Obesity/Diabetes

[Michael Scally MD]

[No full-text, but always of interest is conditions, including how long on TRT and how long for HPTA restoration.]

Zouras S, Stephens JW, Price D. Obesity-related hypogonadism: a reversible condition. BMJ Case Rep. 2017. http://casereports.bmj.com/content/2017/bcr-2017-220416

Obesity is associated with hypogonadism. While this association is widely accepted, the underlying mechanisms remain unclear. Furthermore, obesity is a risk factor for hypogonadism and conversely hypogonadism may be a risk factor for obesity.

We present the case of a morbidly obese man aged 30 years with hypogonadotrophic hypogonadism that underwent a Roux-en-Y gastric bypass operation.

Following the surgical treatment of his obesity, the testosterone level returned to normal with improvements in hypogonadal symptoms, which allowed discontinuation of exogenous testosterone therapy.

This case report demonstrates reversal of hypogonadism following weight loss with restoration of gonadal function.

 

[Michael Scally MD]

Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial.

This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years.

Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels.

Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

Pham NH, Bena J, Bhatt DL, Kennedy L, Schauer PR, Kashyap SR. Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery. Obesity Surgery. Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery

 

[Michael Scally MD]

Hypogonadism and Male Obesity: Focus on Unresolved Questions

Obesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men, and presents as one of the strongest predictors of receiving testosterone treatment.

While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic-pituitary-testicular axis (HPT) suppression.

HPT axis suppression is likely mediated via pro-inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether estradiol-mediated negative hypothalamic-pituitary feedback plays a pathogenic role requires further study.

Although the obesity-hypogonadism relationship is bi-directional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone.

In randomised controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone.

However, longer-term, larger RCTs designed for patient-important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated non-classical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimisation of comorbidities remain first line.

Grossmann M. Hypogonadism and Male Obesity: Focus on Unresolved Questions. Clin Endocrinol (Oxf) 2018. https://onlinelibrary.wiley.com/doi/abs/10.1111/cen.13723

 

[Apexvallen]

Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone.

Wow, the more ya know!

 

[Michael Scally MD]

Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality

This systematic review and meta-analysis aims to establish the effects of bariatric surgery on male sex hormones, sperm parameters, and sexual function. We searched MEDLINE, EMBASE, Web of Science, and Scopus from database inception through June 2018. Articles were eligible for inclusion if they examined the effect of bariatric surgery on male sex hormones and sperm parameters in patients with obesity.

Primary outcomes of interest were sex hormones and sperm quality. Secondary outcome was sexual function (International Index of Erectile Function (IIEF) score). Pooled estimates were calculated using random effects meta-analysis. A total of 28 cohort studies with 1022 patients were identified from 3896 potentially relevant citations.

Both free and calculated testosterone levels were significantly increased after bariatric surgery (mean difference (MD) - 7.47 nM, 95% CI - 8.62 to - 6.31, p < 0.001 and MD - 0.05 nM, 95% CI - 0.07 to - 0.02, p < 0.001, respectively). Consistent with the increase in testosterone, LH, FSH, and SHBG levels were also significantly increased after surgery. In contrast, free and total estradiol and prolactin levels were significantly decreased after bariatric surgery.

From studies that reported the IIEF score, bariatric surgery led to a significant increase in erectile function after surgery (MD - 0.46, 95% CI - 0.89 to - 0.02, p = 0.04). However, bariatric surgery did not affect sperm quality, DHEA, androstenedione, and inhibin B levels.

Sustained weight-loss induced by bariatric surgery had a significant effect on increasing male sex hormones and decreasing female sex hormones in male patients with obesity. However, sperm quality and function were not improved after surgery.

Lee Y, Dang JT, Switzer N, et al. Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality: A Systematic Review and Meta-Analysis. Obes Surg. 2019;29(1):334–346. Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality: a Systematic Review and Meta-Analysis

 

[Michael Scally MD]

[OA] Male Obesity Associated Gonadal Dysfunction and the Role of Bariatric Surgery

Obesity is an ever growing pandemic and a prevalent problem among men of reproductive age that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the precision and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and preclinical data support these findings.

