Key Facts

Male hypogonadism encompasses conditions resulting in inadequate testosterone production and/or impaired spermatogenesis. It significantly impacts physical health, sexual function, mood, and quality of life.

Epidemiology

• Prevalence: 2-6% of men aged 40-79; increases with age
• Late-onset hypogonadism (age-related decline) is increasingly recognised
• Strongly associated with obesity (testosterone aromatised to oestrogen in adipose tissue)
• Metabolic syndrome present in up to 50% of hypogonadal men

Aetiology

Primary (hypergonadotrophic) – testicular failure:

• Klinefelter syndrome (47,XXY)
• Undescended testes (bilateral cryptorchidism)
• Orchitis (mumps), testicular torsion, trauma, surgery
• Chemotherapy/radiotherapy
• Myotonic dystrophy

Secondary (hypogonadotrophic) – hypothalamic/pituitary:

• Pituitary adenoma (especially prolactinoma)
• Kallmann syndrome (GnRH deficiency + anosmia)
• Hyperprolactinaemia
• Haemochromatosis (iron deposition in pituitary)
• Exogenous anabolic steroids
• Obesity, chronic illness, opioids, glucocorticoids
• Congenital hypogonadotrophic hypogonadism (CHH)

Pathophysiology

• Testosterone is produced by Leydig cells under LH stimulation
• Spermatogenesis requires FSH stimulation of Sertoli cells and intratesticular testosterone
• In primary hypogonadism: testicular failure → low testosterone → elevated LH/FSH (feedback)
• In secondary: pituitary/hypothalamic dysfunction → low LH/FSH → low testosterone

Sexual Dysfunction

• Reduced libido (often the earliest symptom)
• Erectile dysfunction
• Reduced morning erections
• Reduced ejaculate volume

Physical Changes

• Loss of muscle mass and strength
• Increased body fat (particularly central/visceral)
• Gynaecomastia
• Decreased facial and body hair
• Hot flushes (if acute onset)

Psychological

• Fatigue and low energy
• Depressed mood, irritability
• Impaired concentration and memory
• Reduced motivation

Bone and Metabolic

• Osteoporosis and increased fracture risk
• Anaemia (normocytic)
• Metabolic syndrome

Red Flags

• Visual field defects → pituitary macroadenoma
• Galactorrhoea → hyperprolactinaemia
• Anosmia → Kallmann syndrome
• Testicular mass → exclude tumour
• Rapid onset in young man → exclude anabolic steroid use

Bedside

• Testicular examination: volume (Prader orchidometer), consistency
• Assess gynaecomastia, body hair, BMI
• Visual field testing if pituitary pathology suspected

Bloods

• Total testosterone: two samples taken fasting, 8-11am (testosterone has diurnal variation)
  • <8 nmol/L: hypogonadal
  • 8-12 nmol/L: borderline – calculate free testosterone or repeat

  • 12 nmol/L: normal

• SHBG: to calculate free testosterone (important if total testosterone is borderline)
• LH and FSH: differentiates primary from secondary
• Prolactin: if secondary hypogonadism suspected
• Ferritin and transferrin saturation: exclude haemochromatosis
• TFTs: exclude hypothyroidism
• FBC: baseline haematocrit (testosterone increases erythropoiesis)
• PSA: baseline before testosterone therapy
• Lipid profile, HbA1c: metabolic assessment

Imaging

• MRI pituitary with contrast: if secondary hypogonadism confirmed (low/normal LH/FSH with low testosterone)
• DEXA scan: if hypogonadism confirmed, assess bone density
• Testicular ultrasound: if testicular abnormality on examination

Special Tests

• Semen analysis: if fertility is a concern
• Karyotype: if primary hypogonadism in younger man
• GnRH stimulation test: rarely needed, to differentiate hypothalamic from pituitary causes

Non-pharmacological

• Weight loss (if obese): 10% weight loss can increase testosterone by 2-3 nmol/L
• Exercise (resistance training particularly effective)
• Treat underlying cause (e.g., dopamine agonist for prolactinoma, iron chelation for haemochromatosis)
• Address contributing medications (opioids, glucocorticoids)

Pharmacological

Testosterone replacement (when fertility is NOT desired):

• Testosterone undecanoate (Nebido) 1000mg IM every 10-14 weeks (after initial loading dose at 6 weeks)
• Testosterone enanthate 250mg IM every 3-4 weeks
• Testosterone gel (Testogel 1%) 50mg daily topically
• Testosterone patches (less commonly used due to skin irritation)

When fertility IS desired:

• Do NOT use testosterone (suppresses spermatogenesis via negative feedback)
• hCG 1500-2000 IU SC 2-3x weekly (stimulates Leydig cells)
• FSH (or hMG) 75-150 IU SC 2-3x weekly (stimulates spermatogenesis)
• Treatment duration: 12-24 months for spermatogenesis to recover

Monitoring on testosterone replacement:

• Testosterone trough levels, FBC (haematocrit <54%), PSA, LFTs at 3, 6, 12 months then annually
• DRE annually in men >50
• DEXA scan every 2-3 years

Referral Criteria

• Secondary hypogonadism → endocrinology (exclude pituitary pathology)
• Infertility → reproductive endocrinology/fertility clinic
• Haematocrit >54% on treatment → haematology
• PSA elevation on treatment → urology

• With appropriate testosterone replacement, most symptoms improve within 3-6 months
• Libido and sexual function improve within 3-6 weeks
• Body composition changes over 3-6 months
• Bone density improvement seen at 6-12 months
• Mood and energy improvements within weeks
• Untreated hypogonadism increases cardiovascular risk, metabolic syndrome, and osteoporotic fractures
• Fertility can often be restored with gonadotrophin therapy in secondary hypogonadism

Classification Summary

Testosterone Replacement Contraindications