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Associations of Steroid Sex Hormones and Sex Hormone–Binding Globulin with the Risk of Type 2 Diabetes in Women: a Population-Based Cohort Study and Meta-Analysis

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Associations of Steroid Sex Hormones and Sex Hormone–Binding Globulin with the Risk of Type 2 Diabetes in Women: a Population-Based Cohort Study and Meta-Analysis Diabetes Volume 66, March 2017 577 Taulant Muka,1,2 Jana Nano,1 Loes Jaspers,1 Cindy Meun,3 Wichor M. Bramer,4 Albert Hofman,1,2 Abbas Dehghan,1 Maryam Kavousi,1 Joop S.E. Laven,2 and Oscar H. Franco1 Associations of Steroid Sex Hormones and Sex Hormone–Binding Globulin With the Risk of Type 2 Diabetes in Women: A Population-Based Cohort Study and Meta-analysis Diabetes 2017;66:577–586 | DOI: 10.2337/db16-0473 It remains unclear whether endogenous sex hormones for being accompanied by an increased risk of cardiovas- (ESH) are associated with risk of type 2 diabetes (T2D) in cular disease and type 2 diabetes (T2D) (1,2). Changes in women. Data of 3,117 postmenopausal women partici- hormonal patterns in menopause, including the decline in pants of the Rotterdam Study were analyzed to examine endogenous estradiol (E) levels and the relative androgen – whether ESH and sex hormone binding globulin (SHBG) excess, contribute to an increase in visceral adiposity that METABOLISM were associated with the risk of incident T2D. Addition- is associated with glycemic traits and therefore may influ- ally, we performed a systematic review and meta-analysis ence the risk of T2D (3,4). Furthermore, polycystic ovary of studies assessing the prospective association of ESH syndrome, a common disorder among women character- and SHBG with T2D in women. During a median follow-up ized by hyperandrogenism, has been identified as a signif- of 11.1 years, we identified 384 incident cases of T2D in icant nonmodifiable risk factor associated with T2D (5). the Rotterdam Study. No association was observed be- Although the relation between sex hormone–binding tween total testosterone (TT) or bioavailable testosterone globulin (SHBG) and T2D has long been recognized (6,7), (BT) with T2D. SHBG was inversely associated with the risk of T2D, whereas total estradiol (TE) was associated literature on the associations of steroid sex hormones, such with increased risk of T2D. Similarly, in the meta-analysis as endogenous E and testosterone (T), with T2D is scarce. of 13 population-based prospective studies involving SHBG, T, and E have been associated with glucose me- – more than 1,912 incident T2D cases, low levels of SHBG tabolism and development of insulin resistance (6 9). and high levels of TE were associated with increased risk Few epidemiological studies investigating the relation of T2D, whereas no associations were found for other between sex hormones and T2D have yielded conflicting hormones. The association of SHBG with T2D did not results (10–12). These studies were limited by their cross- change by menopause status, whereas the associations sectional design, selected samples, or insufficient adjust- of ESH and T2D were based only in postmenopausal ment for diabetes risk factors. To date, no large prospective women. SHBG and TE are independent risk factors for cohort study has examined the association of T2D with the development of T2D in women. SHBG, T, and E in healthy postmenopausal women. Thus, we aimed to investigate the association between SHBG, sex hormones, and T2D in postmenopausal women. Menopause is an important transition in a woman’s life, Furthermore, to clarify the contradictory results, we sys- not only for marking the end of reproductive life but also tematically reviewed and meta-analyzed studies evaluating 1Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands This article contains Supplementary Data online at http://diabetes 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0473/-/DC1. MA T.M., J.N., M.K., and J.S.E.L. contributed equally to this work. 3Department of Obstetrics and Gynecology, Erasmus MC, Rotterdam, the © 2017 by the American Diabetes Association. Readers may use this article as Netherlands long as the work is properly cited, the use is educational and not for profit, and the 4Medical Library, Erasmus MC, Rotterdam, the Netherlands work is not altered. More information is available at http://www.diabetesjournals Corresponding author: Taulant Muka, [email protected]. .org/content/license. Received 13 April 2016 and accepted 4 October 2016. See accompanying article, p. 568. 