What are the causes of low testosterone (hypogonadism)?

Causes of Low Testosterone (Hypogonadism)

Low testosterone results from either testicular dysfunction (primary hypogonadism) or impairment of the hypothalamic-pituitary-gonadal axis (secondary hypogonadism), with the most common reversible causes in clinical practice being obesity, metabolic syndrome, type 2 diabetes, and medications—particularly opioids, glucocorticoids, and anabolic steroids. 1

Classification Framework

Male hypogonadism is categorized into two main types that guide both diagnosis and treatment 1:

• Primary (Hypergonadotropic) Hypogonadism: Caused by testicular dysfunction with elevated LH and FSH levels 1, 2
• Secondary (Hypogonadotropic) Hypogonadism: Results from hypothalamic-pituitary-gonadal axis impairment with low or inappropriately normal LH and FSH 1, 3
• Functional Hypogonadism: Low testosterone without organic HPG axis alterations, primarily driven by comorbidities that should be addressed first 1

Primary Hypogonadism Causes (Testicular Failure)

Common Acquired Causes

• Testicular trauma or torsion 4
• Orchitis (inflammatory testicular damage) 4
• Chemotherapy or radiation causing toxic testicular damage 4
• Alcohol or heavy metal toxicity 4
• Orchiectomy (surgical removal) 4

Congenital/Genetic Causes

• Klinefelter's syndrome (47,XXY)—the most common genetic cause 4
• Cryptorchidism (undescended testes, including INSL3 and LGR8 mutations) 1, 4
• Vanishing testis syndrome 4
• Rare chromosomal abnormalities: XX male, 47 XYY, 48 XXYY syndrome 1, 5
• Down syndrome (Trisomy 21) 1
• Noonan syndrome 1
• Defects of testosterone biosynthesis 1, 5
• Congenital adrenal hyperplasia with testicular adrenal rest tumors 1
• Disorders of sex development (gonadal dysgenesis) 1, 5
• LH receptor gene mutations 1
• Myotonic dystrophy (types I and II) 1
• Bilateral congenital anorchia 1
• Sickle cell disease 1
• Adrenoleukodystrophy 1

Secondary Hypogonadism Causes (Hypothalamic-Pituitary Dysfunction)

Drug-Induced Causes (Critical to Identify)

• Opioids—suppress GnRH secretion, extremely common in chronic pain patients 1, 5, 2
• Glucocorticoids—suppress the HPG axis 1, 5, 2
• Anabolic steroids or exogenous testosterone—negative feedback suppression 1, 5, 6
• Estrogens 1, 5
• Progestogens (including cyproterone acetate) 1, 5
• GnRH agonists or antagonists 1, 5
• Hyperprolactinemia-inducing drugs (antipsychotics, metoclopramide) 1, 5

Structural/Localized Problems

• Pituitary neoplasms (micro/macroadenomas) 1
• Hypothalamic tumors 1
• Traumatic brain injury 1
• Pituitary stalk diseases 1
• Iatrogenic: surgical hypophysectomy, pituitary or cranial irradiation 1
• Inflammatory/infectious diseases: lymphocytic hypophysitis, pituitary infections, granulomatous lesions, sarcoidosis, Wegener's granulomatosis, encephalitis 1
• Langerhans' histiocytosis 1
• Hyperprolactinemia from hypothalamic-pituitary masses 1

Systemic Diseases/Conditions

• Type 2 diabetes mellitus and metabolic syndrome—among the most common reversible causes 1, 5, 7, 8
• Obesity—strongly associated with low testosterone through multiple mechanisms 5, 7, 6, 8
• HIV infection 1, 5
• Chronic organ failure (renal, hepatic, cardiac) 1, 5
• Chronic inflammatory arthritis 1
• Cushing syndrome (glucocorticoid excess) 1, 5
• Eating disorders 1, 5
• Endurance exercise (excessive training) 1, 5
• Acute and critical illness 1
• Aging—testosterone declines approximately 1.6% per year starting in mid-30s, affecting 20% of men over 60,30% over 70, and 50% over 80 1, 5, 7, 9

Congenital Causes

• Idiopathic hypogonadotropic hypogonadism (IHH) 1, 5
• Kallmann syndrome (IHH with anosmia) 1
• Isolated LH gene mutations 1
• Prader-Willi syndrome 1
• Combined pituitary hormone deficiency 1, 5

Androgen Resistance/Peripheral Causes

These conditions involve normal or elevated testosterone but impaired action 1:

• Partial or complete androgen insensitivity 1
• Kennedy disease (spinal and bulbar muscular atrophy with CAG repeat extensions) 1
• 5α-reductase type II deficiency 1
• Aromatase deficiency 1

Drug-Induced Androgen Resistance

• Androgen receptor blockers: cyproterone acetate, spironolactone, flutamide, bicalutamide, nilutamide 1
• 5α-reductase inhibitors: finasteride, dutasteride 1
• Estrogen receptor blockers: clomiphene, tamoxifen, raloxifene 1
• Aromatase inhibitors: letrozole, anastrozole, exemestane 1

Clinical Approach to Identifying the Cause

Step 1: Confirm Hypogonadism

Obtain two separate morning (8-10 AM) total testosterone measurements showing levels <300 ng/dL (<10.5 nmol/L) 2, 4

Step 2: Classify Type with Gonadotropins

• Elevated LH and FSH = Primary hypogonadism (testicular failure) 2, 3
• Low or inappropriately normal LH and FSH = Secondary hypogonadism (HPG axis dysfunction) 2, 3

Step 3: Identify Reversible Causes First

• Medication review: Stop or substitute opioids, glucocorticoids, anabolic steroids if possible 5, 2
• Assess for obesity/metabolic syndrome: Calculate BMI and waist circumference 5, 2, 7
• Screen for diabetes: Fasting glucose, HbA1c 5, 8
• Evaluate thyroid function: TSH, free T4 (affects SHBG) 2
• Assess for excessive alcohol use 5

Step 4: Look for Structural Lesions (if Secondary)

• MRI of pituitary/hypothalamus if secondary hypogonadism without obvious cause 1
• Prolactin level to screen for prolactinoma 1, 2

Step 5: Consider Genetic Testing (if Primary and Young)

• Karyotype for Klinefelter's syndrome in young men with small, firm testes 4, 6
• Genetic panels for congenital causes in adolescents/young adults 6

Critical Pitfalls to Avoid

• Do not measure testosterone during acute illness—levels are artificially suppressed and unreliable 2
• Do not diagnose based on single testosterone measurement—requires two separate morning samples 2, 4
• Do not overlook medication-induced hypogonadism—opioids and glucocorticoids are frequently missed 5, 2
• Do not assume age alone is the cause—obesity and comorbidities are more common culprits than chronological age 5, 7
• Do not start testosterone therapy without measuring gonadotropins—this determines whether primary or secondary hypogonadism and guides fertility-preserving options 2, 6
• Do not ignore fertility desires in young men—testosterone therapy suppresses spermatogenesis; use gonadotropins or selective estrogen modulators instead 5, 4, 6