Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant reactive oxygen species production

Abstract

Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesized that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress, inflammation, and perturbed gene expression. Here, we tested this hypothesis by studying the metabolic, endocrine, and uterine abnormalities in pregnant rats after exposure to daily injection of 5α-dihydrotestosterone (DHT; 1.66 mg·kg body wt−1·day−1) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that whereas DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT + insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared with controls, hyperandrogenism and insulin resistance in the dam were associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization ( Prl8a2, Fxyd2, and Mt1g), placentation ( Fcgr3 and Tpbpa), angiogenesis ( Flt1, Angpt1, Angpt2, Ho1, Ccl2, Ccl5, Cxcl9, and Cxcl10) and insulin signaling (Akt, Gsk3, and Gluts). Moreover, we observed changes in uterine mitochondrial function and homeostasis (i.e., mitochondrial DNA copy number and the expression of genes responsible for mitochondrial fusion, fission, biogenesis, and mitophagy) and suppression of both oxidative and antioxidative defenses (i.e., reactive oxygen species, Nrf2 signaling, and interactive networks of antioxidative stress responses) in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.

Malic enzyme 1 is important for uterine decidualization in response to progesterone/cAMP/PKA/HB‐EGF pathway

“…13 Gravid uterine defects induced by hyperandrogenism and insulin resistance have been proved to be associated with mitochondrial dysfunction and aberrant ROS production. 16 Since ATP is mainly produced in the mitochondria which are associated with energy metabolism, the loss of ATP content is considered to be a powerful indicator of mitochondrial dysfunction. 38,39 In addition to ATP levels, mtDNA copy numbers and mitochondrial membrane potential can also reflect the integrity of mitochondrial function.…”

“…[9][10][11] Accumulating evidence have demonstrated that the mitochondrial function and elevated ROS-induced oxidative stress play a key role in the female reproduction and fertility. [12][13][14][15][16] A latest research showed that gravid uterine defects induced by hyperandrogenism and insulin resistance are related to the mitochondrial dysfunction and aberrant ROS production. 16 Moreover, mitochondrial ROS-dependent signaling involves in the regulation of multiple biological processes including cellular proliferation, differentiation as well as physiological, and pathological outcomes.…”

“…[12][13][14][15][16] A latest research showed that gravid uterine defects induced by hyperandrogenism and insulin resistance are related to the mitochondrial dysfunction and aberrant ROS production. 16 Moreover, mitochondrial ROS-dependent signaling involves in the regulation of multiple biological processes including cellular proliferation, differentiation as well as physiological, and pathological outcomes. 12,16,17 Although it has been well established that Me1 is critical for mitochondrial function and cellular redox maintenance, its physiological role in the process of implantation and decidualization is still unclear.…”

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

“…Given the significant association of PCOS with miscarriage during pregnancy (16, 17), we have recently demonstrated that the effects of HAIR in causing fetal loss is the consequence of uterine and placental defects (18, 19). To this end, we exposed pregnant rats to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day (GD) 7.5 to 13.5 and found that this triggered many features of pregnant PCOS patients (including HAIR), as well as increased fetal loss.…”

“…In particular, our previous animal experiments have shown that maternal HAIR-induced fetal loss is also associated with the inactivation of antioxidative proteins in the gravid uterus and placenta, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 1 (18, 19), which play an inhibitory role in the ferroptosis pathway (6, 10). Moreover, the expression of several other negative regulators of ferroptosis such as Ho1 (heme oxygenase 1) (6) and Mt1g (metallothionein 1G) (20) are downregulated in the gravid uterus after combined maternal exposure to DHT and INS (18). Increased circulating ROS levels have been observed in both non-pregnant and pregnant rodents in which PCOS features have been induced (19, 21).…”