Hormones and Aging: An Endocrine Society Scientific Statement

Anne R. Cappola; Richard J. Auchus; Ghada El-Hajj Fuleihan; David J. Handelsman; Rita R. Kalyani; Michael McClung; Cynthia A. Stuenkel; Michael O. Thorner; Joseph G. Verbalis

Disclosures

J Clin Endocrinol Metab. 2023;108(8):1835-1874.

Abstract and Introduction

Abstract

Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals.

Introduction

Hormones regulate and coordinate multiple physiologic functions. With increasing age, declines in physical and cognitive function occur. The extent to which age-associated changes in hormonal regulation and increases in prevalence of specific endocrine diseases contribute to declines in physical and cognitive function is incompletely understood. This area will only expand in importance as the number of older individuals increases worldwide. Current projections show an increase in those aged 65 years and older from 703 million (1 in 11 people) to 1.5 billion in 2050 (1 in 6 people).^[1]

This Scientific Statement was developed to provide a high-level summary of the current state of research across multiple hormonal axes in aging and to identify areas in need of future research. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The extent to which hormonal changes with age are deemed "normal aging" vs "endocrine disease" can be arbitrary and depends in part on whether treatment is currently indicated. Four hypothalamic-pituitary axes are presented: growth hormone, adrenal, gonadal (divided into ovarian and testicular), and thyroid. These are followed by osteoporosis, vitamin D deficiency, diabetes, and water metabolism topics. Geroscience has emerged as a research approach examining biological mechanisms of aging and their interplay with comorbid disease. In the conclusion, cross-cutting themes of research areas in need of further investigation and the need for geroscience approaches are summarized.

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Next Section

Abstract and Introduction
Growth Hormone Axis
Adrenal Axis
Ovarian Axis
Testicular Axis
Thyroid Axis
Osteoporosis
Type 2 Diabetes
The Hypothalamic-neurohypophyseal-renal Axis
Conclusions
References

Table 1. Randomized primary prevention trials evaluating effects of menopausal hormone therapy on clinical and surrogate cardiovascular outcomes in healthy, recently postmenopausal women
Study name	N	Age at baseline (y)	Dates	Duration (y)
The Massachusetts Women's Health Study (99)	2570	45–55	1981–1986	5
The Melbourne Women's Midlife Health Project (100)	438	45–55	1996–2005	9
Penn Ovarian Aging Study (101)	436	35–47	1996–2014	18
The Seattle Midlife Women's Health Study (102)	508	35–55	1990–2013	23
University of Pittsburgh Healthy Women Study (103)	532	42–50	1983–2008	25
Study of Women's Health Across the Nation (104)	3302	40–55	1994-ongoing	28

Table 2. Randomized primary prevention trials evaluating effects of menopausal hormone therapy on clinical and surrogate cardiovascular outcomes in healthy, recently postmenopausal women
Trial	MHT preparation and dose	N	Age (y)	Duration (y)	Outcomes
Clinical outcomes
WHI E-alone (117)	CEE 0.625 mg/d po	3313	50–59	7.2	Reduced MI, CAC, and revascularization
WHI E + P (117)	CEE 0.625 mg/d and MPA 2.5 mg/d po	5520	50–59	5.6	No benefit
DOPS (134)	17-B E2 2 mg/day and norethisterone acetate 1 mg 10 days/mo po	1006	45–58	10	Reduced composite serious adverse events: death, hospitalized MI, or CHF
Surrogate outcomes
KEEPS (135)	CEE 0.45 mg/d po or TD E2 50 mcg and progesterone 200 mg 12 days/mo po	727	42–58	4	No benefit cIMT or CAC
ELITE (136)	17-B E2 1 mg/d po and progesterone 45 mg vaginal gel 10 days/mo	596	55–64	5	Reduced cIMT early groupNo benefit CAC

Early <6 years since menopause vs late ≥10 years since menopause.
Abbreviations: CAC, coronary artery calcium; CEE, conjugated equine estrogens; CHF, congestive heart failure; cIMT, carotid intima-medial thickness; DOPS, Danish Osteoporosis Prevention Study (randomized, not blinded); E2, estradiol; E-alone, estrogen alone trial; E + P, estrogen plus progestogen; ELITE, Early vs Late Postmenopausal Treatment with Estradiol; KEEPS, Kronos Early Estrogen Prevention Study; MHT, menopausal hormone therapy; MI, myocardial infarction; MPA, medroxyprogesterone acetate; po, oral; TD, transdermal; WHI, Women's Health Initiative; y, years.

