madman
Super Moderator
Abstract
The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords “MOSH” OR “Obesity-related hypogonadism” OR “Testosterone replacement therapy” OR “Selective estrogen receptor modulator” OR “SERM”OR “Guidelines on male hypogonadism” as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long term management.
PATHOPHYSIOLOGY OF MOSH
DIAGNOSIS OF MOSH
-Definition
-Biochemical testing
MANAGEMENT OF MOSH: TO TREAT OBESITY OR HYPOGONADISM OR BOTH?
While obesity and hypogonadism are linked bidirectionally, there is an ongoing debate on whether to focus first on the treatment of obesity which can lead to improvement in gonadal function or to start testosterone replacement to correct hypogonadism first, with expected beneficial effects on body weight and metabolic parameters. In an attempt to address this debate, the following sections focus on the effects of obesity treatment on male hypogonadism and the role of Testosterone therapy on obesity.
-Effect of weight loss on hypogonadism
-Lifestyle changes to treat obesity
PHARMACOLOGICAL MANAGEMENT OF OBESITY
Obesity is a chronic disease associated with a chronic low-grade inflammatory state and immune dysfunction. Significant improvement in metabolic processes as well as decrease in overall mortality has been reported in several studies with multiple modes of treatment. Glucose-lowering medications have been employed in prediabetic and diabetic individuals. Improvements in erectile dysfunction after anti-diabetic drug therapy may be ascribed to indirect mechanisms such as the reduction of hyperglycaemia, excess body weight, high blood pressure, and the amelioration of other detrimental factors.However, a direct effect of glucose-lowering agents on both endothelial and smooth muscle cells is reasonable.
-Metformin
-Pioglitazone
-Sodium-glucose cotransporter-2 inhibitors
-Glucagon-like peptide-1 receptor analogues
BARIATRIC SURGERY
Metabolic and bariatric surgery (MBS) has evolved over the past three decades as a therapeutic strategy for obesity. MBS can reverse obesity-induced hypogonadism in a certain subset of individuals. TRT could be additionally employed if these measures fail to relieve symptoms and normalise testosterone levels. Recent guidelines on MBS and its indications by the American Society for Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders focused on the currently available surgical treatments for severe obesity and the criteria for selection, efficacy, and risks of surgical treatments for severe obesity and nonsurgical programmes that could be the initial therapy for severe obesity[37].
A BMI of 40 kg/m2, or 35 kg/m2 with co-morbidities, is a threshold for surgery that is applied universally. Currently,the dominant procedures are sleeve gastrectomy and Roux-en-Y gastric bypass, and together these procedures account for approximately 90% of all operations performed worldwide. Other procedures are adjustable gastric banding, biliopancreatic diversion with a duodenal switch and one-anastomosis gastric bypass.
A recent clinical study from Spain by Miñambres et al[38] revealed that weight loss attained after bariatric surgery among 12 subjects (five Sleeve gastrectomies and seven Gastric Bypass), increases TT, free testosterone and SHBG,resulting in the complete resolution of MOSH in men with severe obesity. The results demonstrate improved sexual function without an impact on sperm concentration and motility and an overall decline of morphology over time. In another study by Rigon et al[39], among 29 men undergoing bariatric surgery with a mean baseline weight of 155.26 kg ±25.88 kg, there were significant improvements in TT levels from 229.53 ng/dL ± 96.45 ng/dL to 388.38 ng/dL ± 160.91ng/dL (P < 0.001).
A recent systematic review involving 14 studies and 508 patients clearly showed remarkable benefits of improvement of T levels and erectile function in patients following weight loss after bariatric surgery[40]. Trials evaluating the effect of MBS on semen morphology are highly variable and inconsistent, with small prospective studies reporting a decrease in the percentage of sperm with normal morphology. However, a recent meta-analysis described that bariatric surgery had been associated with improved sperm morphology 12 months post-surgery[41].
