Abstract
Male obesity-associated secondary hypogonadism (MOSH) affects metabolic and reproductive health. We evaluated the efficacy of laparoscopic sleeve gastrectomy (LSG) on the remission of MOSH and testosterone concentrations and examined the association between weight loss and changes in testosterone concentrations. In this retrospective study, 304 male patients with obesity who underwent LSG at the Center for Obesity and Hernia Surgery, Huashan Hospital, Fudan University (Shanghai, China) between October 2022 and December 2024 were screened. Metabolic and hormonal parameters were evaluated at baseline and at 6 months, 12 months, and 24 months post-LSG. The primary outcome was the remission of MOSH. Secondary outcomes were changes in total testosterone concentrations and free testosterone concentrations, and their correlations with the percentage of total weight loss (TWL%). Among 304 screened patients, 212 were diagnosed with MOSH and 186 were included (mean ± standard error [s.e.]; age: 33.1 ± 0.6 years; body mass index: 43.0 ± 0.5 kg m−2). MOSH remission rates at 6 months, 12 months, and 24 months post-LSG were 81.4%, 79.7%, and 89.5%, respectively, accompanied by a substantial increase in total testosterone and free testosterone concentrations. TWL% (mean ± s.e.) reached 28.2% ± 0.9%, 34.4% ± 1.2%, and 32.3% ± 2.2% at the respective time points. Linear mixed models showed significant positive correlations between TWL% and total testosterone and free testosterone concentrations after surgery (both P < 0.001). LSG induced the remission of MOSH and restored testosterone concentrations. Sustained weight loss is pivotal in driving endocrine recovery, suggesting that LSG is effective for managing MOSH.
Keywords: male obesity-associated secondary hypogonadism, obesity, sleeve gastrectomy, testosterone, weight loss
INTRODUCTION
Obesity is a global epidemic that has a major effect on metabolic function and contributes to a variety of comorbidities, including male obesity-associated secondary hypogonadism (MOSH).1,2,3,4 MOSH is characterized by low serum testosterone concentrations which are strongly associated with a high body mass index (BMI) and visceral adiposity.5 More than 60% of male patients undergoing metabolic bariatric surgery (MBS) have MOSH.4 MOSH contributes to sexual dysfunction, reduced muscle mass, and metabolic disturbances, such as insulin resistance and dyslipidemia, all of which negatively affect the overall quality of life.6,7,8,9,10,11
The pathophysiology of MOSH involves complex interactions between excess adiposity and the hypothalamic–pituitary–gonadal (HPG) axis.6,12 Increased adipose tissue leads to altered hormone secretion, including elevated levels of aromatase, which converts testosterone to estrogen.13 Additionally, leptin resistance and insulin resistance in individuals with obesity are critical factors contributing to dysfunction of the HPG axis, further exacerbating testosterone deficiency.12,14
Based on the established association between obesity and MOSH, weight management has become central to treatment. While lifestyle modifications offer modest improvements, MBS is more effective in reversing MOSH.15 Several studies have shown that weight loss following MBS leads to considerable improvements in testosterone concentrations and the resolution of hypogonadism.16,17,18 This effect is thought to be mediated by a substantial reduction in adiposity and the subsequent normalization of hormonal imbalance. Notably, approximately 80% of patients with MOSH might experience recovery of normal testosterone concentrations within 6 months after surgery, highlighting the potential for MBS to address this endocrine disorder.4
However, despite these promising findings, important gaps in the understanding of MOSH treatment by MBS remain. Laparoscopic sleeve gastrectomy (LSG) is a safe, effective, and the most commonly performed MBS.19 However, its effects on the remission of MOSH and the associated detailed hormonal changes have not been fully evaluated. Furthermore, the relationship between the degree of weight loss and changes in testosterone concentrations post-LSG warrants further investigation.
Therefore, this study aimed to evaluate the remission of MOSH in patients undergoing LSG during a 24-month follow-up period. We further examined the correlations between the magnitude of weight loss and serum testosterone dynamics, with a focus on the potential for LSG to offer an effective solution for improving hormonal balance in patients with MOSH. Our study could provide important insights into the broader clinical implications of MBS for managing endocrine dysfunction in this patient population.
PATIENTS AND METHODS
Study design and patients
This single-center, retrospective study was conducted at the Center for Obesity and Hernia Surgery, Huashan Hospital, Fudan University (Shanghai, China). We chose a retrospective design to enable timely evaluation of MOSH within a defined time window. Male patients with obesity who underwent primary LSG between October 2022 and December 2024 were screened for eligibility. All patients met established international and Chinese indications for MBS.20,21 The inclusion criteria were as follows: (1) patients aged between 18 years and 65 years; (2) a clinical diagnosis of MOSH defined according to the 2021 European Association of Urology Guidelines on Sexual and Reproductive Health, with BMI ≥30 kg m−2, and either total testosterone (TT) concentrations <12 nmol l−1 (with normal sex hormone-binding globulin [SHBG] concentrations) or free testosterone (FT) concentrations <225 pmol l−1 (with abnormal SHBG concentrations);5,22 and (3) systematic exclusion of other underlying causes of hypogonadism. Patients were excluded if they had concomitant pharmacological treatments targeting MOSH, received androgen supplementation, used weight-loss medications at baseline or during the follow-up, underwent revisional MBS, had incomplete medical records, or suffered from uncontrolled psychological disorders.
