“Men with excessive body fat mass tend to have insufficient androgen levels.”

Our study revealed that men with higher VAI index displayed decreased total testosterone level (β: −11.74, 95% CI: −17.33, −6.15, P<0.0001) and higher risk of testosterone deficiency (OR: 1.24, 95% CI: 1.09, 1.40, P=0.0022).## Discussion To the best of our knowledge, this is the first nationally representative study to explore the associations between VAI index (reflecting the distribution of abdominal fat, and the function of adipose tissue) and total testosterone level and testosterone deficiency in men. Our study revealed that men with higher VAI index displayed decreased total testosterone level (β: −11.74, 95% CI: −17.33, −6.15, P<0.0001) and higher risk of testosterone deficiency (OR: 1.24, 95% CI: 1.09, 1.40, P=0.0022). Additionally, the result remained stable when we categorized VAI index into quartiles. During our subgroup analysis, the association was stronger among aged men, obese men, or men without diabetes. Furthermore, the VAI displayed comparable predictive performance to TyG index (0.66 vs 0.67, P=0.27) for testosterone deficiency, but not better than that of the HOMA-IR index. Generally, obesity can be divided into overall and abdominal obesity [34]. …

The effects of obesity on testicular function are also well known, with reductions in circulating testosterone concentration strongly associated with increasing visceral adiposity and metabolic syndrome (7).## Background Overweight and obesity are risk factors for a large number of chronic diseases spanning numerous organ systems, and improvement in organ function following clinically significant weight loss is well documented (6). The effects of obesity on testicular function are also well known, with reductions in circulating testosterone concentration strongly associated with increasing visceral adiposity and metabolic syndrome (7). Although this relationship is likely bidirectional, by far the strongest relationship is via the effect of obesity on circulating testosterone levels, with much smaller effects of low testosterone on increasing adiposity (8). Incorrectly, lay media and many doctors consider a “low” testosterone concentration in isolation as observed in men with overweight and obesity as constituting a form of hypogonadism. …

VAT area was inversely associated with TT in the crude and adjusted models. … These findings underscore the potential for VAT area as a modifiable indicator for improving testosterone deficiency.… TT in serum was assessed utilizing the isotope dilution liquid chromatography-tandem mass spectrometry technique. Linear regression models assessed the associations between VAT area and TT. A restricted cubic spline model was employed to investigate nonlinear relationships. A two-piecewise linear regression model was applied to determine the threshold effect. Subgroup analyses were conducted. The weighted methods were utilized in all analyses. VAT area was inversely associated with TT in the crude and adjusted models. In the fully adjusted model, VAT area was associated with TT (β = −0.59, 95% confidence interval [CI] = −0.74, −0.43) and compared to the first tertile of VAT area, the second and the third tertile had a lower TT level, the β and 95% CI = −65.49 (−83.72, −47.25) and −97.57 (−121.86, −73.27) respectively. We found these inverse associations were nonlinear. The cutoff point of the VAT area was 126 cm2. When the VAT area was <126 cm2, VAT area was significantly associated with a lower TT level (β = −1.55, 95% CI = −1.93 to −1.17, p < 0.0001). However, when the VAT area was ≥126 cm2, this association was less apparent (β = −0.26, 95% CI = −0.52 to 0.01, p = 0.06). No significant interactions among different ages (<50 or ≥50 years), marital, and physical activity status were found. These findings underscore the potential for VAT area as a modifiable indicator for improving testosterone deficiency. Access through your institution

The findings of this study support a negative association between body fat and testosterone levels in males. … In males, testosterone deficiency can lead to increased fat deposition, fat synthesis, and fat cell proliferation, as well as decreased skeletal muscle mass and basal metabolic rate, thereby exacerbating weight gain, increased body fat percentage, and metabolic syndrome, among other issues [3–5].### Conclusions The findings of this study support a negative association between body fat and testosterone levels in males. ## Introduction … It is mainly synthesized in the testes and to a lesser extent in the ovaries and adrenal glands of females. Testosterone can regulate the development and function of male and female reproductive organs by combining with estrogen, and play an important role in other organs of the body. Testosterone can also affect muscle quality, fat distribution, and metabolic status by regulating protein and fat metabolism [2]. In males, testosterone deficiency can lead to increased fat deposition, fat synthesis, and fat cell proliferation, as well as decreased skeletal muscle mass and basal metabolic rate, thereby exacerbating weight gain, increased body fat percentage, and metabolic syndrome, among other issues [3–5]. However, these studies have been limited by small sample sizes, which may limit their generalizability and statistical power. Therefore, in this study, we aim to investigate the relationship between testosterone levels and obesity using a large dataset from the NHANES (National Health and Nutrition Examination Survey) database. Specifically, we aim to examine the effects of testosterone on body composition, as measured by DXA (Dual-energy X-ray absorptiometry), in both sexes. …