OTHER THERAPEUTIC OPTIONS
Gonadotrophins such as human chorionic gonadotropin (hCG) or FSH are effective in increasing testosterone levels and semen parameters but are costly and require administration via injection. They currently require approval, prescription, and follow-up from specialist centres. Pulsatile GnRH is a less attractive option due to both the cost and the impracticality of continuous infusion. Selective oestrogen receptor modulators (SERMs) such as clomiphene citrate have been shown to increase testosterone levels without a negative impact on fertility, though there is a lack of long-term data regarding their impact on hypogonadal symptoms. The aromatase inhibitors (AIs) may also raise testosterone levels but are associated with reduced oestradiol levels and BMD, and their use requires close, long-term monitoring. Further studies of clomiphene and AIs in conjunction with testosterone therapy are required to confirm whether these agents can be used synergistically. This might mitigate the risk of adverse events of TRT in terms of reduced fertility and symptoms associated with increased oestradiol levels.
Weight reduction and MOSH-summary of the evidence: Overall, results suggest that a significant degree of weight loss does lead to improvement in serum T levels in those with hypogonadism. Lifestyle modification and bariatric surgery for those with severe obesity seem to show the best results in this regard. Some of the pharmacotherapeutic agents have shown a few additional benefits concerning erectile dysfunction or semen motility through unknown mechanisms. The choice of agent should be guided by the presence of other comorbidities like diabetes, or contraindications. The detrimental effects of metformin on sperm production or functioning will have to be elucidated in further studies.
ROLE OF TESTOSTERONE IN THE MANAGEMENT OF MOSH
The management of MOSH should be done with a multipronged approach. The relationship between obesity and T is bidirectional. T exerts multiple effects on body composition, lipid parameters, glycemic parameters, and overall cardiometabolic health. TRT is also fraught with possible adverse effects on cardiovascular events. Ensuring adequate weight loss with an increase in T levels is the cornerstone of therapy in MOSH-the effects of TRT remain controversial. The following section focuses on its role in multiple aspects of MOSH.
-Effects on body weight
-Effects on body composition
-Effects on muscle strength
-Effects on lipid profile
-Effects on glycemic parameters
-Effects on blood pressure
-Effects on cardiovascular events and mortality
-Effects on sexual function in middle-aged and elderly males
-Beneficial effects of TRT on mental health
-Concerns with the use of TRT in MOSH
-Adverse effects of TRT on fertility
-Cardiovascular risks with TRT
-Risks of venous thromboembolism
RECOMMENDATIONS ON THE USE OF TRT IN MOSH
The Endocrine Society (ES), European Association of Urologists and Andrologists (EAU, European Academy of Andrology) and the American Association of Clinical Endocrinologists (AACE) recommend TRT to be used in symptomatic hypogonadal men to induce/maintain secondary sex characteristics and to improve symptoms of sexual satisfaction like libido, erectile function, and emotional satisfaction. These guidelines do not recommend TRT for the sole purpose of weight reduction in obese men, for improved glycemic control or metabolic outcomes in men with MetS orT2DM, to improve exercise capacity, physical functioning, or cognitive functioning in elderly males or as an anti-ageing agent. The recently published SIAMS and SIE guidelines recommend starting TRT in all symptomatic hypogonadal men and older men with hypogonadism for improvement in sexual functioning, to improve BMD and prevent bone loss, to improve major depressive symptoms, to reduce WC and improve body composition and also to reduce fasting and postload glucose status[11].
The EAU recommends lifestyle changes for weight reduction in overweight and obese men with functional hypogonadism as weight loss can lead to increased serum T. It recommends against TRT for weight reduction in obese men or for glucometabolic outcomes[108]. The AACE and American College of Endocrinology recommend consideration of TRT in men with symptomatic hypogonadism and obesity not for fertility, but only as an addition to lifestyle intervention.These guidelines recommend against TRT in men to improve glycemic control, although they do not make any recommendation for or against TRT for weight reduction. The recent SIAMS and SIE recommend TRT to reduce WC and improve body composition by reducing fat mass and increasing lean mass in subjects with hypogonadism with or without MetS or T2DM[11]. They also recommend TRT to improve fasting and postprandial glycemia in subjects with hypogonadism with MetS or prediabetes to reduce the risk of progression to T2DM. However, they recommend against considering TRT to control dyslipidemia or to improve HbA1c% in patients with or without T2DM.
