Androgen backdoor pathway
The androgen backdoor pathway is a metabolic route in which androgens are produced from 21-carbon steroids bypassing testosterone and androstenedione as intermediates.
This process starts with 21-carbon steroids, also known as pregnanes, and involves a step called "5α-reduction". Notably, this pathway does not require the intermediate formation of testosterone, hence the term "bypassing testosterone" is sometimes used in medical literature as the hallmark feature of this way of androgen biosynthesis. This feature is a key distinction from the conventional, canonical androgenic pathway, which necessitates the involvement of testosterone as an intermediate in the synthesis of androgens.
These alternate androgen pathways play a crucial role in early male sexual development. In individuals with congenital adrenal hyperplasia due to enzyme deficiencies like 21-hydroxylase or cytochrome P450 oxidoreductase deficiency, these pathways can activate at any age with increased levels of precursors like progesterone or 17α-hydroxyprogesterone. This activation can lead to symptoms of hyperandrogenism such as acne, hirsutism, polycystic ovarian syndrome, or prostate enlargement.
In the canonical pathway, dihydrotestosterone is directly synthesized from testosterone by the enzyme 5α-reductase, primarily in tissues where it excepts its effect, such as the prostate gland, hair follicles, and skin. Both pathways rely on 5α-reductase, but in the androgen backdoor pathway, this enzyme acts on steroids, initiating a series of chemical reactions that eventually lead to dihydrotestosterone production. In contrast, in the canonical pathway, 5α-reductase targets the 4,5-double bond in testosterone, producing dihydrotestosterone directly.
The backdoor pathway was initially described as a biosynthetic route where 5α-reduction of 17α-hydroxyprogesterone ultimately leads to dihydrotestosterone. Since then, several other pathways have been discovered that lead to 11-oxygenated androgens which are also physiologically significant.
Function
Androgens that bind to and activate the androgen receptor have numerous physiological functions which can broadly divided into androgenic and anabolic. The anabolic effects are important in both males and females, although females have lower circulating levels of androgens. The physiologically most important androgens are testosterone and dihydrotestosterone, which are considered classical androgens because their role in human health was discovered in 1930s. However, much later, in 2010s, the role in human health of 11-oxygenated androgens was established, namely, of 11-ketotestosterone and 11-ketodihydrotestosterone, that both bind and activate the human androgen receptor with affinities, potencies, and efficacies that are similar to that of testosterone and DHT, respectively, although 11-oxygenated androgens were long known to be principal androgens in teleost fishes.The main biochemical route to T and DHT is the canonical pathway that proceeds from pregnenolone. Alternatively, DHT but not T can be produced through a backdoor pathway that proceeds from 17α-hydroxyprogesterone or progesterone. The function of androgen backdoor pathways is to produce physiologically significant androgens in normal conditions where the conventional pathway is insufficient, such as in male early sexual differentiation. Sexual differentiation is a process by which hormones determine anatomic phenotype, mainly the development of the reproductive organs. DHT is the most important androgenic hormone and is a product of both canonical and backdoor pathways. Additionally, 11KDHT but not 11KT can be biosynthesized from the C11-oxy backdoor pathway starting from progesterone. These C11-oxy androgens can contribute to the pathology of congenital adrenal hyperplasia, polycystic ovarian syndrome, and prostate cancer.
The androgen backdoor route is activated during normal prenatal development and leads to early male sexual differentiation. Dihydrotestosterone synthesized by this route plays a critical role in the development of male sexual characteristics, including the differentiation and maturation of the male external genitalia, the prostate gland, and other male reproductive structures. By bypassing the conventional intermediates, this pathway ensures the timely and appropriate development of male sexual traits in early embryonic and fetal stages. Both canonical and backdoor pathways are essential in normal male embryonic development. A disruption in the backdoor pathway can lead to incomplete or altered male sexual differentiation. This disruption may result in abnormalities or underdevelopment of the male external genitalia, prostate gland, and other male reproductive structures. The specific consequences can vary depending on the nature and extent of the disruption and may lead to conditions such as ambiguous genitalia or other disorders of sexual development, where the individual's physical and sexual characteristics do not align clearly with typical male, i.e., undervirilization of male infants. Undervirilization refers to insufficient development of male characteristics due to below-normal effects of androgens during prenatal development. After birth, it may manifest as markedly underdeveloped male genitalia.
