Testosterone Threshold Research Articles

Erythrocytosis Is Rare With Exogenous Testosterone in Gender-Affirming Hormone Therapy.

Studies have found a variable incidence of erythrocytosis among people using testosterone as part of gender-affirming hormone therapy (GAHT). To examine the effect of using exogenous testosterone as GAHT on hematocrit in a large North American cohort. We conducted a cross-sectional analysis of testosterone and hematocrit laboratory values in 6670 patients who were prescribed testosterone through Plume, a national provider of GAHT. The prevalence of erythrocytosis, the mean hematocrit at predetermined testosterone thresholds and with varying routes of testosterone administration were assessed. Among 6670 individuals, 560 (8.4%) had a hematocrit ≥50%, 182 ≥ 52% (2.7%), and 60 ≥ 54% (0.9%). There was significant variation (P < .001) in hematocrit between different clinically relevant testosterone thresholds (T < 50 vs T 50-299 vs T 300-999 vs T ≥ 1000 ng/dL) and when comparing serum testosterone in increments of 50 ng/dL within the target range for males (300-1000 ng/dL) (P < .001). Mean hematocrit ranged from 41.84% (T < 50 ng/dL) to 45.68% (T 900-949 ng/dL). Patients on intramuscular testosterone had a higher mean hematocrit than those on transdermal testosterone (44.96% vs 43.41%, P < .001). Both route of administration (P < .001) and testosterone level (P < .001) had statistically significant associations with hematocrit when controlling for each other. While the magnitude of change in hematocrit with serum level and route of administration of testosterone was statistically significant, the absolute levels were within the normal range, unlikely to be clinically meaningful. These findings, along with the low prevalence of erythrocytosis, should help allay concerns about the use of testosterone as GAHT.

(074) Association of Androgen Receptor Signaling in Human Corpus Cavernosum with Serum Testosterone Levels

Abstract Introduction Testosterone (T) plays an important role in properly developing and maintaining male reproductive tissues. The normal serum testosterone levels can vary between 300 to 1000 ng/dL or 10.4 to 34.7 nmol/L. However, it is unclear whether androgen receptor signaling can vary based on serum T levels or the half-life of testosterone therapy. What remains unknown is whether there is a uniform serum T level above which androgen receptor signaling within the tissue remains similar (saturation hypothesis). Objective We first evaluated whether varying serum levels of T alter androgen receptor (AR) signaling in human penile tissue. Then, we evaluated and compared AR signaling in corpus cavernosum tissue of men treated with short-acting vs. long-acting testosterone. We hypothesized that we would find similar AR signaling in the penile tissue of both eugonadal and hypogonadal men as well as those men receiving short and long-acting testosterone. Methods We obtained human corpus cavernosum (hCC) tissue biopsies during penile surgery (for erectile dysfunction) from 14 men. We recorded their serum T levels on week prior to surgery before 10AM. We used western blot to evaluate adrenergic receptor (AR) and VEGF protein levels. Men without erectile dysfunction undergoing penile surgery for Peyronie's disease were used as controls. Results The median age of participants was 61 (IQR 12) and the median T level was 325ng/dL (IQR 201.45). The results of western blot showed expression of similar levels of VEGF in hCC samples from men with T &amp;gt;200ng/dL. However, men with serum T levels lower than 200 ng/dL had decreased expression of VEGF and AR. Conclusions This finding is significant because it demonstrates that serum testosterone beyond a certain threshold may have a minimal impact on erectile function. If a serum testosterone threshold is identified, this threshold could be a valuable target for future studies on the effects of testosterone on ED. It may alter the treatment threshold for men who have ED as their primary symptom of hypogonadism. This data also suggests the saturation value for penile androgen receptors. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Acerus Pharmaceuticals, Boston Scientific, Coloplast, Endo Pharmaceuticals, Empower Pharmacy, Nestle Health, Olympus, Hims, Inc

Mass spectrometry redefines optimal testosterone thresholds in prostate cancer patients undergoing androgen deprivation therapy.

