Cost-effectiveness of testosterone treatment utilising individual patient data from randomised controlled trials in men with low testosterone levels.

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.

Efficacy and safety assessment of traditional Chinese medicine for erectile dysfunction: A meta-analysis and trial sequential analysis.

BACKGROUND: Several patients with erectile dysfunction do not accept or benefit from conventional therapy with phosphodiesterase type 5 inhibitors; thus, alternative and complementary therapies are in need. Traditional Chinese medicine has been treating erectile dysfunction in China, but its clinical value is inconclusive. OBJECTIVE: To systematically evaluate the efficacy and safety of traditional Chinese medicine in treating erectile dysfunction. METHODS: Randomized controlled trials were retrieved from a comprehensive search in the literature published in the past decade from the Web of Science, PubMed, Embase, Cochrane Library, SinoMed, China National Knowledge Internet, WanFang, and VIP. We performed a meta-analysis of the International Index of Erectile Function 5 questionnaire scores, clinical recovery rates, and testosterone levels using Review Manager 5.4 software. The trial sequential analysis was conducted to check the results. RESULTS: A total of 45 trials with 5016 patients were included. Meta-analysis results showed that traditional Chinese medicine effectively improved the International Index of Erectile Function 5 questionnaire scores (weighted mean difference = 3.78, 95% confidence interval: 3.12, 4.44; p < 0.001), clinical recovery rates (risk ratio = 1.57, 95% confidence interval: 1.38, 1.79; p < 0.001), testosterone levels (weighted mean difference = 2.42, 95% confidence interval: 1.59, 3.25; p < 0.001) compared with the controls. The single and add-on applications of traditional Chinese medicine could improve the International Index of Erectile Function 5 questionnaire score (p < 0.001). The trial sequential analysis confirmed the robustness of the analysis of the International Index of Erectile Function 5 questionnaire scores. A significant difference in the incidence of adverse effects between the treatment and control groups was not observed (risk ratio = 0.82, 95% confidence interval: 0.65, 1.05; p = 0.12). CONCLUSION: Traditional Chinese medicine can gain better responses in improving the International Index of Erectile Function 5 questionnaire scores, clinical recovery rates, and testosterone levels as an alternative and complementary treatment, with no increase in side effects. However, more standardized, long-term, traditional Chinese medicine and integrative therapy clinical trials are needed to support the clinical application of traditional Chinese medicine.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Incidence, Contributing Factors, and Implications for Clinical Management of Polycythemia in Transmasculine Patients on Testosterone.

Purpose: The goal of this study was to evaluate contributing factors and management strategies for polycythemia in transmasculine patients on testosterone therapy. Methods: A retrospective analysis of medical records was performed for transmasculine patients on testosterone for at least 12 months. Data collected from each patient included age, body mass index (BMI), nicotine dependence, pulmonary disease status, obstructive sleep apnea (OSA) status, oophorectomy status, and testosterone route of administration. For patients who developed polycythemia, polycythemia management strategy data were collected. Results: Five-hundred-eleven patients were evaluated and 113 (22%) experienced an episode of polycythemia. Within the polycythemia group, 77% of patients were younger than age 40, 56% had a BMI >30.0, 44% had current or former nicotine dependence, 12% had a pulmonary disease, 12% had OSA, and 47% had received an oophorectomy. The polycythemia group had a significantly higher average age, BMI, and dose of testosterone, and also had a higher proportion of patients with OSA and an oophorectomy. Conclusion: These results revealed that polycythemia is a common side effect for transmasculine patients on testosterone. Importantly, previous oophorectomy may be associated with polycythemia which appears to be a novel finding. This finding requires further research but provides the potential to be an important screening consideration for transmasculine patients after oophorectomy. Polycythemia will continue to be a major concern for patients on testosterone therapy, and this study provided important information for clinical practice and future research that will lead to improved outcomes.

Characterising body composition and bone health in transgender individuals receiving gender-affirming hormone therapy.

BACKGROUND: Gender-affirming hormone therapy (GAHT) is prescribed to produce secondary sex characteristics aligning external anatomy with gender identity to mitigate gender dysphoria. Transgender women are generally treated with oestrogens and anti-androgens, whereas transgender men are treated with testosterone. The objective of this narrative review was to characterise the influence of GAHT on body composition and bone health in the transgender population to help address weight concerns and chronic disease risk. METHODS: Studies were extracted from PubMed and Scopus and limited to only those utilising imaging technologies for precise adipose tissue, lean mass, and bone mineral density (BMD) quantification. RESULTS: Although methodologies differed across the 20 investigations that qualified for inclusion, clear relationships emerged. Specifically, among transgender women, most studies supported associations between oestrogen therapy and decreases in lean mass and increases in both, fat mass and body mass index (BMI). Within transgender men, all studies reported associations between testosterone therapy and increases in lean mass, and although not as consistent, increases in BMI and decreases in fat mass. No consistent changes in BMD noted for either group. CONCLUSIONS: Additional research is needed to appropriately assess and evaluate the implications of these body composition changes over time (beyond 1 year) in larger, more diverse groups across all BMI categories. Future studies should also seek to evaluate nutrient intake, energy expenditure and other important lifestyle habits to diminish health disparities within this vulnerable population. Policies are needed to help integrate registered dietitians into the routine care of transgender individuals.

