Cutaneous Androgen Metabolism: Basic Research and Clinical Perspectives

Abstract

The skin, especially the pilosebaceous unit composed of sebaceous glands and hair follicles, can synthesize androgens de novo from cholesterol or by locally converting circulating weaker androgens to more potent ones. As in other classical steroidogenic organs, the same six major enzyme systems are involved in cutaneous androgen metabolism, namely steroid sulfatase, 3beta-hydroxy-steroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, steroid 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and aromatase. Steroid sulfatase, together with P450 side chain cleavage enzyme and P450 17-hydroxylase, was found to reside in the cytoplasm of sebocytes and keratinocytes. Strong steroid sulfatase immunoreactivity was observed in the lesional skin but not in unaffected skin of acne patients. 3beta-hydroxysteroid dehydrogenase has been mainly immunolocalized to sebaceous glands, with the type 1 being the key cutaneous isoenzyme. The type 2 17beta-hydroxysteroid dehydrogenase isoenzyme predominates in sebaceous glands and exhibits greater reductive activity in glands from facial areas compared with acne nonprone areas. In hair follicles, 17beta-hydroxysteroid dehydrogenase was identified mainly in outer root sheath cells. The type 1 5alpha-reductase mainly occurs in the sebaceous glands, whereby the type II isoenzyme seems to be localized in the hair follicles. 3alpha-hydroxysteroid dehydrogenase converts dihydrotestosterone to 3alpha-androstanediol, and the use of 3alpha-androstanediol glucuronide serum level to reflect the hyperandrogenic state in hirsute women may be a reliable parameter, especially for idiopathic hirsutism. In acne patients it is still controversial if 3alpha-androstanediol glucuronide or androsterone glucuronide could serve as suitable serum markers for measuring androgenicity. Aromatase, localized to sebaceous glands and to both outer as well as inner root sheath cells of anagen terminal hair follicles, may play a "detoxifying" role by removing excess androgens. Pharmacologic development of more potent specific isoenzyme antagonists may lead to better clinical treatment or even prevention of androgen-dependent dermatoses.

Controlled clinical trial for evaluation of hair growth with low dose cyclical nutrition therapy in men and women without the use of finasteride

“…Thus we say, not a raised DHT but a higher sensitivity of the hair roots is responsible for hair loss [11,[29][30][31] . Studies by Sawaya and Price [32] , on the 5-alpha reductase type 1, type 2, aromatase and androgen receptors, along with the cutaneous androgen metabolism studies by Chen et al [33] and Hoffman and Happle [34] current understanding of androgenic alopecia, all support the conclusion that sensitivity of the follicles is of greater concern than raised levels of androgens. We have discovered a limited correction of one of the mechanisms for hair loss by blocking conversion of testosterone to DHT but are attempting to treat all the various types of hair loss with the same approach.…”

“…Various factors affecting hair loss, weaken the hair roots and make them sensitive to normal levels of androgens in the body [9][10][11][12] . Pattern hair loss can occur with normal androgen levels [12,13] , pattern hair loss can occur before puberty [13][14][15] , it has been reported in hypogonadism [16] and also in a case of complete androgen insensitivity syndrome [17] .…”

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

“…A fundamental prerequisite is represented by the fact that if different androgens are needed to fully define hyperandrogenemia in these women, it could be that different mechanisms may be involved in regulating the enzyme activity involved in the androgen production rate or in their metabolic clearance rate (18). In addition, although there is a consensus that increased androgen production in PCOS women is mainly dependent on hyperactivity of the ovarian theca cells, some uncertainty still remains regarding the role of adrenals and extraglandular sites (8), such as the adipose tissue and the liver and possibly the skin cell, as they express the most crucial genes of steroidogenesis and also utilize sex steroid precursors of potent androgens (19,20). This may have some relevance in explaining the presence of hirsutism in women without evidence for an altered blood androgen profile.…”

Is idiopathic hirsutism (IH) really idiopathic? mRNA expressions of skin steroidogenic enzymes in women with IH

“…At least to our knowledge, there is no study investigating the mRNA expression of enzymes having a role in locally produced androgens and their precursors in freshly obtained hair follicles in patients with IH. The cutaneous expression of steroidogenic acute regulatory protein, cytochrome P450 cholesterol sidechain cleavage (P450scc) and cytochrome P450 17-alpha hydroxylase (P450c17) have been demonstrated previously which suggest that the cutaneously derived cholesterol could be further used as a substrate for de novo steroid hormone synthesis in human epidermis and the sebaceous gland (18). Moreover, in peripheral organs, such as the skin, the potent tissue androgen testosterone results from the conversion of circulating DHEAS, a weak but most abundant androgen, through the serial action of STS, 3b-hydroxysteroid dehydrogenase and 17b-HSD (19).…”