Testosterone therapy for functional hypogonadism in middle-aged and elderly males: current evidence and future perspectives
Abstract
Population aging is a global phenomenon driving research focus toward preventing and managing age-related disorders. Functional hypogonadism (FH) has been defined as the combination of low testosterone levels, typically serum total testosterone below 300-350 ng/dL, together with manifestations of hypogonadism, in the absence of an intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis. It is usually seen in middle-aged or elderly males as a product of aging and multimorbidity. This age-related decline in testosterone levels has been associated with numerous adverse outcomes. Testosterone therapy (TTh) is the mainstay of treatment for organic hypogonadism with an identifiable intrinsic pathology of the HPT axis. Current guidelines generally make weak recommendations for TTh in patients with FH, mostly in the presence of sexual dysfunction. Concerns about long-term safety have historically limited TTh use in middle-aged and elderly males with FH. However, recent randomized controlled trials and meta-analyses have demonstrated safe long-term outcomes regarding prostatic and cardiovascular health, together with decreases in all-cause mortality and improvements in various domains, including sexual function, body composition, physical strength, bone density, and hematopoiesis. Furthermore, there are numerous insightful studies suggesting additional benefits of TTh, for instance in cardio-renal-metabolic conditions. Specifically, future trials should investigate the role of TTh in improving symptoms and prognosis in various clinical contexts, including sarcopenia, frailty, dyslipidemia, arterial hypertension, diabetes mellitus, fracture risk, heart failure, stable angina, chronic kidney disease, mood disorders, and cognitive dysfunction.
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Testosterone stimulates myofibrillar protein synthesis via mTOR activation, enhancing muscle anabolism and reducing protein breakdown, while estrogen modulates muscle sensitivity to insulin, supporting metabolic efficiency and indirectly preserving muscle tissue.
“Testosterone stimulates myofibrillar protein synthesis (MPS) via mechanistic target of rapamycin (mTOR) activation, enhancing muscle anabolism and reducing protein breakdown, while estrogen modulates muscle sensitivity to insulin, supporting metabolic efficiency and indirectly preserving muscle tissue [23].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
Differences in AR density and sensitivity modulate individual muscle gain capacity, with higher AR density responding more robustly to testosterone.
“Differences in AR density and sensitivity modulate individual muscle gain capacity, with those exhibiting higher AR density responding more robustly to testosterone [23].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
Testosterone exerts anabolic effects through AR activation, promoting MPS.
“Testosterone exerts anabolic effects through androgen receptor (AR) activation, promoting MPS.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
Testosterone and estrogen play essential roles in muscle preservation, with testosterone promoting MPS via mTOR and estrogen supporting metabolic efficiency and glucose utilization.
“Testosterone and estrogen play essential roles in muscle preservation, with testosterone promoting MPS via mTOR activation and estrogen supporting metabolic efficiency and glucose utilization.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
Men with higher baseline testosterone levels experience less muscle loss due to testosterone's anti-catabolic effects.
“Men with higher baseline testosterone levels experience less muscle loss due to testosterone’s anti-catabolic effects.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
Variations in the AR gene influence testosterone's efficacy in maintaining lean mass, with certain polymorphisms enhancing muscle preservation during caloric restriction.
“Furthermore, variations in the AR gene influence testosterone’s efficacy in maintaining lean mass, with certain polymorphisms enhancing muscle preservation during caloric restriction [23].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [23]
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Self-citationComprehensive Peri-Operative Risk Assessment and Management of Geriatric Patients
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Self-citationTheodorakis, N., Feretzakis, G., Kreouzi, M., Anagnostou, D., Hitas, C., Verykios, V. S., & Nikolaou, M. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae814 · Cited by 19 · see citing works
Self-citation
- Authors
- Theodorakis, N., Feretzakis, G., Vamvakou, G., Verykios, V. S., Polymeris, A., & Nikolaou, M.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- Hellenic Open University (GR)
- Simanogleio-Amalia Fleming General Hospital (GR)
- Corresponding author
- Feretzakis, Georgios
- ORCID
- Venue
- Hormones
- Published
- 2024-07-26
- Volume
- 23
- Issue
- 4
- Pages
- 801-817
- ISSN
- 1109-3099 (ISSN-L)
- 2520-8721
- OpenAlex
- W4401013264
- Cited by
- 28
- References
- 14
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 8
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- HORMONES (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- testosterone replacement therapy, functional hypogonadism, male hypogonadism, aging, sexual dysfunction, long-term safety, cardiovascular outcomes, prostate health, all-cause mortality, body composition, bone mineral density, sarcopenia, frailty, multimorbidity, chronic kidney disease, mood disorders, cognitive impairment
- MeSH terms
- Aged, Aging, Humans, Hypogonadism, Male, Middle Aged, Testosterone, Hormone Replacement Therapy
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