Efficacy of Gonadotropin Treatment for Induction of Spermatogenesis in Men With Pathologic Gonadotropin Deficiency: A Meta-Analysis.

INTRODUCTION: Hypogonadotropic hypogonadism (HH) is a treatable cause of nonobstructive azoospermic male infertility. Gonadotropin treatment can successfully induce spermatogenesis in most patients, although comprehensive quantitative summary data on spermatogenic outcomes like those required to induce pregnancy is lacking in the literature. MATERIALS AND METHODS: Systematic review and meta-analysis of outcomes related to male reproductive function following gonadotropin treatment. RESULTS: Our search strategy identified 41 studies encompassing 1673 patients with a mean age of 25 (± 5) years. Average sperm concentration achieved after a median of 18 months of gonadotropin treatment was 11.6 M/mL of ejaculate (95% CI 8.4-14.9). Sperm concentrations > 0, > 1, > 5, > 10 and > 20 M/mL were achieved by 78%, 55%, 36%, 24% and 15% of patients, respectively. Mean sperm output and the proportion of patients achieving all sperm thresholds were significantly greater following combined hCG/FSH treatment compared with hCG monotherapy. When compared by diagnosis, patients with congenital HH (CHH) had significantly lower mean sperm output compared with patients with hypopituitarism or mixed patient cohorts that did not differentiate between CHH and hypopituitarism. Treatment-related increases in testosterone and testicular volume (TV) were not different between hCG and combined hCG/FSH treated patients, although increases in TV were lower in men with CHH compared with those with hypopituitarism. CONCLUSIONS: Gonadotropin treatment successfully induced spermatogenesis in most men with pathological gonadotropin deficiency. Sperm outputs more consistent with those typically needed to induce a natural pregnancy were less commonly achieved. Despite similar effects on serum testosterone and TV, combined hCG/FSH appeared more efficacious than hCG alone at inducing spermatogenesis.

Testosterone and Erythrocyte Lifespan.

CONTEXT: Endogenous and exogenous androgens increase circulating erythrocytes and hemoglobin but their effects on erythrocyte lifespan is not known. OBJECTIVE: To investigate androgen effects on immature and mature erythrocyte lifespan in humans and mice using novel non-radioactive minimally invasive methods. DESIGN: Human erythrocyte lifespan was estimated using alveolar carbon monoxide concentration and blood hemoglobin in Levitt's formula in hypogonadal or transgender men before and up to 18 weeks after commencing testosterone (T) treatment. Erythrocyte lifespan was estimated in androgen receptor (AR) knockout and wild-type mice after T or dihydrotestosterone (DHT) treatment of intact females or orchidectomized males using in vivo biotin labelling of erythrocyte surface epitopes for reticulocytes (Ter119+CD71+) and two markers of erythrocytes (CD45-, Ter119+CD71-) monitoring their blood disappearance rate by flow cytometry. RESULTS: Before treatment, hypogonadal and transgender men had marked reduction in erythrocyte lifespan compared with controls. T treatment increased erythrocyte lifespan at 6 weeks but returned to pre-treatment levels at 18 weeks while serum T and blood hemoglobin were increased by T treatment remaining elevated at 18-weeks. In mice T and DHT treatment had higher erythrocyte (but not reticulocyte) lifespan but neither orchidectomy nor AR inactivation significantly influenced erythrocyte or reticulocyte lifespan. CONCLUSIONS: We conclude that hypogonadal men have reduced erythrocyte lifespan and acute androgen-induced increase in circulating erythrocyte lifespan may contribute to the well-known erythropoietic effects of androgens, but longer-term effects require further investigation to determine how much they contribute to androgen-induced increases in circulating hemoglobin.

High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model.

