Hypogonadal Men Research Articles

The complex relation between obstructive sleep apnoea syndrome, hypogonadism and testosterone replacement therapy.

Obstructive sleep apnoea syndrome (OSAS) is an under-recognized medical disease. The main risk factors for OSAS are male sex, older age, obesity, and metabolic syndrome, that are also associated with male hypogonadism (MH). Therefore, obesity has been classically identified as the most evident link between OSAS and MH. However, OSAS is per se linked to the development of MH by a combined effect of hypoxia, increased night-time awakenings, reduced sleep efficiency and fragmented sleep. Similarly, MH might represent a risk factor for OSAS, mainly related to sleep disturbances that are frequently associated with low testosterone. Data on testosterone replacement therapy (TRT) in patients with OSAS are limited. Nevertheless, TRT is generally contraindicated by guidelines in the presence of untreated or severe OSAS. TRT might in fact worse OSAS symptoms in different ways. Furthermore, OSAS has been proposed to be a risk factor for secondary polycythaemia and TRT might exacerbate polycythaemia. Therefore, TRT in hypogonadal men affected by untreated OSAS or severe OSAS should be considered with caution and in a personalised way. Nevertheless, the type and dosage of TRT should be considered, as short-term high-dose TRT might worsen OSAS, whereas long-term lower doses could eventually determine a clinical improvement of symptoms of OSAS. Here we reviewed the data on the association between OSAS, MH and TRT, including the opportunity of assessment of patients who develop signs and symptoms of OSAS during TRT by polysomnography.

OR27-01 Upregulated Prdm16 Impairs Adipogenesis And Promotes Myogenesis Via PAX7 And Osteogenesis In Testosterone-treated Hypogonadal Men

Abstract Disclosure: S. Bathina: None. M. Prado: None. L. Aguirre: None. G. Colleluori: None. E. Ballato: None. F. Deepika: None. V. Fuenmayor Lopez: None. D.T. Villareal: None. R.A. Villareal: None. Background: Testosterone (T) therapy increases lean mass; reduces total body and truncal fat mass and increases bone density in hypogonadal men. However, the underlying mechanisms for these changes remain unclear. In this study, we investigated the mechanisms involved for these effects of T on body composition and bone. Objective: Our aims are to evaluate the changes in 1) the gene and protein machinery involved the adipo-myogenic switch, and 2) the cellular osteogenic markers, in-vivo, in response to T therapy. Methods and Study design: Secondary analysis of specimens obtained from a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011-2016 N=105 men (40-74 years old), with average morning T <300 ng/dL who were given intramuscular T cypionate 200 mg every 2 weeks for 18 months As earlier results from our lab, effect of T therapy is maximal after 6 months, we chose to study the specimens at baseline (BL) and 6 months (6M). We measured the adipogenic transcription factors (PPARγ, CEBPa), enzymes (LPL, Adipsin) from subcutaneous fat, and myogenic lineage (Myf5, MyoD), Prdm16 and Pax7 from buffy coat by real-time quantitative PCR at BL and 6M. Serum Follistatin, PRDM16, PAX7 Myostatin, Adipsin were measured by ELISA. Changes in circulating osteogenic precursors (COP) and osteoclast precursors (OCPs) by Flow cytometry, and gene expression of osteoblastic transcription factor, Runx2, by PCR of buffy coat. OCPs in response to testosterone therapy were evaluated from samples of men participating in an ongoing clinical trial (NCT03887936). Results: T therapy decreased PPARg (BL: 2.59±2.2 vs 6M: 1.23±1.0, p=0.03); CEBPa (BL: 3.0±2.57 vs 6M: 1.7±1.2, p=0.10) LPL (BL: 2.81±2.7 vs 6M: 1.74±2.2, p=0.27) in sub-cutaneous fat tissue and increased the expression of MyoD (BL:1.34±1.6 vs 6M: 8.2±12.7, p=0.02) and Myf5 (BL: 6.1±9.7 vs 6M: 12.9±27.7, p=0.26) along with the adipo-myogenic switch, Prdm16 (BL: 1.8±1.9 vs 6M: 4.5±4.1, p< 0.01); Pax7 (BL:1.3±0.8 vs 6M: 1.9±2.0, p=0.2) in buffy coat. T therapy also increased serum Follistatin (BL:2031±1483 vs 6M: 3396 ± 1662pg/ml, p=0.009), the myogenic regulator, PAX7 (BL:21.5±1.9 vs 6M: 34±2.2ng/ml, p=0.002); and PRDM16 (BL:0.20±0.10 vs 6M: 0.49±0.26ng/ml, p=0.29) and decreased serum Myostatin (BL: 3218±738 vs 6M: 2714±62.2pg/ml, p=0.42) Adipsin (BL:15929±10209 vs 6M:12101±4865ng/ml p=0.04). COPs increased in T-treated (T) compared to Placebo (P); (P (6M): -4.3±57 vs T(6M): -20.2±44, p=0.20 & P(12M): -15.7±44.5 vs T(12M): 47.4±74.8, p=0.02)) and Runx2 expression increased (BL: 1.26±0.86 vs 6M: 2.17±1.6, p=0.03). Conclusions: Our results suggested that reciprocal effect of T-therapy on fat mass and lean mass is not only due to shift from adipogenesis to myogenesis but also due to enhanced osteogenesis. Thus, this study can provide unifying mechanism for observed effect of T in hypogonadal men. Presentation Date: Saturday, June 17, 2023

FRI403 The Unintended Consequences Of Applying Topical Testosterone Directly To The Scrotum

Abstract Disclosure: J.G. Melendez-Rivera: None. S.J. Steven: None. Background: Topical testosterone is commonly used to treat hypogonadism in men. A concern associated with its use is the unintentional transfer to partners and children by direct contact with the application site. While prior studies and case reports have demonstrated the effects of direct skin contact with traditional application sites including the axillary regions and the abdomen, scarce data is available regarding the effects of transfer from application to the scrotum. Clinical Case: A 44-year-old woman presented with gradually worsening hirsutism and deepening voice over the past two years along with sudden cessation of menses. Initial laboratory studies revealed elevated testosterone of 1,776 ng/dL [10-55 ng/dL], elevated free testosterone of 14.4 pg/mL [0-4.2 pg/mL], normal androstenedione of 80 ng/dL [41-262 ng/dL) and normal DHEA-S of 57.7 ug/dL [57.3-279.2 ug/dL]. Transvaginal ultrasound revealed no ovarian masses or hyperplasia and CT abdomen and pelvis with and without contrast revealed no adrenal masses or hyperplasia. Ovarian and adrenal vein sampling were unremarkable. Anabolic steroid panel demonstrated a significantly elevated testosterone-to-epitestosterone ratio of 83.5 [<4] confirming an exogenous source of testosterone. Although the woman initially reported that her husband was applying topical testosterone, she reported that he was “obsessive” about being sure to wash the area of application prior to intimacy. Further questioning revealed that her husband was actually applying high concentration topical testosterone directly to his scrotum with sexual intercourse occurring up to five times daily. Conclusion: This case illustrates the dangers of applying topical testosterone directly to the scrotum. Prior studies have demonstrated that it may result in higher levels of serum testosterone in a shorter period of time which makes it seem like an attractive option for men desiring rapid resolution of their hypogonadal symptoms. Despite these perceived benefits, it can be detrimental to the health of their female partners who may experience extraordinarily elevated testosterone levels as a result of direct intravaginal absorption of topical testosterone. Presentation: Friday, June 16, 2023

SAT282 Hypogonadism In Men With Congenital Adrenal Hyperplasia. A Retrospective Longitudinal Analysis With A Special Focus On Testicular Adrenal Rest Tumors And 11-oxygenated Androgens

Abstract Disclosure: M.K. Auer: None. C. Lottspeich: None. M. Bidlingmaier: None. H.F. Nowotny: None. L. Tschaidse: None. R.J. Auchus: None. N. Reisch: None. Background: Hypogonadism is a common issue in men with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). While this is mostly resulting from extra-gonadal steroid production, testicular function may also be impaired due to the presence of testicular adrenal rest tumors (TART). In addition to their local compressive effects, it has recently been demonstrated that TART are a source of 11-oxygenated androgens that might impair testicular function. Little is known about the long-term course of testicular function in men with 21OHD in general and the role of potential influential factors such as presence of TART and 11-oxygenated androgen formation in particular. Methods: Retrospective single-center study in 30 men with classic 21OHD (N = 11 with TART, N = 16 without TART, N = 3 unknown TART status). Median age at baseline was 31.0 years (IQR 26-38). Median observation period was 12 years (IQR 8-13). The median number of outpatient visits and blood samplings per patient during this time was 8.5 (IQR 6-10). Testosterone (T), 17-hydroxyprogesterone (17-OHP), androstenedione (A4) and 11-oxygenated androgens were measured simultaneously from stored serum samples by LC-MS/MS. Results: On average, 43.2% (No TART) and 54.6% (TART) of all T measurements in each patient were below the reference range (n.s.). In most patients, gonadotropin levels were normal or suppressed. In univariate as well as multivariate mixed model analysis, including age, BMI, type of glucocorticoid (GC), GC-equivalence dosage and phenotype (salt wasting vs simply virilizing), T levels were comparable between men with and without TART. While T levels remained stable during the observation period in men without TART (Baseline 11.37 ± 1.52 nmol/l, last visit 12.1 ± 2.1 nmol/l) they increased in those with TART (Baseline 9.48 ± 1.68 vs. last visit 14.9 ± 2.3 nmol/l (Time*Group F1,7.247 = 7.558; p = 0.006). At baseline, the A4/T-ratio as a marker of adrenal T production was significantly higher in men with TART (1.39 ± 1.63) than in those without (0.27 ± 1.63), and there was a Time*Group interaction, again indicating a decrease in the A4/T-ratio in men with TART (F1,47.843 = 2.008; p = 0.04). This resulted in only a trend for the A/T-ratio being higher in men with TART (0.5 ± 1.6 vs 0.3 ± 1.5; p = 0.057) across the whole observation period. 11-ketotestosterone levels were higher in men with TART (1.8 ± 0.006 pg/ml) than in men without TART (0.68 ± 0.006 nmol/l) but remained unchanged over time in both groups. Conclusion: A normal serum T does not exclude hypogonadotropic hypogonadism in men with 21OHD, which is a common problem that appears to remain stable in the long run. The presence of TART does not have a negative effect on T-levels. In contrast, the detection of TART should prompt further assessment, including A4, gonadotropins, and 11-ketotestosterone, followed by treatment optimization to improve gonadal T production. Presentation: Saturday, June 17, 2023