The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109).… There are multilateral relationships between obesity, hypogonadism, type 2 diabetes and metabolic syndrome. Thus, obesity-associated comorbidities are commonly accompanied by low testosterone values and, on the other hand, low testosterone plasma values are associated with obesity, metabolic syndrome and type 2 diabetes (116). The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109). A dysregulation of the hypothalamic–pituitary–adrenal axis inducing functional hypercortisolism in obesity may also play a role in gonadotrophin inhibition and, consequently, reduced testosterone levels (94). As for the general population (111), a routine hormonal screening for male hypogonadism is not recommended in patients with obesity, and testing should be considered when clinical features create the need for investigating hypogonadism (Table 5). …

Obesity with expanded visceral adipose tissue leads to secondary hypogonadism with an 8.7-fold higher risk in patients with a BMI > 30 kg/m 2. … The inverse correlation between visceral fat and testosterone levels is strong[9].… It is important to update the pathobiology and management algorithms for MOSH to inform evidence based clinical practice decisions, especially when we consider androgen replacement therapy. This review is an attempt with the back-up of the most up-to-date review of current global scientific literature. There is a complex interplay of various feedback mechanisms with neural and hormonal signaling molecules contributing to MOSH[6]. Obesity with expanded visceral adipose tissue leads to secondary hypogonadism with an 8.7-fold higher risk in patients with a BMI > 30 kg/m 2. Testosterone (T), even in suboptimal levels, facilitates the differentiation of pluripotent stem cells into adipocytes to increase the aromatization of T into estradiol and to cause a negative feedback mechanism at the hypothalamus and pituitary levels that in turn suppresses the gonadal stimulation and T release. The arcuate nucleus and periventricular nucleus of the hypothalamus release neuropeptide Kisspeptin, which in turn stimulates the release of gonadotrophin-releasing hormone (GnRH)[6]. … This is the acronym for GELDING. Gut microbiota with an average of 1.5 kg (100 trillion) of bacteria residing in the human bowel produce various proinflammatory cytokines. High-calorie and fat-based diets contribute to the release of bacterial endotoxins from the gut. Exposure to these lipopolysaccharides causes impaired testicular function, thereby contributing to T deficiency. Adipose tissue plays a major role in glucose homoeostasis and insulin sensitivity. The inverse correlation between visceral fat and testosterone levels is strong[9]. Testosterone increases lipolysis by increasing the number of β-adrenergic receptors. The action of testosterone on subcutaneous and visceral adipose function is different. Subcutaneous fat accumulation in the truncal area is highly predictive of low plasma concentrations of free testosterone rather than visceral adiposity[9]. There are no mechanistic studies that address the differential response to testosterone in different adipose tissues. …

In population-based studies, obesity is the single most important factor resulting in testosterone deficiency. … Testosterone deficiency is associated with visceral fat dysfunction, subsequent chronic inflammation, insulin resistance and low sex hormone binding globulin (SHBG) levels.… Male hypogonadism has been shown to be associated with excess morbidity and mortality in multiple clinical studies.6–9 Therefore, we aim to discuss the pathophysiology, clinical aspects, diagnostic approach and management options for patients with MOSH in this comprehensive review. ## Pathophysiology of male obesity-related secondary hypogonadism ### Obesity and hypogonadism – bidirectional relationship There is a bidirectional relationship between obesity and hypogonadism.10 In population-based studies, obesity is the single most important factor resulting in testosterone deficiency.11 Similarly, testosterone deficiency can cause increased adipogenesis and visceral obesity as evidenced by rapid weight gain observed in men following androgen deprivation therapy or surgical castration.12–14 Testosterone deficiency is associated with visceral fat dysfunction, subsequent chronic inflammation, insulin resistance and low sex hormone binding globulin (SHBG) levels.15,16 Weight loss achieved pharmacologically with liraglutide17 or with bariatric surgery improved testosterone and gonadotrophin levels, and were able to reverse the hypogonadotrophic hypogonadism caused by obesity.18–20 ### Metabolic syndrome and hypogonadism – bidirectional relationship As is the case with obesity and hypogonadism, there is also a bidirectional relationship between metabolic syndrome and testosterone deficiency. …

Since then, multiple cross-sectional and prospective studies have consistently found negative linear correlations between both total and free testosterone levels and adiposity in men.## OBESITY AND LOW TESTOSTERONE: EVIDENCE FROM POPULATION-BASED STUDIES The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years. 14 Since then, multiple cross-sectional and prospective studies have consistently found negative linear correlations between both total and free testosterone levels and adiposity in men. 15 In a cohort of 3219 men from the European Male Aging Study (EMAS), obesity was associated with an 8.7-fold and overweight with a 3.3-fold increased relative risk (RR) of secondary hypogonadism (defined as total testosterone of <10.5 nmol l -1 and normal luteinizing hormone (LH)), relative to normal weight 3 . …

Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. … Our results suggest that there is a causal effect of BMI on serum testosterone in men.… ✉\* E-mail:claes.ohlsson@medic.gu.se #### Roles **Cheng Hu**:Editor Received 2016 Nov 23; Accepted 2017 Apr 7; Collection date 2017. ©2017 Eriksson et al This is an open access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMC Copyright notice PMCID: PMC5407807  PMID:28448539 ## Abstract ### Context Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. ### Objectives Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. ### Design Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. ### Setting Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden). ### Participants 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs. ### Main outcome measures … ### Results 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42–-0.09, p = 2.8\*10−3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349). ### Conclusions Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men. ## Introduction Observational studies demonstrate that obesity is associated with low serum testosterone (T) [1], but the direction and causality of this relationship is unclear. …