Prescribing Isotretinoin for Transgender Patients: A Call to Action and Recommendations.

Case Scenerio: A 26-year-old patient presents to the dermatology clinic with severe nodulocystic scarring acne. The patient identifies as a transgender male and notes that he has been receiving hormone replacement therapy for the past 4 years with weekly intramuscular testosterone injections.

Care of the Transgender Patient.

Transgender persons are a diverse group whose gender identity differs from their sex recorded at birth. Some choose to undergo medical treatment to align their physical appearance with their gender identity. Barriers to accessing appropriate and culturally competent care contribute to health disparities in transgender persons, such as increased rates of certain types of cancer, substance abuse, mental health conditions, infections, and chronic diseases. Thus, it is important that clinicians understand the specific medical issues that are relevant to this population.

Management of Hypogonadism in Cardiovascular Patients: What Are the Implications of Testosterone Therapy on Cardiovascular Morbidity?

Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.

Compounded Testosterone Troches TO OPTIMIZE HEALTH AND THE TESTOSTERONE CONTROVERSY.

As men age, testosterone levels progressively fall and inflammatory biomarkers increase. The gradual decline in testosterone production with aging, known as andropause, is common and may have deleterious effects on men including decreased overall well-being, increased sarcopenia, increased risk of cardiovascular disease, reduced sexual function, and bone loss. Therefore, it comes as no surprise that an increasing number of men worldwide have begun requesting testosterone replacement therapy from their physicians. Occasionally, physicians discourage male patients from getting testosterone replacement therapy based on a few recent studies indicating the therapy causes cardiovascular events, including myocardial infarctions. Yet, an extensive review of the testosterone replacement therapy literature reveals that the majority of clinical studies show that properly administered testosterone replacement therapy, in which estradiol and dihydrotestosterone levels are also controlled, has no adverse effects on myocardial infarction risk. The current state-of-the-art in testosterone replacement therapy comprises compounded testosterone troches; an aromatase inhibitor, such as generic Anastrazole, to control estradiol levels; and a 5α-reductase inhibitor, such as beneric Dutasteride or Finasteride, to control dihydrotestosterone. Compounded testosterone troches easily raise serum testosterone levels to the optimal range, are highly cost effective at $82 for a 180-day supply, and provide affordable access to testosterone replacement therapy to millions of men requesting it. Yet, the Blue Cross Blue Shield-associated firms have largely denied requests for coverage of compounded medications, including testosterone troches. Despite data demonstrating strong links between testosterone deficiency and significant comorbid conditions (including Type 2 diabetes and other metabolic syndrome diseases) as well as the health benefits of testosterone replacement therapy, some physian have been swayed against prescribing testosterone replacement therapy to their aging male patients. The testosterone controversy stems largely from poorly designed clinical studies in which patients were subjected to testosterone replacement therapy without having their estradiol and dihydrotestosterone levels properly controlled.

Testosterone replacement therapy and the internet: an assessment of providers' health-related web site information content.

OBJECTIVE: To compare how providers of testosterone replacement therapy (TRT) in large metropolitan cities promote androgen replacement on their patient-oriented Web sites. MATERIALS AND METHODS: TRT provider Web sites were identified using Google search and the terms "Testosterone replacement" and the name of the 5 most populous US cities. These Web sites were assessed for (1) type or specialty of medical provider, (2) discussion of the benefits and risks of TRT, and (3) industry affiliations. RESULTS: In total, 75 Web sites were evaluated. Twenty-seven of the 75 clinics (36%) were directed by nonphysicians, 35 (47%) were overseen by nonurology or nonendocrine physicians, and only 13 (17%) were specialist managed. Fourteen of 75 (18.6%) Web sites disclosed industry relationships. Ninety-five percent of Web sites promoted the benefits of TRT including improved sex drive, cognitive improvement, increased muscle strength, and/or improved energy. Only 20 of 75 Web sites (26.6%) described any side effect of TRT. Web sites directed by specialists were twice as likely to discuss risks of TRT compared with nonspecialist providers (41% vs 20%; odds ratio = 2.77; P <.01). Nine of 75 (12%) of all Web sites actually refuted that TRT was associated with significant side effects. CONCLUSION: Urologists and endocrinologists are in the minority of providers promoting TRT on the Internet. Specialists are more likely to discuss risks associated with TRT although the majority of surveyed Web sites that promote TRT do not mention treatment risks. There is substantial variability in quality and quantity of information on provider Web sites, which may contribute to misinformation regarding this prevalent health issue.

