Keywords

Obesity, Male hypogonadism, Testosterone, Estradiol, Cholesterol

Introduction

Obesity is considered a global health problem [1]. In 2016, according to the World Health Organization (WHO), 39% of adults were overweight, of which 13% were obese [2].

In Brazil, obesity increased by 54% between 2006 and 2011, and it is estimated that by 2025, it will be the fifth country to have obesity problems [3].

The Body Mass Index (BMI), used to classify body mass, was developed in Belgium by the statistician, Adolphe Quetelet [4] and is calculated by dividing an individual's weight in kilograms by the square of their height in meters (BMI = weight (kg)/height ² (m ² )).

Obesity is defined as the abnormal or excessive accumulation of fat. The current definitions establishing the cut-offs were agreed upon in 1997 and were published in 2000 (WHO 2000) [5].

According to the WHO, a BMI greater than or equal to 25 kg/m ² is classified as overweight, a BMI greater than 30 kg/m ² is considered obese, and a BMI greater than 40 kg/m ² is considered severe obesity [6].

Obesity is diagnosed clinically by calculating the BMI or using other anthropometric methods to analyze the distribution of body fat, such as measurements of skin folds, waist circumference (WC), waist-to-hip ratio, or sagittal diameter [7].

Obesity is associated with an increased risk of premature mortality [8] and an increased risk of comorbidities. Thus, obesity is associated with the development of other diseases, such as cardiovascular diseases, arterial hypertension, type 2 diabetes mellitus, respiratory diseases, orthopedic diseases, osteoarthritis, dermatological diseases, increased incidence of gallstones, hepatic steatosis, increased cholesterol and triglycerides, and male hypogonadism [9].

More severe obesity (BMI > 35-40 kg/m ² ) is associated with reductions in testosterone (T) although obesity with a BMI of less than 35-40 kg/m ² is also associated with a reduction in total testosterone (TT) and sex hormone-binding globulin (SHBG) [10].

In population-based studies, obesity was the single most important factor that resulted in T deficiency [11].

Physiologically, T is produced in the Leydig cells of the testicles and is stimulated by pituitary secretion of luteinizing hormone (LH). In serum, 50% of T is bound to albumin and free T (FT) represents 2% of TT [12]. T is converted to estradiol (E2) by the enzyme aromatase, which subsequently activates estrogen receptors ERa and ERb [13].

In the European Male Aging Study, obese men (BMI > 30 kg/m ² ) had a 30% lower testosterone concentration, a reduction equivalent to nearly three decades of aging, and a 13-fold increase in the prevalence of late-onset hypogonadism (LOH) [14].

Many men with LOH suffer from chronic metabolic conditions, mainly obesity and diabetes mellitus, but LOH can result from certain medications and conditions such as glucocorticoids, opioids, tricyclic antidepressants, psychosocial stress, sleep apnea, and chronic obstructive pulmonary disease [15].

Clinical evidence suggests that low T levels are a risk factor for cardiovascular disease [16].

There is a bidirectional relationship between obesity and hypogonadism [17]. Thus, evidence highlights that male hypogonadism can lead to increased adiposity, whereas obesity can be a cause of male hypogonadism [18].

T deficiency is associated with visceral fat dysfunction, chronic inflammation, insulin resistance, and low levels of SHBG [19].

In obese individuals, increased amounts of aromatase enzymes produced by adipose tissue reduce T levels and increase estrogen hormone levels. T deficiency further facilitates adipocyte differentiation, inflammation, and insulin resistance. The resulting increase in estrogen, leptin, insulin, and inflammatory cytokines results in the suppression of the hypothalamic-pituitary-testicular (HPT) axis [20].

Male hypogonadism is characterized by inadequate testicular production of sex steroids and sperm [9]. The 2010 Endocrine Society guidelines define hypogonadism in men as “a clinical syndrome arising from failure of the testicles to produce physiological levels of T, androgen deficiency, and a normal number of sperm due to disruption of one or more levels of the HPT axis” [21].

Primary male hypogonadism occurs when there is testicular dysfunction [22] and secondary male hypogonadism (SMH) occurs when the HPT axis is dysfunctional [23]. The most common cause of SMH is obesity [21,22] and 60% of men are obese [24]. The increase induced by obesity in the levels of leptin, insulin, pro-inflammatory cytokines, and estrogen can cause functional hypogonadotropic hypogonadism with defects at the level of gonadotropin-releasing hormone (GnRH) hypothalamic neurons [25].

