Men's Health¶

Chapter 411 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 411

Key Clinical Points¶

Men's health is a distinct discipline recognizing sex differences in disease susceptibility, clinical manifestations, and treatment response.
Testosterone levels decline starting in the third decade; free testosterone declines more than total due to higher SHBG concentrations in older men.
Testosterone replacement therapy (TRT) improves sexual desire, libido, energy, and bone density, but does not improve glycemic control or cognitive function in older men.
TRT is associated with erythrocytosis, venous thromboembolic events, and increased risk of detection of low-grade prostate cancer, but not major adverse cardiovascular events.
Anabolic-androgenic steroid (AAS) abuse is linked to high mortality (suicide, homicide, accidents), cardiomyopathy, hepatotoxicity, and suppression of the hypothalamic-pituitary-testicular axis.
Muscle dysmorphia is a body image disorder characterized by a pathologic preoccupation with muscularity and leanness, often leading to AAS use.
Advanced paternal age is associated with reduced fertility (lower sperm motility/morphology) and increased risk of germline mutations (e.g., RET, FGFR2, FGFR3) and offspring neurodevelopmental disorders.
Diagnosis of hypogonadism requires two or more early morning, fasting testosterone levels below the lower limit of normal plus presence of symptoms.
TRT should be offered on an individualized basis for men >65 years with symptoms and consistently low testosterone, not for population screening.
AAS users often utilize 'stacking' (multiple steroids) and concurrent drugs like hCG, aromatase inhibitors, or insulin.

DEFINITION & OVERVIEW¶

• Core Concept: Men's health is a distinct discipline based on sex differences in disease susceptibility, clinical manifestations, and treatment response. • Barriers to Care: Factors include differing perceptions of illness consequences, varying motivations for seeking care, and sociocultural/institutional barriers (e.g., fear that seeking help is not 'manly'). • Biological Basis of Sex Differences: ◦ Genetic: Men have only one X chromosome (higher risk of X-linked disorders); women have two epigenetically different cell populations due to X inactivation. ◦ Hormonal: Different concentrations of sex hormones affect gene expression; loss of Y chromosome with aging in men is associated with increased risk of heart disease (especially heart failure), certain types of cancers, and shortened life span. ◦ Epigenetic: Effects of sex hormones during fetal life/puberty may epigenetically imprint behavior, body composition, and disease susceptibility. ◦ Pregnancy Impact: Maternal-fetal microchimerism and hormonal shifts affect female disease susceptibility. • Clinical Focus: Includes testosterone deficiency, sexual dysfunction, muscle dysmorphia, AAS use, lower urinary tract symptoms (LUTS), and complications of prostate cancer therapy.

Substance Abuse and Tobacco¶

• Alcohol: More common in men; however, women are less likely to be diagnosed but have higher mortality rates from alcohol-related diseases. ◦ Biological Difference: Women have higher blood alcohol levels for equal amounts due to smaller volume of distribution and slower gastric metabolism (lower activity of gastric alcohol dehydrogenase). ◦ Tobacco: More men smoke than women, but women bear a larger burden of smoking-related disease (e.g., CVD in premenopausal women, lower bone density postmenopause). ◦ Violence Against Women: 15% of women experience intimate partner violence (IPV); IPV is a major risk factor for depression and suicide.

Mortality Trends¶

• Age-Specific Mortality: ◦ Men 15–34: >75% of deaths are from unintentional injuries, homicides, and suicides. ◦ Men 35–64: Leading causes are heart disease, cancer, and unintentional injuries. ◦ Men ≥65: Major causes are heart disease, cancer, lower respiratory infections, and stroke. • Deaths of Despair: Since 2010, rising mortality in young/middle-aged men (especially white non-Hispanics) is linked to drug overdose, alcohol-related liver disease, and suicide.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Age-Related Testosterone Decline: ◦ Starts in the third decade of life; progresses slowly. ◦ Impacted by: Adiposity, weight change, comorbid conditions, and genetic factors. ◦ Free vs. Total: Free testosterone declines more than total because SHBG concentrations are higher in older men. ◦ HPT Axis Dynamics: Rising LH with age suggests testicular dysfunction is the primary driver of decline. • Advanced Paternal Age: ◦ Fertility: Men >40 years have lower sperm motility/morphology, higher frequency of sperm tail defects, and lower fecundity compared to younger men. ◦ Germline Mutations: Increased risk in FGFR2, FGFR3, and RET genes. ◦ Offspring Risks: Higher risk of achondroplasia, Pfeiffer's syndrome, thanatophoric dysplasia, Crouzon's system, Apert's syndrome, multiple endocrine neoplasia (MEN) 2A, and MEN 2B. Additionally, increased risk of neurodevelopmental disorders (e.g., schizophrenia, autism) and cardiac malformations (VSD, ASD, PDA).