Clinical studies on the impact of medically induced weight loss on serum testosterone concentrations and spermatogenesis is promising but may show differential and unsustainable results. In contrast, literature has demonstrated that weight loss after bariatric surgery is correlated with an increase in serum testosterone concentrations that is superior than that obtained with only lifestyle modifications, supporting a further metabolic benefit from surgery that may be specific to the male reproductive system.

The data on sperm and semen parameters is controversial to date. Emerging evidence in the burgeoning field of genetics and epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to a comprehensive view of the impact of obesity on subsequent generations.

Furthermore, conveying the potential impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Healthcare professionals treating male infertility and obesity need to adapt their practice to assimilate these new findings to better counsel men about the importance of paternal preconception health and the impact of novel non-medical therapeutic interventions.

Herein, we summarize the pathophysiology of obesity on the male reproductive system and emerging evidence regarding the potential role of bariatric surgery as treatment of male obesity-associated gonadal dysfunction.

Sultan S, Patel AG, El-Hassani S, et al. Male Obesity Associated Gonadal Dysfunction and the Role of Bariatric Surgery. Front Endocrinol (Lausanne). 2020;11:408. Published 2020 Jun 19. doi:10.3389/fendo.2020.00408 Male Obesity Associated Gonadal Dysfunction and the Role of Bariatric Surgery

 

[Michael Scally MD]

Testosterone Treatment Is Associated with Reduced Adipose Tissue Dysfunction and Nonalcoholic Fatty Liver Disease in Obese Hypogonadal Men

Purpose: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery.

Methods: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies.

Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies.

Results: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes.

In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones.

Conclusions: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged.

Maseroli E, Comeglio P, Corno C, et al. Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men [published online ahead of print, 2020 Aug 8]. J Endocrinol Invest. 2020;10.1007/s40618-020-01381-8. doi:10.1007/s40618-020-01381-8 https://link.springer.com/article/10.1007/s40618-020-01381-8

 

[Michael Scally MD]

[OA] Testosterone Therapy for Prevention and Treatment of Obesity

Testosterone deficiency (TD) is common in men with obesity. The association between TD and obesity is bidirectional; low testosterone (T) is a contributing cause to obesity, and obesity is a contributing cause to low T, creating a vicious circle. Most guidelines recommend weight loss by diet/exercise as the first point of intervention to stop this vicious cycle.

However, it requires a large amount of weight loss that is maintained over time. In clinical practice, this is rarely achieved by lifestyle interventions. Bariatric surgery is currently the main obesity treatment modality that results in a large amount of weight loss with decent weight loss maintenance. However, bariatric surgery is an invasive and expensive procedure, with risk for complications.

Considering the high prevalence of TD in men with obesity, a more practical and sustainable obesity treatment for men is testosterone therapy (TTh). Thanks to the metabolic effects of T, TTh results in more fat loss and preservation of fat-free mass, compared with diet/exercise interventions alone. In contrast to weight loss achieved by diet/exercise and bariatric surgery, TTh significantly preserves both muscle and bone mass. Further, TTh has psychological effects that may increase the motivation and ability of men to adhere to diet/exercise programs.

Real-world evidence studies of long-term TTh for up to 11 years provide compelling evidence that TTh holds tremendous potential as a new treatment modality for obesity in men, with long-term weight loss maintenance and health benefits far exceeding those achieved by lifestyle interventions, approved obesity drugs, as well as bariatric surgery.

Caliber M, Saad F. Testosterone Therapy for Prevention and Treatment of Obesity in Men. Androgens: Clinical Research and Therapeutics 2020;1:40-61. https://doi.org/10.1089/andro.2020.0010

 

[Michael Scally MD]

[OA] Remission of Type 2 Diabetes in A Young, Hypogonadal Man Under Long-Term Testosterone Therapy

Background: The increasing prevalence of obesity, in particular in young patients, represents a growing clinical and health-care cost problem. Young adulthood obesity strongly increases the risk of type 2 diabetes (T2DM), hypertension, myocardial infarction, stroke or venous thromboembolism.