Male Obesity-associated Secondary Hypogonadism (MOSH) is becoming a public health problem and epidemiological studies suggest that prevalence rates are as high as 45.0-57.5% [9]. MOSH impairs fertility, sexual function, mineralization, and fat metabolism resulting in increased fat accumulation, muscle mass deterioration, and body composition alteration [18,26].

Obesity is one of the alarming health problems in modern societies that lead to infertility [27].

According to some authors [28], obesity can negatively impact sperm quality, and consequently, male fertility. It is estimated that 15% of couples are infertile, with male infertility contributing to 50% of the cases [29].

Inflammatory cytokines disrupt the HPT axis and steroidogenesis, causing hypogonadotropic hypogonadism and altered spermatogenesis, with poor semen parameters, including DNA fragmentation and epigenetic damage and modification [30].

Obesity often leads to non-alcoholic fatty liver disease (NAFLD), which covers a broad histological spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma. Since sex steroids are metabolized in the liver and their serum levels depend in part on hepatic SHBG secretion, NAFLD may be related to the observed changes in sex steroid levels in obese men [31].

Hepatic steatosis is defined by the presence of fat encompassing 5% of the liver weight in the absence of inflammation [32] with a reduction in SHBG produced by the liver [33].

Non-alcoholic fatty liver disease (NAFLD) is considered a feature of the metabolic syndrome (MetS) and contributes to cardiovascular disease (CVD) and authors have evaluated the relationship of NAFLD with male sexual problems and infertility [34].

Obesity and metabolic syndrome (MetS) are currently considered epidemics worldwide, driven by an obesogenic pathology of the environment, in which chronic inflammation is an important etiological factor [30].

According to Grossmann [35], obesity is an increasing prevalence worldwide, is the clinical condition most strongly associated with reduced concentrations of T in men, and is one of the strongest predictors of receiving treatment with T.

The objective of this study is to evaluate the effect of decreasing body weight and WC on male sex hormones in obese men.

Patients and Methods

Study design

This was a retrospective review of medical records of patients seen between 2015 and 2018 at the Medical Clinic of Endocrinology in the municipality of Santo André, state of São Paulo, Brazil.

 A total of 42 adult men, aged between 28 and 69 years, from the ABC Region and São Paulo City, State of São Paulo, presented to the Medical Clinic of Endocrinology, in the city of Santo André, State of São Paulo, Brazil for the treatment of obesity.

Data collection

Data from the medical records of patients from the physical examination, such as blood pressure (BP), body weight, height, BMI, WC, and laboratory tests, including total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and very low density lipoproteins (VLDL) cholesterol; liver enzymes such as aspartate transaminase (SGOT/AST), pyruvic transaminase (SGPT/ALT), gamma glutamyl transferase (γGT), alkaline phosphatase (AP), total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH). These data were collected before and after obesity treatment, lasting between 12 and 13 months, which consisted of guidance, dietary education, and regular physical activity to reduce body weight without the use of medication. LDL cholesterol treatment was performed using statins during the entire obesity treatment period.

The age of 42 patients was considered the first medical appointment. The averages of the results obtained by referring to the physical and laboratory examinations before and after treatment for obesity and cholesterol were considered for data analysis.

Patients with type 1 and 2 Diabetes Mellitus, increased triglyceride levels, excessive alcohol, medicines like glucocorticoids, opioids, tricyclic antidepressants were excluded.

The methods and reference values used for each laboratory test are listed in Table 1. All these parameters were analyzed in serum.

Statistical analysis

A descriptive data analysis was performed. Quantitative variables were presented as measures of central tendency and variability according to data distribution using the Shapiro-Wilk test. To compare the clinical variables before and after treatment, the paired t-test and Wilcoxon test were used to analyze the normality of the data. The confidence level adopted was 95%, and the statistical program used was Stata version 14.0.

Results

In this study, 42 adult male patients, aged 28-69 years, were evaluated.

The data obtained from medical records are presented in Table 2 and Table 3.

