madman
Super Moderator
* Male hypogonadism is etiologically heterogeneous, broadly classified as: primary (hypergonadotropic) hypogonadism due to testes failure (e.g. from genetic conditions, trauma or gonadotoxic insults); secondary (hypogonadotropic) hypogonadism due to hypothalamic-pituitary disorders (e.g. tumors, trauma, exogenous opioids); or functional hypogonadism (FH), a reversible form often associated with systemic comorbidities. FH – sometimes termed age-related hypogonadism – occurs typically in older, multimorbid men and represents a combined dysfunction of both central and gonadal regulation [2]. It is crucial to emphasize that aging per se is not a direct cause of testosterone deficiency; rather, common age-associated conditions such as obesity, metabolic syndrome, and type 2 diabetes mellitus precipitate a decline in testosterone through inflammatory mediators and other adipose- derived factors, leading to a “functional” androgen deficiency [4–7]. Thus, the colloquial notion of an inevitable “male menopause” is a misnomer – not every older man develops hypogonadism, only those with specific pathological comorbidities do (5, Fig. 1).
* Optimal outcomes hinge upon meticulous patient selection, exclusion of contraindications (e.g., active prostate carcinoma or current fertility intention), and vigilant monitoring of prostate health and hematocrit. When applied with discernment, testosterone therapy offers a safe and efficacious means of restoring androgen sufficiency, thereby enhancing male health and well-being in its fullest sense.
Fig. 7. Symptoms and systemic interactions of functional hypogonadism. Includes metabolic, musculoskeletal, cardiovascular, sexual, hematologic, and neuropsychiatric domains such as obesity, insulin resistance, osteoporosis, anemia, depression, fatigue, and sexual dysfunction. Adapted from [1–3].
Functional testosterone deficiency in aging men: Clinical impact, diagnostic pathways, and treatment strategies (2026)
Michael Zitzmann, Armin Soave, Simone Bier
ABSRTRACT
Background
Testosterone constitutes an indispensable determinant of male corporeal integrity, psychological resilience, and overall vitality across the life course. Testosterone deficiency (male hypogonadism) represents an endocrine disorder capable of engendering a broad spectrum of somatic derangements and psychosocial sequelae. Its origins may lie in testicular insufficiency, hypothalamic-pituitary dysfunction, or, more subtly, in functional hypogonadism arising from comorbid states such as obesity and type 2 diabetes mellitus.
Methods
This review distills contemporary evidence on the pathophysiology, clinical expression, diagnostic algorithms, and therapeutic armamentarium of male hypogonadism, with particular attention to functional hypogonadism and its repercussions for quality of life. Data from recent randomized trials and large-scale observational studies delineate both the efficacy and the safety of therapeutic strategies.
Results
Hypogonadism—whether primary, secondary, or functional - commonly manifests through disturbances of mood and cognition (including depression, fatigue, and mental decline), sexual dysfunction (diminished libido and impaired erectile capacity), disproportionate visceral adiposity, sarcopenia, osteopenia or osteoporosis, and anemia. These cumulative impairments markedly degrade quality of life. Crucially, aging per se does not precipitate hypogonadism; rather, age-associated comorbidities catalyze the emergence of functional hypogonadism. Epidemiological data corroborate a bidirectional nexus between functional hypogonadism and the metabolic syndrome, both being harbingers of increased cardiovascular mortality. Guideline-directed testosterone therapy, when judiciously prescribed, can reverse many of these perturbations—ameliorating sexual function, mood, vitality, muscle mass, bone density, and anemia—while simultaneously mitigating metabolic derangement.
Conclusions
Converging evidence, including from recent large-scale randomized controlled trials, demonstrates that modern testosterone therapy does not augment cardiovascular risk or mortality. On the contrary, it confers tangible metabolic and quality-of-life advantages, even in advanced age, provided coexistent conditions are addressed concomitantly. Optimal outcomes hinge upon meticulous patient selection, exclusion of contraindications (e.g., active prostate carcinoma or current fertility intention), and vigilant monitoring of prostate health and hematocrit. When applied with discernment, testosterone therapy offers a safe and efficacious means of restoring androgen sufficiency, thereby enhancing male health and well-being in its fullest sense.
