Associations between testosterone and estradiol and development of metabolic syndrome
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
It is well established that both low total testosterone and low sex hormone binding globulin (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 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
What is known
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), hypertension, 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 LDL-C level; therefore, the primary purpose for diagnosing metabolic syndrome is to identify individuals at higher risk of cardiovascular disease that extend beyond LDL-C.11 Indeed most studies12-15, but not all16-18, 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 Score225, provides long term prognostic information about total and cardiovascular mortality.26 For example, in a large community-based sample of 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 factors that are associated with the metabolic syndrome and possibly contribute to its development and/or progression.
Both low total testosterone and low sex hormone binding globulin (SHBG) levels have been associated with an increased risk of both 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. Some studies show that SHBG, but not testosterone, is independently associated with incident metabolic syndrome5,6,34, while another study shows that testosterone is independently associated with incident metabolic syndrome because adjustment for SHBG does not fully explain associations of total testosterone with metabolic syndrome.7
It has also been pointed out that although cross-sectional analyses show a significant inverse association of total testosterone and SHBG with prevalent metabolic syndrome independent of each other, longitudinal analyses show an independent association with incident metabolic syndrome only for SHBG but not for total testosterone, after additional adjustment for the respective sex hormone.6 Further complicating this issue is the finding of an inverse association between total testosterone change (decline) and incident metabolic syndrome independent of SHBG, whereas SHBG change (decline) is not associated with incident metabolic syndrome until adjustment for total testosterone.6 This change analysis suggests a dominant role of the decline in total testosterone, but not SHBG, in future development of the metabolic syndrome.
Further, the potential impact of estradiol, and thus the extent of aromatization, on the risk for incident metabolic syndrome has not previously been investigated prospectively.
What this study adds
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 (range 2.95 - 5.7 years) in 2736 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, and whether sex steroids were associated with change in individual metabolic syndrome components.
It was found that men with lower baseline total testosterone levels were at 1.7-fold higher risk for developing metabolic syndrome (Odds ratio (OR)=1.72, p<0.001), even after adjustment for SHBG (OR=1.43, p=0.001), BMI (OR=1.44, p<0.001) and insulin resistance, measured by HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) (OR=1.64, p<0.001). Notably, in a sub-cohort, this association was also independent of DXA-measured body fat and trunk fat.
Estradiol was not associated with development of metabolic syndrome (OR=1.04; p=0.56). However, a lower estradiol/testosterone ratio, reflecting less aromatisation of testosterone into estradiol, was associated with a 62% reduced risk of incident metabolic syndrome (OR=0.38; p<0.001), even after adjustment for SHBG (OR=0.48; p<0.001), BMI (OR=0.60; p=0.001) or HOMA-IR (OR=0.41; p<0.001). However, the estradiol/testosterone ratio was no longer significantly associated with metabolic syndrome after further adjustment for body fat or trunk fat (by DEXA).
Lower baseline total and free testosterone and SHBG levels were associated with higher triglyceride and glucose levels and lower HDL levels at follow-up. A lower estradiol/testosterone ratio was associated with lower triglyceride and glucose levels and higher HDL levels. Total estradiol was only associated with a higher triglyceride level.
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. Therefore, the association between testosterone and metabolic syndrome cannot solely be attributed to SHBG.
Second, it is notable that the association between testosterone and metabolic syndrome is independent of body fat as well as trunk fat, as measured by DEXA. This is in line with previous data showing that low levels of total testosterone and SHBG, as well as clinical testosterone deficiency, are associated with increased risk of developing metabolic syndrome over time, particularly in non-overweight, middle-aged men (BMI <25).4,7 However, it is in contrast to the previous finding that adjusting for BMI attenuates the strength of the association between testosterone and metabolic syndrome.7 In particular, associations for free testosterone were no longer significant after adjustment for BMI.7 This highlights the importance of accurate measurement of body fat, as opposed to relying on surrogate body fat indices like BMI.
Third, it is the first study to specifically investigate the association of estradiol with incident metabolic syndrome, and shows that less aromatisation of testosterone into estradiol (as indicated by a lower estradiol/testosterone ratio) is associated with a reduced risk of incident metabolic syndrome. However, this association was not independent of body fat, meaning that it is less body fat (which is the main determinant of the degree of aromatisation) that is the main driver behind the relation of a lower estradiol/testosterone ratio and reduced risk of incident metabolic syndrome.
Fourth, it confirms results from previous cross-sectional and longitudinal studies, showing that lower baseline total testosterone levels are prospectively associated with an adverse lipid profile35 and higher blood glucose levels.36
A strength of this study is that testosterone and estradiol levels were measured by liquid and gas chromatography/mass spectrometry, respectively. While the relative merits of therapeutic implications of targeting testosterone versus SHBG cannot be inferred from observational studies37 additional evidence that low testosterone levels increase the risk of metabolic syndrome comes from androgen deprivation treatment of prostate cancer.38,39 Further support comes from the Moscow RCT showing that 30 weeks of testosterone administration, normalizing testosterone levels in hypogonadal men with the metabolic syndrome, improves several components of the metabolic syndrome, as well as a number of inflammatory markers.40 Several other RCTs confirm the improvements in metabolic syndrome components by testosterone therapy.41-44 A notable controlled study shows that testosterone therapy with testosterone undecanoate for 60 months reduces waist circumference, body weight, blood glucose, HbA1c , and blood pressure, and improves insulin sensitivity, lipid profile, as well as bone mineral density compared with controls.45 These results were also found in an observational study of the same duration (60 months), which in addition found a reduction in C-reactive protein and liver enzymes.46 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.