Since then, multiple cross-sectional and prospective studies have consistently found negative linear correlations between both total and free testosterone levels and adiposity in men.## OBESITY AND LOW TESTOSTERONE: EVIDENCE FROM POPULATION-BASED STUDIES The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years. 14 Since then, multiple cross-sectional and prospective studies have consistently found negative linear correlations between both total and free testosterone levels and adiposity in men. 15 In a cohort of 3219 men from the European Male Aging Study (EMAS), obesity was associated with an 8.7-fold and overweight with a 3.3-fold increased relative risk (RR) of secondary hypogonadism (defined as total testosterone of <10.5 nmol l -1 and normal luteinizing hormone (LH)), relative to normal weight 3 . …

These results showed that genetically higher fat mass was associated with lower testosterone levels in men of European ancestry but that genetically predicted fat-free mass was either only weakly associated or not statistically associated with testosterone levels. … Therefore, this MR study suggests that fat mass lowers testosterone levels, while muscle mass may not be related to testosterone levels.## Discussion It is well known that obesity decreases testosterone levels, but it is difficult to determine the causal relationship between body composition and testosterone. This is the first study to investigate potential causal associations of detailed body composition parameters with testosterone levels based on large-scale GWAS data and MR analyses. These results showed that genetically higher fat mass was associated with lower testosterone levels in men of European ancestry but that genetically predicted fat-free mass was either only weakly associated or not statistically associated with testosterone levels. There were no differences between body parts. With the exception of MR-Egger, which may give a biased estimate in a single-sample MR analysis ( 25), different MR methods consistently supported our findings. Therefore, this MR study suggests that fat mass lowers testosterone levels, while muscle mass may not be related to testosterone levels. Various observational studies have reported an association between obesity and low testosterone, but the mechanism is multifactorial and possibly bidirectional, and the exact causal relationship is largely unknown (

All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20–30%). … Both MRI and common measures of adiposity were inversely associated with free testosterone concentrations in a J-shaped manner.### Results Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76–0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43–0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20–30%). ### Conclusion … Further research into other growth factors, IGF-II, and IGF-binding proteins—which may be influenced by body composition—is needed to clarify these associations as well as their potential mechanisms of action [13, 29, 30, 35]. Both MRI and common measures of adiposity were inversely associated with free testosterone concentrations in a J-shaped manner. We also observed differences in the association patterns between total testosterone and free testosterone with body composition measurements. Having greater adipose tissue will lead to higher aromatase activity [36], which may lead to androgens being converted to oestrogens, thus resulting in less circulating testosterone. As well, as observed in this study and others, SHBG is greatly reduced with greater adiposity [14, 37], which will influence free testosterone concentrations.

The inverse relationship between obesity and testosterone levels has been previously reported, and although the exact underlying mechanism remains to be fully elucidated, the hypogonadal-obesity-adipocytokine hypothesis has been proposed [12] [13] [14] : in individuals with obesity, increased aromatase activity caused by the increased number and size of adipocytes results in more testosterone being converted to estradiol, subsequently causing a low level of serum testosterone, which further increases triglyceride storage in adipocytes by increasing lipoprotein lipase activity and promoting adipocyte maturation from pluripotent stem cells.… In addition to undesirable sexual symptoms, including decreased libido and erectile dysfunction, testosterone deficiency also increases the risk of developing osteoporosis, diabetes, metabolic syndrome, and cognitive decline, as well as cardiovascular and all-cause mortality [7] [8] [9] [10] [11] . Testosterone deficiency adversely affects multiple organ systems and causes a significant reduction of quality of life, hence the well-established and significant health issue it has become 4 . The inverse relationship between obesity and testosterone levels has been previously reported, and although the exact underlying mechanism remains to be fully elucidated, the hypogonadal-obesity-adipocytokine hypothesis has been proposed [12] [13] [14] : in individuals with obesity, increased aromatase activity caused by the increased number and size of adipocytes results in more testosterone being converted to estradiol, subsequently causing a low level of serum testosterone, which further increases triglyceride storage in adipocytes by increasing lipoprotein lipase activity and promoting adipocyte maturation from pluripotent stem cells. In turn, the number and size of adipocytes are increased, causing pronounced insulin resistance, which then causes decreased testosterone secretion and increased obesity. …

For appropriately diagnosed hypogonadism due to being overweight or obese (BMI >27) and no other identified cause, weight loss is typically the first-line therapy.… - Healthcare providers must weigh the benefits of testosterone replacement therapy (TRT) against the risks. - Testosterone replacement therapy (TRT) at a dosage that is similar to what a man would typically make has clear benefits for men with appropriately diagnosed hypogonadism and a disease that affects the testes, pituitary, or hypothalamus as the cause. - For appropriately diagnosed hypogonadism due to being overweight or obese (BMI >27) and no other identified cause, weight loss is typically the first-line therapy. 2. While recent studies have addressed some concerns, we need more research to fully understand TRT’s risks.