Ethical approval was granted by the Institutional Ethics Review Board of Huashan Hospital, Fudan University (Approval No. KY2022-546). The study was conducted in accordance with the ethical standards outlined in the Declaration of Helsinki, 1964, and the Declaration of Tokyo, 1975, as revised in 1983. All patients provided written informed consent for the use and publication of their data. The datasets generated in this study are available from the corresponding author upon reasonable request.
Measurements
Clinical outcomes were retrospectively collected from medical records at baseline and follow-ups at 6 months, 12 months, and 24 months post-LSG. Postoperative dietary and physical activity guidelines were provided upon discharge and at the follow-ups. The primary endpoint was the MOSH remission rate, which was defined as the failure to meet the diagnostic criteria specified above. Secondary outcomes included the changes in serum concentrations of TT and FT following surgery and their correlation with the percentage of total weight loss (TWL%). Additional sex hormone parameters analyzed were dehydroepiandrosterone sulfate (DHEAS), estradiol (E2), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and SHBG. FT and bioavailable testosterone (BT) were calculated from TT, albumin, and SHBG concentrations using the Vermeulen formula.23 The free testosterone index (FTI) was calculated as follows: (TT in nmol l−1 × 100)/(SHBG in nmol l−1).23
Changes in lipid and glucose metabolism-related biochemical parameters were also assessed. These parameters included triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), albumin, non-esterified fatty acids (NEFA), uric acid (UA), glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin, fasting C-peptide, and the homeostatic model assessment of insulin resistance (HOMA-IR), which was calculated using the formula: (fasting insulin in mU l−1 × FPG in mmol l−1)/22.5.24 Additionally, serum high-sensitivity C-reactive protein (hs-CRP) concentrations were measured. Body composition was evaluated using the InBody 270 bio-electrical impedance analyzer (InBody Co., Ltd., Seoul, Korea). Data collection was finalized in February 2025.
Sample size justification
The sample size was calculated using G*Power (version 3.1.9.7, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) for repeated measures analysis of variance (ANOVA). Based on the assumption of medium effect size (f = 0.4), α = 0.05, power = 0.9, and correlation among repeated measurements (ρ = 0.5), 13 patients were required to detect differences in testosterone concentrations across four time points (baseline, and 6 months, 12 months, and 24 months post-LSG).
Statistical analyses
Continuous variables are presented as the mean ± standard error (s.e.). A normal distribution and homogeneity of variance were evaluated before analyses. Comparisons of mean values between pre- and postoperative measurements were performed using one-way ANOVA or the Kruskal–Wallis test, followed by Bonferroni correction for multiple comparisons. Bivariate correlations between continuous variables were examined using Pearson’s or Spearman’s correlation analysis. Categorical data are expressed as frequency distributions (n, %), with comparisons conducted using Pearson’s Chi-square test or Fisher’s exact test, as appropriate.
To investigate the associations between changes in TT and FT concentrations with TWL%, two separate linear mixed models were used. TT and FT were included as dependent variables, with TWL% as the primary explanatory variable. The models were adjusted for potential confounders, which were identified through clinical expertise, prior evidence, and statistical evaluation, and included age, HbA1c, HOMA-IR, triglycerides, and HDL-C. All variables in the models were measured at baseline and at 6 months, 12 months, and 24 months post-LSG. Patient-specific random effects were included to account for within-subject correlation.
Statistical analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9.0 (GraphPad Software, San Diego, CA, USA). Statistical significance was set at P < 0.05.
RESULTS
Baseline characteristics of the patients
We screened 304 male patients who underwent primary LSG for eligibility. Among them, 212 (69.7%) were diagnosed with MOSH. After applying the exclusion criteria, 186 patients were ultimately included in the study (Figure 1). The age of the patients (mean ± s.e.) was 33.1 ± 0.6 years, with a BMI (mean ± s.e.) of 43.0 ± 0.5 kg m−2. The waist-to-hip ratio (WHR; mean ± s.e.) was 1.0 ± 0, and the fat percentage (mean ± s.e.) was 41.9% ± 0.4%. Baseline TT and FT concentrations (mean ± s.e.) were low, with values of 7.0 ± 0.2 nmol l−1 and 0.2 ± 0 nmol l−1, respectively. The SHBG concentration (mean ± s.e.) at baseline was 19.6 ± 0.8 nmol l−1. A detailed summary of the demographic and clinical characteristics at baseline is shown in Table 1.
Figure 1.
Flow diagram of patients in the study. LSG: laparoscopic sleeve gastrectomy; MOSH: male obesity-associated secondary hypogonadism; MBS: metabolic bariatric surgery.
Table 1.
