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OR25-01 Longitudinal Changes in the Hypothalamic-Pituitary-Testicular (HPT) Axis in Men with Longevity

Abstract Disclosure: D. He: None. T. Gao: None. N. Barzilai: None. S. Milman: None. S. Aleksic: None. Background: Aging in men is associated with a reduction in testosterone (T) levels. In men aged 50 - 80, the decline in T mainly occurs due to hypothalamic-pituitary dysfunction, which results from unhealthy aging characterized by obesity and metabolic disorders. The changes in the HPT axis in men with longevity are less understood. Our recent cross-sectional study in men aged 90 and older showed high prevalence of testicular dysfunction which was not associated with metabolic health. We now explore the longitudinal changes in the HPT axis in men with longevity to better understand their relationship with metabolic health and survival. Methods: In an observational study of community-dwelling Ashkenazi Jewish men (n = 68, mean age (SD) at baseline sample 84 ± 4 years), levels of total T (TT, LC/MS), LH, and SHBG were measured in longitudinal serum samples (a median of 3 measures per subject, age at final sample 89 ± 3 years). Men were followed for survival after the final sample. Free T (FT) was calculated per Vermeulen et al. Men treated with T or GnRH agonists were excluded. Metabolic measures included BMI, A1c, and serum lipids. Individual longitudinal trajectories of TT, FT, LH, and SHBG were estimated with linear regression. Biochemical gonadal phenotypes were determined based on the levels of TT and LH. Results: Baseline and final levels of TT, FT, LH, and SHBG were, respectively: 417 ± 173 and 346 ± 187 ng/dL (TT), 6.0 ± 2.4 and 4.7 ± 2.5 ng/dL (FT), 8.0 [5.1, 14.4] and 10.0 [5.9, 20.4] mIU/mL (LH), and 58 ± 20 and 63 ± 23 nmol/L (SHBG), with average change rate/year of −17 ± 47 ng/dL (TT), −0.3 ± 0.5 ng/dL (FT), 0.7 ± 2.2 mIU/mL (LH) and 0.9 ± 4.1 nmol/L (SHBG). At baseline, the most prevalent biochemical gonadal phenotype was eugonadism (54%), followed by compensated testicular dysfunction (24%), testicular dysfunction (10%), and hypothalamic-pituitary dysfunction (12%), while respective prevalence rates at the final sample were 40%, 24%, 29%, and 7%. Baseline TT (p=0.002), age (p=0.02), and history of cancer (p=0.01) predicted more negative trajectory, while the history of cardiovascular disease (p=0.02) predicted more positive trajectory of TT. Neither TT, FT, LH nor SHBG trajectories were significant predictors of final BMI, A1c, or serum lipid levels. Positive TT trajectory was associated with shorter survival, after adjustment for SHBG, age, and comorbidities (HR 6.61 [1.46, 29.8], p=0.01). Conclusions: This is one of the first longitudinal studies of the HPT axis in community-dwelling men with longevity. As men survive into the late 80s, they increasingly develop testicular dysfunction while hypothalamic-pituitary dysfunction is rare. Changes in testosterone levels do not seem to predict metabolic dysfunction; however, an increase in total testosterone with aging may be associated with reduced survival. These findings need to be explored further in larger and ethnically diverse cohorts. Presentation Date: Saturday, June 17, 2023

FRI435 A Grave Case Of Gynecomastia

Abstract Disclosure: S. Seltzer: None. A. illiams: None. T. Kader: None. Background: Gynecomastia is a common endocrinology referral. Our team saw a patient in the clinic with an unusual presentation. Clinical Case: A 28 year old male presented with worsening painful gynecomastia affecting one breast initially but eventually progressing to both breasts. His secondary concern was a 40lb weight loss and new onset tremor. He declined hypogonadal symptoms, palpitations, or new testicular growth. Exam revealed a resting pulse of 120 b.p.m., a palpable goiter, visible tremor, hyperdynamic heart sounds and bilateral tender gynecomastia. Labs revealed normal FSH, LH and hCG, high total testosterone (TT), thyroxine (T4) and triiodothyronine (T3) with positive thyroid receptor antibodies. Methimazole and beta blockade were started. He did develop an episode of atrial fibrillation requiring admission. Due to medication intolerance and patient preference the decision was made for total thyroidectomy. Three months post-surgery there was complete resolution of hyperthyroidism and gynecomastia.The differential for true gynecomastia is broad. The initial diagnostic approach includes a thorough history and physical exam followed by measuring serum testosterone (T), LH, hCG and estradiol (E2). Increased LH and low T indicates hypogonadism. Normal values may suggest an idiopathic cause. Elevated hCG warrants testicular imaging and if negative, chest and abdominal imaging to rule out extragonadal germ cell tumors. Elevated total T and LH should prompt measurement of TSH and T4 and if normal androgen resistance should be suspected. Elevated E2 and low/low normal LH should prompt testicular imaging and if normal an adrenal CT to rule out an adrenal neoplasm. If LH and T are low, prolactin should be measured as well as dedicated pituitary imaging.Any state which induces an increased E to T ratio may cause gynecomastia. The true pathophysiology in hyperthyroidism driving the increased sex hormone binding globulin (SHBG) production is unknown. It is postulated that this increase is driven by increased transcription and translation of hepatocyte nuclear factor-4ɑ secondary to elevated T41. SHBG more readily binds androgens than estrogens leading to a relative decrease in free T (FT). The lower FT levels result in negative feedback to the pituitary gland which causes increases in LH resulting in production of androgens, estradiol and peripheral aromatases. The increase in peripheral aromatization of testosterone leads to further elevation of the free estrogen levels. Conclusion: Hyperthyroidism should always be in the differential of gynecomastia as in our case the presentation may be atypical.

