Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

Abstract

Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life.

Predictors of Insulin Resistance and Metabolic Complications in Polycystic Ovarian Syndrome in an Eastern Indian Population

“…Animal models have also shown that prenatal testosterone exposure can induce insulin resistance in early postnatal life [36]. Apter reported that adolescents with functional ovarian hyperandrogenism exhibit disproportionate, early pubertal increases in mean serum insulin levels [37] and Carbould showed that testosterone administration to female rats caused insulin resistance in the skeletal muscles and the adipocytes of women in vitro [20]. Importantly, results of our study keep in track with above observations by showing a significant dependence of the HOMA-IR values on the serum testosterone levels in the PCOS patients (b = 0.498, p = 0.049), which imply that hyperinsulinemia plays a critical intermediary role in androgen induced follicular abnormalities that are the hallmark of the disease.…”

“…Studies demonstrated positive correlations between insulin and androgen levels [5,18] and such correlations existed in both obese and non-obese PCOS women [19]. Although, it is widely accepted that hyperinsulinemia due to insulin resistance causes hyperandrogenism, studies undertaken with reverse aim showed that testosterone administration caused insulin resistance in skeletal muscle of female rats and in adipocytes of women in vitro [20]. On the other hand, the results of some studies suggested that these two conditions might be two separate entities [18].…”

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

“…First, androgens stimulate the hypertrophy of adipocytes by affecting the expression of enzymes and proteins involved in lipid and carbohydrate metabolism, in oxidative stress and in the differentiation of pre-adipocytes into mature adipocytes (42). Secondly, androgens regulate lipolysis, resulting in an increased release of free fatty acids (46). These and other still undefined effects of even modest androgen excess in women may explain the association between visceral fat enlargement and PCOS status in both adolescent and adult women.…”

“…In addition, there is a general consensus that in most women with PCOS, a mild-tomoderate insulin resistance may be responsible for the high prevalence of the metabolic syndrome (39) and that insulin sensitizers, such as metformin, may improve total and free testosterone in these women (1,8). Notably, it should also be recognized that there has been uncertainty as to whether insulin resistance in PCOS has unique characteristics, since androgen excess per se may explain the development of insulin resistance in the insulin-sensitive tissues, such as fat, muscles and liver (46). In any case, the role of severe insulin resistance and very high circulating insulin in determining the PCOS phenotype in patients with SSIR states is confirmed on both clinical and basic research studies (69).…”

Obesity and Female Fertility: The Bridging Role of Leptin

“…On the other hand, peripheral conversion of androgens to estrogen in adipose tissue inhibits gonadotrophin secretion [39]. Increased androgens in turn contribute to 'apple' and not 'pear' shaped obesity [44,45]; thus, a vicious circle evolves, where abdominal fat accumulation increases insulin resistance and androgen production, with hyperandrogenemia promoting hyperinsulinemia and so forth [46,47].…”