FRI444 Testosterone Therapy in Men with Classical vs Functional Hypogonadism: Results from a Controlled 9-year, Real-world Registry Study

Abstract Disclosure: M. Zitzmann: None. Background and Significance: Long-term data on Testosterone therapy (TTh) in hypogonadal men are limited and the clinical value, especially in men with functional hypogonadism (FH) is debated. A long-term, real-world registry study comprising groups of patients with hypogonadism of various etiologies provides a suitable and novel approach to this clinical issue. Methods: A registry spanning 9 years comprising 650 patients with hypogonadism included 188 patients with FH (mean age 42.3±11.3 years) and 462 men with classical hypogonadism (CH). Of these, 266 men had primary hypogonadism (PH, mean age 34.0±11.7 years) and 196 secondary hypogonadism (SH, mean age 31.9±12.0 years). All men uniformly received intramuscular T undecanoate (1000 mg). Effects of TTh on anthropometric parameters, as well as metabolic and safety parameters were compared. Results: The registry contained metabolic and safety parameters in individual duration of TTh spanning 1 to 9 years. Serum T concentrations increased from 6.6±2.4 nmol/L to 19.3±2.9 nmol/L in all patients (duration-of-treatment-dependent averages, mixed linear model for repeated measurements with the fixed variable “time x visit interaction”: p<0.001). In both categories of hypogonadism, TTh was associated with significant weight loss and decrease in waist circumference (WC, both p<0.001). Cox regression and Kaplan-Meier models revealed differences of inter-individual check-points: men with FH were more likely to lose >10% weight and >5% of WC than men with CH (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference between groups for the overall marked increase in hematocrit. Changes in PSA levels were more likely to occur in FH (hazard ratio 1.3 [1.1-1.6], p=0.003). During TTh, patients with FH exhibited significantly more pronounced changes of favourable nature in metabolic parameters than patients with CH (total cholesterol, triglycerides, LDL- and HDL-cholesterol and fasting glucose). The same applied to scores of AMS and IIEF-EF questionnaires. Effects on most parameters, especially hematocrit, were significantly modulated by age and baseline values for weight, WC und T. Conclusions: Findings regarding effects and safety of TTh in different groups of hypogonadal men are provided. Effects on factors associated with cardiovascular health are modulated by diagnosis and age. Patients with FH seem to benefit to a larger extent from TTh, most likely attributable to their more pronounced risk factor profile at baseline. Presentation Date: Friday, June 16, 2023

FRI431 Erythrocytosis Associated With Oral Testosterone Replacement

Abstract Disclosure: A.A. Engel: None. J.L. Sarvaideo: None. Background: A growing prevalence in male hypogonadism has led to increased interest in the most common adverse event, erythrocytosis. Defined by hematocrit (HCT) > 49-51%, the incidence varies depending on the testosterone formulation.3 The formulations with the lowest risk of erythrocytosis are intranasal testosterone (0-2%) and oral testosterone (0.03%).3 A phase 3 clinical trial of testosterone undecanoate (Jatenzo) reported 4.8% patients experienced an increase in hematocrit, although not severe enough to warrant therapy discontinuation.2 We present a case of erythrocytosis with oral testosterone undecanoate that prompted a change in therapy. Clinical Case: Our patient is a 55-year-old male with secondary hypogonadism potentially related to obesity (BMI 37 kg/m²). AM total testosterone (TT) 151 (348-1197 ng/dL), free testosterone 4.6 pg/mL (6.8-21.5 pg/mL) and LH 3.8 mIU/mL. Labs confirmed. Secondary work-up negative. HCT 43.6% prior to any therapy. Patient treated with injectable testosterone. Despite decreasing to testosterone cypionate 80 mg weekly his HCT increased to 52.7% with a TT of 544 ng/dL. He was switched to oral testosterone undecanoate 237 mg twice daily given presumably lower risk of erythrocytosis. However, HCT increased to 55.1% and TT to 1542 ng/dL. Patient donated blood and oral testosterone dose decreased to 158 mg twice daily with starting HCT 48.9%, but this increased to 53.7%. TT 522 ng/dL. Therapy stopped with improvement of HCT to 45.8%-48.9%, TT 192 ng/dL, and SHBG 20 g/dL. Erythropoietin remained normal. Patient does not smoke cigarettes nor has OSA. Conclusion: We present a case of oral testosterone undecanoate complicated by persistent erythrocytosis despite dose reduction. Testing for contributing etiology was unrevealing. Oral testosterone replacement is considered the formulation least likely to cause erythrocytosis. Certain patient characteristics like OSA, advanced age, obesity, type II diabetes mellitus and an elevated HCT > 50% can predict the likelihood of erythrocytosis although its specific etiology is unclear.3 Proposed mechanisms include elevation in dihydrotestosterone, erythropoietin stimulation, suppression of hepcidin and relation to androgen receptor CAG repeat length.1 Providers should be aware of the possibility of erythrocytosis on oral testosterone. Further research is needed to determine predictive characteristics for erythrocytosis and etiology. Reference: 1. Aghazadeh, M, et al. Elevated dihydrotestosterone is associated with testosterone induced erythrocytosis. J Urol. 2015; 194(1): 160-165. 2. Swerdloff, S, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020; 105)8): 1-17. 3. White, J, et al. Testosterone therapy and secondary erythrocytosis. IJIR: Your Sexual Medicine Journal. 2022; 34: 693-697. Presentation: Friday, June 16, 2023

