Estrogen levels in young women with hormone receptor-positive breast cancer on ovarian function suppression therapy.

Ovarian function suppression (OFS) benefits young women with hormone receptor (HR)-positive breast cancer but they are at risk for ovarian function breakthrough. We assessed endocrine effects of gonadotropin-releasing hormone agonist (GnRHa) treatment in a prospective cohort of patients aged ≤ 40 years with HR-positive breast cancer. Plasma estradiol (E2), estrone, and follicule-stimulating hormone (FSH) levels were measured from blood samples drawn 1 and 4 years after diagnosis. Patient characteristics, invasive breast cancer-free survival (iBCFS), and overall survival (OS) were compared between those with and without E2 > 2.72 pg/mL during GnRHa treatment. Among eligible patients, 54.7% (46/84) and 60% (15/25) had E2 > 2.72 pg/mL at 1 and 4 years, respectively. Factors associated with E2 > 2.72 pg/mL at 1 year were no prior chemotherapy (P = 0.045) and tamoxifen use (P = 0.009). After a median follow-up of 7 years, among patients with stage I-III breast cancer (N = 74), iBCFS events were seen in 6 (8.1%) with E2 > 2.72 pg/mL and 5 (6.8%) with E2 ≤ 2.72 pg/mL (P = 0.893). Among patients with de novo metastatic breast cancer (N = 12), 6 (50%) with E2 > 2.72 pg/mL and 3 (25%) with E2 ≤ 2.72 pg/mL died during follow-up (P = 0.052). Larger studies exploring the clinical implications of incomplete E2 suppression by GnRHa are needed to ensure optimal OFS treatment strategies are being employed for this population.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Prostate Risk and Monitoring During Testosterone Replacement Therapy.

ABSTRACT: Men with hypogonadism have reduced risk of prostate cancer mortality; whether testosterone treatment increases the risk of prostate safety events in men with hypogonadism remains controversial. Several studies including 4 larger randomized trials-the Testosterone Trials, TEstosterone and Atherosclerosis Progression in Aging Men (TEAAM) trial, Testosterone for Diabetes Mellitus trial, and Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) trial-treated men with testosterone or placebo for 1 year or longer and reported prospectively ascertained prostate safety data. The TRAVERSE Trial, because of its large size, longer duration, and adjudication of prostate events, has provided comprehensive data on the risk of adverse prostate events during testosterone replacement therapy (TRT). Among men with hypogonadism, carefully screened to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract symptoms were low and did not differ between the testosterone and placebo groups. Testosterone did not worsen lower urinary tract symptoms. TRT was associated with a greater increase in prostate-specific antigen than placebo in the first year of treatment. CONCLUSION: Testosterone treatment of men with hypogonadism, screened to exclude those at high risk of prostate cancer, is associated with low risk of adverse prostate events. Baseline evaluation of prostate cancer risk and a standardized monitoring plan can minimize the risk of unnecessary prostate biopsy while enabling the detection of high-grade prostate cancers in men receiving TRT.

Maternal Steroid Hormone Levels in Early Pregnancy and Autism in the Offspring: A Population-Based, Nested Case-Control Study.

BACKGROUND: A role for prenatal steroid hormones in the etiology of autism has been proposed, but evidence is conflicting. METHODS: Here, we examined serum levels of maternal estradiol, testosterone, 17-hydroxyprogesterone (OHP), and cortisol from the first trimester of gestation (mean = 10.1 weeks) in relation to the odds of diagnosed autism with and without co-occurring intellectual disability (ID) in the offspring (n = 118 autism with ID, n = 249 autism without ID, n = 477 control). Levels of maternal hormones were measured using highly sensitive liquid chromatography tandem mass spectrometry, standardized according to gestational timing of sample collection, and analyzed with restricted cubic spline logistic regression models adjusting for child's sex and maternal health, demographic, and socioeconomic factors. RESULTS: We observed significant nonlinear associations between maternal estradiol, 17-OHP, and cortisol with autism, which varied with the presence of co-occurring ID. Compared to mean levels, lower levels of estradiol were associated with higher odds of autism with ID (odds ratio for concentrations 1 SD below the mean = 1.66; 95% CI, 1.24-2.11), while higher cortisol levels were associated with lower odds (odds ratio for 1 SD above the mean = 0.55; 95% CI, 0.36-0.88). In contrast, higher 17-OHP was associated with increased odds of autism without ID (odds ratio for 1 SD above the mean = 1.49; 95% CI, 1.11-1.99). We observed no evidence for interaction with sex of the child. CONCLUSIONS: These findings support the notion that the maternal steroid hormonal environment in early pregnancy may contribute to autism, but also emphasize the complex relationship between early-life steroid exposure and autism.

