Low Bioavailable Testosterone Research Articles

High SHBG and Low Bioavailable Testosterone are Strongly Causally Associated with Increased Forearm Fracture Risk in Women: An MR Study Leveraging Novel Female-Specific Data

The effects of androgens on women’s bone health are not fully understood. Mendelian randomization (MR) studies using sex-combined data suggest that sex hormone-binding globulin (SHBG) and bioavailable testosterone (BioT) causally affect bone traits. Given significant sex differences in hormone regulation and effects, female-specific MR studies are necessary. In the current study, we explored the causal relationships of SHBG, BioT, and total testosterone (TT) with forearm fracture (FAFx) risk in women using two-sample MR analyses. We utilized a unique female-specific FAFx outcome dataset from three European biobanks (UFO, HUNT, Estonian Biobank) comprising 111,351 women and 8823 FAFx cases, along with female-specific genetic instruments of SHBG, BioT, and TT identified in the UK Biobank. We also assessed bone mineral density (BMD) at the forearm (FA), femoral neck (FN), and lumbar spine (LS) using female-specific GWAS data from the GEFOS consortium. High SHBG (odds ratio per standard deviation increase (OR/SD): 1.53, 95% confidence intervals (CIs): 1.34–1.75), low BioT (OR/SD: 0.77, 0.71–0.84) and low TT (OR/SD 0.90, 0.83–0.98) were causally associated with increased FAFx risk. BioT was positively, and SHBG inversely, causally associated with especially FA-BMD, but also LS-BMD and FN-BMD, while TT was only significantly positively associated with FA-BMD and LS-BMD. We propose that endogenous androgens and SHBG are important for women’s bone health at distal trabecular-rich bone sites such as the distal forearm and may serve as predictors for FAFx risk.

FRI430 A Case Of Elevated Sex Hormone-binding Globulin Secondary To Variegate Porphyria In A Patient With Hypogonadotropic Hypogonadism

Abstract Disclosure: J. Law: None. C. Yip: Research Investigator; Self; Eli Lilly & Company. Background: Acute porphyria is a group of disorders characterized by enzymatic defects in the heme biosynthetic pathway. The liver is the source of both acute intermittent porphyria (AIP) and variegate porphyria. AIP is known to cause an elevation in sex hormone-binding globulin (SHBG) levels, likely secondary to impaired hepatic function and hepatocyte abnormalities1. We describe a case of elevated SHBG secondary to variegate porphyria, in a male with hypogonadotropic hypogonadism. Case Report: A 44-year-old male presented with an elevated SHBG and symptoms of hypogonadism with low libido, weakness, and fatigue. Fasting morning bloodwork revealed an elevated SHBG at 89 nmol/l (13.5- 71.0), a normal total testosterone level at 12.95 nmol/l (8-32), and a low bioavailable testosterone at 0.82 nmol/l (2.5-10), with confirmatory repeat blood work. His history was significant for longstanding variegate porphyria, manifesting as frequent attacks of abdominal pain. He was on opioids for greater then 10 years for his chronic pain, as well as metoclopramide. On assessment of causes for his elevated SHBG, his TSH was normal at 1.49 mIU/L (0.35-4.30). He did not have cirrhosis, hepatitis, hereditary hemochromatosis, and was not on anticonvulsants. No other cause was found, and his elevated SHBG was deemed secondary to his variegate porphyria. His normal total testosterone level was due to his elevated SHBG, but as mentioned, his bioavailable testosterone was low. His LH and FSH were both inappropriately normal, with his LH being 4.67 IU/L (0.6-12.0) and his FSH 4.7 IU/L (1.0-12.0), in keeping with hypogonadotropic hypogonadism. He went through normal pubertal development and had no anosmia. Workup revealed an elevated prolactin level of 73.8 ug/l (3.5-19.4). He had no galactorrhea or gynecomastia and an MRI sella revealed a normal pituitary gland. His elevated prolactin level was determined to be secondary to his opioid medication and/or metoclopramide use. His hypogonadotropic hypogonadism was deemed secondary to his opioid medications and/or hyperprolactinemia. Conclusion: This case demonstrated variegate porphyria as a likely cause of elevated SHBG, similar to AIP. In patients with variegate porphyria and symptoms of hypogonadism, the SHBG should be measured and if it is elevated, the bioavailable or free testosterone levels should be used in assess instead of relying on the total testosterone levels. As has been previously shown, this case also illustrated the use of opioid medications as a cause of hypogonadotropic hypogonadism.

