What are the causes of asymptomatic testicular atrophy in men?

Causes of Asymptomatic Testicular Atrophy

Asymptomatic testicular atrophy in men results from diverse etiologies including genetic disorders (Klinefelter syndrome being most common), prior gonadotoxic exposures (chemotherapy, radiation), varicocele, cryptorchidism, testicular torsion, and systemic conditions affecting the hypothalamic-pituitary-gonadal axis. 1

Primary Testicular Causes (Hypergonadotropic Hypogonadism)

Genetic and Congenital Disorders

• Klinefelter syndrome (47,XXY) is the most frequent genetic cause, presenting with small testes, elevated FSH, and a spectrum from eunuchoid hypogonadism to normally virilized but sterile males 1, 2
• Rare chromosomal abnormalities including XX male syndrome, 47 XYY, 48 XXYY syndrome, and 21 Trisomy (Down syndrome) 1
• Y-chromosome microdeletions (AZFa, AZFb, AZFc regions) cause progressive testicular dysfunction 3
• Disorders of sex development (gonadal dysgenesis) and defects of testosterone biosynthesis 1
• Myotonic dystrophy (Curschmann-Steinert dystrophic myotonia) 1, 2
• Uncorrected cryptorchidism, including INSL3 and LGR8 mutations 1
• Bilateral congenital anorchia 1

Acquired Testicular Damage

• Cryptorchidism causes prenatal testicular damage resulting in an "incompetent" small testis even after surgical correction; post-orchidopexy atrophy may also result from vascular injury during surgery 1, 2
• Testicular torsion causes ischemic injury and subsequent atrophy 1
• Mumps orchitis is a classic infectious cause of testicular atrophy 2
• Varicocele causes progressive testicular dysfunction through elevated scrotal temperature, hypoxia, and reflux of toxic metabolites, present in 15% of normal males and associated with testicular atrophy 1
• Trauma severe enough to cause testicular atrophy is a putative but not definitively proven risk factor 4

Iatrogenic Causes

• Inguinal hernioplasty causes testicular atrophy through thrombosis of spermatic cord veins from surgical dissection trauma, not from incorrect reconstruction or infection 5, 6, 7
• Chemotherapy and radiation are highly gonadotoxic, with spermatogenesis typically recovering 1-4 years after treatment but Leydig cell dysfunction persisting even in the contralateral testis 1
• Immunosuppressive medications and certain chemotherapeutic agents directly damage testicular tissue 2

Systemic Diseases Affecting Testes

• Liver cirrhosis and chronic alcoholism disrupt hormonal metabolism 2
• Hemochromatosis causes iron deposition in testicular tissue 2
• Sickle cell disease affects testicular vasculature 1
• Adrenoleukodystrophy 1

Secondary Causes (Hypogonadotropic Hypogonadism)

Drug-Induced Suppression

• Exogenous testosterone or androgenic anabolic steroids completely suppress FSH and LH through negative feedback, causing reversible but potentially prolonged testicular atrophy 1, 3
• Opiates suppress gonadotropin secretion 1
• GnRH agonists or antagonists 1
• Glucocorticoids 1
• Progestogens including cyproterone acetate 1
• Hyperprolactinemia-inducing drugs 1

Hypothalamic-Pituitary Disorders

• Idiopathic hypogonadotropic hypogonadism (IHH), including normosmic IHH and Kallmann syndrome 1
• Pituitary neoplasms (micro/macroadenomas) and hypothalamic tumors 1
• Traumatic brain injury 1
• Inflammatory and infectious diseases: lymphocytic hypophysitis, sarcoidosis, Wegener's granulomatosis, encephalitis 1
• Iatrogenic: surgical hypophysectomy, pituitary or cranial irradiation 1
• Langerhans' histiocytosis 1

Systemic Conditions Affecting HPG Axis

• Type 2 diabetes mellitus/metabolic syndrome 1
• HIV infection, particularly with protease inhibitors and NRTIs causing insulin resistance and direct pancreatic β-cell effects 1
• Chronic organ failure 1
• Chronic inflammatory arthritis 1
• Glucocorticoid excess (Cushing syndrome) 1
• Eating disorders and endurance exercise 1
• Acute and critical illness 1
• Aging 1

Androgen Receptor Disorders

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

Clinical Associations and Risk Factors

Testicular Microcalcification

• Testicular microcalcification (TM) is observed in 0.6-9% of men and is associated with cryptorchidism, infertility, testicular torsion and atrophy, Klinefelter syndrome, hypogonadism, and disorders of sex development 1
• Men with atrophic testes and TM are at high risk for testicular germ cell neoplasia and may be offered testicular biopsy 1

Post-Cancer Treatment

• Testicular cancer survivors have higher risk of hypogonadism, with risk greatest at 6-12 months post-treatment, though some Leydig cell function improvement may occur over time 1

Important Clinical Pitfalls

• Avoid prescribing exogenous testosterone to men with testicular atrophy who desire future fertility, as it will worsen testicular atrophy through complete suppression of gonadotropins 1, 3
• Distinguish primary from secondary hypogonadism through hormonal evaluation (FSH, LH, testosterone), as treatment approaches differ fundamentally 1, 3
• Consider sperm cryopreservation before any gonadotoxic therapy in men with reduced testicular reserve 3
• Evaluate for reversible causes including thyroid dysfunction, metabolic disorders, and medications before concluding testicular atrophy is permanent 1, 3
• Screen for testicular cancer in men with atrophic testes, particularly those with cryptorchidism history or testicular microcalcification 1