Ovarian Androgens Maintain High GnRH Neuron Firing Rate in Adult Prenatally-Androgenized Female Mice

Abstract

Changes in gonadotropin-releasing hormone (GnRH) release frequency from the brain help drive reproductive cycles. In polycystic ovary syndrome (PCOS), persistent high GnRH/luteinizing hormone (LH) frequency disrupts cycles and exacerbates hyperandrogenemia. Adult prenatally-androgenized (PNA) mice exhibit increased GnRH neuron firing rate, elevated ovarian androgens, and disrupted cycles, but before puberty, GnRH neuron activity is reduced in PNA mice compared with controls. We hypothesized that ovarian feedback mediates the age-dependent change in GnRH neuron firing rate in PNA vs control mice. Extracellular recordings of green fluorescent protein (GFP)-identified GnRH neurons were made 5 to 7 days after sham-surgery, ovariectomy (OVX), or, in adults, after OVX plus replacement of sub-male androgen levels with dihydrotestosterone implants (OVX + DHT). In 3-week-old mice, OVX did not affect GnRH neuron firing rate in either group. In adult controls, OVX increased GnRH neuron firing rate, which was further enhanced by DHT. In adult PNA mice, however, OVX decreased GnRH neuron firing rate, and DHT restored firing rate to sham-operated levels. In contrast to the differential effects of ovarian feedback on GnRH neuron firing rate, serum LH increased after OVX in both control and PNA mice and was not altered by DHT. Pituitary gene expression largely reflected changes expected with OVX, although in PNA but not control mice, DHT treatment increased Lhb expression. These results suggest prenatal androgen exposure programs marked changes in GnRH neuron regulation by homeostatic steroid feedback. PNA lowers GnRH neuron activity in low-steroid states (before puberty, OVX), and renders activity in adulthood dependent upon ongoing exposure to elevated ovarian androgens.

Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice

“…Previous findings strongly indicate that PNA exposure change the reproductive neuroendocrine system 35,36,41 . Adult PNA wt mice exhibit increased GnRH neuron firing rate 41 and increased LH pulsatility, 36 but often unaltered LH levels 24,36,40,41 .…”

“…Functional ovarian hyperandrogenism has been identified in some, 25,35,38,39 but not all, 24,25,40,41 publications utilizing PNA-exposed offspring, an effect that seems to be age dependent. Ovarian steroidogenesis has, to our knowledge not been published on PNA offspring.…”

Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

“…Increased GnRH neuronal activity in PCOS-like PNA mice [ 15 , 19 , 21 ] may reflect a modified balance in the excitatory and inhibitory afferent input that GnRH neurons receive. While GABAergic signaling to GnRH neurons is largely excitatory through GABA A receptors [ 60 ], and selective optogenetic and chemogenetic activation of GABA ARN inputs to GnRH neurons promotes LH secretion [ 17 ], NPY and AgRP likely promote inhibition of the GnRH neurons and LH release.…”

“…Functional and anatomical findings in both ovine and murine models of PCOS suggest that altered afferent GABAergic input to GnRH neurons may play a role in elevated GnRH/LH secretion [ 11-19 ]. Prenatally androgenized (PNA) mice, which reflect the cardinal features and neuroendocrine impairments of PCOS [ 20 ], display a greater frequency of GABAergic postsynaptic currents in GnRH neurons [ 13 , 15 ] and elevated GnRH neuron firing frequency [ 15 , 19 , 21 ] compared with fertile controls. This is associated with a greater number of closely associated presynaptic GABAergic terminals and a dramatically increased projection of GABAergic fibers from the arcuate nucleus (ARN) [ 14 ].…”

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…Of great importance for normalization of the steroidogenic function in the ovaries can be MF-induced decrease in the blood LH level and the LH/FSH ratio, which are significantly increased in PCOS [ 216 , 217 , 218 , 219 ] ( Figure 2 ). An increase in the LH/FSH ratio due to abnormal gonadotropin pulsatility and hypersecretion of LH by the pituitary is a significant factor responsible for the deterioration of folliculogenesis and oogenesis in PCOS [ 219 , 220 , 221 , 222 , 223 , 224 ]. In most cases, gonadotropin imbalance is found in PCOS women with obesity, and level of increase in LH is correlated with the severity of obesity [ 220 ].…”