Associations of sex-related steroid hormones and proteins with alcohol dependence: A United Kingdom Biobank study

BackgroundSex-related steroid hormones and proteins may contribute to the sex differences in the characteristics and health consequences of alcohol use disorder. This study aimed to examine the associations between alcohol dependence (AD) and sex-related hormones/proteins using a population-based dataset. MethodsWe retrieved serum total testosterone (TT) and estradiol (TE2), sex hormone binding globulin (SHBG), and albumin levels along with clinical data from the UK Biobank. Hormone/protein levels were compared between AD (lifetime AD and/or related diagnoses; 2218 males; 682 females) and control (no aforementioned diagnoses and AUDIT<8; 198,058 males; 250,830 females) groups with sex-dependent linear regression models adjusting for age and body mass index. Moderation and mediation analyses were performed to test whether SHBG was a moderator and/or mediator between hormones and AD or current drinking. ResultsAD males had higher TT, TE2, and SHBG levels but lower bioavailable testosterone, bioavailable estradiol, and albumin levels than controls (padjusted<0.001). After adjusting for menopause, AD females had higher TT and lower albumin levels than controls (padjusted<0.001). These differences remained after accounting for current drinking frequency (p < 0.001). SHBG moderated TT’s effect on AD in males (pinteraction<0.001). SHBG was a positive mediator between TT and AD in both sexes and between TE2 and AD in males (p < 0.001), but a negative mediator between TT and current drinking in controls (both sexes) and AD males (p < 0.001). ConclusionsTestosterone and estradiol levels are altered in males and females with AD distinctly regardless of current drinking frequency. SHBG may play a critical role in these associations.

Individual and joint association of bioavailable testosterone and aging with neutrophil-to-lymphocyte ratio in Chinese middle-aged and elderly men

Background and objectivesAccumulating evidences suggest that chronic systemic inflammation (CSI) is independently associated with large number of major non-communicable chronic diseases (NCDs) ranging from metabolic disorders to cancers, and neutrophil-to-lymphocyte ratio (NLR) has been accepted as a novel, convenient marker for CSI response. Testosterone deficiency in men is linked to high risk of NCDs. This cross-sectional study aimed to investigate the individual and joint association of bioavailable testosterone (BIOT) and aging with NLR.MethodsA total of 132 male adults were enrolled during Jan. 2011 and Oct. 2017 in the first affiliated hospital of University of Science and Technology of China. Local weighted regression (LOESS) and multivariable generalized linear regression models were utilized to comprehensively examine the individual and joint association between BIOT and age with NLR.ResultsObvious linear relationships between NLR and BIOT or age were observed with the LOESS models. NLR was negatively correlated to BIOT after adjusting for some potential confounding factors (P = 0.034). As compared to the lowest quartile of BIOT, the adjusted decrease of NLR for the 2nd, 3rd and 4th quartiles were 0.40, 0.64 and 0.72, respectively. Meanwhile, NLR was observed to be independently correlated to elevated age (P = 0.043). Furthermore, as compared to the counterparts, men over 70 years combined with plasma BIOT less than 4.7 nmol/L had the highest NLR level, which suggested that low BIOT and aging jointly correlated to the level of NLR (P = 0.005).ConclusionBIOT deficiency and aging were individually and jointly correlated to CSI. Men over 70 years combined with BIOT < 4.7 nmol/L were more like to have higher grade of CSI than others.

SUN-LB039 Novel Use of Thromboelastography (TEG) to Investigate the Prothrombotic Effects of Testosterone Replacement Therapy (TRT) for Androgen Deficiency (AD) Established with Diagnostic Rigor (DR)

