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to reduced synthesis of testosterone as a consequence of impaired activity of

CYP17A1 in testes, whereas genital ambiguity in 46,XX newborn is a result of

reduced aromatization of fetal adrenal androgens because of impaired activity of

CYP19A1 (aromatase) and synthesis of androgens via “backdoor pathway.” One

of the peculiar features of CAH due to POR defi ciency is that virilization is

nonprogressive after birth. The maternal virilization is also a result of impaired

activity of CYP19A1 and synthesis of androgens via “backdoor pathway.”

Skeletal malformations are the characteristic manifestation of this variant of

CAH and are due to impaired action of CYP51A1, which is required for sterol

synthesis in the bone tissue. These malformations include midfacial hypoplasia,

craniosynostosis, radiohumeral synostosis, and bowing of the femur and resem-

ble Antley–Bixler syndrome. Mineralocorticoid defi ciency is uncommon in

these patients; however, they may manifest glucocorticoid defi ciency.

78. What is “ backdoor pathway ” of androgen synthesis?

In humans there are two classical pathways for the synthesis of androgens in

testes and adrenals. The classical Δ 5 pathway involves conversion of 17-hydroxy-

pregnenolone to DHEA and to testosterone, while the Δ 4 pathway involves con-

version of 17-hydroxyprogesterone to androstenedione and to testosterone. The

classical Δ 5 pathway predominates in both testes and adrenals. In addition to

these classical pathways, there is also an alternative pathway of androgen bio-

synthesis which is termed as “backdoor pathway.” This pathway involves con-

version of 17-hydroxyprogesterone to dihydrotestosterone (DHT) without the

formation of two major intermediates, DHEA or testosterone. The “backdoor

pathway” is functional during fetal life and in early infancy. The “classical and

backdoor pathways” are depicted in the fi gure given below (Fig. 10.18 ).

‘Backdoor pathway’ of androgen synthesis

Cholesterol

Pregnenolone

Progesterone

DOC

Corticosterone

Aldosterone

Cortisol

17OH-progesterone

SRDA 1/2

AKR1C 2/4

CYP17A1

HSD17β3/AKR1C3

AKR1C2/HSD17β 3

Classic Δ^4 pathway

Classic Δ^5 pathway

DHEA

Androstenedione

Testosterone

DHT

Androstanediol

5 α-pregnane-diol-one Androsterone

Backdoor

pathway

5 α-pregnane-ol-dione

17OH-pregnenolone

11-deoxycortisol

Fig. 10.18 Backdoor pathway of androgen biosynthesis

10 Congenital Adrenal Hyperplasia