Clinical characteristics at baseline and at 6 months, 12 months, and 24 months post-laparoscopic sleeve gastrectomy in patients with male obesity-associated secondary hypogonadism
| Parameter | Baseline ( n =186) | 6 months post-LSG ( n =102) | 12 months post-LSG ( n =64) | 24 months post-LSG ( n =38) | Overall P value |
|---|---|---|---|---|---|
| Age (year) | 33.1±0.6 | 32.5±0.7 | 33.1±0.8 | 33.0±1.1 | 0.948 |
| BMI (kg m−2) | 43.0±0.5 | 31.0±0.4a | 28.3±0.6a | 29.4±0.8a | <0.001 |
| WHR | 1.0±0 | 0.9±0a | 0.9±0a | 0.9±0a | <0.001 |
| Body lean ratio (%) | 58.2±0.4 | 70.6±0.8a | 75.5±1.1a | 74.1±1.3a | <0.001 |
| Body fat percentage (%) | 41.9±0.4 | 28.8±0.6a | 25.5±1.0a | 26.5±1.1a | <0.001 |
| TWL% | - | 28.2±0.9a | 34.4±1.2a,b | 32.3±2.2a,c | <0.001 |
| TT (nmol l−1) | 7.0±0.2 | 16.1±0.5a | 17.0±0.8a | 18.4±1.0a | <0.001 |
| FT (nmol l−1) | 0.2±0 | 0.3±0a | 0.4±0a | 0.4±0a,c,d | <0.001 |
| BT (nmol l−1) | 4.2±0.1 | 8.3±0.2a | 8.5±0.4a | 9.9±0.6a,c,d | <0.001 |
| FTI | 40.3±1.3 | 55.5±2.3a | 54.8±3.3a | 62.5±3.8a | <0.001 |
| DHEAS (µmol l−1) | 8.2±0.3 | 7.7±0.3 | 9.0±0.4 | 9.3±0.6 | 0.028 |
| E2 (pmol l−1) | 146.0±4.6 | 132.8±5.0 | 115.8±4.8a | 118.2±5.7a | <0.001 |
| E2/TT | 0.3±0 | 0.1±0a | 0.1±0a | 0.1±0a | <0.001 |
| PRL (ng ml−1) | 27.3±6.7 | 13.6±1.4a | 20.5±8.2a | 11.7±1.2a | <0.001 |
| LH (IU l−1) | 5.1±0.2 | 5.4±0.3 | 5.6±0.3 | 5.3±0.3 | 0.462 |
| FSH (IU l−1) | 4.2±0.2 | 4.6±0.4 | 5.4±0.5 | 4.4±0.3 | 0.044 |
| SHBG (nmol l−1) | 19.6±0.8 | 32.6±1.4a | 36.2±2.0a | 31.1±1.4a | <0.001 |
| HbA1c (%) | 6.8±0.1 | 5.3±0a | 5.2±0a | 5.3±0.1a | <0.001 |
| FPG (mmol l−1) | 6.9±0.2 | 4.8±0.1a | 4.7±0.1a | 4.8±0.1a | <0.001 |
| OGTT 2-h glucose (mmol l−1) | 10.0±0.4 | 4.6±0.2a | 4.4±0.2a | 4.6±0.3a | <0.001 |
| Fasting insulin (mU l−1) | 45.9±2.7 | 10.5±0.6a | 9.0±0.8a | 12.0±1.5a | <0.001 |
| OGTT 2-h insulin (mU l−1) | 156.5±7.3 | 44.0±9.8a | 39.3±7.2a | 29.7±6.4a | <0.001 |
| Fasting C-peptide (µg l−1) | 5.2±0.2 | 2.6±0.1a | 2.3±0.1a | 2.4±0.1a | <0.001 |
| OGTT 2-h C-peptide (µg l−1) | 11.7±0.3 | 7.7±0.6a | 6.6±0.6a | 6.0±0.4a | <0.001 |
| HOMA-IR | 14.5±1.2 | 2.3±0.1a | 1.9±0.2a | 2.7±0.4a | <0.001 |
| Triglyceride (mmol l−1) | 2.5±0.2 | 1.1±0a | 1.0±0.1a | 1.0±0.1a | <0.001 |
| TC (mmol l−1) | 4.9±0.1 | 4.7±0.1 | 4.6±0.1 | 4.5±0.2 | 0.020 |
| HDL-C (mmol l−1) | 1.0±0 | 1.1±0a | 1.3±0a,b | 1.3±0.1a,c | <0.001 |
| LDL-C (mmol l−1) | 3.2±0.1 | 3.1±0.1 | 2.8±0.1 | 2.8±0.1a | 0.008 |
| Albumin (g l−1) | 44.2±0.3 | 45.0±0.5 | 45.2±0.7 | 45.0±0.8 | 0.701 |
| NEFA (mmol l−1) | 0.6±0 | 0.6±0 | 0.5±0a | 0.4±0a,c,d | <0.001 |
| UA (mmol l−1) | 0.5±0 | 0.5±0 | 0.4±0a | 0.4±0a | <0.001 |
| hs-CRP (mg l−1) | 6.0±0.2 | 3.1±0.3a | 1.9±0.3a,b | 0.6±0.1a,c | <0.001 |
aP<0.05, the marked group vs baseline; bP<0.05, 6 months post-LSG vs 12 months post-LSG; cP<0.05, 6 months post-LSG vs 24 months post-LSG; dP<0.05, 12 months post-LSG vs 24 months post-LSG, by the Bonferroni correction post hoc test. All data are presented as the mean±s.e. “-” indicates that data were not applicable at baseline. LSG: laparoscopic sleeve gastrectomy; MOSH: male obesity-associated secondary hypogonadism; BMI: body mass index; WHR: waist-to-hip ratio; TWL%: percentage of total weight loss; TT: total testosterone; FT: free testosterone; BT: bioavailable testosterone; FTI: free testosterone index; DHEAS: dehydroepiandrosterone sulfate; E2: estradiol; PRL: prolactin; LH: luteinizing hormone; FSH: follicle-stimulating hormone; SHBG: sex hormone-binding globulin; HbA1c: glycosylated hemoglobin; FPG: fasting plasma glucose; OGTT: oral glucose tolerance test; HOMA-IR: homeostatic model assessment of insulin resistance; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; NEFA: non-esterified fatty acids; UA: uric acid; hs-CRP: hypersensitive C-reactive protein; s.e.: standard error
Pearson correlation analyses showed significant negative correlations between the baseline BMI and serum concentrations of TT (r = −0.3447, 95% confidence interval [CI]: −0.4655 to −0.2114, P < 0.001) and FT (r = −0.3232, 95% CI: −0.4463 to −0.1880, P < 0.001), as shown in Figure 2. These findings suggested that a higher BMI was associated with lower TT and FT concentrations in patients with MOSH. Spearman correlation analyses showed non-significant correlations between baseline age and TT (r = 0.1216, P = 0.0983) and FT concentrations (r = 0.0074, P = 0.9179), as shown in Supplementary Figure 1 (105.7KB, tif) .
