What are the causes of testicular atrophy?

Causes of Testicular Atrophy

Testicular atrophy results from diverse etiologies that disrupt spermatogenesis through primary testicular dysfunction, secondary hormonal suppression, or vascular compromise, with the most common causes being cryptorchidism, testicular torsion, varicocele, chronic liver disease, exogenous testosterone/anabolic steroid use, chemotherapy, and Klinefelter syndrome. 1

Primary Testicular Dysfunction (Hypergonadotropic Hypogonadism)

These conditions directly damage testicular tissue, resulting in elevated FSH as the pituitary attempts to compensate for impaired spermatogenesis:

Congenital and Developmental Causes

• Klinefelter syndrome (47,XXY) is the most common genetic cause of primary testicular failure, presenting with testicular volumes <12 mL and elevated FSH 1
• Bilateral cryptorchidism (undescended testes), especially when uncorrected or surgically corrected after puberty, markedly increases the risk of testicular atrophy 1, 2
• Post-orchiopexy atrophy occurs frequently after standard orchiopexy and especially after orchiopexy for high undescended testis, caused by ischemic injury during surgical manipulation 3

Vascular and Ischemic Causes

• Testicular torsion causes atrophy through twisting of the spermatic cord and compromising blood flow, particularly when surgical exploration is delayed beyond 6-8 hours 2
• Intrauterine and prepuberal testicular torsion are the most frequent causes of ischemia-related primary and secondary testicular atrophy 3
• Scrotal trauma produces testicular atrophy in approximately 50% of cases, with significant volume reduction observed months to years following blunt injury 4
• Varicocele is present in 15% of normal males and 35-40% of men with infertility, with higher varicocele grade and age correlating with worse semen parameters and testicular dysfunction 2
• Atherosclerosis is directly linked to mixed testicular atrophy through reduced testicular vascular volume fraction, as demonstrated in animal models showing diminished testis volume, reduced testosterone levels, and disturbed spermatogenesis 5

Infectious and Inflammatory Causes

• Epididymoorchitis leads to progressive inflammation and testicular damage 2
• Autoimmune orchitis may affect both testes and produce a relatively painless atrophic process 1

Genetic and Systemic Conditions

• Myotonic dystrophy (type I and II) presents with painless bilateral testicular atrophy due to primary gonadal failure 1
• Sickle-cell disease with recurrent vaso-occlusive crises leads to chronic testicular hypoperfusion and atrophy 1

Toxic and Iatrogenic Causes

• Chemotherapy disrupts spermatogenesis by targeting Leydig cells, Sertoli cells, and germ cells, activating molecular pathways involved in germ cell death, with azoospermia and long-lasting testicular atrophy being common adverse consequences 6
• Pelvic or testicular radiation causes irreversible testicular shrinkage 1
• Cisplatin produces male reproductive toxicity by targeting multiple cell types in the testis 6

Secondary Testicular Dysfunction (Hypogonadotropic Hypogonadism)

These conditions suppress the hypothalamic-pituitary-gonadal axis, resulting in low LH/FSH and subsequent testicular atrophy:

Exogenous Hormone Suppression

• Anabolic steroids or exogenous testosterone use causes complete suppression of spermatogenesis through negative feedback on the hypothalamic-pituitary axis, producing persistent atrophy that can take months to years to recover after cessation 1
• Chronic opioid use suppresses GnRH secretion, resulting in low gonadotropins and bilateral testicular atrophy 1

Pituitary and Hypothalamic Disorders

• Hyperprolactinemia from pituitary adenoma or prolactin-raising medications leads to secondary hypogonadism and testicular shrinkage 1
• Kallmann syndrome or idiopathic hypogonadotropic hypogonadism present with low LH/FSH and small testes 1

Systemic Conditions Associated with Testicular Atrophy

Chronic Organ Dysfunction

• Chronic liver disease (cirrhosis) causes testicular atrophy through multiple mechanisms: low testosterone from hypogonadotropic hypogonadism, increased peripheral conversion of androgens to estrogen, elevated sex hormone-binding globulin (SHBG), and elevated estrogen levels from portosystemic shunting that suppress the hypothalamic-pituitary axis 7
• Type 2 diabetes mellitus and metabolic syndrome are linked to functional hypogonadism and reduced testicular volume 1
• Chronic kidney disease is associated with decreased testosterone production and testicular size 1
• HIV infection causes both primary and secondary gonadal dysfunction leading to atrophy 1

Alcohol-Related Dysfunction

• Excess alcohol intake affects the hypothalamic-pituitary axis or directly impairs ovarian and testicular function 7

Environmental and Toxic Exposures

• Phthalates act as anti-androgens and cause cryptorchidism in rodents, with human studies showing an association between high phthalate exposure and high LH/testosterone ratios 8
• Estrogens and anti-androgens down-regulate INSL3 (insulin-like factor 3) and disturb testicular descent, with a reduced androgen-estrogen ratio potentially influencing cryptorchidism rates 8

Critical Diagnostic Approach

When evaluating testicular atrophy (defined as volume <12 mL), obtain the following:

• Morning serum FSH, LH, and total testosterone on two separate days (08:00-10:00 h) to differentiate primary (elevated FSH/LH) from secondary (low or normal FSH/LH) hypogonadism 1
• Karyotype analysis when FSH is elevated and testicular volume is <12 mL to screen for Klinefelter syndrome 1
• Serum prolactin to exclude hyperprolactinemia 1
• Scrotal ultrasound with Doppler to quantify testicular volume (using the Lambert formula: Length × Width × Height × 0.71), assess architecture, and rule out masses 1

Red-Flag History Elements

• Prior undescended testes dramatically raises the risk of atrophy and testicular cancer (3.6-7.4 times higher risk) 1
• Use of anabolic steroids, testosterone, opioids, or glucocorticoids 1
• History of chemotherapy or radiation to the pelvis/testes 1
• Scrotal trauma history 4
• Presence of systemic disease (diabetes, liver disease, chronic infection) 1

Cancer Risk Considerations

Men younger than 30-40 years with testicular volume <12 mL have a ≥34% risk of intratubular germ cell neoplasia (TIN) in the contralateral testis if testicular cancer develops, and if TIN is left untreated, approximately 70% progress to invasive testicular cancer within 7 years. 1

• History of cryptorchidism combined with testicular volume <12 mL markedly increases malignancy risk and mandates intensified surveillance 1
• At the time of orchidopexy for adult cryptorchidism, testicular biopsy is recommended to exclude intratubular germ cell neoplasia, particularly when testicular volume is <12 mL 2

Common Pitfalls to Avoid

• Never initiate testosterone replacement without first clarifying fertility intentions, as exogenous testosterone suppresses spermatogenesis and can cause azoospermia requiring months to years for recovery 1
• Testicular volume alone cannot definitively predict fertility status; semen analysis is mandatory even with "normal-sized" testes in the context of infertility 1
• The histological condition of a cryptorchid testis does not predict atrophy; immediate detorsion and/or prophylactic fixation as well as subtle technique in orchiopexy are essential 3