Laparoscopic ovarian drilling vs. step-up gonadotropin therapy in infertile anovulatory polycystic ovary syndrome women resistant to sequential letrozole and gonadotropin-based ovulation induction cycles: a randomized controlled trial

OBJECTIVE: To study the effect of laparoscopic ovarian drilling (LOD) vs. step-up gonadotropin therapy on follicular response in infertile anovulatory polycystic ovary syndrome (PCOS) women resistant to sequential letrozole + human menopausal gonadotropin (HMG)-based ovulation induction (OVI) cycles. DESIGN: Open-labeled, pilot, randomized controlled trial. SUBJECTS: Infertile anovulatory PCOS women (diagnosed according to modified Rotterdam criteria), resistant to sequential letrozole 5 mg + HMG-based OVI cycle (no dominant follicle >10 mm after 14 days of stimulation). Other inclusion criteria were: age 19-38 years; body mass index ≤35 kg/m2; patent fallopian tubes documented on either hysterosalpingography/saline infusion sonography or laparoscopy; antimüllerian hormone (AMH) levels >6 ng/mL. Exclusion criteria were AMH ≤6 ng/mL; moderate to severe male factor infertility and endometriosis. INTERVENTION: Participants in group 1 (N = 35) underwent LOD, after which OVI cycles were started with letrozole 5 mg from the following menses. Gonadotropin were added in a sequential manner if required as per the follicular response. Women in group 2 (N = 35) were administered injection of HMG (75 IU) from day 2 of menses and dose increments were done from day 9 onward as per response. MAIN OUTCOME MEASURES: Primary outcome was follicular response (dominant follicle >16 mm). Secondary objectives were gonadotropin requirement per cycle, duration of stimulation, time to conception (months), clinical pregnancy rate and ongoing pregnancy rate (>12 weeks). The study also compared the effect of LOD on hormonal parameters (AMH, serum testosterone) and metabolic parameters (fasting insulin, fasting blood glucose, lipid profile, homeostasis model assessment of insulin resistance) after 1-2 months of procedure. RESULTS: Majority of the study participants (82.85%) belonged to PCOS phenotype A. The baseline clinical, hormonal, and metabolic characteristics and phenotype distribution were comparable in both groups. The follicular response was significantly higher in the LOD group (93.25%; 83/89) compared with step-up gonadotropin group (28.20%; 11/39). With four spontaneous conceptions, the median time to conception in LOD group was 3.9 (0-8.4) months. The clinical pregnancy rate per patient was significantly higher in LOD group [54.28% (19/35)] as compared with step-up gonadotropin group [8.57% (3/35)]. The ongoing pregnancy rate in the LOD group was 45.71% (16/35) vs. 0% (0/35) in the gonadotropin group. There was a significant fall in the AMH levels from 15.2 ± 2.7 ng/mL to 10.2 ± 4.4 ng/mL after LOD. Although statistically insignificant, the levels of luteinizing hormone/follicle-stimulating hormone ratio, testosterone, fasting insulin, fasting glucose and homeostasis model assessment of insulin resistance levels were also lowered. CONCLUSION: Laparoscopic ovarian drilling significantly improves the follicular response compared with step-up gonadotropin-based ovulation induction and results in higher clinical and ongoing pregnancy rates along with a significant reduction in gonadotropin requirement. The procedure may be considered for PCOS women resistant to sequential letrozole + HMG-based ovulation induction, especially phenotype A with high AMH and high follicle number per ovary. TRIAL REGISTRATION: CTRI/2023/04/052083.