Androgen deprivation therapy (ADT) is the standard of care for prostate cancer treatment. Studies suggest that patients with testosterone levels below 0.7 nM have a longer time to castration resistance. Using the most accurate testosterone measurement method, namely mass spectrometry (MS), we sought to determine if a lower testosterone level under ADT could be associated with longer time to castration resistance. This retrospective study included 138 prostate cancer patients undergoing noncurative continuous ADT for which we had access to testosterone measurements assessed by MS. For 108 samples, paired immunoassays (IA) testosterone measurement was available. Primary outcome was time to castration-resistant prostate cancer (CRPC). The Contal and O'Quigley method was used to determine the optimal testosterone castration cut-off point considering the outcome and time-to-event variables. Relationship between testosterone levels assessed either by IA or MS and time to CRPC was evaluated using Cox regression. Mean testosterone level was 0.370 nM by IA and 0.275 nM as assessed by MS. The optimal testosterone cut-off point identified to predict time to CRPC was of 0.705 nM for IA and of 0.270 nM for MS. While no significant difference for time to CRPC was found between patients showing IA testosterone level ≥0.705 nM versus <0.705 nM (hazard ratio [HR]: 1.579; 95% confidence interval [CI]: 0.908-2.745), patients with MS testosterone ≥0.270 nM had an increased risk of progression to CRPC compared to MS testosterone <0.270 nM in univariate (HR: 1.717; 95% CI: 1.160-2.541) and multivariate analysis (HR: 1.662; 95% CI: 1.043-2.648). The higher sensitivity of MS testosterone measurement methods allows the identification of a lower castration threshold and leads to early identification of patients more likely to progress to CRPC. These patients would likely benefit from treatment intensification by androgen receptor axis-targeted therapies to delay disease progression.

A Scoping Review of Transgender Policies in the 15 Most Commonly Played UK Professional Sports

There has been much debate recently on the participation of transgender and gender-diverse (TGD) athletes in sport, particularly in relation to fairness, safety and inclusion. The 2021 IOC Framework on Fairness, Inclusion and Non-discrimination acknowledges the central role that eligibility criteria play in ensuring fairness, particularly in the female category, and states that athletes should not be excluded solely on the basis of their TGD identity. To identify policies that address TGD athlete participation in the 15 major United Kingdom (UK) sporting organisations and to summarise the evidence for each of these policies. A scoping review of TGD policies from the 15 major UK sporting organisations. Eleven of the governing bodies had publicly available TGD policies. Most of the sporting associations drew guidance from the official 2015 IOC Consensus Meeting on Sex Reassignment and Hyperandrogenism, particularly with regard to physiological testosterone levels. Many organisations referenced their policies as a guide for decision making but stated that they ultimately made case-by-case decisions on an athlete's eligibility. Relevant considerations not addressed in most policies included pre- versus post-pubertal athletes, justification for testosterone thresholds, the length of time out of competitive action (if any) for transitioning athletes, the irreversible advantage from male puberty (if any), the responsibility for and frequency of follow up for hormonal testing and the consequences for athletes outside set testosterone limits. There is a lack of consensus among the top 15 UK sporting organizations relating to elite sport participation for TGD athletes. It would be useful for sport organizations to work together to develop greater standardization/consensus for TGD athlete policies, taking into consideration fairness, safety and inclusion in each sport.

Exercise capacity benefit in relation to endogenous testosterone, coronary and central vascular physiology, and the Mediterranean regime in hypertensive males with erectile dysfunction