The statistical results are presented in Table 4 and Table 5, respectively. The treatments performed on the patients in this study were guidance, dietary education and regular physical activity to reduce body weight without the use of medication or\statins for LDL cholesterol during throughout the obesity treatment period. There was a significant decrease in SGOT, SGPT, γGT, SHBG, weight, BMI, WC, TC, LDL, VLDL and E2 values. HDL, TT, and FT levels were significantly higher after treatment than before treatment. The AP level did not change during this period. There was a decrease in FSH and an increase in LH levels, but this was not statistically significant.

Table 4 shows the statistical results of variables with a normal distribution.

Table 5 shows the statistical results of variables with non-normal distributions.

Figure 1 shows the mean values of BMI results and sex hormones such as TT and FT, and E2 and LH before and after treatment. There was a decrease in BMI and E2 levels, and an increase in FT, TT, and LH levels after treatment.

Figure 2 shows the mean values of the WC results, HDL cholesterol, LDL cholesterol, SGOT/AST, SGPT/ALT, and γGT levels before and after treatment. There was a reduction in WC, SGOT/AST, SGPT/ALT, γGT, and LDL cholesterol and an increase in HDL cholesterol after treatment.

Discussion

Our results demonstrated that the decrease in BMI and WC led to a substantial improvement in TT and FT levels and a statistically significant decrease in E2 levels (Table 5).

According to some studies [36], obesity is the most important factor associated with low T levels, surpassing the effects of age and comorbidities. Furthermore, some authors [37] claim that the conversion of TT into E2 by aromatase is greater in the adipose tissue.

In adipose tissue, androgens are converted into estrogens in a reaction known as aromatization, which is catalyzed by the cytochrome P450 aromatase enzyme produced in Leydig cells. In obese men, estrone and E2 levels increase due to increased peripheral aromatization of androgens [38].

Data from the literature [38,39] report that obese men have higher levels of E2, which promotes the inhibition of the HPT axis, and causes a decrease in the stimulation of LH, which acts on the Leydig cells of the testicle, leading to the production of T and FSH, which acts on testicular Sertoli cells, stimulating spermatogenesis. Thus, there is a decrease in circulating T levels, which contributes to the development of hypogonadotropic hypogonadism.

Adipose tissue signals that interfere with hypothalamic function include the release of pro-inflammatory cytokines, increased conversion of T to E2, and release of the hormone leptin, which directly inhibits the stimulatory action of pituitary gonadotropins in testicular Leydig cells to further decrease T production. All of these signs can accentuate the expansion of fat deposits and lead to a state of hypogonadotropic hypogonadism, obesity, and metabolic syndrome [40].

In this study, we observed a decrease in FSH, an increase in LH (Table 4 and Table 5), and an increase in TT and FT with a decrease in BMI and WC (Table 5). GnRH stimulates the pituitary gland to release LH, which stimulates Leydig cells to produce T. The inverse relationship between T levels and adipose tissue expansion can affect the hypothalamus, resulting in a decrease in LH secretion by hypophysis.

Numerous epidemiological studies have shown a negative correlation between obesity and T levels, and several meta-analyses have shown that weight loss produces a proportional increase in T concentrations. It is generally accepted that hypogonadism secondary to obesity is functional, as it is reversible after weight loss [41].

De Lorenço, et al. [26] observed a significant increase in TT and a reduction of 17-β estradiol levels after nutritional intervention.

These data corroborate the results of our study, as we observed that after the treatment of obesity, in the period of 12 and 13 months, which consisted of guidance, nutritional education, and physical activity, without the use of medication, there was a decrease in E2 and an increase in TT and TL (Figure 1 and Table 5).

Androgens also play an important role in regulating body fat distribution in humans. They directly affect the differentiation, size, and expansion of the fat compartment of adipocytes. They also directly affect adipocyte function, including insulin signaling, lipid metabolism, fatty acid uptake, and adipokine production [42].

T reduces central fat deposition and in men, its deficiency is associated with increased visceral adipose tissue and insulin resistance, in addition to the dysregulation of lipid metabolism [43].

In a study by Rotter, et al. [44], in men with TT deficiency and presenting with sexual dysfunction, variables related to obesity were measured, such as BMI, waist/hip ratio, and visceral adiposity index, and it was found that in 40% of these cases, particularly for the visceral adiposity index, which was the strongest predictor of low TT among the non-diabetic male population.

In this study, diabetic men were excluded, and we observed that the mean BMI found before treatment indicated that these patients had grade I obesity, and the mean WC before treatment was above 90 cm, showing that they were at risk of metabolic complications increased substantially [45].