Thus, it might be a prudent decision to start TRT in obese men with MOSH, especially if they have dysglycemia. However, if used in the elderly or those at high risk for cardiovascular events, this must be weighed against potential risks and done under close supervision, as outlined in section 8.
AVAILABLE T PREPARATIONS
The available formulations of T, dosing schedule and formulation-specific adverse effects are listed in Table 1. The SIAMS guidelines recommend gel formulation of T for the treatment of older adults with hypogonadism, especially if potentially reversible conditions like obesity are present.
-Do different formulations of T have different effects and side effects?
-Contraindications of TRT
MONITORING OF PATIENTS RECEIVING TRT
-Monitoring for efficacy
-Monitoring for adverse effects
ROLE OF OTHER THERAPEUTIC INTERVENTIONS FOR MOSH
-SERMs and AI
-hCG with TRT
CONCLUSION
Treatment of MOSH should involve approaches in an integrated fashion combining lifestyle modifications with TRT. Diet, along with a combination of aerobic and muscle-strengthening exercises, forms the cornerstone of obesity management. Given the effects of TRT on body composition, particularly an increase in muscle mass and strength, TRT facilitates the ability to exercise more. A combination of TRT along with appropriate lifestyle modifications is expected to result in better outcomes. A limited number of studies have, however, addressed this issue. Small RCTs have suggested that a combination of TRT and LSM can lead to improvements in glycemic control, insulin resistance indices, atherogenic lipid profile, blood pressure, body composition, fatty liver indices and even reversal of MetS. Randomised controlled trials comparing the effects of obesity management, TRT and other agents like SERMs on different aspects of MOSH are necessary to make recommendations regarding their pragmatic use. Patients who are on TRT should be regularly monitored as per the current international guidelines to ensure they receive the benefits of therapy and to detect potential complications on time. Prompt selection of the appropriate individuals and optimal management strategies for the underlying conditions including obesity should be planned in curtailing the problems posed by MOSH.
The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords “MOSH” OR “Obesity-related hypogonadism” OR “Testosterone replacement therapy” OR “Selective estrogen receptor modulator” OR “SERM”OR “Guidelines on male hypogonadism” as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long term management.
PATHOPHYSIOLOGY OF MOSH
DIAGNOSIS OF MOSH
-Definition
-Biochemical testing
MANAGEMENT OF MOSH: TO TREAT OBESITY OR HYPOGONADISM OR BOTH?
While obesity and hypogonadism are linked bidirectionally, there is an ongoing debate on whether to focus first on the treatment of obesity which can lead to improvement in gonadal function or to start testosterone replacement to correct hypogonadism first, with expected beneficial effects on body weight and metabolic parameters. In an attempt to address this debate, the following sections focus on the effects of obesity treatment on male hypogonadism and the role of Testosterone therapy on obesity.
-Effect of weight loss on hypogonadism
-Lifestyle changes to treat obesity
PHARMACOLOGICAL MANAGEMENT OF OBESITY
Obesity is a chronic disease associated with a chronic low-grade inflammatory state and immune dysfunction. Significant improvement in metabolic processes as well as decrease in overall mortality has been reported in several studies with multiple modes of treatment. Glucose-lowering medications have been employed in prediabetic and diabetic individuals. Improvements in erectile dysfunction after anti-diabetic drug therapy may be ascribed to indirect mechanisms such as the reduction of hyperglycaemia, excess body weight, high blood pressure, and the amelioration of other detrimental factors.However, a direct effect of glucose-lowering agents on both endothelial and smooth muscle cells is reasonable.
-Metformin
-Pioglitazone
-Sodium-glucose cotransporter-2 inhibitors
-Glucagon-like peptide-1 receptor analogues
BARIATRIC SURGERY
Metabolic and bariatric surgery (MBS) has evolved over the past three decades as a therapeutic strategy for obesity. MBS can reverse obesity-induced hypogonadism in a certain subset of individuals. TRT could be additionally employed if these measures fail to relieve symptoms and normalise testosterone levels. Recent guidelines on MBS and its indications by the American Society for Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders focused on the currently available surgical treatments for severe obesity and the criteria for selection, efficacy, and risks of surgical treatments for severe obesity and nonsurgical programmes that could be the initial therapy for severe obesity[37].
