A 13-year-old male with micropenis has normal morning cortisol and normal thyroid-stimulating hormone but markedly low total testosterone; what is the most likely diagnosis and recommended treatment?

Diagnosis and Treatment of Micropenis with Low Testosterone in a 13-Year-Old Male

This 13-year-old boy with micropenis and markedly low total testosterone (0.19 ng/mL or 19 ng/dL) most likely has hypogonadotropic hypogonadism (secondary hypogonadism), and requires immediate testosterone replacement therapy with intramuscular testosterone enanthate 25-50 mg every 2-4 weeks to induce penile growth and pubertal development. 1

Diagnostic Confirmation Required

Before initiating treatment, you must measure LH and FSH to distinguish primary from secondary hypogonadism—this single test determines the entire treatment approach and fertility prognosis. 2

• Low or low-normal LH/FSH with low testosterone = secondary (hypothalamic-pituitary) hypogonadism 2, 3
• Elevated LH/FSH with low testosterone = primary (testicular) hypogonadism 2, 3
• The normal cortisol (6.6 µg/dL) and TSH (1.38) make isolated gonadotropin deficiency the most likely diagnosis rather than panhypopituitarism 4

Additional essential workup:

• Repeat morning total testosterone (8-10 AM) to confirm persistent hypogonadism 2, 5
• Measure serum prolactin if LH/FSH are low, as hyperprolactinemia causes secondary hypogonadism 5, 3
• Consider MRI of the pituitary/hypothalamus if multiple pituitary hormone deficiencies are present 4
• Karyotype assessment to exclude disorders of sex development, especially if cryptorchidism or hypospadias are present 6
• Baseline hemoglobin/hematocrit before starting testosterone 2, 5

Treatment Algorithm Based on Etiology

If Secondary Hypogonadism (Low LH/FSH) AND Fertility Preservation Desired

Gonadotropin therapy (recombinant hCG plus FSH) is mandatory and testosterone is absolutely contraindicated, as exogenous testosterone will suppress spermatogenesis and cause prolonged, potentially irreversible azoospermia. 2, 1

• Combined hCG and FSH therapy provides optimal outcomes for both testosterone production and fertility restoration 2
• This directly stimulates the testes rather than suppressing the hypothalamic-pituitary axis 2

If Secondary Hypogonadism AND Fertility NOT a Current Concern

Intramuscular testosterone enanthate is the treatment of choice for micropenis in adolescence, as it induces both penile growth and normal pubertal development. 7, 1

Recommended dosing protocol:

• Start with testosterone enanthate 25-50 mg intramuscularly every 2-4 weeks for 3 months (one course) 7, 1, 8
• This short course induces significant penile growth without excessive bone age advancement 7
• At pubertal age, gradually increase to 200 mg monthly, then transition to adult replacement (100-200 mg every 2 weeks) 1
• Intramuscular testosterone produces superior and durable penile growth compared to topical preparations due to hyperplastic effects on penile cellular tissues 7

Expected outcomes with treatment:

• Studies show boys with micropenis secondary to hypogonadotropic hypogonadism achieve mean adult penile length of 10.3 ± 2.7 cm (range 8-14 cm) with testosterone therapy, which is within 2 SD of normal adult mean (12.4 ± 2.7 cm) 1
• Greatest growth response occurs in prepubertal patients, with 60% increase in length and 52.9% increase in girth with testosterone therapy 8
• Six of 8 men in one study were sexually active as adults, with normal male gender identity 1

If Primary Hypogonadism (Elevated LH/FSH)

Testosterone replacement is the only option, as the testes cannot respond to gonadotropin stimulation—fertility will be permanently compromised. 2

• Use the same testosterone enanthate protocol as above 7, 1
• Counsel family that fertility preservation is not possible with primary testicular failure 2

Alternative Topical Testosterone Option (Less Preferred)

Topical testosterone 10% cream applied twice daily for 3 weeks can be considered, but produces less durable results than intramuscular therapy. 8

• Topical testosterone produced 60% increase in penile length and 52.9% increase in girth in one study 8
• However, intramuscular testosterone enanthate is superior for inducing normal and durable penile growth due to hyperplastic action on penile tissues 7
• Topical preparations may be useful for initial short-course therapy in infancy, but intramuscular is preferred for adolescents 7, 8

Monitoring Requirements During Treatment

Measure testosterone levels 2-3 months after treatment initiation and after any dose change, targeting mid-normal values (500-600 ng/dL). 2

• For injectable testosterone, measure levels midway between injections (days 5-7 after injection) 2
• Monitor hematocrit at each visit—withhold treatment if >54% and consider phlebotomy 2
• Monitor bone age radiographs every 6-12 months to avoid excessive advancement 7
• Assess penile length at each visit to document growth response 1, 8
• Once stable on adult replacement, monitor testosterone levels every 6-12 months 2

Critical Pitfalls to Avoid

Never start testosterone without first measuring LH and FSH—this is the single most important test to guide treatment and determine fertility potential. 2, 3

Never initiate testosterone therapy without confirming the patient/family does not desire fertility preservation, as this causes irreversible suppression of spermatogenesis. 2, 1

Do not diagnose hypogonadism based on a single testosterone measurement—repeat morning testing (8-10 AM) is required due to diurnal variation. 2, 5

Do not delay treatment in adolescence—the greatest penile growth response occurs in prepubertal and early pubertal patients, and early treatment achieves normal adult penile size. 1, 8

Do not recommend sex reassignment—studies demonstrate that testosterone therapy in infancy and childhood produces adult penile size within 2 SD of normal, with normal male gender identity and sexual function. 1

Genetic Considerations

Even with "normal" testosterone response to hCG stimulation, consider genetic testing for androgen receptor (AR), 5α-reductase (5αR), and steroidogenic factor 1 (SF1) mutations if micropenis is isolated. 9

• AR and SF1 mutations have been reported as the first presenting symptom of isolated micropenis 9
• Measure anti-Müllerian hormone and inhibin B—low inhibin B may indicate SF1 mutation 9
• Detection of gene mutations is helpful for diagnosis, treatment optimization, and genetic counseling 9