Several well-designed studies have reported the high prevalence of testosterone deficiency in men with obesity. … Our study revealed that men e941394-4 ## DATABASE ANALYSIS with higher VAI index displayed decreased total testosterone level (b: -11.74, 95% CI: -17.33, -6.15, P<0.0001) and higher risk of testosterone deficiency (OR: 1.24, 95% CI: 1.09, 1.40, P=0.0022).… Testosterone deficiency has become a prevalent issue in adult men, and needs to receive increased public attention. Presently, there is evidence that metabolic syndrome (Mets) is a combination of risk factors for testosterone deficiency, which included dyslipidemia, hypertension, insulin resistance, and obesity [11] . Among these risk factors of Mets, obesity is considered as the core manifestation, and has attracted more attention from researchers [12, 13] . Several well-designed studies have reported the high prevalence of testosterone deficiency in men with obesity. For instance, Zumoff et al reported an inverse correlation between free testosterone and body mass index (BMI) in adult men with a BMI ranging from 21 to 95 kg/ m2 [14] . Another study, by Hofstra et al, also reached similar conclusions, and reported that about 35% of men with obesity had testosterone level under 300 ng/dl, diagnosed as testosterone deficiency [15] . … ## Discussion To the best of our knowledge, this is the first nationally representative study to explore the associations between VAI index (reflecting the distribution of abdominal fat, and the function of adipose tissue) and total testosterone level and testosterone deficiency in men. Our study revealed that men e941394-4 ## DATABASE ANALYSIS with higher VAI index displayed decreased total testosterone level (b: -11.74, 95% CI: -17.33, -6.15, P<0.0001) and higher risk of testosterone deficiency (OR: 1.24, 95% CI: 1.09, 1.40, P=0.0022). Additionally, the result remained stable when we categorized VAI index into quartiles. During our subgroup analysis, the association was stronger among aged men, obese men, or men without diabetes. Furthermore, the VAI displayed comparable predictive performance to TyG index (0.66 vs 0.67, P=0.27) for testosterone deficiency, but not better than that of the HOMA-IR index. Generally, obesity can be divided into overall and abdominal obesity [34] . …

It is known that obesity in men is associated with low testosterone and reduced sex hormone-binding globulin (SHBG) levels (19, 20, 21, 22, 23) . … Evidence indicates that testosterone deficiency induces increased adiposity while increased adiposity induces hypogonadism (22, 25) .… However, available randomized trials are still very few and of limited size and duration (15, 16) . Furthermore, some recent observational studies have suggested caution about the benefits of bariatric surgery, showing no improvement in mortality when compared with standard care (17) and a high rate of long-term surgical complications especially for laparoscopic gastric banding procedures (18) . It is known that obesity in men is associated with low testosterone and reduced sex hormone-binding globulin (SHBG) levels (19, 20, 21, 22, 23) . An obesityassociated decline in SHBG might partially explain the observed fall in testosterone levels (19, 20, 21, 22, 23) . However, it is important to note that an increased BMI was associated with a low measured, or calculated, free and bioavailable testosterone (24) . Specific pathogenetic mechanisms involved in this phenomenon are complex and not completely understood. Evidence indicates that testosterone deficiency induces increased adiposity while increased adiposity induces hypogonadism (22, 25) . Few randomized clinical studies have specifically evaluated the impact of diet and physical activity on testosterone levels in obese men. The results of these studies are essentially conflicting: some of them showed an increase of testosterone (26, 27, 28, 29, 30, 31, 32, 33, 34) , others showed no change (35, 36, 37, 38, 39) , and one small study has shown even a decrease in testosterone levels (40) . …

In men, an increased visceral adiposity leads to androgen deficiency, including male obesity-related secondary hypogonadism.… comorbidities, adipose tissue strongly affects the metabolism of several hormones, including sex hormones, in both men and women.10-12 Interestingly, the impact of the gonadal function demonstrates a clear sexual dimorphism.13 In women, obesity could lead to polycystic ovary syndrome and androgens excess disorders or to idiopathic hyperandrogenism.13 In particular, the prevalence of PCOS in obese populations approaches 30%, with a great impact on ovulation and fertility outcome.14, 15 In men, an increased visceral adiposity leads to androgen deficiency, including male obesity-related secondary hypogonadism.16-19 Despite accepted evidence highlighting a strict relationship between obesity and sex hormones homeostasis, the relationship between obesity and human fertility is still unclear. …

Among men, higher total and free testosterone concentrations at both 53 and 60-64 years were associated with lower fat mass at 60-64 years (Table2; categorical analyses shown in Supporting Information Table S1).… At 53 years, women who were post-menopausal had lower total testosterone (*P*(trend) = 0.02) and lower SHBG (*P*(trend) = 0.01) than pre or peri-menopausal women but there was no difference in free testosterone (*P*(trend) = 0.58). ### Testosterone and fat mass Among men, higher total and free testosterone concentrations at both 53 and 60-64 years were associated with lower fat mass at 60-64 years (Table2; categorical analyses shown in Supporting Information Table S1). Unlike men, women with higher testosterone at 53 years and 60-64 years had higher fat mass, though in the latter confidence intervals overlapped with the null (Table2and Supporting Information Table S1; sex interaction tests all*P*< 0.05). Higher SHBG at both ages was associated with lower fat mass in both sexes—more strongly in women than men. …