SAT286 Effect of Tildacerfont On Gonadotropins And Testicular Steroidogenesis In Men With Classic 21-hydroxylase Deficiency

Abstract Disclosure: R. Charlton: Employee; Self; Spruce Biosciences, Inc. A. Khattab: Consulting Fee; Self; Antares Pharma, Inc. R.J. Auchus: Grant Recipient; Self; Spruce Biosciences, Inc. Research Investigator; Self; Spruce Biosciences, Inc. Impaired testicular function is a common comorbidity of classic 21-hydroxylase deficiency (21OHD). Testicular adrenal rest tumors (TART) can disrupt testicular architecture and cause primary hypogonadism. Both supraphysiologic glucocorticoid doses and adrenal-derived androgens and estrogens can suppress gonadotropins and cause secondary hypogonadism. We conducted a post-hoc analysis of gonadal axis function in men with 21OHD participating in SPR001-201 and SPR001-202, two phase 2 studies of tildacerfont, a once-daily oral corticotrophin-releasing factor receptor 1 (CRFR1) antagonist, designed to reduce ACTH and adrenal steroid production, including androstenedione (A4). Study 201 included 3 cohorts: Cohort A, 5 men who received tildacerfont in a 6-week dose escalation - 2 weeks at 200 mg QD, 2 weeks at 600 mg QD, and 2 weeks at 1000 mg QD without washout between doses; Cohort B, 1 man who received tildacerfont for 2 weeks at 200 mg BID; and Cohort C, 4 men who received tildacerfont for 2 weeks at 100 mg BID. Study 202 included 4 men who received tildacerfont 400 mg QD for 12 weeks. Participants continued their previously prescribed glucocorticoid ± mineralocorticoid replacement without dose adjustments. Geometric means were used to describe hormone levels due to the small participant numbers. Mean and median ages were 46/32y in Study 201 and 32/35y in Study 202 (range 18-54 in both studies). All participants reported race as white except one who identified as white and Asian. Four reported ethnicity as Hispanic or Latino. At baseline, testosterone (T) levels were normal except for four 201 participants that had T <300 ng/dL. At baseline, 6/11 (55%) had suppressed LH (including the four with low T), and 11/14 (79%) had A4/T ratios >1, indicating a predominantly adrenal origin of T. In Study 201, mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, mean T levels were 448.4 ng/dL at baseline and 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4) (normal 1.8-8.6IU/L). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Of the four men who had low T and suppressed LH (hypogonadotropic hypogonadism), LH rose in all 4 and normalized in 3/4 (75%). Mean A4/T ratios decreased across both studies. In Study 201, the mean declined from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T ratio decreased from baseline of 2.44 to 0.68 at week 12. All the hypogonadal men experienced reductions in A4/T ratios, and 3/4 (75%) achieved A4/T <1. This post-hoc analysis highlights that gonadal axis disruption is common in men with 21OHD and suggests that modulation of adrenal androgen production via CRFR1 antagonism may improve testicular function. Presentation: Saturday, June 17, 2023

OR25-06 The Effect of Testosterone Replacement Therapy on NAFLD in Elderly Hypogonadal Men

Abstract Disclosure: H. Lee: None. S. Han: None. R.S. Swerdloff: None. Y. Pak: None. M.J. Budoff: None. C.C. Wang: None. The Effect of Testosterone Replacement Therapy on NAFLD in Elderly Hypogonadal Men Background: Aging increases body weight, visceral fat, insulin resistance and metabolic syndrome, leading to increased prevalence of nonalcoholic fatty liver disease(NAFLD) in elderly. Testosterone deficiency, more prevalent in elderly men, is associated with metabolic syndrome and increased visceral fat. The T Trials evaluated the effect of testosterone treatment on sexual function, physical function, and vitality. A substudy on the effect of testosterone on cardiovascular markers showed decrease in total cholesterol, LDL cholesterol, HDL cholesterol, fasting insulin level and HOMA-IR in testosterone treatment group compared to placebo. We hypothesized that testosterone replacement in elderly male with hypogonadism will improve NAFLD. Methods: Data from the T Trial was used to evaluate prevalence of NAFLD using 3 clinical scores in testosterone treatment group and placebo group; Lipid accumulation product (LAP) index, hepatic steatosis index (HSI) and NAFLD-MS score. A randomized sub-group of the placebo and testosterone treated subjects had cardiac CT (Computed tomography) that includes liver and spleen. Liver Hounsfield unit (HU) and spleen HU were obtained to evaluate NAFLD by CT criteria. Clinical liver fat scores and CT findings were evaluated at baseline and 12 months post treatment. Correlation between each liver fat score (LAP index, HSI and NAFLD-MS score) and liver CT findings were analyzed. Results: 502 male of age 65 and over with total testosterone <275ng/dL were analyzed (testosterone group n= 246, placebo group n=233). Baseline testosterone levels were not different between the two groups at baseline. Testosterone level was increased by 285.5±266.4ng/dL in the treatment group compared to 1.98±73.6ng/dL in the placebo group (p= 0.0001). Prevalence of NAFLD in elderly hypogonadal men by LAP index, HSI and NAFLD-MS were 89.77%, 88.93% and 3.96% respectively. 30% of subjects had liver HU<40, 21.36% had liver-to-spleen HU ratio (LSR)<1. There were no statistically significant changes in liver fat scores and CT findings in each arm at baseline and after 12 months treatment. Subgroup analysis on subjects with NAFLD defined by LAP index, liver HU or LSR did not show improvement of NAFLD after 12 months of testosterone replacement. Among the 3 liver fat scores, only LAP index showed inverse correlation with liver HU. Conclusion: Our study did not show improvement of NAFLD in elderly hypogonadal male after 12 months of testosterone replacement compared to placebo, assessed by lipid accumulation product index, hepatic steatosis index, NAFLD-MS score, liver HU and liver-to-spleen ratio. Future studies with longer treatment duration and additional modalities to define NAFLD as primary outcome may be warranted. Presentation Date: Saturday, June 17, 2023