578 Steroid Sex Hormones, SHBG, and T2D Diabetes Volume 66, March 2017 the association between SHBG, sex hormones, and T2D and ,5%. The free androgen index (FAI), calculated as in women. (T/SHBG)*100,isusedasasurrogatemeasureofbio- available testosterone (BT) (16). RESEARCH DESIGN AND METHODS Population of Analysis The Rotterdam Study The current study used data from the third visit of the The Rotterdam Study is a prospective cohort study which first cohort (RSI-3) and the baseline examinations of the started since 1990 in the Ommoord district, in the city of second (RSII-1) cohort. Overall, there were 3,683 post- Rotterdam, the Netherlands. Details regarding the design, menopausal women eligible for blood measurements. objectives, and methods of the Rotterdam Study have Among them, 122 women did not come for a blood been described in detail elsewhere (13). In brief, in 1990, measurement at the research center and 32 did not have all inhabitants of a well-defined district of Rotterdam T2D follow-up data and were excluded from the analysis. were invited, of whom 7,983 agreed (78.1%). In 2000, Furthermore, 412 women with prevalent T2D were an additional 3,011 participants were enrolled (RS-II), excluded, leaving 3,117 for our final analysis. Potential consisting of all people living in the study district who confounding variables are described in detail in Supple- had become 55 years of age. Follow-up examinations were mentary Appendix 1. performed periodically, approximately every 3–5 years (13). There were no eligibility criteria to enter the Rotterdam Statistical Analysis Study cohorts except the minimum age and residential Person-years of follow-up were calculated from study area based on ZIP codes. The Rotterdam Study has been entrance (March 1997 to December 1999 for RSI-3 and approved by the medical ethics committee according to the February 2000 to December 2001 for RSII-1) to the date Population Screening Act: Rotterdam Study, executed by of diagnosis of T2D, death, or the censor date (date of the Ministry of Health, Welfare and Sport of the Nether- last contact of the living), whichever occurred first. lands. All participants in the present analysis provided Follow-up was until 1 January 2012. Cox proportional written informed consent to participate and to obtain hazards modeling was used to evaluate whether SHBG, TT, information from their treating physicians. TE, and BT were associated with T2D. Relative risks (RRs) and 95% CIs were reported. All sex hormone variables were Ascertainment of T2D assessed in separate models, continuously and in tertiles. The participants were followed from the date of baseline For E, first tertile included all women with levels of E center visit onwards. At baseline and during follow-up, cases lower than the detection limit (n = 992). To study the of T2D were ascertained through active follow-up using relations across increasing tertiles, trend tests were general practitioners’ records, glucose hospital discharge let- computed by entering the categorical variables as con- ters, and glucose measurements from Rotterdam Study vis- tinuous variables in multivariable Cox proportional hazards its, which take place approximately every 4 years (14). T2D fi models. To achieve approximately normal distribution, was de ned according to recent World Health Organization skewed variables (SHBG, TT, BT, plasma triglyceride, guidelines, as a fasting blood glucose $7.0 mmol/L, a non- LDL cholesterol [LDL-C], C-reactive protein [CRP], fasting blood glucose $11.1 mmol/L (when fasting samples thyroid-stimulating hormone [TSH], and insulin) were were absent), or the use of blood glucose–lowering medica- natural log transformed. In the base model (model 1), tion (15). Information regarding the use of blood glucose– we adjusted for age, cohort (1,2), and fasting status (fast- lowering medication was derived from both structured home ing sample vs. nonfasting sample). To examine whether interviews and linkage to pharmacy records (14). At base- the relations of sex hormones and SHBG with risk of T2D line, .95% of the Rotterdam Study population was covered were independent of established risk factors for T2D, by the pharmacies in the study area. All potential events model 2 included the terms of model 1, BMI (continuous), of T2D were independently adjudicated by two study glucose (continuous), and insulin (continuous). BMI and physicians. In case of disagreement, consensus was sought waist circumference were highly correlated (Pearson cor- with an endocrinologist. Follow-up data were complete relation coefficient = 0.81, P , 0.001), so only BMI was until 1 January 2012. used as a measure of adiposity, consistent with previous Sex Steroid Measurements studies (10,12). Model 3 included all covariates in model All blood samples were drawn in the morning (#11:00 A.M.) 2 and further potential intermediate factors, including and were fasting. Total estradiol (TE) levels were mea- metabolic risk factors (total cholesterol, systolic blood sured with a radioimmunoassay and SHBG with the Im- pressure [continuous], indication for hypertension [yes mulite platform (Diagnostic Products Corporation, vs. no], and use of lipid-lowering medications [yes vs. Breda, the Netherlands). The minimum detection limit no]), lifestyle factors (alcohol intake [continuous] and
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