Sex Hormone Arms Men, Harms Women Facing Diabetes

The same sex hormone that signals a lower risk of type 2 diabetes in men appears to increase the risk of the disease in women, according to a comprehensive analysis of the world’s best available evidence.

The results clarify a peculiar sex discrepancy in the scientific literature and set the stage for researchers to investigate how and why sex hormones differentially influence and predict type 2 diabetes and its complications in men and women.

Photo by Liza Green, HMS Media Services

In a systematic review of 43 observational studies, Eric Ding (right), Vasanti Malik, and their co-authors found that high testosterone levels are associated with higher risk of type 2 diabetes in women, but with lower risk in men.

Men with type 2 diabetes had significantly lower testosterone levels, while men with higher testosterone levels had a 42 percent lower risk of the disease, according to the pooled analyses.

Testosterone seemed to have the opposite effect in women, the same analyses showed. Women with type 2 diabetes had higher levels of the sex hormone. Further calculations seemed to confirm the different relationship. High levels of a binding protein believed to render testosterone less active in the blood were more protective in women than in men. The study also showed that elevated estradiol, an estrogenic hormone, predicted type 2 diabetes in both men and postmenopausal women, but the evidence was weaker.

“Aside from cases of polycystic ovarian syndrome and type 2 diabetes in women, researchers and clinicians may not be aware of these associations between testosterone levels and risk of type 2 diabetes, because most of the individual studies are too small to be statistically significant,” said JoAnn Manson, the Elizabeth F. Brigham professor of women’s health at HMS and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital. “This meta-analysis helps to establish that these associations are actually quite strong and consistent.” Manson was not involved in the paper, but she is collaborating with the authors on larger prospective follow-up studies of these sex-based differences in the Women’s Health Study and Physicians’ Health Study.

Class Act
Led by Eric Ding, a doctoral candidate at the Harvard School of Public Health, the systematic review started as an assignment for last spring’s research synthesis and meta-analysis course, taught by thesis adviser and senior author, Simin Liu, an adjunct professor of epidemiology at HSPH.

Systematic reviews rigorously summarize original research following a scientific protocol that has been specified in advance and made explicit at every step, according to Robert and Suzanne Fletcher, HMS professors emeritus of ambulatory care and prevention and co-authors of Clinical Epidemiology. The results are transparent so readers can check for themselves the validity of the procedure and the strength of its conclusions. Often, researchers also combine statistically compatible studies for a more precise estimate of the effects in a meta-analysis.

The method helps to synthesize the ever growing mountains of data and to resolve inconsistencies in the literature, said Liu, whose primary academic affiliation is now as a professor at the UCLA School of Public Health. Systematic reviews are a cornerstone of evidence-based medicine, he said, because they incorporate the core scientific principle of reproducibility and help minimize some of the biases of individual studies.

Sex Differences
In this case, the systematic review focused on a single question: what are the sex differences in the relationship between levels of endogenous sex hormones and the risk of type 2 diabetes? “These age-old sex hormones are extremely powerful and had yet to be carefully evaluated in a comprehensive and formal manner,” Liu said.

The review began with a comprehensive search of 40 years of literature in EMBASE and MEDLINE, using the keyword diabetes combined with testosterone, sex hormone–binding globulin (SHBG), and estradiol. The researchers chased down more studies by searching the references and obtained additional information directly from authors.

Ultimately, the team selected 43 cross-sectional and prospective studies. In a twist on the usual meta-analysis, they futher subdivided the pooled studies into three categories. Forty-one of the studies addressed sex differences in the effects of testosterone; 32 examined the effects of SHBG; and 14 addressed estradiol.

Following the protocol, Ding and co-author Vasanti Malik, also a graduate student, independently extracted and tabulated the data. Then they compared datasets and resolved discrepancies by going back to the original article and having group discussions. In each category—testosterone, SHBG, and estradiol—the cross-sectional and prospective studies were pooled separately. Yiqing Song, an HMS instructor in medicine in Manson’s division at BWH, supervised the data collection and statistical analysis.

“A controversy is that hormones may simply be serving as a marker of adiposity, which is already established as a risk factor for type 2 diabetes,” Ding said. So he and his colleagues conducted sensitivity analyses in the subset of studies that could be adjusted for body mass index (BMI) and found persistent significant associations in the effects of sex hormones on type 2 diabetes for men and women, independent of body fat.

Several short-term randomized trials of testosterone and androgen treatment in men and women have shown similar divergent effects—less fat and insulin resistance in men and increased body fat and insulin resistance in women, Ding said.

Having It Both Ways
There are many layers of biological complexity underlying the associations reported in the study, Manson said. “It’s difficult to fully adjust for adiposity,” she said. “There can be a good deal of residual confounding.” In postmenopausal women, for example, fat tissue is the primary site of estrogen synthesis. In men, supplemental testosterone or higher endogenous levels decrease body fat and increase muscle mass, increasing insulin sensitivity and glucose uptake.

Seeing the forest for the trees. This forest plot summarizes the 36 cross-sectional testosterone studies of 3,825 men and 4,795 women with type 2 diabetes. The sizes of the boxes reflect the relative number of people in each study. Most of the studies would have been reported as not statistically significant, as can be seen by the horizontal lines depicting the confidence intervals that cross zero. The bottom diamonds (red) display the overall pooled meta-analysis results by sex, which found lower levels of testosterone in men with type 2 diabetes and slightly higher levels in women.

In another example familiar to doctors, women with polycystic ovarian syndrome also have higher testosterone levels than normal, which increase insulin resistance and the risk of type 2 diabetes. Yet higher insulin levels lead to greater testosterone production in the ovaries. Interestingly, the antidiabetes medications used to treat the syndrome improve insulin sensitivity and also lower androgen levels. “It’s fascinating,” Manson said. “It seems to go in both directions.”

The results were published as the featured Clinician’s Corner article in the March 15 Journal of the American Medical Association. The immediate clinical implications are that doctors might consider an increased risk of type 2 diabetes in women to whom they prescribe testosterone patches to improve sexual function, Ding said. And physicians may also want to consider the additional risk of type 2 diabetes in men undergoing anti-androgen therapy for prostate cancer.

“At the present time, I don’t think sex steroid hormones should be measured routinely to predict risk of type 2 diabetes,” Manson said, “but if additional research indicates that they add important predictive information, then these markers may eventually be used to help predict the risk of diabetes and, perhaps, to identify higher risk patients who may benefit from early lifestyle or pharmacologic interventions.” Further experimental research that helps to elucidate biological mechanisms may also have therapeutic implications, Liu said.

—Carol Cruzan Morton

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