A BMI of 40 kg/m2, or 35 kg/m2 with co-morbidities, is a threshold for surgery that is applied universally. Currently,the dominant procedures are sleeve gastrectomy and Roux-en-Y gastric bypass, and together these procedures account for approximately 90% of all operations performed worldwide. Other procedures are adjustable gastric banding, biliopancreatic diversion with a duodenal switch and one-anastomosis gastric bypass.
A recent clinical study from Spain by Miñambres et al[38] revealed that weight loss attained after bariatric surgery among 12 subjects (five Sleeve gastrectomies and seven Gastric Bypass), increases TT, free testosterone and SHBG,resulting in the complete resolution of MOSH in men with severe obesity. The results demonstrate improved sexual function without an impact on sperm concentration and motility and an overall decline of morphology over time. In another study by Rigon et al[39], among 29 men undergoing bariatric surgery with a mean baseline weight of 155.26 kg ±25.88 kg, there were significant improvements in TT levels from 229.53 ng/dL ± 96.45 ng/dL to 388.38 ng/dL ± 160.91ng/dL (P < 0.001).
A recent systematic review involving 14 studies and 508 patients clearly showed remarkable benefits of improvement of T levels and erectile function in patients following weight loss after bariatric surgery[40]. Trials evaluating the effect of MBS on semen morphology are highly variable and inconsistent, with small prospective studies reporting a decrease in the percentage of sperm with normal morphology. However, a recent meta-analysis described that bariatric surgery had been associated with improved sperm morphology 12 months post-surgery[41].
OTHER THERAPEUTIC OPTIONS
Gonadotrophins such as human chorionic gonadotropin (hCG) or FSH are effective in increasing testosterone levels and semen parameters but are costly and require administration via injection. They currently require approval, prescription, and follow-up from specialist centres. Pulsatile GnRH is a less attractive option due to both the cost and the impracticality of continuous infusion. Selective oestrogen receptor modulators (SERMs) such as clomiphene citrate have been shown to increase testosterone levels without a negative impact on fertility, though there is a lack of long-term data regarding their impact on hypogonadal symptoms. The aromatase inhibitors (AIs) may also raise testosterone levels but are associated with reduced oestradiol levels and BMD, and their use requires close, long-term monitoring. Further studies of clomiphene and AIs in conjunction with testosterone therapy are required to confirm whether these agents can be used synergistically. This might mitigate the risk of adverse events of TRT in terms of reduced fertility and symptoms associated with increased oestradiol levels.
Weight reduction and MOSH-summary of the evidence: Overall, results suggest that a significant degree of weight loss does lead to improvement in serum T levels in those with hypogonadism. Lifestyle modification and bariatric surgery for those with severe obesity seem to show the best results in this regard. Some of the pharmacotherapeutic agents have shown a few additional benefits concerning erectile dysfunction or semen motility through unknown mechanisms. The choice of agent should be guided by the presence of other comorbidities like diabetes, or contraindications. The detrimental effects of metformin on sperm production or functioning will have to be elucidated in further studies.
ROLE OF TESTOSTERONE IN THE MANAGEMENT OF MOSH
The management of MOSH should be done with a multipronged approach. The relationship between obesity and T is bidirectional. T exerts multiple effects on body composition, lipid parameters, glycemic parameters, and overall cardiometabolic health. TRT is also fraught with possible adverse effects on cardiovascular events. Ensuring adequate weight loss with an increase in T levels is the cornerstone of therapy in MOSH-the effects of TRT remain controversial. The following section focuses on its role in multiple aspects of MOSH.
