Hypogonadal Men Research Articles

The Impact of Testosterone Therapy on Benign Prostatic Hyperplasia in Hypogonadal Men.

To determine the impact of testosterone therapy on the incidence of benign prostatic hyperplasia in a large cohort of hypogonadal men, and to evaluate the relationship between testosterone therapy in hypogonadal men and prostatic interventions. We used the 2011-2020 IBM MarketScan database to identify hypogonadal males above 18 years old and determine if they received testosterone therapy. ICD-9, -10, CPT, HCPCS, and NDC codes were used for diagnoses, interventions, and medications. We ran Cox proportional hazard models to determine the effect of testosterone therapy on receiving a diagnosis of benign prostatic hyperplasia and interventions. Models were adjusted for age, region, population density, and comorbidities, with testosterone therapy within the last 6 months considered a time-varying covariate. In our total cohort of 882,570 hypogonadal men, 157,185 (17.8%) were diagnosed with benign prostatic hyperplasia. For the first 2.5 years after hypogonadism diagnosis, there was no significant difference in the diagnosis of prostatic hyperplasia between patients on testosterone therapy and those who were not (HR:1, 95%CI:0.98-1.01, p=0.66). However, from 2.5 years onward, men who were on testosterone therapy had a 32% higher risk of receiving a diagnosis of benign prostatic hyperplasia (HR:1.32, 95%CI:1.28-1.36, p<0.001). Hypogonadal men with benign prostatic hyperplasia who received testosterone therapy showed no significant difference in interventions compared to those who did not receive testosterone (HR:0.95, 95%CI:0.89-1, p=0.08). In the long term, testosterone therapy increased the risk of receiving a diagnosis of benign prostatic hyperplasia in hypogonadal men. Testosterone therapy in hypogonadal men with benign prostatic hyperplasia did not change the need for interventions.

Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury.

Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. To validate the secondary findings of the TRAVERSE trial. We utilized the TriNetX Research Network to identify a cohort of men ages 45-80years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3years. New-onset AF and AKI within 3years. There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66ng/dL vs 246 ± 140ng/dL, P< 0.001). Kaplan-Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results.

Numerically higher fractures found in hypogonadal men on testosterone

Numerically higher fractures found in hypogonadal men on testosterone

The Promise and Challenges of Oral Testosterone Therapy

In recent years, the landscape of testosterone replacement therapy (TRT) has evolved significantly, offering new hope for hypogonadal men seeking effective and convenient treatment options. The introduction of oral testosterone undecanoate (TU) marks a pivotal advancement in this field, as highlighted in the comprehensive review by Dr. Julian Borges. This editorial aims to explore the implications of these findings and the future of oral TRT in clinical practice.

7778 Factors Predicting Recovery of Hypogonadism in Men with Prolactinoma Treated with Dopamine Agonists

Abstract Disclosure: S. Constantinescu: None. O. Alexopoulou: None. D.M. Maiter: None. Introduction: Recovery of hypogonadism is an important objective of dopamine agonist (DA) treatment in men with prolactinoma. However, the extent, timeline, and predictive factors of gonadotrope axis recovery are still unclear. Methods: We report data from a large cohort of 89 men with prolactinoma, looking at the evolution of testosterone levels after 6 and 12 months of treatment with DA. We excluded patients with peripheral hypogonadism, surgical treatment performed less than 12 months after onset of DA treatment, and patients with small tumors (≤ 5 mm and prolactin ≤ 50 µg/l) who did not achieve tumor shrinkage during treatment. We defined low testosterone as a morning value &amp;lt; 10 nmol/l. Patients who had started testosterone supplementation were considered as having persistent hypogonadism. Results: Among the 89 men (mean age ± SD: 44 ± 14 years; 65/89 with a macroprolactinoma), 14 (16%) had normal initial testosterone levels (NT) and 75 (84%) had low testosterone at diagnosis (LT). Compared to LT, NT patients had significantly lower PRL (median 53 µg/l versus 490 µg/l, p=0.009) and smaller tumors (median 6.5 mm versus 21.2 mm, p=0.013). In the NT group, after 6 (n=11) and 12 months (n=10), testosterone rose from a median of 13.4 to 16.6 (p=0.266) and 17.9 nmol/l (p=0.012), respectively. In LT patients, after 6 (n=56) and 12 months (n=42), testosterone rose significantly from a median of 5.8 to 10.7 (p&amp;lt;0.001) and 12.5 nmol/l (p&amp;lt;0.001).In the LT group, 45% (32/71) had recovered eugonadism at 6 months and 57% (40/70) at 12 months. These proportions rose to 61% (22/36) and 67% (n=26/39) at 6 and 12 months when prolactin concentrations were normalized. Factors associated with persistent hypogonadism after one year were chiasmal compression at diagnosis (p=0.05), cavernous sinus invasion (p=0.042), cystic tumoral component (p=0.038), a greater tumoral diameter (mean 25 mm vs 15 mm, p&amp;lt;0.01), lower testosterone concentrations at diagnosis (mean 3.6 nmol/l vs 6.8 nmol/l, p&amp;lt;0.001) and at 6 months (mean 6.0 nmol/l vs 13.0 nmol/l, p&amp;lt;0.03), and higher prolactin levels at one year (median 17.15 µg/l vs 8.4 µg/l, p=0.064). Testosterone &amp;lt; 6.7 nmol/l at 6 months predicted the long-term persistence of hypogonadism with 72% sensitivity and 92% specificity. Conclusion: The sensitivity of the gonadotrope axis to high prolactin levels is highly variable in men with prolactinoma and 16% of them retain normal testosterone concentrations. However, this finding does not exclude partial inhibition of the gonadotrope axis that will improve with DA treatment. In patients with low testosterone levels, the recovery rate of hypogonadism is 45% at 6 months and 57% at 12 months, increasing to 67% if prolactin is normalized. Testosterone supplementation could be started early in patients with large, invasive, cystic and/or compressive tumors, with a testosterone concentration lower than 6.7 nmol/L after 6 months of treatment. Presentation: 6/3/2024

