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

Abstract

Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signalling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodelling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPY ARN) of ARN GABA neurons (GABA ARN) is also affected in prenatally androgenized (PNA) PCOS-like NPY ARN reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPY ARN neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPY ARN neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPY ARN neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPY ARN neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPY ARN neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPY ARN neurons are not remodelled like the wider GABA ARN population by prenatal androgen excess, indicating GABA-to-GnRH neuron circuit remodelling occurs in a presently unidentified non-NPY/AgRP population of GABA ARN neurons. NPY ARN neurons do, however, show independent changes in the form of elevated androgen sensitivity

Chronic androgen excess in female mice does not impact luteinizing hormone pulse frequency or putative GABAergic inputs to GnRH neurons

“…Here, the number of AR immunoreactive cells in the brain was increased by 4–6‐fold in females chronically exposed to DHT. Although the phenotypes of those neurons with upregulated AR remain to be determined, increased AR expression in the PNA model has been identified in agouti‐related protein neurons, 54 as well as in ARN kisspeptin neurons 55 . This robust upregulation of AR supports direct androgen excess actions in the brain; however, the specific circuits and mechanisms involved remain to be determined.…”

“…4-6-fold in females chronically exposed to DHT. Although the phenotypes of those neurons with upregulated AR remain to be determined, increased AR expression in the PNA model has been identified in agouti-related protein neurons,54 as well as in ARN kisspeptin +, presence of a few positively labelled cells.++, presence of many positively stained cells with enough to clearly demarcate specific nuclei.+++, robust expression of positively labelled cells. DHT, dihydrotestosterone.…”

β-Sitosterol Ameliorates Endometrium Receptivity in PCOS-Like Mice: The Mediation of Gut Microbiota

“…PCOS is characterized by excessive androgen secretion, low ovulation rate, and polycystic ovary (3), and is often accompanied by obesity and insulin resistance (4). Nowadays, research on women with infertility and PCOS mainly focuses on the aspects of ovulation dysfunction, sex hormones, and insulin resistance (5)(6)(7). However, insulin resistance could lead to insufficient glucose supply of endometrial cells, interfering with their growth and activity, thereby affecting endometrium receptivity (8), indicating that PCOS was closely related to endometrium receptivity.…”

Mechanism of leptin-NPY on the onset of puberty in male offspring rats after androgen intervention during pregnancy

“…NPY was identified as the main regulator of GnRH pulse secretion ( 30 ), which is the ‘gatekeeper’ of adolescence ( 31 ). As a regulator, NPY neurons are located in the ARC ( 32 ), which can directly exert an inhibitory effect on GnRH neurons ( 33 ). This effect is achieved by the direct binding of NPY to NPY1R on GnRH neurons ( 34 ).…”