Many men with LOH suffer from chronic metabolic conditions, and LOH can result from certain medications such as glucocorticoids, opioids and tricyclic antidepressants [15], however, in this study, these drugs were excluded.

Regarding lipid parameters, we observed an increase in the mean values of SGPT and LDL cholesterol, with low mean values of HDL cholesterol (Table 2, Table 3, Table 4 and Table 5) before treatment with obesity and cholesterol.

After the decrease in BMI and WC with guidance, nutritional education, and regular physical activity, without the use of medication, and cholesterol treatment with statins (Table 2, Table 3, Table 4 and Table 5), we observed a significant decrease in the values of SGOT, SGPT, γGT, TC, LDL, and VLDL (Figure 2, Table 4 and Table 5), higher HDL values (Table 4), and no variations in AP (Table 4).

According to the authors [46], hypoandrogenism is associated with the reduction of HDL cholesterol and elevation of LDL cholesterol, TC, and triglycerides.

In a study of obese young men with MOSH (age ranging from 20 to 60 years, mean 38 ± 15 years), the authors evaluated, in addition to low TT and lipid levels, and observed an increase in TC, triglycerides and LDL [47].

In this study, men with increased triglycerides levels were excluded.

Obesity also reflects reduced concentrations of SHBG [35], which is secreted by hepatocytes, and sex steroids are metabolized in the liver.

According to some authors [48] inhibition of hepatic synthesis and SHBG release results in negative regulation of TT production.

According to Michalakis , et al. [49], a reduction in total TT and SHBG concentrations during a 9-year follow-up in overweight men compared to lean men in the Massachusetts Male Aging Study and did not observe differences in FT.

 

In this study, we observed a decrease in SHBG and E2 levels and an increase in TT and FT levels after a decrease in BMI and WC in obese patients (Figure 1, Table 4 and Table 5).

There is increasing evidence linking NAFLD to male sexual and reproductive dysfunction [34,50].

Some studies [51] have investigated whether the severity and histologic components of NAFLD are associated with sex steroid levels in obese men and among the histological components of NAFLD, only steatosis was independently associated with TT (rs = -0.331, p = 0.003) and FT levels (rs = -0.255, p = 0.025).

Imaging examinations and liver histological components were not observed after reviewing the medical records of this study. We observed a significant decrease in the values of SGOT, SGPT, and γGT after a decrease in BMI and WC with guidance, dietary education, and regular physical activity, without the use of medication (Figure 2, Table 4 and Table 5), and no variations in AP (Table 4). Therefore, we cannot consider that the patients in this study had NAFLD, although we excluded obese patients who excessively used alcohol.

Obesity negatively affects conventional and biofunctional sperm parameters and induces epigenetic changes that can be transferred to offspring. Furthermore, obesity-related diseases are linked to dysregulation of adipocyte function and microenvironmental inflammatory processes [52].

Recent studies have suggested an interaction between low testosterone and increased risk of mortality [53] as well as a possible cause of reproductive difficulties and infertility due to low sperm count [23].

According to Giagulli, et al. [41], diet with or without physical activity improves body weight and hypogonadism in obese adult and elderly men, with or without type 2 diabetes mellitus.

This study excluded patients with type 1 and 2 diabetes mellitus, but it also demonstrated that weight loss is an important factor for improving TT and FT levels (Table 4 and Table 5).

According to some authors [54] the treatment of primary male hypogonadism involves only exogenous T and although recent evidence does not indicate an increased risk of cardiovascular events, the use of exogenous T still raises doubts regarding its cardiovascular safety.

Other authors [55] have reported that the use of exogenous T affects the feedback mechanism of the HPT axis and, as a consequence, impairs spermatogenesis and testicular atrophy in the long term; thus, the use of exogenous T becomes a harmful option in young men with hypogonadism who wish to maintain fertility.

In 2015, the United States Food and Drug Administration issued a warning about potential cardiovascular risks from the use of exogenous T, and fertility preservation is another reason to look for viable alternatives [56]. Other side effects of the exogenous use of T have also been reported, such as erythrocytosis [57], male infertility, atrophy and gynecomastia [58].

