Receptor antagonist reduces luteinizing hormone, testosterone in PCOS

The kisspeptin-neurokinin B receptor antagonist AZD4901 was successful in reducing serum luteinizing hormone, luteinizing hormone pulse frequency and serum testosterone in women with polycystic ovary syndrome, according to recent study findings presented at the Society for Endocrinology Annual Conference.

“There are currently no licensed therapies for [PCOS], the most common endocrine pathology in women,” Jyothis T. George, MBBS, PhD, FACE, FRCP, of the Oxford Centre for Diabetes, Endocrinology and Metabolism at Churchill Hospital, England, told Endocrine Today.

George and colleagues evaluated 67 women (mean age, 28 years; BMI, 31.5 kg/m²) randomly assigned to 20 mg, 40 mg or 80 mg per day of oral AZD4901 (AstraZeneca) or placebo for 28 days. Researchers sought to determine whether the pharmacologic blockade of kisspeptin-neurokinin B (NKB) addresses the central pathophysiology of luteinizing hormone hypersecretion and hyperandrogenism in PCOS.

Jyothis T. George

Mean luteinizing hormone area under the curve (AUC) decreased from 67.4 IU/L at baseline to 36 IU/L per hour at day 7, a reduction of 52% in the 80-mg/day group compared with the placebo group (P = .0003). Luteinizing pulse frequency decreased in the 80-mg/day group from 5.79 pulses per 8 hours to 3.73 pulses per 8 hours, a reduction of 3.55 pulses per 8 hours compared with the placebo group (P < .0001). Testosterone also decreased in this group from 2.16 nmol/L at baseline to 1.55 nmol/L at day 7, a 29% reduction compared with placebo (P = .0006).

At day 28, all endpoints remained significantly reduced. However, no changes were seen in luteinizing hormone or testosterone with the lower doses.

“The novel approach of blocking hypothalamic neurokinin B activity halved luteinizing hormone (the primary outcome) and reduced testosterone secretion (key secondary endpoint) by almost a third in this phase 2 randomized controlled trial,” George said.

According to the researchers, current therapies for PCOS are mainly symptomatic and the “findings present NKB antagonism as a potential therapeutic approach to treat the central neuroendocrine pathophysiology of this common clinical condition.” – by Amber Cox

Reference:

George JT, et al. Abstract #0095. Presented at: Society for Endocrinology Annual Conference; Nov. 2-4, 2015; Edinburgh, Scotland.

Disclosure: George reports being the international coordinating investigator for this study and
Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi.