Male Reproductive Ageing

Learning Objectives

• Describe age-related changes in male reproductive anatomy, function, hormones and fertility.
• Evaluate changes in male fertility and reproductive hormones associated with ageing.
• Explain indications, benefits, limits and risks of androgen (testosterone) replacement therapy (TRT).

Major Anatomical & Functional Changes With Age

• Testes
  • No appreciable change in volume across lifespan.
  • Some sclerotic changes in seminiferous tubules, yet spermatogenesis remains continuous until death (unlike finite ovarian reserve in females).
• Prostate
  • Benign prostatic hyperplasia (BPH) affects >70\% of men aged \ge 70 \, \text{yrs}.
  • Urethra traverses prostate ⇒ hypertrophy ➞ bladder-outflow obstruction → urinary retention, dysuria, ↑ urinary‐tract infections.
  • Multifactorial aetiology – three non-mutually-exclusive hypotheses:
  1. ↑ 5\alpha-reductase activity + ↑ androgen‐receptor (AR) density ⇒ greater DHT-mediated growth sensitivity.
  2. Stromal–epithelial interaction shift toward an embryonic developmental pattern that re-initiates growth programmes.
  3. Inflammatory hypothesis – chronic, age-related inflammation or inflammatory mediators promote hyperplasia.
• Penis / Erectile Tissue
  • Progressive atherosclerosis of penile arteries + ↓ nitric-oxide (NO) production due to neuronal loss → ↓ arterial inflow.
  • Fewer smooth-muscle cells & elastic fibres in corpora cavernosa ⇒ impaired sinusoidal expansion → defective veno-occlusion → venous leakage ⇒ inability to attain or maintain erection (erectile dysfunction).

Epidemiology of Erectile Dysfunction (ED)

• Definition: persistent inability to attain and maintain erection sufficient for satisfactory intercourse.
• Western Australian random sample:
  • <65\, \text{yrs}: \approx 80\% normal erectile function.
  • >65\, \text{yrs}: \approx 67\% have ED.

Physiology Refresher: Normal Erection

• Parasympathetic release of NO ➞ arteriolar dilation ➞ blood fills corpora cavernosa sinusoids.
• Expansion compresses subtunical veins against tunica albuginea → occludes venous outflow ➞ rigidity.
• Age-related vascular changes disrupt both inflow (arterial) and outflow (veno-occlusive) mechanisms.

Historical & Cultural Context of Testosterone

• Antiquity: testes & semen viewed as essence of potency.
• 1869 – Brown-Séquard injected himself with dog-testis extract claiming rejuvenation.
• 1920s – Voronoff transplanted monkey or executed-prisoner testes into men.
• Most early results now known to be placebo; yet cultural belief in "male rejuvenation" via androgens persists.

Androgen Physiology & Diagnostic Thresholds

• Serum testosterone circulates bound (mainly to SHBG) and unbound (free); biologic activity resides in free fraction.
• Young men (19–39 yrs) morning reference range: 9.2 – 31.8\, \text{nmol·L}^{-1}.
  • Hypogonadism diagnosed when:
  • Two separate morning readings <9.2\, \text{nmol·L}^{-1} and compatible symptoms (↓ libido, ED, lethargy, ↓ muscle/bone mass, mood changes).
• Common transient causes in youth: severe illness, malnutrition, over-exercise.

Does Testosterone Decline With Age?

• Cross-sectional & longitudinal data:
  • Total testosterone declines modestly from ~3rd decade.
  • Free testosterone declines faster because SHBG rises with age.
  • Even men in their 80\text{s} still have mean values above hypogonadal threshold.
• Circadian pattern:
  • Young men: marked early-morning peak, mid-day decline, nocturnal rise.
  • Older men: blunted/lost morning peak; daytime levels similar to young.
  • Hence population decline largely reflects disappearance of morning surge.

Confounders: Obesity & Comorbidities

• European study stratified by BMI:
  • Obese (BMI ≥30) and overweight (BMI 25–29.9) men show lower total, free T and SHBG at all ages vs normal BMI.
• After adjusting for BMI, diabetes, CVD, etc., age effect becomes non-significant ⇒ observed decline often secondary to comorbidities.
• WA cohort (Yip et al.): healthy, never-smoked men 70–89 yrs without major disease had reference range 6.4 – 25.6\, \text{nmol·L}^{-1}; value <9.2 in an asymptomatic older man does not necessarily equal clinical androgen deficiency.