8. Updating and verification
The search was updated in January 2026 to ensure incorporation of the most recent evidence, including emerging analyses on cardiovascular safety, hematologic responses, and metabolic outcomes. Statements were cross-checked against primary data and guideline recommendations to maintain scientific accuracy.
9. Pathophysiology of male hypogonadism
10. Hypogonadism in older men: Clinical manifestations and quality-of-life impact
The clinical presentation of male hypogonadism is heterogeneous, ranging from subtle symptoms to pronounced, debilitating changes. The phenotype in an individual patient depends on the degree and duration of T deficiency, the age of onset (e.g. pre- vs. post-puberty), and intrinsic sensitivity to androgens. In older men with functional hypogonadism, symptoms may be mistakenly attributed to “normal aging,” but often an underlying androgen deficit is contributing to their severity [1–3,7]. Key manifestations involve multiple organ systems [14,15]:
• Sexual Dysfunction
• Mood and Motivation
• Physical Composition and Strength
• Metabolic and Hematologic Effects
11. Diagnostic approach to male hypogonadism
11.1. Clinical evaluation
11.2. Laboratory tests
12. Management of hypogonadism: Testosterone therapy (TTh) and other modalities
1. General remarks
The treatment of male hypogonadism is centered on TTh to restore physiological androgen levels and alleviate symptoms, alongside management of any underlying conditions. Prior to initiating therapy, two critical considerations guide the treatment strategy:
(a) Etiology – primary, secondary, or functional hypogonadism: This determines whether direct testosterone replacement is appropriate (primary hypogonadism) or whether other approaches (e.g. gonadotropin therapy) are indicated (particularly in secondary cases where fertility is desired) or, in FH, treatment of the underlying disease is paramount [1–3].
(b) Presence of Contraindications: Certain medical conditions preclude or postpone the use of exogenous testosterone, and these must be screened for in every patient.
TTh is indicated for men with clinically significant hypogonadism (both symptoms and biochemical evidence of low testosterone) in the absence of contraindications. Before prescribing, it is imperative to exclude conditions that could be worsened by testosterone. According to consensus guidelines [1–3], absolute or relative contraindications to testosterone therapy include:
• Active or suspected prostate cancer (and untreated high-grade prostatic intraepithelial neoplasia)
• Notwithstanding, although active or suspected prostate cancer has for decades been regarded as an absolute contraindication to testosterone replacement therapy, this long-standing paradigm has been increasingly questioned.
• Severe benign prostatic hyperplasia (BPH) with obstructive urinary symptoms
• Male breast cancer (untreated)
• Polycythemia (hematocrit above ~ 50%) of unclear origin
• Known thrombophilia
• Obstructive sleep apnea (OSA) that is untreated
• Uncontrolled congestive heart failure (especially class III-IV) or recent myocardial infarction/stroke
• Desire for fertility in the near-term
• High-risk or aggressive behavior potentially exacerbated by T
If any of these conditions are present, clinicians should either treat/ resolve the condition first or, if permanent, refrain from testosterone therapy and consider alternative management for hypogonadal symptoms.
2. Therapeutic Options for Testosterone Restoration
3. Management of Functional Hypogonadism
4. Monitoring and Follow-Up
5. Symptomatic and Functional Benefits of Testosterone Therapy in Functional Hypogonadism
6. Cardiovascular and other Safety Considerations
14. Conclusion
Male hypogonadism, including the prevalent functional (age- related) form, is a significant but treatable cause of reduced quality of life and increased health risks in men. Through comprehensive evaluation and adherence to evidence-based guidelines, clinicians can Maturitas 207 (2026) 108870 diagnose this condition accurately and implement therapy that profoundly improves patients' well-being (see Fig. 7). TTh, when indicated, offers multi-dimensional benefits – enhancing sexual function, mood, cognition, muscle and bone strength, and metabolic profile – which in concert restore much of what hypogonadal men often feel they have “lost” with the decline in their hormonal milieu. Particularly in older men with FH, management must be holistic: addressing lifestyle factors and comorbid illnesses is as important as prescribing the hormone itself. By treating the whole patient, including encouragement of weight loss and exercise (facilitated by the patient's renewed vigor on testosterone), clinicians can break the vicious cycle of obesity, inflammation, and hormone deficiency.