-Effects on body weight
-Effects on body composition
-Effects on muscle strength
-Effects on lipid profile
-Effects on glycemic parameters
-Effects on blood pressure
-Effects on cardiovascular events and mortality
-Effects on sexual function in middle-aged and elderly males
-Beneficial effects of TRT on mental health
-Concerns with the use of TRT in MOSH
-Adverse effects of TRT on fertility
-Cardiovascular risks with TRT
-Risks of venous thromboembolism
RECOMMENDATIONS ON THE USE OF TRT IN MOSH
The Endocrine Society (ES), European Association of Urologists and Andrologists (EAU, European Academy of Andrology) and the American Association of Clinical Endocrinologists (AACE) recommend TRT to be used in symptomatic hypogonadal men to induce/maintain secondary sex characteristics and to improve symptoms of sexual satisfaction like libido, erectile function, and emotional satisfaction. These guidelines do not recommend TRT for the sole purpose of weight reduction in obese men, for improved glycemic control or metabolic outcomes in men with MetS orT2DM, to improve exercise capacity, physical functioning, or cognitive functioning in elderly males or as an anti-ageing agent. The recently published SIAMS and SIE guidelines recommend starting TRT in all symptomatic hypogonadal men and older men with hypogonadism for improvement in sexual functioning, to improve BMD and prevent bone loss, to improve major depressive symptoms, to reduce WC and improve body composition and also to reduce fasting and postload glucose status[11].
The EAU recommends lifestyle changes for weight reduction in overweight and obese men with functional hypogonadism as weight loss can lead to increased serum T. It recommends against TRT for weight reduction in obese men or for glucometabolic outcomes[108]. The AACE and American College of Endocrinology recommend consideration of TRT in men with symptomatic hypogonadism and obesity not for fertility, but only as an addition to lifestyle intervention.These guidelines recommend against TRT in men to improve glycemic control, although they do not make any recommendation for or against TRT for weight reduction. The recent SIAMS and SIE recommend TRT to reduce WC and improve body composition by reducing fat mass and increasing lean mass in subjects with hypogonadism with or without MetS or T2DM[11]. They also recommend TRT to improve fasting and postprandial glycemia in subjects with hypogonadism with MetS or prediabetes to reduce the risk of progression to T2DM. However, they recommend against considering TRT to control dyslipidemia or to improve HbA1c% in patients with or without T2DM.
Thus, it might be a prudent decision to start TRT in obese men with MOSH, especially if they have dysglycemia. However, if used in the elderly or those at high risk for cardiovascular events, this must be weighed against potential risks and done under close supervision, as outlined in section 8.
AVAILABLE T PREPARATIONS
The available formulations of T, dosing schedule and formulation-specific adverse effects are listed in Table 1. The SIAMS guidelines recommend gel formulation of T for the treatment of older adults with hypogonadism, especially if potentially reversible conditions like obesity are present.
-Do different formulations of T have different effects and side effects?
-Contraindications of TRT
MONITORING OF PATIENTS RECEIVING TRT
-Monitoring for efficacy
-Monitoring for adverse effects
ROLE OF OTHER THERAPEUTIC INTERVENTIONS FOR MOSH
-SERMs and AI
-hCG with TRT
CONCLUSION
Treatment of MOSH should involve approaches in an integrated fashion combining lifestyle modifications with TRT. Diet, along with a combination of aerobic and muscle-strengthening exercises, forms the cornerstone of obesity management. Given the effects of TRT on body composition, particularly an increase in muscle mass and strength, TRT facilitates the ability to exercise more. A combination of TRT along with appropriate lifestyle modifications is expected to result in better outcomes. A limited number of studies have, however, addressed this issue. Small RCTs have suggested that a combination of TRT and LSM can lead to improvements in glycemic control, insulin resistance indices, atherogenic lipid profile, blood pressure, body composition, fatty liver indices and even reversal of MetS. Randomised controlled trials comparing the effects of obesity management, TRT and other agents like SERMs on different aspects of MOSH are necessary to make recommendations regarding their pragmatic use. Patients who are on TRT should be regularly monitored as per the current international guidelines to ensure they receive the benefits of therapy and to detect potential complications on time. Prompt selection of the appropriate individuals and optimal management strategies for the underlying conditions including obesity should be planned in curtailing the problems posed by MOSH.