6597 An Unusual Case of Klinefelter Syndrome with Both Primary and Superimposed Secondary Hypogonadism

Abstract Disclosure: A. Krueger: None. E. Pelley: None. Introduction: Klinefelter syndrome (KS) (47, XXY) is a sex-chromosome disorder that is a common cause of infertility and hypogonadism in men. Clinical phenotype includes tall stature, delayed or incomplete puberty, small testes (&amp;lt;4ml), gynecomastia, and oligo or azoospermia. The extra X chromosome leads to fibrosis and hyalinization of seminiferous tubules resulting in impaired sperm production. Leydig cells also function abnormally and fail to stimulate with LH. Common biochemical evaluation results in low serum testosterone, elevated FSH and LH concentrations, and azoospermia. Case Report: 37-year-old male presented with long standing history of low libido and a perception that he had never fully progressed through puberty. Physical exam was notable for a height of 6’ 4”, obesity, fine pubic and axillary hair, and testes &amp;lt;4mL bilaterally. Initial biochemical work up revealed low serum total testosterone 43 (ref 300-1080 ng/dL), low free testosterone 8.1 (ref 47-244 pg/mL), inappropriately normal LH 10.8 (ref 0.6-12.1 mlU/mL), and elevated FSH 28.3 (ref 1.0-12.0 mlU/mL). Patient was referred to Endocrinology. Labs were repeated with consistent results in addition to chromosome analysis which confirmed diagnosis of Klinefelter syndrome with (47, XXY) karyotype. Due to inappropriately normal LH and mixed picture of primary and superimposed secondary hypogonadism, an MRI of the pituitary was obtained and revealed an 8mm x7mm x 14mm pituitary macroadenoma. Evaluation for pituitary hypersecretion and other deficiencies was unremarkable. Conclusion: Data from the Danish National registry shows that only 25% of Klinefelter patients are correctly diagnosed. Klinefelter syndrome should be considered in the differential for the evaluation of hypogonadism and infertility. Diagnosis can be made by karyotyping. The degree of impaired spermatogenesis and testosterone production in Klinefelter syndrome can be variable. Biochemical evaluation should be interpreted in conjunction with clinical context. Patients with known causes of primary hypogonadism who demonstrate an inappropriate gonadotropin response require evaluation for causes of secondary hypogonadism. In this case, the inappropriately normal LH was the sole clue leading to the identification of his pituitary macroadenoma. Presentation: 6/1/2024

8073 Association Between Serum GDF15 Level And Metabolic Parameters in Severely Obese Men Undergoing Weight Loss From Lifestyle Intervention

