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Summary

The belief that having high testosterone is bad for cardiometabolic health is entrenched in medical training. This has been explored again by Rasmussen and colleagues in their recent paper published in the Journal of the Endocrine Society [1]. They have reported on associations between baseline total testosterone, SHBG and calculated free testosterone and development of type 2 diabetes (T2D) in a sample of 8876 women, mean age 38.5 years and a median follow up of 8.1 years. The sample was recruited from the national database of Danish women who underwent first-time measurement of endogenous androgens at the Nationally approved laboratory, Danish State Serum Institute, Copenhagen, Denmark, from January 1, 2007, until December 31, 2015. It was not stated why women were having their androgens measured. Eligible women were aged 18 to 50 years, with no established chronic morbidity, including no history of PCOS, hirsutism and were not known to be taking oral contraception, androgens, diuretics, cardiovascular or anti-glycemic medications at the time blood was drawn. The investigators did not appear to have information regarding menopause status, smoking behaviour, or body mass index (BMI) to include in the analysis. During the follow-up period, 69 women developed T2D. The investigators reported that women in the lowest quartile of SHBG, and highest quartiles of estimated free testosterone and total testosterone were more likely to develop T2D. Their conclusion was that “Higher levels of plasma total and free testosterone were associated with increased risk of type 2 diabetes among women”.

Commentary

Does this study reassure us that higher testosterone is indeed bad? I would suggest no. Rather, this paper reaffirms a strong association between low SHBG and T2D, as previously reported [2], and indicates a need for a greater understanding of the association between SHBG and T2D. The analysis unfortunately is missing important variables, such as smoking and menopause status, as well as BMI. It has been clearly established that women who smoke have higher testosterone levels [3, 4]. Furthermore, smoking is associated with an increased risk of T2D [5]. In Denmark in 2010, approximately 20% of women were smokers, and this percentage may have been higher in 2007. BMI and menopausal status each influence diabetes risk and higher BMI is associated with lower SHBG. Additionally, the clinical indication for the measurement of testosterone in these women was not known. Testosterone is not something measured routinely in otherwise well women. With respect to the results, women were evaluated according to which quartile of total testosterone, SHBG and calculated free testosterone they fitted into. The adjusted risk of T2D was not increased for women in the second or third quartile of total testosterone versus the lowest quartile, and only just reached significance for the highest, versus the lowest, quartile (IRR 1.97 (95%Ci 1.01-3.85). In contrast, the association between SHBG and T2D risk is striking; women in the highest quartile of SHBG versus the lowest were substantially less likely to develop T2D (IRR 0.06, 95% CI 0.02-0.21). There is evidence that SHBG may be metabolically active. SHBG levels vary in women, with levels inversely linked to central adiposity and insulin levels [6-8]. SHBG is a strong independent marker of insulin resistance and T2D risk [2] and has been implicated in the pathogenesis of type 2 diabetes and CVD [2]. Strong, inverse relationships between both insulin resistance and SHBG [9], independent of sex steroids have been demonstrated. Taken together this study is a reminder that testosterone physiology in women is complex, that the understanding of the role of testosterone in women needs a multidimensional perspective, that includes an understanding of the role of SHBG.

Susan Davis
Director, the Women’s Health Research Program, School of Public Health and Preventive Medicine,
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

References

  1. Rasmussen JJ, Selmer C, Frøssing S, Schou M, Faber J, Torp-Pedersen C, Gislason GH, Køber L, Hougaard DM, Cohen AS, Kistorp C. Endogenous testosterone levels are associated with risk of type 2 diabetes in women without established comorbidity, Journal of the Endocrine Society, May 15, 2020.
    https://doi.org/10.1210/jendso/bvaa050
  2. Ding EL, Song Y, Manson JE, et al.: Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361:1152-1163.
    https://pubmed.ncbi.nlm.nih.gov/19657112/
  3. Davison SL, Bell R, Donath S, Montalto JG, Davis SR: Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90:3847-3853.
    https://pubmed.ncbi.nlm.nih.gov/15827095/
  4. Skiba MA, Bell RJ, Islam RM, Handelsman DJ, Desai R, Davis SR: Androgens during the reproductive years, what’s normal for women? J Clin Endocrinol Metab. 2019.
    https://pubmed.ncbi.nlm.nih.gov/31390028/
  5. Jee SH, Foong AW, Hur NW, Samet JM: Smoking and risk for diabetes incidence and mortality in Korean men and women. Diabetes Care. 2010;33:2567-2572.
    https://pubmed.ncbi.nlm.nih.gov/20823342/
  6. Nestler JE, Strauss JF, 3rd. Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinology and metabolism clinics of North America. 1991;20:807-823.
    https://pubmed.ncbi.nlm.nih.gov/1778178/
  7. Goodman-Gruen D, Barrett-Connor E: Sex hormone-binding globulin and glucose tolerance in postmenopausal women. The Rancho Bernardo Study. Diabetes Care. 1997;20:645-649.
    https://pubmed.ncbi.nlm.nih.gov/9096996/
  8. Randolph JF, Jr., Sowers M, Gold EB, et al.: Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab. 2003;88:1516-1522.
    https://pubmed.ncbi.nlm.nih.gov/12679432/
  9. Davis SR, Robinson PJ, Moufarege A, Bell RJ: The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol (Oxf). 2012;77:541-547.
    https://pubmed.ncbi.nlm.nih.gov/22106826/
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