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Abstract Study question What is the prevalence of letrozole-resistance in infertile women with polycystic ovary syndrome (PCOS) and what is the course of clinical management for such women? Summary answer Even after 10 mg/day dose of letrozole, 2.7% women did not ovulate. Clomiphene citrate (CC) should be tried first in these women, followed by gonadotrophins What is known already Letrozole is the preferred drug for ovulation induction (OI) in infertility associated with PCOS because it results in better pregnancy and live birth rates than CC. Women not responding to conventional dose of letrozole, may require alternate regimens like two-step, higher and extended dose. But some women may remain refractory even to the maximum dose of letrozole. While CC-resistance and its management are well established, clinical management of women with PCOS resistant to the maximum dose of letrozole remains largely undocumented. Study design, size, duration A prospective observational study was conducted in a Fertility Centre between April 2018 and March 2023 after obtaining Institutional Ethics Committee approval and informed written consent from all the participants. Out of total 1851 women with PCOS and infertility, 1522 were included in the study, of which 50 were found to be resistant to letrozole. Participants/materials, setting, methods Infertile women with PCOS (defined by Rotterdam criteria), age 21-35 years, with patent fallopian tubes and normal semen reports of partner, who received no previous OI were recruited. Women who failed to ovulate (confirmed with transvaginal ultrasound) after 3 consecutive cycles of incremental (5, 7.5 and 10 mg/day) doses of letrozole were switched to CC. In case of CC-resistance, options of laparoscopic ovarian drilling (LOD) or gonadotrophins were offered. Clinical and pregnancy-associated parameters were assessed. Main results and the role of chance Out of 50 letrozole-resistant women, 19 (38%) ovulated after subsequent OI with CC, of which seven (36.8%) conceived and two (28.8%) had twin pregnancy. Out of 31 CC-resistant women, seven were lost to follow up. The singlet woman who opted for LOD did not have subsequent spontaneous ovulation and therefore, required gonadotrophins later on. All 24 women who received gonadotrophins ovulated. Most of them developed one (11, 45.83%) or two (12, 50%) follicles. However, one woman developed 10 follicles leading to ovarian hyperstimulation syndrome, for which the OI cycle was converted to in-vitro fertilization (IVF). With gonadotrophins, nine (37.5%) women conceived and one (11.1%) had triplet pregnancy that miscarried in the first trimester. The remaining 16 women who failed to conceive were offered three cycles of intrauterine insemination followed by IVF. The mean time to pregnancy from the start of treatment was 10.81 (±7.71) months. The live birth rate was similar (P = 0.0416) between gonadotrophins (6, 27.2%) and CC (5, 22.7%), Between CC-resistant and CC-responsive women, all clinical, biochemical and biophysical parameters were similar except the mean levels of luteinizing hormone, which were significantly higher in CC-resistant group (16.3 ±5.3 versus 13.2 ±4.7 mU/ml, P = 0.036). Limitations, reasons for caution The study was conducted in a single center and the results may be difficult to extrapolate on women belonging to other ethnicities. The sample size was small. Wider implications of the findings Some women with PCOS may not respond even to the maximum dose (10 mg/day) of letrozole. Correct identification of letrozole-resistance and choosing the subsequent appropriate methods of OI are of paramount importance in timely management of infertility in these couples. Trial registration number NA
Sonali Dasgupta (Mon,) studied this question.