Figure 2.
Scatter plot of Pearson’s correlation between BMI and TT/FT in patients with MOSH. (a) The correlation between BMI and TT. (b) The correlation between BMI and FT. The blue dots represent individual data points for patient BMI and TT/FT concentrations. The solid red line indicates the best-fit line from the linear regression analysis, and the dashed red lines represent the 95% confidence bands. BMI: body mass index; TT: total testosterone; FT: free testosterone; MOSH: male obesity-associated secondary hypogonadism; CI: confidence interval.
Weight loss and metabolic improvements following LSG
Among the 186 patients, 102, 64, and 38 completed follow-up assessments at 6 months, 12 months, and 24 months post-LSG, respectively (Figure 1). This progressive attrition was primarily attributable to non-medical factors, namely geographic relocation (n = 4), economic burden (n = 9), travel restrictions (n = 6), and refusal to repeat blood collection (n = 5), which were within 6 months of follow-up. The reasons for loss of follow-up assessments after 6 months were the loss of contact despite ≥3 telephone attempts (n = 4) and undocumented discontinuation (n = 1).
The patients experienced substantial weight loss following LSG, achieving TWL% (mean ± s.e.) of 34.4% ± 1.2% at 12 months post-LSG and 32.3% ± 2.2% at 24 months post-LSG. Correspondingly, BMI (mean ± s.e.) significantly decreased to 28.3 ± 0.6 kg m−2 at 12 months post-LSG and remained at 29.4 ± 0.8 kg m−2 at 24 months post-LSG. Additionally, the fat percentage (mean ± s.e.) significantly reduced to 25.5% ± 1.0% at 12 months post-LSG and 26.5% ± 1.1% at 24 months post-LSG, accompanied by an increase in lean ratio (mean ± s.e.) to 75.5% ± 1.1% and 74.1% ± 1.3%, respectively (Table 1).
In parallel with the weight loss, significant metabolic improvements were observed. HbA1c levels (mean ± s.e.) decreased from 6.8% ± 0.1% to 5.2% ± 0 at 12 months post-LSG (P < 0.001). FPG (mean ± s.e.) declined significantly from 6.9 ± 0.2 mmol l−1 to 4.8 ± 0.1 mmol l−1 (P < 0.001), alongside improvements in insulin resistance, evidenced by a decrease in HOMA-IR (mean ± s.e.) from 14.5 ± 1.2 to 1.9 ± 0.2 at 12 months post-LSG (P < 0.001). Significant lipid profile improvements included reductions in triglycerides (mean ± s.e.) from 2.5 ± 0.2 mmol l−1 to 1.0 ± 0.1 mmol l−1 (P < 0.001) and increases in HDL-C (mean ± s.e.) from 1.0 ± 0 mmol l−1 to 1.3 ± 0 mmol l−1 (P < 0.001) at 12 months post-LSG. These metabolic improvements were sustained at the 24-month follow-up. Furthermore, hs-CRP levels decreased significantly postoperatively (P < 0.001), indicating that LSG effectively ameliorates chronic inflammation. Complete postoperative demographic and metabolic parameters are detailed in Table 1.