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.3 mg estradiol by silastic implant, implanted intraperitoneally, for 12 weeks. Controls included vehicle treated intact females and males. High-dose estradiol treatment in males stimulated the endocortical deposition of bone at the femoral mid-diaphysis, increasing cortical thickness and bone area. This led to higher stiffness, maximum force, and the work required to fracture the bone compared to male controls, while post-yield displacement was unaffected. Assessment of the material properties of the bone showed an increase in both elastic modulus and ultimate stress in the estradiol treated males. Treatment of male mice with high dose estradiol was also anabolic for trabecular bone, markedly increasing trabecular bone volume, number and thickness in the distal metaphysis which was accompanied by an increase in the histomorphometric markers of bone remodelling, mineralizing surface/bone surface, bone formation rate and osteoclast number. In conclusion, a high dose of estradiol is anabolic for cortical and trabecular bone in a male to female transgender mouse model, increasing both stiffness and strength. These findings suggest that increasing the current dose of GAHT administered to trans women, while considering other potential adverse effects, may be beneficial to preserving their bone microstructure and strength.

Cross-Sectional Associations between Nutrient Intake and Tooth Decay in Older Australian Men: The Concord Health and Ageing in Men Project.

Poor nutrition is a risk factor for dental decay in younger people. However, except for sugar, it is unclear if this is true in older age groups. The aim of this study was to analyze the possible associations between overall dietary intake of nutrients and diet quality and the presence of dental decay in community-dwelling older men. A cross-sectional analysis of a longitudinal study with a standardized validated diet history assessment and comprehensive oral health examination in 520 community-dwelling men (mean age: 84 years) participating in the Concord Health and Ageing in Men Project. Nutrient reference values were used to determine if individual micronutrients and macronutrients were meeting recommendations. Acceptable macronutrient distribution ranges (AMDRs) were attained for fat and carbohydrate intakes and were incorporated into a dichotomous variable to determine if the participants were consuming a high fat-low carbohydrate diet. Diagnosis of coronal caries was based on visual criteria and inspection and was completed on each of the five coronal surfaces. Root surface caries was textual changes across four root surfaces. This diagnosis was used to categorize participants by the presence and severity of coronal and root caries. The adjusted logistic regression showed not meeting the recommended intakes for thiamin (odds ratio [OR]: 2.32 95% confidence interval [CI] 1.15-4.67), and zinc (OR: 3.33, 95% CI: 1.71-6.48) were associated with presence of severe root decay. Adjusted analysis also showed that participants who were outside the recommended AMDR for fat (OR: 0.61, 95% CI: 0.38-0.98) and those who consumed a high fat and low carbohydrate diet (OR: 0.56, 95% CI: 0.35-0.91) were less likely to have coronal tooth decay. Our study shows associations between micronutrients and macronutrients and coronal and root surface decay. Although this study cannot prescribe causality or be generalized to all older adults, diet has a possible association with dental decay in older men.

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).

Toward a Robust Definition of Sport Sex.

Elite individual sports in which success depends on power, speed, or endurance are conventionally divided into male and female events using traditional binary definitions of sex. Male puberty creates durable physical advantages due to the 20- to 30-fold increase in circulating testosterone producing a sustained uplift in men's muscle, bone, hemoglobin, and cardiorespiratory function resulting from male puberty and sustained during men's lives. These male physical advantages provide strong justification for a separate protected category of female events allowing women to achieve the fame and fortune from success they would be denied if competing against men. Recent wider social acceptance of transgender individuals, together with the less recognized involvement of intersex individuals, challenge and threaten to defeat the sex classifications for elite individual female events. This can create unfair advantages if seeking inclusion into elite female events of unmodified male-bodied athletes with female gender identity who have gained the physical advantages of male puberty. Based on reproductive physiology, this paper proposes a working definition of sport sex based primarily on an individual's experience of male puberty and can be applied to transgender and various XY intersex conditions. Consistent with the multidimensionality of biological sex (chromosomal, genetic, hormonal, anatomical sex), this definition may be viewed as a multistrand cable whose overall strength survives when any single strand weakens or fails, rather than as a unidimensional chain whose strength is only as good as its weakest link.

Single and multi-dose pharmacology of recombinant and urinary human chorionic gonadotrophin in men.

