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The effects of androgen signaling on AVPV kisspeptin neurons and the estradiol-induced LH surge

Abstract

Men and women require androgens for proper fertility. However, elevated androgen levels suppress the reproductive axis in women with polycystic ovarian syndrome (PCOS) and transgender men undergoing androgen hormone therapy. The mechanisms behind this reproductive deficit are not fully understood. We therefore investigated how elevated androgens affect a model of the preovulatory LH surge and the critically associated anteroventral periventricular nucleus (AVPV) kisspeptin neurons in the brain. C57BL/6 female mice were implanted with 3 different doses of the androgen dihydrotestosterone (DHT; implant length: 4 mm, 10 mm or 16 mm) which acts exclusively through the androgen receptor (AR). A week after implantation, mice were ovariectomized and implanted with an estradiol (E2) pellet to promote an exogenous LH surge two days later. Brain and blood samples were collected 2 days later either in the morning (AM; non-surge time) or evening (PM; surge time). We measured serum LH levels by radioimmunoassay. Kiss1 expression in the AVPV was measured by in situ hybridization, while AVPV kisspeptin neuron activation was assessed using Kiss1/cfos double-label RNAscope. We found that DHT potently suppressed the LH surge, even at the lowest dose tested. Additionally, AVPV Kiss1 expression was lowered in DHT-treated animals compared to control females. Lastly, AVPV kisspeptin neuron activation during the LH surge was strongly suppressed by DHT. These three experiments demonstrate that the female reproductive axis is sensitive to androgen signaling and is inhibited, in part, through the suppression of AVPV kisspeptin neurons.

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