FRI297 Hemoglobin Decline As A Signal For Hyperprolactinemia Onset Prior To Prolactinoma Diagnosis In Hypogonadal Men

Abstract Disclosure: Y. Rudman: None. H. Duskin-Bitan: None. I. Richter: None. G. Tsvetov: None. H. Masri-Iraqi: None. A. Akirov: None. I. Shimon: None. Background: Men harboring prolactinomas frequently suffer from central hypogonadism with secondary anemia. They present insidious and non-specific symptoms of hypogonadism, making it difficult to diagnose the disease and determine its duration. The result is a delay in diagnosis, which may have harmful hormonal and metabolic consequences. We hypothesized that a decrease in hemoglobin (HB) levels prior to prolactinoma diagnosis, may signal hyperprolactinemia onset and estimate disease duration. Methods: We retrospectively evaluated the pre-diagnosis temporal trends in HB levels of 70 males with prolactinoma, diagnosed from January 2010 to July 2022. Men without hypogonadism, patients that received testosterone, and those with unrelated anemia were excluded. Results: Sixty-one of seventy men (87%) with prolactinoma presented with hypogonadism, and forty men (57%) had HB levels ≤13.5 g/dl at diagnosis. We identified 25 patients with “informative” HB curves (mean age, 46.1±14.9 years; median prolactin, 952 ng/ml; median follow-up, 14.0 years), demonstrating an obvious pre-diagnosis HB decrease (greater than 1.0 g/dl), from a pre-diagnosis baseline HB of 14.4±0.3 g/dl to 12.9±0.5 g/dl at diagnosis. The median “low-HB duration” (from the first low HB measurement to hyperprolactinemia diagnosis) was 6.1 years (IQR, 3.3-8.8 years). In symptomatic patients, we identified a correlation between “low-HB duration” and patient-reported sexual dysfunction duration (n=17, R=0.502, p=0.04). The “low-HB duration” was significantly longer than the reported sexual dysfunction duration (7.0±4.5 vs 2.9±2.5 years, p=0.01). Conclusions: In our cohort of men with prolactinomas and hypogonadism, we found a marked decrease in HB levels that preceded prolactinoma diagnosis by a median of 6.1 years, with a mean delay of 4.1 years between HB decrease and hypogonadal symptoms appearance. These results suggest that HB decline prior to prolactinoma diagnosis may serve as a marker for hyperprolactinemia onset in a subset of hypogonadal men and allow a more accurate assessment of disease duration. Presentation: Friday, June 16, 2023

Cardiovascular Outcomes of Hypogonadal Men Receiving Testosterone Replacement Therapy: A Meta-analysis of Randomized Controlled Trials

ObjectiveTo investigate the impact of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men. MethodsA meta-analysis of 26 randomized controlled trials involving 10 941 participants was conducted. Various clinical outcomes, including all-cause mortality, cardiovascular-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis, were assessed. ResultsNo statistically significant differences were observed between the TRT group and the control group in terms of these clinical outcomes. Sensitivity analysis and publication bias assessment supported the robustness of the findings. Meta-regression analysis found no significant associations between clinical outcomes and potential covariates, including age, diabetes, hypertension, dyslipidemia, and smoking. DiscussionPrevious research on TRT and cardiovascular events, with comparisons to studies like the Testosterone Trials and the studies conducted by Vigen et al, Finkle et al, Layton et al, and Wallis et al, is provided. The significance of the systematic review and meta-analysis approach is emphasized, particularly its exclusive focus on hypogonadal patients. ConclusionThis study offers reassurance that TRT does not increase mortality risk or worsen cardiovascular outcomes in hypogonadal men. However, further research, especially long-term studies involving diverse populations, is essential to strengthen the evidence base and broaden the applicability of these findings.

571 Assessing rates of hypogonadism in men with cystic fibrosis

571 Assessing rates of hypogonadism in men with cystic fibrosis

Peyronie's disease response to intralesional collagenase clostridium histolyticum therapy is independent of baseline testosterone.

