Pituitary luteinizing hormone responses to single doses of exogenous GnRH in female social Cape ground squirrels exhibiting low reproductive skew

The Cape ground squirrel Xerus inauris is unusual among social mammals as it exhibits a low reproductive skew, being a facultative plural breeder with not all females breeding within a group. We investigated pituitary function to assess whether there was reproductive inhibition at the level of the pituitary and potentially the hypothalamus in breeding and non-breeding female Cape ground squirrels. We did so during the summer and winter periods by measuring luteinizing hormone (LH) responses to single doses of 2 g exogenous gonadotropin-releasing hormone (GnRH) and physiological saline administered to 42 females from 11 colonies. Basal LH concentrations of females increased in response to the GnRH challenge. Basal plasma LH concentrations were greater during winter, when most oestrus events are observed. However, we found no differences in plasma LH concentrations between breeding and non-breeding females. We showed that the anterior pituitary of non-breeding female ground squirrels is no less sensitive to exogenously administered GnRH than that of breeding females. We therefore concluded that the pituitary is no more active in breeding than non-breeding females. The lack of differentiation in response to GnRH suggests that either non-breeding females have ovaries that are less sensitive to LH or that they refrain from sexual activity with males through an alternative mechanism of self-restraint.Our work was supported financially by National Science Foundation Grant No. IBN-0130600, awarded to J.M.W., through the University of Central Florida. The National Research Foundation (GUN 2069070) provided additional financial support to NCB

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55). We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Multiple Sclerosis Society of the United Kingdom