Lean tissue mass and energy expenditure are retained in hypogonadal men with spinal cord injury after discontinuation of testosterone replacement therapy.

OBJECTIVE: To determine whether favorable changes to lean tissue mass (LTM), resting energy expenditure (REE), and testosterone (T) that occurred with 12 months of physiological testosterone replacement therapy (TRT) were retained 6 months after discontinuing treatment. DESIGN: Prospective, open-label, controlled drug intervention trial. SETTING: Metropolitan area hospitals. SUBJECTS: Eugonadal (n = 11) and hypogonadal (n = 13) men with chronic spinal cord injury (SCI). INTERVENTIONS: Hypogonadal subjects received a 5 or 10 mg transdermal T patch daily for 12 months, with adjustment of the dose to normalize the serum T concentration; TRT was discontinued after 12 months (TRT-12M) and subjects were followed for an additional 6 months and re-evaluated (Post-TRT). Total body dual energy X-ray absorptiometry and blood draws were performed at baseline (BL) prior to TRT, TRT-12M, and Post-TRT. Eugonadal subjects did not receive treatment and were evaluated at comparable time points. RESULTS: There were no significant differences between groups prior to TRT at BL for any of the study endpoints. In the hypogonadal group, a significant increase in LTM was observed from BL to TRT-12M (50.2 ± 7.4 vs. 52.9 ± 6.8 kg, P < 0.01), which persisted Post-TRT compared to BL (52.2 ± 7.8 kg, P < 0.05). The increase in REE from BL to TRT-12M (1283 ± 246 vs. 1410 ± 250 kcal/day) was also retained at Post-TRT (1393 ± 220 kcal/day). These sustained improvements in LTM and REE after termination of anabolic hormonal therapy may be associated with persistent beneficial effects on health and physical function of hypogonadal men with chronic SCI.

Assessment and management of male androgen disorders: an update.

BACKGROUND: Male hypogonadism, caused by intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis, is an under-diagnosed condition not to be missed. By contrast, late onset hypogonadism (LOH), due to functional suppression of the HPT axis from age-related comorbidities, may be less common than previously believed. OBJECTIVE: This article outlines the aetiology, clinical features, investigation and management of male hypogonadism and discusses the more controversial area of LOH. DISCUSSION: Pathologically based hypogonadism is, after a thorough diagnostic work-up, treated with testosterone replacement therapy, unless fertility is desired. LOH with modest reductions in testosterone levels should primarily be managed by attention to lifestyle measures, especially weight loss, and optimisation of comorbidities. Clear treatment goals should be identified, and efficacy and safety should be monitored according to published clinical practice guidelines.

Is testosterone replacement therapy in males with hypogonadism cost-effective? An analysis in Sweden.

INTRODUCTION: Testosterone replacement therapy (TRT) has been recommended for the treatment of primary and secondary hypogonadism. However, long-term implications of TRT have not been investigated extensively. AIM: The aim of this analysis was to evaluate health outcomes and costs associated with life-long TRT in patients suffering from Klinefelter syndrome and late-onset hypogonadism (LOH). METHODS: A Markov model was developed to assess cost-effectiveness of testosterone undecanoate (TU) depot injection treatment compared with no treatment. Health outcomes and associated costs were modeled in monthly cycles per patient individually along a lifetime horizon. Modeled health outcomes included development of type 2 diabetes, depression, cardiovascular and cerebrovascular complications, and fractures. Analysis was performed for the Swedish health-care setting from health-care payer's and societal perspective. One-way sensitivity analyses evaluated the robustness of results. MAIN OUTCOME MEASURES: The main outcome measures were quality-adjusted life-years (QALYs) and total cost in TU depot injection treatment and no treatment cohorts. In addition, outcomes were also expressed as incremental cost per QALY gained for TU depot injection therapy compared with no treatment (incremental cost-effectiveness ratio [ICER]). RESULTS: TU depot injection compared to no-treatment yielded a gain of 1.67 QALYs at an incremental cost of 28,176 EUR (37,192 USD) in the Klinefelter population. The ICER was 16,884 EUR (22,287 USD) per QALY gained. Outcomes in LOH population estimated benefits of TRT at 19,719 EUR (26,029 USD) per QALY gained. Results showed to be considerably robust when tested in sensitivity analyses. Variation of relative risk to develop type 2 diabetes had the highest impact on long-term outcomes in both patient groups. CONCLUSION: This analysis suggests that lifelong TU depot injection therapy of patients with hypogonadism is a cost-effective treatment in Sweden. Hence, it can support clinicians in decision making when considering appropriate treatment strategies for patients with testosterone deficiency.

