Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a Hyperandrogenic PCOS Mouse Model

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterised by a range of endocrine, reproductive and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signalling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels and blood glucose iAUC. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.

Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions

“…The effect of GC on leptin in the center is necessary for female fertility [ 17 ]. A high level of leptin may be a key pathological characteristic of hyperandrogenic PCOS [ 18 ], although aerobic exercise can reduce the level of PCOS leptins by affecting the hypothalamus-pituitary-ovarian axis (HPOA) and improving high androgen. Hyperandrogenemia and sex hormone disorder in PCOS cannot yet be completely improved [ 13 ].…”

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

“…We show that females chronically exposed to the non-aromatisable androgen DHT from a peri-pubertal timepoint for 3 months develop the PCOS-like traits of impaired oestrous cyclicity and increased body weight, as shown previously. 13,15,36,37,38 Although this mouse model incorporates some of the reproductive and metabolic features typical of clinical PCOS, serial tail-tip blood sampling identified that the LH pulse frequency in this model is no different from that in healthy control mice. Likewise, chronic DHT exposure from 3 weeks of age had no significant impact on GnRH neuron spine density or on putative GABAergic inputs to GnRH neurons.…”

Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS)

“…50 There was an improvement in the metabolic traits with a reduction in body weight and adiposity following treatment, but without resolution of the reproductive phenotypes. 50 This may in part reflect the postnatal androgenised model used, which does not display overactivity of arcuate KNDy neurons, 50 and thus may not exclude an effect on reproductive phenotype in other PCOS-like mouse models.…”