Background Endocrine Society recommends ≥2 low bioavailable (BAT) or free Testosterone (T) levels in the early AM by tandem mass spectroscopy to establish AD with DR. They also advise against TRT with a recent history of vascular events (VEs). Data from our center affirm these recommendations. TRT increased VE risk four-fold without DR versus with DR, and eight-fold with a history of recent VEs versus without, suggesting that inappropriate TRT might provoke VEs in the absence of AD, or with high vascular risk. The etiopathogenesis of VEs on TRT is not understood, nor is it known if TRT induces a prothrombotic state, but two putative mechanisms might be involved. First, T increases platelet receptors for thromboxane A2, a potent vasoconstrictor and platelet aggregant. Second, T is aromatized to estradiol (E2), a potent activator of the clotting cascade, inhibitor of antithrombin III, and platelet aggregant. Objective To determine (a) whether TEG, a clinically validated tool for assessing platelet function and clotting can be used to identify a prothrombotic state during TRT for AD proven with DR, and (b) if changes are related to estradiol levels. Methods Male veterans >18 years of age referred for suspected AD, and with no contraindications to TRT, were recruited for the study. After AD was established according to guidelines, blood samples were drawn for TEG and E2 before TRT initiation and after 3 months of TRT, and the following TEG parameters were assessed: Reaction Time for initial fibrin formation (R), reflecting the clotting cascade, Kinetic Time for fibrin cross linkage (K), reflecting fibrinogen and platelet number, Angle (α), reflecting the speed of clot strengthening, and Maximum Amplitude (MA), reflecting platelet function. Results In 7 subjects (median age 64 [IQR 38,68]), on TRT for 88±5d (Mean±SE), calculated BAT increased from 82±17ng/dl to 143±32ng/dl (p=0.046), but E2 did not change significantly (14.3±2.5 vs 19.6±4.2pg/ml, p=0.4). R increased 17% on TRT compared to before (∆=0.9±0.2min, p=0.012), showing that time to initial fibrin formation was prolonged, while remaining within the normal range. However, there was no significant change in K, α, or MA. ConclusionsOur data, based on the novel use of TEG to study a potentially prothrombotic effect of TRT, show for the first time that TRT inhibits, not activates the kinetics of the enzymatic process of coagulation. In other words, appropriate TRT had no prothrombotic effect in an admittedly small number of patients with AD established with DR. This accords with both the four-fold decrease in VEs we observed earlier on TRT prescribed appropriately with DR, as well as some prior reports of a lower risk of VEs on TRT. It is conceivable that TRT might induce a prothrombotic state when prescribed inappropriately in the absence of AD, given that many studies showing that TRT increases VE risk have not employed DR to establish AD conclusively. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Extremely Low Testosterone due to Relative Energy Deficiency in Sport: A Case Report

Recognize extremely low testosterone due to hypothalamic dysfunction from overtraining syndrome in a male athlete with relative energy deficiency in sport (RED-S). Clinical and laboratory information are described. A 20-year-old male division I collegiate swimmer was found to have strikingly low total, free, and bioavailable testosterone levels with normal sex hormone-binding globulin and inappropriately normal follicle-stimulating hormone and luteinizing hormone. Lab testing ruled out hyperprolactinemia and hypothyroidism as etiologies, and pituitary imaging was normal. A diagnosis of RED-S was made, and the patient worked with the sports medicine team to increase nutrition and modify physical activity. His repeat testosterone levels improved after minor weight gain and decreased training regimen and eventually returned to normal. Secondary hypogonadism with extremely low testosterone can be seen in male athletes with suspected RED-S.

Association between serum levels of insulin-like growth factor-1, bioavailable testosterone, and pathologic Gleason score.

BackgroundWe evaluated the association between serum levels of insulin‐like growth factor‐1 (IGF‐1), bioavailable testosterone, and surgical Gleason score (GS).MethodsWe analyzed 793 patients who underwent radical prostatectomy and 272 men with negative prostate biopsy. Serum levels of IGF‐1 and testosterone were measured before surgery or biopsy.ResultsThe mean IGF‐1 levels of prostate cancer patients and men with a negative biopsy were 143.8 and 118.9 ng/mL, respectively (P < 0.001). Men with high serum IGF‐1 were more likely to have prostate cancer (highest vs lowest quartile, odds ratio [OR] = 3.35; P trend < 0.001). However, among men with prostate cancer, the mean IGF‐1 levels of those with low (GS ≤ 6), intermediate (GS = 7), and high surgical GS (GS ≥8) were 151.7, 144.1, and 132.9 ng/mL, respectively (P < 0.001). Using quartile analysis, high serum IGF‐1 levels were shown to be associated with a low risk of high surgical GS (OR = 0.464; P trend = 0.006). Serum bioavailable testosterone concentration was positively correlated with serum IGF‐1 level (r = 0.157, P < 0.001). High bioavailable testosterone level was also associated with a low risk of high surgical GS in patients without diabetes mellitus (OR = 0.569; P trend = 0.040). Among men with biopsy GS ≤ 3 + 4 (n = 460), upgrading to high surgical GS was more frequent in patients with low IGF‐1 level (≤116.0 ng/mL; 9.9%) or low bioavailable testosterone level (≤0.85 ng/mL; 9.3%) than in patients with normal IGF‐1 and bioavailable testosterone levels (2.6%; P = 0.004).ConclusionsSerum levels of IGF‐1 and bioavailable testosterone show inverse associations with high surgical GS. This suggests that high‐grade prostate cancer develops independently of these two substances.

Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial.

To determine the predictive value of free and bioavailable testosterone levels on the detection of high-grade prostate cancer proven by histopathological examination of transrectal prostate biopsy specimens. A total of 405 patients who underwent transrectal prostate biopsy due to high prostatic specific antigen (PSA) (>2.5 ng/mL) and/or abnormal findings at digital rectal examination were included in this study. Blood free and bioavailable testosterone levels were calculated by the formula recommended by International Society for the Study of the Aging Male (ISSAM). The patients were stratified according to the D'Amico classification based on PSA levels and histological outcomes of prostate biopsies as benign, low, intermediate and high-risk prostate cancer. Patients were also divided into five groups according to the percentage of cancerous cores. Prostate cancer was detected in 160 of 405 (39.5%) patients. Total, free and bioavailable testosterone levels did not differ significantly between the patients with benign or malign histology. However, mean free (6.2 vs. 5.2 ng/dL, p=0.02) and bioavailable (151 vs. 125 ng/dL, p=0.001) testosterone levels were found to be significantly different in men with low-intermediate and high-risk prostate cancer. Moreover, a significant correlation was found between free, and bioavailable testosterone levels and percentage of cores with cancer (p=0.002 for free and p=0.016 for bioavailable testosterone, respectively). This prospective clinical study demonstrates that reduced levels of calculated blood free and bioavailable testosterone levels are associated with an increased risk of high-grade prostate cancer. Based on these findings blood free and bioavailable testosterone levels may be be thought to be an adjunctive factor in the prediction of high-risk prostate cancer.

Nandrolone decanoate interferes with testosterone biosynthesis altering blood–testis barrier components

The aim of this study was to investigate whether nandrolone decanoate (ND) use affects testosterone production and testicular morphology in a model of trained and sedentary mice. A group of mice underwent endurance training while another set led a sedentary lifestyle and were freely mobile within cages. All experimental groups were treated with either ND or peanut oil at different doses for 6 weeks. Testosterone serum levels were measured via liquid chromatography–mass spectrometry. Western blot analysis and quantitative real‐time PCR were utilized to determine gene and protein expression levels of the primary enzymes implicated in testosterone biosynthesis and gene expression levels of the blood–testis barrier (BTB) components. Immunohistochemistry and immunofluorescence were conducted for testicular morphological evaluation. The study demonstrated that moderate to high doses of ND induced a diminished serum testosterone level and altered the expression level of the key steroidogenic enzymes involved in testosterone biosynthesis. At the morphological level, ND induced degradation of the BTB by targeting the tight junction protein‐1 (TJP1). ND stimulation deregulated metalloproteinase‐9, metalloproteinase‐2 (MMP‐2) and the tissue inhibitor of MMP‐2. Moreover, ND administration resulted in a mislocalization of mucin‐1. In conclusion, ND abuse induces a decline in testosterone production that is unable to regulate the internalization and redistribution of TJP1 and may induce the deregulation of other BTB constituents via the inhibition of MMP‐2. ND may well be considered as both a potential inducer of male infertility and a potential risk factor to a low endogenous bioavailable testosterone.

The Utility of Sex Hormone-Binding Globulin in Hypogonadism and Infertile Males

We sought to determine the role of sex hormone-binding globulin in patients with male infertility. We retrospectively reviewed the records of 168 males seen at a fertility clinic from 2012 to 2014 to investigate the accuracy of total testosterone in the biochemical diagnosis of hypogonadism using calculated bioavailable testosterone as the reference value. We used multivariable analysis to assess sex hormone-binding globulin as an independent predictor of infertility. Computations using calculated bioavailable testosterone as a standard in the measurement of definitive biochemical hypogonadism (less than 156 ng/dl) revealed 81% sensitivity, 83% specificity, 81% positive predictive value and 82% negative predictive value for diagnosing hypogonadism with total testosterone alone. Of the 90 men with total testosterone greater than 300 ng/dl, 20% had low bioavailable testosterone less than 156 ng/dl, 52% had borderline low bioavailable testosterone less than 210 ng/dl and only 48% could be considered biochemically eugonadal according to calculated bioavailable testosterone. Of the 80 patients with total testosterone less than 300 ng/dl, 19% had free testosterone levels greater than 6.5 ng/dl and, thus, could be considered to be eugonadal. By a magnitude similar to that of follicle-stimulating hormone, sex hormone-binding globulin independently predicted decreased sperm concentration (p = 0.0027) and motility (p = 0.0447). After excluding men with azoospermia, only sex hormone-binding globulin levels differed significantly in classically hypogonadal men (group 1-total testosterone less than 300 ng/dl) and those missed but hypogonadal (group 2-calculated bioavailable testosterone less than 210 ng/dl) (p = 0.0001). At a more stringent cutoff of calculated bioavailable testosterone less than 156 ng/dl, sperm motility was significantly different for groups 1 and 2 (p = 0.014). Adding sex hormone-binding globulin to total testosterone serum testing facilitates more accurate diagnosis with free testosterone and calculated bioavailable testosterone, and clinical implications of decreased semen parameters to a magnitude similar to that of follicle-stimulating hormone. This warrants further study of the role of sex hormone-binding globulin in male infertility.