Bone microarchitectural alterations associated with spinal cord injury: Relation to sex hormones, metabolic factors, and loading.

CONTEXT: People living with spinal cord injury (SCI) are at high risk for bone fractures. Neural, hormonal and metabolic contributors to bone microarchitectural alterations are incompletely understood. OBJECTIVE: To determine the relationship of physical, metabolic and endocrine characteristics with bone microarchitecture, characterized using high-resolution peripheral quantitative computed tomography (HRpQCT) in SCI. DESIGN: Cross-sectional analyses of bone properties in people with SCI. PARTICIPANTS: Twenty adults with SCI and paraplegia (12) or motor incomplete quadriplegia (8). OUTCOME MEASURES: Distal tibia and radius HRpQCT parameters, including density, microstructure and strength by microfinite element anaysis (µFEA); sex hormones; metabolic and inflammatory markers. RESULTS: The mean age of the participants with SCI was 41.5 ± 10.3 years, BMI 25.7 ± 6.2 kg/m2, time since injury 10.4 ± 9.0 years. Participants with SCI had significantly lower median total (Z score - 3.3), trabecular (-2.93), and cortical vBMD (-1.87), and Failure Load by µFEA (-2.48) at the tibia than controls. However, radius vBMD, aBMD and microarchitecture were similar in participants with SCI and un-injured controls. Unexpectedly, C-Reactive Protein (CRP) was positively associated with tibial trabecular vBMD (ß = 0.77, p = 0.02), thickness (ß = 0.52, p = 0.04) and number (ß = 0.92, p = 0.02). At the radius, estradiol level was positively associated with total vBMD (ß = 0.59, p = 0.01), trabecular thickness (ß = 0.43, p = 0.04), cortical thickness (ß = 0.63, p = 0.01) and cortical porosity (ß = 0.74 p = 0.04). CONCLUSIONS: Radius vBMD and microarchitecture is preserved but tibial total, cortical and trabecular vBMD, and estimated bone strength are markedly lower and bone microarchitectural parameters substantially degraded in people with SCI. The alterations in bone microarchitecture in people with SCI are likely multifactorial, however marked degradation of bone microarchitecture in tibia but not radius suggests that unloading is an important contributor of site-specific alterations of bone microarchitecture after SCI. Fracture prevention in SCI should focus on strategies to safely increase bone loading. CLINICALTRIALS: gov registration #: (NCT03576001).

Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial.

Importance: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown. Objective: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism. Design, Setting, and Participants: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023. Intervention: Participants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo. Main Outcomes and Measures: The primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model. Results: A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men. Conclusions and Relevance: In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Optimizing the Design of Clinical Trials to Evaluate the Efficacy of Function-Promoting Therapies.

BACKGROUND: Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies. METHODS: Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints. RESULTS: Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements. CONCLUSIONS: Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training.

Synergistic Strategies to Accelerate the Development of Function-Promoting Therapies: Lessons From Operation Warp Speed and Oncology Drug Development.

BACKGROUND: Functional limitations and physical disabilities associated with aging and chronic disease are major concerns for human societies and expeditious development of function-promoting therapies is a public health priority. METHODS: Expert panel discussion. RESULTS: The remarkable success of Operation Warp Speed for the rapid development of COVID-19 vaccines, COVID-19 therapeutics, and of oncology drug development programs over the past decade have taught us that complex public health problems such as the development of function-promoting therapies will require collaboration among many stakeholders, including academic investigators, the National Institutes of Health, professional societies, patients and patient advocacy organizations, the pharmaceutical and biotechnology industry, and the U.S. Food and Drug Administration. CONCLUSIONS: There was agreement that the success of well designed, adequately powered clinical trials will require careful definitions of indication/s, study population, and patient-important endpoints that can be reliably measured using validated instruments, commensurate resource allocation, and versatile organizational structures such as those used in Operation Warp Speed.

Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns.

Recent research has unveiled an expansive role of NAD+ in cellular energy generation, redox reactions, and as a substrate or cosubstrate in signaling pathways that regulate health span and aging. This review provides a critical appraisal of the clinical pharmacology and the preclinical and clinical evidence for therapeutic effects of NAD+ precursors for age-related conditions, with a particular focus on cardiometabolic disorders, and discusses gaps in current knowledge. NAD+ levels decrease throughout life; age-related decline in NAD+ bioavailability has been postulated to be a contributor to many age-related diseases. Raising NAD+ levels in model organisms by administration of NAD+ precursors improves glucose and lipid metabolism; attenuates diet-induced weight gain, diabetes, diabetic kidney disease, and hepatic steatosis; reduces endothelial dysfunction; protects heart from ischemic injury; improves left ventricular function in models of heart failure; attenuates cerebrovascular and neurodegenerative disorders; and increases health span. Early human studies show that NAD+ levels can be raised safely in blood and some tissues by oral NAD+ precursors and suggest benefit in preventing nonmelanotic skin cancer, modestly reducing blood pressure and improving lipid profile in older adults with obesity or overweight; preventing kidney injury in at-risk patients; and suppressing inflammation in Parkinson disease and SARS-CoV-2 infection. Clinical pharmacology, metabolism, and therapeutic mechanisms of NAD+ precursors remain incompletely understood. We suggest that these early findings provide the rationale for adequately powered randomized trials to evaluate the efficacy of NAD+ augmentation as a therapeutic strategy to prevent and treat metabolic disorders and age-related conditions.

Development and Validation of Quality Measures for Testosterone Prescribing.

Context: Accurate measures to assess appropriateness of testosterone prescribing are needed to improve prescribing practices. Objective: This work aimed to develop and validate quality measures around the initiation and monitoring of testosterone prescribing. Methods: This retrospective cohort study comprised a national cohort of male patients receiving care in the Veterans Health Administration who initiated testosterone during January or February 2020. Using laboratory data and diagnostic codes, we developed 9 initiation and 7 monitoring measures. These were based on the current Endocrine Society guidelines supplemented by expert opinion and prior work. We chose measures that could be operationalized using national VA electronic health record (EHR) data. We assessed criterion validity for these 16 measures by manual review of 142 charts. Main outcome measures included positive and negative predictive values (PPVs, NPVs), overall accuracy (OA), and Matthews Correlation Coefficients (MCCs). Results: We found high PPVs (>78%), NPVs (>98%), OA (≥94%), and MCCs (>0.85) for the 10 measures based on laboratory data (5 initiation and 5 monitoring). For the 6 measures relying on diagnostic codes, we similarly found high NPVs (100%) and OAs (≥98%). However, PPVs for measures of acute conditions occurring before testosterone initiation (ie, acute myocardial infarction or stroke) or new conditions occurring after initiation (ie, prostate or breast cancer) PPVs were much lower (0% to 50%) due to few or no cases. Conclusion: We developed several valid EHR-based quality measures for assessing testosterone-prescribing practices. Deployment of these measures in health care systems can facilitate identification of quality gaps in testosterone-prescribing and improve care of men with hypogonadism.

Testosterone replacement in prostate cancer survivors with testosterone deficiency: Study protocol of a randomized controlled trial.