Abstract Background The Mediterranean diet (Med-diet) benefits cardiovascular health, and erectile dysfunction (ED) often coexists in the hypertensive aging male population were endogenous testosterone (TT) typically declines. Coronary flow reserve (CFR) displays the ability of the coronary circulation to increase flow. Wave reflection amplification as expressed by augmentation index (AIx) exhibits a vital parameter of central vascular stiffness. Purpose To investigate the possible benefits of the Med-diet in exercise capacity, central physiology, CFR and erectile ability in relation to endogenous TT in the middle aged male hypertensive population with ED. Methods 250 hypertensive males (mean age 56 yo) with ED enrolled the study. All underwent a treadmill stress test (Bruce protocol). Exercise capacity was validated as metabolic equivalents (METs). We measured separately the CFR of the left anterior descending artery by an adenosine protocol (max dose 140μg/kg/min over 6 minutes). PW Doppler measurements were achieved at the middle/distal LAD segment under the guidance of color Doppler flow mapping. CFR was validated as ratio between peak diastolic flow velocity following drug infusion and rest. Ratios ≥2 are considered as non-ischemic response, higher values indicate microvascular coronary integrity. TT was measured on blood samples taken before 09:00 am. ED severity and adherence to the Med-diet were assessed by the SHIM-5 (range: 0–25) and the Med-diet (range: 0–55) scores. Higher values indicate a better erectile ability and Med-diet compliance respectively. Finally, central pulse pressure (cPP) and AIx were noninvasively estimated as parameters of central hemodynamic load and wave reflection amplification (Sphygmocor device). Results In bivariate analysis METs were positively associated to the Med-diet, CFR, TT and the SHIM-5 score (all p&amp;lt;0,005) and negatively to the AIx and cPP (both p&amp;lt;0,025). There was also positive association of the Med-diet to the CFR, TT and the SHIM-5 score (p&amp;lt;0,02) and negative to the AIx and cPP (p&amp;lt;0,025). By linear regression analysis association of METs to TT, CFR and Med-diet remained significant after adjustment for age, BMI, diabetes mellitus, use of statins and smoking status (p&amp;lt;0,005). We further subdivide our population according to the TT threshold of hypogonadism (≤3 ng/ml). Hypogonadism patients exhibit a lower exercise capacity comparing to the normal TT group (picture). Conclusion The Med-diet regime benefits exercise tolerance and erectile performance in hypertensive males with ED by enhancing endogenous testosterone and so coronary and central vascular physiology. We strongly recommend this culinary preference promoting thus vascular health and the sense of well being. Funding Acknowledgement Type of funding sources: None.

The Relevant Hormonal Levels and Diagnostic Features of Polycystic Ovary Syndrome in Adolescents.

Relevance: The clinical picture of polycystic ovary syndrome (PCOS) is extremely polymorphic, especially in adolescence. At the same time, the diagnostic criteria of PCOS in adolescence are still under discussion, and the hormonal parameters, including anti-Mullerian hormone range and hyperandrogenism, are not determined. The aim of the present study was to characterize the pivotal clinical and hormonal features of PCOS in adolescents and to establish the age-specific thresholds of the most essential hormonal parameters. Design: A case-control study. Methods: The study included 130 girls with PCOS according to the complete Rotterdam criteria, aged 15 to 17 years. The control group consisted of 30 healthy girls with a regular menstrual cycle of the same age. A complete clinical and laboratory examination, hormonal assays, and ultrasound of the pelvic organs were performed. The serums anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH, prolactin, estradiol, 17α-OH progesterone (17α-OHP), androstenedione, testosterone (T), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), leptin, and free androgen index (FAI) were analyzed. The diagnostic accuracy of AMH, FAI, LH/FSH, T, and androstenedione levels in predicting PCOS in adolescents was established using a logistic regression model and calculating area under the receiver operator characteristic (ROC) curve (AUC). Results: The serum levels of LH (9.0 (5.4–13.8) vs. 3.7 (2.5–4.7) IU/L; p < 0.0001), LH/FSH (1.6 (1.0–2.3) vs. 0.7 (0.5–1.1); p < 0.0001), 17α–OHP (4.1 (3.2–5.1) vs. 3.4 (2.7–3.8) nmol/L; p = 0.0071), cortisol (464.0 ± 147.6 vs. 284.0 ± 129.7 nmol/L; p < 0.0001), prolactin (266.0 (175.0–405.0) vs. 189.0 (142.0–269.0) mIU/L; p = 0.0141), T (1.9 (1.2–2.5) vs. 0.8 (0.7–1.1) nmol/L; p < 0.0001), androstenedione (15.8 (11.6–23.2) vs. 8.3 (6.5–10.8) ng/mL; p < 0.0001), AMH (9.5 (7.5–14.9) vs. 5.8 (3.8–6.9) ng/mL; p < 0.0001), FAI (5.5 (2.8–7.0) vs. 1.6 (1.1–2.3); p < 0.0001), SHBG (37.0 (24.7–55.5) vs. 52.9 (39.0–67.6) nmol/L; p = 0.0136), DHEAS (6.8 ± 3.2 vs. 5.1 ± 1.5 μmol/L; p = 0.0039), and leptin (38.7 ± 27.1 vs. 23.7 ± 14.0 ng/mL; p = 0.0178) were significantly altered in the PCOS patients compared to the controls. Multivariate analysis of all studied hormonal and instrumental parameters of PCOS in adolescents revealed as the most essential: AMH level > 7.20 ng/mL, FAI > 2.75, androstenedione > 11.45 ng/mL, total T > 1.15 nmol/L, LH/FSH ratio > 1.23, and the volume of each ovary > 10.70 cm3 (for each criterion sensitivity ≥ 75.0–93.0%, specificity ≥ 83.0–93.0%). The diagnostic accuracy of PCOS determination was 90.2–91.6% with the combined use of either four detected indexes, which was significantly higher than the use of each index separately. The accuracy of PCOS diagnostics reached 92% using AMH and leptin concentrations when the value of the logistic regression function [85.73 − (1.73 × AMH) − (0.12 × Leptin)] was less than 70.72. Conclusions: The results of the study estimate the threshold for AMH, FAI, androstenedione, testosterone, LH/FSH, and ovarian volume, which could be suggested for use in the PCOS diagnostics in adolescents with a high sensitivity and specificity. Moreover, the combination of either four determined indexes improved the diagnostic accuracy for the PCOS detection in adolescents.

