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Abstract Context Powerful demographic trends toward reproductive aging of human populations, older age at first childbirth, and lower birth rates will profoundly influence the health, vitality, and economies of human societies and deserve greater attention in health policy and research. Evidence Acquisition Information on birth rates, fertility rates, and outcomes of assisted reproductive technologies were obtained from databases of government agencies (census data, Centers for Disease Control and Prevention). Evidence Synthesis Fecundity declines with advancing age, especially in women >35 years and men >50 years. Advanced parental age adversely affects pregnancy outcomes for the mother and the offspring and increases the offspring’s risk of chromosomal disorders, neurodegenerative diseases, and birth defects. Because of increased life expectancy, today people will spend a major portion of life in a period of reproductive senescence; diseases associated with reproductive senescence will influence the health and well-being of middle-aged and older adults. Inversion of the population age pyramid will affect health care costs, retirement age, generational distribution of wealth, and the vitality of societies. Actions can be taken to mitigate the societal consequences of these trends. An educational campaign to inform young people about the trade-offs associated with postponement of childbirth will enable them to make informed choices. Some repositioning of research agenda and health care policies is needed to address the public health threat posed by reproductive aging. Conclusion The consequences of low fertility rates and delayed parenthood on our nation’s health, vitality, and economic growth should be considered when crafting research, health, and economic policies. Reproductive aging will profoundly influence health, vitality, and economies of human societies; redirection of health and economic policies is needed to mitigate its adverse societal consequences.

Background:Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men.Objective:To establish harmonized reference ranges for total testosterone in men that can be applied across laboratories by cross-calibrating assays to a reference method and standard.Population:The 9054 community-dwelling men in cohort studies in the United States and Europe: Framingham Heart Study; European Male Aging Study; Osteoporotic Fractures in Men Study; and Male Sibling Study of Osteoporosis.Methods:Testosterone concentrations in 100 participants in each of the four cohorts were measured using a reference method at Centers for Disease Control and Prevention (CDC). Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. Normalizing equations, generated using Passing-Bablok regression, were used to generate harmonized values, which were used to derive standardized, age-specific reference ranges.Results:Harmonization procedure reduced intercohort variation between testosterone measurements in men of similar ages. In healthy nonobese men, 19 to 39 years, harmonized 2.5th, 5th, 50th, 95th, and 97.5th percentile values were 264, 303, 531, 852, and 916 ng/dL, respectively. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men.Conclusion:Harmonized normal range in a healthy nonobese population of European and American men, 19 to 39 years, is 264 to 916 ng/dL. A substantial proportion of intercohort variation in testosterone levels is due to assay differences. These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator.We cross-calibrated cohort-specific assays to a reference method at CDC and generated harmonized reference ranges for circulating testosterone levels in men, including age-adjusted reference ranges.

Abstract Context The efficacy and safety of testosterone replacement therapy (TRT) in hypogonadal men remain incompletely understood. Objective To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to determine the effects of TRT on patient important outcomes and adverse events in hypogonadal men. Data Sources We searched Ovid Medline, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus, from inception to 2 March 2017. Study Selection Randomized clinical trials assessing the efficacy and adverse events of TRT of at least 12 weeks compared with placebo in adult men with hypogonadism, defined by morning total testosterone ≤300 ng/dL and at least one symptom or sign of hypogonadism. Data Extraction Reviewers working independently and in duplicate assessed the quality of RCTs and collected data on patient characteristics, interventions, and outcomes. Results We found four RCTs (including 1779 patients) at low risk of bias. Compared with placebo, TRT was associated with a small but significant increase in sexual desire or libido [standardized mean difference (SMD): 0.17; 95% confidence interval (CI), 0.01, 0.34; n = 1383], erectile function (SMD: 0.16; 95% CI, 0.06, 0.27; n = 1344), and sexual satisfaction (SMD: 0.16; 95% CI, 0.01, 0.31; n = 676) but had no effect on energy or mood. TRT was associated with an increased risk of developing erythrocytosis (relative risk: 8.14; 95% CI, 1.87, 35.40; n = 1579) compared with placebo but had no significant effect on lower urinary tract symptoms. Conclusion In hypogonadal men, TRT improves sexual desire, erectile function and sexual satisfaction; however, it increases the risk of erythrocytosis. This study shows that in hypogonadal men, testosterone replacement therapy improves sexual desire, erectile function, and sexual satisfaction; however, it increases the risk of erythrocytosis.

