Significant advances in health and social wellbeing have led to linear gains in life expectancy and an accompanying increase in the burden imposed by age-related morbidities. Complex alterations in hormonal networks which regulate homeostasis and survival may underlie this poor adaptation to later life, as exemplified by an increased fracture risk amongst post-menopausal women. Beyond overt under- or overactivity of hormonal axes, changes in the concentrations of regulatory hormones may also impact on health and disease. Subclinical hyperthyroidism, a disorder characterised by normal thyroxine levels in the presence of decreased thyroid-stimulating hormone, is, for instance, independently associated with an increased risk of atrial fibrillation amongst elderly populations. Both the menopause and subclinical thyroid disease demonstrate the difficulty in reversing endocrine changes in later life, with minimal impact from thyroxine therapy in subclinical hypothyroidism and multiple reports of harm resulting from hormone replacement therapy in peri- and post-menopausal women. Given these findings, strategies to locally regulate hormone bioavailability by altering pre-receptor metabolism may offer greater therapeutic potential in the fight against age-related disease. This review aims to provide an overview of the ageing endocrine system and its potential impact on health and disease in the elderly. It will postulate that strategies to coordinate pre-receptor hormone metabolism and a greater understanding of putative hormonal longevity pathways may offer key new drug targets in the fight against ageing, and will argue against applying the conventional endocrine maxim of ‘block and replace' to hormonal changes seen during ageing.

Keywords:
Ageing, Endocrine, Hormone, Elderly, Longevity, Metabolism
1.
Christensen K, Doblhammer G, Rau R, Vaulpel JW: Ageing populations: the challenges ahead. Lancet 2009;374:1196-1208.
2.
Russell SJ, Kahn CR: Endocrine regulation of ageing. Nat Rev Mol Cell Biol 2007;8:681-691.
3.
Masoro EJ: Overview of caloric restriction and ageing. Mech Ageing Dev 2005;126:913-922.
4.
Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS: A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 2001;292:107-110.
5.
Arantes-Oliveira N, Berman JR, Kenyon C: Healthy animals with extreme longevity. Science 2003;302:611.
6.
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A: Dwarf mice and the ageing process. Nature 1996;384:33.
7.
Katic M, Kennedy AR, Leykin I, Norris A, McGettrick A, Gesta S, Russell SJ, Bluher M, Maratos-Flier E, Kahn CR: Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice. Aging Cell 2007;6:827-839.
8.
Batrinos ML: The aging of the endocrine hypothalamus and its dependent endocrine glands. Hormones 2012;11:241-253.
9.
El Khoudary SR, McClure CK, VoPham T, Karvonen-Gutierrez CA, Sternfeld B, Cauley JA, Khalil N, Sutton-Tyrrell K: Longitudinal assessment of the menopausal transition, endogenous sex hormones, and perception of physical functioning: the Study of Women's Health Across the Nation. J Gerontol A Biol Sci Med Sci 2014;69:1011-1017.
10.
Marioribanks J, Farquhar C, Roberts H, Lethaby A: Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2012;7:CD004143.
11.
Somboonporn W, Davis S, Seif MW, Bell R: Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev 2005;4:CD004509.
12.
Cunningham GR: Andropause or male menopause? Rationale for testosterone replacement therapy in older men with low testosterone levels. Endocr Pract 2013;19:847-852.
13.
Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT; EMAS Group: Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123-135.
14.
El-Sakka AI, Hassoba HM: Age related testosterone depletion in patients with erectile dysfunction. J Urol 2006;176:2589-2593.
15.
Janicki SC, Schupf N: Hormonal influences on cognition and risk for Alzheimer's disease. Curr Neurol Neurosci Rep 2010;10:359-366.
16.
Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O'Connell D, Cranny A; Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group: Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:529-539.
17.
Scopacasa F, Wishart JM, Need AG, Horowitz M, Morris HA, Nordin BE: Bone density and bone-related biochemical variables in normal men: a longitudinal study. J Gerontol A Biol Sci Med Sci 2002;57:M385-M391.
18.
Stanworth RD, Jones TH: Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging 2008;3:25-44.
19.
Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91-95.
20.
Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS: Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056-1061.
21.
Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL: Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 1998;83:2266-2274.
22.
Vigen R, O'Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi L, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836.
23.
Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN: Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e85805.
24.
Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S: Adverse events associated with testosterone administration. N Engl J Med 2010;363:109-122.
25.
