[Show abstract][Hide abstract] ABSTRACT: Context:
Advancing age is accompanied by accumulation of ill-health and shortening of chromosomal telomeres signifying biological ageing. Testosterone (T) is metabolised to dihydrotestosterone (DHT) by 5|ga-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro.
To establish whether circulating T or its metabolites DHT or E2, and single nucleotide polymorphisms (SNPS) in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men.
Participants and methods:
Early morning serum T, DHT and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 snps and LTL analysed by PCR in 980 men from the Western Australian Busselton Health Survey. LTL was expressed as the T/S ratio.
Men were aged (mean±SD) 53.7±15.6 years. LTL decreased linearly with age, from T/S ratio 1.89±0.41 at <30 years to 1.50±0.49 at 70 to <80 years (r=-0.225, p<0.0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT r=0.069, p=0.030; E2 r=0.068, p=0.034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2 59.3 vs 68.6 pmol/L, p<0.0001; T/S ratio 1.54 vs 1.62, p=0.045), rs10046 C (60.5 vs 68.1 pmol/L, p=0.0005, 1.54 vs 1.62, p=0.035) and rs700518 A (59.9 vs 68.9 pmol/L, p<0.0001, 1.54 vs 1.63, p=0.020). A single copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL.
In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include 3 dominant alleles which are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo thus warranting further studies to examine whether hormonal interventions might slow biological ageing in men.
Full-text · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: To investigate the effects of number of medications and Drug Burden Index (DBI) on transitions between frailty stages and death in community-dwelling older men. Cohort study. Sydney, Australia. Community-dwelling men aged 70 and older (N = 1,705). Self-reported questionnaires and clinic visits were conducted at baseline and 2 and 5 years. Frailty was assessed at all three waves according to the modified Fried frailty phenotype. The total number of regular prescription medications and DBI (a measure of exposure to sedative and anticholinergic medications) were calculated over the three waves. Data on mortality over 9 years were obtained. Multistate modeling was used to characterize the transitions across three frailty states (robust, prefrail, frail) and death. Each additional medication was associated with a 22% greater risk of transitioning from the robust state to death (adjusted 95% confidence interval (CI) = 1.06–1.41). Every unit increase in DBI was associated with a 73% greater risk of transitioning from the robust state to the prefrail state (adjusted 95% CI = 1.30–2.31) and a 2.75 times greater risk of transitioning from the robust state to death (adjusted 95% CI = 1.60–4.75). There was no evidence of an adjusted association between total number of medications or DBI and the other transitions. Although the possibility of confounding by indication cannot be excluded, additional medications were associated with greater risk of mortality in robust community-dwelling older men. Greater DBI was also associated with greater risk of death and transitioning from the robust state to the prefrail state.
No preview · Article · Jan 2016 · Journal of the American Geriatrics Society
[Show abstract][Hide abstract] ABSTRACT: Objective:
To review the doping status of dehydroepiandrosterone (DHEA) for female athletes with adrenal insufficiency within the framework of Therapeutic Use Exemption (TUE) applications for this proandrogen, which is included on the World Anti-Doping Agency (WADA)'s Prohibited List.
Data sources and main results:
Current knowledge of adrenal pathophysiology with a focus on the physiological role and pharmacological effects of DHEA in female athletes including placebo-controlled clinical trials of DHEA and consensus clinical practice and prescribing guidelines.
Because there is no convincing clinical evidence to support the use of DHEA replacement therapy in women with adrenal failure, a TUE for DHEA is not justified by definite health benefit for either secondary or primary adrenal failure. This is consistent with the 2014 update of the US Endocrine Society guidelines, meta-analyses of DHEA treatment in women with or without adrenal failure, current WADA TUE guidance document for adrenal insufficiency and recent case law of WADA's Court of Arbitration for Sport.
Full-text · Article · Dec 2015 · Clinical Journal of Sport Medicine
[Show abstract][Hide abstract] ABSTRACT: Background/Aims
The longitudinal relationships of within-individual hormone and anthropometric changes during puberty have not ever been fully described. The objectives of this study were to demonstrate that 3 monthly urine collection was feasible in young adolescents and to utilise liquid chromatography-tandem mass spectrometry assay methods for serum and urine testosterone (T), estradiol (E2) and luteinizing hormone (LH) in adolescents by relating temporal changes in urine and serum hormones over 12 months to standard measures of pubertal development.
A community sample of 104 adolescents (57 female) was studied over 12 months with annual anthropometric assessment, blood sampling and self-rated Tanner staging and urine collected every 3 months. Serum and urine sex steroids (T, E2) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LH by immunoassay.
A high proportion (92%) of scheduled samples were obtained with low attrition rate of 6.7% over the 12 months. Urine hormone measurements correlated cross-sectionally and longitudinally with age, anthropometry and Tanner stage.
We have developed a feasible and valid sampling methodology and measurements for puberty hormones in urine, which allows a sampling frequency by which individual pubertal progression in adolescents can be described in depth.
[Show abstract][Hide abstract] ABSTRACT: Background:
Depression in older men has been associated with low circulating testosterone concentration but data from prospective studies are limited.
We conducted a prospective longitudinal study in a community representative cohort of 3179 older men free of clinically significant depressive symptoms at baseline. The main objective of this study was to determine if low serum testosterone, dihydrotestosterone and estradiol concentrations are associated with the development of depressive symptoms. Incident depression was assessed with the Patient Health Questionnaire and via an electronic health record database (The West Australian Data Linkage System). The main exposures of interest were serum testosterone, dihydrotestosterone and estradiol measured by liquid chromatography-mass spectrometry and calculated free testosterone in baseline blood samples (collected between 2001 and 2004).