Optimizing Aging Male Symptom Questionnaire Through Genetic Algorithms Based Machine Learning Techniques.

PurposeGenetic algorithm (GA) is a machine learning optimization strategy where sample strategies compete for fitness to evolve an optimum solution. This study evolves the Aging Male Symptoms (AMS) with GA to better identify late onset hypogonadism (LOH) with serum testosterone.Materials and MethodsGA was trained on a training set of standard AMS questionnaire on a nationwide LOH epidemiology study. Random matrices of selectors for particular items were generated. Each generation of was evolved through a fitness function determined by sensitivity. Threshold to determine positive serum testosterone level for LOH was randomized for each competing strategy. After 2,000 runs, with each run producing the best result out of a set of 3,000 randomly generated sets evolved through 300 generations, the best AMS selection matrix was then applied to a separately enrolled validation set to compare outcomes.ResultsPredictability for serum testosterone levels dropped markedly above 3.5 ng/mL during pilot training. Limiting the training to testosterone thresholds between 2.5 and 3.5 ng/mL the GA 93 different strategies. Only a selection of 5 items, determining for a threshold of 20 points and determining for a serum testosterone level of 3.16 ng/mL, showed robust reproducibility within the internal validation set. Applying these conditions to the independent validation set showed sensitivity improved from 0.66 to 0.77, with a specificity of 0.07 to 0.19, respectively.ConclusionsGA method of selecting questionnaires improved AMS questionnaire significantly. This method can be easily applied to other questionnaires that do not correlate with physiological markers.

Good enough? The ‘wicked’ use of testosterone for defining femaleness in women’s sport

Since the 1930s, sports administrators have insisted on various mechanisms to assess ‘femaleness’ for the purpose of competition in women’s sport. Most recently, the criterion has turned to testosterone. Specifically, if a woman naturally produces testosterone that registers in what sport authorities consider an ‘unnatural’ range, she must suppress that testosterone to compete in women’s events. The testosterone threshold will undoubtedly expand to include cis, intersex, and trans sportswomen, despite their respective and significant differences. Taken together, these types of regulations are confusing and contradictory, quite possibly sexist, and most assuredly ‘wicked’, as Rittel and Webber formulated with regard to ‘wicked problems’. A historical analysis of the regulations for ‘femaleness’ in sport, contextualized with other testosterone-related policies, reveals the impossibility of sex determination, the faulty assertion that testosterone is a ‘male hormone’, and the prioritization of sporting rights over human rights.

Monitoring dehydroepiandrosterone (DHEA) in the urine of Thoroughbred geldings for doping control purposes.

The use of testosterone and its pro-drugs, such as dehydroepiandrosterone (DHEA), is currently regulated in horseracing by the application of international testosterone thresholds. However, additional steroidomic approaches, such as steroid ratios, to distinguish overall adrenal stimulation from drug administrations and an equine biological passport for longitudinal steroid profiling of individual animals could be advantageous in equine doping testing. Thus, DHEA concentrations and related ratios (testosterone [T] to DHEA and DHEA to epitestosterone [E]) were assessed in the reference population by quantitative analysis of 200 post-race gelding urine samples using liquid chromatography-tandem mass spectrometry. DHEA concentrations ranged between 0.9 and 136.6ng/mL (mean 12.8ng/mL), T:DHEA ratios between 0.06 and 1.85 (mean 0.43), and DHEA:E ratios between 0.21 and 13.56 (mean 2.20). Based on the reference population statistical upper limits of 5.4 for T:DHEA ratio and 48.1 for DHEA:E ratio are proposed with a risk of 1 in 10 000 for a normal outlier exceeding the value. Analysis of post-administration urine samples collected following administrations of DHEA, Equi-Bolic® (a mix of DHEA and pregnenolone) and testosterone propionate to geldings showed that the upper limit for T:DHEA ratio was exceeded following testosterone propionate administration and DHEA:E ratio following DHEA administrations and thus these ratios could be used as additional biomarkers when determining the cause of an atypical testosterone concentration. Additionally, DHEA concentrations and ratios can be used as a starting point to establish reference ranges for an equine biological passport.

EAA clinical guideline on management of bone health in the andrological outpatient clinic.

Male osteoporosis is now a well-recognized medical disorder with established clinical guidelines for both diagnosis and management. Prevention as well as management of osteoporosis in men consulting the andrological outpatient clinic because of low testosterone, however, is not well established. This gap of knowledge is-at least partly-explained by the controversy with respect to the threshold of testosterone needed for skeletal maintenance. However, testosterone deficiency may be clearly associated with bone loss as well as frailty in men. If anything, andrologists should therefore be aware of the potential silent presence of osteoporosis in men with confirmed hypogonadism. Therefore, the management of patients with potential hypogonadism should include a complete bone health assessment, besides clinical and biochemical evaluation of gonadal status. Such bone health assessment should include specific items in medical history and physical examination related to fracture risk. Furthermore, dual-energy absorptiometry is indicated to evaluate fracture risk in men with confirmed clinical hypogonadism. Regarding treatment, besides general measures to prevent or manage male osteoporosis testosterone replacement can be initiated (as described in guidelines for hypogonadism), but data on its efficacy in preventing fractures are lacking. Thus, additional anti-osteoporotic may be needed, especially in men with very low testosterone who are at high risk of bone loss and/or in men not able to receive testosterone replacement.

Perioperative hypogonadism in men undergoing radical cystoprostatectomy for bladder cancer.

470 Background: Radical cystectomy (RC) is associated with significant morbidity, and loss of body weight is a common after RC, even in patients without significant nutritional deficiencies. Prior studies have demonstrated a high prevalence of hypogonadism (HG) in men with cancer and who undergo anesthesia/major surgery. The suppression of testosterone persists up to seven days following surgery. We hypothesize that hypogonadism is prevalent in male patients undergoing RC for bladder cancer (BC), and that it persists in the post-operative period. Methods: We implemented a prospective, IRB-approved trial (Clinical trials.gov # NCT03063125) to prospectively enroll 25 men with no prior history of treatment for HG or other hormonal disorders with a new diagnosis of non-metastatic bladder cancer undergoing RC. Pre-operative total, free testosterone and luteinizing hormone (LH) were obtained. These labs were then repeated on post-operative days 2, 3, 30, and 90. The threshold for normal total testosterone was defined as &gt; 250 ng/dl. Demographic data were recorded. Results: Between March and September 2017, 9 patients have been enrolled into the study. Mean patient age is 68.5 years (52-85). The mean pre-operative total testosterone was 247 ng/dl (range 50-496 ng/dl) and 6/9 (66.7%) patients had HG. Two patients had abnormal pre-operative LH levels (range 21-57 mIU/L). Testosterone decreased by a mean of 99 ng/dl between pre-op assessment and post-operative day 2 [95% CI 66.2, 131.8]; all 6 men who initially had HG remained below 250 ng/dl. Two men moved from eugonadal (347 ng/dl, 316 ng/dl) to hypogonadal (213 ng/dl,192 ng/dl, respectively) by post-operative day 2. At 30 days post-op, the mean T level was 206 ng/dl. No patients had returned to levels at or above their pre-operative baseline and 8/9 (88.9%) had HG (range 40-356 ng/dl). Conclusions: Hypogonadism is prevalent in men undergoing RC; our trial demonstrates a pre- and 30 day post-operative prevalence of 66.7% and 88.9%%. Furthermore, HG persisted beyond the immediate post-operative period. Treatment of peri-operative HG with correction to a eugonadal state may represent a therapeutic intervention to reduce the morbidity associated with radical cystectomy. Clinical trial information: NCT03063125.

