Inadequate virilization of male infants (male pseudohermaphroditism)

Inadequate virilization of male infants 

(male pseudohermaphroditism)

This condition is caused by inadequate androgen production or incomplete end-organ response to androgen. 

These patients have a 46,XY karyotype and exclusively testicular tissue and majority of these patients require extensive laboratory investigation before an exact diagnosis can be determined.

1. Decreased androgen production: This can be caused by one of several rare enzyme defects that are inherited (autosomal recessive). Some of these defects also cause cortisol deficiency and nonvirilizing adrenal hyperplasia, and

others are specific to the testosterone pathway. Other causes of decreased androgen production include deficiency of Müllerian-inhibiting substance (the most common presentation is a male infant with inguinal hernias that contain a uterus or fallopian tubes); testicular unresponsiveness to human chorionic gonadotropin (hCG) and luteinizing hormone (LH); and anorchia (absent testes caused by loss of vascular supply to the testis during fetal life). Presence of microphallus/micropenis and hypoglycemia suggests a pituitary deficiency with absence of gonadotropins, ACTH, and/or growth hormone.

2. Decreased end-organ response to androgen: Also referred to as testicular feminization, can be caused by a defect in the androgen receptor or an unknown defect with normal receptors. It can be total (labial testes with otherwise normal appearing female genitalia) or, more commonly, partial (incomplete virilization of a male).

3. 5α-Reductase deficiency: Results in failure of the external genitalia to undergo male differentiation because of the lack of DHT . The outcome is a neonate with a 46,XY karyotype and female or atypical genitalia with internal testes and male ducts.Diagnosis

Laboratory studies:

Normal 46,XY karyotype. 

The differential diagnosis of an incompletely virilized genetic male is extremely complex and includes in utero testicular damage, defects of testosterone synthesis, end-organ resistance, and an enzymatic defect in the conversion of testosterone to DHT. The laboratory evaluation is correspondingly complex and usually proceeds through a number of steps.

a. Testosterone and dihydrotestosterone: 

These hormone levels should be measurable and are higher in newborns than later in childhood. In the male pseudohermaphrodite, testosterone is low in any defect in testosterone production. The testosterone-to-DHT ratio should be between 5:1 and 20:1 when expressed in similar units. A high testosterone-to-DHT ratio suggests 5α-reductase deficiency. Androstenedione levels are measured to diagnose 17-ketosteroid reductase deficiency.

b. Luteinizing hormone and follicle-stimulating hormon: 

These hormones are also higher in infancy than they are in childhood. A diagnosis of gonadotropin deficiency is suspected if these values are low in a reliable assay but can be confirmed in infancy only if there are other pituitary hormone deficits. Note that growth hormone and ACTH deficiency may manifest in the newborn period as hypoglycemia. In primary gonadal defects and some androgen-resistant states, LH and follicle-stimulating hormone are elevated.

c. Human gonadotropin stimulation test: 

Administration of hCG to assess the stimulation of gonadal steroid production when testosterone values are low (as in gonadotropin deficiency or a defect in testosterone synthesis).

Gonadal response to hCG is assessed: a rise in the testosterone level confirms the presence of Leydig cells and, by implication, testicular tissue. 

In patients with 5α-reductase deficiency, the basal testosterone-to-DHT ratio may be normal but elevated after hCG stimulation. 

d. Assessment of pituitary function: 

If gonadotropin deficiency due to impairment of pituitary function is suspected (eg, microphallus/micropenis combined

with hypoglycemia), thyroid function tests, growth hormone levels, ACTH stimulation test, and imaging studies of the pituitary gland may be indicated.