Table 3. Drugs approved in United States for treating osteoporosis
Drug	Drug class	Dose, route of administration and dosing interval	Approved for treating men with osteoporosis	Fracture risk reduction (in primary analyses of registration trials)			Subgroup analysis of older study participants
Drug	Drug class	Dose, route of administration and dosing interval	Approved for treating men with osteoporosis	Vertebral fracture	Nonvertebral fracture	Hip fracture	Subgroup analysis of older study participants
Raloxifene	EAA	60 mg po daily		✓
Alendronate	bisphosphonate	70 mg po once weekly	✓	✓		✓	✓
Risedronate	bisphosphonate	35 mg po once weekly or 150 mg po once monthly	✓	✓	✓	✓	✓
Ibandronate	bisphosphonate	150 mg po once monthly or 3 mg IV every 3 months		✓
Zoledronate	bisphosphonate	5 mg IV every year	✓	✓	✓	✓	✓
Denosumab	RANK ligand inhibitor	60 mg SQ once every 6 months	✓	✓	✓	✓	✓
Teriparatide	PTH receptor agonist	20 mcg SQ daily	✓	✓	✓		✓
Abaloparatide	PTH receptor agonist	80 mcg SQ daily		✓	✓		✓
Romosozumab	sclerostin inhibitor	210 mg SQ once monthly		✓	✓	✓
Calcitonin-salmon	calcitonin	200 USP units by nasal spray daily		✓

Abbreviations: EAA, estrogen agonist/antagonist; IV, intravenous; PTH, parathyroid hormone; SQ, subcutaneous.

Table 4. Major placebo-controlled megatrials ^a of vitamin D therapy and impact on major outcomes
Trial	N	Baseline 25OHD ng/mL	Age years/gender	Doses & frequency	Median duration	Primary outcomes
Trivedi, 2003 (312)	2686	NA	65–85; both	Monthly 100 000 IU oral vitamin D3	5 years	Vitamin D reduced any first fracture (RR = 0.78 [0.61–0.99]) and first hip, wrist or forearm, or vertebral fracture (RR = 0.67 [0.48–0.93]) and did not significantly reduce mortality (RR = 0.88 [0.74–1.06]).
RECORD Grant, 2005 (316)	5292	15.2 ± 6.5 [n = 60]	>70; both	Daily 800 IU oral vitamin D3	45 months	Vitamin D did not significantly reduce the incidence of new, low-trauma fractures (HR = 1.02 [0.88–1.19]).
WHI Jackson, 2006 (317)	36 282	NA^b	50–79; women	Daily 400 IU oral vitamin D3	7 years	Vitamin D with calcium did not significantly reduce hip fracture (HR = 0.88 [0.72–1.08]), clinical spine fracture (HR = 0.90 [0.74–1.10]), and total fractures (HR = 0.96 [0.91–1.02]).
CAPS Lappe, 2017 (318)	2303	32.8 ± 10.5	≥55 women	Daily 2000 IU oral vitamin D3	4 years	Vitamin D did not reduce cancer incidence (difference of 1.69% [−0.06–3.46%]).
ViDa Study Scragg, 2017 (319)	5110	26.5 ± 9	50–84; both	Monthly 100 000 IU oral vitamin D3	3.3 years	Vitamin D did not significantly reduce the primary endpoint of incident cardiovascular disease (HR = 1.02 [0.87–1.20]).
D2d Pittas, 2019 (320)	2423	28.0 ± 10.2	>30; both	Daily 4000 IU oral vitamin D₃	2.5 years	Vitamin D did not significantly reduce the risk of diabetes among persons at high risk for type 2 diabetes (HR = 0.88 [0.75–1.04]).
VITAL Manson, 2019 (321)	25 871	30.8 ± 10.0 [n = 15 787]	Men ≥50 Women ≥55	Daily 2000 IU oral vitamin D3	5.3 years	Vitamin D did not significantly reduce the co-primary endpoints of any invasive cancer incidence (HR = 0.96 [0.88–1.06]) or major cardiovascular events (HR = 0.97 [0.85–1.12]).
DO-HEALTH Bischoff-Ferrari, 2020 (322)	2157	22.4 ± 8.4	≥70; both	Daily 2000 IU oral vitamin D3	3 years	Vitamin D did not significantly reduce incident nonvertebral fractures, cognitive decline, or rate of infections, or improve physical performance or systolic and diastolic blood pressure.
D-Health Trial Neale, 2022 (323)	21 315	NA^c	≥60; both	Monthly 60 000 IU oral vitamin D3	5.7 years	Vitamin D did not significantly reduce mortality (HR = 1.04 [0.93–1.18]).
FIND Virtanen, 2022 (324)	2495	29.9 ± 7.3 [n = 551]	Men ≥60 Women ≥65	Daily 1600 IU or 3200 IU oral vitamin D3	5 years	Vitamin D did not significantly reduce the incidence of major cardiovascular events (HR = 0.90 [0.62–1.32]) or invasive cancer (HR = 1.04 [0.72–1.51]).