Testosterone plays an important role in collagen metabolism, transforming growth factor-β1 expression, and wound healing, which are all critical factors in pathogenesis of Peyronie's disease. Some clinical studies have suggested an association between Peyronie's disease and hypogonadism. We sought to investigate whether baseline total testosterone levels influence response to intralesional collagenase clostridium histolyticum in Peyronie's disease. A retrospective review of patients receiving collagenase clostridium histolyticum injections with available total testosterone levels within 1 year of initial injection was conducted at a single institution. Baseline demographics, hypogonadal status, total testosterone, number of collagenase clostridium histolyticum cycles, and pre- and post-treatment degrees of curvature were collected. Hypogonadism was defined as total testosterone <300ng/dL. Thirty-six men were included with mean age of 58.2 years (SD 10.4) and mean body mass index 26.8 (SD 3.2). The mean total testosterone was 459.2ng/dL (SD 144.0), and four (11.1%) were hypogonadal. Mean pre-treatment curvature was 47.6°, and mean post-treatment curvature was 27.8°, with mean improvement of 19.9° (40.1%). Hypogonadal status was not significantly associated with more severe curvature, 46.4° among hypogonadal men as to 57.5° among eugonadal men (p=0.32). On linear regression analysis, total testosterone did not significantly predict improvement in degrees (β=-0.02; R2=0.06; p=0.14) or percent (β=0.0; R2=0.05; p=0.18). Improvement in neither degrees nor percent differed significantly by hypogonadal status (p=0.41 and 0.82, respectively). The cycle number did significantly predict greater improvement in curvature on both univariate and multivariate analyses (β=5.7; R2=0.34; p<0.01). Neither total testosterone nor hypogonadism is associated with a degree of improvement after collagenase clostridium histolyticum treatment.

Testosterone Replacement Therapy and Cardiovascular Disease: Balancing Safety and Risks in Hypogonadal Men.

PURPOSEOF REVIEW: The purpose of this review is to analyze the link between testosterone replacement therapy (TRT) and adverse cardiovascular (CV) events. RECENT FINDINGS: A few published studies suggest a link between TRT and CV events. These studies contained flaws, and many other studies reveal a reduction in CV events. Hypogonadism is associated with increased mortality in men with CVD. TRT in hypogonadal men can improve many CVD risk factors, reduce QT interval prolongation, lead to better outcomes in heart failure patients, and slow the progression of atherosclerosis. The use of TRT to achieve physiologic testosterone concentrations in men does not pose a threat to CV health and has demonstrated a cardioprotective effect.

The Effect of Testosterone Replacement Therapy on Nonalcoholic Fatty Liver Disease in Older Hypogonadal Men.

Male hypogonadism is associated with visceral obesity and the metabolic syndrome: factors important for the development of nonalcoholic fatty liver disease (NAFLD). The Testosterone Trials (The T Trials) showed testosterone (T) treatment compared with placebo in older hypogonadal men was associated with decreases in cholesterol and insulin levels suggesting that T treatment may improve NAFLD. Compare effects of T vs placebo treatment on NAFLD scores and liver scans in elderly hypogonadal men. Secondary data analyses from 479 older hypogonadal men with total T < 275 ng/dL from The T Trials were performed. Three clinical liver fat scores-lipid accumulation product index, hepatic steatosis index, nonalcoholic fatty liver disease-metabolic syndrome score-and liver computed tomography (CT) Hounsfield units and liver to spleen ratio were evaluated at baseline and 12 months after treatment. There were no statistically significant differences of change in lipid accumulation product index (P = .98), hepatic steatosis index (P = .67), and nonalcoholic fatty liver disease-metabolic syndrome (P = .52) in 246 men treated with T compared with 233 treated with placebo for 12 months. Liver CT showed no statistically significant difference of change in Hounsfield units (P = .24; n = 71 for T, n = 69 for placebo) and liver to spleen ratio (P = .74; n = 55 for T, n = 62 for placebo) between the 2 groups. Our study did not show improvement of NAFLD in older hypogonadal men after 12 months of T vs placebo treatment, as assessed by 3 clinical scores and liver CT for hepatic steatosis. Future studies with longer treatment duration and additional NAFLD diagnostic modalities as primary outcome are warranted.

The association of hypogonadism with depression and its treatments.

According to World Health Organization estimates, 5% of the adult population worldwide suffers from depression. In addition to the affective, psychomotor and cognitive symptoms which characterize this mood disorder, sexual dysfunction has been frequently reported among men suffering from depression. The most common sexual manifestations are decreased libido, erectile dysfunction and orgasmic disorder. In addition, epidemiological studies have documented a reduction of testosterone concentrations in men with depression and, for these reasons, depressive disorders appear as one possible cause of male functional hypogonadism. Moreover, some largely used antidepressant medications can cause or worsen sexual complaints, thus depression and its treatments rise several andrological-relevant issues. The other way round, men with hypogonadism can manifest depressed mood, anxiety, insomnia, memory impairment which, if mild, may respond to testosterone replacement therapy (TRT). However, the prevalence of functional hypogonadism in depression, and of depressive symptoms in hypogonadal men, is not known. Severe depressive symptoms do not respond to TRT, while the effect of treating major depression on functional hypogonadism, has not been investigated. Overall, the clinical relevance of each condition to the other, as well as the physiopathological underpinnings of their relationship, are still to be clarified. The present review summarizes current evidence on the influence of testosterone on mood and of depression on the hypothalamic-pituitary-testis axis; the clinical association between male hypogonadism and depression; and the reciprocal effects of respective treatments.

Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men with Low to Low-Normal Testosterone Levels: A Systematic Review and Meta‐Analysis

Background: Previous studies and meta-analyses have explored the relationship among testosterone, muscle strength, and physical function, to the best of our knowledge, no meta-analysis has investigated the effects of testosterone replacement therapy (TRT) on subgroup of relatively hypogonadal older men. Objective: The aim of this study was to evaluate the effect of TRT in older men with low testosterone levels. Methods: PubMed, Embase, and Web of Science were systematically searched for articles published between January 1990 and April 2020. We included randomized controlled studies that investigated the effect of TRT and included older men (age >60 years) with relatively low testosterone levels. Studies were extracted following the PRISMA flowchart, and the included randomized controlled trials were evaluated using RoB 2.0. Our main outcome was muscle strength changes after TRT evaluated using a metaregression of confounding factors. Secondary outcomes included changes in physical performance and the risk ratio of adverse events. Random-effects meta-analyses of TRT on muscle strength and physical function were performed. Results: Thirteen studies with 2,043 patients were included. The mean age of subjects in various studies ranged from 65.9 years to 76 years. Transdermal testosterone dosages ranged from 5 to 10 g/day, while intramuscular options were 125 mg/week or 200 mg every 2 weeks. Oral testosterone supplementation was given at 160 mg/day in one study. Pooled meta‐analyses revealed greater muscle strength improvement after TRT compared with placebo (Hedges’ g = 0.21; 95% CI: = 0.15–0.28). Intramuscular administration of TRT had greater efficacy (Hedges’ g = 0.74; 95% CI: = 0.34–1.14) than transdermal and oral TRT (p < 0.001). A metaregression revealed that baseline serum total testosterone was associated with muscle strength improvement (β = −0.004, p = 0.002). The risk ratios of adverse events, including elevated prostate-specific antigen, acute coronary syndrome, and prostate cancer, were not significantly different. Conclusion: TRT improved muscle strength in older, relatively hypogonadal men. The effect was more pronounced in populations with lower baseline testosterone levels.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men

/Objective: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180-days prior to surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P<.001) that was in the lower extremity. At 5-years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P<.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (HR:1.94, 95%CI:1.4-2.7; P<.001) compared to controls. This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Update on acquired hypogonadism in men living with HIV: pathogenesis, clinic, and treatment.

Hypogonadism is a frequent finding among men living with HIV (MLWH) and it seems to occur earlier in comparison with the general male population. Although the prevalence of hypogonadism in MLWH has significantly lowered thanks to advancements in medical management, it remains high if compared with age-matched HIV-uninfected men, ranging from 13% to 40% in the age group of 20-60 years. Signs and symptoms of low serum testosterone (T) in MLWH are cause of concern since they are non-specific, of mild-to-moderate degree, and often overlapping with those of infection per se. For these reasons, hypogonadism can be underestimated in the absence of targeted laboratory blood examinations. With regard to the etiological factors involved in the T decrease, emerging evidence has suggested the functional nature of hypogonadism in MLWH, pointing out the mutual relationship between sex steroids, health status, comorbidities, and HIV-related factors. In agreement with this hypothesis, a therapeutic approach aiming at improving or reversing concomitant diseases through lifestyle changes (e.g. physical activity) rather than pharmacological T treatment should be theoretically considered. However, considering both patient's barriers to lifestyle changes to be maintained overtime and the lack of evidence-based data on the efficacy of lifestyle changes in normalizing serum T in MLWH, T therapy remains an option when other non-pharmacological interventions are ineffective as well as for all other functional forms of hypogonadism. From this perspective, the traditional therapeutic management of male hypogonadism in MLWH, especially the role of T supplementation, should be revised in the light of the probable functional nature of hypogonadism by considering a good balance between benefits and harmful. This narrative review presents an overview of current knowledge on hypogonadism in MLWH, deepening the factors driving and taking part in T decrease, providing advice for the clinical approach, and underlining the importance of individualized treatment aiming at optimizing non-gonadal comorbidities and thus avoiding over-, or even unnecessary, treatment with T.

P-086 Prevalence and clinical factors associated with biochemical hypogonadism in infertile men with non-obstructive azoospermia: a single-center cohort study including 761 patients