Global increases in T prescriptions [59] and a marked increase in the prevalence of obesity, together with secular trends of reductions in circulating T, have likely contributed to an increasing number of obese men receiving T treatment.

In comments by authors Warrick J Inder & Mathis Grossmann on Obesity and “functional hypogonadism”- mechanisms and management: on EJE-22-1110 “leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind RCT”, published in the European Journal of Endocrinology, Jones, et al. [60], conducted a double-blind randomized controlled trial of weekly leflutrozole - an aromatase inhibitor, for the treatment of “functional hypogonadism” associated with obesity. These authors [60] showed a dose-dependent increase in serum TT, LH, and FSH, along with an improvement in semen volume and motile sperm count in the subset of participants who provided semen samples. Symptoms of sexual dysfunction were not alleviated, nor was there any improvement in fatigue or general health. Adverse effects have been observed, particularly at the highest weekly dose of 1.0 mg, most commonly elevated hematocrit, hypertension, headache and increased prostate specific antigen. Bone mineral density fell significantly in the lumbar spine at all doses compared to placebo.

In the context of obesity with a BMI, 30-40 kg/m ² , TT and SHBG are low, but FT concentrations are maintained within the normal range [60].

According to Fernandez, et al. [25], obesity-induced hypogonadism is reversible with substantial weight loss. Lifestyle measures are the cornerstone of treatment.

In this study, we did not report the use of exogenous T as a treatment for male hypogonadism resulting from obesity. Dietary guidance and regular physical activity to decrease body weight and WC were the factors that contributed to the increase in TT and FT levels, decrease in E2 levels, and improvement in the patients' quality of life. In Conclusion our results demonstrate that obese men have low mean serum values of TT and FT, high E2, normal LH and FSH, high LDL cholesterol, and SGPT. After treatment for obesity, with guidance, dietary education, and physical activity, without the use of medication, and with a decrease in BMI and WC, there was an increase in the mean serum values of TT and FT and a decrease in E2. We observed a decrease in LDL cholesterol after statin treatment and a decrease in SGPT. We did not observe variations in AP before and after the obesity treatment. Thus, obesity-induced male hypogonadism is reversible with substantial weight loss.

Therefore, the treatment of obesity with proper nutrition and regular physical activity is recommended, thus avoiding the use of exogenous testosterone, which can lead to testicular atrophy and late infertility.

Acknowledgments

The authors are grateful to patients.

Ethical Considerations

The objectives and methods of this study were clearly stated for all the patients. This study was approved by the Committee of Ethics in Research of the Medical School of the ABC Foundation, SP, Brazil, and registered under number 4.915.336.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

All authors have contributed significantly and agree with the content of the manuscript. NGMC, JFMA, ADB, and OAMG prepared the study design, the data collection, wrote paper, literature review and manuscript review. MAZM performed acquisition of data, interpretation of the results, literature review and the coordination of the study. Besides, the manuscript had not been published elsewhere and is not under consideration in any journal. All authors have seen and given their approval for submission of the revised manuscript.