Remission of MOSH and changes in sex hormones following LSG
The remission rates of MOSH at 6 months, 12 months, and 24 months post-LSG were 81.4% (83/102), 79.7% (51/64), and 89.5% (34/38), respectively. These remission rates were accompanied by significant improvements in androgenic hormones. Specifically, TT and FT levels (mean ± s.e.) increased to 18.4 ± 1.0 nmol l−1 (P < 0.001) and 0.4 ± 0 nmol l−1 (P < 0.001), respectively, at 24 months post-LSG. BT (mean ± s.e.) also rose significantly from 4.2 ± 0.1 nmol l−1 at baseline to 9.9 ± 0.6 nmol l−1 (P < 0.001). In parallel, SHBG levels (mean ± s.e.) increased to 31.1 ± 1.4 nmol l−1 at 24 months post-LSG (P < 0.001). As a result, the FTI (mean ± s.e.) significantly improved, rising from 40.3 ± 1.3 before surgery to 62.5 ± 3.8 after 24 months (P < 0.001). In contrast, E2 levels (mean ± s.e.) significantly decreased from 146.0 ± 4.6 pmol l−1 to 118.2 ± 5.7 pmol l−1 at 24 months post-LSG (P < 0.001), leading to a notable reduction in the E2/TT ratio (mean ± s.e.) from 0.3 ± 0 to 0.1 ± 0 (P < 0.001). PRL levels (mean ± s.e.) also dropped significantly, from 27.3 ± 6.7 ng ml−1 at baseline to 11.7 ± 1.2 ng ml−1 at 24 months post-LSG (P < 0.001). Gonadotropin levels showed divergent trends: LH (mean ± s.e.) remained stable, with no significant change (5.1 ± 0.2 IU l−1 vs. 5.3 ± 0.3 IU l−1, P = 0.462), while FSH (mean ± s.e.) increased modestly from 4.2 ± 0.2 IU l−1 to 4.4 ± 0.3 IU l−1 (P = 0.044). Detailed postoperative sex hormone levels are summarized in Table 1.
Additionally, subgroup analyses stratified by the MOSH remission status were performed at 6 months, 12 months, and 24 months post-LSG to assess weight loss and changes in testosterone concentrations in remission versus non-remission subgroups. Compared with remission subgroup, the non-remission subgroup showed a similar weight loss, with no significant difference in BMI or TWL% (all P > 0.05). However, the non-remission subgroup showed persistently low TT and FT concentrations (all P < 0.001; Supplementary Table 1).
Supplementary Table 1.
Comparison of weight loss and testosterone concentrations between male obesity-associated secondary hypogonadism remission and non-remission subgroups at 6, 12, and 24 months post-laparoscopic sleeve gastrectomy
| 6 months po st-LSG | Remission subgroup ( n =83) | Non-remission subgroup ( n =19) | P |
|---|---|---|---|
| BMI (kg m-2) | 30.6±0.4 | 32.8±1.4 | 0.104 |
| TWL% | 28.7±0.9 | 26.0±2.6 | 0.261 |
| TT (nmol l-1) | 17.8±0.4 | 8.6±0.5 | <0.001 |
| FT (nmol l-1) | 0.4±0.0 | 0.2±0.0 | <0.001 |
|
| |||
| 12 months post-LSG | Remission subgroup ( n =51) | Non-remission subgroup ( n =13) | P |
|
| |||
| BMI (kg m-2) | 28.4±0.6 | 27.9±1.6 | 0.443 |
| TWL% | 34.6±1.4 | 30.9±3.0 | 0.824 |
| TT (nmol l-1) | 18.7±0.9 | 10.4±1.0 | <0.001 |
| FT (nmol l-1) | 0.4±0.0 | 0.2±0.0 | <0.001 |
|
| |||
| 24 months post-LSG | Remission subgroup ( n =34) | Non-remission subgroup ( n =4) | P |
|
| |||
| BMI (kg m-2) | 29.1±0.9 | 32.2±3.3 | 0.276 |
| TWL% | 33.2±2.3 | 24.4±7.3 | 0.447 |
| TT (nmol l-1) | 19.6±0.9 | 9.0±0.9 | <0.001 |
| FT (nmol l-1) | 0.4±0.0 | 0.2±0.0 | <0.001 |
LSG: laparoscopic sleeve gastrectomy; BMI: body mass index; TWL%: percentage of total weight loss; TT: total testosterone; FT: free testosterone
Correlations between TT, FT, and TWL% following LSG
The changes in TT and FT concentrations and TWL% from baseline to 24 months post-LSG are shown in Figure 3. Linear mixed models showed a significant positive association between TT concentrations and TWL%. Specifically, each 1% increase in TWL% was associated with a 0.3007 nmol l−1 rise in TT (95% CI: 0.2462 to 0.3552, P < 0.001). Similarly, FT concentrations showed a significant positive correlation with TWL%, with each 1% increase in TWL% corresponding to a 0.0049 nmol l−1 elevation in FT concentrations (95% CI: 0.0037 to 0.0060, P < 0.001). These associations remained significant after adjusting for potential confounders, namely age, HbA1c, HOMA-IR, triglycerides, and HDL-C, which were selected on the basis of clinical relevance, prior evidence, and statistical analysis. However, the effect size was slightly attenuated after adjustment (Table 2).
Figure 3.
Changes in TT/FT concentrations and TWL% at 24 months post-LSG in patients with MOSH. (a) The changes in TT concentrations and TWL%. (b) The changes in FT concentrations and TWL%. The blue line represents the change in TWL%, the dark red line represents the change in TT, and the light red line represents the change in FT. TT: total testosterone; FT: free testosterone; TWL%: percentage of total weight loss; LSG: laparoscopic sleeve gastrectomy; MOSH: male obesity-associated secondary hypogonadism.
Table 2.
