Studies have observed a relationship between low testosterone and the components of metabolic syndrome [
21], which would suggest that a hypogonadal population would have an increased prevalence of MetS. However, in the TRiUS population of hypogonadal men, 37% of the evaluated patients met the criteria for metabolic syndrome at baseline, which is consistent with the prevalence of metabolic syndrome in US adult men (34.8%-41.9%) [
22]. We did find that low TT levels (<206 ng/dL [<7.1 nmol/L]) increased the risk of being classified as MetS+ and that TT levels significantly correlated with some MetS components before and after TRT. We found that TRT significantly increased testosterone levels in both MetS+ and MetS- hypogonadal populations and both achieved similar TT levels. Changes in MetS components, however, were only seen in MetS+ patients, including decreased fasting blood glucose levels, waist circumference, and BP. Although these changes were significant, no MetS+ patients changed MetS status. Given the patients' high baseline measurements, the need to have improvement across 1-3 components concurrently to change status, and the fact that the mean improvements did not break through the lower thresholds for MetS criteria, this may not be surprising.
In the literature, there is robust evidence of an association between metabolic conditions and low testosterone and/or SHBG [
21,
23-
26]. Low testosterone levels are associated with, and predictive of, weight gain [
27], central obesity [
8,
28], hypertension [
29], MetS [
8], insulin resistance [
30], and type 2 diabetes [
9,
24,
30,
31]. Low testosterone is found in 33% of type 2 diabetes patients, including those younger than 35 years, as compared to only 6% in men with type 1 diabetes [
26]. In prostate cancer patients who undergo chemical castration therapy, testosterone levels are suddenly and drastically reduced, resulting in increased fat deposition, increased insulin levels, impaired insulin sensitivity, and increased risk of diabetes and MetS classification [
32,
33]. The evidence for the association between hypogonadism and diabetes is strong enough to warrant its inclusion in the most current treatment guidelines for hypogonadism [
2], which recommend screening for low testosterone in patients with type 2 diabetes. Our findings that TT levels correlated with waist circumference and fasting blood glucose in a hypogonadal population are in line with these observations.
However, it is unclear to what extent TRT can improve metabolic symptoms in hypogonadal men. Studies of TRT in hypogonadal men have shown improvements in body composition (fat-to-lean mass ratio) [
11] and insulin sensitivity that can reliably be seen early in TRT (1-6 weeks) [
34]. Changes in BMI are not always seen since a loss of fat weight can be replaced by lean muscle weight after TRT [
35]. Recently, in a hypogonadal male population with type 2 diabetes and/or metabolic syndrome, Jones and colleagues [
17] showed a 15.2% reduction in HOMA-IR (homeostasis model of assessment--insulin resistance) compared to placebo after 6 months of TRT use. This was maintained through the 12 months of the study. We found that TRT resulted in lowered waist circumference (visceral fat) and fasting blood glucose, but only in patients with very low testosterone levels (<206 ng/dL [<7.1 nmol/L]) or in MetS+ patients. We saw neither improvement, nor worsening, in lipid parameters in either MetS+ or MetS- cohorts; this reflects the results reported in a review by Jones [
34], which found that the effect of TRT on HDL cholesterol is reduction in 25% of the studies, increase in 25% of the studies, and no effect in 50% of the studies.
In the MetS+ population of our study, improvements were generally seen at later time points: at 12 months for waist circumference and fasting blood glucose levels, and at 6 months for BP. This generally agrees with the literature, and it is possible that metabolic benefits of TRT may not be seen until later time points. At 3 months TRT, placebo-controlled studies in men with type 2 diabetes demonstrated mixed results; there were significant reductions in waist circumference but not BMI [
13], reductions in waist circumference and fasting blood glucose, but not BP [
12], and reductions in body weight and blood glucose [
36]. In a longer, 8-month placebo-controlled trial of TRT in hypogonadal obese men, improvements over placebo were seen in visceral (abdominal) fat mass, blood glucose, diastolic BP, and serum cholesterol, but not BMI [
37]. In a 12-month study of hypogonadal men with MetS, improvements were seen at 6 months in insulin sensitivity, waist circumference, and fat mass, and further improvements were seen at 12 months [
15]. In a 2-year study by Haider et al of hypogonadal men treated with parenteral testosterone undecanoate, BMI, waist size, and weight continued to decrease over the full 24 months, while improvements in fasting glucose and lipid levels were seen only during the first 12 months [
38]. It should be noted that in this study, 77% (37/47) of men with MetS no longer met the criteria for the condition after receiving TRT for 2 years [
38].
In addition to prolonged use, metabolic benefit has also been seen when TRT is used in combination with weight loss. Heufelder et al conducted a 12-month, placebo controlled study of diet and exercise with or without TRT in 32 hypogonadal men with MetS and newly diagnosed type 2 diabetes [
14]. They found that while there were improvements in all MetS components in both groups, addition of TRT to diet and exercise significantly improved glycemic control and waist circumference over diet and exercise alone. Using the ATP III definition of MetS as we did in the current study, they found that 81.3% of the TRT+diet+exercise group and 31.3% of the diet+exercise group no longer met the criteria for MetS after 12 months in the study. Our patient registry showed that TRT alone in MetS+ patients can improve two of the five criteria for MetS (ie, decreased fasting blood glucose levels and waist circumference). This result may be more realistic in clinical practice since many patients struggle with diet and exercise regimens outside of a structured clinical study. Heufelder et al also found a small improvement in TT levels with diet and exercise alone, emphasizing the bidirectional link between testosterone and MetS criteria. Because we did not record changes in diet and exercise in our study, it is unknown if improved MetS criteria had any impact on testosterone levels in our study.
Importantly for prediabetic men, we found that TRT improved fasting glucose levels in MetS+ men. This relationship between testosterone and insulin was highlighted in Yialamas et al [
32], who found decreased insulin sensitivity and increased fasting blood glucose levels after withdrawal of TRT in young, healthy men with idiopathic hypogonadotropic hypogonadism. Similar results have been reported by Pitteloud et al [
39,
40], though Rabiee et al [
41] found no change in insulin sensitivity in response to serum testosterone suppression in healthy non-hypogonadal men. Thus, insulin sensitivity may be related to a chronic hypogonadal state, though the mechanism for this is currently unclear.
An important limitation of our study was the lack of data regarding concomitant medication use for diabetes, dyslipidemia, or hypertension; because the registry was not designed specifically to evaluate metabolic syndrome, this information was not systematically collected. Without consistent documentation of the use of these concomitant medications, it is not possible to accurately determine the extent to which the effects on metabolic parameters reflect effects of TRT, or an optimization of medications these patients may be using. Other limitations of our study were typical of an observational study or patient registry. Patient behavior and physician protocol and practice were not defined by the registry protocol. Thus, we observed a high degree of variability due to inconsistency in patient follow-up visits, hypogonadism defined at the physician's discretion, no testosterone washout period before enrollment, no placebo control, and no centralized laboratory testing facility. This last limitation may have contributed to the inconsistent change we observed in free testosterone after TRT; it is unclear why free testosterone did not correlate with TT, although it should be noted that a uniform method of free testosterone assessment was not stipulated in the registry (ie, calculated vs measured; analog assay vs mass spectrometry). Because our data reflect the natural behavior of patients and physicians, the findings can be generalized to patients seeking medical attention for hypogonadal symptoms and those being treated for hypogonadism.
#1 Mohit Khera,#2 Gary Blick,#3 Harvey Kushner,#4 Dat Nguyen,#4 and Martin M Miner#5
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