Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Abstract

Objective: In hyperandrogenic women, hyperinsulinaemia amplifies 17a-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects. Design and methods: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80 mU/m 2 !min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5 mg/h) was carried out. Serum cortisol, progesterone, 17a-hydroxyprogesterone (17-OHP), 17a-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion. Results: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P!0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5a-reductase activity. Conclusions: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

Management of adolescents with congenital adrenal hyperplasia

“…However, in women with hyperandrogenism due to other causes, an acute increase in insulin increases adrenocorticotropic hormone-mediated adrenal androgens. 26 …”

Hypothalamic-Pituitary-Adrenocortical Axis Hypersensitivity and Glucocorticoid Receptor Expression and Function in Women with Polycystic Ovary Syndrome

“…These results imply that the mechanisms other than HPA axis dysfunction may be included in maintaining adrenal androgen excess in PCOS. One of these mechanisms could be adrenocortical hyperresponsiveness to ACTH observed in PCOS patients with adrenal androgen excess ( Moran et al, 2004, Tosi et al, 2011. In additon, there are data suggesting that some extra-adrenal factors, including ovarian hormones and factors related to glucose/insulin axis and obesity, may play a role in adrenal androgen overproduction in PCOS ( Yildiz and Azziz, 2007 ).…”

Significado cardiometabólico do excesso de peso/obesidade numa população de 263 mulheres inférteis com síndrome do ovário poliquístico

“…A análise comparativa evidenciou proporções mais elevadas de hiperandrogenismo clínico e/ou bioquímico, hipertrigliceridemia, níveis baixos de colesterol-HDL, hipertensão arterial, insulino-resistência, bem como maior perímetro da cinturanas SOP-ob. Estes dados estão globalmente em concordância com a literatura científica 11,26,29,34,35,36 . Apesar da insulino-resistência e dos distúrbios metabólicos poderem estar associados ao SOP independentemente da obesidade, a verdade é que mulheres obesas com SOP exibem maior insulino-resistência e prevalência/gravidade de desequilíbrios metabólicos, o que imputa ao peso/massa corporal um papel relevante na condição de SOP.…”

“…Têm sido reportados níveis mais elevados de testosterona total nas mulheres obesas com SOP do que nas com peso normal 29,33 . Tal parece estar associado à hiperprodução androgénica quer pelo ovário, quer pela supra-renal, estimulada pela hiperinsulinemia na obesidade 11,34 . Por outro lado, o tecido adiposo é um importante reservatório de hormonas esteróides sexuais, incluindo os androgénios 11,39 .…”