Association between late-onset hypogonadism syndrome plus metabolic syndrome and prostate cancer and its aggressiveness

ObjectiveTo assess the relationship between prostate cancer (PC) and the presence of metabolic syndrome and late-onset hypogonadism (LOH) syndrome. Material and methodA retrospective study was conducted on 686 patients who underwent prostate biopsy. We analyzed the demographic variables, clinical data and biopsy results. To diagnose metabolic syndrome, we employed the criteria of the American Heart Association. For the diagnosis of LOH syndrome, we employed the Androgen Deficiency in the Aging Male questionnaire and testosterone levels (TT). We evaluated the relationship between free testosterone (FT) and bioavailable testosterone (BT) on one hand and PC and its aggressiveness on the other, as well as the usefulness of the TT to prostate specific antigen (TT/PSA) ratio in the PC diagnosis. ResultsThe patient's median age was 65 years. Metabolic syndrome is not associated with PC (39.4% vs. 35%; p=0.1) but is associated with a PC Gleason score>7 (50.4% vs. 29.44%; p=0.002). LOH, low FT and low BT are associated with an increased presence of PC (51% vs. 35%, p=0.02; 44.86% vs. 33.33%, p=0.03; and 46.46% vs. 33.08%, p=0.01, respectively) and with an increased probability of a PC Gleason score>7 (61.54% vs. 37.5%, p=0.02; 54.17% vs. 34.12%, p=0.02; 54.35% vs. 34.48%, p=0.02, respectively). Additionally, the median TT/PSA ratio was significantly lower in patients with positive biopsies (p=0.022). ConclusionsMetabolic syndrome was not associated with the probability of having PC but was associated with a PC Gleason score>7. Moreover, LOH syndrome had a higher percentage of PC and a greater presence of PC Gleason score>7, as did low levels of FT and low levels of BT.

Asociación del síndrome de hipogonadismo tardío y síndrome metabólico con el cáncer de próstata y su agresividad

ObjectiveTo assess the relationship between prostate cancer (PC) and the presence of metabolic syndrome and late-onset hypogonadism (LOH) syndrome. Material and methodA retrospective study was conducted on 686 patients who underwent prostate biopsy. We analysed the demographic variables, clinical data and biopsy results. To diagnose metabolic syndrome, we employed the criteria of the American Heart Association. For the diagnosis of LOH syndrome, we employed the Androgen Deficiency in the Aging Male questionnaire and testosterone levels (TT). We evaluated the relationship between free testosterone (FT) and bioavailable testosterone (BT) on one hand and PC and its aggressiveness on the other, as well as the usefulness of the TT to prostate specific antigen (TT/PSA) ratio in the PC diagnosis. ResultsThe patient's median age was 65 years. Metabolic syndrome is not associated with PC (39.4% vs. 35%; P=.1) but is associated with a PC Gleason score >7 (50.4% vs. 29.44%; P=.002). LOH, low FT and low BT are associated with an increased presence of PC (51% vs. 35%, P=.02; 44.86% vs. 33.33%, P=.03; and 46.46% vs. 33.08%, P=.01, respectively) and with an increased probability of a PC Gleason score >7 (61.54% vs. 37.5%, P=.02; 54.17% vs. 34.12%, P=.02; 54.35% vs. 34.48%, P=.02, respectively). Additionally, the median TT/PSA ratio was significantly lower in patients with positive biopsies (P=.022). ConclusionsMetabolic syndrome was not associated with the probability of having PC but was associated with a PC Gleason score >7. Moreover, LOH syndrome had a higher percentage of PC and a greater presence of PC Gleason scores >7, as did low levels of FT and low levels of BT.