Crucially, the fear that TTh might precipitate cardiovascular events or prostate cancer – which had often made practitioners reluctant to treat older men – has been largely mitigated if not eliminated by controlled trials. The latest evidence, including the rigorous TRAVERSE study, demonstrates that TTh does not increase cardiovascular risk when used appropriately. This affirmation of safety allows healthcare providers to treat eligible hypogonadal men with greater confidence, provided that sound clinical practices are observed: exclude contraindications (no therapy for those with active prostate or breast cancer, uncontrolled polycythemia, etc.), monitor diligently (regular checks of testosterone levels, hematocrit, PSA, and symptom response), and individualize therapy (tailor form and dose of TTh, and involve the patient in decision-making). In all cases, patients should be educated about the goals of therapy, the importance of follow-up, and the need to report any adverse symptoms promptly.
By following these principles, clinicians can optimize the benefits of TTh while minimizing risks. Treating hypogonadism is not merely about normalizing a laboratory value; it is about restoring a man's quality of life, vitality, and health trajectory. A man with FH who was once fatigued, depressed, and frail can, after appropriate treatment, regain significant physical and mental function, improving not only his own life but also often his engagement in family, work, and society. Modern androgen replacement should thus be viewed as an integral component of healthy aging in men who need it – analogous to hormone therapy in other endocrine disorders – rather than an optional or dangerous indulgence. With the growing evidence base and refined clinical guidelines, testosterone therapy has secured its role as a safe and efficacious intervention for men suffering from the bona fide hypogonadism syndrome.
In conclusion, functional or age-related testosterone deficiency is a genuine medical condition that can severely impair men's quality of life, but it is one that tools to treat safely are available. Through judicious patient selection and guideline-concordant management [1–3], physicians can help hypogonadal men reclaim their health, strength, and well-being, while carefully navigating and monitoring the therapy to ensure sustained safety. The result is not only the mitigation of symptoms, but potentially an improvement in broader health outcomes, making testosterone replacement an important therapy in the care of aging men.
* Optimal outcomes hinge upon meticulous patient selection, exclusion of contraindications (e.g., active prostate carcinoma or current fertility intention), and vigilant monitoring of prostate health and hematocrit. When applied with discernment, testosterone therapy offers a safe and efficacious means of restoring androgen sufficiency, thereby enhancing male health and well-being in its fullest sense.
Fig. 7. Symptoms and systemic interactions of functional hypogonadism. Includes metabolic, musculoskeletal, cardiovascular, sexual, hematologic, and neuropsychiatric domains such as obesity, insulin resistance, osteoporosis, anemia, depression, fatigue, and sexual dysfunction. Adapted from [1–3].
Functional testosterone deficiency in aging men: Clinical impact, diagnostic pathways, and treatment strategies (2026)
Michael Zitzmann, Armin Soave, Simone Bier
ABSRTRACT
Background
Testosterone constitutes an indispensable determinant of male corporeal integrity, psychological resilience, and overall vitality across the life course. Testosterone deficiency (male hypogonadism) represents an endocrine disorder capable of engendering a broad spectrum of somatic derangements and psychosocial sequelae. Its origins may lie in testicular insufficiency, hypothalamic-pituitary dysfunction, or, more subtly, in functional hypogonadism arising from comorbid states such as obesity and type 2 diabetes mellitus.