Abbreviations: 25(OH)D, 25-hydroxyvitamin D (calcifediol); HR, hazard ratio; NA, not available; RR, relative risk.
^aMegatrials are trials that included ≥2000 study subjects.
^bMean 25(OH)D in a nested case-control assessment was 18.42 ± 9.1 ng/mL for participants who had hip fracture and 19.39 ± 9.41 ng/mL among their controls (P = .17).
^cPredicted de-seasonalized serum 25(OH)D concentration [N (%)]: <50 [2562 (24.0)] Vitamin D group; [2638 (24.8)] placebo group ≥50 [8099 (76.0)] Vitamin D group; [8011 (75.2)] placebo group.

Authors and Disclosures

Anne R. Cappola¹, Richard J. Auchus^2,3, Ghada El-Hajj Fuleihan⁴, David J. Handelsman⁵, Rita R. Kalyani⁶, Michael McClung^7,8, Cynthia A. Stuenkel⁹, Michael O. Thorner^10,11 and Joseph G. Verbalis¹²

¹Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
²Departments of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
³Endocrinology and Metabolism Section, Medical Service, LTC Charles S. Kettles Veteran Affairs Medical Center, Ann Arbor, MI 48015, USA
⁴Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Division of Endocrinology, Department of Internal Medicine, American University of Beirut, Beirut 1107–2020, Lebanon
⁵ANZAC Research Institute, University of Sydney and Andrology Department, Concord Repatriation General Hospital, Sydney 2139, Australia
⁶Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
⁷Oregon Osteoporosis Center, Portland, OR 97213, USA
⁸Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia
⁹Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
¹⁰Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22903, USA
¹¹Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA 02115, USA
¹²Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC 20057, USA

Correspondence
Anne R. Cappola, MD, ScM, Division of Diabetes, Endocrinology, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Bldg 521, Philadelphia, PA 19041, USA. Email: acappola@pennmedicine.upenn.edu.

Disclosures
R.A. has performed contracted research for Corcept Therapeutics and Sparrow Pharmaceuticals and has served as a consultant for Quest Diagnostics, Corcept Therapeutics, PhaseBio Pharmaceuticals, Crinetics Pharmaeuticals, Xeris Pharmaceuticals, and Recordati Rare Diseases. G.E.H.F. is a member of the panel of experts convening at the International Conference on Controversies in Vitamin D in September 2023. Travel and housing to the meeting are covered by Abiogen for all participants, no honorarium received. M.M. has received honorarium and consulting fees from Amgen, honorarium from Alexion, and consulting fees from Myovant. C.A.S. serves as a member of the Data and Safety Monitoring Board for Mithra Pharmaceuticals. M.O.T. is a consultant for and has an equity position in Lumos Pharma Inc. The other authors declare no conflicts.

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Hormones and Aging: An Endocrine Society Scientific Statement

Abstract and Introduction

Abstract

Introduction

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Tables

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Tables

References

Authors and Disclosures

Authors and Disclosures

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