Abstract Study question What is the prevalence, and which factors are associated with hypogonadism in infertile men with non-obstructive azoospermia (NOA)? Summary answer The prevalence of biochemical hypogonadism among NOA males is significant. The condition is associated with testicular volume, estradiol levels, paternal age, and testicular histopathology results. What is known already NOA is a severe and irreversible condition that accounts for approximately 60% of azoospermia cases, primarily associated with intrinsic testicular deficiencies of various causes. NOA men can present signs of hypogonadism, associated or not with elevated circulating FSH levels; however, the exact prevalence is ill-reported. There is also a lack of data on the clinical factors associated with hypogonadism. We, therefore, estimated the prevalence of biochemical hypogonadism using real-world data and investigated its relationship with clinical factors. Study design, size, duration An observational cohort study was conducted, including 767 consecutive NOA patients with primary spermatogenic failure seeking fertility treatment at a University-affiliated tertiary center for male reproductive health between January 2014 and September 2021. Biochemical hypogonadism was defined as total testosterone (T) levels &amp;lt;350 ng/dL, measured by chemiluminescence immunoassay from a venous sample, collected in the morning, from 8:00 to 10:00 am, and confirmed on a second analysis at least one week apart. Participants/materials, setting, methods All included patients (age range: 23-55 years) had complete clinical, hormonal, genetic, seminal, and histopathology data and were naïve concerning previous sperm retrieval attempts. Patients with NOA due to hypogonadotropic hypogonadism and those using hormonal therapy were excluded. Prevalence rates were computed by Goodman’s method. The relationship between clinical factors and hypogonadism was assessed by logistic regression analysis. We also assessed the frequency of patients with high and within-range FSH levels in the cohort. Main results and the role of chance NOA patients with biochemical hypogonadism represented 80.3% (95% confidence interval [CI] 77.3–43.7) of the studied population. The median (interquartile range [IQR]) of T and FSH levels in hypogonadal men were 276 ng/dL (233.0-303 ng/dL) and 12.3 IU/L (8.9-18.2). Among them, hypergonadotropic (FSH&amp;gt;12 IU/L) and normogonadotropic (within-range FSH levels 1.5-12.0 IU/L) patients were 52.1% (95% CI 48.1-56.0) and 47.8% (43.9-51.8) of studied individuals, respectively. Logistic regression analyses revealed that testicular volume (p &amp;lt; 0.0001) and estradiol levels (p = 0.0005) had a significant inverse relationship with hypogonadism, whereas paternal age (p = 0.02) showed a positive relationship. Moreover, testicular histopathology was a relevant predictor (p = 0.003), with an inverse relationship between hypogonadism and germ cell maturation arrest and a positive relationship between hypogonadism and hypospermatogenesis or Sertoli cell-only. Using these variables, a model constructed to predict hypogonadism had an area under the ROC curve of 0.72. Limitations, reasons for caution Limitations include possible unmeasured confounding factors and the intra- and inter-assay electrochemiluminescence method variability. Another limitation is that the study center is a referral facility for azoospermic patients; thus, hypogonadism prevalence rates reported herein might not represent that of the general population of NOA males attending general fertility centers. Wider implications of the findings Efforts are needed to provide adequate care for this population due to its association with poor quality of life. Moreover, as recent evidence has suggested that hormonal therapy to boost T production might increase sperm retrieval success rates, studies investigating hormonal therapy in such patients may be warranted. Trial registration number Not applicable

P-044 Outcomes of spermatogenesis induction in hypogonadal men over a 5-year period at a UK Male Fertility Centre

Abstract Study question Assess the effectiveness of treatments at a Male Endocrine Fertility Clinic, over a five-year period, through spermatogenesis rates and fertility outcomes via a patient-centred questionnaire Summary answer Rate of successful spermatogenesis was 68% and live birth (LB) 36%. Trend towards lower odds ratio for LB was noted, if partners reported subfertility. What is known already Approximately half of infertility cases are due to male factor, with up to 70% being idiopathic. The remaining 30% of male factor infertility is attributed to primary testicular or central endocrine disorders. Identifying the aetiology of male hypogonadism is important to determine treatment strategies, such as gonadotrophin therapy and surgical testicular sperm extraction (TESE). Although treatment pathways for hypogonadal men with infertility have been established over the last thirty years, the effectiveness of such pathways is diverse and data from large studies are scanty. Study design, size, duration A questionnaire, covering basic demographic data about both partners, as well as health conditions affecting fertility, was prospectively sent out to 168 men who had received gonadotrophins for induction of spermatogenesis between 2017 and 2021. Men presented with azoospemia or severe oligospermia (&amp;lt;5million/ml). Eighty-four questionnaires (50%) were completed. Medical records were reviewed, to validate participant responses, identify baseline endocrine biochemistry from the start of spermatogenesis and seminal parameters at the end of the process. Participants/materials, setting, methods Mean age of participants was 38 years (range 21-63). Twenty-two men had primary (26%) and the remaining 74% central hypogonadism. The questionnaire was sent via email and responses were anonymised with each participant given a unique study identification number. All statistical analysis was performed using Graph Pad Prism. All hypothesis testing was two-tailed; p &amp;lt; 0.05 was considered statistically significant. Main results and the role of chance 58% of men (49/84) had sperm seen in their ejaculate and 10% of men (8/84) after microTESE. Men with persistent azoospermia were more likely to have a diagnosis of primary hypogonadism (PH) and small testicular size. 28% (13/47) had partners, who conceived spontaneously and delivered healthy babies. 9% (4/47) had a live birth after ART. Only 1 of 2 men with PH seeking fertility, had a partner with a positive pregnancy test, which resulted in a miscarriage. Age, body mass index, alcohol intake, baseline LH, FSH and testosterone were not significantly different between men with or without a live birth. Men without a live birth trended towards having partners with subfertility (pelvic inflammatory disease, endometriosis or polycystic ovarian syndrome), though this did not reach statistically significance (Odds ratio 6.9, 95%CI: 0.8 – 59.9, p = 0.07). Also, LBR was lower for female partners above 35 years, compared to LBR for younger female partners; 35% (6/17) for couples with partners above 35 years, versus 65% (11/17) for couples with partners below 35 years. Seminal parameters were not statistically different between men with or without live births, which supports the possibility that factors other than male reproductive status affected fertility outcomes. Limitations, reasons for caution The 50% response rate to our questionnaire-based study means outcomes may not be representative of all patients attending our clinic and can introduce bias with differences between responders and non-responders. Furthermore, the questionnaire used was not externally validated and its data may not be representative of outcomes in other centers. Wider implications of the findings Our study highlighted successful spermatogenesis and comparable live birth rates to other male fertility services worldwide. It is the first to compare the clinical, biochemical and seminal characteristics between men with live births versus those without a live birth. Ensuring couples are well informed is essential to further successful outcomes. Trial registration number not applicable