Methods
This review distills contemporary evidence on the pathophysiology, clinical expression, diagnostic algorithms, and therapeutic armamentarium of male hypogonadism, with particular attention to functional hypogonadism and its repercussions for quality of life. Data from recent randomized trials and large-scale observational studies delineate both the efficacy and the safety of therapeutic strategies.
Results
Hypogonadism—whether primary, secondary, or functional - commonly manifests through disturbances of mood and cognition (including depression, fatigue, and mental decline), sexual dysfunction (diminished libido and impaired erectile capacity), disproportionate visceral adiposity, sarcopenia, osteopenia or osteoporosis, and anemia. These cumulative impairments markedly degrade quality of life. Crucially, aging per se does not precipitate hypogonadism; rather, age-associated comorbidities catalyze the emergence of functional hypogonadism. Epidemiological data corroborate a bidirectional nexus between functional hypogonadism and the metabolic syndrome, both being harbingers of increased cardiovascular mortality. Guideline-directed testosterone therapy, when judiciously prescribed, can reverse many of these perturbations—ameliorating sexual function, mood, vitality, muscle mass, bone density, and anemia—while simultaneously mitigating metabolic derangement.
Conclusions
Converging evidence, including from recent large-scale randomized controlled trials, demonstrates that modern testosterone therapy does not augment cardiovascular risk or mortality. On the contrary, it confers tangible metabolic and quality-of-life advantages, even in advanced age, provided coexistent conditions are addressed concomitantly. Optimal outcomes hinge upon meticulous patient selection, exclusion of contraindications (e.g., active prostate carcinoma or current fertility intention), and vigilant monitoring of prostate health and hematocrit. When applied with discernment, testosterone therapy offers a safe and efficacious means of restoring androgen sufficiency, thereby enhancing male health and well-being in its fullest sense.
8. Updating and verification
The search was updated in January 2026 to ensure incorporation of the most recent evidence, including emerging analyses on cardiovascular safety, hematologic responses, and metabolic outcomes. Statements were cross-checked against primary data and guideline recommendations to maintain scientific accuracy.
9. Pathophysiology of male hypogonadism
10. Hypogonadism in older men: Clinical manifestations and quality-of-life impact
The clinical presentation of male hypogonadism is heterogeneous, ranging from subtle symptoms to pronounced, debilitating changes. The phenotype in an individual patient depends on the degree and duration of T deficiency, the age of onset (e.g. pre- vs. post-puberty), and intrinsic sensitivity to androgens. In older men with functional hypogonadism, symptoms may be mistakenly attributed to “normal aging,” but often an underlying androgen deficit is contributing to their severity [1–3,7]. Key manifestations involve multiple organ systems [14,15]:
• Sexual Dysfunction
• Mood and Motivation
• Physical Composition and Strength
• Metabolic and Hematologic Effects
11. Diagnostic approach to male hypogonadism
11.1. Clinical evaluation
11.2. Laboratory tests
12. Management of hypogonadism: Testosterone therapy (TTh) and other modalities
1. General remarks
The treatment of male hypogonadism is centered on TTh to restore physiological androgen levels and alleviate symptoms, alongside management of any underlying conditions. Prior to initiating therapy, two critical considerations guide the treatment strategy:
(a) Etiology – primary, secondary, or functional hypogonadism: This determines whether direct testosterone replacement is appropriate (primary hypogonadism) or whether other approaches (e.g. gonadotropin therapy) are indicated (particularly in secondary cases where fertility is desired) or, in FH, treatment of the underlying disease is paramount [1–3].
(b) Presence of Contraindications: Certain medical conditions preclude or postpone the use of exogenous testosterone, and these must be screened for in every patient.
TTh is indicated for men with clinically significant hypogonadism (both symptoms and biochemical evidence of low testosterone) in the absence of contraindications. Before prescribing, it is imperative to exclude conditions that could be worsened by testosterone. According to consensus guidelines [1–3], absolute or relative contraindications to testosterone therapy include:
• Active or suspected prostate cancer (and untreated high-grade prostatic intraepithelial neoplasia)
• Notwithstanding, although active or suspected prostate cancer has for decades been regarded as an absolute contraindication to testosterone replacement therapy, this long-standing paradigm has been increasingly questioned.