Background Transgender, nonbinary, and gender diverse (TGD) people experience stigma in healthcare settings impacting healthcare utilization, including avoidance of care due to anticipated discrimination. Gender-affirming care refers to care for medical gender affirmation, such as gender-affirming hormones and surgery, as well as general care that affirms and respects TGD patients. This study sought to explore the experiences of TGD adults to inform gender-affirming care delivery and develop an actionable framework for practice. Methods Between May–October 2021, one-time individual in-depth interviews were conducted with 27 TGD adults receiving any healthcare in the greater Boston Massachusetts area to gather data about gender-affirming care. Interviews were semi-structured, explored prior and current experiences in healthcare and ideal gender-affirming care models, and conducted virtually via a secure Zoom platform. Analyses were conducted using immersion crystallization and reflexive thematic analysis; interview transcripts were double coded by two coders. Results Participants had a mean age of 28.5, ranging 18–45 years, and were: 7 transgender men, 6 transgender women, 8 nonbinary, 3 genderqueer, 1 agender, and 2 gender not specified. Themes about gender-affirming care coalesced into the acronym AFFIRM: (1) Affirms in individual interactions: Participants called for affirmation of TGD identity, lived expertise, and competent TGD providers and staff. (2) Flexible and accessible: Participants expressed the need for gender-affirming care to be available beyond urban population-specific clinics, in a timely fashion without long wait lists, and in a community-centered manner such as offering non-traditional times and settings. (3) Fights systemic oppression: Participants emphasized the need for providers and health systems to eliminate gatekeeping practices for gender-affirming care and create care models that resist intersecting oppressive systems such as racism and cisgenderism. (4) Interacts with community: Patients desired intentional interaction with TGD community to holistically address health and unmet gender affirmation needs. (5) Retains patients in care: Patients shared the need to collaboratively identify and problem-solve obstacles to gender-affirming care with providers and healthcare systems to optimize TGD-specific retention strategies. (6) Multidisciplinary: Patients called for interdisciplinary teams with co-located services such as primary care and mental healthcare with letter-writing for surgical care, and incorporation of peer navigators to meet the broader social, health, and well-being needs of TGD people. Conclusions Findings from this study and the AFFIRM Framework which emerged from TGD patient narratives can be applied to improve current care and set benchmarks for high-quality gender-affirming care delivery and practice.

Among men receiving androgen-deprivation therapy for prostate cancer, there is a high frequency of the metabolic syndrome and an increased risk of cardiovascular death. How the loss of anabolic signals leads to sarcopenia and metabolic abnormalities may be informative. The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic. The first of a series of occasional articles drawing attention to the bedside-to-bench flow of information is presented here, under the Basic Implications of Clinical Observations rubric. We hope our readers will enjoy these stories of discovery, and we invite them to submit their own examples of clinical findings that have . . .

Bhasin discusses testosterone replacement in aging men. The deluge of advertisements marketing erectile dysfunction medications and testosterone products has empowered many older men to seek medical help for their sexual and genitourinary problems. As a reflection of this historical transition toward increased attention on men's sexual health, men's health clinics have sprung up across the US; concomitantly, testosterone prescription sales increased from about $100 million US dollars in the year 2000 to nearly $2.7 billion in 2013. Testosterone levels decline gradually with advancing age after peaking in the second and third decades of life. Genetic factors, adiposity, and comorbid conditions affect the trajectory of age-related decline in testosterone levels.

Abstract Context Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design Double-blind, placebo-controlled trial. Setting Twelve academic medical centers in the United States. Participants In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Intervention Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcome Measures Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Results Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, −6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, −2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, −2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, −1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, −0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Conclusions and Relevance Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes. Compared with placebo, testosterone treatment of older men with low testosterone was associated with small reductions in total, HDL, and LDL cholesterol and in insulin and HOMA-IR but not glucose.

Endocrine disease frequently interrupts sexual function, and sexual dysfunction may signal serious endocrine disease. Diabetic autonomic neuropathy and endothelial dysfunction impair erectile function, and phosphodiesterase inhibition produces only moderate benefit. The effect of diabetes on women's sexual function is complex: the most consistent finding is a correlation between sexual dysfunction and depression. Reductions in testosterone level in men are associated with low sexual desire and reduced nocturnal erections and ejaculate volume, all of which improve with testosterone supplementation. The age-dependent decline in testosterone production in men is not associated with precise sexual symptoms, and supplementation has not been shown to produce sexual benefit. In women, sexual dysfunction has not been associated with serum testosterone, but this may be confounded by limitations of assays at low concentrations and by the greater importance of intracellular production of testosterone in women than in men. Testosterone supplementation after menopause does improve some aspects of sexual function in women, but long-term outcome data are needed. More research on the sexual effects of abnormal adrenal and thyroid function, hyperprolactinaemia, and metabolic syndrome should also be prioritised. We have good data on local management of the genital consequences of oestrogen lack, but need to better understand the potential role of systemic oestrogen supplementation from menopause onwards in sexually symptomatic women.

Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p  = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p  = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p  = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline. The predictive value of blood levels of GDF11/8 proteins in humans for future disease outcomes has been unclear. Here, the authors show that low levels of specific activated GDF11/8 subforms are strongly associated with future cardiovascular events, mortality, and dementia risk.

Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression. AAV-mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes.