Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice

Abstract

Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. We determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropins. Hypothalamic KiSS1 neurons are believed to be critical in the onset of puberty and are the target of leptin. Adult NTM showed lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity and decreased energy expenditure. They developed a delayed increase in subcutaneous white adipose tissue. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…42 , 77 PCOS has been linked to metabolic syndrome particularly insulin resistance 78 and hypertension. 79 −82 When a pregnant mother with PCOS is subsequently diagnosed with hyperinsulinemia, hypertension, or hyperandrogenemia during pregnancy this increases maternal and fetal morbidity and mortality. 83 −85 The likelihood of developing obstetric complications during pregnancy such as gestational diabetes, preeclampsia, and early termination of pregnancy increase.…”

Developmental androgenization programs metabolic dysfunction in adult mice

“…In contrast, littermate NTM displayed an early reduction in lean mass and had a delayed increase in subcutaneous white adipose tissue without accompanying decreases in adiponectin or active osteocalcin. 6 They also showed decreased locomotor activity and energy expenditure that could be related to decreased lean mass. 6 NTF displayed adipose tissue hyperplasia that demonstrated more cells in the adipose depots were committed to the adipocyte lineage.…”

“…6 They also showed decreased locomotor activity and energy expenditure that could be related to decreased lean mass. 6 NTF displayed adipose tissue hyperplasia that demonstrated more cells in the adipose depots were committed to the adipocyte lineage. However, classical genetic markers of adipose differentiation (CEBPs and PPARγ) were not increased.…”

“…When these mice matured, we compared female mice exposed to neonatal testosterone (NTF) with control females (CF), control males (CM), and male mice exposed to neonatal testosterone (NTM). [6][7][8] Importantly, littermate males and females were androgenized at the same time, thereby facilitating comparison of their phenotypes in adulthood.…”

“…Rather, they displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropins. 6 Hypothalamic KiSS1 neurons are believed to be critical in the onset of puberty and are a target of leptin. Adult NTM showed lower hypothalamic Kiss1 expression and failure of leptin to upregulate Kiss1 expression.…”