The Effect of Gender-Affirming Hormone Therapy on Measures of Kidney Function: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Gender-affirming hormone therapy modifies body composition and lean muscle mass in transgender persons. We sought to characterize the change in serum creatinine, other kidney function biomarkers, and GFR in transgender persons initiating masculinizing and feminizing gender-affirming hormone therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov from inception to September 16, 2020 for randomized controlled trials, observational studies, and case series that evaluated the change in serum creatinine, other kidney function biomarkers, and GFR before and after the initiation of gender-affirming hormone therapy in adult transgender persons. Two reviewers independently screened and abstracted data, and disagreements were resolved by a third reviewer. A random effects meta-analysis was performed to determine the change in outcomes over follow-up of 3, 6, and 12 months. RESULTS: Of the 4758 eligible studies, 26 met the inclusion criteria, including nine studies that recruited 488 transgender men and 593 women in which data were meta-analyzed. There was heterogeneity in study design, populations, gender-affirming hormone therapy routes, and dosing. At 12 months after initiating gender-affirming hormone therapy, serum creatinine increased by 0.15 mg/dl (95% confidence interval, 0.00 to 0.29) in 370 transgender men and decreased by -0.05 mg/dl (95% confidence interval, -0.16 to 0.05) in 361 transgender women. No study reported the effect of gender-affirming hormone therapy on albuminuria, proteinuria, cystatin C, or measured GFR. CONCLUSIONS: Gender-affirming hormone therapy increases serum creatinine in transgender men and does not affect serum creatinine in transgender women. The effect on gender-affirming hormone therapy on other kidney function biomarkers and measured GFR is unknown. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Change in Kidney Function Biomarkers in Transgender Persons on Gender Affirmation Hormone Therapy-A Systematic Review and Meta-Analysis, CRD42020214248.

Chronic Kidney Disease in the Transgender, Nonbinary, or Gender Diverse Person.

Nephrologists are increasingly providing care to transgender, nonbinary, and gender diverse (TNBGD) individuals with chronic kidney disease. This narrative review discusses the care of TNBGD individuals from a nephrology perspective. TNBGD individuals are under-represented in the nephrology literature. TNBGD individuals are at an increased risk of adverse outcomes compared with the cisgender population including mental health, cardiovascular disease, malignancy, sexually transmitted infections, and mortality. Gender-affirming hormone therapy (GAHT) with estradiol in transfeminine individuals potentially increases the risk of venous thromboembolism and cardiovascular disease. GAHT with testosterone in transmasculine individuals potentially increases the risk of erythrocytosis and requires careful monitoring. GAHT modifies body composition and lean muscle mass, which in turn influence creatinine generation and excretion, which may impact the performance of estimated glomerular filtration rate (GFR) equations and the estimation of 24-hour urine values from spot urine albumin/protein to creatinine ratios. There are limited studies regarding TNBGD individuals with chronic kidney disease. Additional research is needed to evaluate the effects of GAHT on GFR and biomarkers of kidney function and the performance of the estimated GFR equation in TNBGD populations.

Genetics of hypogonadotropic hypogonadism.

Male congenital hypogonadotropic hypogonadism (CHH) is a heterogenous group of genetic disorders that cause impairment in the production or action of gonadotropin releasing hormone (GnRH). These defects result in dysfunction of the hypothalamic-pituitary-gonadal hormone axis, leading to low testosterone levels and impaired fertility. Genetic testing techniques have expanded our knowledge of the underlying mechanisms contributing to CHH including over 30 genes to date implicated in the development of CHH. In some cases, non-reproductive signs or symptoms can give clues as to the putative genetic etiology, but many cases remain undiagnosed with less than 50% identified with a specific gene defect. This leads to many patients labelled as "idiopathic hypogonadotropic hypogonadism". Medical and family history as well as physical exam and laboratory features can aid in the identification of hypogonadotropic hypogonadism (HH) that is associated with specific medical syndromes or associated with other pituitary hormonal deficiencies. Genetic testing strategies are moving away from the classic practice of testing for only a few of the most commonly affected genes and instead utilizing next generation sequencing techniques that allow testing of numerous potential gene targets simultaneously. Treatment of CHH is dependent on the individual's desire to preserve fertility and commonly include human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) to stimulate testosterone production and spermatogenesis. In situations where fertility is not desired, testosterone replacement therapies are widely offered in order to maintain virilization and sexual function.

Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis.

OBJECTIVE: To assess the relative effects of individual testosterone products among hypogonadal men. DESIGN: Systematic review and network meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for ≥3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane's risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS). RESULTS: Eighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) -0.26, 95% CI -0.41 to -0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD -0.23, 95% CI -0.44 to -0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs. CONCLUSION: Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer-term high-quality trials are needed to fully assess the risk of harm. PROSPERO REGISTRATION NUMBER: CRD42014009963.

A survey of Canadian urologists' opinions and prescribing patterns of testosterone replacement therapy in men on active surveillance for low-risk prostate cancer.