Abstract Disclosure: S. Bathina: None. V. Fuenmayor Lopez: None. M. Prado: None. G. Colleluori: None. D.T. Villareal: None. R.C. Villareal: None. Background: Growth Differentiation factor (GDF-15), member of TGF-β superfamily was identified as marker of aging, frailty, and metabolic disorders. Several clinical studies demonstrated an association between GDF15 with obesity and cardiovascular disease. However, information on the changes in GDF15 and its relationship to changes in metabolic and body composition parameters in the population of severely obese subjects undergoing weight loss (WL) remains lacking. Objective: The objective of this study is to evaluate the influence of WL on serum GDF15 level and its relationship to glucometabolic parameters in severely obese hypogonadal men. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention±anastrozole, aged 35-65 years old (NCT03490513) were analyzed. Hemoglobin A1C (A1C) was measured by HPLC, lipid profile by colorimetric method (except LDL was calculated), testosterone (T) and estradiol (E2) LC-MS and GDF-15 by ELISA. Body composition was measured by DXA. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At baseline, serum GDF15 positively correlated with age (r=0.25, p=0.01), fasting blood glucose (r=0.29, p=0.004) and A1C (r=0.39, p&amp;lt;0.001) but no correlation was found for lipid parameters and with T and E2. GDF15 was negatively correlated with total lean mass (r= -0.23, p=0.03), appendicular lean mass (r= -0.30, p=0.02), and fat-free mass (r= -0.22, p=0.03), but positively correlated with visceral adipose tissue volume (r=0.22, p=0.03). Average WL was 4.2±4.7% and 5.8±8.5% at 6months (6M) and 12 months (12M), respectively. Overall GDF15 levels increased by 9.4±84.7% at 6M and 18.4±128.0% at 12M. At 12M, changes in GDF15 levels positively correlated with changes in A1C (r= 0.26, p&amp;lt;0.05), and negatively with changes in total cholesterol ( r= -0.30, p=0.05), Triglycerides (r= -0.35, p=0.02) and E2 (r=-0.31, p=0.028). For LDL cholesterol changes, a negative correlation with GDF15 changes was observed at 6M (r= -0.27, p=0.047). There was no correlation between changes in GDF15 with changes in body weight and changes in body composition parameters. A comparison for those with significant WL (≥5%) vs. those with less WL showed that at 6M, GFD15 levels were reduced among those with WL of ≥5% (-19.5±42.3%) vs &amp;lt;5% (+19.8±93.9%), p=0.07, and at 12M (≥5% (-29.5±38.7) vs &amp;lt;5% (+0.61±69%), p&amp;lt;0.1). Conclusion: We demonstrated that changes in serum GDF15 in severely obese men undergoing WL was associated with alteration in cardiometabolic parameters. Our results show a new perspective on the potential role of GDF15 in cardiometabolic disorders associated with severe obesity. Aside from GDF15 used as a biomarker for health, it may also be used as target for drug development in modifying potential cardiometabolic complications in severe obesity. Presentation: 6/1/2024

6979 Effect of Orchiectomy on Muscle Growth and Differentiation Factors in Male Mice With Kidney Disease

Abstract Disclosure: O. Marks: None. J. Bruno: None. D. Wu: None. A. Patwardhan: None. Y. Komaru: None. G. Ling: None. E. Kefalogianni: None. R. Aurora: None. S.S. Dhindsa: None. A. Herrlich: None. Background: Sarcopenia and frailty are major clinical concerns in participants with chronic kidney disease (CKD). In males, an additional factor contributes to the development of sarcopenia. Around half of the men with CKD have subnormal serum testosterone (T) concentrations. The mechanisms that underlie the effect of low T concentrations on muscle growth in CKD are not known. In this study, we performed orchiectomy in male mice with kidney disease and evaluated the expression and protein content of the following muscle growth and differentiation factors. Methods: Forty mice were divided into 4 groups: 1) renal injury, induced by ischemia-induced reperfusion (IRI, N=11) at 2 months of age; 2) orchidectomy (ORX), performed 4 weeks after IRI (IRI + ORX, N=9); 3) sham-IRI and ORX (sham-ORX, N=8); and 4) sham-sham surgery (N=12). The mice were sacrificed when they were ∼7 months old (mean age 206±13 days). Gastrocnemius and levator ani muscles were harvested to measure expression by RT-qPCR of muscle catabolism markers (Atrogin-1 and ubiquitin ligase MuRF1), muscle growth inhibitors, myostatin and myogenic regulatory factor (Mrf4), fibroblast growth factor-2 (FGF2, a stimulator of satellite stem cells) and its receptor FGFR2, androgen receptor (AR) and IGF-1. Results: The mean BUN (blood urea nitrogen) at the time of sacrifice was higher in the IRI/ORX (32±4 mg/dl) and IRI/Sham (26±5 mg/dl) groups as compared to sham-sham (21±5 mg/dl, p&amp;lt;0.05 for both). There was a significant reduction (p&amp;lt;0.05) in the expression of myostatin (by 41%), Mrf4 (29%), atrogin-1 (51%) and MuRF1 (32%) in gastrocnemius muscle from the ORX-IRI and ORX-sham groups, while there was no difference in FGF2 and FGFR2, as compared to sham-sham group. Data from levator ani muscle (the most androgen sensitive muscle in mammals) showed increases in AR (64%) and Atrogin-1 (66%); and decreases in IGF-1 (88%) and myostatin (86%) in ORX-IRI and ORX-sham groups. Consistent with the mRNA expression, we found a drastic decline in protein content of myostatin in gastrocnemius (85%) in ORX-IRI and ORX-sham groups as compared to sham-sham (p=0.04). Conclusions: These data show that ORX in mice with renal injury is associated with changes in muscle growth and differentiation factors. Myostatin was the most affected gene, with 41-86% decline in mRNA and protein. These data are informative for attempts to develop treatments for sarcopenia in patients with kidney disease. Limitations: Our experimental model differs in some respects from hypogonadal men with CKD. ORX results in complete elimination of T, and thus much lower T concentrations than in men with kidney disease. There is a recovery of kidney function after IRI. We sacrificed the mice 5 months after renal injury was inflicted. Hence, the effect of IRI on muscle growth genes may have been different immediately following IRI. Thus, the impact of ORX was more apparent than of IRI in our study. Presentation: 6/1/2024