Testosterone deficiency in adults and corresponding treatment patterns across the globe.

The global prevalence of testosterone deficiency (TD) ranges from 10–40%. The actual diagnosis of TD is controversial, as a wide range of total testosterone (TT) thresholds are used for diagnosis (200–400 ng/dL), and physicians differ in their emphasis placed on clinical symptoms. There are also significant global differences in the prescription patterns of testosterone replacement therapy (TRT). In the United States, prescription of TRT is significantly higher than the rest of the world, increasing 3-fold over the last 10 years and more so in eugonadal men. The majority of treating physicians emphasizes clinical symptomology of TD over laboratory values, and up to one-fourth of their patients do not even have serum testosterone levels. There are significant inter-physician differences in willingness to prescribe TRT in the setting of prostate cancer. Data is scarce on testosterone prescribing patterns in Africa, Asia, and the Middle East. More literature is needed to better characterize how physicians from different regions diagnose TD.

Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer.

Testosterone suppression, or androgen-deprivation therapy (ADT), is an established treatment for recurrent and metastatic prostate cancer (PCa). Based on the accuracy and sensitivity of early assays (c. 1960-1970), the castrate testosterone level was set at ≤1.7 nmol/l. Improved sensitivity of testosterone assays shows that both surgical and medical castration can achieve levels <0.7 nmol/l. However, the clinical implications and importance of maximum testosterone suppression remains a subject of controversy. This evidence-based review assesses prospective and retrospective clinical data, linking maximum suppression of testosterone with improved outcomes from ADT. PubMed and conference proceedings were searched for studies assessing the impact of low testosterone on clinical outcomes from ADT. The key search terms included combinations of prostate cancer and testosterone, predictive/prognostic, and androgen deprivation. Results were limited to studies investigating the relationship between testosterone levels and clinical outcomes. Both prospective and retrospective data support a relationship between testosterone levels below the historical standard of 1.7 nmol/l and improved outcomes. Eight studies showed significant improvements in survival-related outcomes, with the majority of data supporting a testosterone level cutoff of ≤0.7 nmol/l. Tracking both testosterone and prostate-specific antigen (PSA) levels has significant clinical benefits, and the serum testosterone threshold of ≤0.7 nmol/l is a practical goal. The relative levels of testosterone and PSA may indicate continued hormone responsiveness or progression toward castration-resistant prostate cancer (CRPC) and should, therefore, inform treatment strategy. Standardization of assay methods and clinical coordination to facilitate widespread access to state-of the art laboratory equipment is necessary to ensure accurate decision-making.

Testosterone Threshold for Increased Cardiovascular Risk in Middle-Aged and Elderly Men: A Locally Weighted Regression Analysis

IntroductionAlthough testosterone deficiency has a well-known association with increased risk of cardiovascular disease (CVD), the threshold remains to be determined. AimTo investigate whether there is a discriminatory testosterone level below which the CVD risk increases. MethodsThe study included 876 men 45 to 74 years old who underwent a general health checkup. The Framingham Risk Score was used to estimate the 10-year CVD risk; a high-sensitivity C-reactive protein (hsCRP) level of at least 1 mg/L was considered an indicator of increased CVD risk. Aging symptoms and sexual function were evaluated with the Aging Males’ Symptom Scale. Main Outcome MeasuresLocally weighted regression was performed to determine the testosterone threshold for Framingham CVD risk and increased hsCRP. ResultsThe mean age was 56.6 ± 7.0 years. The mean total testosterone level was 394.3 ± 115.7 ng/dL. The mean 10-year Framingham CVD risk was 16.6 ± 10.7%, and 169 (19.3%) had increased hsCRP. The locally weighted regression showed that total testosterone levels of 440 and 480 ng/dL were associated with increased Framingham CVD risk and an increased probability of increased hsCRP, respectively. Men with sexual dysfunction (poor sexual performance, decreased morning erection, and loss of libido) had significantly greater CVD risk. Their risk appeared to increase at a relatively higher testosterone level, and it reached a plateau at a testosterone level of 300 to 350 ng/dL. In contrast, the risk in those with no or less sexual dysfunction remained low at a higher testosterone level, and a threshold level of 425 to 475 ng/dL was associated with increased CVD risk. A similar pattern and threshold were identified in the analyses of the relation between testosterone and hsCRP. ConclusionThese data showed that a testosterone threshold of 440 ng/dL was associated with increased Framingham 10-year CVD risk in middle-aged and elderly men. Poor sexual performance, decreased morning erection, and loss of libido had an impact on the testosterone threshold for CVD risk. The threshold level was higher in men with sexual dysfunction. Further study is required to evaluate the validity of these testosterone thresholds for CVD risk.