CLINICAL FEATURES¶

• Hypogonadism Symptoms: ◦ Sexual: Decreased desire, poor erections, diminished early morning erections. ◦ Physical/Metabolic: Lower muscle mass/strength, higher visceral fat, insulin resistance, type 2 diabetes, lower bone mineral density (BMD), and increased fracture risk. ◦ Systemic: Reduced telomere length, increased all-cause/cardiovascular mortality, and high frequency of depressive symptoms. • Muscle Dysmorphia: ◦ Definition: Body image disorder with a pathologic preoccupation with muscularity and leanness. ◦ Behavior: High rates of mood/anxiety disorders; nearly all are engaged in weightlifting and use AAS. • AAS Risks: ◦ Mortality: 32% of deaths among AAS users were suicidal, 26% homicidal, 35% accidental (median age of death: 24 years). ◦ Physiological: Proatherogenic dyslipidemia, thrombosis risk, vasospasm, and cardiomyopathy.

Table 1: Association of Testosterone Levels with Outcomes in Older Men¶

• Positively associated with: Muscle mass/strength, physical function, sexual desire, bone mineral density/quality. • Negatively associated with risk of: Coronary artery disease, Type 2 diabetes, Metabolic syndrome, all-cause mortality, falls/fractures, dementia, frailty, and late-onset low-grade persistent depressive disorder (dysthymia). • Not associated with: Lower urinary tract symptoms (LUTS), erectile dysfunction, major depressive disorder.

Table 2: Potential Benefits of TRT¶

• Strong Evidence: Improves sexual activity/desire, relieves hypogonadal symptoms, improves energy, corrects anemia, increases muscle mass, reduces fat, and increases BMD. • Suggestive Evidence: Modestly improves mobility in older men. • Lack of Efficacy: Improving cognitive function (without deficit) or major depressive disorder.

DIAGNOSTIC APPROACH¶

Hypogonadism Diagnosis:
Identify symptoms (e.g., low libido, poor erections).
Perform testing: Require two or more early morning, fasting testosterone levels < lower limit of normal.
AAS Detection:
Clinical signs: "V" muscular phenotype, reduced testicular volume (<15 mL), excessive concern about leanness/muscularity.
Laboratory indicators: Suppressed LH, FSH, and SHBG; increased hematocrit.
Confirmatory tests:
LC-MS/MS analysis of urine (for AAS).
Urinary testosterone-to-epitestosterone ratio (for exogenous testosterone).
Isotope ratio mass spectrometry to detect 13C:12C ratio differences.

MANAGEMENT & TREATMENT¶

Testosterone Replacement Therapy (TRT):
Indications: Men >65 with symptoms and consistently low testosterone.
Benefits: Improved sexual desire, energy, muscle mass, and bone density.
Monitoring/Safety: Monitor for erythrocytosis, venous thromboembolic events, and increased risk of detection of low-grade prostate cancer. Note: No significant increase in major cardiovascular events or LUTS.
Anabolic-Androgenic Steroid (AAS) Management:
Identify usage via clinical/lab indicators (Table 5).
Address complications: Manage cardiomyopathy, hepatotoxicity, and neuropsychiatric issues (e.g., mood disorders, rage reactions).
Androgen Deprivation Therapy (ADT) Optimization:
Baseline assessment: Fasting glucose, plasma lipids, blood pressure, bone mineral density, and FRAX score.
Bone health: Optimize Calcium/Vitamin D; consider pharmacologic therapy if 10-year risk of a major osteoporotic fracture >20%.
Metabolic: Consider metformin for metabolic disorders.
Side effects: Use venlafaxine for hot flushes (if severe); add medroxyprogesterone acetate or gabapentin if venlafaxine is ineffective. Use tamoxifen for painful breast enlargement.

