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Background: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain., Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports., Results: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided., Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objectives: Anaemia is a key cause of morbidity in chronic kidney disease (CKD). Androgen deficiency (AD) in males can contribute to anaemia of all causes, including in CKD. We sought to examine the prevalence of AD in men with CKD, the extent to which it contributed to anaemia and whether it was independently associated with long-term survival., Methods: This cross-sectional observational study was conducted among males aged 18 years and over with CKD stages 4 and 5. The study analysed morning blood samples with regard to their full blood count, urea and electrolytes, albumin, lipids, testosterone (T) and sex hormone binding globulin, with calculation of free testosterone by mass action equation. Mortality data were obtained 15 years later for survival analysis., Results: Among 322 patients with a mean age of 63 years, the overall prevalence of AD was 68.9%. There was a statistically significant negative correlation between erythropoiesis stimulating agent (ESA) dose and testosterone concentrations (Pearson correlation -0.193, p = 0.05). There was a positive correlation between haemoglobin (Hb) and free testosterone level among patients not on ESA therapy (Pearson correlation 0.331, p < 0.001). Kaplan-Meier plots showed p < 0.001 on log-rank analysis, indicating that AD was significantly associated with worse survival. However, in Cox regression analysis, free testosterone was not associated with survival (95% CI for free testosterone 0.997-1.000)., Conclusions: AD is highly prevalent among this population, and increases further with older age and more severe CKD warranting haemodialysis. Association of lower Hb and higher ESA dose with lower T concentration might be causative, which has important pharmaco-economic as well as clinical implications. Lower survival in men with low T, more likely reflects overall poor health rather than causation. A properly constituted randomised controlled study evaluating the effect of native T replacement is warranted in men with CKD and AD., (© 2024 John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

This review assesses the evidence of the physiological effects of testosterone on cardiovascular health, the association between male hypogonadism and cardiovascular health, and the effects of testosterone therapy on cardiovascular health in male hypogonadism. Preclinical studies suggest complex effects of testosterone on cardiovascular risk by acting on skeletal muscle, cardiomyocytes, vasculature, adipocytes, insulin action, and erythropoiesis. Furthermore, low testosterone has a bi-directional association with cardiometabolic risk. Observational studies have reported worse metabolic profiles in men with organic hypogonadism. However, a consistent association between major cardiovascular events and male hypogonadism has not been established. Hematocrit increases with testosterone therapy; however, most studies do not report an increase in venous thromboembolism risk. Although some observational studies and a small randomized controlled study reported an increased risk of cardiovascular disease, recent data confirm the medium-term cardiovascular safety of testosterone therapy in middle-aged and older men with low testosterone., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. Health optimisation remains the gold-standard management strategy. Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism. Although testosterone improves bone mineral density and insulin sensitivity in these men, trials from the last decade suggest insufficient evidence to determine the safety and effectiveness of use of this hormone for the prevention of fractures or type 2 diabetes. This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition., Competing Interests: Declaration of interests MG has received research funding from Bayer and Otsuka; and speaker's honoraria from Besins, Health Care, and Novartis. LA participated in advisory boards for Androlabs, Merck, and Galapagos; and receives a senior clinical research fellowship from Research foundation Flanders (1800923N). RQ participated in an advisory board for Roche Diagnostics. CNJ received investigator-led grants from Logixx Pharma; and received a National Institute for Health and Care Research post-doctoral fellowship. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Identifying metabolic and cardiovascular risks of gender-affirming hormone therapy (GAHT) is challenging due to other confounding variables that affect patient outcomes and the diversity of treatment regimes. Masculinising hormone therapy produces atherogenic lipid profiles, while effects on other metabolic parameters are not consistent. There is insufficient evidence to conclude if cardiovascular disease risk among transmen is increased. The effects of feminising hormone therapy on metabolic parameters do not demonstrate a consistent pattern in the available literature. However, the risk of venous thromboembolism is greater in transwomen than in cis-gender men and women with a possible increase in cardiovascular disease risk. It is recommended to discuss the potential effects of GAHT on cardiovascular health and encourage patients seeking GAHT to adopt a healthy lifestyle. Performing baseline and periodic assessments of cardiovascular risk factors would enable early identification and interventions. In high-risk individuals, the cardiovascular effects of hormonal regimes might impact the treatment decision., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Morbidity management of filarial lymphedema remains a challenge even during the post-lymphatic filariasis elimination era in Sri Lanka despite provision of the predominantly hygiene-based WHO Essential Package of Care. Because prior studies have suggested that 6 weeks of doxycycline may reduce progression of limb lymphedema, we conducted a randomized, placebo-controlled, superiority study to evaluate this possibility in Sri Lanka. Patients aged 14 to 65 years with lymphedema in one or both legs received either 200 mg of doxycycline daily for 6 weeks or matching placebo. The primary efficacy endpoint was improvement or lack of progression in lymphedema stage at 24 months postenrollment. Secondary endpoints included change in lymphedema stage at 12 and 24 months, frequency of acute adenolymphangitis episodes, and perceived disability measured by the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Training and supplies for limb hygiene were provided throughout the study. Two hundred participants (100 in each arm) with lymphedema of Dreyer stages 1 to 3 were enrolled. By the end of the 2-year study, 29% of the doxycycline patients and 34% of those on placebo showed improvement (i.e., a decrease in lymphedema stage), whereas 11% and 15% of the two groups showed worsening of the lymphedema. Adenolymphangitis rates were comparable in the two groups (43 doxycycline and 38 placebo recipients), although attacks lasted slightly longer in placebo patients (6.5 days versus 5.2 days). In both groups, perceived disability improved initially, with partial rebound in the second year. Only 34 adverse events affecting 24 patients (11%) occurred during the 6-week treatment period. Although doxycycline did not significantly impact lymphedema progression in this study, the results clearly indicate that clinical and personal benefits can be obtained from intensive hygiene management alone.