In males, testosterone deficiency can lead to increased fat deposition, fat synthesis, and fat cell proliferation, as well as decreased skeletal muscle mass and basal metabolic rate, thereby exacerbating weight gain, increased body fat percentage, and metabolic syndrome, among other issues… It is mainly synthesized in the testes and to a lesser extent in the ovaries and adrenal glands of females. Testosterone can regulate the development and function of male and female reproductive organs by combining with estrogen, and play an important role in other organs of the body. Testosterone can also affect muscle quality, fat distribution, and metabolic status by regulating protein and fat metabolism [2] . In males, testosterone deficiency can lead to increased fat deposition, fat synthesis, and fat cell proliferation, as well as decreased skeletal muscle mass and basal metabolic rate, thereby exacerbating weight gain, increased body fat percentage, and metabolic syndrome, among other issues [3] [4] [5] . However, these studies have been limited by small sample sizes, which may limit their generalizability and statistical power. Therefore, in this study, we aim to investigate the relationship between testosterone levels and obesity using a large dataset from the NHANES (National Health and Nutrition Examination Survey) database. Specifically, we aim to examine the effects of testosterone on body composition, as measured by DXA (Dual-energy X-ray absorptiometry), in both sexes. …

Obesity in men is associated with low serum testosterone and both are associated with sev eral diseases and increased mortality. … Our results suggest that there is a causal effect of BMI on serum testosterone in men.Context Obesity in men is associated with low serum testosterone and both are associated with sev eral diseases and increased mortality. Objectives … Conclusions Our results suggest that there is a causal effect of BMI on serum testosterone in men. Popu lation level interventions to reduce BMI are expected to increase serum testosterone in men. #### Introduction

The content of adipose tissue is related to the concentration of androgen in men and affects the balance between androgens and estrogens. … According to that concept, T is aromatized in adipose tissue to 17-β estradiol. High expression of aromatase in adipocytes leads to a reduction in circulating T, which in turn leads to an increase in the number of adipocytes and the accumulation of adipose tissue, and so a further decrease in T levels.## 1. Introduction Numerous studies and meta-analyses indicate the existence of mutual relationships between low levels of testosterone (T) and obesity [1,2,3,4]. The content of adipose tissue is related to the concentration of androgen in men and affects the balance between androgens and estrogens. In 1999, Cohen presented the hypothesis of the hypogonadal-obesity cycle, which explained why the low concentration of T contributed to the accumulation of adipose tissue, and how the deposition of adipose tissue reduced the concentration of T [5]. According to that concept, T is aromatized in adipose tissue to 17-β estradiol. High expression of aromatase in adipocytes leads to a reduction in circulating T, which in turn leads to an increase in the number of adipocytes and the accumulation of adipose tissue, and so a further decrease in T levels. The excess aromatase activity from increased adipocyte numbers in obese men results in the suppression of gonadotrophin-mediated T secretion, leading to progressive hypogonadism [3,6]. The pituitary gland, reacting to an increase in E2 concentration, inhibits the formation of T in the testes. A decreased T concentration leads to the accumulation of triacylglycerols (TAG) in abdominal fat tissue and to visceral obesity [7,8]. …

Our findings demonstrated that obese men have increased levels of TT and FT across all post-operative intervals. … Obese individuals experience hypogonadotropic hypogonadism which is characterized by reduced testosterone and testicular function (15, 17, 18) .… Accordingly, this meta-analysis synthesizes the available evidence to evaluate the impact of MBS on male sex hormone profiles, semen parameters, and sexual function. Our findings illustrated that MBS leads to significant improvements in the sex hormone status among obese men. However, its effect on semen quality appears to be challenging. The MBS has distinct effects on semen quality based on various surgical techniques and follow-up duration. Our findings demonstrated that obese men have increased levels of TT and FT across all post-operative intervals. This consistent elevation in circulating androgens offers endocrinological responses to MBS. Obese individuals experience hypogonadotropic hypogonadism which is characterized by reduced testosterone and testicular function (15, 17, 18) . Likewise, the MBS is able to reverse this process and exert its beneficial effects on TT and FT levels. Also, mechanistically MBS contribute to reduced adipose tissue which is accompanied with diminished activity of aromatase to converts androgens to estrogens (19, 20) . Despite the consistency in the direction and statistical significance of MBS, there was a statistical significance heterogeneity in pooled estimates for TT and FT. …

