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Steroid Metabolism in Human Skin: Its Relation to Sebaceous-Gland
Growth and Acne Vulgaris
MALCOLM B. HODGINS and JOSEPH B. HAY
Department of Dermatology, University of Glasgow, Glasgow GI I 6NU, Scotland, U.K.
The growth and secretory activity of sebaceous glands are androgen-dependent. It has
been shown that in normal adult men, the testes are the major source of sebotrophic
hormones, whereas in women the secretions of the adrenal cortex and ovaries are
important (Strauss & Pochi, 1963; Pochi & Strauss, 1967).
C19-steroidmetabolism in human skin
Hydroxy steroid dehydrogenase activity was detected histochemically in human
sebaceous glands by Baillie el al. (1965). They suggested that the adrenal androgens,
dehydroepiandrosterone and 4-androstene-3,l’I-dione (androstenedione) could
stimulate sebaceous-gland growth through conversion into testosterone in the glands.
It was considered that testosterone was the active androgen, but initial studies of steroid
metabolism in skin could find only trace conversion of dehydroepianodrosterone into
testosterone (Cameron et af., 1966). After the discovery that 5 a-dihydrotesterone may
be the active form of androgen (Bruchovsky & Wilson, 1968a,b) it seemed that the
formation of 5 a-dihydrotestosterone rather than testosterone should be sought in
skin. It was found that testosterone is converted into 5a-dihydrotestosterone in human
skin (Gomez & Hsia, 1968; Wilson & Walker, 1969). Clearly the failure of testosterone
to accumulate as a metabolite in incubations of skin with dehydroepiandrosterone
could be due to further metabolism into 5a-dihydroteststerone. It has now been shown
Vol. 4
BIOCHEMICAL SOCIETY TRANSACTIONS
1
Dehydroepiandrosteronesulphate
TI
IJ-
* Dehydroepiandrosterone
___L
1
1
*4-Androstene-3,17-dione
7
* 5-Androstcne-3B.178-diol
*Testosterone
I
i3
Sa-Androstane-3.17-dione
5-Androstene-3~,17~-diol
3-sulphate
1
d
7
-
*5x-DihyJrotestosterone
1
*Androsterone
L
T_
Sa-Androstane-3a,l7fi-diol
Scheme 1. Pathways of formation and metabolism of Sa-dihydrotestosterone in human skin
Steroids used as substrates in incubation experiments with human skin are marked with
an asterisk. For details of other steroid metabolic pathways in skin, see Hay & Hodgins
(1973). Explanation of numbers: 1, l7g-hydroxy steroid dehydrogenase; 2, 3B-hydroxy
steroid dehydrogenase A4-5isomerase; 3, Sa-reductase; 4,3a-hydroxy steroid dehydrogenase.
that seven different CI9-steroids, present in human blood, are converted into Sa-dihydrotestosterone by human skin incubated in vitro (Hodgins, 1971; Hay, 1973; Hay &
Hodgins, 1973; Hodgins & Hay, 1974) (Scheme 1). Testosterone did not accumulate as
a metabolite in any of the experiments; this appeared to result from the high A4-30x0 steroid Sa-reductase (Sa-reductase) activity in skin.
Distribution of steroid-metabolizing enzymes in human skin
It was found that different enzyme activities vary with body site of the skin. For
example, in facial and scalp skin the rate of conversion of l7B-hydroxy steroids into
17-0x0 steroid metabolites is much greater than the reverse reaction, whereas in axillary
and pubic skin the opposite is found (Hay & Hodgins, 1973; Hay, 1974). Studies of the
178-hydroxy steroid dehydrogenases of human skin have shown that there are two forms
of enzyme. One (the main enzyme in forehead skin) is NAD(H)-dependent, localized in
the microsomal fraction and exhibits a lower apparent K , value for testosterone than for
androstenedione. This is similar to the enzyme isolated from the skin of the rat by
Davies et al. (1972). The other form of 178-hydroxy steroid dehydrogenase (the main
enzyme in axillary skin) is NADP(H)-dependent, localized in the loOOoOg supernatant
of skin homogenates and has an approximately 30-fold lower apparent K , value for
androstenedione than for testosterone (Table 1).
The presence of the two forms of 17B-hydroxy steroid dehydrogenase in skin may
provide a mechanism which regulates the formation and catabolism of testosterone and
So-dihydrotestosterone in the tissue. The urinary excretion of 17fi-hydroxy steroid
androgen metabolites in women is increased in acne and hirsutism (Mauvais-Jarvis
et al., 1973).