We aimed to estimate the proportions of childhood parental neglect, abuse, and rejection and to evaluate the co-occurrence of these experiences among transgender women in Rio de Janeiro, Brazil. This was a cross-sectional study with a convenience sample enrolled between July 2019 and March 2020, using an adapted version of the Childhood Trauma Questionnaire. Proportions and corresponding confidence intervals (CI) were calculated. Kendall correlation with Tau-b estimator was used in the bivariate analyses. We gathered data from 139 participants. The most prevalent types of childhood traumas were emotional abuse (60.43%, 95% CI [51.79, 68.62]), physical abuse (57.55%, 95% CI [48.90, 65.89]) and sexual abuse (44.60%, 95% CI [36.18, 53.27]). Severe to extreme physical and emotional abuse occurred among 40.29% (95% CI [32.06, 48.93]) and 5.75% (95% CI [2.51, 11.02]) of participants, respectively. The proportion of parental rejection (eviction) was 32.37% (95% CI [25.04, 40.69]) and occurred with the other forms of abuse, except sexual abuse. Multiple types of childhood abuse, neglect, and parental rejection were observed among transgender women in our sample. The harmful effects of childhood abuse on the mental and physical health of people in the transgender population are of concern, particularly considering the cumulative effect produced by the co-occurrence of such events and their harmful lifetime effects. It is urgently necessary to debate and formulate public policies to ensure the right to gender expression from childhood., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

In visceral and mucocutaneous leishmaniasis, humoral immune response can reflect disease severity and parasite burden. Cutaneous leishmaniasis (CL) in Sri Lanka is caused by a usually visceralizing parasite, Leishmania donovani. We assessed the parasite burden (relative quantity-RQ) in 190 CL patients using quantitative real-time PCR (qPCR-with primers designed for this study) and smear microscopy, then correlated it with clinical parameters and IgG response. RQ of parasite DNA was determined with human-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the internal control. The qPCR sensitivity was tested with serially diluted DNA from cultured L. donovani parasites. Smears were assigned a score based on number of parasites per high power field. Data from previous studies were used for comparison and correlation; nested Internal Transcribed Spacer 1 (ITS1) PCR as reference standard (RS) and IgG antibody titers to the Leishmania rKRp42 antigen as the immune response. The qPCR amplified and quantified 86.8% of the samples while demonstrating a fair and significant agreement with ITS1-PCR and microscopy. Parasite burden by qPCR and microscopy were highly correlated (r = 0.76; p = 0.01) but showed no correlation with the IgG response (r = 0.056; p = 0.48). Corresponding mean RQs of IgG titers grouped by percentiles, showed no significant difference (p = 0.93). Mean RQ was higher in early lesions (p = 0.04), decreased with lesion size (p = 0.12) and slightly higher among papules, nodules and wet ulcers (p = 0.72). Our study established qPCR's efficacy in quantifying parasite burden in Sri Lankan CL lesions but no significant correlation was observed between the parasite burden and host IgG response to the Leishmania rKRP42 antigen., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context: Clinical endocrinology encompasses many diseases requiring long-term drug therapy. Prohibitive pricing of some endocrine drugs classified as essential by the World Health Organization has created suboptimal care of patients with endocrine disorders., Evidence Acquisition: This review is based on evidence obtained from several databases and search engines including PubMed, Google, and Google Scholar; reference searches; manual searching for web pages of international regulatory bodies; and the authors' experience from different healthcare settings., Evidence Synthesis: After the expiry of a patent, generic versions with the opportunity for increased availability and a price reduction are expected. There are access barriers worldwide for many off-patent endocrine drugs. The high price is the main issue for several medicines including insulin, hydrocortisone, testosterone, and gonadotropins. This is caused by several factors including the market monopoly due to the lack of registered generics or suppliers limiting the benefit of competition and a complex supply chain. Additionally, the lack of some medicines has been concerning due to market factors such as the relatively small number of patients, making it less attractive for the manufacturers. Commissioning of nonprofit manufacturers and state manufacturing as well as strict price control measures could alleviate this situation., Conclusion: Lack of availability and disproportionate price inflation affecting essential off-patent endocrine therapies is common due to several interrelated factors. Global collaboration among healthcare organizations with the support of policymaking bodies might be needed to mitigate this., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