The role of male hypogonadism, aging, and chronic diseases in characterizing adult and elderly men with erectile dysfunction: a cross-sectional study

BackgroundErectile function depends on a complex interaction between demographic, metabolic, vascular, hormonal, and psychological factors that trigger erectile dysfunction (ED). In the present study we carried out a cross-sectional study assessing the impact of non-communicable chronic diseases (NCDs), male hypogonadism, and demographic factors in characterizing men with ED. Four hundred thirty-three consecutive outpatients with ED were extracted from the electronic database from January 2017 to December 2019. The International Index of Erectile Function (IIEF) 5 score was used to diagnose ED and stratify its severity, standardized values of serum testosterone (10.5 nM/L) and luteinizing hormone (LH 9.4 IU/L) to diagnose and classify male hypogonadism and the Charlson Comorbidity Index (CCI) to weigh the role of each NCD on ED. ResultsForty-six percent of participants were eugonadal (EuG), 13% had organic hypogonadism (OrH), and the remaining 41% had functional hypogonadism (FuH). Hypogonadal men had a significantly lower IIEF 5 score (p < .0001) than EuG. FuH had a higher CCI than OrH and EuG (all p < .0001). In a multivariable model, only free T (FT) and Sex Hormone Binding Globulin (SHBG) showed a direct correlation with the IIEF 5 score (all p < .0001). Age and CCI had an inverse correlation with IIEF 5 score (all p < .0001).ConclusionSerum FT, SHBG, and CCI are the leading determinants of ED severity. Besides overt hypogonadism, a relevant burden of severe NTCDs in middle-aged or older adults features the patient’s characteristics who will suffer from severe ED. Appropriate clinical approaches and, when necessary, treatments are required in these clusters of patients.

PD47-04 ANALYZING THE IMPACT OF TESTOSTERONE ON BONE DENSITY LOSS

You have accessJournal of UrologyCME1 May 2022PD47-04 ANALYZING THE IMPACT OF TESTOSTERONE ON BONE DENSITY LOSS Jose M. Flores, Nicole Benfante, Elizabeth Schofield, and John P. Mulhall Jose M. FloresJose M. Flores More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Elizabeth SchofieldElizabeth Schofield More articles by this author , and John P. MulhallJohn P. Mulhall More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002615.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The prevalence of bone density loss (BDL), including osteopenia and osteoporosis, is higher in men with low testosterone (T). It is unclear if total T (TT) of free T (FT) levels are more important in BDL development. This retrospective study aimed to evaluate the associations of TT and FT to BDL. METHODS: Men with low serum T (<300 ng/dl on 2 early morning levels) routinely undergo dual-energy X-ray absorptiometry (DEXA). The sample included men who had a DEXA scan and T labs collected within 6 months of each other. Total hip, femoral neck, and lumbar spine were scanned. TT was measured using LCMS, FT using equilibrium dialysis. On DEXA, osteopenia was defined as T score -1.1 to -2.5, osteoporosis T score lower than -2.5. Comorbidities assessed included history of diabetes, and obstructive sleep apnea(OSA). We report rates of osteopenia and osteoporosis and attempted to define the ability of TT and FT to predict BDL. RESULTS: 744 men were analyzed with mean age of 62±11 years. Mean TT and FT were 320±194 ng/dL and 29±37 ng/dL. Median number of comorbidities was 2 (1,2). 21% had DM, 31% reported OSA, and 51% of the men had ≥2 comorbidities. DEXA showed 38% had osteopenia, 5% osteoporosis. Free T (OR per 10 ng/dL= 1.05, 95% CI = 1.00 – 1.09), but not total T, was significantly associated with bone density loss (either osteopenia or osteoporosis), even after adjustment for age, diabetes, and OSA. CONCLUSIONS: In our cohort of men with low T, BDL is highly prevalent. Age, diabetes and OSA are significant predictors of BDL. Lower FT increased the likelihood of BDL after adjusted by age, diabetes and OSA. This was not observed with TT. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e794 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jose M. Flores More articles by this author Nicole Benfante More articles by this author Elizabeth Schofield More articles by this author John P. Mulhall More articles by this author Expand All Advertisement PDF DownloadLoading ...