• Severe benign prostatic hyperplasia (BPH) with obstructive urinary symptoms
• Male breast cancer (untreated)
• Polycythemia (hematocrit above ~ 50%) of unclear origin
• Known thrombophilia
• Obstructive sleep apnea (OSA) that is untreated
• Uncontrolled congestive heart failure (especially class III-IV) or recent myocardial infarction/stroke
• Desire for fertility in the near-term
• High-risk or aggressive behavior potentially exacerbated by T
If any of these conditions are present, clinicians should either treat/ resolve the condition first or, if permanent, refrain from testosterone therapy and consider alternative management for hypogonadal symptoms.
2. Therapeutic Options for Testosterone Restoration
3. Management of Functional Hypogonadism
4. Monitoring and Follow-Up
5. Symptomatic and Functional Benefits of Testosterone Therapy in Functional Hypogonadism
6. Cardiovascular and other Safety Considerations
14. Conclusion
Male hypogonadism, including the prevalent functional (age- related) form, is a significant but treatable cause of reduced quality of life and increased health risks in men. Through comprehensive evaluation and adherence to evidence-based guidelines, clinicians can Maturitas 207 (2026) 108870 diagnose this condition accurately and implement therapy that profoundly improves patients' well-being (see Fig. 7). TTh, when indicated, offers multi-dimensional benefits – enhancing sexual function, mood, cognition, muscle and bone strength, and metabolic profile – which in concert restore much of what hypogonadal men often feel they have “lost” with the decline in their hormonal milieu. Particularly in older men with FH, management must be holistic: addressing lifestyle factors and comorbid illnesses is as important as prescribing the hormone itself. By treating the whole patient, including encouragement of weight loss and exercise (facilitated by the patient's renewed vigor on testosterone), clinicians can break the vicious cycle of obesity, inflammation, and hormone deficiency.
Crucially, the fear that TTh might precipitate cardiovascular events or prostate cancer – which had often made practitioners reluctant to treat older men – has been largely mitigated if not eliminated by controlled trials. The latest evidence, including the rigorous TRAVERSE study, demonstrates that TTh does not increase cardiovascular risk when used appropriately. This affirmation of safety allows healthcare providers to treat eligible hypogonadal men with greater confidence, provided that sound clinical practices are observed: exclude contraindications (no therapy for those with active prostate or breast cancer, uncontrolled polycythemia, etc.), monitor diligently (regular checks of testosterone levels, hematocrit, PSA, and symptom response), and individualize therapy (tailor form and dose of TTh, and involve the patient in decision-making). In all cases, patients should be educated about the goals of therapy, the importance of follow-up, and the need to report any adverse symptoms promptly.
By following these principles, clinicians can optimize the benefits of TTh while minimizing risks. Treating hypogonadism is not merely about normalizing a laboratory value; it is about restoring a man's quality of life, vitality, and health trajectory. A man with FH who was once fatigued, depressed, and frail can, after appropriate treatment, regain significant physical and mental function, improving not only his own life but also often his engagement in family, work, and society. Modern androgen replacement should thus be viewed as an integral component of healthy aging in men who need it – analogous to hormone therapy in other endocrine disorders – rather than an optional or dangerous indulgence. With the growing evidence base and refined clinical guidelines, testosterone therapy has secured its role as a safe and efficacious intervention for men suffering from the bona fide hypogonadism syndrome.
In conclusion, functional or age-related testosterone deficiency is a genuine medical condition that can severely impair men's quality of life, but it is one that tools to treat safely are available. Through judicious patient selection and guideline-concordant management [1–3], physicians can help hypogonadal men reclaim their health, strength, and well-being, while carefully navigating and monitoring the therapy to ensure sustained safety. The result is not only the mitigation of symptoms, but potentially an improvement in broader health outcomes, making testosterone replacement an important therapy in the care of aging men.