The WHO-recommended essential package of care (EPC) for filarial limb lymphedema consists of daily limb washing, entry lesion management, limb protection, exercises, and elevation. Decongestive therapy (DT) with compression bandaging by trained lymphedema therapists adds additional benefit but is unavailable for most in low- and middle-income countries (LMICs). To determine whether DT using self-adjustable, short-stretch compression garments (SSCG), prefitted using portable, three-dimensional infrared imaging (3DII), would be effective and feasible in LMIC settings, we conducted a pilot 6-week, interventional, single-group, open-label pilot study in Galle, Sri Lanka. Ten participants with Dreyer stage 3 lymphedema used SSCG for 2 weeks after a 4-week lead-in EPC period. Effect of EPC and compression on quality of life was assessed using the 12-item WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Median participant age was 73 years (range: 32-85 years). Median percent limb volume reduction due to compression was 11.3% (range: 1.1-27.2%). WHODAS 2.0 scores did not change significantly between enrollment and study end. Garment acceptability was high throughout the study. These results provide proof of concept for 3DII-enabled SSCG in LMICs where trained therapists for filarial lymphedema may not be available.

A 45-year-old woman presented with sudden complete vision loss in her left eye and retroorbital pain worsened by eye movements. A previous milder episode of vision loss had occurred in the same eye 1 year before, with complete recovery after high-dose intravenous methylprednisolone. She had no light perception in the left eye with a swollen optic disc, but with a normal right optic disc. There were no systemic manifestations or infections. MR scan of the brain showed extensive enlargement and enhancement of the left optic nerve and optic chiasm. After excluding infections and autoimmune markers, a left optic nerve biopsy confirmed non-caseating granulomas, leading to a diagnosis of neurosarcoidosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment., Methods: A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios., Results: Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality., Conclusions and Future Research: Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion., (© 2024 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism., Objectives: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism., Materials and Methods: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE., Results: Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I 2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I 2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m 2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found., Discussion and Conclusion: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Near infrared (NIR) spectroscopy is a valuable analytical technique for monitoring chemical composition of powder blends in continuous pharmaceutical processes. However, the variation in density captured by NIR during spectral collection of dynamic powder streams at different flow rates often reduces the performance and robustness of NIR models. To overcome this challenge, quantitative NIR measurements are commonly collected across all potential manufacturing conditions, including multiple flow rates to account for the physical variations. The utility of this approach is limited by the considerable quantity of resources required to run and analyze an extensive calibration design at variable flow rates in a continuous manufacturing (CM) process. It is hypothesized that the primary variation introduced to NIR spectra from changing flow rates is a change in the density of the powder from which NIR spectra are collected. In this work, powder stream density was used as an efficient surrogate for flow rate in developing a quantitative NIR method with enhanced robustness against process rate variation. A density design space of two process parameters was generated to determine the conditions required to encompass the apparent density and spectral variance from increases in process rate. This apparent density variance was included in calibration at a constant low flow rate to enable the development of a density-insensitive NIR quantitative model with limited consumption of materials. The density-insensitive NIR model demonstrated comparable prediction performance and flow rate robustness to a traditional NIR model including flow rate variation ("gold standard" model) when applied to monitoring drug content in continuous runs at varying flow rates. The proposed platform for the development of in-line density-insensitive NIR methods is expected to facilitate robust analytical model performance across variable continuous manufacturing production scales while improving the material efficiency over traditional robust modeling approaches for calibration development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carl A. Anderson reports administrative support and equipment, drugs, or supplies were provided by Duquesne University. Carl A. Anderson reports a relationship with Duquesne University that includes: employment. Carl A. Anderson has patent pending to Duquesne University., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Near-infrared (NIR) spectroscopy is a powerful process analytical tool for monitoring chemical constituents in continuous pharmaceutical processes. However, the density variation introduced when quantitative NIR measurements are performed on powder streams at different flow rates is a potential source of a lack of model robustness. Since different flow rates are often required to meet the production requirements (e.g., during scale-up) of a continuous process, the development of efficient strategies to characterize, understand, and mitigate the impact of powder density on NIR measurements is highly desirable. This study focused on assessing the effect of powder physical variation on NIR by enabling the in-line characterization of powder stream density in a simulated continuous system. The in-line measurements of powder stream density were facilitated through a unique analytical interface to a flowing process. Powder streams delivered at various design levels of flow rate and tube angle were monitored simultaneously by NIR diffuse reflectance spectroscopy, live imaging, and dynamic mass characterization. Statistical analysis and multivariate modeling confirmed powder density as a significant source of spectral variability due to flow rate. Besides providing broader process understanding, results elucidated potential mitigation strategies to facilitate effective continuous process scale-up while ensuring NIR model robustness against density., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)