Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice

Abstract

The present study examined the mechanism by which metformin prevents dehydroepiandrosterone (DHEA)-induced embryonic resorption in mice. Treatment with DHEA (6 mg/100 g bodyweight, 24 and 48 h post implantation) induced 88 +/- 1 % embryonic resorption and the diminution of both serum oestradiol (E) and progesterone (P) levels. However, when metformin (50 mg/kg bodyweight) was given together with DHEA, embryo resorption (43 +/- 3% v. 35 +/- 5% in controls) and both serum E and P levels were not significantly different from controls. Glucose and insulin levels were increased in the DHEA-treated mice but when metformin was administered together with DHEA these parameters were similar to control values. Treatment with DHEA increased ovarian oxidative stress and diminished uterine nitric oxide synthase (NOS) activity; however, when metformin was administered together with DHEA, both ovarian oxidative stress and uterine NOS activity were not different from controls. Metformin treatment did not modify the percentage of CD4(+) and CD8(+) T cells from both axillar and retroperitoneal lymph nodes but prevented the increase of serum tumour necrosis factor +/- produced in DHEA-treated mice. These results show that metformin acts in DHEA-induced embryonic resorption in mice by modulating endocrine parameters, ovarian oxidative stress and uterine NOS activity.

Peroxisome proliferator-activated receptor gamma and early folliculogenesis during an acute hyperandrogenism condition

“…The activation of PPARg regulates the synthesis of steroid hormones in the granulosa cells (14), and the disruption of PPARg in the ovary leads to female subfertility (15). We previously reported that hyperandrogenization of BALB/c mice prevents ovulation (5,(16)(17)(18)(19)(20) by modulating AMPK (5). These findings, together with the fact that AMPK and PPARg control the energy balance in the ovary (21), have led us to study whether hyperandrogenism interferes with early folliculogenesis by modulating the PPARg pathway.…”

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

“…Met or other AMPK agonists are often studied for their positive effects on maternal metabolism or when pathogenic insults are present. In vivo AMPK can reverse 88 % resorption rate caused by dehydroepiandrosterone (DHEA); however, rescue to 45 % resorption does not match 35 % normal resorption rate [26]. Similarly, clomiphene and Met reverse low fecundity of PCOS patients, but there is loss of chemical pregnancy in Met metformin alone compared with clomiphene and metformin [12].…”

Detrimental effects of hyperandrogenism on uterine functions

“…Since dehydroepiandrosterone (DHEA) is one of the most abundant androgens produced by ovaries of women with PCOS, a rodent model was early developed by injection of a dose of DHEA equivalent to the concentration of DHEA in women with PCOS [2]. Subsequent studies established that the DHEA-PCOS murine model exhibits many of the salient features of human PCOS, such as hyperandrogenism, insulin resistance, abnormal maturation of ovarian follicles and anovulation [3][4][5][6][7][8][9][10][11]. In previous studies we have reported that hyperandrogenization of BALB/c mice with DHEA induces ovarian cysts and insulin resistance and increases both ovarian steroidogenesis and oxidative stress [7,8,10].…”