[When is testosterone substitution a medically necessary treatment?]. / Wann stellt Testosteronsubstitution eine medizinisch notwendige Heilbehandlung dar?

The expert questioning of when a treatment with testosterone is medically necessary has increased by several 100% in the daily work of the insurance medical expert in the past years. The reason for this is that testosterone is prescribed a lot more often nowadays than it was 10 years ago. One can suspect that testosterone has become part of a popular lifestyle medication. However, the clinical meaning of the age-dependent decrease of testosterone in men is controversial. Unfortunately, there are only few study data about hypogonadism in ageing men. Testosterone treatment has a very narrow application field and is only medically necessary if the low testosterone level has been clinically proven as well as in a medical lab examination. This is decisive because testosterone treatment has numerous limitations of application and has a wide range of side effects. This article shows the controversy surrounding the discussion on testosterone treatment and the pitfalls of issuing the insurance medical expert's report.

Finger bone immaturity and 2D:4D ratio measurement error in the assessment of the hyperandrogenic hypothesis for the etiology of autism spectrum disorders.

Emerging hypotheses suggest a causal role for prenatal androgen exposure in some cases of autism spectrum disorders (ASD). The ratios of the lengths of the bones of the 2nd to the 4th digit (2D:4D) are purported to be markers for prenatal androgen exposure and to be established early in gestation. Elongation of the 4th digit in response to testosterone is said to reduce 2D:4D in males versus females. We examined the ratios of bones from the left hand radiographs of 75 boys and 6 girls 4-8 years of age, diagnosed with ASD, to evaluate digit ratio as a marker for gestational androgen exposure. Contrary to our expectations, girls had reduced 2D:4D compared to boys but the difference was not significant (Cohen's D 0.51-0.66, P>0.05). The limited sample size for this study and the absence of a referent group precluded providing robust estimates for girls and identifying possible statistical differences between the sexes. Tanner-Whitehouse 3 (TW3) rating of finger bone growth suggested relative immaturity of the 4th relative to the 2nd digits. Positive correlations were detected for 2D:4D ratios, body mass index (r=0.23, P=0.039), chronologic age (r=0.35, P=0.001), and skeletal age (r=0.42, P<0.0001). The TW3 ratings and associations between 2D:4D ratios and indicators of growth suggest that digits develop at different rates. This asynchronous development may produce differences in 2D:4D over time which could lead to erroneous interpretation of androgen exposure in utero among young ASD children.

Maternal longevity and the sex of offspring in pre-industrial Sweden.

BACKGROUND: Helle et al. (2000. Sons reduced maternal longevity in preindustrial humans. Science, 296, 1085) argued that giving birth to sons reduced maternal longevity in pre-industrial societies due to higher physiological costs of bearing sons and the elevated testosterone levels observed in mothers carrying male foetuses. AIM: The present study examined this hypothesis using a more comprehensive dataset and evaluated the merits of the statistical approach used in previous studies to identify the cost of giving birth to sons in terms of maternal old-age longevity. SUBJECTS AND METHODS: The analysis in Helle et al. (2002. Sons reduced maternal longevity in preindustrial humans. Science 296, 1085) was extended by using a considerably larger dataset of pre-industrial Swedish women, and with careful consideration paid to methodological problems of sample selection and omitted variable bias. We argue that the previous literature has underestimated the difficulties in quantifying the trade-off between parity and longevity due to unobserved heterogeneity in health. However, under less restrictive assumptions, one can estimate the marginal impact of a son for a fixed family size. RESULTS: No evidence was found of a negative relative impact of sons. Neither was any evidence found in favour of the male-biased intra-household resource competition hypothesis proposed elsewhere in the literature, despite the poverty of the study population. These results are robust to a wide range of specifications tested. CONCLUSION: The failure to reproduce earlier findings and the fact that studies in this area of research seem to continue to yield conflicting results warrant much caution in discussing and evaluating results. It is likely that the negative effect of sons, if it existed, only manifested itself under conditions that are not yet fully understood. We also argue that the previous literature on this topic has not fully acknowledged the inference problems associated with omitted variable bias and sample selection.

Regulatory perspective on clinical trials and end points for female sexual dysfunction, in particular, hypoactive sexual desire disorder: formulating recommendations in an environment of evolving clinical science.

This article examines the history, current status, and potential future challenges in the development of drugs for female sexual dysfunction (FSD) from the perspective of the United States Food and Drug Administration. In particular, the article focuses on testosterone therapy for hypoactive sexual desire disorder (a component of FSD), and the role of the Division of Reproductive and Urologic Products in facilitating the development of safe and effective therapies for this indication.