Androgen backdoor pathway
The androgen backdoor pathway is a collective name for all metabolic pathways where physiologically significant androgens are synthesized from 21-carbon (C
21) steroids (pregnanes) by their 5α-reduction, bypassing testosterone and/or androstenedione.
A backdoor pathway is an alternative to the conventional, canonical androgenic pathway that involves testosterone and/or androstenedione. In the canonical pathway, 5α-dihydrotestosterone is synthesized directly from testosterone through the action of the enzyme 5α-reductase in tissues where 5α-reductase enzymes are highly expressed, such as the prostate gland, hair follicles, and skin. In both pathways (canonical and backdoor), the enzyme 5α-reductase plays a crucial role. However, in the androgen backdoor pathway, 5α-reductase acts on the C
21 steroids (pregnanes), leading to the reduction of the 4,5-double bond in these C
21 steroids, starting a long chain of transformations to 5α-dihydrotestosterone, whereas in a canonical pathway 5α-reductase acts on the 4,5-double bond in testosterone to produce 5α-dihydrotestosterone directly.
Initially described as a pathway where 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other pathways have been since then discovered that lead to 11-oxygenated androgens which are also physiologically significant androgens.
The role of these backdoor pathways relates to early male sexual differentiation, hair growth patterns, regulation of secretory functions, sebum production by skin cells, and various biological processes where androgens are involved. Understanding these processes is essential for developing effective treatments for conditions associated with hyperandrogenism. In individuals with congenital adrenal hyperplasia due to enzyme deficiencies like 21-hydroxylase deficiency or cytochrome P450 oxidoreductase deficiency, activation of these alternate routes can occur at any age when there is an increase in circulating levels of certain precursors such as progesterone or 17α-hydroxyprogesterone, and can lead to symptoms of hyperandrogenism, such as acne, hirsutism (growth of hair where they should not normally grow), polycystic ovary syndrome or prostate gland enlargement.