Longitudinal associations between total testosterone/free testosterone and percentage of total weight loss after laparoscopic sleeve gastrectomy in patients with male obesity-associated secondary hypogonadism
| Dependent variable | Unadjusted | Adjusted a | ||
|---|---|---|---|---|
|
|
|
|||
| Estimate (95% CI) | P | Estimate (95% CI) | P | |
| TT (nmol l−1) | 0.3007 (0.2462 to 0.3552) | <0.001 | 0.2450 (0.1754 to 0.3147) | <0.001 |
| FT (nmol l−1) | 0.0049 (0.0037 to 0.0060) | <0.001 | 0.0038 (0.0023 to 0.0053) | <0.001 |
aAdjusted for age, HbA1c, HOMA-IR, triglycerides, and HDL-C. TT: total testosterone; FT: free testosterone; CI: confidence interval; HbA1c: glycosylated hemoglobin; HOMA-IR: homeostatic model assessment of insulin resistance; HDL-C: high-density lipoprotein cholesterol
DISCUSSION
Our study showed that MOSH was highly prevalent (69.7%) in patients who underwent MBS, which is consistent with previous literature, highlighting the strong association between obesity and secondary hypogonadism.4 Our baseline analysis also identified a significant negative correlation between BMI and serum testosterone concentrations, which suggested an effect of increased adiposity on testosterone production. These results are consistent with previous studies, further supporting the role of obesity in disrupting the HPG axis.25,26,27 Proposed mechanisms include adiposity-induced hormonal imbalances, elevated aromatase activity, leptin resistance, insulin resistance, and chronic inflammation, which contribute collectively to diminished testosterone production and MOSH.28 Our findings reinforce these mechanistic insights and emphasize the clinical importance of effective weight management to restore endocrine function in patients with obesity.
Following LSG, patients with MOSH achieved significant and sustained weight loss, and TWL% exceeded 30% at both 12 months and 24 months post-LSG. This weight loss was accompanied by remarkable metabolic improvements, including substantial reductions in the fat percentage, HbA1c values, insulin resistance, and dyslipidemia. These findings support the literature, affirming the potent metabolic benefits of MBS.29,30 Importantly, these metabolic improvements likely contribute to the parallel restoration of testosterone concentrations, suggesting the integrated metabolic–endocrine benefits achievable through effective weight reduction. Additionally, the marked reduction in hs-CRP concentrations after LSG suggests that attenuated adipose tissue inflammation is a potential mechanism facilitating improvement in the HPG axis in patients with MOSH.
Of particular clinical relevance, we found high remission rates of MOSH following LSG, and these reached 81.4%, 79.7%, and 89.5% at 6 months, 12 months, and 24 months post-LSG, respectively. These findings are in agreement with previous reports by Calderón et al.,16 Pellitero et al.,17 and Jedamzik et al.,18 validating the efficacy of MBS as a robust therapeutic intervention for MOSH. Our analysis of sex hormone profiles further showed significant increases in TT, FT, BT, and SHBG concentrations, accompanied by marked decreases in E2 and PRL concentrations after LSG. Notably, the E2/TT ratio was significantly decreased post-LSG, which suggested decreased aromatase activity within adipose tissue following substantial fat mass reduction. Interestingly, although elevated SHBG concentrations typically reduce testosterone bioavailability, the magnitude of TT and FT recovery post-LSG substantially exceeded the elevation in SHBG concentrations, which resulted in a net increase in BT concentrations. This finding demonstrates the predominance of weight loss-driven androgen restoration over SHBG-mediated binding effects.
Despite substantial weight loss and testosterone restoration, stable LH concentrations and a modest increase in FSH concentrations observed in our cohort suggested partial recovery of gonadotropin secretion and incomplete restoration of the HPG axis. This incomplete recovery could be attributed to several factors. First, while weight loss typically reverses metabolic inhibitors, such as hyperinsulinemia and hyperestrogenemia, residual adiposity (mean BMI: 29.4 kg m−2 at 24 months post-LSG) may continue to exert subtle inhibitory effects on the hypothalamus, contributing to persistent hypothalamic suppression. Moreover, the observed modest increase in FSH concentrations and stable LH concentrations could reflect gradual recovery of the HPG axis, which might require more time or sustained weight stability to fully normalize.
Additionally, while we did not observe proportional increases in gonadotropins, testosterone bioavailability significantly improved through the restoration of testosterone concentrations. This finding suggests that gonadotropin responses may not be required for full normalization of testosterone. These findings further support the hypothesis that MOSH represents functional impairment of the HPG axis, which remains weight loss reversible, as demonstrated by consistent testosterone recovery following MBS, even without full normalization of gonadotropins.