6979 Effect of Orchiectomy on Muscle Growth and Differentiation Factors in Male Mice With Kidney Disease

Abstract Disclosure: O. Marks: None. J. Bruno: None. D. Wu: None. A. Patwardhan: None. Y. Komaru: None. G. Ling: None. E. Kefalogianni: None. R. Aurora: None. S.S. Dhindsa: None. A. Herrlich: None. Background: Sarcopenia and frailty are major clinical concerns in participants with chronic kidney disease (CKD). In males, an additional factor contributes to the development of sarcopenia. Around half of the men with CKD have subnormal serum testosterone (T) concentrations. The mechanisms that underlie the effect of low T concentrations on muscle growth in CKD are not known. In this study, we performed orchiectomy in male mice with kidney disease and evaluated the expression and protein content of the following muscle growth and differentiation factors. Methods: Forty mice were divided into 4 groups: 1) renal injury, induced by ischemia-induced reperfusion (IRI, N=11) at 2 months of age; 2) orchidectomy (ORX), performed 4 weeks after IRI (IRI + ORX, N=9); 3) sham-IRI and ORX (sham-ORX, N=8); and 4) sham-sham surgery (N=12). The mice were sacrificed when they were ∼7 months old (mean age 206±13 days). Gastrocnemius and levator ani muscles were harvested to measure expression by RT-qPCR of muscle catabolism markers (Atrogin-1 and ubiquitin ligase MuRF1), muscle growth inhibitors, myostatin and myogenic regulatory factor (Mrf4), fibroblast growth factor-2 (FGF2, a stimulator of satellite stem cells) and its receptor FGFR2, androgen receptor (AR) and IGF-1. Results: The mean BUN (blood urea nitrogen) at the time of sacrifice was higher in the IRI/ORX (32±4 mg/dl) and IRI/Sham (26±5 mg/dl) groups as compared to sham-sham (21±5 mg/dl, p&amp;lt;0.05 for both). There was a significant reduction (p&amp;lt;0.05) in the expression of myostatin (by 41%), Mrf4 (29%), atrogin-1 (51%) and MuRF1 (32%) in gastrocnemius muscle from the ORX-IRI and ORX-sham groups, while there was no difference in FGF2 and FGFR2, as compared to sham-sham group. Data from levator ani muscle (the most androgen sensitive muscle in mammals) showed increases in AR (64%) and Atrogin-1 (66%); and decreases in IGF-1 (88%) and myostatin (86%) in ORX-IRI and ORX-sham groups. Consistent with the mRNA expression, we found a drastic decline in protein content of myostatin in gastrocnemius (85%) in ORX-IRI and ORX-sham groups as compared to sham-sham (p=0.04). Conclusions: These data show that ORX in mice with renal injury is associated with changes in muscle growth and differentiation factors. Myostatin was the most affected gene, with 41-86% decline in mRNA and protein. These data are informative for attempts to develop treatments for sarcopenia in patients with kidney disease. Limitations: Our experimental model differs in some respects from hypogonadal men with CKD. ORX results in complete elimination of T, and thus much lower T concentrations than in men with kidney disease. There is a recovery of kidney function after IRI. We sacrificed the mice 5 months after renal injury was inflicted. Hence, the effect of IRI on muscle growth genes may have been different immediately following IRI. Thus, the impact of ORX was more apparent than of IRI in our study. Presentation: 6/1/2024