Concentrations of endogenous sex steroid hormones and SHBG in healthy postmenopausal women

Studies reporting age-specific reference ranges of endogenous sex steroid hormones in postmenopausal women are relatively scarce. If levels differ by age, dosing and treatment regimens should vary among postmenopausal women accordingly. Our objective was to establish reference ranges for sex steroid hormones and sex hormone binding globulin (SHBG) by age group and overall, and to investigate their association with demographic characteristics.Serum samples were obtained from 1207 healthy postmenopausal women aged 41–92, not using hormone therapy, at the baseline visit of 3 clinical trials. Estrone (E1), estradiol (E2), and total testosterone (T) were measured by radioimmunoassay with preceding purification steps; SHBG was measured by direct chemiluminescent immunoassay. Free T (FT) was calculated.Women were categorized by 5-year age groups. There was little change in the mean estrogen levels among the different age groups (E2: 9−12 pg/mL; E1: 33−35 pg/mL). Mean total T levels increased gradually with age from 19.9–26.2 ng/dL, but FT mean levels were relatively constant (3.7–4.6 pg/mL). Mean SHBG levels increased with age from 43–68 nmol/L. A generalized linear model tested the association of each demographic characteristic with the hormones and SHBG. A significant association was derived.Our study provides valuable insight into the profiles of serum sex steroid hormones and SHBG in different healthy postmenopausal women aged 41–92 years.

OR02-06 Sexual Symptoms Predict All-Cause Mortality Independently of Sex Steroids in Ageing Men

Background: The association between low testosterone (T) and higher mortality in men remains controversial. Most studies focus only on the association between total T (TT) and mortality. While TT declines with age, free T (FT) shows a greater fall, due to the rise in SHBG. Moreover, higher LH as well as sexual dysfunction, often co-existing with low T, have also been associated with mortality in ageing men. Objective: To study the interrelationships between sex steroids, gonadotrophins and sexual symptoms with all-cause mortality in a large prospective cohort of European men. Methods: 1913 community-dwelling men, aged 40-79, participated in the European Male Ageing Study (EMAS) between 2003-2005. Sexual symptoms were assessed via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. In 5 of 8 EMAS centres, survival status was available until 1 April 2018. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Because of the wide age range at study entry, age was used as time-scale, instead of years since inclusion adjusting for age. Results were expressed as hazard ratios (HR) with 95% confidence intervals, adjusted for centre, BMI and smoking. Results: 483 (25.3%) men died during a mean follow-up of 12.4±3.3 years. Men who died had a higher BMI (p=0.002), but smoking status did not differ. TT levels were similar in both groups, but FT was lower in those who died (mean±SD: 312±86 pmol/L vs 270±84, p<0.001) and LH was higher (5.7±3.3 U/L vs 7.8±5.8, p<0.001). Men in the lowest FT quartile had higher mortality risk compared to men in the highest quartile (HR 1.43 (1.06-1.95); p=0.021). Also men in the highest FSH quartile had increased mortality risk (HR 1.38 (1.02-1.88); p=0.036). However, there was no association with TT, E2 or LH. Men with 3 sexual symptoms had a higher mortality risk compared to men with no sexual symptoms (HR 1.77 (1.28-2.41); p<0.001). In particular erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.15-1.73); p=0.001; HR 1.30 (1.06-1.60); p=0.012; HR 1.14 (0.93-1.40); p=0.203 respectively). Further adjusting for TT and FT did not influence the observed HRs. Also in men with normal TT (>12 nmol/L), the presence of sexual symptoms increased mortality risk (HR 1.51 (1.15-1.97); p=0.003). Finally, men with TT<8 nmol/L and sexual symptoms had a higher mortality risk compared to men with normal TT and no sexual symptoms (HR 1.92 (1.05-3.52); p=0.035). Conclusions: Men with the lowest FT and highest FSH levels have an increased mortality risk. Sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of T levels. As both vascular disease and low T can influence erectile function, sexual symptoms can be an early sign for increased cardiovascular risk and mortality, as well as a sequela of low T.

Associations of Endogenous Sex Hormones with Carotid Plaque Burden and Characteristics in Midlife Women.

