Endogenous Testosterone Levels Are Associated With Risk of Type 2 Diabetes in Women Without Established Comorbidity

Jon J. Rasmussen; Christian Selmer; Signe Frøssing; Morten Schou; Jens Faber; Christian Torp-Pedersen; Gunnar H. Gislason; Lars Køber; David M. Hougaard; Arieh S. Cohen; Caroline Kistorp


J Endo Soc. 2020;4(6) 

In This Article

Abstract and Introduction


Purpose: The impact of endogenous androgen levels on the risk of type 2 diabetes in women remains uncertain. The objective was to investigate associations between endogenous androgen levels and risk of type 2 diabetes in young women without established comorbidity.

Methods: In this retrospective cohort study, women aged 18 to 50 years who underwent measurement of plasma testosterone, dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) for the first time from January 2007 to December 2015 were included. Androgens were analyzed using tandem liquid chromatography mass spectrometry. Women with established comorbidity were excluded, using Danish healthcare registries. We calculated incidence rate ratios (IRRs, 95% confidence intervals) of type 2 diabetes according to quartiles of plasma androgens using multivariate Poisson regression models.

Results: A total of 8876 women, with a mean ± SD age of 38.5 ± 4.6 years and a median (interquartile range [IQR]) follow-up duration of 8.1 (6.6–9.4) years, were eligible for analyses. During 69 728 person-years, 69 women were diagnosed with type 2 diabetes. Women in the highest quartile of plasma total testosterone and calculated free testosterone displayed increased risk of type 2 diabetes compared with the lowest quartile: IRR 1.97 (1.01; 3.85), P = .048 and IRR 7.32 (2.84; 18.83), P < .001. SHBG was inversely associated with type 2 diabetes, Q4 versus Q1; IRR 0.06 (0.02; 0.21), P < .001. Plasma DHEA-S and DHT were not associated with incident type 2 diabetes.

Conclusions: Higher levels of plasma total and free testosterone were associated with increased risk of type 2 diabetes among women.


The impact of endogenous androgens on risk of type 2 diabetes is well established in women with established hyperandrogenism such as polycystic ovary syndrome (PCOS),[1,2] a condition strongly associated with increased insulin resistance, but knowledge on plasma testosterone level per se as a risk factor in women without established hyperandrogenism is warranted. Only few prospective studies have investigated the relation between and with conflicting results.[3–8] The available literature is predominantly based on postmenopausal women, whereas longitudinal studies among premenopausal women are scarce.[3,4] Furthermore, information on the association between other endogenous androgens than testosterone and type 2 diabetes in women is virtually nonexistent. The impact of hyperandrogenism on insulin resistance in women has been investigated in several observational studies; although not fully understood, the potential mechanisms include hyperandrogenism induced: hepatic steatosis increased visceral adipose tissue, and dysfunctional adipose tissue.[9–11] In women, endogenous androgen levels decrease steadily following the age of 30 years.[12–15] When reaching menopause, women have lost approximately 60% of their total androgen pool,[14] which, in theory, could limit the impact of androgens on the risk of type 2 diabetes among postmenopausal women. The female adrenal pool consist of various androgens which differ in plasma levels and affinity for the androgen receptor.[16] Plasma levels of testosterone and dihydrotestosterone (DHT) are very low in women but have high affinity for the androgen receptor and therefore hold solid androgenic properties whereas the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) is found in high plasma concentrations but possesses low affinity for the androgen receptor and is mainly considered a precursor androgen.[13]

The objective of this study was to investigate the relation between risk of incident type 2 diabetes and plasma levels of total testosterone (TT), calculated free testosterone (cFT), DHT, DHEA-S, and sexual hormone-binding globulin (SHBG) using a retrospective cohort of young women who had no established comorbidities.