Diagnostic and prognostic biomarkers of a sellar melanocytic tumor mimicking pituitary adenoma: Case report and literature review

Primary or metastatic melanocytic tumors in the sellar region are rare and can pose a diagnostic challenge. Here we describe a case of a 74-year-old man who underwent radiological investigations for a transient episode of blurred vision. Based on the clinical and endocrinological findings and MRI results, the patient was assumed to have a clinically non-functioning pituitary macroadenoma, which was followed-up over a 2-year period. He did not have any endocrine symptoms or progressive visual deterioration, and no history of past malignancy, including melanoma. Endocrinological investigation was unremarkable; blood hormone levels were within the normal ranges except for low serum total testosterone and bioavailable testosterone levels without symptoms of hypogonadism. The longitudinal MRI follow-up demonstrated a gradual increase in the size of the tumor over the course of 11 months. For this reason, the patient underwent surgery. Pathologic examination including histology, immunohistochemistry and electron microscopy achieved the correct diagnosis of melanocytic tumor of the sellar region morphologic examination is essential in the diagnosis of melanocytic tumors. Hmb-45 is an important diagnostic biomarker in melanocytic lesions. The use and exploration of miRNA, Ki67 and osteopontin are important in understanding the genesis, progression, and prognosis in treatment of patients with melanocytic tumors.

Low circulating free and bioavailable testosterone levels as predictors of high-grade tumors in patients undergoing radical prostatectomy for localized prostate cancer

ObjectiveControversy exists regarding the propensity of hypogonadism and metabolic disorders to promote the development of high-risk prostate cancer (PCa). Our aim was to prospectively test whether preoperative circulating testosterone levels, obesity, and metabolic syndrome (MetS) were correlated with aggressive pathological features after radical prostatectomy (RP). Material and methodsOverall, 354 patients undergoing robot-assisted RP at our academic institution, between 2010 and 2013, to treat clinically localized PCa were included in this prospective study. Pelvic lymphadenectomy was performed in 116 (32.8%) patients and confirmed the absence of nodal metastases in all of them. Cardiovascular risk factors and body-mass index (BMI) were used to define MetS and obesity, respectively. Total testosterone (TT) levels were assessed using an immunoassay method, whereas bioavailable testosterone (BT) and free testosterone (FT) levels were estimated using Vermeulen׳s formula. Multivariate logistic regression analyses assessed independent predictors for postoperative aggressive pathological features (i.e., a pathological Gleason score [GS]≥7, extracapsular extension [ECE], seminal vesicle invasion [SVI], and positive surgical margins [PSM]) and GS upgrading. ResultsLow TT, BT, and FT levels were found in 54 (15.2%), 70 (19.8%), and 62 (17.5%) patients, respectively. Median BMI was 26.3kg/m2 (range: 17.4–43.9), and prevalence of MetS was 18.9%. Significantly higher rates of pathological GS≥7 were observed in groups with a low TT level (46.3% vs. 33.3%; P = 0.01), low BT level (44.3% vs. 33.1%; P<0.001), and low FT level (46.8% vs. 32.9%; P = 0.001). Multivariate analyses demonstrated that only low BT and FT levels were independent predictors of pathological GS≥7 (odds ratio [OR] = 1.76; P<0.001 and OR = 1.39; P<0.001, respectively) and GS upgrading (OR = 2.82; P<0.001 and OR = 1.71; P<0.001, respectively), but there was no significant correlation between low circulating testosterone levels and ECE, SVI, or PSM. Furthermore, BMI (OR = 1.28; P = 0.04) and MetS (OR = 1.19; P = 0.01) were only correlated with PSM. ConclusionHypogonadism, obesity, and MetS were not independent predictors of pathological GS ≥7, ECE, or SVI after RP. Our data suggest that only low BT and FT levels, which might logically result in an active androgen-depleted environment, were linked with high-grade PCa.

Race differences in obesity and its relationship to the sex hormone milieu

A sexual dimorphism exists in which increased abdominal and visceral adipose tissue (VAT) - found in women and marked by low sex hormone binding globulin (SHBG) and high bioavailable testosterone (BT) - is related to the metabolic risk profile. In men, increased BT is related to decreased abdominal obesity and a decrease in the metabolic risk profile. In women, race differences have been found in androgenic sex steroids including SHBG and BT as well as central fat distribution, creating inherently greater metabolic risk for certain populations. Estrogen and estrogen receptor isoforms play a role in fat deposition and distribution and may influence the changes that occur during the menopausal transition. Androgenic sex steroids serve a mediating role, influencing VAT accumulation and its associated metabolic risk factors while VAT also serves a mediating role influencing the androgenic sex steroid-metabolic risk relationship in women. Furthermore, androgenic sex steroids and VAT may independently contribute to the variance in several metabolic variables associated with cardiovascular disease, type 2 diabetes, and their antecedent conditions such as the metabolic syndrome. Race has been shown to modify the relationship between androgenic sex steroids and metabolic variables associated with risk for diabetes in Black and White women. Further research is warranted to examine the mechanisms involved in race differences. Total adiposity and central fat distribution in accordance with changes in the hormone and metabolic milieu influence breast cancer risk, which varies by race and menopausal status. These findings have broader implications for the study of health promotion/disease prevention in women.