Endogenous sex hormones may be involved in the pathogenesis of cardiovascular disease (CVD) in women. Carotid plaque characteristics, such as echogenicity, an ultrasound measure that reflects plaque composition, may identify unstable plaques that are more likely to rupture, precipitating a CVD event. However, few studies have considered sex steroids in relation to carotid plaque and its characteristics. To evaluate estrone (E1), estradiol (E2), testosterone (T), sex hormone binding globulin (SHBG), and free T (FT) in relation to carotid plaque in women. In MsHeart, a cross-sectional study of 304 women aged 40 to 60 years, participants underwent a carotid artery ultrasound assessment. The current analysis included MsHeart participants with carotid plaque (n = 141, 46%). E1, E2, and T were assayed using liquid chromatography-tandem mass spectrometry; FT was estimated using ensemble allostery models. Regression models were adjusted for sociodemographic characteristics and CVD risk factors. Carotid plaque burden (number of plaques, total plaque area [TPA]) and characteristics (calcification, echogenicity) were determined using semi-automated software. SHBG was inversely related to TPA (odds ratio [OR] 0.39; 95% confidence interval [CI] 0.21, 0.74; multivariable) and higher FTs were associated with greater TPA (OR 2.89; 95% CI 1.31, 6.37; multivariable). Higher E1 was related to echogenicity (OR 2.31; 95% CI 1.26, 4.33; multivariable), characteristic of more stable plaque. SHBG and FT are related to TPA while E1 is related to plaque echogenicity, suggesting these hormones have different roles in the development of carotid plaque. Our findings highlight the importance of sex hormones in the development of carotid plaque in midlife women.

OR18-3 Gonadal Function in Human Immunodeficiency Virus (HIV)-Infected Men Assessed by Isotopic Dilution-Liquid Chromatography-Tandem Mass Spectrometry (ID-LC-MS/MS) and Chemiluminescent Immunoassay

BACKGROUND: HIV-infection is associated to premature decline of serum T1,2. However, prevalence and biochemical characterization of hypogonadism in HIV-infected men are still to be well defined1,2. AIM: To evaluate the gonadal status in HIV-infected men by assessing circulating total T (TT) with either ID-LC-MS/MS or chemiluminescent immunoassay. METHODS: Prospective, cross-sectional, observational study on HIV-infected men with ongoing Highly Active Antiretroviral Therapy (HAART). Serum TT, gonadotropins and sex hormone-binding globulin (SHBG) were measured by chemiluminescent immunoassay. TT was also assessed by the gold standard ID-LC-MS/MS. Free T (FT) was calculated by Vermeulen equation. Hypogonadism was defined as serum TT levels below 320 ng/dL and/or free T levels below 64 pg/ml. Statistical analysis: Categorical variables were compared using Chi-Square test, while correlations were performed using linear regression models. RESULTS: 315 consecutive HIV-infected men were enrolled (mean age 45.56±5.61 years; average duration of HIV-infection 16.57±10.45 years). Considering serum TT levels assessed by LC-MS/MS and immunoassay, 11 patients out of 233 (4.8%) and 10 patients out of 315 (3.2%) had T deficiency, respectively. TT combined with luteinizing hormone (LH) levels was used to classify hypogonadism. No difference was found comparing the two methodologies used for TT measurement (p=0.914). 56 patients (17.8%) showed SHBG above the normal range (>71.4 nmol/L). Considering calculated FT, the incidence of hypogonadism raised to 6.9% using either immunoassay or LC-MS/MS, with no difference between methodologies (p=0.895). Including compensated form of hypogonadism, the prevalence raised to 13% for TT and to 15% for FT. FT showed an inverse relation with age (-0.340,p<0.0001,R2=0.116), years of infection (-0.339,p<0.0001,R2=0.120) and years of HAART (-0.346,p<0.0001,R2=0.117), but not with BMI of patients. CONCLUSIONS: To the best of our knowledge, this is the first properly-designed prospective study aiming to investigate the gonadal status of HIV-infected men with both LC-MS/MS and chemiluminescent assay, together with gonadotropins. In HIV-infected patients a) the two methodologies have equivalent reliability in TT measurement; b) SHBG for calculated FT is essential for the detection of T deficiency, revealing the real prevalence of hypogonadism in this context; c) duration of HIV-infection and HAART seem to be potent predictive factors for serum FT levels, suggesting a concomitant negative effect of virus per se and antiretroviral drugs on gonadal function. REFERENCES1Rochira V et al. Premature decline of serum total testosterone in HIV-infected men in the HAART-era. PLoS One. 2011;6(12):e28512. 2Rochira V & Guaraldi G. Hypogonadism in the HIV-infected man. Endocrinol Metab Clin North Am. 2014 Sep;43(3):709-30.