References

1. Pasquali R, Casanueva F, Haluzik M, Van Hulsteijn L, Ledoux S, et al. (2020) European society of endocrinology clinical practice guideline: Endocrine work-up in obesity. Eur J Endocrinol 182: G1-G32.
2. World Health Organization (2018) Obesity and overweight.
3. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, et al. (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors. JAMA 289: 76-79.
4. Quetelet A (1871) Antropométrie ou Mesure des Différences Facultés de l’Homme.
5. WHO (2000) Obesity: Preventing and managing the global epidemic Report of a WHO consultation. World Health Organ Tech Rep Ser 894: 1-253.
6. World Health Organization (2015) Obesity and Overweight. Fact Sheet N_311 January 2015.
7. Goran MI (1998) Measurements issues related to studies of childhood obesity: Assessment of body composition, body fat distribution, physical activity and food intake. Pediatric 101: 505-518.
8. De Lorenzo A, Gratteri S, Gualtieri P, Cammarano A, Bertucci P, et al. (2019) Why primary obesity is a disease? J Transl Med 17: 169.
9. Calderon B, Gomez-Martin JM, Vega-Pinero B, Martin-Hidalgo A, Galindo J, et al. (2016) Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight. Andrology 4: 62-67.
10. Grossmann M, Ng Tang Fui M, Cheung AS (2020) Late-onset hypogonadism: Metabolic impact American Society of Andrology and European Academy of Andrology. Andrology 8: 1519-1529.
11. Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ, et al. (2010) Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European male ageing study. J Clin Endocrinol Metab 95: 1810-1818.
12. Dunn JF, Nisula BC, Rodbard D (1981) Transport of steroid hormones: Binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid- binding globulin in human plasma. J Clin Endocrinol Metab 53: 58-68.
13. Pardridge WM (1986) Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab 15: 259-278.
14. Kelly DM, Jones TH (2013) Testosterone: A metabolic hormone in health and disease. J Endocrinol 217: R25-45.
15. Irvine DS (1998) Epidemiology and etiology of male infertility. Hum Reprod 13: 33-44.
16. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, et al. (2010) Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 363: 123-135.
17. Khera M, Broderick GA, Carson CC, Dobs AS, Fara­day MM, et al. (2016) Adult-onset hypogonadism. Mayo Clin Proc 91: 908-926.
18. Vlachopoulos C, Ioakeimidis N, Miner M, Aggelis A, Pietri P, et al. (2014) Testosterone deficiency: A determinant of aortic stiffness in men. Atherosclerosis 233: 278-283.
19. Rao PM, Kelly DM, Jones TH (2013) Testosterone and insulin resistance in the metabolic syndrome and T2 DM in men. Nat Rev Endocrinol 9: 479-493.
20. Carrageta DF, Oliveira PF, Alves MG, Monteiro MP (2019) Obesity and male hypogonadism: Tales of a vicious cycle. Obes Rev 20: 1148-1158.
21. Haymana C, Sonmez A, Aydogdu A, Tapan S, Basaran Y, et al. (2017) Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism. Arch Endocrinol Metab 61: 282-287.
22. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al. (2010) Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95: 2536-2559.
23. Rey RA, Grinspon RP, Gottlieb S, Pasqualini P, Knoblovits S, et al. (2013) Male hypogonadism: An extended classification based on a developmental, endocrine physiology-based approach. Andrology 1: 3-16.
24. Dandona P, Dhindsa S (2011) Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab 96: 2643-2651.
25. Calderón B, Galdón A, Calanas A, Peromingo R, Galindo J, et al. (2014) Effects of bariatric surgery on male obesity-associated secondary hypogonadism: Comparison of laparoscopic gastric bypass with restrictive procedures. Obes Surg 24: 1686-1692.
26. Fernandez CJ, Chacko EC, Pappachan JM (2019) Male Obesity-related Secondary Hypogonadism - Pathophysiology, Clinical Implications and Management. Eur Endocrinol 15: 83-90.
27. De Lorenzo A, Noce A, Moriconi E, Rampello T, Marrone G, et al. (2018) MOSH Syndrome (Male Obesity Secondary Hypogonadism): Clinical Assessment and Possible herapeutic Approaches. Nutrients 10: 474.
28. Cabler S, Agarwal A, Flint M, Du Plessis SS (2010) Obesity: modern man’s fertility nemesis. Asian J Androl 12: 480-489.
29. Cazzaniga W, Candela L, Boeri L, Capogrosso P, Pozzi E, et al. (2020) The impact of metabolically healthy obesity in primary infertile men: Results from a cross-sectional study. Andrology 8: 1762-1769.
30. Leisegang K, Henkel R, Agarwal A (2019) Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. Am J Reprod Immunol 82: e13178.
31. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55: 2005-2023.
32. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, et al. (2012) Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 91: 319-327.
33. Luo J, Chen Q, Shen T, Wang X, Fang W, et al. (2018) Association of sex hormone-binding globulin with non-alcoholic fatty liver disease in Chinese adults. Nutr Metab (Lond) 15: 79.
