What is the differential diagnosis for a male patient with a history of surgically repaired undescended testicle (cryptorchidism) in childhood, now presenting with right-sided testicular pain, a severely atrophied left testicle, and mildly reduced size of the right testicle on ultrasound, with elevated Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels indicating primary hypogonadism?

Differential Diagnosis for Right-Sided Testicular Pain with Bilateral Testicular Atrophy and Elevated Gonadotropins

The most critical differential to rule out immediately is testicular torsion or testicular malignancy, followed by consideration of primary testicular failure from the underlying cryptorchidism history, with the elevated LH/FSH indicating established primary hypogonadism and the acute pain requiring urgent evaluation for surgical emergencies.

Immediate Life/Organ-Threatening Conditions (Rule Out First)

Testicular Torsion

• Must be excluded urgently despite atrophy, as even atrophic testes can undergo torsion 1
• History of cryptorchidism increases torsion risk even after surgical correction 2
• Ultrasound with Doppler flow assessment is essential to evaluate vascular compromise 3

Testicular Malignancy

• This is the highest priority non-emergent diagnosis given the clinical context 3, 1
• History of cryptorchidism increases testicular cancer risk 2.75-8 times, with lifetime risk of 2-6% 2, 4
• Testicular atrophy (<12 mL) is itself an independent risk factor for testicular germ cell tumors 1
• The combination of cryptorchidism history plus testicular atrophy creates an 18-fold increased risk if testicular microcalcifications are present 3, 1
• Even the contralateral (left) atrophied testis carries elevated cancer risk 1
• Ultrasound should specifically assess for testicular masses, microcalcifications, and heterogeneous echotexture 1

Primary Testicular Failure (Most Likely Underlying Diagnosis)

Cryptorchidism-Related Testicular Damage

• The severely atrophied left testicle and mildly reduced right testicle with elevated FSH/LH (2× upper limit) indicate established primary hypogonadism from bilateral testicular dysfunction 1, 5
• Even unilateral cryptorchidism affects the contralateral descended testis, causing smaller volume, softer consistency, and reduced function 2, 4
• Germ cell damage progresses after 15-18 months of age in undescended testes, with ongoing deterioration even after surgical correction 2, 6
• FSH levels above 7.6 IU/L with testicular atrophy strongly indicate spermatogenic failure 1
• Cryptorchidism impairs both Sertoli cell function (elevated FSH) and Leydig cell function (elevated LH), explaining the hormonal profile 5

Klinefelter Syndrome (47,XXY)

• This is the most common chromosomal abnormality associated with testicular atrophy and primary hypogonadism 1
• Presents with bilateral small/atrophic testes, elevated FSH/LH, and azoospermia or severe oligospermia 1, 7
• Karyotype testing is strongly recommended for males with severe oligospermia or non-obstructive azoospermia with testicular atrophy 1
• Coexistence of Klinefelter syndrome and cryptorchidism is not uncommon 7

Y-Chromosome Microdeletions

• Should be tested if sperm concentration is <1 million/mL or azoospermia is present 1
• Y-chromosome microdeletion testing is recommended for men with testicular atrophy and severe oligozoospermia or non-obstructive azoospermia 1

Pain-Specific Differential Diagnoses

Epididymitis/Orchitis

• Infectious or inflammatory process affecting the right testis or epididymis 3
• Ultrasound should assess for epididymal enlargement, increased vascularity, and scrotal wall thickening 1
• Sexual partners should be evaluated if sexually transmitted infection is suspected 3

Varicocele

• Present in 15% of normal males and 35-40% of infertile men 3
• Can cause testicular pain and progressive testicular atrophy 3
• Higher varicocele grade and age are associated with worse semen parameters 3
• However, only palpable varicoceles (not subclinical ultrasound findings) warrant treatment consideration 1

Post-Surgical Complications

• Late complications from childhood orchiopexy including chronic pain, testicular ischemia, or adhesions 4, 6
• Testicular atrophy risk after orchiopexy is <2%, but can occur 4

Testicular Microcalcifications with Intratubular Germ Cell Neoplasia

• Testicular microcalcifications increase cancer risk 18-fold in infertile men with cryptorchidism history 3, 1
• Men with atrophic testes and testicular microcalcifications should be offered testicular biopsy 1
• Can present with dull aching pain before frank malignancy develops 1

Secondary Causes to Exclude

Exogenous Hormone Use

• Anabolic steroids or exogenous testosterone cause reversible testicular atrophy and suppressed gonadotropins (opposite of this patient's elevated LH/FSH) 1
• History should specifically query performance-enhancing drug use, opioids, or corticosteroids 1

Systemic Diseases

• HIV/AIDS, diabetes, prior chemotherapy, or radiation can cause progressive testicular damage 1
• These typically present with gradual onset rather than acute pain 1

Critical Next Steps

Immediate Evaluation Required

• Scrotal ultrasound with Doppler to assess for torsion, masses, microcalcifications, and blood flow 3, 1
• Repeat hormonal evaluation with morning FSH, LH, and total testosterone on at least two separate occasions to confirm primary hypogonadism 1
• Semen analysis (at least two samples separated by 2-3 months) to assess fertility potential 1

Genetic Testing Indicated

• Karyotype testing for Klinefelter syndrome given bilateral atrophy and elevated gonadotropins 1
• Y-chromosome microdeletion testing if severe oligospermia or azoospermia confirmed 1

Cancer Surveillance

• If testicular microcalcifications present on ultrasound, strongly consider testicular biopsy given the combined risk factors 1
• Lifelong surveillance with regular self-examination and periodic ultrasound monitoring 2, 4
• Men with testicular volume <12 mL have significantly increased risk of intratubular germ cell neoplasia 1

Fertility Preservation

• If any sperm present in ejaculate, immediate sperm banking is recommended (2-3 separate collections) 1
• Microsurgical testicular sperm extraction (micro-TESE) may be considered for non-obstructive azoospermia, with 1.5 times higher success than conventional extraction 1
• Even in Klinefelter syndrome with cryptorchidism history, sperm retrieval rates of 22-35% are achievable in young men 7

Common Pitfalls to Avoid

• Do not dismiss acute testicular pain in an atrophic testis—torsion and malignancy remain possible 1, 2
• Do not treat subclinical varicoceles found only on ultrasound—only palpable varicoceles improve fertility outcomes after repair 1
• Do not assume bilateral disease is symmetric—the right testis may have different pathology than the left despite both being affected 1
• Do not delay genetic testing—chromosomal abnormalities occur in 10% of men with severe oligospermia/azoospermia 1
• Do not prescribe testosterone replacement if fertility is desired—it will completely suppress remaining spermatogenesis 1