Effects of Confirmed Testosterone Deficiency & TRT Outcomes

• Bone
  • TRT ↑ bone mineral density (BMD) only in hypogonadal men.
  • No BMD benefit in eugonadal men; first-line geriatric osteoporosis Rx = bisphosphonates.
• Body Composition & Physical Function
  • Natural ageing: by 80 yrs, average male has 35–40 % loss of muscle mass vs age 20.
  • TRT:
  • ↑ lean mass, ↓ fat mass.
  • However no consistent improvements in muscle strength, power, balance, or gait vs placebo.
  • 2021 UWA RCT (men 50–70 yrs, waist >95 cm, low–low-normal T):
  • 4 groups: Placebo-NoEx, Testosterone-NoEx, Placebo-Exercise, Testosterone-Exercise.
  • Exercise alone superior to TRT for ↑ aerobic capacity & ↓ total fat.
  • TRT added only modest extra lean‐mass gain; no functional edge over exercise.
  • Conclusion: prescribe exercise as primary anti-ageing intervention, reserve TRT for true deficiency.
• Psychosomatic & Sexual Effects
  • In hypogonadal older men: TRT may ↑ libido, improve mood/well-being, modestly aid ED.
  • Majority of ED in ageing is vasculogenic or drug‐induced, not androgen-driven.

ED as Cardiovascular Sentinel

• Shared risk factors/etiology (atherosclerosis, endothelial dysfunction).
• Penile arteries are smaller ⇒ manifestation of vascular disease can precede coronary symptoms by years.
• ED thus regarded as early warning sign for cardiovascular risk stratification.

Fertility Considerations & HPT Axis Suppression

• Exogenous testosterone → negative feedback on hypothalamus (GnRH) & pituitary (LH, FSH).
  • ↓ LH + FSH → ↓ Leydig cell intratesticular T & suppressed spermatogenesis.
  • Within 3–4\, \text{months} of TRT: oligo- or azoospermia.
  • Recovery: only \approx 50\% achieve baseline sperm production by 6\, \text{months} post-cessation.
• Therefore always assess future paternity desires before instituting TRT.

Male Ageing & Fertility

• No fixed age cut-off; oldest documented natural father: 94\, \text{yrs}.
• Observed trends (starting ~40 yrs):
  • ↓ sperm concentration & motility.
  • ↑ chromosomal & DNA fragmentation.
• Mechanistic driver: oxidative stress via intrinsic ageing and cumulative exposures (smoking, endocrine disruptors, illness).
• Effect size small relative to female reproductive decline, yet may lengthen time-to-pregnancy, especially with concurrent decline in coital frequency and ED.
• Paradox: more frequent ejaculation can lower DNA fragmentation; reduced sexual frequency in older men may therefore further impair fertility.

Comparison With Female Reproductive Ageing (Menopause vs Male Ageing)

Professional Guidelines & Consensus

• Healthy Male (Andrology Australia): "There is no such thing as male menopause / andropause analogous to female menopause."
• Routine TRT not justified in older men with normal T; evidence for anti-ageing claims is weak, risks unknown.
• Indication: clinically confirmed hypogonadism with symptoms — regardless of age.

Ethical, Practical & Risk Considerations

• Over-medicalisation: marketing of "Low-T" exploits non-specific ageing symptoms.
• Fertility suppression: essential counselling for reproductive‐age & mid-life men.
• Potential adverse events under investigation (cardiovascular, prostate, erythrocytosis) — stresses need for judicious use.

Key Takeaways

• Fertility and sexual function do decline with age, but continuous spermatogenesis differentiates male from female ageing.
• Erectile dysfunction rises mainly from vascular disease; its presence warrants cardiovascular risk assessment.
• Serum testosterone shows small average decline; much is attributable to comorbidities (obesity, chronic illness) not to age itself.
• Exercise eclipses TRT for improving body composition and physical function in older, slightly low-T men.
• Testosterone replacement is effective therapy only for bona fide hypogonadism; indiscriminate use is unsupported and may compromise fertility.

Additional Resource

• Healthy Male (formerly Andrology Australia): comprehensive consumer & professional information hub – https://www.healthymale.org.au/