Androgen Deficiency as a Biological Determinant of Frailty: Hope or Hype?

The role of androgen deficiency as a biological determinant of frailty has received considerable attention. Cross-sectional studies have shown that low bioavailable testosterone (BT) is associated with prevalent frailty. High levels of luteinizing hormone and sex hormone binding globulin are also associated with prevalent frailty. Longitudinal studies have had mixed results, suggesting, for the most part, that a decline in BT over time is associated with progression of frailty. A number of potential biases were found in the current body of evidence, including misclassification bias (due to testosterone assays that were insensitive in lower ranges), selection bias (due to preferential inclusion of healthier individuals), and residual confounding (due to correlation of low testosterone with several disease states and adverse health characteristics). Consideration of these biases is vital to ensure that future epidemiological studies and interventional trials generate valid conclusions.

Association between hypogonadism, symptom burden, and survival in male patients with advanced cancer

A high frequency of hypogonadism has been reported in male patients with advanced cancer. The current study was performed to evaluate the association between low testosterone levels, symptom burden, and survival in male patients with cancer. Of 131 consecutive male patients with cancer, 119 (91%) had an endocrine evaluation of total (TT), free (FT), and bioavailable testosterone (BT); high-sensitivity C-reactive protein (CRP); vitamin B12; thyroid-stimulating hormone; 25-hydroxy vitamin D; and cortisol levels when presenting with symptoms of fatigue and/or anorexia-cachexia. Symptoms were evaluated by the Edmonton Symptom Assessment Scale. The authors examined the correlation using the Spearman test and survival with the log-rank test and Cox regression analysis. The median age of the patients was 64 years; the majority of patients were white (85 patients; 71%). The median TT level was 209 ng/dL (normal: ≥ 200 ng/dL), the median FT was 4.4 ng/dL (normal: ≥ 9 ng/dL), and the median BT was 22.0 ng/dL (normal: ≥ 61 ng/dL). Low TT, FT, and BT values were all associated with worse fatigue (P ≤ .04), poor Eastern Cooperative Oncology Group performance status (P ≤ .05), weight loss (P ≤ .01), and opioid use (P ≤ .005). Low TT and FT were associated with increased anxiety (P ≤ .04), a decreased feeling of well-being (P ≤ .04), and increased dyspnea (P ≤ .05), whereas low BT was only found to be associated with anorexia (P = .05). Decreased TT, FT, and BT values were all found to be significantly associated with elevated CRP and low albumin and hemoglobin. On multivariate analysis, decreased survival was associated with low TT (hazards ratio [HR], 1.66; P = .034), declining Eastern Cooperative Oncology Group performance status (HR, 1.55; P = .004), high CRP (HR, 3.28; P < .001), and decreased albumin (HR, 2.52; P < .001). In male patients with cancer, low testosterone levels were associated with systemic inflammation, weight loss, increased symptom burden, and decreased survival. A high frequency of hypogonadism has been reported in male patients with advanced cancer. In the current study, an increased symptom burden, systemic inflammation, weight loss, opioid use, and poor survival were found to be associated with decreased testosterone levels in male patients with cancer. Cancer 2014;120:1586-1593. © 2014 American Cancer Society.

Prevalence and Clinical Correlates of Sarcopenia in Community-Dwelling Older People: Application of the EWGSOP Definition and Diagnostic Algorithm

