Postnatal Testosterone Exposure Results in Insulin Resistance, Enlarged Mesenteric Adipocytes, and an Atherogenic Lipid Profile in Adult Female Rats: Comparisons with Estradiol and Dihydrotestosterone

Abstract

Postnatal events contribute to features of the metabolic syndrome in adulthood. In this study, postnatally administered testosterone reduced insulin sensitivity and increased the mesenteric fat depot, the size of mesenteric adipocytes, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and the atherogenic index in adult female rats. To assess the involvement of estrogen and androgen receptors in these programming effects, we compared testosterone-exposed rats to rats exposed to estradiol or dihydrotestosterone (DHT). Estradiol-treated rats had lower insulin sensitivity than testosterone-treated rats and, like those rats, had enlarged mesenteric adipocytes and increased triglyceride levels. DHT also reduced insulin sensitivity but did not mimic the other metabolic effects of testosterone. All treated rats were probably anovulatory, but only those treated with testosterone had reduced testosterone levels. This study confirms our previous finding that postnatal administration of testosterone reduces insulin sensitivity in adult female rats and shows that this effect is accompanied by unfavorable changes in mesenteric fat tissue and in serum lipid levels. The findings in the estradiol and DHT groups suggest that estrogen receptors exert stronger metabolic programming effects than androgen receptors. Thus, insults such as sex hormone exposure in early life may have long-lasting effects, thereby creating a predisposition to disturbances in insulin sensitivity, adipose tissue, and lipid profile in adulthood.

Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

“…35 mg oestradiol benzoate used in this study is based on our previous study (Alexanderson et al 2007) since this dose is known to affect insulin sensitivity and metabolism in adult female rats. There is no standardised dose or administration procedure when studying the postnatal effects of oestrogenisation, several different doses and administration regimes have been used (Arai 1964, Pinilla et al 2002, Sotomayor-Zarate et al 2008.…”

“…In a recent study, we showed that an early postnatal injection of oestradiol, testosterone or dihydrotestosterone causes insulin resistance in adult female rats, and that testosterone and oestradiol exposed rats also displayed increased mesenteric weight and/or adipocyte size. Oestradiol having the most pronounced effect suggests oestrogen receptors exert stronger metabolic programming effects than androgen receptors (Alexanderson et al 2007). However, the mechanisms for the effects of early exposure to sex steroids on glucose metabolism in adulthood have not been studied as yet.…”

Developmental androgenization programs metabolic dysfunction in adult mice

“…21,22 Similarly, female rhesus monkeys exposed to prenatal androgen excess manifest a predominant abdominal visceral fat accumulation during adulthood, independent of obesity, reflecting a masculinized pattern of fat accumulation. 23 Importantly, NT exposure in female rats increases visceral adiposity distribution in adults 24,25 and this is true in mice, as noted above. 6 Second, in humans, females from opposite sex twin pairs exposed to prenatal testosterone from testes of a male co-twin develop masculinized eating behaviors as adults, 26 a finding we observed in our mice.…”

Metabolic Aspects of Polycystic Ovary Syndrome

“…Long-term administration of testosterone in female-to-male transsexuals induces abdominal adiposity and insulin resistance [50], and androgen excess during fetal life and infancy is associated with increased risk of developing abdominal adiposity later in life [51][52][53]. Thus, chronic androgen excess in PCOS patients could favor insulin resistance by determining a predominantly abdominal distribution of body fat (Figure 1).…”