Obesity and metabolic syndrome are all considered to be risk factor of low serum TT levels. We provided precise insight into the association between different metabolic obesity phenotypes and low serum TT levels in a large-scale population of Chinese middle-aged and elderly men. It demonstrated that different metabolic obesity phenotypes including MHO, MUNW and MUO can both increase the risk of low serum TT levels, especially significantly in MUO group.
In our study, we draw a conclusion that both obese men and metabolic unhealthy men had a higher risk of developing low serum TT levels than normal weight and metabolic healthy individuals, which is consistent with the results in previous study [8-11, 13]. It demonstrated that serum TT levels in male population were associated with BMI and different components of metabolic syndrome. A Korean study have shown that serum TT levels was negatively associated with BMI, WC, FPG, TG and blood pressure, and positively associated with HDL-L levels [11]. A meta-analysis that included 9,525 men of different ethnics proved that serum TT levels were negatively correlated with each component of metabolic syndrome [8]. It has been reported that hyperinsulinemia which was associated with metabolic syndrome can inhibit the secretion of testosterone through insulin receptors which were expressed on Leydig cells [22]. And excess adiposity tissue could lead to high levels of leptin, which can inhibit the steroidogenesis and the secretion of testosterone. Inflammatory cytokines, specially IL-1β, IL-6 and TNF-α, which were elevated in obesity or metabolic unhealthy individuals, can directly inhibit the steroidogenesis and subsequent testosterone production [23]. Although there are several studies investigating the association of obesity and metabolic syndrome components with testosterone levels separately, there is still quite a gap in the literature considering the relationship of different metabolic obesity phenotypes with total testosterone levels.
As we have proved, different metabolic obesity phenotypes except for MHNW group are at a high risk of developing low serum TT levels. Among these groups, MUO individuals are more likely to have a low level of serum TT than others. Studies have demonstrated that age, smoking status and alcohol consumption were associated with different metabolic obesity phenotypes [24,25]. However, after adjusting these above confounding factors, the relationship between TT levels and metabolic obesity phenotypes remained significant. To the best of our knowledge, the only study on this topic was performed and explored male sexual dysfunction with different metabolic obesity phenotypes [19]. It showed that the men with MHO and metabolically complicated obesity (MCO) had lower testosterone levels and only MCO men had worse erectile function compared with normal weight men. However, the results were derived from male patients with sexual dysfunction or infertility, which could have different characteristics with the general male population. What’s more, the definition of MCO was the presence of at least 1 abnormality among hypertension, low HDL-C and diabetes in obese men, and the contrast group was men with normal weight regardless of metabolic status.
In our study, there was a higher risk of developing hypotestosteronemia in male patients in MHO compared to MHNW group, but a lower risk than MUO group. MHO individuals referred to obese people without the risk factor of metabolic syndrome, and several studies have reported that these individuals were fat but fit with a more favorable inflammatory and metabolic profiles [26]. However, the recent systematic review and meta-analysis showed that MHO subjects had an increased risk for the development of cardiovascular diseases and all-cause mortality in contrast to MHNW subjects [27]. And our results indicated that MHO individuals had a decreased total testosterone level compared to MHNW individuals. It has been reported that metabolic healthy obese individuals have certain difference in multiple aspects, such as, fat distribution, inflammatory status, insulin resistance and postprandial lipaemia, compared with metabolic unhealthy obese [28,29]. Compared with MUO individuals, MHO was shown to have increased subcutaneous fat relative to visceral fat, lower liver fat and insulin sensitivity. Excessive visceral fat or insulin resistance rather than general adiposity in obese individuals were high risk of pre-diabetes and type 2 diabetes mellitus. Metabolic healthy subjects displayed lower postprandial response of plasma TG and hs-CRP, compared with those metabolic unhealthy, independently whether or not they were obese. We also observed that testosterone levels were decreased in male subjects with MUO compared to MHO. Clinical features and metabolism difference caused by metabolic healthy obesity phenotype can partly explain the alternations of testosterone concentration in MHO group compared to MHNW and MUO group. Since MHO is a dynamic state (with a significant proportion of MHO subjects progressing to MUO over time), it is necessary to encourage weight control in MHO phenotypes to prevent the development of metabolic related disease including hypotestosteronemia.