COMPLICATIONS & PROGNOSIS¶

• TRT Safety (Table 3): - Strong Evidence of Risk: Erythrocytosis, Venous thromboembolic events, Reduced sperm production/fertility, Acne. - No Increased Risk: Major cardiovascular events, Lower urinary tract symptoms. - Weak/Insufficient Evidence: Atrial fibrillation, bone fractures, acute kidney injury, male pattern balding, gynecomastia. • AAS Adverse Effects (Table 4): - Cardiovascular: Hypertension, sudden death, cardiomyopathy, diastolic dysfunction, accelerated atherosclerosis, dyslipidemia. - Endocrine: HPT axis suppression (leading to infertility/atrophy), Gynecomastia. - Neuropsychiatric: Mood disorders (hypomania/mania during use; depression/suicidality during withdrawal), rage reactions, aggression, dependence/addiction. - Hepatotoxicity: Inflammatory/cholestatic damage (with 17α-alkyl-substituted steroids), peliosis hepatis, hepatic adenoma, hepatocellular carcinoma. - Other: Acne, scalp hair loss, increased body hair, striae, acute kidney injury (from rhabdomyolysis), focal glomerulosclerosis. • ADT Side Effects (Table 6): - Skeletal: Fracture risk (Hazard Ratio: 1.66). - Metabolic: Diabetes (Hazard Ratio: 1.44). - Cardiovascular: Myocardial infarction (1.11), Peripheral vascular disease (1.16), Coronary heart disease (1.16), Sudden death (1.16).

KEY PEARLS & CLINICAL TRAPS¶

• TRT Evidence: Strong evidence for sexual desire and muscle mass; no evidence for cognitive improvement or major depressive disorder. • AAS Detection: Use LC-MS/MS for AAS and testosterone-to-epitestosterone ratio for exogenous testosterone. • Paternal Age: Advanced age (>40) significantly increases risk of neurodevelopmental disorders and specific genetic mutations (RET, FGFR2, FGFR3). • Decision Making: TRT is not indicated in all men with low testosterone; decision must balance symptom severity against risks of treatment/monitoring.

FLOWCHARTS¶

Approach to Individualized, Shared Treatment Decision-Making (Figure 411-3): 1. Input: Clinical presentation of testosterone deficiency in an older male. 2. Evaluation (The Weighing Scale): - Evaluate Severity of symptoms. - Evaluate Strength of evidence of deficiency. - Evaluate Risk of adverse effects. - Evaluate Risks of monitoring. 3. Integration: Incorporate Clinician's judgment/preference and Patient's values/risk tolerance. 4. Synthesis (Outcome): Determine Individualized Treatment Plan. - If appropriate, include TRT. - Consider alternative strategies: Weight loss, improved glycemic control, or use of selective phosphodiesterase-5 inhibitors (PDE5Is).

Reference Tables¶

TABLE 411-1 Association of Testosterone Levels with Outcomes in Older Men 1. Positively associated with:¶

Harrison's 22e, p.3169

1. Positively associated with:
  • Muscle mass and muscle strength
  • Self-reported and performance-based measures of physical function
  • Sexual desire
  • Bone mineral density, bone geometry and quality, and volumetric bone
  mineral density
  2. Negatively associated with risk of:
  • Coronary artery disease
  • Type 2 diabetes mellitus
  • Metabolic syndrome
  • All-cause mortality
  • Falls and fracture risk
  • Dementia and Alzheimer’s disease
  • Frailty
  • Late-onset low-grade persistent depressive disorder (dysthymia)
  3. Not associated with:
  • Lower urinary tract symptoms
  • Erectile dysfunction
  • Major depressive disorder

TABLE 411-2 The Potential Benefits of Testosterone Replacement Therapy in Middle-Aged and Older Men with Hypogonadism…¶

Harrison's 22e, p.3170

Strong Evidence of Efficacy
1. Improves overall sexual activity and sexual desire in men with low libido
2. Relieves hypogonadal symptoms
3. Improves depressive symptoms in men with significant depressive symptoms
4. Improves energy level
5. Corrects unexplained anemia and prevents the development of anemia
6. Increases skeletal muscle mass, reduces whole-body and abdominal fat
mass
7. Increases areal and volumetric bone mineral density and estimated bone
strength
Suggestive Evidence of Efficacy
1. Modestly improves mobility in older men with mobility limitation
Evidence of Lack of Efficacy
1. Improves cognitive function in older men without cognitive deficit
2. Improves depressive symptoms with major depressive disorder

TABLE 411-3 Adverse Events Associated with Testosterone Replacement Therapy in Middle-Aged and Older Men Adverse Events…¶