8125 Long-term Effects of Gender Affirming Hormone Therapy (GAHT) on Lipid Profile

Abstract Disclosure: G. Le: None. S. Pinkson: None. J. Trejo: None. D. Tripathy: None. Long-term Effects of Gender Affirming Hormone Therapy (GAHT) on Lipid Profile There is differential effect of long-term Estrogen and Testosterone therapy on lipid profile. While oral estradiol therapy in post-menopausal women has been associated with increased serum triglyceride and HDL, testosterone therapy in hypogonadal men decreases total cholesterol, LDL and HDL cholesterol. However, the long-term effects of Estrogen and Testosterone on lipid profile in transgender patients are not clear. We conducted a retrospective study to analyze the long-term effects of GAHT in transgender men and women followed in Endocrinology Clinic at Veterans Affairs Hospital. 36 transgender men (age 38 ± 2 years, on IM Testosterone cypionate) and 54 transgender women (age 46 ± 2 years, 36 on E2 tablet, 12 on patch, 6 on IM) were followed for 46 ± 5 months and 61 ± 5 months, respectively. Total cholesterol, triglyceride, HDL, LDL cholesterol, systolic and diastolic blood pressures, and BMI were compared before and after initiation of therapy. As expected, following GAHT, total testosterone was higher (546 ± 48 vs. 35 ± 9 ng/dL, P&amp;lt;0.001) in transgender men; in transgender women, serum E2 was higher (110 ± 9 vs. 26 ± 2 pg/dL, P&amp;lt;0.001) and total testosterone was suppressed (444 ± 29 ng/dL vs. 66 ± 13 ng/dL). In transgender men, after a follow-up period of approximately 4 years, there were no significant changes in lipid profile (total cholesterol 178 ± 8 vs. 175 ± 8 mg/dL, triglyceride 121 ± 4 vs 134 ± 12 mg/dL, HDL 47 ± 2 vs. 44 ± 2 mg/dL, LDL 107 ± 7 vs. 106 ± 8 mg/dL, all p=NS). Similarly in transgender women, no difference in lipid profile (total cholesterol 170 ± 5 vs. 175 ± 4 mg/dL, triglyceride 118 ± 7 vs 140 ± 9 mg/dL, HDL 49 ± 2 vs. 53 ± 3 mg/dL, LDL 99 ± 4 vs. 97 ± 4 mg/dL, all p=NS) was observed after 5 years of GAHT. There were no differences in lipid profile regardless of E2 tablet, patch or IM therapy. In transgender men, there was an increase in diastolic blood pressure (72 ± 3 vs. 76 ± 2 mmHg, P&amp;lt;0.05) while in transgender women there was decrease in systolic blood pressure (124 ± 2 vs. 118 ± 2 mmHg, p&amp;lt;0.005), and slight increase in BMI (28 ± 0.9 vs. 30 ± 1 kg.m2, P&amp;lt;0.005). In conclusion, long-term testosterone therapy in transgender men and estrogen therapy in transgender women was not associated with worsening lipid profile. Estrogen therapy was associated with lower BP in transgender women and testosterone therapy led to higher BP in transgender men. Presentation: 6/2/2024

8125 Long-term Effects of Gender Affirming Hormone Therapy (GAHT) on Lipid Profile

Abstract Disclosure: G. Le: None. S. Pinkson: None. J. Trejo: None. D. Tripathy: None. There is differential effect of long-term Estrogen and Testosterone therapy on lipid profile. While oral estradiol therapy in post-menopausal women has been associated with increased serum triglyceride and HDL, testosterone therapy in hypogonadal men decreases total cholesterol, LDL and HDL cholesterol. However, the long-term effects of Estrogen and Testosterone on lipid profile in transgender patients are not clear. We conducted a retrospective study to analyze the long-term effects of GAHT in transgender men and women followed in Endocrinology Clinic at Veterans Affairs Hospital. 36 transgender men (age 38 ± 2 years, on IM Testosterone cypionate) and 54 transgender women (age 46 ± 2 years, 36 on E2 tablet, 12 on patch, 6 on IM) were followed for 46 ± 5 months and 61 ± 5 months, respectively. Total cholesterol, triglyceride, HDL, LDL cholesterol, systolic and diastolic blood pressures, and BMI were compared before and after initiation of therapy. As expected, following GAHT, total testosterone was higher (546 ± 48 vs. 35 ± 9 ng/dL, P&amp;lt;0.001) in transgender men; in transgender women, serum E2 was higher (110 ± 9 vs. 26 ± 2 pg/dL, P&amp;lt;0.001) and total testosterone was suppressed (444 ± 29 ng/dL vs. 66 ± 13 ng/dL). In transgender men, after a follow-up period of approximately 4 years, there were no significant changes in lipid profile (total cholesterol 178 ± 8 vs. 175 ± 8 mg/dL, triglyceride 121 ± 4 vs 134 ± 12 mg/dL, HDL 47 ± 2 vs. 44 ± 2 mg/dL, LDL 107 ± 7 vs. 106 ± 8 mg/dL, all p=NS). Similarly in transgender women, no difference in lipid profile (total cholesterol 170 ± 5 vs. 175 ± 4 mg/dL, triglyceride 118 ± 7 vs 140 ± 9 mg/dL, HDL 49 ± 2 vs. 53 ± 3 mg/dL, LDL 99 ± 4 vs. 97 ± 4 mg/dL, all p=NS) was observed after 5 years of GAHT. There were no differences in lipid profile regardless of E2 tablet, patch or IM therapy. In transgender men, there was an increase in diastolic blood pressure (72 ± 3 vs. 76 ± 2 mmHg, P&amp;lt;0.05) while in transgender women there was decrease in systolic blood pressure (124 ± 2 vs. 118 ± 2 mmHg, p&amp;lt;0.005), and slight increase in BMI (28 ± 0.9 vs. 30 ± 1 kg.m2, P&amp;lt;0.005). In conclusion, long-term testosterone therapy in transgender men and estrogen therapy in transgender women was not associated with worsening lipid profile. Estrogen therapy was associated with lower BP in transgender women and testosterone therapy led to higher BP in transgender men. Presentation: 6/2/2024

