title: Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Bu B
authors.initials: BB
authors.lastname: Yeap
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Knuiman
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Divitini
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Jennie
authors.initials: J
authors.lastname: Hui
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Arscott
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Susan V
authors.initials: SV
authors.lastname: McLennan
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Twigg
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Brendan
authors.initials: B
authors.lastname: McQuillan
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hung
authors.affiliation: School of Medicine and Pharmacology (B.B.Y., B.M., J.Hun.), School of Population Health (M.W.K., M.L.D.), and School of Pathology and Laboratory Medicine (J.P.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; PathWest Laboratory Medicine (J.Hui., G.M.A., J.P.B.) and Department of Cardiovascular Medicine (B.M., J.Hun.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2138, Australia; and Department Endocrinology (S.V.M., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Beilby
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D001141:Aromatase / Q000235:genetics; D013196:Dihydrotestosterone / Q000097:blood*; D004958:Estradiol / Q000097:blood*; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016615:Telomere / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*; D014904:Western Australia / Q000453:epidemiology; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D013196:Dihydrotestosterone; D004958:Estradiol; D001141:Aromatase; C561410:CYP19A1 protein, human; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human