Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation

Abstract

BackgroundMetformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS)-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function.MethodsWe utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization (progesterone production) in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype.ConclusionsOur data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their response to metformin is related to elevated leptin levels and/or if a subset of PCOS women with hyperleptinemia may be responsive to metformin therapy. Further study is needed to better define a subset of women with PCOS that may be responsive to metformin.

The mechanism of mTOR (mammalian target of rapamycin) in a mouse model of polycystic ovary syndrome (PCOS)

“…The disrupted hypothalamic-pituitary synchrony, increased gonadotropin pulsatile secretion, destroyed oocyte-granulosa cell interaction, increased ovarian androgen production, hyperinsulinemia, and insulin resistance included the etiologies of PCOS [13]. Studies confirmed that the DHEA-treated PCOS murine model exhibits many of the salient features of human PCOS [14,15].…”

Rodent models of polycystic ovary syndrome

“…Adult ob/ob and db/db females are infertile and exhibited acyclicity, anovulation, and increased follicular atresia [89][90][91][92]. Hormone changes in ob/ob mice included significantly increased serum T, E2, and P levels [93,94] and reduced serum FSH levels [95], while db/db females exhibited a significant decrease in serum E2 and P levels. Metabolic features of PCOS exhibited by both mutant mice include severe obesity, a diabetes-like syndrome of hyperglycemia, glucose intolerance, and elevated plasma insulin [91,94,[96][97][98].…”

“…Hormone changes in ob/ob mice included significantly increased serum T, E2, and P levels [93,94] and reduced serum FSH levels [95], while db/db females exhibited a significant decrease in serum E2 and P levels. Metabolic features of PCOS exhibited by both mutant mice include severe obesity, a diabetes-like syndrome of hyperglycemia, glucose intolerance, and elevated plasma insulin [91,94,[96][97][98]. However unlike human PCOS, polycystic ovaries were not present in either model, and serum LH levels were unchanged in ob/ob mice [95].…”

Vitamin D3 regulates steroidogenesis in granulosa cells through AMP‐activated protein kinase (AMPK) activation in a mouse model of polycystic ovary syndrome

“…13 AMPK is a multi-substrate enzyme that is activated in response to physiological and pharmacological stimuli, which have important roles not only in metabolism but also in reproduction and, more precisely, in the ovary. 14,19 Metformin, as an insulin sensitizer drug, could decrease estradiol and progesterone secretion through an AMPK-dependent mechanism in bovine granulosa cells. 15 The upstream kinases of AMPK, LKB1, and calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) activate it by phosphorylating Thr172 in the activation loop of the catalytic α-subunit.…”

“…18 It has been shown that Aicar, an activator of AMPK, could reduce progesterone secretion by decreasing 3β-HSD production in rat granulosa cells. 14,19 Metformin, as an insulin sensitizer drug, could decrease estradiol and progesterone secretion through an AMPK-dependent mechanism in bovine granulosa cells. 18 Considering the role of AMPK in energy homeostasis and its possible role in ovarian function, some studies have declared, it may be involved in the interactions between metabolism and reproduction.…”