

Adding exogenous human chorionic gonadotropin or gonadotropin-releasing hormone agonist when at least 1 follicle has a diameter of >18 mm is a routine procedure in the management of women with ovulatory dysfunction. From authors' perspective, the administration of exogenous trigger drugs is unnecessary. Because of the short half-life of LE (approximately 45 hours), serum E2 values could gradually rise after LE treatment is discontinued. Thus, one can just wait for the spontaneous LH surge and the subsequent rupture of dominant follicles. There are concerns about the potential risk of ovulation failure of larger follicles, as follicles >22 mm were related to a higher incidence of unruptured follicles in a previous study. In this study, follicles >25 mm were observed in 11 patients. All of them spontaneously ovulated without the addition of exogenous human chorionic gonadotropin or gonadotropin-releasing hormone.

Endometrial Development

During the ovulation induction cycle using the 2-step extended LE regimen, the endometrium was thin at the early follicular phase owing to the daily administration of LE at a dose of 5 mg, which could decrease the E2 levels by 97%–99%. Once circulating E2 levels increased, endometrial development accelerated. The strategy of waiting for spontaneous ovulation ensured that there was sufficient time for patients to achieve adequate endometrial thickness before ovulation. The mean endometrial thickness before ovulation was 10.58 ± 2.63 mm in the 7-day regimen recipients and 10.8 ± 2.74 mm in the 10-day regimen recipients. These values were not less than the mean endometrial thickness values in those who underwent a 5-day regimen of LE, 2.5 or 5 mg daily. A duration-dependent reduction in the endometrial thickness was not observed in study.

Conclusion

In conclusion, study findings demonstrated that extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance. Whether extending LE duration for a longer time will be effective in patients who do not respond to a 10-day regimen of 5 mg LE daily remains our further explorations. Large-scale prospective studies are needed to validate our findings and provide evidence for the individual usage of LE in the ovulation induction of women with PCOS.

Source: Xiuxian Zhu and Yonglun Fu; Fertility and Sterility

https://doi.org/10.1016/j.fertnstert.2022.09.018