A 5α-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally.

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.

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.

CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. PARTICIPANTS AND METHODS: We used cross-sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. RESULTS: Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = -0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient -0.013, P = 0.037) associated with T/S ratio. CONCLUSIONS: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

Serum testosterone and sex hormone-binding globulin are inversely associated with leucocyte telomere length in men: a cross-sectional analysis of the UK Biobank study.

OBJECTIVE: Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men. DESIGN: Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years. METHODS: Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL. RESULTS: In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001). CONCLUSIONS: Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.

U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.

BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain. METHOD: We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease. RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007). CONCLUSIONS: In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.

Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men.

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.

Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men.

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.