Polycystic ovary syndrome (PCOS) affects 5% to 10% of women of reproductive age. PCOS is characterized by accelerated luteinizing hormone (LH) pulse frequency and elevated serum testosterone concentrations, menstrual irregularity, and polycystic ovaries. Currently, there is no approved treatment for PCOS. Recently, hypothalamic neurokinin B (NKB) has been characterized as playing a key role in reproductive regulation, specifically as a modulator of gonadotropin-releasing hormone secretion [Topaloglu AK et al. Nat Genet. 2009]. The aim of this study [NCT01872078], presented by Jyothis T. George, PhD, University of Oxford, Oxford, United Kingdom, was to assess the effect of the NKB receptor antagonist, AZD4901, on LH secretion and testosterone levels in women with PCOS.

A total of 67 women with PCOS were randomized to receive AZD4901 20, 40, or 80 mg/day, or placebo for 28 days. All of the patients had a clinical diagnosis of PCOS with polycystic ovarian morphology, free testosterone (> 0.85 upper limit of normal), and oligomenorrhea. The patients had intensive LH and testosterone sampling at baseline (day −1), day 7, and day 28. The primary end point was the change in 8-hour LH area under the curve (AUC) between baseline and day 7. The secondary end points were the change in total testosterone levels from baseline to days 7 and 28 and in LH pulse frequency at days 7 and 28.

The LH AUC was 67.4 ± 1.6 IU/L*h at baseline and 36 ± 2.3 IU/L*h at day 7 in the AZD4901 80-mg group compared with 61.1 ± 1.9 IU/L*h at baseline and 69.8 ± 1.7 IU/L*h at day 7 in the placebo group (a 52% reduction relative to placebo, adjusted for baseline; 95% CI, 30% to 67%; P = .0003). LH pulse frequency was 5.8 ± 2.1 pulses/8 hours at baseline and 3.7 ± 2.1 pulses/8 hours at day 7 in the AZD4901 80-mg group compared with 7.2 ± 2.3 pulses/8 hours at baseline and 6.8 ± 2.6 pulses/8 hours at day 7 in the placebo group, an adjusted mean change of −3.55 pulses/8 hours vs placebo (P < .0001).

Total testosterone levels were 2.2 ± 1.3 nmol/L at baseline and 1.6 ± 1.5 nmol/L at day 7 in the AZD4901 80-mg group compared with 1.5 ± 1.7 nmol/L at baseline and 1.6 ± 1.9 nmol/L at day 7 in the placebo group (a 29% adjusted reduction relative to placebo; 95% CI, 14% to 41%; P = .0006). At day 28, testosterone was reduced by 17% in the AZD4901 80-mg group.

A post hoc analysis in the anovulatory patients, defined as patients with serum P ≥ 6 ng/mL throughout the study, showed that LH AUC was reduced in the ADZ4901 80-mg group by 46% at day 7 (P = .0004) and by 35% at day 28 (P = .0203); LH pulse frequency was −3.9 pulses/8 hours at day 7 (P < .0001) and −1.89 pulses/8 hours at day 28 (P = .0205); and testosterone was reduced by 27% at day 7 (P = .0005) and by 20% at day 28 (P = .0111) compared with placebo.

After 7 days of treatment with AZD4901 80 mg, women with PCOS had significant reductions in LH, LH pulse frequency, and total testosterone. These effects persisted for 28 days in nonovulating women. AZD4901 was safe and well tolerated. Longer-duration studies are needed to further evaluate its therapeutic potential, including metabolic responses.