Another major finding of this study was the significant positive correlations between TWL% and an increase in TT and FT concentrations. This indicates a direct relationship between the magnitude of weight loss and hormonal recovery. Our linear mixed model analysis showed that each 1% increment in TWL% corresponded to measurable increases in testosterone concentrations. Even after adjusting for age and metabolic confounders, such as HbA1c, HOMA-IR, triglycerides, and HDL-C, these relationships remained significant but slightly attenuated. These data indicate that, while metabolic improvements contribute to the resolution of MOSH, weight loss itself remains the predominant factor driving endocrine recovery. These findings are consistent with a previous study, reinforcing the role of sustained weight loss for hormonal restoration in populations with obesity.18
Interestingly, our subgroup analysis of non-remission patients showed that despite achieving similar weight loss to those with remission of MOSH, they showed persistently low testosterone concentrations. This finding suggests that non-remission of MOSH may be due to weight loss-independent endocrine resistance, potentially involving unresolved hypothalamic–pituitary dysregulation or adipose tissue-driven hormonal dysfunction. However, the small sample size of patients without remission limits mechanistic investigation. Therefore, future large-scale studies should prioritize this subgroup to investigate the mechanism involved.
Our findings highlight the pivotal role of effective weight management in the treatment of MOSH. Interestingly, a previous study has shown that weight loss achieved through lifestyle and dietary interventions can also lead to modest increases in testosterone concentrations.31 This observation raises intriguing questions regarding the potential effects of pharmacological weight loss treatments, particularly glucagon-like peptide-1 receptor agonists (GLP-1RA), in managing MOSH and testosterone restoration, especially for patients not meeting the criteria for MBS. Future research investigating the effects of GLP-1RA and other pharmacological interventions on MOSH is warranted.
This study has some limitations. One limitation is inherent to retrospective analyses, including potential selection biases and incomplete data. Attrition during the follow-up might have affected the interpretation of outcomes. Therefore, the results should be interpreted with caution. Furthermore, our study primarily focused on biochemical remission of MOSH. While normalization of testosterone is strongly associated with symptomatic improvement in hypogonadism, the lack of systematic clinical symptom assessment is a limitation. Future prospective studies should integrate validated patient-reported outcomes to comprehensively evaluate functional recovery along with biochemical markers.
In conclusion, our study shows that MOSH is highly prevalent in male patients undergoing MBS, and that considerable weight loss achieved by surgery effectively restores testosterone concentrations and improves associated metabolic dysfunction. These findings indicate the clinical significance of weight reduction, particularly by MBS, for the management and potential reversal of obesity-induced secondary hypogonadism. Future prospective, multicenter studies incorporating broader clinical assessments are necessary to further determine the long-term outcomes of MBS in managing endocrine disorders associated with obesity.
AUTHOR CONTRIBUTIONS
YAZ contributed to data collection. CC performed data analysis. YAZ and CC performed generation of figures and tables and wrote the manuscript. YXC performed data interpretation. RH, BX, QWS, and XJF participated in the literature search. YKS and QYY performed critical revision of the manuscript for important intellectual content. All authors contributed to the study design and read and approved the final manuscript.
COMPETING INTERESTS
All authors declare no competing interests.
Scatter plot of Spearman’s correlation between age and TT/FT in patients with MOSH. (a) The correlation between age and TT. (b) The correlation between age and FT. Note: The blue dots represent individual data points for patient age and TT/FT concentrations. The solid red line indicates the best-fit line from the linear regression analysis, and the dashed red lines represent the 95% confidence bands. TT: total testosterone; FT: free testosterone; MOSH: male obesity-associated secondary hypogonadism.
ACKNOWLEDGMENTS
We express sincere gratitude to all patients and their families in this study for their invaluable contributions.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
REFERENCES
- 1.GBD 2021 Adult BMI Collaborators. Global, regional, and national prevalence of adult overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet. 2025;405:813–38. doi: 10.1016/S0140-6736(25)00355-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bray GA, Kim KK, Wilding JP World Obesity Federation. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev. 2017;18:715–23. doi: 10.1111/obr.12551. [DOI] [PubMed] [Google Scholar]
- 3.Quek J, Chan KE, Wong ZY, Tan C, Tan B, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8:20–30. doi: 10.1016/S2468-1253(22)00317-X. [DOI] [PubMed] [Google Scholar]
- 4.Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of ‘obesity-associated gonadal dysfunction’ in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. 2017;23:390–408. doi: 10.1093/humupd/dmx012. [DOI] [PubMed] [Google Scholar]
- 5.Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clin Endocrinol (Oxf) 2013;78:330–7. doi: 10.1111/cen.12092. [DOI] [PubMed] [Google Scholar]
- 6.Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5:673–81. doi: 10.1038/nrendo.2009.212. [DOI] [PubMed] [Google Scholar]