Application of testosterone to epitestosterone ratio to horse urine – a complementary approach to detect the administrations of testosterone and its pro‐drugs in Thoroughbred geldings

Detection of testosterone and/or its pro-drugs in the gelding is currently regulated by the application of an international threshold for urinary testosterone of 20 ng/mL. The use of steroid ratios may provide a useful supplementary approach to aid in differentiating between the administration of these steroids and unusual physiological conditions that may result in atypically high testosterone concentrations. In the current study, an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed to quantify testosterone (T) and epitestosterone (E). The method was used to analyze 200 post-race urine samples from geldings in order to generate the ratios for the reference population. Following statistical analysis of the data, an upper limit of 5 for T:E ratio in geldings is proposed. Samples collected from 15 geldings with atypical urinary testosterone concentrations (>15 ng/mL) but otherwise normal steroid profile, had T:E ratios within those observed for the reference population. The applicability of an upper T:E ratio to detect an administration was demonstrated by the analysis of a selection of incurred samples from testosterone propionate, dehydroepiandrosterone (DHEA), and a mixture of DHEA and pregnenolone (Equi-Bolic®) administrations. These produced testosterone concentrations above the threshold of 20 ng/mL, but also T:E ratios above the proposed limit of 5. In conclusion, consideration of the T:E ratio appears to be a valuable complementary aid to evaluate whether an atypical testosterone concentration could be caused by a natural biological outlier as opposed to the administration of these steroids. Copyright © 2016 John Wiley & Sons, Ltd.

Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies.

IntroductionAndrogen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs is a standard treatment for advanced prostate cancer. GnRH analog therapy can reduce testosterone to “castrate” levels, historically defined as <50 ng/dL. With the advent of newer assays, a lower threshold of <20 ng/dL has recently been proposed. We report the results of a retrospective analysis of two Phase III trials of 4- and 6-month depot microsphere formulations of leuprolide acetate (LA), a GnRH agonist that has previously demonstrated efficacy in testosterone suppression to <50 ng/dL in patients on ADT. This analysis investigates the ability of these LA formulations to suppress to ≤20 ng/dL levels.MethodsIn two of five AbbVie/Abbott clinical trials of microsphere formulations of LA for ADT, analytic technology permitting testosterone detection as low as 3 ng/dL was used and thus was selected for this analysis. Both trials were open-label, fixed-dose studies in prostate cancer patients, naïve to ADT. Patients received either 30 mg (4-month formulation; n=49) or 45 mg (6-month formulation; n=151) depot injections of LA microspheres. Treatment duration was up to 32 weeks for the 4-month formulation and 48 weeks for the 6-month formulation. The proportion of patients achieving the 20 ng/dL threshold was determined every 4 weeks.ResultsPooled analysis showed that 152 of 193 (79%) of patients achieved serum testosterone levels of ≤20 ng/dL at 4 weeks, and sustained the improvement at week 24 (169/189, 89%). Additionally, in the 6-month study, 127/135 (94.1%) patients were suppressed to ≤20 ng/dL at 48 weeks.ConclusionBoth 4- and 6-month intramuscular depot formulations of LA achieved and maintained mean serum testosterone levels ≤20 ng/dL in the vast majority of patients as early as 4 weeks following treatment initiation. Additional research on the clinical relevance of this lower testosterone threshold is warranted.