INTRODUCTION: Attitudes regarding the safety of testosterone replacement therapy (TRT) in hypogonadal men with prostate cancer (PCa) have changed over the past few years with the emergence of case studies suggesting a low risk of cancer progression and a better understanding of the interaction of different levels of androgen with prostate cellular metabolism. This new view has the potential to change clinical practice. METHODS: Active members of the Canadian Urological Association were surveyed about their opinions on the safety of TRT in men with low-risk PCa, as well as their current prescribing habits. RESULTS: Of 57 responding urologists, 86% actively prescribe TRT in men with testosterone deficiency syndrome (TDS), 93% are involved in the treatment of men with PCa, and 95% offer active surveillance as a management option for low-grade/low-stage disease. Furthermore, 65% stated that they would offer TRT to men with TDS who were on active surveillance for PCa and 63% believed that TRT did not increase the risk of progression of PCa in these men. In terms of treatment methods, 96% believed TRT was safe for men who have undergone radical prostatectomy, while a smaller number felt it was safe for patients who have undergone brachytherapy (86%) or external beam radiation (84%). Despite these figures, only 35% of the surveyed physicians had ever offered TRT for men on active surveillance and only 42% actually had men in their practice who were taking testosterone while on active surveillance. CONCLUSIONS: The discrepancy between urologists' beliefs about the safety of TRT and their clinical practice patterns may be due to multiple factors, such as hesitation in recommending treatment in real-life practice, low numbers of eligible patients, absence of screening for testosterone deficiency in patients on active surveillance, and patient preference or fears. Furthermore, the difference in perceived safety in men treated by radical prostatectomy vs. radiation therapy suggests that some urologists are concerned that the radiated gland remaining in-situ may be "reactivated" by TRT. The results from this survey will be used as the basis of developing a national Canadian registry of men with low-grade/stage PCa who are receiving TRT while on active surveillance.

Predicting low testosterone in aging men: a systematic review.

BACKGROUND: Physicians diagnose and treat suspected hypogonadism in older men by extrapolating from the defined clinical entity of hypogonadism found in younger men. We conducted a systematic review to estimate the accuracy of clinical symptoms and signs for predicting low testosterone among aging men. METHODS: We searched the MEDLINE and Embase databases (January 1966 to July 2014) for studies that compared clinical features with a measurement of serum testosterone in men. Three of the authors independently reviewed articles for inclusion, assessed quality and extracted data. RESULTS: Among 6053 articles identified, 40 met the inclusion criteria. The prevalence of low testosterone ranged between 2% and 77%. Threshold testosterone levels used for reference standards also varied substantially. The summary likelihood ratio associated with decreased libido was 1.6 (95% confidence interval [CI] 1.3-1.9), and the likelihood ratio for absence of this finding was 0.72 (95% CI 0.58-0.85). The likelihood ratio associated with the presence of erectile dysfunction was 1.5 (95% CI 1.3-1.8) and with absence of erectile dysfunction was 0.83 (95% CI 0.76-0.91). Of the multiple-item instruments, the ANDROTEST showed both the most favourable positive likelihood ratio (range 1.9-2.2) and the most favourable negative likelihood ratio (range 0.37-0.49). INTERPRETATION: We found weak correlation between signs, symptoms and testosterone levels, uncertainty about what threshold testosterone levels should be considered low for aging men and wide variation in estimated prevalence of the condition. It is therefore difficult to extrapolate the method of diagnosing pathologic hypogonadism in younger men to clinical decisions regarding age-related testosterone decline in aging men.

Functional cardiac paraganglioma associated with a rare SDHC mutation.

Paragangliomas are catecholamine-secreting tumors external to the adrenal glands, most commonly arising in the head and neck, followed by the abdominal and thoracic cavities. The heart is a rare location for paragangliomas to originate from, with fewer than 50 cases as described in the literature. Functional paragangliomas of the right atrium are even more unusual, with only five cases reported to date. The investigations and therapies of a 41-year-old male presenting with a clinically functional cardiac paraganglioma are discussed. We performed a detailed pathology review of the primary cardiac tumor and a lung nodule to examine morphologic changes, along with an immunohistochemical profile (chromogranin A, tyrosine hydroxylase, MIB-1, and succinate dehydrogenase subunit B (SDHB)) of both tumors. Genetic testing of germline mutations in SDH genes was also completed. Both the 9.5-cm cardiac mass and 0.5-cm lung nodule were positive for chromogranin A and tyrosine hydroxylase and showed a global loss of SDHB expression. The MIB-1 labeling index of the smaller lesion and the bulk of the larger lesion was <5 %, but there were cellular foci of the larger lesion that had a labeling index of 10%. Genetic testing yielded an intronic frameshift mutation in the SDHC gene, c.IVS 5 + 1, G > A. We report the first case of a functional cardiac paraganglioma associated with an intronic frameshift SDHC gene mutation.