OBJECTIVE: Human choriogonadotrophin (hCG) treatment of gonadotrophin-deficient infertile men uses hCG of urinary (uhCG) or recombinant (rhCG) origin, but these treatments have not been compared nor are there studies defining rhCG dosing in men. DESIGN: hCG products were studied in randomized cross-over single-dose studies of standard (Study 1, 1500 IU and 62.5 µg, respectively) or high (Study 2, 5000 IU and 250 µg) dose and a multi-dose population pharmacology study of hCG use. PARTICIPANTS: Eight (Study 1) and seven (Study 2) volunteers in cross-over and 52 gonadotrophin-deficient men in the multi-dose study MEASUREMENTS: In cross-over studies, serum testosterone (T), dihydrotestosterone (DHT) and estradiol by liquid chromatography-mass spectrometry (LCMS) and serum hCG, LH, FSH, SHBG and T (observational study) by immunoassays. RESULTS: After standard and high-dose injection, serum hCG and testosterone responses had similar timing and peak concentrations except for a mildly lower early (<48 h) serum testosterone with uhCG. In the multi-dosing study, both hCGs had similar pharmacokinetics (pooled half-life 5.8 days, p < .001), while serum testosterone concentrations were stable after injection and did not differ between hCG products. Bench testing verified that 20% of pens from 4/10 individuals were used inappropriately. CONCLUSIONS: Although hCG pharmacokinetics are not formally bioequivalent, the similar pharmacodynamic effects on serum testosterone indicate that at the doses tested both hCGs provide comparable clinical effects. The starting dose of rhCG for treating gonadotrophin-deficient men should be 62.5 µg (6 clicks) of the rhCG pen.

Dried blood spot sampling of testosterone microdosing in healthy females.

Capillary dried blood spot (DBS) analysis coupled with multi-analyte steroid liquid chromatography mass spectrometry (LCMS) is attractive for field studies, home-based self-sampling as well as clinical trials by eliminating costly and laborious sample processing involving venipuncture and frozen storage/shipping while providing multiple steroid measurements from a single small sample. We investigated steroid measurements in DBS samples stored for four years at room temperature prior to analysis compared with the original venipuncture serum samples. Healthy women (n=12) provided paired DBS and blood samples over two weeks run-in before seven days treatment with daily transdermal T gel (12.5 mg) and after the end of treatment on days 0, 1, 2, 4, 7 and 14. Compliance with treatment and sampling was high and no adverse effects were reported. Testosterone (T), androstenedione (A4), 17 hydroxyprogesterone (17OHP) and progesterone (P4) were measured in extracted DBS samples as whole blood concentrations with and without adjustment for hematocrit. Using the same LCMS methods, DBS T and A4 measurements had high correlation with minimal bias from prior serum measurements with DBS T displaying the same pattern as serum, with or without hematocrit adjustment. However, serial whole blood measurements of T without hematocrit adjustment provided the best fitting model compared with serum, urine, or hematocrit-adjusted whole blood T measurements. These finding facilitate and simplify DBS methodology for wider field and home-based self-sampling studies of reproductive steroids indicating the need for hematocrit adjustment may be superfluous.

Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women.

BACKGROUND: Oestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort. METHODS: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components. FINDINGS: The median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk. INTERPRETATION: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue. FUNDING: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).

