What is the differential diagnosis of primary male hypergonadism?

Differential Diagnosis of Primary Male Hypergonadism

Primary male hypergonadism (hypergonadotropic hypogonadism with elevated testosterone) is exceedingly rare, and the differential diagnosis centers on testosterone-secreting tumors and conditions causing autonomous androgen production independent of pituitary control.

Key Distinguishing Feature

Primary hypergonadism differs fundamentally from the more common primary hypogonadism—in hypergonadism, the testes or other tissues produce excessive testosterone despite normal or suppressed gonadotropins (LH/FSH), whereas primary hypogonadism involves testicular failure with elevated gonadotropins 1, 2.

Main Differential Diagnoses

Testicular Tumors

• Leydig cell tumors are the most common testosterone-secreting testicular neoplasms, typically presenting with precocious puberty in children or virilization symptoms in adults 3
• These tumors may present as palpable testicular masses on physical examination, requiring scrotal ultrasound for definitive imaging 4
• Bilateral testicular masses in the setting of elevated androgens should prompt consideration of adrenal pathology rather than primary testicular tumors 3

Adrenal Tumors and Adrenal Rest Tissue

• Androgen-secreting adrenocortical carcinomas can cause virilization in men, though they more commonly present with mixed hormone secretion or mass effect 4
• Testicular adrenal rest tumors (TART) occur in males with congenital adrenal hyperplasia (CAH), particularly 21-hydroxylase deficiency, presenting as bilateral testicular masses with markedly elevated 17-hydroxyprogesterone, DHEA, ACTH, and androstenedione 3
• These TART lesions are stimulated by ACTH and represent ectopic adrenal tissue rather than true Leydig cell tumors, requiring corticosteroid suppression rather than orchiectomy 3

Congenital Adrenal Hyperplasia (CAH)

• 21-hydroxylase deficiency is the most common form, causing excessive androgen production from the adrenal glands with secondary testicular changes 3
• Patients present with precocious puberty, bilateral testicular masses, and markedly elevated adrenal androgens (17-hydroxyprogesterone, DHEA, androstenedione) with mildly elevated testosterone 3
• The biochemical profile shows elevated ACTH driving adrenal androgen overproduction, distinguishing this from primary testicular pathology 3

Exogenous Androgen Administration

• Anabolic steroid abuse causes suppressed gonadotropins with elevated testosterone or synthetic androgens 4, 1
• History of performance-enhancing drug use, bodybuilding, or testosterone supplementation is critical 1
• Physical examination may reveal testicular atrophy due to negative feedback suppression of the HPG axis 4

Aromatase Deficiency

• This rare congenital disorder prevents conversion of testosterone to estrogen, resulting in elevated testosterone with absent estrogen feedback 4, 1
• Patients present with tall stature, delayed epiphyseal closure, and virilization without gynecomastia 4

Critical Diagnostic Pitfalls

Misdiagnosis of Adrenal Rest Tumors as Leydig Cell Tumors

• Bilateral testicular masses in boys with precocious puberty should never undergo orchiectomy without complete endocrinological profiling including 17-hydroxyprogesterone, DHEA, ACTH, and cortisol 3
• Leydig cell tumors are typically unilateral, whereas TART lesions are characteristically bilateral 3
• Histologically, TART can mimic Leydig cell tumors, requiring clinical correlation with biochemical markers 3

Distinguishing Primary from Secondary Causes

• True primary hypergonadism shows suppressed LH/FSH due to negative feedback from elevated testosterone 1, 2
• If gonadotropins are elevated alongside high testosterone, consider mixed pathology or assay interference 5

Essential Diagnostic Workup

Biochemical Testing

• Morning serum total testosterone (repeat if borderline) to confirm elevation 4, 1
• LH and FSH levels to assess pituitary suppression (should be low-normal or suppressed in true hypergonadism) 4, 1
• DHEA, DHEA-S, androstenedione, and 17-hydroxyprogesterone to evaluate adrenal androgen contribution 3
• ACTH and cortisol (including dexamethasone suppression test if CAH suspected) 4, 3
• Estradiol to assess aromatase function 4

Imaging Studies

• Scrotal ultrasound with high-frequency transducer (7.5 MHz) is mandatory for any palpable testicular abnormality 4
• CT abdomen and pelvis to evaluate for adrenal masses if adrenal androgens are elevated 4
• Testicular MRI may help distinguish intratesticular from extratesticular masses when ultrasound is equivocal 4

Physical Examination Findings

• Assess for testicular size and symmetry—atrophy suggests exogenous androgen use, while enlargement or masses suggest tumor 4
• Evaluate for virilization signs: increased muscle mass, acne, male pattern baldness, deepening voice 4
• Check for gynecomastia (absence suggests aromatase deficiency or pure androgen excess) 4
• Document Tanner staging in adolescents to assess for precocious puberty 3

Management Approach Based on Etiology

For Suspected Testicular Tumors

• Unilateral Leydig cell tumors require radical inguinal orchiectomy with high ligation of the spermatic cord 4
• Obtain tumor markers (AFP, β-HCG) preoperatively, though these are typically normal in Leydig cell tumors 4

For Adrenal Rest Tumors in CAH

• Initiate corticosteroid replacement (hydrocortisone or dexamethasone) to suppress ACTH and reduce tumor size 3
• Monitor tumor response with serial ultrasound—regression confirms diagnosis and avoids unnecessary orchiectomy 3
• Long-term glucocorticoid therapy prevents tumor recurrence 3

For Adrenal Tumors

• Androgen-secreting adrenocortical carcinomas require open adrenalectomy due to rupture risk 4
• Benign aldosterone-secreting adenomas can undergo laparoscopic resection 4