Comparison of Five-Day Anastrozole Therapy and Clomiphene Citrate Therapy in the Treatment of Anovulatory Infertile Women

Abstract

Background: First-line treatment of anovulatory WHO Group II infertility has primarily consisted of clomiphene citrate (CC). Recently, aromatase inhibitors were proposed for induction of ovulation. Study 25550 was a phase II, prospective, randomized, double-blind, multicenter, dose finding study of multiple-dose administration of anastrozole (AST) versus CC in stimulating follicular development and ovulation in infertile anovulatory women.Materials and Methods: Patients were allocated to four treatment arms: a 5-day course of AST 1, 5, 10 mg or CC 50 mg per day. On cycle day 2–3, treatment was initiated and monitored by ultrasound (US) and serum estradiol until LH surge. Within 24 hours of LH surge, insemination occurred. Patients returned in the mid-luteal phase for US and serum Progesterone (P) to document ovulation (P ≥10 ng/mL). A pregnancy test was performed days 15–18 post-LH surge in ovulatory cycles. Clinical pregnancy was confirmed by US. Up to three treatment cycles were permitted. Non-inferiority of AST vs. CC was determined if the 97.5% one-sided lower confidence bound of the difference in ovulation rates was ≥−20%.Tabled 1CC 50 mgAST 1 mgAST 5 mgAST 10 mgaTreatment group discontinued at time of interim analysis.Cycle 1 subjectsbAll treated patients. Subjects treated77797639 Subjects completing cycle 1 (%)68 (88.3)65 (82.3)66 (86.8)22 (56.4) Subjects ovulating (%) (primary endpoint)64.930.436.835.9 Ovulation rate difference AST-CC (lower bound 97.5% CI)—−34.6 (−49.3)28.1 (−43.3)— Subjects pregnant (%)11 (14.3)7 (8.9)8 (10.5)1 (2.6) Subjects clinically pregnant (%)135.19.20 Clinical pregnancy rate in ovulatory cycles (%)cOf those who ovulated.20.016.725.00Cycle 2 subjectsbAll treated patients. Subjects treated43425241 Subjects completing cycle 2 (%)39 (90.7)31 (73.8)36 (69.2)17 (41.5) Subjects ovulating (%)30 (69.8)17 (40.5)19 (36.5)16 (39.0) Subjects pregnant (%)10 (23.3)3 (7.1)2 (3.8)5 (12.2) Subjects clinically pregnant (%)8 (18.6)1 (2.4)2 (3.8)4 (9.8) Clinical pregnancy rate in ovulatory cycles (%)cOf those who ovulated.26.75.910.525.0Cycle 3 subjectsbAll treated patients. Subjects treated23262422 Subjects completing cycle 2 (%)23 (100.0)25 (96.2)23 (95.8)21 (95.5) Subjects ovulating (%)13 (56.5)13 (50.0)12 (50.0)6 (36.4) Subjects pregnant (%)003 (12.5)1 (4.5) Subjects clinically pregnant (%)002 (8.3)1 (4.5) Clinical pregnancy rate in ovulatory cycles (%)cOf those who ovulated.0016.712.5Cumulative (3 cycles)bAll treated patients. No. of treatment cycles143147152102 No. of treatment cycles completed (%)130 (90.9)121 (82.3)125 (82.2)60 (58.8) Ovulatory cycles (%)bAll treated patients.93 (65.0)54 (36.7)59 (38.8)38 (37.3) Cycles resulting in pregnancy (%)18 (12.6)5 (3.4)11 (7.2)5 (4.9) Clinical pregnancy rate in ovulatory cycles (%)cOf those who ovulated.19.49.318.613.2Note: Subjects were allowed to escalate dose in cycles 2 and 3. The numbers presented here are for those receiving the same dose for all cycles.a Treatment group discontinued at time of interim analysis.b All treated patients.c Of those who ovulated. Open table in a new tab Conclusions: Three AST multiple dose regimens (1, 5, and 10 mg) were safe and well tolerated. Although non-inferiority of AST 1 and 5 mg for cycle 1 ovulation rates compared with CC 50 mg was not demonstrated, there were no multiple pregnancies in any of the AST groups. Background: First-line treatment of anovulatory WHO Group II infertility has primarily consisted of clomiphene citrate (CC). Recently, aromatase inhibitors were proposed for induction of ovulation. Study 25550 was a phase II, prospective, randomized, double-blind, multicenter, dose finding study of multiple-dose administration of anastrozole (AST) versus CC in stimulating follicular development and ovulation in infertile anovulatory women. Materials and Methods: Patients were allocated to four treatment arms: a 5-day course of AST 1, 5, 10 mg or CC 50 mg per day. On cycle day 2–3, treatment was initiated and monitored by ultrasound (US) and serum estradiol until LH surge. Within 24 hours of LH surge, insemination occurred. Patients returned in the mid-luteal phase for US and serum Progesterone (P) to document ovulation (P ≥10 ng/mL). A pregnancy test was performed days 15–18 post-LH surge in ovulatory cycles. Clinical pregnancy was confirmed by US. Up to three treatment cycles were permitted. Non-inferiority of AST vs. CC was determined if the 97.5% one-sided lower confidence bound of the difference in ovulation rates was ≥−20%. Note: Subjects were allowed to escalate dose in cycles 2 and 3. The numbers presented here are for those receiving the same dose for all cycles. Conclusions: Three AST multiple dose regimens (1, 5, and 10 mg) were safe and well tolerated. Although non-inferiority of AST 1 and 5 mg for cycle 1 ovulation rates compared with CC 50 mg was not demonstrated, there were no multiple pregnancies in any of the AST groups.