Cynthia Fox, Science Writer

Men’s Heart Disease Partly Due to Low Estrogen

One reason men have more heart disease than women is the very fact that they are men, reports Harvard University endocrinologist Evelyn Yu, M.D., MS.c. Both men’s higher testosterone levels and their lower estrogen levels, play a role.

But like all interplays involving the hormones of the sexes, the situation is complicated, Yu found in her study of 400 healthy men aged 20 to 50.

“Although we found that gonadal steroids in men regulated HDL [“good” cholesterol] and glycemic indices [blood sugar levels], we were surprised to find that neither LDL [“bad” cholesterol] nor total cholesterol appeared to be regulated by testosterone or estrogen,” Yu told Drug Discovery & Development. “LDL is arguably the strongest predictor of cardiovascular disease, and therefore understanding its regulation is very important.”

Another surprising finding, Yu said, was that “leptin, an adipocytic hormone, was regulated solely by testosterone in men, despite the fact that body fat mass is regulated by estrogen in men. This suggests that testosterone has direct effects on leptin production and/or secretion, independent of fat mass.”

The study

The study was presented at the Endocrine Society's 97th annual meeting this month. In addition to finding that higher levels of testosterone led to lower HDL, and that estrogen didn’t affect HDL, Yu’s team found that low levels of estrogen led to higher fasting blood sugar levels, worsening insulin resistance and increasing fat in muscles. The latter indicates developing diabetes, a risk factor for heart disease.

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Yu and her team distinguished whether estrogen or testosterone regulated certain heart disease risk factors by contrasting two groups of men with hormone levels temporarily altered by drugs. In the beginning, all participants received goserelin (Zoladex, AstraZeneca) to tamp their own levels of testosterone and estrogen. The 198 men in Group One were given four months of either a daily placebo gel, or one of four doses of testosterone gel (AndroGel, AbbVie), ranging from low to high (1.25 to 10 grams). This established the men's testosterone levels at very low (as occurs pre-puberty) to high-normal.

The 202 men in Group Two received the same treatment, plus anastrozole (Arimidex, AstraZeneca) to block conversion of testosterone to estrogen. Men normally convert a portion of their testosterone supplies to estrogen. Blocking this conversion resulted in very low levels of estrogen among men in Group Two.

All men were weighed and administered fasting blood tests to look for markers of heart disease and diabetes. At the outset, and at the end, all men were given a thigh scan with quantitative computed tomography (CT) to measure muscle fat.

The team found that testosterone and estrogen did not regulate changes in LDL, blood pressure, or body weight. This indicated that, in men aged 20 to 50, these common heart disease risk factors are not governed by sex hormones. Still, as noted, higher testosterone levels and lower estrogen levels in men were found to heart disease risk factors in many other ways.

Men versus women

The study, if validated by publication in a peer-reviewed journal and supported by future work, should add understanding to differences between the way the sexes contract and combat heart disease.

“We found that estrogen deficiency worsens glycemic indices in men, inducing higher levels of fasting glucose and worsened insulin resistance,” Yu told Drug Discovery & Development. “Estrogen deficiency is thought to have a similar effect in women. We found that testosterone, and not estrogen deficiency, negatively regulates HDL in men. In contrast, estrogens are thought to increase HDL levels in women.”

More work needs to be done.

“It is important to evaluate whether other cardiovascular risk factors are similarly regulated by gonadal steroids in men,” Yu concluded. “For example, we plan to study effects of testosterone and estrogen on inflammatory markers as well as hormones related to fat metabolism and cardiovascular function. An improved understanding of these effects may help to explain sex differences in cardiovascular disease.”

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