Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics

Abstract

Among the premenopausal women, Polycystic Ovary Syndrome (PCOS) is the most prevalent endocrinopathy affecting the reproductive system and metabolic rhythms leading to disrupted menstrual cycle. Being heterogeneous in nature it is characterized by complex symptomology of oligomennorhoea, excess of androgens triggering masculine phenotypic appearance and/or multiple follicular ovaries. The etiology of this complex disorder remains somewhat doubtful and the researchers hypothesize multisystem links in the pathogenesis of this disease. In this review, we attempt to present several hypotheses that tend to contribute to the etiology of PCOS. Metabolic inflexibility, aberrant pattern of gonadotropin signaling along with the evolutionary, genetic and environmental factors have been discussed. Considered a lifelong endocrinological implication, no universal treatment is available for PCOS so far however; multiple drug therapy is often advised along with simple life style intervention is mainly advised to manage its cardinal symptoms. Here we aimed to present a summarized view of pathophysiological links of PCOS with potential therapeutic strategies.

Keywords: Environmental toxins; Etiology; Genetics; Neuroendocrine; PCOS; Potential therapeutics.

Fig. 1

Two-cell, two-gonadotropin theory depicting ovarian sterodgenesis; theca cells produces androgens in response to LH which are later converted into estrogens in granulosa cells under the action of FSH, governed by the series of various enzymes. The androgen synthesis and conversion to estrogens needs to be properly coordinated for the optimized ovarian function, which seems to be disturbed in PCOS women resulting in hyperandrogenism and anovulation [39]

Fig. 2

Depiction of the possible mechanism involved in triggering the hyperandogenism via defective insulin signaling pathway. Increased serine phosphorylation of IRS-1 hampers the activation of PI3K leading to reduced uptake of glucose by GLUT4 favoring I.R. I.R interferes with the SHBG, acts on theca cells and provokes LH excess to aggravate hyperandrogenism. On the other hand, the picture becomes further exaggerated when HA downregulates the aromatase activity leading to follicular atresia. MAPK-ERK1/2 impairment inhibits GCs proliferation resulting in follicular atresia [–75]

Fig. 3

Potential impact of environmental toxins on female reproductive health linked to PCOS phenotypes and adverse health effects

Fig. 4

Neuroendocrine circuit disruption leading to PCOS

Fig. 5

Interplay between the potential pathways that gets disrupted, eventually leading to reproductive and metabolic failure witnessed in PCOS