Grodstein F, Lifford K, Resnick NM, Gurhan GC: Postmenopausal hormone therapy and risk of developing urinary incontinence. Obstet Gynecol 2004;103:254-260.
26.
Chahal HS, Drake WM: The endocrine system and ageing. J Pathol 2007;211:173-180.
27.
Panay N, Hamoda H, Arya R, Savvas M; British Menopause Society and Women's Health Concern: The 2013 British Menopause Society & Women's Health Concern recommendations on hormone replacement therapy. Menopause Int 2013;19:59-68.
28.
US Preventive Services Task Force: Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 2002;137:834-839.
29.
Johnson JR, Lacey JV Jr, Lazovich D, Geller MA, Schairer C, Shatzkin A, Flood A: Menopausal hormone therapy and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009;18:196-203.
30.
Perrini S, Laviola L, Natalicchio A, Giorgino F: Associated hormonal declines in aging: DHEAS. J Endocrinol Invest 2005;28(3 suppl): 85-93.
31.
Salvini S, Stampfer MJ, Barbieri RL, Hennekens CH: Effects of age, smoking and vitamins on plasma DHEAS levels: a cross-sectional study in men. J Clin Endocrinol Metab 1992;74:139-143.
32.
Kedziora-Kornatowska K, Beszczynska-Oles R, Kornatowski T, Szadujkis-Szadurski L: The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007;52(suppl 1):126-130.
33.
Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Fauconau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharriere O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F: Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci U S A 2000;97:4279-4284.
34.
Laughlin GA, Barrett-Connor E: Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85:3561-3568.
35.
Veldhuis JD, Sharma A, Roelfsema F: Age-dependent and gender-dependent regulation of hypothalamic-adrenocorticotropic-adrenal axis. Endocrinol Metab Clin North Am 2013;42:201-225.
36.
Zaidi SK, Shen W-J, Azhar S: Impact of aging on steroid hormone biosynthesis and secretion. Open Longev Sci 2012;6:1-30.
37.
Boelaert K: Thyroid dysfunction in the elderly. Nat Rev Endocrinol 2013;9:194-204.
38.
Roberts CG, Ladenson PW: Hypothyroidism. Lancet 2004;363:793-803.
39.
Boelaert K, Torlinska B, Holder RL, Franklyn JA: Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study. J Clin Endocrinol Metab 2010;95:2715-2726.
40.
Haugen BR: Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 2009;23:793-800.
41.
Franklyn JA: The thyroid - too much and too little across the ages. The consequences of subclinical thyroid dysfunction. Clin Endocrinol (Oxf) 2013;78:1-8.
42.
Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG: Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292:2591-2599.
43.
Vadiveloo T, Donnan PT, Cochrane L, Leese GP: The Thyroid Epidemiology, Audit, and Research Study (TEARS): the natural history of endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 2011;96:E1-E8.
44.
Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP: Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest 1981;67:1361-1369.
45.
Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ: The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 2013;9:366-376.
46.
Roelfsema F, Pijl H, Keenan DM, Veldhuis JD: Prolactin secretion in healthy adults is determined by gender, age and body mass index. PLoS One 2012;7:e31305.
47.
Bubenik GA, Konturek SJ: Melatonin and aging: prospects for human treatment. J Physiol Pharmacol 2011;62:13-19.
48.
Kushner JA: The role of aging upon β cell turnover. J Clin Invest 2013;123:990-995.
49.
Gunasekaran U, Gannon M: Type 2 diabetes and the aging pancreatic beta cell. Aging 2011;3:565-575.
50.
Atalayer D, Astbury NM: Anorexia of aging and gut hormones. Aging Dis 2013;4:264-275.
51.
Tuohimaa P: Vitamin D and aging. J Steroid Biochem Mol Biol 2009;114:78-84.
52.
Grant WB: Critique of the U-shaped serum 25-hydroxyvitamin D level-disease response relation. Dermatoendocrinol 2009;1:289-293.
53.
Tiganescu A, Tahrani AA, Morgan SA, Ontranto M, Desmoulière A, Abrahams L, Hassan-Smith Z, Walker AE, Rabbitt EH, Cooper MS, Amrein K, Lavery GG, Stewart PM: 11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest 2013;123:3051-3060.
54.
Yau JL, Noble J, Seckl JR: 11β-Hydroxysteroid dehydrogenase type 1 deficiency prevents memory deficits with aging by switching from glucocorticoid receptor to mineralocorticoid receptor-mediated cognitive control. J Neurosci 2011;31:4188-4193.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.