34. Hawksworth DJ, Burnett AL (2020) Non-alcoholic fatty liver disease, male sexual dysfunction, and infertility: Common links, common problems. Sex Med Rev 8: 274-285.
35. Grossmann M (2018) Hypogonadism and male obesity: Focus on unresolved questions. Clin Endocrinol (Oxf) 89: 11-21.
36. Tajar A, Forti G, O'Neill TW, Lee DM, Silman AJ, et al. (2010) Characteristics of secondary, primary, and compensated hypogonadism in aging men: Evidence from the European male ageing study. J Clin Endocrinol Metab 95: 1810-1818.
37. Suzuki R, Allen NE, Appleby PN, Key TJ, Dossus L, et al. (2009) Lifestyle factors and serum androgens among 636 middle aged men from seven countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 20: 811-821.
38. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H (2007) Utility, limitations, and pitfalls in measuring testosterone: an endocrine society position statement. J Clin Endocrinol Metab 92: 405-413.
39. Stárka L, Hill M, Pospisilova H, Duskova M (2020) Estradiol, obesity and hypogonadism. Physiol Res Sep 69: S273-S278.
40. Hermoso DAM, Bizerra PFV, Constantin RP, Ishii-Iwamoto EL, Gilglioni EH (2020) Association between metabolic syndrome, hepatic steatosis, and testosterone deficiency: evidences from studies with men and rodents. The Aging Male 23: 1296-1315.
41. Giagulli VA, Castellana M, Murro I, Pelusi C, Guastamacchia E, et al. (2019) The role of diet and weight loss in improving secondary hypogonadism in men with obesity with or without Type 2 Diabetes Mellitus. Nutrients 11: 2975.
42. O'Reilly MW, House PJ, Tomlinson JW (2014) Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol 143: 277-284.
43. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, et al. (2006) Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab 91: 843-850.
44. Rotter I, Ryl A, Grzesiak K, Szylinska A, Pawlukowska W, et al. (2018) Cross-sectional inverse associations of obesity and fat accumulation indicators with testosterone in non-diabetic aging men. Int J Environ Res Public Health 15: 1207.
45. Junqueira CLC, da Costa GM, Magalhaes MEC da (2011) Síndrome Metabólica: o risco cardiovascular é maior que o risco dos seus componentes isoladamente? Revista Brasileira de Cardiologia, Rio de Janeiro 24: 308-315.
46. Dougherty RH, Rohrer JL, Hayden D, Rubin SD, Leder BZ (2005) Effect of aromatase inhibition on lipids and inflammatory markers of cardiovascular disease in elderly men with low testosterone levels. Clin Endocrinol 62: 228-235.
47. Li FP, Wang CZ, Huang JM, Yang WT, Lan BY, et al. (2020) Obesity-associated secondary hypogonadism in young and middle-aged men in Guangzhou: A single-centre cross-sectional study. Int J Clin Pract 74: e13513.
48. Allen NE, Appleby PN, Davey GK, Key TJ (2002) Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men. Cancer Causes Control 13: 353-363.
49. Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG (2013) The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. Metabolism 62: 457-478.
50. Phillips KP, Tanphaichitr (2010) Mechanisms of obesity-induced male infertility. Expert Rev Endocrinol Metab 5: 229-251.
51. Van de Velde F, Bekaert M, Hoorens A, Geerts A, T’Sjoen G, et al. (2020) Histologically proven hepatic steatosis associates with lower testosterone levels in men with obesity. Asian J Androl 22: 252-257.
52. Barbagallo F, Condorelli RA, Mongioì LM, Cannarella R, Cimino L, et al. (2021) Molecular mechanisms underlying the relationship between obesity and male infertility. Metabolites 11: 840.
53. Lopez DS, Qiu X, Advani S, Tsilidis KK, Khera M, et al. (2018) Double trouble: Co-occurrence of testosterone deficiency and body fatness associated with all-cause mortality in US men. Clin Endocrinol 88: 58-65.
54. Morgentaler A, Zitzmann M, Traish AM, Fox AW, Jones TH, et al. (2016) Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc 91: 881-896.
55. Katz DJ, Nabulsi O, Tal R, Mulhall JP (2012) Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int 110: 573-578.
56. Lo EM, Rodriguez KM, Pastuszak AW, Khera M (2018) Alternatives to testosterone therapy: A review. Sex Med Rev 6: 106-113.
57. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, et al. (2010) Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis. J Clin Endocrinol Metab 95: 2560-2575.
58. Ohlander SJ, Lindgren MC, Lipshultz LI (2016) Testosterone and male infertility. Urol Clin North Am 43: 195-202.
59. Handelsman DJ (2013) Global trends in testosterone prescribing, 2000-2011: Expanding the spectrum of prescription drug misuse. Med J Aust 199: 548551.
60. Jones TH, Dobs AS, Randeva H, Moore W, Parkin JM (2023) Leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind randomised controlled trial. Eur J Endocrinol 189: 297-308.

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