BACKGROUND: Most men diagnosed with prostate cancer today have organ-confined disease and low risk of disease recurrence after radical prostatectomy. Testosterone deficiency in prostate cancer survivors contributes to impaired health-related quality of life but testosterone treatment is viewed as a contraindication in this population. OBJECTIVES: We describe the design of the first randomized trial to determine the safety and efficacy of testosterone treatment in men who have undergone prostatectomy for non-aggressive prostate cancer and have symptomatic testosterone deficiency. METHODS: Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial is a randomized, placebo-controlled, double-blind, parallel group trial in 142 men, ≥ 40 years, who have undergone radical prostatectomy for organ-confined prostate cancer, Gleason score ≤ 7 (3+4), Stage pT2, N0, M0 lesions and have symptomatic testosterone deficiency and undetectable prostate specific antigen for > 2 years after surgery. Eligible participants are randomized to weekly intramuscular injections of 100-mg testosterone cypionate or placebo for 12 weeks and followed for another 12 weeks. Primary endpoint is change from baseline in sexual activity. Secondary outcomes include change in sexual desire, erectile function, energy, lean and fat mass, physical and cognitive performance. Safety is assessed by monitoring prostate-specific antigen, lower urinary tract symptoms, hemoglobin, and adverse events. RESULTS: The trial is being conducted at two trial sites in Boston, MA and Baltimore, MD. As of July 30, 2022, 42 participants have been randomized. No prostate-specific antigen or clinical recurrence has been noted to-date. DISCUSSION: Recruitment was slowed by coronavirus disease 2019-related closures, slow subsequent ramp-up of research activities, and patient concerns about safety of testosterone treatment. Despite these challenges, participant retention has been high. CONCLUSION: The Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial, a placebo-controlled, randomized trial, will determine whether testosterone replacement therapy is safe and efficacious in correcting symptoms of testosterone deficiency in prostate cancer survivors, and potentially inform clinical practice.

Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal: Secondary Analysis of a Randomized Clinical Trial.

Importance: Half of women who are postmenopausal have genitourinary discomfort after menopause. Recommended therapies include low-dose vaginal estrogen. Individuals with a history of breast cancer or venous thromboembolism may have concerns about the safety of this intervention. Objective: To compare serum estrogen concentrations with the use of vaginal estrogen, 10 µg, tablet vs placebo in women who are postmenopausal. Design, Setting, and Participants: This is a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to severe genitourinary syndrome in women who are postmenopausal. The study was conducted at Kaiser Permanente Washington Health Research Institute and the University of Minnesota from April 11, 2016, to April 23, 2017. Measurements and data analysis were performed from November 3, 2020, to September 23, 2022. Interventions: Participants were randomly assigned to vaginal estradiol tablet (10 µg/d for 2 weeks and then twice weekly) plus placebo gel (3 times weekly) or dual placebo for 12 weeks. Main Outcomes and Measures: In this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone-binding globulin (SHBG) concentrations were measured by a chemiluminescent assay. Week 12 values of the 3 analytes were compared by baseline participant characteristics. Linear models compared week 12 estradiol concentrations between treatment groups, adjusted for baseline characteristics. Results: A total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain. Trial Registration: ClinicalTrials.gov Identifier: NCT02516202.

Benefits and Risks of Testosterone Treatment of Older Men with Hypogonadism.

Total and free testosterone levels decline in men with advancing age due to defects at all levels of the hypothalamic-pituitary-testicular axis. Testosterone treatment of older men with low testosterone levels is associated with improvements in sexual activity, sexual desire, and erectile function; lean body mass, muscle strength, and stair climbing power, and self-reported mobility; areal and volumetric bone mineral density, and estimated bone strength; depressive symptoms; and anemia. Long-term risks of cardiovascular events and prostate cancer during testosterone treatment remain unknown. Testosterone treatment may be offered on an individualized basis to older men with unequivocally low testosterone levels and symptoms or conditions associated with testosterone deficiency after consideration of potential benefits and risks, burden of symptoms, and patient's values.

Accurate measurement of total and free testosterone levels for the diagnosis of androgen disorders.

The circulating concentrations of total and free testosterone vary substantially in people over time due to biologic factors as well as due to measurement variation. Accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders. Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry, in a laboratory that is certified by an accuracy-based benchmark. Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone.

Changes in serum endogenous estrogen concentrations are mediators of the effect of low-dose oral estradiol on vasomotor symptoms.