The backdoor pathway of DHT biosynthesis from 17OHP to DHT was first described in the marsupials and later confirmed in humans. Both the canonical and backdoor pathways of DHT biosynthesis are required for normal development of male genitalia in humans. As such, defects in the backdoor pathway from 17α-hydroxyprogesterone or progesterone to DHT lead to undervirilization in male fetuses because placental P4 is the precursor of DHT via the backdoor pathway.
In 21-hydroxylase deficiency or cytochrome P450 oxidoreductase deficiency, even a mild increase in circulating P4 or 17-OHP levels may activate this pathway, regardless of the patient's age and sex.
Mechanism
Androgen signaling
The androgen response mechanism involves androgens binding to androgen receptors in the cytoplasm, which then move into the nucleus and control gene transcription by interacting with specific DNA regions called androgen response elements. This response mechanism plays a crucial role in male sexual differentiation and puberty, as well as other tissue types and processes, such as the prostate gland, hair follicles, skin, and muscle. Such tissues, where androgens exert their effects, are called 'androgen target tissues'.Different androgens have different effects on androgen receptors because they have different degrees of binding and activating the receptors. Physiologically significant androgens are those androgens that have a strong influence on the development and functioning of male sexual characteristics, unlike physiologically insignificant androgens, which have low biological activity or are quickly metabolized into other steroids. Physiologically insignificant androgens do not have a notable influence on the development and functioning of male or female sexual characteristics, they can be products of the metabolism of more active androgens, such as testosterone, or their precursors.
Androgen biosynthesis
The androgen backdoor pathways are vital for creating androgens from 21-carbon steroids, known as pregnanes. A 21-carbon steroid is a steroid molecule with 21 carbon atoms, hence, their chemical formula contains . For example, the chemical formula of progesterone is. That's why 21-carbon steroids are denoted as -steroids, 19-carbon steroids are denoted as steroids, and so on. The androgen backdoor pathways occur without the involvement of testosterone and/or androstenedione, which are part of the conventional, canonical androgenic pathway.In the canonical pathways of androgen biosynthesis, DHT is synthesized from T via 5α-reduction, so that 5α-reduction of T, a steroid, is the last step of the pathway. In the backdoor pathways, to the contrary, 5α-reduction of steroids is the first step. The 5α-reduction is a chemical reaction where a functional group attached to the carbon in position 5α of the steroid nucleus is reduced, and a double bond between carbon atoms numbered 4 and 5 in the steroid molecule is replaced to the single bond in a chemical reaction catalyzed by the SRD5A1 enzyme.
The androgen backdoor pathways can be also activated in pathologic conditions, such as congenital adrenal hyperplasia, leading to hyperandrogenism.
Biochemistry
Canonical biosynthesis
In the canonical androgen biosynthesis pathway, dihydrotestosterone is synthesized irreversibly from testosterone by the enzyme 5α-reductase, while T is synthesized from androstenediol or androstenedione, which all are steroids. The 5α-reduction of T occurs in various tissues including the genitals, prostate gland, skin, hair follicles, liver, and brain. Around 5 to 7% of T undergoes 5α-reduction into DHT in male adults. The liver is the main source of circulating DHT in both genders. Sex hormone-binding globulin transports the majority of circulating T to the cells of androgen target tissues, where it is then 5α-reduced to DHT. In adult males, approximately 70% of circulating DHT is produced by the peripheral conversion of T in non-gonadal tissues, with the remaining 30% directly secreted by the testes or adrenals; the prostate does not contribute to circulating DHT. In females, particularly from puberty onward, circulating DHT is almost entirely generated by peripheral conversion, resulting in levels that are only 3-10% of those found for T.Backdoor biosynthesis
What distinguishes the androgen backdoor from the classical pathway is whether 5α-reduction initiates or terminates the pathway. In the backdoor pathway, 5α-reduction of progesterone or 17α-hydroxyprogesterone occurs at or near the beginning of the pathway respectively. Conversely, in the classical pathway, 5α-reduction is the final step, where testosterone is converted into dihydrotestosterone.The backdoor pathway splits into two subpathways at P4, proceeding through either 17OHP or 5α-DHP before merging again at 5α-Pdiol. The biosynthetic intermediate 5α-Pdiol in turn is converted into DHT in two chemical steps.