One hundred and thirty five men (4.2%) developed depression over a median follow up time of 9.4 years (range 8.4-10.9). Men with incident depression were older (median age 77.7 vs 76.1 years, z=-3.82, p=0<0.001) and were more likely to have cardiovascular disease (43.0% vs 32.6%, χ(2)=6.32, p=0.012) and diabetes (22.2% vs 13.2%, χ(2)=8.95, p=0.003). Low serum total testosterone (<6.4nmol/L) was associated with incident depression (HR 2.07, 95%CI 1.17-3.68) and this remained significant after adjustment for relevant potential confounding factors (HR 1.86, 95%CI 1.05-3.31). Low serum dihydrotestosterone, estradiol and calculated free testosterone were not associated with risk of depression.
Low serum total testosterone, but not calculated free testosterone, was associated with incident depression in this sample of older men.
No preview · Article · Nov 2015 · Psychoneuroendocrinology
[Show abstract][Hide abstract] ABSTRACT: Background:
Comorbidity and multimorbidity are common in older people. Here we used a novel analytic approach called Association Rules together with network analysis to evaluate multimorbidity (two or more disorders) and comorbidity in old age.
A population-based cross-sectional study was undertaken where 17 morbidities were analyzed using network analysis, cluster analysis, and Association Rules methodology. A comorbidity interestingness score was developed to quantify the richness and variability of comorbidities associated with an index condition. The participants were community-dwelling men aged 70 years or older from the Concord Health and Ageing in Men Project, Sydney, Australia, with complete data (n = 1,464).
The vast majority (75%) of participants had multimorbidity. Several morbidity clusters were apparent (vascular cluster, metabolic cluster, neurodegenerative cluster, mental health and other cluster, and a musculoskeletal and other cluster). Association Rules revealed unexpected comorbidities with high lift and confidence linked to index diseases. Anxiety and heart failure had the highest comorbidity interestingness scores while obesity, hearing impairment, and arthritis had the lowest (zero) scores. We also performed Association Rules analysis for the geriatric syndromes of frailty and falls to determine their association with multimorbidity. Frailty had a very complex and rich set of frequent and interesting comorbidities, while there were no frequent and interesting sets associated with falls.
Old age is characterized by a complex pattern of multimorbidity and comorbidity. Single disease definitions do not account for the prevalence and complexity of multimorbidity in older people and a new lexicon may be needed to underpin research and health care interventions for older people.
No preview · Article · Oct 2015 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
[Show abstract][Hide abstract] ABSTRACT: While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotype in global AR knockout (ARKO) female mice. As AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium (uge) specific AR knockout (ugeARKO) to determine the role of endometrial gland specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function as ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in absence of estrogens the ARKO and ugeARKO females were ovariectomized (OVX) and treated with supraphysiological doses of testosterone or dihydrotestosterone (DHT, non-aromatizable androgen). Both DHT and testosterone supported full uterine regrowth in wild-type (WT) females while ARKO females had no regrowth (comparable to OVX only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in endometrium may indirectly modify myometrial development. Additionally, to confirm the Cre function in endometrial glands, we generated uterine glandular epithelium specific PTEN knockout (ugePTENKO) mouse model. The ugePTENKO females developed severe endometrial hyperplasia and therefore present a novel model for future research.
Full-text · Article · Oct 2015 · Biology of Reproduction
[Show abstract][Hide abstract] ABSTRACT: Background:
Age-specific trends of serum testosterone (T) and sex hormone binding globulin (SHBG) across the full lifespan have not been reported.
We deduced age-specific trends in serum testosterone and SHBG in males and females between ages 10 and 90 from a large sample of consecutive results from a single large pathology laboratory. Coded results of 110,712 consecutive blood samples requesting serum testosterone over 7 years (2007-13) comprising blood T, SHBG and calculated free T (cFT) together with gender and age were analyzed create smoothed age-specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females.
These identified the pubertal increases in serum T in males peaking at 20 years of age and remaining stable thereafter until the 8(t) (h) decade. In women circulating T peaked in late adolescence and declined gradually over the next 2 decades but remained stable across menopause and beyond. After early childhood, serum SHBG declines to a nadir in men the age of 20 years and remain stable till the 6(t) (h) decade with a gradual, progressive rise thereafter. In women the SHBG nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Women also exhibit a second SHBG peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of women.
This large sample of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age.
No preview · Article · Oct 2015 · Annals of Clinical Biochemistry
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters
and influences upon testicular function for a population not selected with regard to fertility?
No preview · Article · Sep 2015 · Human Reproduction
[Show abstract][Hide abstract] ABSTRACT: Context:
The age-specific population profiles in men of circulating testosterone (T) and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described.
To deduce smoothed age-specific centiles of circulating testosterone T, DHT and E2 in men using pooled data from population-based studies in 3 Australian cities from liquid chromatography-mass spectrometry (LC-MS) steroid measurements in a single laboratory.
Design, setting and participants:
Pooled data of 10,904 serum samples (serum T, DHT, E2, age, height, weight) from observational population-based studies in 3 major cities across Australia.
Main outcome measures:
Age-specific smoothed centiles for serum T, DHT and E2 in men aged 35 to 100 years deduced by large sample data analysis methods.
Serum T, DHT and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, body mass index (BMI) and body surface area (BSA) as well as shorter stature are associated with reduced serum T, DHT and E2.
Among Australian men, there is gradual progressive population-wide decline in androgen status during male ageing until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.
No preview · Article · Sep 2015 · European Journal of Endocrinology