Harrison's 22e, p.3171

Adverse Events for Which There Is Strong Evidence
Erythrocytosis
Venous thromboembolic events
Growth of metastatic prostate cancer
Reduced sperm production and fertility
Acne
Increased risk of detection of low-grade prostate cancer
Adverse Events for Which There Is Strong Evidence That Testosterone
Treatment Does NOT Increase Risk
Major adverse cardiovascular events
Lower urinary tract symptoms
Adverse Events for Which There Is Weak Evidence
Atrial fibrillation
Bone fractures
Acute kidney injury
Male pattern balding
Adverse Events for Which There Is Insufficient Evidence to Assess Risk
Gynecomastia
Growth of breast cancer

TABLE 411-4 Potential Adverse Effects Associated with the Use of Anabolic-Androgenic Steroids A. F our Major Categories…¶

Harrison's 22e, p.3173

A. F our Major Categories of Serious Adverse Effects Associated with the Use
of Anabolic-Androgenic Steroids
1. Cardiovascular
a. Hypertension
b. Sudden death
c. Cardiomyopathy
d. Diastolic dysfunction
e. Accelerated atherosclerosis
f. Dyslipidemia
2. Endocrine
a. Suppression of the hypothalamic-pituitary-testicular axis
i. Anabolic steroid withdrawal hypogonadism
ii. Infertility
iii. Testicular atrophy
b. Gynecomastia
3. Neuropsychiatric
a. Major mood disorders
i. Hypomania and mania during periods of high-dose anabolic-
androgenic steroids use
ii. Depression and even suicidality during anabolic steroid withdrawal
b. Other behavioral disorders
i. Rage reactions
ii. Aggressive responding and violence
c. Dependence and addiction behaviors
d. Cognitive deficits
4. Musculoskeletal Injuries
a. Tendon injuries
b. Other musculoskeletal injuries
B. Other Adverse Events
1. Hematologic
a. Erythrocytosis
b. Venous thromboembolic events
2. Hepatotoxicity
a. Inflammatory or cholestatic hepatic damage with the use of 17α-alkyl-
substituted steroids
b. Peliosis hepatis
c. Hepatic adenoma
d. Hepatocellular carcinoma
3. Hair and skin
a. Acne
b. Scalp hair loss in genetically predisposed men
c. Increased body hair
d. Striae
4. Renal
a. Acute kidney injury due to rhabdomyolysis
b. Focal glomerulosclerosis

TABLE 411-5 Detection of the Use of Anabolic-Androgenic Steroids Clinical indicators that should raise suspicion of…¶

Harrison's 22e, p.3174

Clinical indicators that should raise suspicion of anabolic-androgenic steroid use
1. “V” muscular phenotype
2. Reduced testicular volume (<15 mL)
3. Excessive concern about leanness and muscularity.
Laboratory indicators
1. Suppressed LH, FSH, and SHBG levels
2. Increased hematocrit
Detection of anabolic-androgenic steroids
1. LC-MS/MS analysis of urine
Detection of exogenous testosterone use
1. Urinary testosterone-to-epitestosterone ratio
2. Isotope ratio mass spectrometry analysis to detect differences in 13C:12C ratio
in exogenous and endogenous testosterone

TABLE 411-6 Checklist for Men Undergoing Androgen Deprivation Therapy (ADT) 1. Weigh the risks and benefits of ADT and…¶

Harrison's 22e, p.3176

1. Weigh the risks and benefits of ADT and whether intermittent ADT is a
  feasible and safe option.
  2. Perform a baseline assessment including fasting glucose, plasma lipids,
  blood pressure, bone mineral density, and FRAX score.
  3. Optimize calcium and vitamin D intake, encourage structured physical activity
  and exercise, and consider pharmacologic therapy in men with a previous
  minimal trauma fracture and those with a 10-year risk of a major osteoporotic
  fracture >20%, unless contraindicated.
  4. Monitor body weight, fasting glucose, plasma lipids, blood pressure, and
  bone mineral density, and encourage smoking cessation and physical
  exercise. Consider metformin in those with metabolic disorder.
  5. In men who are receiving ADT and who experience bothersome hot flushes,
  as indicated by sleep disturbance or interference with work or activities
  of daily living, consider initial therapy with venlafaxine. If ineffective, add
  medroxyprogesterone acetate or gabapentin.
  6. In men who experience painful breast enlargement, consider therapy with an
  estrogen receptor antagonist, such as tamoxifen.