WITHDRAWN: Current opinion in the role of testosterone in the development of prostate cancer: A dynamic model

Abstract Since the landmark studies conducted by Huggins and Hodges in 1941, a failure to distinguish the etiological role of testosterone from its role in prostate cancer progression has led to the prevailing opinion that high levels of testosterone increase the risk of prostate cancer. To date, this claim remains unproven and epidemiological evidence is inconsistent. In this study, we present a novel dynamic model regarding the relationship between testosterone and prostate cancer to advance our understanding of the current findings and to guide future prostate cancer research. In our model, we theorize that it is the magnitude of the age-related declines in testosterone rather than the static level of testosterone measured at a single point that may trigger and promote the development of prostate cancer. After body testosterone falls below a threshold level, the prostate cells cannot maintain their normal functions and eventually some turn into tumor cells. Individual threshold of testosterone may be positively associated with a peak testosterone level of this individual during young adulthood. Our dynamic model can satisfactorily explain the observed age pattern of prostate cancer incidence, the seemingly conflict of findings from epidemiological studies on testosterone and risk of prostate cancer, racial disparities in prostate cancer incidence, many risk factors associated with prostate cancer, and the role of testosterone in prostate cancer growth. Our dynamic model may also have implications for testosterone replacement therapy. We conclude that this dynamic model provides a new perspective to enhance our understanding the role of testosterone in the onset and development of prostate cancer, to guide future studies, and to promote and improve testosterone replacement therapy in prevention of prostate cancer.

Hypotestosteronaemia in the aging male: should we treat it?

The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse and may be genetically determined (e.g. Klinefelter's syndrome) or acquired (tumours, infections, haemochromatosis). Classical hypogonadism linked to an underlying disease, such as a pituitary tumour, is a distinct indication for androgen substitution. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. We searched the literature for randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, and identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.

Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading.

To compare histological feature of prostate cancer (PCa) according androgenic status in patients who underwent radical prostatectomy (RP). Between March 2007 and September 2013, we prospectively analysed 937 patients who were referred to our centre for RP. Clinical, pathological and biological data have been prospectively collected. Preoperative total testosterone (TT) and bioavailable testosterone (BT) serum determinations were carried out. The threshold for low serum testosterone was set at TT<3 ng/ml. Preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern were determined in prostate biopsies and in prostate tissue specimens, crosschecked by two uro-pathologists. Nine hundred and thirty-seven consecutive patients were included. In all, 14.9% patients had low TT in the population. An exact match between biopsy and prostate specimens in GS grading was observed for 50.6% patients (n=474). Also, 40.9% of all patients were upgraded (n=383): 45.3% (n=63) in low serum testosterone patients and 40.1% (n=320) in normal serum testosterone patients. For prostate specimens, the proportion of patients with predominant Gleason pattern 4 was higher in patients with low TT compared with normal TT (41.7% vs 29.1%, P=0.0029). In all, 20.1% were upgraded from predominant Gleason pattern 3 on biopsies specimen to predominant Gleason 4 pattern on the prostate specimen in patients with low TT, whereas 11.6% were upgraded for normal TT patients (P=0.002). Low serum testosterone is an independent risk factor for predominant Gleason pattern 4 on prostate specimen after RP and for upgrading from low- to high-grade cancer between prostate needle biopsies and RP specimen. This observation should be taken into account in localised PCa management, especially for active surveillance or when a nerve-sparing approach is considered.

Identification of late-onset hypogonadism in middle-aged and elderly men from a community of China

In this study, we investigated the essential criteria for late-onset hypogonadism (LOH) syndrome based on the presence of symptoms associated with low testosterone levels in Han Chinese men. Blood tests for total testosterone (TT) and sex hormone–binding globulin (SHBG) were performed, and the aging male symptoms (AMS) questionnaire was conducted in a randomly selected cohort composed of 944 Chinese men aged 40 to 79 years from nine urban communities. Three sexual symptoms (decreased ability/frequency of sexual activity, decreased number of morning erections, and decreased libido) were confirmed to be related to the total and free testosterone levels. The thresholds for TT were approximately 12.55 nmol l−1 for a decreased ability/frequency to perform sex, 12.55 nmol l−1 for decreased frequency of morning erections, and 14.35 nmol l−1 for decreased sexual desire. The calculated free testosterone (CFT) thresholds for these three sexual symptoms were 281.14, 264.90, and 287.21 pmol l−1, respectively. TT <13.21 nmol l−1 (OR = 1.4, 95%CI: 1.0–1.9, P = 0.037) or CFT <268.89 pmol l−1 (OR = 1.5, 95%CI: 1.1–20, P = 0.020) was associated with an increase in the aforementioned three sexual symptoms. The prevalence of LOH was 9.1% under the criteria, including all three sexual symptoms with TT levels <13.21 nmol l−1 and CFT levels <268.89 pmol l−1. Our results may improve the diagnostic accuracy of LOH in older men.