Conditions that lower SHBG [e.g., obesity, type 2 diabetes mellitus (T2DM), or androgen use] can lower TT concentrations to below the normal range, although FT concentrations might remain within the normal range.… CT scan may be sufficient if macroadenoma is suspected or to assess parasellar bone involvement. FSH, follicle-stimulating hormone; LH, leutinizing hormone. male sexual development and spermatogenesis (26). Clinicians should measure FT in men who have conditions that alter SHBG levels (Table 2) (24). Conditions that lower SHBG [e.g., obesity, type 2 diabetes mellitus (T2DM), or androgen use] can lower TT concentrations to below the normal range, although FT concentrations might remain within the normal range. Conditions that increase SHBG (e.g., advanced age, some anticonvulsants, or HIV infection) can raise TT concentrations to well above 400 ng/dL and sometimes into the high normal range or even above the normal range, even though FT concentrations might be low. Clinicians should also measure FT in men whose serum TT concentration is modestly above or below the lower limit of normal (e.g., 200 to 400 ng/dL) (27). …

It is estimated that approximately 35% of men older than 45 years of age and 30-50% of men with obesity or type 2 diabetes have hypogonadism.# Hypogonadism in Men Hypogonadism is a common condition in the male population, with a higher prevalence in older men, obese men, and men with type 2 diabetes. It is estimated that approximately 35% of men older than 45 years of age and 30-50% of men with obesity or type 2 diabetes have hypogonadism. #### Endocrine Connection

Obesity and male hypogonadism are often associated. This is consistent with our findings that further indicates visceral fat mass or dysfunction may be associated with hypogonadism.… However, this was not observed for WC 8 . This further indicates WC alone could not well distinguish subcutaneous and visceral fat mass 14 . Given the association between hypogonadism and obesity, in our study we also found the VAI had significantly larger AUC than other common obesity indices including WC, BMI, neck circumference, hip circumference, WHR and BAI. Thus VAI may be used as a surrogate of visceral fat dysfunction and we added new evidence to the application of VAI. Obesity and male hypogonadism are often associated. This is consistent with our findings that further indicates visceral fat mass or dysfunction may be associated with hypogonadism. How obesity induces hypogonadism is not completely clear. Hypothalamic dysfunction with a decreased gonadotropin-releasing hormone release seems to drive part or most of the mechanisms explaining hypogonadism in obese subjects 5, 15 . From our data, we could also speculate that the hypothalamic-pituitary level is the probable origin of the hypogonadal condition, because in the hypogonadal group, E2, FSH and LH were lower, which was more evident when quartiles of VAI were considered. …

Our systematic review results indicated that overweight and/or obesity were associated with low semen quality parameters (i.e., semen volume, sperm count and concentration, sperm vitality and normal morphology) and some specific reproductive hormones (e.g., inhibin B, total testosterone and sex hormone-binding globulin).… We conducted a systematic search of the literature published in MEDLINE-PubMed and EMBASE through June 2019. Based on the criteria in our review, 169 eligible publications were used for data abstraction. Finally, 60 articles were included in the qualitative analysis and 28 in the quantitative analysis. Our systematic review results indicated that overweight and/or obesity were associated with low semen quality parameters (i.e., semen volume, sperm count and concentration, sperm vitality and normal morphology) and some specific reproductive hormones (e.g., inhibin B, total testosterone and sex hormone-binding globulin). Overweight and/or obesity were also positively associated with high estradiol concentrations. Meta-analysis indicated that overweight and/or obesity categories were associated with lower sperm quality (i.e., semen volume, sperm count and concentration, sperm vitality, total motility and normal morphology), and underweight category was likewise associated with low sperm normal morphology. …

From a pathophysiological point of view, patients with an obesity-related functional AD (ORFAD) may represent ideal candidates for SERMs, as in the presence of fat mass excess, relative hyperestrogenism is generated that plays a pivotal role in determining AD.… This effect results in an increased release of gonadotropins that stimulate T biosynthesis.22From a pathophysiological point of view, patients with an obesity-related functional AD (ORFAD) may represent ideal candidates for SERMs, as in the presence of fat mass excess, relative hyperestrogenism is generated that plays a pivotal role in determining AD.23,24Furthermore, advantages of SERMs over TRT include oral administration, maintenance of fertility, avoidance of T supra-physiologic levels,21and a reported lower risk of erythrocytosis.25Although SERMs have been proposed as a treatment for men with central hypogonadism,26-30their use is off-label, the evidence supporting their efficacy on hypogonadism symptoms is lacking and only a few data have been produced in obese men with AD. …

Male AD can also be induced by obesity (61). … The concept of a hypogonadal– obesity–adipokine cycle is a proposed mechanism behind this association (50, 63, 64): Obesity has been suggested to lead to enhanced aromatisation of androgens to oestrogens by aromatase (CYP19A1, Fig. 2) in adipose tissue, thereby reducing the level of active androgens.… Ageing affects the hypothalamic–pituitary–gonadal (HPG) axis and can lead to late-onset AD, which is defined as low T levels if any form of classical causes of AD can be excluded (57). Ageing can result in gradual development of testicular failure due to a decreased number and response to LH of Leydig cells, and in reduced hypothalamic– pituitary signalling (58, 59). This manifests in an age related decline of T levels of around 0.1nmol/L per year starting during the third decade of life (60). Male AD can also be induced by obesity (61). Obesity significantly increases the age-related T decline and is associated with disordered gonadotrophin release (60). Conversely, weight loss can reverse obesity-associated hypogonadism (62). The concept of a hypogonadal– obesity–adipokine cycle is a proposed mechanism behind this association (50, 63, 64): Obesity has been suggested to lead to enhanced aromatisation of androgens to oestrogens by aromatase (CYP19A1, Fig. 2) in adipose tissue, thereby reducing the level of active androgens. Oestrogens may suppress the HPG axis, which reduces gonadal T synthesis (65). Treatment of obese men with the CYP19A1 inhibitor letrozole normalises T levels (66). Additionally, elevated levels of adipocyte-derived inflammatory cytokines (67, 68) have been shown to inhibit the HPG axis in healthy men and a contribution of leptin excess to the reduction of androgens in obesity has been suggested (69).