B-178 A Sensitive LC-MS/MS Assay for Total Testosterone Quantification

Abstract Background Total testosterone immunoassay is a commonly ordered test for the diagnosis of gonadal disorders. However, immunoassays suffer from low specificity and sensitivity, which leads to inaccuracy especially in the low concentration range (&amp;lt; 100 ng/dL). As a result, commercial testosterone immunoassays have difficulties to accurately measure total testosterone levels for women, children, and hypogonadal men. LC-MS/MS has emerged as the method of choice for the accurate quantitation of steroid hormones. We presented here a sensitive laboratory-developed total testosterone assay, which was validated on two LC-MS/MS instruments. Methods An internal standard containing [2,3,4-13C3]-testosterone was added to each sample. The spiked serum sample was loaded on a supported liquid extraction (SLE) cartridge and eluted using methylene chloride. The elute was dried down under nitrogen and reconstituted in sample reconstitution buffer. Chromatographic separation was achieved using a Restek Ultra C18, 50 x 2.1 mm, 3µm analytical column and a total run time of each sample was 5 minutes. The assay was validated on two triple quadrupole mass spectrometers, API 6500 and API 4500. Results were compared with those of a reference laboratory. Results The assay was linear in the range of 1 to 1200 ng/dL for total testosterone and the AMR was set at 2-1200 ng/dL. The interday and intraday imprecision were less than 8%. Split sample comparison to a reference laboratory demonstrated acceptable accuracy with the slope of 1.053 and correlation coefficient (R2) of 0.991. The limit of detection (LOD) was 0.2 ng/dL and the limit of quantitation (LOQ) was 0.5 ng/dL. Results obtained from two instruments agreed well with the slope of 0.996 and the R2 of 0.999. No carryover or interferences was observed for this assay. Conclusions A LC-MS/MS based method was developed and validated for measuring total testosterone levels for female and children. This sensitive and specific assay will improve the diagnosis of hypogonadism and monitoring of testosterone-suppressing treatment.

Prevalence of hypogonadism in men with and without chronic obstructive pulmonary disease: A cross-sectional study

BackgroundHypogonadism is a common finding of chronic obstructive pulmonary disease (COPD). However, the prevalence of hypogonadism in COPD varies among studies. The aim of this study was to determine and compare the prevalence of hypogonadism in men with and without COPD. MethodsWe conducted a cross-sectional study with 134 patients with stable COPD and 70 age-matched men with non-COPD. Hypogonadism was defined by the presence of symptoms according to the Androgen Deficiency in Aging Males questionnaire, along with total testosterone deficiency (<300ng/dL). ResultsPatients had a mean age of 68 years (SD, 6), a body mass index of 28kg/m2 (SD, 6), and 17% were current smokers. The prevalence of hypogonadism was 41.8% in COPD men (N=56, 95%CI, 33–51) and 10.0% in non-COPD men (N=7, 95%CI, 4–20), with a prevalence ratio of 4.2 (95%CI, 2.0–8.7, p<0.001). The prevalence of low total testosterone concentrations (<300ng/dL) were significantly higher in COPD patients vs the control group (47.0% vs 15.7%, p=<0.001). In the COPD group, 89.3% of patients had hypogonadotropic hypogonadism and 10.7%, hypergonadotropic hypogonadism. The prevalence of hypogonadism was higher in severe vs non-severe COPD patients (55.8% vs 35.2%; p=0.024). ConclusionsThe prevalence of hypogonadism was high and greater in COPD vs non-COPD men. This study suggests that COPD patients should be screened for hypogonadism.

Mechanisms in Endocrinology: Hypogonadism and metabolic health in men - novel insights into pathophysiology.

Hypogonadism in men is associated with an adverse metabolic phenotype and increased mortality. Reciprocally, obesity and insulin resistance can suppress the hypothalamic-pituitary-gonadal axis in the absence of structural organic disease, further perpetuating a cycle of metabolic dysfunction and low testosterone. The mechanisms underpinning this bidirectional association are complex as hypogonadism is a heterogenous syndrome, and obesity is associated with metabolic perturbations in glucose and lipid metabolism even in the presence of normal testicular function. However, distinct molecular defects specific to testosterone deficiency have been identified in pathways relating to glucose and lipid metabolism in target metabolic depots such as adipose tissue and skeletal muscle. This review discusses the aetiology and prevalence of metabolic disease in male hypogonadism, with a specific focus on both disease mechanisms and novel potential approaches to enhance our understanding.

Association of Obesity, Inflammation, and Hypogonadism: A Cross-Sectional Study in Males Under 60 Years of Age.