We also observed that testosterone levels in male subjects with MUNW were decreased compared to MHNW group, but these were increased in MUNW group than MUO group, and no significant difference to MHO group. MUNW individuals displayed several metabolic abnormal risks including insulin resistance, atherogenic lipid profiles, visceral adiposity accumulation and lower physical energy expenditures, despite having a normal BMI, and eventually had the increased risk of cardiovascular disease [30]. It has been reported that MUNW phenotype exhibited increased arterial stiffness and carotid atherosclerosis compared to MHNW or MHO subjects [31]. And another report has shown that MUNW individuals had a higher risk of cardiovascular disease than MHO, as well as reduced morbidity and mortality [32]. The MHO phenotype was associated with a better overall metabolic profile and less oxidative stress than that observed in MUNW individuals [33]. In our study, there is no significant difference of testosterone levels between MUNW and MHO group, which indicated that both MUNW and MHO can exert an influence on total testosterone levels. The underlying mechanism needs further study. It was shown that male subjects in MUO group have a decreased serum TT levels compared to MHO and MUNW groups, which can be explained by synergistic effect of obesity and metabolic unhealthy on TT levels in patients with MUO. It also indicated that male patients with MHO or MUNW should pay attention to losing weight or improving metabolic status in order to prevent the further drop of TT levels.
It is well known that testosterones are mainly synthesized in Leydig cell, which could be modulated by hypothalamus-pituitary levels. In our study, we also found that gonadotropins FSH and LH was significantly reduced in MHO and MUO group compared to MHNW. However, there was no significant difference of FSH and LH levels between MHNW and MUNW, as well as MHO and MUO group. There was an increasing conversion of androgen precursors into estrogens by aromatase system in adipose tissue among obese male population. Inappropriate effects of increasing estrogens might reduce LH secretory mass per secretory burst without any alternation in burst number [34]. The exact mechanism for decreased gonadotrophins in male obesity could also include leptin, inflammatory mediators and hypothalamic kisspeptin affecting gonadotropins- releasing hormone secretion [35]. These results indicated that low levels of gonadotropins can partly explain the decreasing total testosterone levels in obesity participants, but not affected by metabolic status. To observe the effect of metabolic obesity phenotypes on pituitary or testicular levels, we further compared the difference of prevalence of secondary hypotestosteronemia and primary hypotestosteronemia in four metabolic obesity phenotypes. It showed that the difference of prevalence of secondary hypotestosteronemia and primary hypotestosteronemia in four groups was similar to hypotestosteronemia. The results were confusing, which was inconsistent with the results that LH and FSH levels were only affected by obesity. Although we didn’t get information about the pulse and frequency of LH and FSH secretory, which also played important role in regulating the production of testosterone levels. Therefore, further studies about the pulse and frequency of LH and FSH secretory, the alternations of structure and function in testis are needed to perform in different metabolic obesity phenotypes.
This is the first study to investigate the relation of different metabolic obesity phenotypes with serum TT concentration in a large-scale male population. In our study, other potential risk factors of low TT levels such as age, LH levels, smoking status and alcohol consumption were taken into account to make the result more convincing. However, several limitations also existed in our study. We didn’t obtain information about other sex hormone such as SHBG, estrogen, which can have an effect on TT levels. Meanwhile, we can’t draw a conclusion about the association about different metabolic obesity phenotypes and other sex hormones. What’s more, the cross-sectional study was unable to detect any causal relationship between different metabolic obesity phenotypes and testosterone levels. Large prospective studies are needed to validate this relationship.
In conclusion, both obese men and metabolic unhealthy men have a higher risk of developing low serum TT levels. Different metabolic obesity phenotypes groups have influence on lower serum testosterone level in different degree, especially in MUO group with a lowest serum TT concentration. Male subjects in MHO and MUNW groups had significantly decreased testosterone levels compared to MHNW group, however, there was no significant difference of testosterone levels between MUO and MUNW groups. Clinical physicians should pay attention to the weight combined with metabolic status of patients when we explored the reason of decreasing concentration of serum TT in male populations. Individuals weight control and prevention of metabolic syndrome may be used for the primary prevention of male hypotestosteronemia. Patients with low level of serum TT can get improved by losing weight or improving metabolic status.