Patients with hypogonadism have increased fat mass and visceral adiposity, and the latter is associated with an increased risk of developing diabetes, hypertension, dyslipidemia, and atherosclerosis (28, 29) .… Total testosterone level was the only significant independent determinant of ADMA level, whereas WC was an independent determinant of HOMA-IR level. fundamental contributors to increased cardiometabolic risk (4) (5) (6) (7) (8) . In our previous studies, we reported metabolic derangements and endothelial dysfunction, inflammation, and insulin resistance in young and treatment-naïve patients with hypogonadism (9) (10) (11) . Patients with hypogonadism have increased fat mass and visceral adiposity, and the latter is associated with an increased risk of developing diabetes, hypertension, dyslipidemia, and atherosclerosis (28, 29) . We hypothesized that VAI, as an applicable marker for evaluating visceral adipose function, is useful for assessing increased cardiometabolic risk in patients with hypogonadism. VAI has been recently developed as a novel sexspecific index based on WC, BMI, TG, and HDL-C (12) . VAI is a marker of visceral adipose dysfunction and is strongly associated with cardiovascular events and type 2 diabetes (12, 30, 31) . …

We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. … In this study we investigated the effects of chronic testosterone deficiency on fatty acid (FA) metabolism by comparing a group of hypogonadal men to a group of eugonadal men.## Abstract Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [ 3 H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U- 13 C]palmitate and [1- 14 C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). … In contrast, testosterone administration to men over 65 years old with somewhat low serum testosterone concentrations decreased fat mass principally in the arms and legs [4]. How testosterone affects body fat patterning is of interest because an upper body fat distribution in obese individuals increases disease risk relative to those with a predominantly lower body fat distribution. The mechanism by which testosterone causes fat to be stored preferentially in some depots is presently unknown. In this study we investigated the effects of chronic testosterone deficiency on fatty acid (FA) metabolism by comparing a group of hypogonadal men to a group of eugonadal men. Fatty acids stored in adipose tissue largely derive from triglyceride rich lipoproteins (chylomicron and VLDL). A portion of fatty acids are redistributed between depots from the circulating free (F)FA pool that we've referred to as the direct FFA storage pathway. Dietary FA in chylomicrons require lipoprotein lipase (LPL) in order to be taken up by adipocytes and testosterone treatment of hypogonadal men decreases LPL activity [5]– [7]. …

Forty-eight middle-aged men, with type 2 diabetes, (visceral) obesity and symptoms of androgen deficiency, were included in this open-label study.## Abstract The objective of this study was to assess the effects of oral testosterone supplementation therapy on glucose homeostasis, obesity and sexual function in middle-aged men with type 2 diabetes and mild androgen deficiency. Forty-eight middle-aged men, with type 2 diabetes, (visceral) obesity and symptoms of androgen deficiency, were included in this open-label study. Twenty-four subjects received testosterone undecanoate (TU; 120 mg daily, for 3 months); 24 subjects received no treatment. Body composition was analyzed by bio-impedance. Parameters of metabolic control were determined. Symptoms of androgen deficiency and erectile dysfunction were scored by self-administered questionnaires. …

AIs block this conversion thereby minimizing the negative effects of estradiol on gonadotropin secretion and intratesticular T production. The subsequent increase in levels LH, FSH and T consequently improve spermatogenesis (41) . Such medications are most commonly indicated in the treatment of male infertility in obese patients or when the testosterone to estradiol ratio is less than ten.## Aromatase inhibitors (AIs) (anastrozole and letrozole) Aromatase is an enzyme that belongs to the cytochrome P-450 family. It is present in the testis, liver, brain, and adipose tissue and is responsible for converting T to estradiol. AIs block this conversion thereby minimizing the negative effects of estradiol on gonadotropin secretion and intratesticular T production. The subsequent increase in levels LH, FSH and T consequently improve spermatogenesis (41) . Such medications are most commonly indicated in the treatment of male infertility in obese patients or when the testosterone to estradiol ratio is less than ten. AIs are classified into steroidal or non-steroidal. Anastrozole (1 mg) and letrozole (2.5 mg) are third generation AIs that are highly specific and well-tolerated. AIs have been largely evaluated for the management of age-related hypogonadism. In a recent study by Dias et al. (42) , AIs consistently increased serum T levels and, more importantly, improved patients' bone mineral density (BMD). Fear of a presumed negative effect on BMD emerged initially. …