- 7.Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5462–8. doi: 10.1210/jc.2004-0804. [DOI] [PubMed] [Google Scholar]
- 8.Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf) 2005;63:239–50. doi: 10.1111/j.1365-2265.2005.02299.x. [DOI] [PubMed] [Google Scholar]
- 9.Saad F, Gooren LJ. The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes 2011. 2011:471584. doi: 10.1155/2011/471584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Molina FD, Suman M, Carvalho TB, Piatto VB, Taboga SR, et al. Evaluation of testosterone serum levels in patients with obstructive sleep apnea syndrome. Braz J Otorhinolaryngol. 2011;77:88–95. doi: 10.1590/S1808-86942011000100015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ponikowska B, Jankowska EA, Maj J, Wegrzynowska-Teodorczyk K, Biel B, et al. Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease. Int J Cardiol. 2010;143:343–8. doi: 10.1016/j.ijcard.2009.03.072. [DOI] [PubMed] [Google Scholar]
- 12.Kelly DM, Jones TH. Testosterone and obesity. Obes Rev. 2015;16:581–606. doi: 10.1111/obr.12282. [DOI] [PubMed] [Google Scholar]
- 13.Genchi VA, Rossi E, Lauriola C, D’Oria R, Palma G, et al. Adipose tissue dysfunction and obesity-related male hypogonadism. Int J Mol Sci. 2022;23:8194. doi: 10.3390/ijms23158194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999;84:3673–80. doi: 10.1210/jcem.84.10.6082. [DOI] [PubMed] [Google Scholar]
- 15.Corona G, Rastrelli G, Monami M, Saad F, Luconi M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013;168:829–43. doi: 10.1530/EJE-12-0955. [DOI] [PubMed] [Google Scholar]
- 16.Calderón B, Galdón A, Calañas A, Peromingo R, Galindo J, et al. Effects of bariatric surgery on male obesity-associated secondary hypogonadism: comparison of laparoscopic gastric bypass with restrictive procedures. Obes Surg. 2014;24:1686–92. doi: 10.1007/s11695-014-1233-y. [DOI] [PubMed] [Google Scholar]
- 17.Pellitero S, Olaizola I, Alastrue A, Martínez E, Granada ML, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22:1835–42. doi: 10.1007/s11695-012-0734-9. [DOI] [PubMed] [Google Scholar]
- 18.Jedamzik J, Bichler C, Felsenreich DM, Brugger J, Eichelter J, et al. The male patient with obesity undergoing metabolic and bariatric surgery: changes in testosterone levels correlate with weight loss after one-anastomosis gastric bypass and Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2023;19:699–705. doi: 10.1016/j.soard.2022.12.034. [DOI] [PubMed] [Google Scholar]
- 19.Angrisani L, Santonicola A, Iovino P, Ramos A, Shikora S, et al. Bariatric surgery survey 2018: similarities and disparities among the 5 IFSO chapters. Obes Surg. 2021;31:1937–48. doi: 10.1007/s11695-020-05207-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Eisenberg D, Shikora SA, Aarts E, Aminian A, Angrisani L, et al. 2022 American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): indications for metabolic and bariatric surgery. Surg Obes Relat Dis. 2022;18:1345–56. doi: 10.1016/j.soard.2022.08.013. [DOI] [PubMed] [Google Scholar]
- 21.Wang Y, Liang H, Zhang P, Yang JG, Zhu LY. [Chinese clinical guidelines for the surgery of obesity and metabolic disorders (2024 edition)] Chin J Pract Surg. 2024;44:841–9. [Article in Chinese] [Google Scholar]
- 22.Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, et al. European Association of Urology Guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol. 2021;80:333–57. doi: 10.1016/j.eururo.2021.06.007. [DOI] [PubMed] [Google Scholar]
- 23.Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72. doi: 10.1210/jcem.84.10.6079. [DOI] [PubMed] [Google Scholar]
- 24.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9. doi: 10.1007/BF00280883. [DOI] [PubMed] [Google Scholar]
- 25.Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, et al. Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study. Cancer Epidemiol Biomarkers Prev. 2002;11:1041–7. [PubMed] [Google Scholar]
- 26.Jensen TK, Andersson AM, Jørgensen N, Andersen AG, Carlsen E, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril. 2004;82:863–70. doi: 10.1016/j.fertnstert.2004.03.056. [DOI] [PubMed] [Google Scholar]
- 27.Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men? J Urol. 2006;176:1524–7. doi: 10.1016/j.juro.2006.06.003. [DOI] [PubMed] [Google Scholar]
- 28.Di Vincenzo A, Busetto L, Vettor R, Rossato M. Obesity, male reproductive function and bariatric surgery. Front Endocrinol (Lausanne) 2018;9:769. doi: 10.3389/fendo.2018.00769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Barzin M, Heidari Almasi M, Mahdavi M, Khalaj A, Valizadeh M, et al. Body composition changes following sleeve gastrectomy vs. one-anastomosis gastric bypass: Tehran obesity treatment study (TOTS) Obes Surg. 2021;31:5286–94. doi: 10.1007/s11695-021-05722-1. [DOI] [PubMed] [Google Scholar]
- 30.Huang X, Zhao Y, Liu T, Wu D, Shu J, et al. β-cell function and insulin dynamics in obese patients with and without diabetes after sleeve gastrectomy. Diabetes. 2024;73:572–84. doi: 10.2337/db22-1048. [DOI] [PubMed] [Google Scholar]
- 31.De Lorenzo A, Noce A, Moriconi E, Rampello T, Marrone G, et al. MOSH syndrome (male obesity secondary hypogonadism): clinical assessment and possible therapeutic approaches. Nutrients. 2018;10:474. doi: 10.3390/nu10040474. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Scatter plot of Spearman’s correlation between age and TT/FT in patients with MOSH. (a) The correlation between age and TT. (b) The correlation between age and FT. Note: The blue dots represent individual data points for patient age and TT/FT concentrations. The solid red line indicates the best-fit line from the linear regression analysis, and the dashed red lines represent the 95% confidence bands. TT: total testosterone; FT: free testosterone; MOSH: male obesity-associated secondary hypogonadism.