Young obese T2DM men have a high prevalence of low testosterone concentrations indicating eugonadotropic hypogonadism. An existing but undetected testosterone deficiency will substantially hamper weight loss or render it impossible. In such cases, returning the testosterone level to normal range is therefore the necessary pre-condition to fight obesity and thus the related comorbidities.

Case presentation: A 20-year-old man with grade III obesity complained of fatigue, dry mouth, and erectile dysfunction (ED). Medical examination revealed uncontrolled T2DM, pronounced dyslipidemia, severe vitamin D deficiency, and a remarkably low testosterone level. Medication with metformin and vitamin D was initiated and testosterone therapy (TTh) was started.

Under TTh, the patient continuously lost weight, and his blood sugar and lipid profi le progressively normalized. Finally, a complete remission of T2DM was reached and all baseline complaints including ED were fully gone. Even after TTh was stopped, all respective values remained in the normal range.

Conclusions: We conclude that TTh worked as a necessary stimulus along with standard therapy for consequential facilitation of weight reduction and associated recovery of the body’s own production of testosterone in particular in terms of a complete remission of T2DM.

Mskhalaya G, Tishova Y, Alfaradzh A, Kalinchenko S (2020) Remission of type 2 diabetes in a young, hypogonadal man under long-term testosterone therapy: A case report. Glob J Obes Diabetes Metab Syndr 7(2): 024-028. DOI: Remission of type 2 diabetes in a young, hypogonadal man under long-term testosterone therapy: A case report

 

[Michael Scally MD]

[OA] Testosterone Therapy for Prevention and Treatment of Obesity

Testosterone deficiency (TD) is common in men with obesity. The association between TD and obesity is bidirectional; low testosterone (T) is a contributing cause to obesity, and obesity is a contributing cause to low T, creating a vicious circle. Most guidelines recommend weight loss by diet/exercise as the first point of intervention to stop this vicious cycle. However, it requires a large amount of weight loss that is maintained over time.

In clinical practice, this is rarely achieved by lifestyle interventions. Bariatric surgery is currently the main obesity treatment modality that results in a large amount of weight loss with decent weight loss maintenance. However, bariatric surgery is an invasive and expensive procedure, with risk for complications.

Considering the high prevalence of TD in men with obesity, a more practical and sustainable obesity treatment for men is testosterone therapy (TTh). Thanks to the metabolic effects of T, TTh results in more fat loss and preservation of fat-free mass, compared with diet/exercise interventions alone.

In contrast to weight loss achieved by diet/exercise and bariatric surgery, TTh significantly preserves both muscle and bone mass. Further, TTh has psychological effects that may increase the motivation and ability of men to adhere to diet/exercise programs.

Real-world evidence studies of long-term TTh for up to 11 years provide compelling evidence that TTh holds tremendous potential as a new treatment modality for obesity in men, with long-term weight loss maintenance and health benefits far exceeding those achieved by lifestyle interventions, approved obesity drugs, as well as bariatric surgery.

Caliber M, Saad F. Testosterone Therapy for Prevention and Treatment of Obesity in Men. Androgens: Clinical Research and Therapeutics 2020;1:40-61. https://doi.org/10.1089/andro.2020.0010

 

[Michael Scally MD]

[OA] Rationale and Current Evidence for Testosterone Therapy in The Management of Obesity and Its Complications

Overt hypogonadism in men adversely affects body composition and metabolic health, which generally improve upon testosterone (TS) therapy. As obese men often display lower serum TS levels, in particular when they present with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), there have been claims that androgen therapy prevents or reverses obesity and improves metabolic health. This has contributed to the increase in TS prescriptions during the past two decades.

In this narrative review, based on findings from larger observational studies and randomized controlled intervention trials, we evaluate whether low TS predicts or predisposes to obesity and its metabolic consequences, and whether obese men with low TS are truly hypogonadal. We further describe the mechanisms underlying the bi-directional relationships of TS levels with obesity and metabolic health, and finally assess the evidence for TS therapy in men with obesity, MetS and/or T2DM, considering efficacy, safety concerns and possible alternative approaches.