The prevalence of the metabolic syndrome (MetS) is increasing, especially in patients with low testosterone levels, who are at increased risk for later development of MetS. … Aging is associated with increased body fat mass, visceral adipose tissue (VAT), and ectopic fat deposition, which in turn is related to worse health conditions in the elderlyIntroduction Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome in ageing men (who have had normal pubertal development and normal male secondary characteristics) associated with low testosterone, age-related comorbidities, and deterioration in general health status, including obesity. 1 The prevalence of the metabolic syndrome (MetS) is increasing, especially in patients with low testosterone levels, who are at increased risk for later development of MetS. 2 Patients with MetS commonly suffer from combinations of risk factors, like central abdominal obesity, high blood pressure, increased fasting glucose levels, hyperinsulinemia/insulin resistance (IR), and dyslipidemia in the form of elevated triglycerides and reduced high-density lipoprotein. 3, 4 Aging increases the prevalence of the MetS and is associated with hypogonadism 5 and erectile dysfunction (ED). 6– 8 Hypogonadism, ED, visceral adiposity, IR, and MetS often coexist in the same population, increasing the risk of development of diabetes and cardiovascular disease, and affecting life expectancy. 9 Although the etiology of MetS is multifactorial, visceral obesity is a key modulator in the development of this syndrome. 10 Aging is an important factor in promoting visceral adiposity. 11 Aging is associated with increased body fat mass, visceral adipose tissue (VAT), and ectopic fat deposition, which in turn is related to worse health conditions in the elderly 12 with an enhanced cardiovascular disease risk profile. 13, 14 Although VAT and subcutaneous adipose tissue (SAT) are both associated with adverse cardiometabolic risk factors, VAT is more correlated with these risk factors. 11 Accumulation of visceral fat may lead to development of IR, which is strongly associated with progression of cardiovascular disease. …

It is increasingly apparent that a low testosterone level impairs general physical and mental health in men.## Abstract Testosterone is a sex hormone produced by testicular Leydig cells in males. Blood testosterone concentrations increase at three time-periods in male life-fetal, neonatal (which can be separated into newborn and infant periods), and pubertal stages. After peaking in the early 20s, the blood bioactive testosterone level declines by 1-2% each year. It is increasingly apparent that a low testosterone level impairs general physical and mental health in men. Here, this review summarizes recent systematic reviews and meta-analyses of epidemiological studies in males (including cross-sectional, longitudinal, and androgen deprivation studies, and randomized controlled testosterone replacement trials) in relation to testosterone and obesity, body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity. …

Several studies have demonstrated that a low testosterone concentration in men is associated with coronary heart disease, visceral obesity and insulin resistance.#### Abstract BACKGROUND Increased body fat, abdominal obesity and insulin resistance are important clinical features in hypogonadal men. Several studies have demonstrated that a low testosterone concentration in men is associated with coronary heart disease, visceral obesity and insulin resistance. In this study, the effects of testosterone replacement therapy on the abdominal visceral fat and cardiovascular risk factors in hypogonadal men were investigated. METHODS: We selected 26 men with secondary hypogonadism (mean serum testosterone+/-SD 0.39+/- 0.57ng/mL), who were then treated with testosterone for 12 months. …

Several studies in western and other modernised countries have found an age-independent secular decline in men’s serum total testosterone (TT) of approximately 1% per year, beginning in the 1970s [[5], [6], [7], [8], [9], [10], [11], [12]]. This downwards secular trend in T is only partly explained by the concurrent rise in BMI over the late 20th century [5,6].## Introduction Testosterone (T) plays a fundamental role in male physiology and reproductive health. Low endogenous T levels are associated with a higher risk of chronic disease [[1], [2], [3]]; and all-cause mortality [4]. Several studies in western and other modernised countries have found an age-independent secular decline in men’s serum total testosterone (TT) of approximately 1% per year, beginning in the 1970s [[5], [6], [7], [8], [9], [10], [11], [12]]. This downwards secular trend in T is only partly explained by the concurrent rise in BMI over the late 20th century [5,6]. The other factors responsible for this trend remain to be elucidated. Western dietary patterns have changed substantially over the 20th century, with processed food consumption more than doubling in western countries [13,14]. The trend towards increased processed food and decreased whole food consumption, has contributed to a change in macronutrient intakes since the mid-20th century. …

We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density.… We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International …

Prevalence of hypogonadism ranged from 22.9 to 78.8% and from 0 to 51.5% depending on whether low TT or low FT was used to define hypogonadism, respectively. … The pooled prevalence of hypogonadism when TT was measured was 42.8%,Prevalence of hypogonadism Prevalence of hypogonadism ranged from 22.9 to 78.8% and from 0 to 51.5% depending on whether low TT or low FT was used to define hypogonadism, respectively. In studies including patients with T2DM, prevalence ranged from 22.6 to 57.9%. In studies describing subgroups of patients with morbid/severe obesity, prevalence ranged from 15.2 to 78.8%. The pooled prevalence of hypogonadism when TT was measured was 42.8%, 95% CI 37.6–48.0% (13 studies, I 2 =89%, P<0.01). The pooled prevalence of hypogonadism when FT was measured was 32.7%, 95% CI 23.1–43.0% (11 studies, I 2 =96%,