Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

Abstract

Background: Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. Results: The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). Conclusions: We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.

Relationship between gut environment, feces-to-food ratio, and androgen deficiency-induced metabolic disorders

“…that androgen-related gut microbiota changes are involved in PCOS pathophysiology. Fetal or neonatal androgen excess is also associated with dysbiosis in a model of PCOS, 47,48 supporting the idea that fetal and neonatal development affects longterm gut microbiota composition.…”

Correlation Between Fecal Metabolomics and Gut Microbiota in Obesity and Polycystic Ovary Syndrome

“…Gut DHEAS may come from the excessive serum DHEAS and partly may be converted by the gut microbiota. Disordered gut microbiota and metabolites may act on multiple organs throughout the body by damaging the intestinal mucosal barrier, affecting the serum sex hormone levels, glycogen biosynthesis and metabolism, and causing systemic chronic inflammation (45,46). DHEAS in the intestinal and peripheral circulation of obese patients with PCOS may be freely exchanged, whereas too much androgens can affect the diversity and richness of gut microbiota (47).…”

Fecal Microbiota Changes in Patients With Postpartum Depressive Disorder

“…A recent study has demonstrated that the regulation of sex hormones–microbiota–inflammation axis could ameliorate polycystic ovary syndrome (PCOS), including Faecalibacterium, Parabacteroides, Bifidobacterium , and so on (Wang et al, 2020 ). Another study showed that prenatal androgen exposure causes hypertension and gut microbiota dysbiosis (Sherman et al, 2018 ). Moreover, a study found that small amounts of brain E2 and PROG could improve menopausal symptoms by decreasing serum FSH levels and maintaining the diversity of the gut microbiome in estrogen-deficient rats (Park et al, 2018 ).…”