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In normal, non-pregnant women, the main source of oestrogen is, of course, the ovary. However, in men and postmenopausal women, peripheral aromatization of circulating androgens is a significant source. Radioisotope infusion has identified adipose tissue, skeletal muscle and skin as sites of peripheral oestrogen synthesis (Longcope, Pratt, Schneider & Fineberg, 1978). In ovarian granulosa cells, follicle-stimulating hormone (FSH) regulates aromatase activity by stimulating adenylate cyclase. The FSH-induced increase in aromatase appears to be an example of a cyclic AMP-dependent activation of gene expression, although there is also evidence for post-translational regulation of enzyme activity (Steinkampf, Mendelson & Simpson, 1988). Do analogous mechanisms regulate aromatase in peripheral tissues? An unequivocal answer to this question cannot yet be given, but recent studies in tissue culture have raised the tantalizing possibility that peripheral aromatase may be under complex control by local tissue factors released during the response to damage, injection or stress.
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Binding of [3H]testosterone and 5α-dihydro[3H]testosterone ([3H]DHT) to specific androgen-receptor sites of 5α-reductase-deficient human genital skin fibroblasts (five cell-lines) was studied in the intact cultured cells at 37 °C. Under the conditions of the experiments, conversion of [3H]testosterone into [3H]DHT was negligible. Both steroids bound to the same set of high-affinity saturable sites in cytoplasmic and nuclear fractions of the cells. Unlabelled testosterone, DHT and methyltrienolone competed effectively with the labelled steroids. Progesterone and oestradiol were weaker competitors; cortisol did not compete. The dissociation constant (K d) for high-affinity complexes with [3H]testosterone (0·44 ± 0·035 nmol/l) was higher than that for [3H]DHT complexes (0·20 ± 0·090 nmol/l). Unlabelled DHT was more effective than unlabelled testosterone in competing with either radioactive steroid. Complexes of [3H]DHT and receptor dissociated more slowly than [3H]testosterone-receptor complexes and [3H]DHT bound more extensively to low-affinity non-saturable sites in fibroblasts. As judged by competition with the radioactive androgens, progesterone bound to the androgen receptor with a K d of about 7 nmol/l. 5α-Pregnane-3,20-dione had an approximately fivefold lower affinity than progesterone for androgen receptors; 3α/β- or 20α-reduction lowered its affinity further. It is suggested that in 5α-reductase deficiency in man, progesterone in amniotic fluid and blood could effectively inhibit testosterone binding to androgen receptors in the male embryonic external genitalia. One function of the high levels of 5α-reductase activity normally found in embryonic external genitalia and urogenital sinus may be to protect these tissues from the potentially antiandrogenic action of progesterone.
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SUMMARY
Human skin from forehead, cheek and axilla was incubated in vitro with [7α-3H]dehydroepiandrosterone (DHA), [7α-3H]DHA sulphate, [7α-3H]-androstenedione and [7α-3H]testosterone. The following enzyme activities were detected: 3β-hydroxysteroid dehydrogenase Δ4-5 isomerase, 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, 5α-reductase, 5β-reductase, sulphotransferase, sulphatase, steroid hydroxylase. 5α-Reduced steroids were the major metabolites. All four substrates were converted to 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol. In axillary skin, conversion of 17-oxosteroids to 17β-hydroxysteroids was favoured, 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol being major metabolites. In facial skin, formation of 17-oxosteroids predominated with little accumulation of 5α-dihydrotestosterone or 5α-androstane-3α,17β-diol. 5α-Androstane-3β,17β-diol was a metabolite of DHA, androstenedione and testosterone but was found in lower amounts than 5α-androstane-3α,17β-diol. Similarly conversions to epiandrosterone were much lower than to androsterone in all the skin specimens.
It was concluded that the differences in accumulation of 5α-dihydrotestosterone were determined by the differences in 17β-oxidoreduction rather than differences in 5α-reductase, the activity of which was high in all skin specimens.
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SUMMARY
The metabolism of [7α-3H]dehydroepiandrosterone (DHA), [7α-3H]-androstenedione and [7α-3H]testosterone was studied in the ventral sebaceous gland patch of the Mongolian gerbil in vitro. The main enzyme activities found were 17β-hydroxysteroid dehydrogenase, 5α-reductase, 17α-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, sulphotransferase and hydroxylase. The active androgen 5α-dihydrotestosterone was formed in appreciable amounts from both testosterone and androstenedione. The 17β-hydroxysteroid dehydrogenase actively formed both 17-oxo and 17β-hydroxysteroids in this tissue. The conversion of DHA to C4–5 unsaturated steroids and 5α-steroids was not observed presumably due to a lack of 3β-hydroxysteroid dehydrogenase Δ4–5isomerase. The metabolism was compared with that in human and rat skin and its significance discussed.
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SUMMARY
Testosterone metabolism was studied in tissues associated with a keratin-filled cutaneous cyst. Instead of the 5α-reduced metabolites usually associated with skin steroid metabolism, considerable amounts of 5β-reduced steroids were found. These included 5β-androstane-3,17-dione, 17β-hydroxy-5β-androstan-3-one, and 5β-androstane-3β,17β-diol. This change in metabolic pattern is discussed.
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The distribution of androgen metabolism in human skin was studied using tissues isolated either by direct dissection of axillary skin or by dissection of collagenase-digested forehead and axillary skin. All tissues (epidermis, sweat glands, sebaceous glands, hair follicles and dermis) were found to contain 17β-, 3β- and 3α-hydroxysteroid dehydrogenase (HSD) activities, 3β-hydroxysteroid dehydrogenase-Δ4–5 isomerase (Δ5-3β-HSD) activity and 5α-reductase activity. All tissues converted testosterone into 5α-dihydrotestosterone. In confirmation of previous histochemical studies, over 90% of the Δ5-3β-HSD of forehead skin was found in the sebaceous glands. In forehead skin, 40–66% of the 5α-reductase activity was in the sebaceous glands, while in axillary skin 50–70% was in the sweat glands, especially the apocrine glands. There was a more even distribution of 17β-HSD activity in skin tissues than histochemical studies have indicated previously. Knowledge of the distribution of these enzymes has helped in the understanding of the function of androgen metabolism in skin.
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ABSTRACT
Pre-incubation of monolayer cultures of human skin fibroblasts with 1,25-dihydroxycholecalciferol (1,25-D3; 0.1-10 nmol/l) increased the rate of conversion of androstenedione into oestrone (aromatase activity) when measured subsequently in the presence of a 5α-reductase inhibitor (10 umol/l). Maximal stimulation (14- to 89-fold with 10 nmol 1,25-D3/l) occurred 12 h after addition of the hormone and was maintained for up to 48 h. Stimulation was prevented by cycloheximide. In one cell line high 1,25-D3 concentrations (>30 nmol/l)prevented the increase in aromatase activity; this did not appear to result from direct enzyme inhibition by 1,25-D3. The possibility is considered that 1,25-D3 could act as a physiological regulator of peripheral aromatase. As oestrogens can prevent postmenopausal bone loss, it is speculated that 1,25-D3 might protect against bone resorption by maintaining peripheral oestrogen biosynthesis.
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Human forehead skin incubated in vitro is known to metabolize testosterone to 17-oxosteroids faster than the reverse reaction, while axillary skin rapidly metabolizes androstenedione to 17β-hydroxysteroids, such as testosterone and 5α-dihydrotestosterone, While this has been confirmed using a larger number of patients, some indication has been found that 17β-hydroxysteroid oxidoreductase activity declines with age in the axilla. The relative rates of 17β-oxidation and reduction (direction of operation of skin 17β-hydroxysteroid oxidoreductase activity) were not altered by a variety of incubation conditions. Large amounts of a membrane-bound 17β-hydroxysteroid oxidoreductase, showing preference for NAD as coenzyme and testosterone (rather than androstenedione) as steroid substrate, were found in forehead skin from one patient. On the other hand, the main axillary skin enzyme in skin from another patient was soluble and showed preference for NADP and androstenedione. It is postulated that 17β-oxidation and reduction in skin is controlled by the relative amount, the coenzyme preferences and the kinetic properties of these two enzymes.
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SUMMARY
Fresh scalp, genital, chest and axillary skin from human foetuses of 12–41 weeks' maturity was incubated in Krebs' improved Ringer I medium with [7α-3H]dehydroepiandrosterone, [7α-3H]testosterone and [7α-3H]androstenedione. The metabolites identified were androstenedione, 5α-androstane-3,17-dione, androsterone, 3-epiandrosterone, 5α-dihydrotestosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, 5-androstene-3β,17β-diol and testosterone. The results provide evidence for the presence of 3β-hydroxysteroid dehydrogenase, Δ4–5 isomerase, 17β-hydroxysteroid dehydrogenase, Δ4-3-oxosteroid-5α-reductase and 3α-hydroxysteroid dehydrogenase in human foetal skin. There were quantitative differences in the various enzyme activities between different body sites and skin specimens of different gestational age. 5α-Reductase activity was particularly high in genital skin. 3β-Hydroxysteroid dehydrogenase Δ4–5 isomerase activity was low in skin from a 12-week foetus, but high in skin specimens from 28-, 38- and 41-week foetuses. 17β-Hydroxysteroid dehydrogenase activity was already high in the skin of the 12-week foetus and remained so in the older foetuses. These results were correlated with the development of the foetal sebaceous glands, and were in general agreement with a parallel enzyme histochemical study. The role of androgen metabolism in human foetal skin is discussed.
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ABSTRACT
A mouse monoclonal antibody against the N-terminal region of human androgen receptor (AR) was used to identify receptors by immunoperoxidase staining in frozen serial sections of skin from scalp, face, limb and genitalia of men and women aged 30–80 years. AR staining was restricted to cell nuclei.
In sebaceous glands, AR were identified in basal and differentiating sebocytes. The percentage of receptor-positive basal sebocyte nuclei in the temple/forehead region was greater in males (65%) than in females (29%).
AR staining was restricted to the cells of dermal papillae in anagen and telogen hair follicles. The percentage of dermal papillae containing AR was greater in males (58%) than in females (20%). The number of positively stained dermal papillae was lowest in female scalp skin. In 163 hair follicles sectioned, AR were absent from germinative matrix, outer root sheath (including the bulge region), inner root sheath, hair shaft and hair bulb, and from the capillaries present in some large dermal papillae.
AR were present in pilosebaceous duct keratinocytes, suggesting that androgens may influence pilosebaceous duct keratinization. AR were also identified in interfollicular epidermal keratinocytes and dermal fibroblasts although, in both cell types, intensity and frequency of staining were greatest in genital skin. AR were identified in luminal epithelial cells of apocrine glands in genital skin and in certain cells of the secretory coils of eccrine sweat glands in all body sites.
This study indicates that androgens regulate sebaceous gland and hair growth by acting upon two different types of target cells, the epithelial sebocytes of sebaceous glands and the mesenchymal cells of the hair follicle dermal papilla. AR staining in either cell type was not influenced by age in adults. The distribution of AR in human skin is consistent with the diverse effects of androgens on the structure and function of skin and its appendages.
Journal of Endocrinology (1992) 133, 467–475