Background Obesity is a significant global health issue closely associated with numerous metabolic disorders, including hypogonadism. Male obesity-related secondary hypogonadism (MOSH) is characterized by reduced testosterone levels, leading to various health complications. The bidirectional relationship between obesity and hypogonadism creates a vicious cycle, with obesity exacerbating hypogonadism and hypogonadism contributing to further obesity. Chronic inflammation, indicated by elevated C-reactive protein (CRP) levels, plays a crucial role in this interplay. The primary aim of this study is to investigate the role of obesity as an isolated factor contributing to hypogonadism. Materials and methods This observational, cross-sectional study was conducted from September 2022 to July 2024 at Dr. D.Y. Patil Medical College and Hospitals in Pune, India. A total of 80 male participants, all under 60 years of age with a BMI greater than 25 kg/m², were included in the study and classified as overweight or obese according to WHO criteria. Exclusion criteria included diabetes, age over 60 years, a BMI less than 25 kg/m², any testicular pathologies, and significant risk factors. After obtaining informed consent, participants underwent thorough clinical examinations and laboratory investigations. Patients who met the criteria were included in the study, with measurements taken for central obesity (waist circumference (WC) and waist-hip ratio (WHR)) and BMI. CRP levels were measured as an inflammatory marker indicative of chronic disease states. Statistical analyses, including correlation and regression analyses, were performed using SPSS software, version 22 (IBM SPSS Statistics, Version 22). Statistical significance was set at p < 0.05. Results The majority of participants fell within the 50-59 age group, with a mean age of 45.95 years. The study found strong positive correlations between BMI (r = 0.76), WC (r = 0.81), and WHR (r = 0.78) with CRP levels, indicating that central obesity is closely linked to systemic inflammation. Additionally, there were significant negative correlations between free testosterone and these anthropometric measures: BMI (r = -0.65), WC (r = -0.70), and WHR (r = -0.67), suggesting that increased adiposity is associated with lower testosterone levels. The strongest negative correlation observed was between CRP and free testosterone (r = -0.82), highlighting the impact of chronic inflammation on hypogonadism. Regression analysis further confirmed that CRP was a significant predictor of free testosterone levels (R-squared = 0.674), emphasizing the crucial role of inflammation in the pathophysiology of hypogonadism in obese individuals. Conclusion This study underscores the intricate relationship between obesity, chronic inflammation, and hypogonadism in men. The bidirectional nature of this relationship suggests that managing obesity and reducing systemic inflammation could potentially alleviate hypogonadism. Interventions focusing on weight loss, improving insulin sensitivity, and anti-inflammatory treatments may thus hold promise in restoring normal testosterone levels in obese men. Understanding and addressing the impact of obesity on male reproductive health is crucial, given the rising prevalence of obesity worldwide. Future research should explore therapeutic avenues and further elucidate the underlying mechanisms of this complex interplay.

Beyond T-Trials, T4DM and TRAVERSE: the next large testosterone randomized controlled trial.

Lower testosterone concentrations have been associated with poorer health outcomes in ageing men, but proving causality and demonstrating potential for therapeutic benefit requires randomized clinical trials (RCTs). This review discusses recent observational findings and results of major testosterone RCTs, to explore the need for another, larger trial. Evidence of Leydig cell impairment emerges in men above the age of 70 years. Lower testosterone is associated with diabetes risk, and also risk of incident dementia. An individual participant data meta-analysis found that below thresholds of testosterone of 7.4 nmol/L and 5.3 nmol/l respectively, risks of all-cause mortality and cardiovascular deaths in men increased. Testosterone for the Prevention of Type 2 Diabetes Mellitus (T4DM), a multicentre RCT, showed that testosterone treatment prevented or reverted type 2 diabetes in men at high risk. Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE), a cardiovascular safety trial, demonstrated cardiovascular and prostate safety of testosterone treatment in men with or at risk of cardiovascular disease. T4DM confirmed findings from the Testosterone Trials (T-Trials) that testosterone improved sexual function, and bone microarchitecture and density. However, in TRAVERSE, testosterone-treated men had a higher risk of clinical bone fractures, but not major osteoporotic fractures. Men with disorders of the hypothalamic-pituitary-testicular (HPT) axis causing androgen deficiency warrant consideration for testosterone therapy. In men with an intact HPT axis, testosterone treatment is a pharmacological intervention which requires justification from high quality RCT data. Currently, there is insufficient evidence to justify wider use of testosterone for prevention of cardiometabolic disease. However, there is scope for another large testosterone RCT to investigate whether testosterone treatment might, in older men, extend disability-free survival.

Testosterone and resistance training improved physical performance and reduced fatigue in frail older men: 1 year follow-up of a randomized clinicaltrial.

To improve health conditions among hypogonadal men ≥70 years of age using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium, and protein. This study is a 1-year follow-up of a double-blind RCT lasting 20 weeks, including 148 older men ≥70 years old with low testosterone levels and mobility problems. During 52 weeks, 4 groups received either testosterone therapy (TU) or progressive resistance training (Training), both (Combo), or no intervention (Controls). Physiotherapists supported the training groups until week 20, while these participants continued trained on their own during weeks 21 to 52. The main outcome measure was the 30-s chair stand test. The following numbers of participants completed the trial: 20 (Combo), 20 (Controls), 24 (TU), and 14 (Training). When examining 30-s chair stand test performance within each group at baseline, and at weeks 4, 20 and 52, only the Combo group improved (p = 0.001, Friedman Test). Compared to controls, only the Combo group experienced reduced fatigue and tiredness (p < 0.05). Fifty-two weeks of testosterone supplementation combined with progressive resistance training may enhance physical performance, alleviate fatigue, and had no notable detrimental impacts among males aged ≥70 suffering from mobility issues and testosterone insufficiency.Trial registration - Clinical Trials NCT02873559.

