Prenatal androgen treatment impairs the suprachiasmatic nucleus arginine-vasopressin to kisspeptin neuron circuit in female mice

Abstract

Polycystic ovary syndrome (PCOS) is associated with elevated androgen and luteinizing hormone (LH) secretion and with oligo/anovulation. Evidence indicates that elevated androgens impair sex steroid hormone feedback regulation of pulsatile LH secretion. Hyperandrogenemia in PCOS may also disrupt the preovulatory LH surge. The mechanisms through which this might occur, however, are not fully understood. Kisspeptin (KISS1) neurons of the rostral periventricular area of the third ventricle (RP3V) convey hormonal cues to gonadotropin-releasing hormone (GnRH) neurons. In rodents, the preovulatory surge is triggered by these hormonal cues and coincident timing signals from the central circadian clock in the suprachiasmatic nucleus (SCN). Timing signals are relayed to GnRH neurons, in part, via projections from SCN arginine-vasopressin (AVP) neurons to RP3VKISS1 neurons. Because rodent SCN cells express androgen receptors (AR), we hypothesized that these circuits are impaired by elevated androgens in a mouse model of PCOS. In prenatally androgen-treated (PNA) female mice, SCN Ar expression was significantly increased compared to that found in prenatally vehicle-treated mice. A similar trend was seen in the number of Avp-positive SCN cells expressing Ar. In the RP3V, the number of kisspeptin neurons was preserved. Anterograde tract-tracing, however, revealed reduced SCNAVP neuron projections to the RP3V and a significantly lower proportion of RP3VKISS1 neurons with close appositions from SCNAVP fibers. Functional assessments showed, on the other hand, that RP3VKISS1 neuron responses to AVP were maintained in PNA mice. These findings indicate that PNA changes some of the neural circuits that regulate the preovulatory surge. These impairments might contribute to ovulatory dysfunction in PNA mice modeling PCOS.

Maternal androgen excess significantly impairs sexual behavior in male and female mouse offspring: Perspective for a biological origin of sexual dysfunction in PCOS

“…In view of the recent evidences highlighting the role of RP3V Kisspeptin and VMHvl nNOS neurons in lordosis behavior in healthy female mice ( 65 ) as well as in the PAMH mouse model of PCOS ( 76 ), we would have expected some changes in cFOS in the RP3V and VMHvl region. As noted earlier RP3V Kisspeptin neurons remain unchanged in the PNA mice (data showed here and recently published ( 79 ). Similarly, a previous study from our group showed no changes in arcuate nucleus nNOS neurons in the PNA mice contrary to the PAMH mouse model ( 76 ).…”

“…The levels of three domains of male-like sexual behaviors (latency to mount, mounting behavior and pelvic thrusting) were indistinguishable between PNAF mice and control females. These behavioral findings were supported by anatomical data demonstrating a feminized AVPV kisspeptin population as already described ( 79 ). AVPV kisspeptin neurons are a clearly sexually differentiated population in the brain, with the number of neurons decreased by the male-typical prenatal testosterone rise ( 67 ).…”

Serotonin stimulates female preoptic area kisspeptin neurons via activation of type 2 serotonin receptors in mice

“…Brain slices were prepared as previously described ( 52 , 53 ). Briefly, mice were decapitated following isoflurane anesthesia, and their brains quickly removed.…”