SUN-230 Association of Estrogens and Androgens with Sexual Function after Hematopoietic Stem Cell Transplant

Background: Hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for hematologic malignancies, but is associated with negative side effects, including reduced sexual function. It was recently reported that estradiol may exert an effect on sexual desire & erectile function, independent to that of testosterone, in healthy men. We hypothesized that changes in estrogen would be directly associated with changes in sexual function in men undergoing HCT. Methods: Nineteen men planning autologous HCT completed the International Index of Erectile Function (IIEF) & provided a morning, fasted blood sample at Baseline (before initiating preparatory chemotherapy) & 30±10 days post-HCT (FU). IIEF contains sub-categories of Erectile Function (EF), Orgasmic Function (OF), Sexual Desire (SD), Intercourse Satisfaction (IS), & Overall Satisfaction (OS). Plasma samples were analyzed for total testosterone (TT), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), sex-hormone binding globulin (SHBG), 17-OHprogesterone, 17-OHpregnenelone, androstenedione, androsterone, pregnenolone, progesterone, estrone (E1), & estradiol (E2) via LCMS; bioavailable (BT) & free T (FT) were calculated using local laboratory-derived albumin levels. Follicle-stimulating hormone (FSH) was analyzed via ELISA. Non-parametric, paired t-tests compared Baseline to FU & multiple regression identified significant predictors of sexual function changes using forced variables (age, HCT-comorbidity index (CI), cumulative steroid exposure, post-HCT testing day, diagnosis) & conditional variables (change scores for each hormone & relative fat mass change). Data are median ± SEM. Results: Men were 68±3 years of age (multiple myeloma, N=15; leukemia, N=6). Significant changes were observed at FU for E2 (-5.2±1.9 pg/mL, p=0.048), E1 (-6.6±2.2 pg/mL, p=0.002), FSH (4.6±0.9 IUL, p=0.002), TT (1.3±0.4 ng/mL, p=0.02), SHBG (41.2±5.5 nmol/L, p=0.001), DHT (0.06±0.03 ng/mL, p=0.03), androsterone (0.02±0.02 ng/mL, p=0.045), androstenedione (0.54±0.16 ng/mL, p=0.001), progesterone (0.02±0.01 ng/mL, p=0.01), & 17-OHprogesterone (0.27±0.08 ng/mL, p=0.001). Sexual function significantly decreased at FU for EF (p=0.003), OF (p=0.01), SD (p=0.009), IS (p=0.03), & IIEF Total (p=0.004). There were no significant predictors of OF, SD, or OS change scores. Diagnosis, HCT-CI, & change scores for E2 & 17-OHpregnenolone were significant predictors of EF change (F=13.3, p=0.005). Age, diagnosis, HCT-CI, & change scores for E2 androstenedione were significant predictors of IS change (F=14.5, p=0.004). Age, diagnosis, HCT-CI, & change scores for E2 & DHEA were significant predictors of Total IIEF changes (F=20.1, p=0.002). Conclusion: Acute changes in sexual function after HCT are likely influenced by HCT-induced reductions in estradiol, independent of changes in testosterone.

Reproductive Hormones and Subclinical Cardiovascular Disease in Midlife Women.

Reproductive hormones are important to the pathophysiology of cardiovascular disease (CVD) in women. However, standard estradiol (E2) and testosterone (T) assays lack sensitivity at the levels of postmenopausal women. Investigate relations of mass spectrometry-assessed estrone (E1), E2, and T and SHBG and subclinical CVD in women. Three hundred and four perimenopausal and postmenopausal women aged 40 to 60 years underwent subclinical CVD measurements. E1, E2, and T were assayed using liquid chromatography-tandem mass spectrometry; free T (FT) was estimated using ensemble allostery models. Regression models were adjusted for CVD risk factors. Carotid artery intima media thickness, interadventitial diameter (IAD), and plaque; brachial flow mediated dilation (FMD). Higher E1 was related to higher FMD [β(SE) = 0.77 (0.37), P = 0.04], indicating better endothelial function. Higher E2 was related to lower IAD [β(SE) = -0.07 (0.02), P = 0.004], indicating less carotid remodeling. Higher SHBG was related to higher FMD [β(SE) = 1.31 (0.40), P = 0.001], yet higher IAD [β(SE) = 0.15 (0.06), P = 0.02] and plaque [OR (95% CI) = 1.84 (1.16 to 2.91), P = 0.009]; FT showed a similar yet inverse pattern of relations as SHBG. Thus, higher SHBG and lower FT were associated with better endothelial function, yet greater carotid remodeling and plaque. Endogenous E1 levels were related to endothelial function and E2 to vascular remodeling, suggesting distinct roles of these estrogens. SHBG and FT have complex roles depending on the vessel under study.

Can the positive association of osteocalcin with testosterone be unmasked when the preeminent hypothalamic-pituitary regulation of testosterone production is impaired? The model of spinal cord injury.