Muscle impairment is a common condition in older people and a powerful risk factor for disability and mortality. The aim of this study was to apply the European Working Group on Sarcopenia in Older People criteria to estimate the prevalence and investigate the clinical correlates of sarcopenia, in a sample of Italian community-dwelling older people. Cross-sectional analysis of 730 participants (74% aged 65 years and older) enrolled in the InCHIANTI study. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People criteria using bioimpedance analysis for muscle mass assessment. Logistic regression analysis was used to identify the factors independently associated with sarcopenia. Sarcopenia defined by the European Working Group on Sarcopenia in Older People criteria increased steeply with age (p < .001), with 31.6% of women and 17.4% of men aged 80 years or older being affected by this condition. Higher education (odds ratio: 0.85; 95% CI: 0.74-0.98), lower insulin-like growth factor I (lowest vs highest tertile, odds ratio: 3.89; 95% CI: 1.03-14.1), and low bioavailable testosterone (odds ratio: 2.67; 95% CI: 1.31-5.44) were independently associated with the likelihood of being sarcopenic. Nutritional intake, physical activity, and level of comorbidity were not associated with sarcopenia. Sarcopenia identified by the European Working Group on Sarcopenia in Older People criteria is a relatively common condition in Italian octogenarians, and its prevalence increases with aging. Correlates of sarcopenia identified in this study might suggest new approaches for prevention and treatment of sarcopenia.

Higher sex hormone-binding globulin and lower bioavailable testosterone are related to prostate cancer detection on prostate biopsy

Objective. Recent studies show an inverse relationship between testosterone levels and prostate cancer (PCa). The usefulness of hormonal patterns in PCa diagnosis is controversial. This study aimed to determine the relationship between hormonal patterns and PCa, and to find a cut-off point of hormone levels to assess PCa risk. Material and methods. A prospective analysis was undertaken of 279 patients referred for first or second prostate biopsy in the Hospital Clínic Barcelona from November 2006 to May 2009. The indication for prostate biopsy was suspicion of PCa based on the results of digital rectal examination (DRE) and/or elevation of serum prostate-specific antigen (PSA). Screening was carried out with a 5+5-core transrectal ultrasound-guided prostate biopsy. Age, prostate volume, DRE (normal or abnormal), biopsy findings (normal or report of PCa), PSA, free-to-total PSA, PSA density, testosterone and sex hormone-binding globulin (SHBG) were also prospectively recorded. Free and bioavailable testosterone were calculated using Vermeulen's formula. Results. In the multivariate analysis, abnormal DRE [odds ratio (OR = 5.46, p < 0.001], SHBG levels ≥ 66.25 nmol/l [OR = 3.27; 95% confidence interval (CI) 1.52 to 7.04, p < 0.002] and bioavailable testosterone levels ≤ 104 ng/dl (OR = 4.92, 95% CI 1.78 to 13.59, p = 0.002) were related to the diagnosis of prostate adenocarcinoma. Age, free testosterone, PSA, testosterone, PSA/testosterone, PSA/free testosterone and PSA/bioavailable testosterone were not related to PCa diagnosis. Conclusions. Low bioavailable testosterone levels and high SHBG levels were related to a 4.9- and 3.2-fold risk of detection of PCa on prostate biopsy owing to PSA elevation or abnormal DRE. This fact may be useful in the clinical scenario in counselling patients at risk for PCa.

Osteoprotegerin Levels Decrease During Testosterone Therapy in Aging Men and are Associated with Changed Distribution of Regional Fat

The cardiovascular effects of testosterone treatment are debated. Osteoprotegerin (OPG) is an independent marker of cardiovascular risk. We investigated the effect of testosterone therapy on OPG levels in aging men with low normal bioavailable testosterone levels. A randomized, double-blinded, placebo-controlled study of 6 months testosterone therapy (gel) in 38 men aged 60-78 years with bioavailable testosterone <7.3 nmol/l and waist circumference >94 cm was performed. Clinical evaluation, OPG, and C-reactive protein (CRP) measurements were carried out. Lean body mass (LBM), total fat mass, and bone mineral density (BMD) were established by dual X-ray absorptiometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured by magnetic resonance imaging. Power calculation was based on an increase in LBM during testosterone therapy and responders were defined as testosterone treated patients with increased LBM (Δ LBM positive), n=14. Data are presented as median (interquartile range). Testosterone therapy decreased total fat mass and SAT, whereas VAT was unchanged (n=38). OPG levels decreased during testosterone therapy (from 2.0 (1.9-2.5) to 1.9 (1.6-2.2) ng/ml, p<0.05 vs. placebo), whereas CRP levels were unchanged (n=38). In responders to testosterone therapy (n=14), ΔOPG levels were inversely associated with ΔSAT (r= - 0.60, p=0.03) and positively associated with ΔVAT (r=0.56, p=0.04). OPG levels decreased during testosterone therapy suggesting decreased cardiovascular risk. Decreased OPG levels were associated with changes in regional fat distribution and future studies are needed to further evaluate the association between OPG and regional fat mass distribution.