OBJECTIVES: The aim of this study was to quantify changes in serum total estradiol (E2) and estrone (E1) concentrations with initiation of low-dose oral estradiol treatment and evaluate whether changes in concentrations mediate the effect of treatment in reducing vasomotor symptom (VMS) frequency. METHODS: We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17ß estradiol ( n = 72) and placebo ( n = 99) groups of a randomized clinical trial. RESULTS: From baseline to W8, women in the low-dose estradiol group had a fourfold increase in E2, resulting in a W8 E2 of 23 pg/mL, and a fivefold increase in E1, resulting in a W8 E1 of 110.7 pg/mL. In contrast, E2 and E1 among women in the placebo group were unchanged from baseline to W8. Changes in E2 and E1 from baseline to W8 met criteria for mediating the effect of low-dose estradiol treatment on VMS frequency. With change in estrogen concentration added to treatment assignment in a regression model predicting W8 VMS frequency, the effect of treatment with low-dose estradiol versus placebo was attenuated, with change in E2 representing a 44.1% reduction ( P = 0.03) and change in E1 representing a 69.5% reduction ( P = 0.02) in total intervention effect. CONCLUSION: Among perimenopausal and postmenopausal women with VMS, treatment with low-dose oral estradiol versus placebo results in four- to fivefold increases in serum E2 and E1. The increases in serum E2 and E1 with low-dose oral estradiol treatment seem to mediate in part the effect of treatment in reducing VMS frequency.

Effect of Selective Androgen Receptor Modulator on Cholesterol Efflux Capacity, Size, and Subspecies of HDL Particles.

Context: Selective androgen receptor modulators (SARMs), because of their preferential muscle vs prostate selectivity, are being developed for muscle-wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown. Objective: To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies. Methods: We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5, or 15 mg of an oral SARM (OPK-88004). Results: SARM significantly suppressed HDL-C (P < .001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (change + 0.016, -0.036, +0.070, and -0.048%/µmol-HDL/L-1 at 0, 1, 5, and 15 mg SARM, P = .045). SARM treatment suppressed APOAI (P < .001) but not APOB (P = .077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement C3, or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) (P < .001). Conclusion: SARM treatment suppressed HDL-C but had minimal effect on its size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Are serum estrogen concentrations associated with menopausal symptom bother among postmenopausal women? Baseline results from two MsFLASH clinical trials.

OBJECTIVES: To evaluate whether single measurements of serum estradiol (E2), estrone (E1) and sex hormone-binding globulin (SHBG) concentration distinguishes between women with and without menopausal symptom bother. STUDY DESIGN: We analyzed baseline data from two clinical trials conducted in 2012-2017: MsFLASH 03 (178 peri-/post-menopausal women aged 40-62 years with bothersome vasomotor symptoms, mean age 54) and MsFLASH 05 (181 post-menopausal women aged 45-70 years with moderate-to-severe vulvovaginal symptoms, mean age 61). MAIN OUTCOME MEASURES: Symptom bother (hot flushes or flashes, night sweats, sweating, aching in muscles and joints, change in sexual desire, vaginal dryness during intercourse, and avoiding intimacy) in the past month was assessed using the Menopause-Specific Quality of Life questionnaire. Using logistic regression, we calculated the area under the receiver operating characteristic curve (AUC) values for E1, E2, and SHBG concentration in relation to being at least somewhat bothered (symptom bother score ≥3) by each symptom within each trial study population. RESULTS: AUC values (95% confidence interval) ranged between 0.51 (0.41-0.60) and 0.62 (0.53, 0.72) for MsFLASH 03 and between 0.51 (0.42, 0.59) and 0.64 (0.53, 0.75) for MsFLASH 05. There was little evidence of associations between serum hormone levels and bother by a given menopausal symptom. CONCLUSION: These findings do not support the clinical utility of a single measurement of serum of E1, E2, or SHBG concentrations in differentiating between women who are bothered by a given menopausal symptom and those who are not.

Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials.

CONTEXT: Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol. OBJECTIVE: To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism. METHODS: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests. RESULT: Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone. CONCLUSION: Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.