It is concluded that low serum sex hormone-binding globulin and total TS levels are highly prevalent in obese men, but that only those with low free TS levels and signs or symptoms of hypogonadism should be considered androgen deficient. These alterations are reversible upon weight loss. Whether low TS is a biomarker rather than a true risk factor for metabolic disturbances remains unclear.

Considering the limited number of sound TS therapy trials have shown beneficial effects, the modest amplitude of these effects, and unresolved safety issues, one cannot in the present state-of-the-art advocate TS therapy to prevent or reverse obesity-associated metabolic disturbances. Instead, the focus should remain on lifestyle measures and management of obesity-related consequences.

Lapauw B, Kaufman JM. MANAGEMENT OF ENDOCRINE DISEASE: Rationale and current evidence for testosterone therapy in the management of obesity and its complications. Eur J Endocrinol. 2020 Dec;183(6):R167-R183. doi: 10.1530/EJE-20-0394. PMID: 33105105. https://eje.bioscientifica.com/view/journals/eje/183/6/EJE-20-0394.xml

 

[Michael Scally MD]

[OA] Estradiol, Obesity and Hypogonadism

Obesity increases the incidence of hypogonadism in men, and hypogonadism in turn plays a role in obesity. One of the first mechanisms proposed to explain this was a hypothesis based on the principle that obese men have higher estrogen levels, and that increased estrogens provide feedback to the hypothalamic-pituitary-testicular axis, reducing the secretion of gonadotropins and leading to a decrease of overall testosterone levels. This concept has since been questioned, though never completely disproven.

In this study we compared hormone levels in three groups of men with differing BMI levels (between 18-25, 25-29, and 30-39), and found correlations between lowering overall testosterone, SHBG and increased BMI. At the same time, there were no significant changes to levels of free androgens, estradiol or the gonadotropins LH and FSH. These findings are in line with the idea that estrogen production in overweight and obese men with BMI up to 39 kg/m(2) does not significantly influence endocrine testicular function.

Stárka L, Hill M, Pospíšilová H, Dušková M. Estradiol, obesity and hypogonadism. Physiol Res. 2020 Sep 30;69(Suppl 2):S273-S278. PMID: 33094625. http://www.biomed.cas.cz/physiolres/pdf/2020/69_S273.pdf

 

[Michael Scally MD]

[OA] How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity

In adipocytes, fat cells, a particular estrogen receptor appears critical for energy-supplying mitochondria to function properly. The discovery points to a potential drug target for boosting fat tissue metabolism, which could help combat obesity and other metabolic conditions.

The research addresses a vexing problem that many middle-aged adults face as they get older—added fat tissue and weight gain due to a slowing metabolism. The problem is especially prominent for women, as estrogen deprivation after menopause leads to an increase in total body fat.

Previous studies have offered a potential explanation in a link between fat accumulation, mitochondria-related dysfunction, and lower expression of the gene ESR1, which encodes a form of the estrogen receptor called ERα. Indeed, healthy identical twins who differ by body mass index have different mitochondria-related RNA signatures in their fat cells, indicating a link between mitochondrial dysfunction and adiposity. In addition, ESR1 expression is reduced in fat tissue from women with obesity and adipocyte ERα deletion disrupts metabolic balance in rodents.

With this knowledge in mind, investigators first examined the clinical relationships between ESR1 expression and markers of metabolic health.

Hampton T. How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity. JAMA. 2020;324(21):2146. https://jamanetwork.com/journals/jama/fullarticle/2773543

 

[Michael Scally MD]

[OA] How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity

In adipocytes, fat cells, a particular estrogen receptor appears critical for energy-supplying mitochondria to function properly. The discovery points to a potential drug target for boosting fat tissue metabolism, which could help combat obesity and other metabolic conditions.

The research addresses a vexing problem that many middle-aged adults face as they get older—added fat tissue and weight gain due to a slowing metabolism. The problem is especially prominent for women, as estrogen deprivation after menopause leads to an increase in total body fat.

Previous studies have offered a potential explanation in a link between fat accumulation, mitochondria-related dysfunction, and lower expression of the gene ESR1, which encodes a form of the estrogen receptor called ERα. Indeed, healthy identical twins who differ by body mass index have different mitochondria-related RNA signatures in their fat cells, indicating a link between mitochondrial dysfunction and adiposity. In addition, ESR1 expression is reduced in fat tissue from women with obesity and adipocyte ERα deletion disrupts metabolic balance in rodents.

With this knowledge in mind, investigators first examined the clinical relationships between ESR1 expression and markers of metabolic health.

Hampton T. How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity. JAMA. 2020;324(21):2146. https://jamanetwork.com/journals/jama/fullarticle/2773543

[Mice] Estrogen Receptor Α Controls Metabolism in White and Brown Adipocytes

The estrogen receptor α (ERα; encoded by ESR1) is implicated in aging-related obesity. Zhou et al. now provide evidence that ERα affects metabolism by controlling mitochondrial dynamics and function in both white and brown adipose tissue. Expression of ESR1 in adipose tissue associated with reduced visceral adiposity and increased insulin sensitivity in two independent human cohorts and a panel of mice.

Follow-up experiments in mice indicated that Esr1 deletion in white adipose tissue promoted parkin-driven mitophagy, whereas Esr1 deletion in brown adipose tissue reduced thermogenesis. Mechanistically, the authors tied these metabolic responses to direct ERα-driven control of a mitochondrial DNA polymerase subunit in both types of fat.

Zhou Z, Moore TM, Drew BG, et al. Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling. Science Translational Medicine 2020;12:eaax8096. http://stm.sciencemag.org/content/12/555/eaax8096.abstract

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood.

Here, we show that adipose tissue ESR1/Esr1 expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel.

To determine the anti-obesity actions of ERα in fat, we selectively deleted Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice.

In brown fat centrally involved in body temperature maintenance, Esr1 was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1).

In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1.

We identified Polg1 as an ERα target gene by showing that ERα binds the Polg1 promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.

 

[Michael Scally MD]

[OA] Testosterone Metabolites Differentially Regulate Obesogenesis and Fat Distribution

Highlights

Hypogonadism-associated impairments in glucose metabolism are driven by elevated fat mass rather than reduced muscle mass.

Testosterone-derived estradiol and DHT exert opposite effects on body fat distribution by controlling depot-specific adipocyte hypertrophy.

Androgen signaling blocks obesogenic adipogenesis in vivo and this is mediated by testosterone rather than DHT under normal physiologic conditions.

Objective Low testosterone in men (hypogonadism) is associated with obesity and type II diabetes. Testosterone replacement therapy has been shown to reverse these effects. However, the mechanisms by which testosterone regulates total fat mass, fat distribution and metabolic health are unclear. In this study, we clarify the impact of hypogonadism on these parameters, as well as parse the role of testosterone from its downstream metabolites, dihydrotestosterone (DHT) and estradiol, in the regulation of depot-specific adipose tissue mass.

Methods To do this, we utilized mouse models of male hypogonadism coupled with hormone replacement therapy, magnetic resonance imaging (MRI), glucose tolerance tests (GTTs), flow cytometry and immunohistochemical techniques.

Results We find that castrated mice develop increased fat mass, reduced muscle mass and impaired glucose metabolism compared to gonadally intact males. Interestingly, obesity is further accelerated in castrated mice fed a high fat diet, suggesting hypogonadism increases susceptibility to obesogenesis when dietary consumption of fat is elevated. By performing hormone replacement therapy in castrated mice, we show that testosterone impedes visceral and subcutaneous fat mass expansion.

Whereas testosterone-derived estradiol selectively blocks visceral fat growth and DHT selectively blocks the growth of subcutaneous fat. These effects are mediated by depot-specific alterations in adipocyte size. In addition, we show that high fat diet induced adipogenesis is elevated in castrated mice and that this can be rescued by androgen treatment. Obesogenic adipogenesis is also elevated in mice where androgen receptor activity is inhibited.

Conclusion These data indicate hypogonadism impairs glucose metabolism and increases obesogenic fat mass expansion through adipocyte hypertrophy and adipogenesis. In addition, our findings highlight distinct roles for testosterone, DHT and estradiol in the regulation of total fat mass and fat distribution and reveal that androgen signaling blocks obesogenic adipogenesis in vivo.

Sebo ZL, Rodeheffer MS. Testosterone metabolites differentially regulate obesogenesis and fat distribution. Molecular Metabolism 2020:101141. http://www.sciencedirect.com/science/article/pii/S2212877820302155

 

[Michael Scally MD]

Rapid Changes in Serum Testosterone in Men with Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin

OBJECTIVE To investigate the effect of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS Seventy men with newly diagnosed drug-naive T2DM and HbA1c >9.0% (75 mmol/mol) were treated with intensive insulin pump therapy for 5 days to achieve glucose normalization. They were randomized to control (continued on intensive insulin only) and metformin (plus metformin) groups (1:1) for 1 month. Testosterone was measured at baseline, randomization, and after 1-month treatment.

RESULTS Total, free, and bioavailable testosterone increased significantly within 5 days (all P < 0.001). After 1 month, compared with the control group, the metformin group had lower total (12.7 vs. 15.3 nmol/L), free (0.20 vs. 0.24 nmol/L), and bioavailable (4.56 vs. 5.31 nmol/L) testosterone (all P < 0.05).

CONCLUSIONS In men with T2DM, 1-month oral metformin may decrease serum testosterone levels independent of blood glucose control. The effects of long-term metformin on testosterone in men need further study.

Hu Y, Ding B, Shen Y, et al. Rapid Changes in Serum Testosterone in Men with Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin. Diabetes Care 2021:dc201558. Rapid Changes in Serum Testosterone in Men with Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin

 

[Michael Scally MD]

Once-Weekly Semaglutide in Adults with Overweight or Obesity

BACKGROUND - Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

METHODS - In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention.

The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

RESULTS - The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001).

More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds).

The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo.

Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

CONCLUSIONS - In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight.

Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 2021. https://doi.org/10.1056/NEJMoa2032183

 

[Michael Scally MD]

Ingelfinger Julie R., Rosen Clifford J.. (2021) STEP 1 for Effective Weight Control — Another First Step?. N Engl J Med DOI: 10.1056/NEJMe2101705. https://www.nejm.org/doi/full/10.1056/NEJMe2101705

Given the worldwide increase in obesity, with attendant coexisting conditions and increased risk of death, there is a pressing need to address weight loss and maintenance strategies. Behavioral methods of weight control fail more often than not, and bariatric surgery is invasive and, often, eventually followed by regain of weight.

Medications approved for weight loss by the Food and Drug Administration, the European Medicines Agency, and other regulatory bodies have had a troubling history, with withdrawal of several approved drugs owing to serious adverse events; among these are various amphetamines (addiction), fenfluramine (cardiac toxicity), and, most recently, lorcaserin (cancer risk).

Currently available agents in the United States include the lipase inhibitor orlistat (which decreases intestinal fat absorption), phentermine–topiramate, and naltrexone–bupropion. However, none have been shown to prevent or treat type 2 diabetes mellitus, which is often associated with or develops in conjunction with obesity.

During clinical trials for the two most recently approved agents for treating type 2 diabetes — the glucagon-like peptide-1 (GLP-1) agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors (Table 1) — weight loss was noted to be substantial. However, a major limiting factor with regard to treating obesity with the GLP-1 agonists was their daily subcutaneous administration. Oral preparations of the GLP-1 agonists have recently been approved, and that has propelled initiation of trials for both classes of drugs in persons with obesity.