ASSESSING CARDIOVASCULAR SAFETY OF TESTOSTERONE REPLACEMENT THERAPY FOR MALE HYPOGONADISM: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: This study aims to comprehensively assess TRT's cardiovascular safety in males with hypogonadism, providing valuable insights for treatment decisions. Material &amp; Methods: Adhering to PRISMA guidelines, we registered our PROSPERO protocol and analyzed relevant English-language randomized clinical trials published from 2008 to 2023. Results: Among 1187 initial papers, 7 studies met inclusion criteria, with 6 in quantitative analysis and all 7 in qualitative assessment. Our findings indicate that TRT does not significantly increase the risk of cardiovascular events compared to placebo. Specifically, the analysis of major adverse cardiac events (MACE) yielded an OR of 0.90 (95% CI: 0.74, 1.10; I² = 26%; p = 0.25), while the evaluation of all cardiovascular adverse events revealed an OR of 1.37 (95% CI: 0.73, 2.55; I² = 75%; p = 0.001). Conclusion: This study offers reassurance for clinical decision-making by suggesting that TRT is not significantly associated with an elevated cardiovascular risk in hypogonadal men, addressing the ongoing debates on this issue. Keywords: Cardiovascular safety, hypogonadism, testosterone replacement therapy.

Androgen receptor gene CAG-trinucleotide repeat length affects function of endothelium in men with hypogonadism and type 2 diabetes mellitus

Introduction. The influence of the length of the number of CAG repeats in the androgen receptor gene (nCAG AR) on endothelial dysfunction (EnD) is currently understudied.Objective. The study aimed to evaluate the relationship between the nCAG AR and the dynamics of biochemical and ultrasound markers of EnD in men with functional hypogonadism and type 2 diabetes mellitus (T2DM) receiving testosterone replacement therapy (TRT).Materials &amp; methods. This study included 45 hypogonadal men with T2DM, receiving TRT for 1 year. Patients were assessed for carbohydrate and lipid metabolism parameters; total and free T; sex hormone-binding globulin; biochemical markers of EnD (NO, eNOS3, endothelin) and the nCAG AR; brachial artery (BA) vasoreactivity. Patients were divided into 3 groups: group I — 9 men with nCAG AR &lt; 19; group II — 27 men with nCAG AR &gt; 19 – 24; and group III — 9 men with nCAG AR &gt;24.Results. Patients with nCAG AR &lt; 19 exhibited a 2-fold greater and faster increase in BA vasoreactivity on TRT compared to patients with nCAG AR 19-24 and 3-fold greater than men with nCAG AR &gt;24 (p &lt; 0.05). Patients with nCAG AR &lt; 19 also demonstrated the most pronounced rise in NO and eNOS3 on TRT compared to men with nCAG AR &gt; 24. Patients with nCAG AR &lt; 19 experienced the most pronounced decreases in weight, waist circumference, and HbA1c on TRT compared to other patients (p &lt; 0.05).Conclusion. The nCAG AR length significantly affects the response to TRT in men with hypogonadism and T2DM. The most significant improvements are seen in patients with short nCAG AR.

A PRDM16-driven signal regulates body composition in testosterone-treated hypogonadal men.

Testosterone (T) therapy increases lean mass and reduces total body and truncal fat mass in hypogonadal men. However, the underlying molecular mechanisms for the reciprocal changes in fat and lean mass in humans are not entirely clear. Secondary analysis of specimens obtained from a single-arm, open-label clinical trial on pharmacogenetics of response to T therapy in men with late-onset hypogonadism, conducted between 2011 and 2016 involving 105 men (40-74 years old), who were given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subcutaneous fat (SCF), peripheral blood mononuclear cells (PBMC) and serum were obtained from the participants at different time points of the study. We measured transcription factors for adipogenesis and myogenesis in the SCF, and PBMC, respectively, by real-time quantitative PCR at baseline and 6 months. Serum levels of FOLLISTATIN, PAX7, MYOSTATIN, ADIPSIN, and PRDM16 were measured by ELISA. As expected, there was a significant increase in T and estradiol levels after 6 months of T therapy. There was also a reduction in fat mass and an increase in lean mass after 6 months of T therapy. Gene-protein studies showed a significant reduction in the expression of the adipogenic markers PPARγ in SCF and ADIPSIN levels in the serum, together with a concomitant significant increase in the expression of myogenic markers, MYOD in PBMC and PAX7 and FOLLISTATIN levels in the serum after 6 months of T therapy compared to baseline. Interestingly, there was a significant increase in the adipo-myogenic switch, PRDM16, expression in SCF and PBMC, and in circulating protein levels in the serum after 6 months of T therapy, which is likely from increased estradiol. Our study supports that molecular shift from the adipogenic to the myogenic pathway in men with hypogonadism treated with T could be mediated directly or indirectly by enhanced PRDM16 activity, in turn a result from increased estradiol level. This might have led to the reduction in body fat and increase in lean mass commonly seen in hypogonadal men treated with T.