Osteocalcin (OCN), released from the bone matrix during the resorption phase, in its undercarboxylated form, stimulates testosterone (T) biosynthesis in mouse and a loss-of-function mutation of its receptor was associated with hypergonadotropic hypogonadism in humans. Nevertheless, when population-based studies have explored the OCN-T association, conflicting results have been reported. Hypothesizing that the evidence of a positive association between OCN and T could have been hindered by the preeminent role of a well-functioning hypothalamus-pituitary axis in promoting T biosynthesis, we explored this association in men with chronic spinal cord injury (SCI), exhibiting high prevalence of non-hypergonadotropic androgen deficiency. Fifty-five consecutive men with chronic SCI underwent clinical/biochemical evaluations, including measurements of total T (TT), OCN and 25(OH)D levels. Free T (FT) levels were calculated by the Vermeulen formula. Comorbidity was scored by Charlson comorbidity index (CCI). A biochemical androgen deficiency (TT < 300ng/dL) was observed in 15 patients (27.3%). TT was positively correlated with OCN, 25(OH)D and leisure time physical activity and negatively correlated with age, BMI and CCI. OCN was also positively correlated with calculated FT and negatively correlated with BMI and HOMA-IR. At the multiple linear regression analyses, a positive association of OCN with TT and calculated FT persisted after adjustment for confounders. The positive association here found between OCN and T levels in men with chronic SCI reinforces the notion that a bone-testis axis is also functioning in humans and suggests that it can be unmasked when the preeminent hypothalamic-pituitary regulation of T production is impaired.

Growth Hormone Secretagogue Treatment in Hypogonadal Men Raises Serum Insulin-Like Growth Factor-1 Levels.

Realizing the reported misuse of human growth hormone (GH), investigation of a safe alternative mechanism for increasing endogenous GH is needed. Several GH secretagogues are available, including GH-releasing peptides (GHRPs) GHRP-2 and GHRP-6, and the GH-releasing hormone analog, sermorelin (SERM). Insulin-like growth factor 1 (IGF-1) serves as a surrogate marker for GH. Here, the effect of GHRP/SERM therapy on IGF-1 levels is evaluated. A retrospective review of medical records was performed for 105 men on testosterone (T) therapy seeking increases in lean body mass and fat loss who were prescribed 100 mcg of GHRP-6, GHRP-2, and SERM three times daily. Compliance with therapy was assessed, and 14 men met strict inclusion criteria. Serum hormone levels of IGF-1, T, free T (FT), estradiol (E), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were evaluated. Mean (SD) age of the cohort was 33.2 (2.9) years, and baseline IGF-1 level was 159.5 (26.7) ng/mL. Mean (SD) duration of continuous GHRP/SERM treatment was 134 (88) days. Mean posttreatment IGF-1 level was 239.0 (54.6) ng/mL (p < .0001). Three of the 14 men were on an aromatase inhibitor and/or tamoxifen prior to treatment and another 4 men were coadministered an aromatase inhibitor and/or tamoxifen during treatment. Inhibition of E production or estrogen receptor blockade resulted in smaller increases in IGF-1 levels. GHRP/SERM therapy increases serum IGF-1 levels with strict compliance to thrice-daily dosing. The results suggest that combination therapy may be beneficial in men with wasting conditions that can improve with increased GH secretion.

The Effect of Steroid Hormones on the Physical Performance of Boys and Girls During an Olympic Weightlifting Competition.

To examine the steroid hormone effect on the physical performance of young athletes during an Olympic weightlifting competition. 26 boys and 26 girls were monitored across 2 weightlifting competitions. Pre- and post-competition testosterone (T), cortisol (C) and dehydroepiandrosterone-sulfate (DHEA-s) were measured in blood, with pre-event free T (FT) and the free androgen index (FAI) calculated. Body mass (BM) and weightlifting performance were recorded. The boys had a larger BM, superior performance with more T, FT and a higher FAI than girls (p < .01). Although C (32%) and DHEA-s (8%) levels were elevated across competition, no sex differences in hormone reactivity were seen. In boys, DHEA-s correlated with performance (r = .46), but not after controlling for BM (r = .14). For girls, T correlated with performance (r = -0.51) after BM was controlled. The sex differences that emerge during puberty were observable, whereby the boys were larger and stronger with a more anabolic profile than girls. Individual DHEA-s (boys) and T (girls) levels were related to performance, but BM appeared to be acting as a mediating (boys) or suppressing (girls) variable. This adds new insight regarding the hormonal contribution to competitive performance in young athletes.