…



Daniel Drucker is a clinician scientist at LTRI @sinaihealth @uoft @uoftmedicine who studies peptide hormones diabetes, obesity and the gut endocrine system. https://twitter.com/DanielJDrucker

[Thread] Classic GLP-1 Editorial @nejm from Rosen and Ingelfinger “It is important to note that oral semaglutide has been associated with pancreatitis”
View: https://twitter.com/DanielJDrucker/status/1359660642265952258?s=20


It is also important to note that a review of the actual data from the entire oral semaglutide PIONEER program #T2D shows zero association with pancreatitis. NEJM fairy tales. https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(21)00009-7/fulltext

…

 

[Michael Scally MD]

Metabolism of Testosterone During Weight Loss in Men With Obesity

Highlights

Three weeks after bariatric surgery SHBG and testosterone serum levels increase.

Decreased aromatization contributes to restoration of sex steroid profile.

Decreased metabolism of testosterone by the 5alpha-reductase pathway.

Increased production of testosterone is possible after bariatric surgery.

Objective: Men with obesity often have low total and, with increasing adiposity, also low free testosterone (T) levels, which can partially restore during weight loss. Although this is partly explained by lower sex hormone binding globulin (SHBG) production and hypothalamic-pituitary downregulation, it is still not unravelled whether changes in androgen metabolism contribute to this phenomenon. Therefore, early changes in urinary excretion of T and its metabolites, during weight loss, in men with obesity are investigated.

Design: Longitudinal study.

Methods: Fourteen men with obesity (age 52(45-60)years, BMI 42.6(41.8-44.8)kg/m²) underwent gastric bypass surgery (GBS). Before surgery and 3 weeks, 6 weeks, 6 months and 1 year thereafter, 24 h urine and fasting serum samples were collected. Serum T and estradiol (E2) levels were analyzed using LC-MS/MS and urinary metabolites of T with GC-MS/MS.

Results: Already three weeks after GBS, serum SHBG and total T levels increased and remained increased as compared to baseline (all,p < 0.0125). Gonadotropins and (free) E2 levels were unchanged, serum E2/T ratio decreased (p < 0.0125). Total amount of urinary T increased non-significantly with mean increases of 53% one year after GBS (p = 0.026). Urinary E2/T, estrone/T, 3α-androstanediol/T and androsterone/T ratios decreased after GBS (p < 0.0125).

Conclusions: Restoration of circulating T levels during weight loss in this population is not only brought about by normalization of circulating SHBG levels, but increased production of and alterations in T metabolism also contribute. More specifically, relative decreases in aromatization and lower 5α-reductase activity might also be involved in restoring T levels in men with obesity.

Van de Velde F, Deventer K, Van Gansbeke W, et al. Metabolism of testosterone during weight loss in men with obesity. J Steroid Biochem Mol Biol. 2021 Feb 18:105851. doi: 10.1016/j.jsbmb.2021.105851. Epub ahead of print. PMID: 33610798. Metabolism of testosterone during weight loss in men with obesity

 

[Michael Scally MD]

Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes

Context: Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk.

Objective: Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared to hypogonadal men without T2D.

Design, method and participants: Single arm, open-label clinical (NCT01378299) trial involving 105 men (40-74 years old), with average morning testosterone<300ng/dl. Subjects were injected intramuscularly with testosterone cypionate (200mg) every 2 weeks for 18 months.

Testosterone and estradiol assessed by liquid-chromatography/mass-spectroscopy; serum C-telopeptide (CTX), osteocalcin and sclerostin by ELISA; A1C by high performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography.

Results: Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups.

Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared to non-T2D men (p<0.01). T2D men increased lumbar spine aBMD (p<0.05), total area at 38% tibia (p<0.01) and periosteal and endosteal circumferences at the same site (p<0.01 for both).

T2D men had reduced tibial vBMD (p<0.01), but with preserved bone mineral content (p=0.01). Changes in A1c or body composition were similar between the 2 groups.

Conclusions: Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their non-diabetic counterparts.

Colleluori G, Aguirre L, Napoli N, Qualls C, Villareal DT, Armamento-Villareal R. Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes. J Clin Endocrinol Metab. 2021 Mar 18:dgab181. doi: 10.1210/clinem/dgab181. Epub ahead of print. PMID: 33735389. Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes