Associations between Sex Steroids and the Development of Metabolic Syndrome: a Longitudinal Study in European Men.
Antonio L, Wu FC, O'Neill TW, Pye SR, Carter EL, Finn JD, Rutter MK, Laurent MR, Huhtaniemi IT, Han TS, Lean ME, Keevil BG, Pendleton N, Rastrelli G, Forti G, Bartfai G, Casanueva FF, Kula K, Punab M, Giwercman A, Claessens F, Decallonne B, Vanderschueren D. J Clin Endocrinol Metab. 2015 Jan 30

Sex hormone binding globulin (SHBG) is a “hormone carrier” that binds and transports testosterone in the blood. It is well established that both low total testosterone and low SHBG levels are associated with an increased risk of existing and incident metabolic syndrome in men.^1-7

However, it is still debated whether testosterone and SHBG are independently associated with incident development of the metabolic syndrome. In addition, the potential role of estradiol (the main estrogen) in this association is unknown. A recently published study specifically investigated these issues, using data from the European Male Aging Study (EMAS), a prospective study of aging in European men.⁸

• Both low total testosterone and low SHBG levels are associated with an increased risk of both existing and incident metabolic syndrome in men.
• Men with lower baseline total testosterone levels are at 1.7-fold higher risk for developing metabolic syndrome, regardless of SHBG, BMI, body fat and insulin resistance.
• Estradiol is not associated with development of metabolic syndrome. However, a lower estradiol/testosterone ratio, reflecting less conversion of testosterone into estradiol, is associated with a 62% reduced risk of incident metabolic syndrome.
• Lower baseline levels of total and free testosterone, and SHBG, are associated with higher triglyceride and glucose levels and lower HDL levels at follow-up.

The metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes, and reflects the expanding waist lines of the world.⁹ The risk factors included in the diagnosis are dyslipidemia (elevated triglyceride and reduced HDL levels), high blood pressure, increased fasting glucose and elevated waist circumference; any 3 of these 5 constitute diagnosis of metabolic syndrome.¹⁰

The metabolic syndrome taken in aggregate increases the risk for coronary heart disease at any given level of LDL (popularly known as “bad cholesterol”); therefore, the primary purpose for diagnosing metabolic syndrome is to identify individuals at higher risk of cardiovascular disease that extend beyond just LDL.¹¹ Indeed most studies^12-15, but not all^16-18, show that the metabolic syndrome as a whole confers a greater risk of developing diabetes and/or cardiovascular disease compared to its individual components in isolation. As expected, the more components of the metabolic syndrome that are present, the greater the cardiovascular risk.^19-24

It is especially notable that the metabolic syndrome, in contrast to short-term (10 year) risk calculators like the Framingham Risk Score²⁵, provides long term prognostic information about total and cardiovascular mortality.²⁶ For example, in middle-aged men, the presence of the metabolic syndrome increased the risk for total and cardiovascular mortality by 40-60%, even after having taken into account established risk factors for cardiovascular disease.¹⁵ In contrast to short-term risk calculators, which heavily weight age into the risk calculation, the metabolic syndrome does not include age and can therefore indicate and predict high risk at any age, even in younger populations. This was demonstrated in a recent study showing that the cardiovascular disease event risk associated with metabolic syndrome is independent of age in men.²² This is an important consideration as the prevalence of metabolic syndrome among young adults is rising.^27-30

The prevalence of the metabolic syndrome among the general male population is around 30 to 40%^22,31,32, and thus afflicts a large proportion of men. Therefore, it is important to identify and treat factors that are associated with the metabolic syndrome and possibly contribute to its development and/or progression.

Both low total testosterone and low SHBG levels have been associated with an increased risk of existing and incident metabolic syndrome in men.^1-7 However, levels of total and free testosterone are strongly linked to SHBG, especially in men with obesity³³, and it is still debated whether testosterone and SHBG are independently associated with incident development of the metabolic syndrome. In addition, the potential impact of conversion of testosterone to estradiol, and estradiol levels, on the risk for incident metabolic syndrome has not previously been investigated.

Using data from the European Male Aging Study (EMAS), Antonio et al. investigated the association between baseline testosterone and estradiol levels, and the risk of developing metabolic syndrome after a median follow-up time of 4.3 years among men aged 40-79 years.⁸ This study specifically analyzed whether this association was independent of SHBG, body mass index (BMI), insulin resistance and body fat measurements.

It was found that men with lower baseline total testosterone levels were at 1.7-fold higher risk for developing metabolic syndrome, even after adjustment for SHBG, BMI, insulin resistance, as well as total body fat and trunk fat (measured by DEXA).

Estradiol was not associated with development of metabolic syndrome. However, a lower estradiol/testosterone ratio, reflecting less conversion of testosterone into estradiol, was associated with a 62% reduced risk of incident metabolic syndrome, even after adjustment for SHBG, BMI and insulin resistance. However, when taking into consideration total body fat and trunk fat, the estradiol/testosterone ratio was no longer significantly associated with metabolic syndrome.

The conclusions drawn from this study are that lower testosterone levels are linked with an increased risk of developing the metabolic syndrome, independent of SHBG, BMI or insulin resistance, and that a lower estradiol/testosterone ratio may be protective against development of the metabolic syndrome.

The study by Antonio et al. demonstrates three important findings. First, it confirms that testosterone levels are associated with both prevalent and incident metabolic syndrome, independently of SHBG.

Second, it is notable that the association between testosterone and metabolic syndrome is independent of body fat as well as trunk fat. This is in line with previous data showing that low levels of total testosterone and SHBG, as well as testosterone deficiency, are associated with increased risk of developing metabolic syndrome over time, particularly in non-overweight, middle-aged men (BMI below 25).^4,7

Third, it is the first study to specifically investigate the association of estradiol with incident metabolic syndrome, and shows that less conversion of testosterone into estradiol, primarily due to less body fat, is associated with a reduced risk of incident metabolic syndrome.

Fourth, it confirms results from previous studies which showed that lower baseline total testosterone levels are associated with development of an adverse cholesterol (lipid) profile³⁴ and higher blood glucose levels.³⁵

Further evidence that low testosterone levels increase the risk of metabolic syndrome comes from androgen deprivation treatment of prostate cancer.^36,37 Moreover it has been demonstrated that testosterone replacement therapy in hypogonadal men with the metabolic syndrome for 30 weeks improves several components of the metabolic syndrome, as well as a number of inflammatory markers.³⁸

Several other studies confirm the improvements in metabolic syndrome components by testosterone replacement therapy.^39-42 A notable controlled study shows that testosterone therapy with testosterone undecanoate for 60 months reduces waist circumference, body weight, blood glucose, HbA_1c (glycated hemoglobin, a marker is average blood glucose levels) and blood pressure, and improves insulin sensitivity, lipid profile, as well as bone mineral density.⁴³ Thus, several different lines of evidence support the treatment of low testosterone levels in order to prevent the development of the metabolic syndrome and its complications.