1976
563rd MEETING. LONDON
607
Table 1. Apparent K,,, valuesfor the 178-hydroxy steroid dehydrogenasesof human skin
Reactions were carried out at 37°C in 0.05M-Tris/HC1 buffer, pH7.4. Six to twelve
different steroid concentrations from 0.16 to 1 6 . 9 were
~ ~ used. With the microsomal
enzyme the cofactors were NADt ( 0 . 7 m ~ )for testosterone, and NADH ( 0 . 7 m ~ )for
4-androstene-3,17-dione.
With the soluble enzyme the cofactors were NADPt ( 0 . 6 2 m ~ )
for testosterone, and NADPH (0.62 mM) for 4-androstene-3,17-dione.Apparent K,,,
values were determined by least-squares analysis of Lineweaver-Burk plots.
Apparent K,,, ( p ~ )
Microsomal enzyme
Soluble enzyme
Testosterone
11
39
4-Androstene-3,17-dione
29
1.o
As the skin is a structurally complex organ, it is important to discover whether each
of the enzymes concerned in steroid metabolism is distributed uniformly in the different
tissue and cell types, or if some enzymes are specifically located in certain sites. Histochemical methods (Baillie et a[., 1965) detected 178- and 38-hydroxy steroid dehydrogenase activities only in the sebaceous glands. However, it has been found that the
conversion of testosterone into androstenedione occurs in plucked hair follicles (Fazekas
& Lanthier, 1971). This reaction has also been demonstrated in human foetal skin, at a
stage before the pilosebaceous unit starts to develop (Sharp etal., 1976). By contrast, the
results of biochemical studies of the conversion of dehydroepianodrosterone into
androstenedione in skin are consistent with a concentration of 3B-hydroxy steroid
dehydrogenase A4-5 isomerase in the sebaceous glands (Chakraborty et al., 1970;
Hay & Hodgins, 1973,1974~;Sharp et al., 1976). There is no histochemical method for
detection of Sa-reductase activity, but studies of the conversion of testosterone into
Sa-dihydrotestosterone have shown that the dermal fibroblasts, especially those of
genital skin, contain high concentrations of Sa-reductase (Wilson & Walker, 1969;
Shanies ei al., 1972; Keenan et al., 1975). Plucked hair roots also are able to convert
testosterone into Sa-dihydrotestosterone (Northcutt et al., 1969; Fazekas & Lanthier,
1971), but the distribution of Sa-reductase activity between the hair-follicle cells and the
fibroblasts of the dermal papilla has not been determined. Circumstantial evidence for
the presence of Sa-reductase in sebaceous glands has come from studies that have
demonstrated rapid conversion of testosterone into Sa-dihydrotestosterone in specialized
sebaceous-gland patches of the Mongolian Gerbil (Hodgins & Hay, 1973a) and Syrian
Hamster (Takayasu & Adachi, 1972), as well as in the rat preputial glands (Hodgins &
Hay, 19736).
A method of dissecting skin, after collagenase treatment, into separate components
has been developed (Hay & Hodgins, 19746; J. B. Hay & M. B. Hodgins, unpublished
work). The distribution of steroid metabolism in facial and axillary skin has been studied
by using this method. Sa-Reductase, 3a- and l7B-hydroxy steroid dehydrogenases are
distributed in epidermis, hair follicles, sebaceous glands, apocrine sweat glands and
fibrous dermis. In the axillary skin the apocrine glands are the major site of steroid
metabolism (Hay & Hodgins, 19746). 3B-Hydroxy steroid dehydrogenase A4-5isomerase
is located mainly in the sebaceous glands of facial skin (Table 2). This direct denionstration of 38-hydroxy steroid dehydrogenase A4-5 isomerase activity in the sebaceous
glands confirms the results of earlier histochemical and indirect biochemical studies.
Function of 3b-hydroxy steroid dehydrogenase A4--5 isomerase in sebaceous glands
The conversion of A5-3B-hydroxy-C19-steroids
into 5a-dihydrotestosterone depends
on the 38-hydroxy steroid dehydrogenase A4-5 isomerase. Both dehydroepiandrosterone
and dehydroepiandrosterone sulphate stimulate sebaceous secretion in man (Pochi
& Strauss, 1969; Drucker et al., 1972). It is likely, therefore, that the38-hydroxysteroid
dehydrogenase
isomerase in human sebaceous glands enables them to utilize
Vol. 4
21
608
BIOCHEMICAL SOCIETY TRANSACTIONS
Table 2. Distribution of 38-hydroxy steroid dehydrogenase
forehead skin
isomerase in male
Two pieces were cut from a specimen of forehead skin. One piece (3 1 mg wet wt. of tissue)
was partially digested with collagenase in phosphate-buffered saline; the other
(36mg wet wt. of tissue; whole-tissue control) was incubated without collagenase. The
digested skin was dissected as completely as possible into separate components.
38-Hydroxy steroid dehydrogenase activity was determined in the tissues and
collagenase-digesting medium (soluble fraction) by incubation with [7a-’H]dehydroepiandrosterone (Hay & Hodgins 1974~).Tissue DNA content was measured after
extraction of steroids.
Conversion of
dehydroepiandrosterone/2h (%) DNA b g )
Whole skin
Sebaceous glands
Hair follicles
Epidermis
Sweat glands
Dermis
Soluble
6.5
7.9
0.07
0.07
0.06
0.7
0.08
73.1
10.5
6.9
15.3
5.4
22.3
-
circulating AS-3j3-hydroxy C19-steroids as androgens. This may be important at
puberty and also during intra-uterine life, when the sebaceous glands develop in male
and female to a state of functional maturity (Sharp et af.,1976).
Studies of the metabolism and biological activity of dehydroepiandrosterone and
5-androstene-3/7,17&diolin the rat preputial glands and prostate gland have provided
evidence for a specific role of these steroids in the control of sebaceous-gland function.
Dehydroepiandrosterone and 5-androstene-3B,17~-diol
are much less active than
testosterone in stimulating prostatic growth. Dehydroepiandrosterone is incapable of
maintaining epithelial growth in rat prostate in organ culture; this has been attributed
to the absence or very low activity of 38-hydroxy steroid dehydrogenase
isomerase
in the rat prostate gland (Roy et af.,1972). However both dehydroepiandrosterone and
5-androstene-3B,17fl-diol
are powerful stimulators of sebaceous-gland growth in the
rat (Archibald, 1973). Indeed 5-androstene-3/?,178-diolis as active as testosterone. We
have found that 5-androstene-3/3,178-diolis rapidly metabolized into testosterone and
5a-dihydrotestosterone in rat sebaceous glands, but not in the prostate (Hodgins & Hay,
1974). Thus the androgenic activities of the AS-3B-hydroxysteroids correlate with the
activity of 38-hydroxy steroid dehydrogenase A4-5 isomerase in these target organs.
Steroids and acne vuIgaris
The growth of the sebaceous glands at puberty is commonly accompanied by acne.
It is now clear that there is a positive correlation between sebaceous-gland secretory
activity and the clinical severity of acne (Burton & Shuster, 1971 ;Cotterill et al., 1971).
Two hypotheses have been advanced to account for the increased sebum secretion in
acne. The first proposes that excessivesebaceous-gland secretion results from abnormally
high plasma androgen concentrations. The second proposes that in acne, the sebaceous
glands are abnormally sensitive to ‘normal’ plasma-androgen concentrations, possibly
owing to increased synthesis of Sa-dihydrotestosterone in the skin. Studies of acne in
women have found increased plasma concentrations of unbound 178-hydroxysteroids
(Lim & James, 1974), testosterone (Forstrom et al., 1974) and dehydroepiandrosterone
sulphate (Walker et al., 1975). Increased plasma-androgen concentrations have not so
far been found in men with acne (Pochi et al., 1965; Lim & James, 1974; Forstrom
et at., 1974). Sansone & Reisner (1971) found that skin from acne patients had higher
Sa-reductase activity than skin from control subjects. However Hay & Hodgins (1974a)
1976
563rd MEETING, LONDON
609
could not find any clear cut differences between male acne patients and controls in the
metabolism of testosterone, androstenedione or dehydroepiandrosterone in skin.
I t seems unlikely that either of the hypotheses alone will explain the pathogenesis of
acne in male and female. If increased sebum secretion in acne results from androgenic
stimulation, this will depend on the plasma concentrations of all of the circulating
CI9steroids, together with their rates of metabolism in the skin.The relative contributions
of plasma-steroid concentrations and androgen sensitivity of the sebaceous glands to the
increased sebum secretion in acne may vary widely between individuals.
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Effects of Topical Corticosteroids on Proliferative Disease of the
Epidermis
R. M A R K S
Department of Medicine, W d s h NationaI School of Medicine, Heafh Park, C a r d i r
CF4 4 X X , U.K.
Vol. 4