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Objective: Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70-84 years., Methods: Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups., Results: Mean age was 76.7 ± 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 µg/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018)., Conclusions: Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.

Context: Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5α-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations., Design: Cross-sectional analysis of 1865 community-dwelling men aged 50.4 ± 16.8 years., Measurements: Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors., Results: SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P < 0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P < 0.001). These haplotypes were associated primarily with differences in E2 in men <65 years and LH in men ≥65 years., Conclusions: A 5α-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study., (© 2018 John Wiley & Sons Ltd.)

Context: Lower testosterone (T) is associated with poorer health outcomes in older men, however, the relationship between T, dihydrotestosterone (DHT) and estradiol (E2) with cardiovascular disease (CVD) in younger to middle-aged men remains unclear., Objectives: We assessed associations between endogenous sex hormones with mortality (all-cause and CVD) and CVD events, in a cohort of men aged 17-97 years., Participants and Methods: Sex hormones were assayed using mass spectrometry in 2143 men from the 1994/5 Busselton Health Survey. Outcomes to December 2010 were analysed., Results: Of the 1804 men included in the analysis, mean age was 50·3 ± 16·8 years and 68·9% of men were aged <60. Mean follow-up period was 14·9 years. There were 319 deaths, 141 CVD deaths and 399 CVD events. Compared to the full cohort, men who died had lower baseline T (12·0 ± 4·4 vs 13·6 ± 4·9 nmol/l), free T (181·9 ± 52·9 vs 218·3 ± 63·8 pmol/l) and DHT (1·65 ± 0·64 vs 1·70 ± 0·72 nmol/l), but higher E2 (64·0 ± 32 vs 60·1 ± 30·2 pmol/l). After adjustment for risk factors, T was not associated with mortality (adjusted HR = 0·90, 95% CI 0·79-1·04; P = 0·164 for every increase in 1 SD of T), CVD deaths (adjusted HR = 1·04, 95% CI 0·84-1·29; P = 0·708) or CVD events (adjusted HR = 1·03, 95% CI 0·92-1·15, P = 0·661). No associations were found for free T, DHT or E2. Results were similar for men older and younger than 60 years., Conclusions: In predominantly middle-aged men, T, DHT and E2 do not influence mortality or CVD outcomes. This neutral association of hormones with CVD contrasts with prior studies of older men., (© 2016 John Wiley & Sons Ltd.)

Context: Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro., Objective: The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms 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 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio., Results: Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030; E2, r = 0.068, P = .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 < .0001; T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .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., Conclusions: In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that 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 aging in men.

Context: In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers., Participants: PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia., Main Outcome Measures: Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry., Results: Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover., Conclusions: Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.

Clarifying the relationship of sex hormones to preclinical atherosclerosis could illuminate pathways by which androgens are associated with cardiovascular events and mortality. Our aim was to determine hormone profiles associated with carotid intima-media thickness (CIMT) and carotid atheroma, in men with and without known coronary artery disease (CAD). We included 492 community-based men aged 20-70 years (Group A) and 426 men with angiographically proven CAD aged <60 years (Group B). Fasting early morning sera were assayed for testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) using mass spectrometry. CIMT and carotid plaque were assessed ultrasonographically. Mean (±SD) age was Group A: 53.8±12.6 and Group B: 49.6±5.1 years. Higher T was associated with reduced CIMT (-0.011 mm per 1-SD increase, p=0.042) and lower prevalence of carotid plaque (odds ratio [OR] per 1-SD increase, 0.68, p=0.012) in Group A, but not B. E2 was associated with increased CIMT in Group A (0.013 mm, p=0.011) but not B. Higher DHT and E2 were associated with reduced carotid plaque in Group B (DHT: OR=0.77, p=0.024; E2: OR=0.75, p=0.008), but not A. In community-dwelling men, higher T is associated with favourable CIMT and lower prevalence of carotid plaque, while higher E2 is associated with worse CIMT. In men with CAD, higher DHT or E2 are associated with less carotid plaque. T, DHT and E2 are differentially associated with preclinical carotid atherosclerosis in a cardiovascular phenotype-specific manner. Interventional studies are needed to examine effects of exogenous T and its metabolites DHT and E2, on atherogenesis.

Objectives: Lower testosterone (T) levels are associated with poorer health outcomes in older men, but associations in younger or middle-aged men are uncertain, and data for dihydrotestosterone (DHT) and oestradiol (E2) are limited. We assessed the associations of circulating T, DHT and E2 with physical and health-related factors in a cohort comprising men aged 17-97 years., Participants and Methods: Serum from 2143 community-dwelling men from the 1994/95 Busselton Health Survey was assayed for T, DHT and E2 using liquid chromatography-tandem mass spectrometry. Men receiving hormonal therapy or reporting the use of testosterone, or with prostate cancer or orchidectomy were excluded., Results: Of the men, 43% had never smoked, 6·1% had diabetes and 16·8% cardiovascular disease (CVD). Mean (±SD) age was 50·3 ± 17·0 years. Total T was moderately correlated with DHT (r = 0·56), E2 (r = 0·35) and sex hormone-binding globulin (r = 0·53). In age-, smoking-, body mass index (BMI)- and sex hormone-binding globulin (SHBG)-adjusted analyses, T was inversely associated with metabolic syndrome score, while DHT and E2 were not associated. In multivariable models, higher total T was associated with lower age, BMI and C-reactive protein, and with higher creatinine and haemoglobin, independently of SHBG. Higher DHT was associated with lower age, BMI and glucose level, and higher creatinine and haemoglobin. E2 was positively associated with age, BMI and haemoglobin., Conclusions: In men spanning younger, middle and older ages, circulating androgens are more related to age and metabolic factors than CVD or chronic disease. Further investigation is required to clarify whether androgens and oestrogens have contrasting roles as risk predictors for CVD., (© 2014 John Wiley & Sons Ltd.)

Objective Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy ( ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. Design We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). Methods We measured leucocyte telomere length ( LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference ( MAD) (95% confidence interval) between groups during follow-up. Results Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [−0.004; 0.213], P=.235). Conclusions Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]