Empirically derived dietary patterns are associated with major adverse cardiovascular events, all-cause mortality, and congestive cardiac failure in older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet is associated with major adverse cardiovascular events (MACE). OBJECTIVE: We evaluated the associations between empirically derived dietary patterns and MACE. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 539 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Cox regression analyses were conducted between MACE and the three dietary patterns identified from factor analysis. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality. RESULTS: At a median of 5.3 (IQR 4.6-6.3) years of follow-up, the incidences were: five-point MACE 31.2% (n = 168); four-point MACE excluding all-cause mortality 17.8% (n = 96); all-cause mortality 20.1% (n = 111); CCF 11.3% (n = 61); MI 3.7% (n = 20); stroke 3.2% (n = 17); and coronary revascularisation 3.1% (n = 15). In fully adjusted analyses, compared to the bottom tertile, the middle tertile of 'vegetables-legumes-seafood' dietary pattern was associated with reduced five-point MACE (HR 0.67 [95% CI: 0.45, 0.99, P = .047]), and CCF (HR 0.31 [95% CI: 0.15, 0.65, P = .002]), whilst the middle tertile of 'wholegrains-milk-other fruits' dietary pattern was associated with increased five-point MACE (HR 1.78 [95% CI: 1.17, 2.70, P = .007]), four-point MACE (HR 1.92 [95% CI: 1.12, 3.30, P = .018]), and CCF (HR 2.33 [95% CI: 1.17, 4.65, P = .016]). For the 'discretionary-starchy vegetables-processed meats' dietary pattern, a higher score was associated with increased five-point MACE (HR 1.33 [95% CI: 1.09, 1.62, P = .004]), and all-cause mortality (HR 1.63 [95% CI: 1.26, 2.12, P < .001]), and compared to the bottom tertile, the top tertile was associated with increased all-cause mortality (HR 2.26 [95% CI: 1.27, 4.00, P = .005]). CONCLUSION: Older men may benefit from consuming a 'vegetables-legumes-seafood' dietary pattern rather than 'discretionary-starchy vegetables-processed meats' and 'wholegrains-milk-other fruits' dietary patterns for the prevention of MACE.

Intra-generational social mobility and mortality among older men in the Concord Health and Ageing in Men Project: A cohort study.

Objectives: We examined associations between intra-generational social mobility (reflected in life-course socioeconomic trajectories) and mortality, among older men. Methods: Data came from a prospective Australian community-based cohort of older men. Social mobility was defined by socioeconomic indicators from three points in the life-course: educational attainment (late adolescence-early adulthood), occupation (mid-life), and current sources of income (older age). We defined indicators of social mobility trajectory (6 categories; reflecting the direction of social mobility) and social mobility status (2 categories; mobile or non-mobile). We used Cox regression to examine associations with mortality, adjusting for age, country of birth, and living arrangement. Results: We followed 1568 men (mean age 76.8, SD 5.4) for a mean duration of 9.1 years, with 797 deaths recorded. Moving upward was the predominant social mobility trajectory (36.0%), followed by mixed trajectories (25.1%), downward (15.1%), stable low (12.2%), stable high (7.6%), and stable middle (4.0%). Men with downward (Hazard ratio 1.58, 95% CI 1.13 to 2.19) and stable low socioeconomic trajectories (1.77, 1.25 to 2.50) had higher mortality risks than men with stable high socioeconomic trajectories, while men with upward trajectories had similar risks to those with stable high trajectories. 76.2% of the participants were classified as having mobile status; no associations were evident between binary social mobility status and mortality. Discussions: These findings suggest cumulative and persistent exposure to disadvantaged socioeconomic conditions across the life-course, rather than social mobility, is associated with increased mortality. For each stage of the life-course, addressing socioeconomic disadvantage may reduce inequities in mortality.

The association of dietary antioxidants and the inflammatory potential of the diet with poor physical function and disability in older Australian men: the Concord Health and Ageing in Men Project.

Our objective was to evaluate the association of antioxidant intake and the inflammatory potential of the diet with functional decline in older men. A diet history questionnaire was used to collect dietary intake data from men aged ≥ 75 years (n 794) participating in the Concord Health and Aging in Men Project cohort study. Intake of vitamins A, C, E and Zn were compared with the Australian Nutrient Reference Values to determine adequacy. The Energy-adjusted Dietary Inflammatory Index (E-DIITM) was used to assess the inflammatory potential of the diet. Physical performance data were collected via handgrip strength and walking speed tests, and activities of daily living (ADL) and instrumental activities of daily living (IADL) questionnaires, at baseline and 3-year follow-up (n 616). Logistic regression analysis was used to identify associations between diet and incident poor physical function and disability. Both poor antioxidant intake and high E-DII scores at baseline were significantly associated with poor grip strength and ADL disability at 3-year follow-up. No significant associations with walking speed or IADL disability were observed. Individual micronutrient analysis revealed a significant association between the lowest two quartiles of vitamin C intake and poor grip strength. The lowest quartiles of intake for vitamins A, C, E and Zn were significantly associated with incident ADL disability. The study observed that poor antioxidant and anti-inflammatory food intake were associated with odds of developing disability and declining muscle strength in older men. Further interventional research is necessary to clarify the causality of these associations.

Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy.

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

Cross-sectional and longitudinal associations between empirically derived dietary patterns and frailty among older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet may be associated with frailty. OBJECTIVE: We aimed to evaluate the associations between empirically derived dietary patterns and frailty in older men. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 785 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Factor analysis identified three dietary patterns. Multinomial logistic regression was conducted between frailty and dietary patterns for cross-sectional analyses and longitudinal analyses over a 3-year follow-up. Frailty was defined by the Fried frailty phenotype. RESULTS: Of the 785 men, pre-frailty was prevalent in 47.1% (n = 370), and frailty in 8.3% (n = 65). In fully adjusted cross-sectional analyses, the top tertile and a higher 'vegetables-legumes-seafood' dietary pattern score were associated with reduced prevalence of frailty (OR 0.34 [95% CI: 0.12, 0.93, P = .036]) and OR 0.50 [95% CI: 0.30, 0.83, P = .007] respectively). The top tertile of the 'discretionary-starchy vegetables-processed meats' dietary pattern was also associated cross-sectionally with increased prevalence of pre-frailty (OR 1.75 [95% CI: 1.08, 2.83, P = .022]). Of the 296 robust men in fully adjusted longitudinal analyses, the incidence of pre-frailty was 52.4% (n = 155), and frailty was 5.4% (n = 16) over a 3-year follow-up. The middle tertile of the 'vegetables-legumes-seafood' dietary pattern had a non-significant trend towards reduced incident pre-frailty (OR 0.52 [95% CI: 0.27, 1.00, P = .050]). CONCLUSION: Consumption of a 'vegetables-legumes-seafood' dietary pattern appears to be less favoured by frail older men.

Testicular function after non-cytotoxic and immunotherapy drug treatment.

BACKGROUND: The effects of novel non-cytotoxic and immunotherapy drugs for cancer treatment on human testicular function have not been studied systematically. OBJECTIVES: The present study aimed to characterize effects of non-cytotoxic and immunotherapy drugs in patients with cancers who had not been previously treated with gonadotoxic chemo- or radiotherapy. MATERIALS AND METHODS: This study involved 34 men, not previously treated with gonadotoxic regimens, in a mixed longitudinal (Cohort 1: 19 men about to start and approximately 1 year on non-cytotoxic and immunotherapy treatment) and cross-sectional (Cohort 2: 15 men already on non-cytotoxic and immunotherapy treatment) study using data modeling to estimate within-person time-course changes in testicular exocrine and endocrine functions. Cohort 1 provided 45 paired semen and blood samples (34 prior to and nine during treatment) and Cohort 2 provided 45 sets of samples (15 pre-treatment, 30 on treatment), including six men in Cohort 2 who had pre-treatment spermatozoa cryostorage prior to the study. Men on non-cytotoxic and immunotherapy treatment had undergone a median of 33.5 months long-term treatment. RESULTS: Spermatozoa output and concentration were reduced by about 50%, with corresponding increases in serum follicle-stimulating hormone and decreases in serum inhibin B. Serum testosterone, luteinizing hormone, and sex hormone-binding globulin were unaffected by non-cytotoxic and immunotherapy treatment. CONCLUSION: Within limits of the present study of sample size and duration of on-non-cytotoxic and immunotherapy treatment, non-cytotoxic and immunotherapy drugs have a modest effects on testicular exocrine function (sperm production) or its hormonal correlates (follicle-stimulating hormone, inhibin B), with minimal impact on testicular endocrine (testosterone, luteinizing hormone) function.