Low testosterone in non-responsive coeliac disease: A case series, case–control study with comparisons to the National Health and Nutrition Examination Survey

BackgroundAdults with coeliac disease (CD) often report persistent fatigue, even when CD appears well controlled for unknown reasons. AimsTo evaluate common indications for testosterone panel (TP) testing and prevalence of low testosterone (T) in CD. MethodsIn our case series, we determined common indications for checking TP in CD. Next, we conducted a case–control study to compare TP in CD vs. healthy controls (HC). We compared mean total T (TT), free T (FT) based on serologic, histologic disease activity. Finally, we assessed TT in tissue transglutaminase (tTG)+ vs. tTG− subjects and CD vs. HC obtained from the National Health and Nutrition Examination Survey (NHANES). Results53 coeliac males had TP tested. Common indications included osteoporosis and fatigue. Low FT was observed in 7/13 men with osteoporosis and 5/6 with fatigue. In our case–control study (n=26 each), there was no difference in mean TT or FT between CD vs. HC, tTG+ vs tTG− or Marsh 0 vs. Marsh 3 groups. NHANES data showed no difference in mean TT between tTG+ vs tTG− (n=16 each) or CD vs. HC subjects (n=5 each). ConclusionsLow T occurs in CD patients at a similar rate as the general population. Common presentations of low T may mimic non-responsive CD symptoms.

Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis.

Whether endogenous sex hormones play a role in cardiovascular disease (CVD) risk in men is unclear. Few studies have examined associations of sex hormones with atherosclerosis measured by coronary artery calcium score (CACS) and carotid intima-media thickness (cIMT). We evaluated the association of testosterone (T) and other sex hormones with CACS and cIMT. Using the large multi-ethnic cohort of 3164 men without known CVD in the Multi-Ethnic Study of Atherosclerosis (MESA), cross-sectional associations of tertiles of endogenous sex hormones with CACS and cIMT were analysed. In regard to CAC, there was a significant negative trend (P-trend = 0·02) for CACS>0 over tertiles of free T (FT) with RRs (95% CI) for the lowest to highest tertiles. There was also a marginally significant positive trend (P-trend = 0·06) for CACS>0 over tertiles of sex hormone-binding globulin (SHBG) with RRs for the lowest to highest tertiles. There were no significant associations with CACS >0 for tertiles of TT (Total T), bioavailable T (BT), oestradiol (E2) and dehydroepiandrosterone (DHEA). There was significantly higher log CACS after adjustment for CVD risk factors for lower TT levels, compared to higher levels, using 9·54 and 10·4 nmol/l as cut-off points. In regard to cIMT, there was a significant positive trend (P = 0·003) in mean cIMT over the tertiles of BT, but not for TT, FT, E2, DHEA and SHBG. There was significantly lower cIMT after adjustment for CVD risk factors for lower TT levels compared to higher levels. In a population of male subjects with no known CVD, lower FT is associated with higher RR of CACS>0 and lower TT is associated with higher log CACS. Lower BT and TT are associated with lower cIMT. While these findings support the positive correlation between low T and coronary atherosclerosis, the opposite findings on cIMT warrant further evaluation.

Implications of Androgen Assay Accuracy in the Phenotyping of Women With Polycystic Ovary Syndrome.

Hyperandrogenism is a common feature of women with polycystic ovary syndrome (PCOS) and is considered a cardinal element for the diagnosis and phenotyping of this condition. Unfortunately, routinely available methods for measuring serum androgens suffer from major limitations. No data are available on the impact of androgen assay quality on the assignment of PCOS women to the different clinical phenotypes of PCOS, when defined according to the Rotterdam criteria for diagnosis. Two hundred four consecutive Caucasian women with PCOS, diagnosed by the Rotterdam criteria participated in the study. Assessment of total T (TT), free T (FT), and androstenedione (A) by both a chemiluminescent assay, routinely available in our hospital, and gold standard methodology, ie, liquid chromatography-mass spectrometry and equilibrium dialysis, was performed. The results were compared and the associations of these data with clinical and metabolic features of PCOS women were analyzed. By using gold standard assays, TT was high in 36.3% of women, whereas A only marginally contributed to identifying hyperandrogenemic patients. However, gold standard FT measurement was elevated in 70.6% of the PCOS patients, identifying them as hyperandrogenemic. Routine TT and A assays, and the derived calculated FT, were strikingly inaccurate, with substantial overestimation. These assays erroneously classified 60 patients (29.4%), 32 as false hyperandrogenemic, and 28 as false normoandrogenemic, with incorrect assignment of many patients to the clinical phenotypes of PCOS and inappropriate estimation of their metabolic risk. In particular, women misclassified as normoandrogenic had a more severe metabolic profile than true normoandrogenic subjects. FT alone, as measured by equilibrium dialysis or calculated by using the Vermeulen formula, provided that TT is assayed by gold standard methodology, can be used to identify hyperandrogenemic PCOS subjects. The use of routine androgen assays may misclassify the phenotype of many PCOS women, with errors in the estimation of individual metabolic risk.

Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen.

IntroductionNumerous testosterone (T) formulations are available, each with differing effects on serum parameters.AimThe aim of this study was to compare the long-term effects of topical, injectable, and implantable pellet T formulations in hypogonadal men.MethodsRetrospective review of hypogonadal men treated with a single T formulation was performed: 47 men on T gels, 57 on injectable T, and 74 on T pellets were identified. Total T (TT), calculated free T (FT), estradiol (E), hemoglobin (Hgb), hematocrit (Hct), prostate-specific antigen (PSA), total cholesterol (Tchol), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were evaluated at baseline and every 3–6 months for 3 years. Serum parameters were compared using a mixed model linear regression for repeated measures.Main Outcome MeasuresEffects of topical, injectable, and pellet T formulations on serum hormone levels, Hgb, Hct, lipid parameters and PSA.ResultsMen in the injectable T group were younger (42.5 ± 12.3 years) than in the gel (54.1 ± 9.8 years) or pellet groups (53.8 ± 13.0 years), and baseline FT, Hgb, and Hct were higher in the injectable T group than in gel or pellet groups. Increases in TT and FT were observed throughout follow-up in all groups. Increases in E were observed at in all T groups and throughout follow-up in injectable and gel groups. No PSA increases were observed. Erythrocytosis (Hct > 50%) was more common with injectable T (66.7%) than with T gels (12.8%) or pellets (35.1%, P < 0.0001). Transient changes in cholesterol, TG, and LDL were observed, and no significant changes were seen in HDL for any group.ConclusionsAll T formulations increase serum T and FT. More significant increases in E occur with injectable T and T gels. Changes in Hgb and Hct are most significant with injectable T, and effects on lipids are variable and inconsistent. Selection of T formulations must account for individual patient preferences and the effects of each formulation.

Is serum sex hormone-binding globulin a dominant risk factor for metabolic syndrome?

This multi-center, cross-sectional study investigated the association between serum testosterone (T) levels, serum sex hormone-binding globulin (SHBG) levels, and the risk of metabolic syndrome (MS) in 3332 adult Chinese men. The prevalence of MS was 34.7%, and men with MS had lower serum levels of total T (TT) and SHBG than those without MS (P < 0.001). There was no significant difference in serum free T (FT) levels between subjects with and without MS (P = 0.627). In logistic regression analysis, the association between MS and serum SHBG levels persisted after adjusting for age, body mass index (BMI), smoking and drinking status, and serum TT (odds ratio [OR] 0.962, 95% confidence interval [95% CI] 0.954−0.969, P< 0.01). However, the association between serum TT level and the risk of MS was weak after adjusting for age, BMI, SHBG level, and smoking and drinking status (OR 0.981, 95% CI 0.960−1.007). Our study reveals that both serum TT and SHBG levels, but not serum FT, are inversely associated with the prevalence of MS and that serum SHBG is an independent and dominant risk factor for MS.

Lower free testosterone level is correlated with left ventricular diastolic dysfunction in asymptomatic middle-aged men with type 2 diabetes mellitus.

Low testosterone (T) level is associated with cardiovascular risk factors. However, the relationship between T level and heart function in asymptomatic men with type 2 diabetes mellitus (T2DM) is unknown. A total of 325 men were recruited who had no history, symptoms, or signs of heart disease. T2DM had significantly lower free T (FT) levels than those with normal glucose metabolism (NGM) (428 ± 38 pmol/l vs. 444 ± 38 pmol/l, p = 0.0002), and had an increased risk of LVDD (66.1% vs. 31.8%). There was a significant difference in FT level between subjects with and without LVDD among those with T2DM (421 ± 37 pmol/l vs. 442 ± 40 pmol/l, p = 0.0007), but not among those with NGM (439 ± 37 pmol/l vs. 447 ± 39 pmol/l, p = 0.247) or in the group overall (426 ± 38 pmol/l vs. 445 ± 38 pmol/l, p = 0.156). Lower FT level was significantly associated with LVDD [univariate odds ratio (OR) = 0.63, p = 0.032; multivariate OR = 0.71, p = 0.039]. Receiver operating characteristic curve analysis of the usefulness of FT level for predicting LVDD showed an area under the curve (AUC) of 0.85 for T2DM (p < 0.001) and 0.66 for NGM (p < 0.05). FT level had a high predictive value for LVDD in T2DM (83% for FT < 414 pmol/l), but a low predictive value in NGM (61% for FT < 423 pmol/l). Comparison of the AUCs showed that FT level was more strongly correlated with LVDD in T2DM than in NGM. Lower FT level is correlated with LVDD in asymptomatic middle-aged men with T2DM.

Sex steroids in relation to sexual and skeletal maturation in obese male adolescents.

Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatography-tandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys.