![Steroidogenesis in human skin. Left panel: The complete pathway of sex hormone synthesis from cholesterine. StAR = steroidogenic acute regulatory protein, P450scc = cytochrome P450 side chain cleavage enzyme, 5α-DHT = 5α-dihydrotestosterone, ER = estrogen receptor. Middle panel: Sebocytes (S) but neither keratinocytes (K) nor melanocytes (M) express 3β-hydroxysteroid dehydrogenase-Δ5–4-isomerase (Δ5–3β-HSD), the enzyme converting dehydroepiandrosterone and androstenedione to testosterone at the mRNA level (RT-PCR). Right pannel: Sebocytes but not keratinocytes are able to metabolize 3H-dehydroepiandrosterone ([3H-] DHEA) to downstream androgen compounds.](https://www.researchgate.net/profile/Christos-Zouboulis/publication/11753875/figure/fig1/AS:281200196374579@1444054759822/Steroidogenesis-in-human-skin-Left-panel-The-complete-pathway-of-sex-hormone-synthesis_Q320.jpg)
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Horm Res 2000;54:230–242
Human Skin: An Independent Peripheral
Endocrine Organ
Christos C. Zouboulis
Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin,
Berlin, Germany
Prof. Dr. Christos C. Zouboulis
Department of Dermatology, University Medical Center Benjamin Franklin
The Free University of Berlin, Fabeckstrasse 60–62
D–14195 Berlin (Germany)
Tel. +49 30 8445 6910, Fax +49 30 8445 6908, E-Mail zouboulis@medizin.fu-berlin.de
ABC
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2001 S. Karger AG, Basel
0301–0163/00/0546–0230$17.50/0
Accessible online at:
www.karger.com/journals/hre
Key Words
Endocrinology W Hormone synthesis W Hormone
receptors W Hormone metabolism W Hormone activity
Abstract
The historical picture of the endocrine system as a set of
discrete hormone-producing organs has been substi-
tuted by organs regarded as organized communities in
which the cells emit, receive and coordinate molecular
signals from established endocrine organs, other distant
sources, their neighbors, and themselves. In this wide
sense, the human skin and its tissues are targets as well
as producers of hormones. Although the role of hor-
mones in the development of human skin and its capaci-
ty to produce and release hormones are well estab-
lished, little attention has been drawn to the ability of
human skin to fulfil the requirements of a classic endo-
crine organ. Indeed, human skin cells produce insulin-
like growth factors and -binding proteins, propiomelano-
cortin derivatives, catecholamines, steroid hormones
and vitamin D from cholesterol, retinoids from diet caro-
tenoids, and eicosanoids from fatty acids. Hormones
exert their biological effects on the skin through interac-
tion with high-affinity receptors, such as receptors for
peptide hormones, neurotransmitters, steroid hormones
and thyroid hormones. In addition, the human skin is
able to metabolize hormones and to activate and inacti-
vate them. These steps are overtaken in most cases by
different skin cell populations in a coordinated way indi-
cating the endocrine autonomy of the skin. Characteristic
examples are the metabolic pathways of the corticotro-
pin-releasing hormone/propiomelanocortin axis, ste-
roidogenesis, vitamin D, and retinoids. Hormones exhib-
it a wide range of biological activities on the skin, with
major effects caused by growth hormone/insulin-like
growth factor-1, neuropeptides, sex steroids, glucocorti-
coids, retinoids, vitamin D, peroxisome proliferator-acti-
vated receptor ligands, and eicosanoids. At last, human
skin produces hormones which are released in the circu-
lation and are important for functions of the entire organ-
ism, such as sex hormones, especially in aged individu-
als, and insulin-like growth factor-binding proteins.
Therefore, the human skin fulfils all requirements for
being the largest, independent peripheral endocrine or-
gan.
Copyright © 2001 S. Karger AG, Basel
Introduction
The human skin is the target for a wide range of chemi-
cal messengers. These include several hormones, which in
the classical sense are defined as substances secreted into
Human Skin as Endocrine Organ
Horm Res 2000;54:230–242
231
the blood stream by specific ductless glands. Their effects
have long been recognized and in some instances well
characterized. For example, hair follicles and sebaceous
glands are the targets for androgen steroids secreted by the
gonads and the adrenal cortex [1, 2] and melanocytes are
directly influenced by polypeptide hormones of the pitu-
itary [3]. However, the historical picture of the endocrine
system as a set of discrete hormone-producing organs,
most of them under the control of a master gland, the
pituitary, has become extended and modified to the point
of metamorphosis. The skin and other tissues can no lon-
ger be regarded simply as the recipients of signals from
distant transmitters. They must rather be viewed as orga-
nized communities in which the cells emit, receive and
coordinate molecular signals from a seemingly unlimited
number of distant sources in addition to the established
endocrine organs (modern and classic endocrine func-
tions, respectively), their neighbors (paracrine and juxta-
crine function), and themselves (autocrine and intracrine
function) (fig. 1). In the widest sense the human skin and
its tissues are thus the targets as well as the producers of
hormones.
In addition to the modified determination of the endo-
crine skin functions, the results of current research have
blurred the distinction between hormones secreted into
the blood stream and locally active factors. Epithelial skin
cells share common properties with secretory neurons
exhibiting a complete hypothalamic-pituitary-like axis [4]
and the skin converts the circulating androgen steroids
dehydroepiandrosterone (DHEA) and androstenedione
to testosterone and further to 5·-dihydrotestosterone (5·-
DHT) by the intracellular enzyme 5·-reductase but is also
responsible for large amounts of the circulating testoster-
one and 5·-DHT levels [2, 5]. Finally, the identification
of a number of pharmacologically active peptides in a
range of tissues throughout the body focused attention on
the ubiquity of locally acting hormones.
Although the role of hormones in the development of
human skin tissues and their capacity to produce and
release further hormones are well established [6, 7], little
attention has been drawn to the ability of human skin to
fulfil the requirements of a classic endocrine organ, name-
ly synthesis of hormones from major classes of com-
pounds used by the body for general purposes, binding
and regulation of specific receptors by the derived hor-
mones, organized metabolism, activation, inactivation,
and elimination of the hormones in specialized cells of the
tissue, exertion of biological activity, and release of hor-
mones in the circulation.
Fig. 1.
Modes of hormone action. Classical and modern endocrine
functions: Hormones produced by established endocrine organs or
other distant sources, respectively, reach target tissues through the
circulation. Paracrine function: Hormones act locally on cells other
than those that produce them. Juxtacrine function: Hormones pro-
duced in one cell interact directly with a receptor of an immediate
neighboring cell. Autocrine function: Hormones act on the cell in
which they are produced. Intracrine function: Hormones get acti-
vated in the cell in which they are produced and act on it by binding
to nuclear receptors.
Synthesis of Hormones in Human Skin
All types of small molecules can practically represent
precursors of skin hormones which can be proteins,
including glycoproteins, smaller peptides or peptide de-
rivatives, amino acid analogs or lipids (fig. 2).
Polypeptide hormones are direct translation products
of specific mRNA, such as growth hormone (GH), and
cleavage products of large precursor proteins, such as pro-
piomelanocortin (POMC) derivatives and prolactin. Al-
though there is no evidence that GH or GH-like peptides
are produced in the skin, its downstream peptide, insulin-
like growth factor-I (IGF-I), is synthesized in the skin,
mainly by dermal fibroblasts and melanocytes and also
possibly by keratinocytes of the stratum granulosum [8,
9]. Dermal fibroblasts are also source for IGF-II and IGF-
binding protein (IGFBP)-3 [10, 11].
POMC derivatives, such as adrenocorticotropic hor-
mone (ACTH), melanocyte stimulating hormone (MSH)
isotypes and ß-endorphin are produced in several skin cell
types in vivo and in vitro [4, 12–15]. ACTH and ·-MSH
are mainly expressed in epidermal keratinocytes, melano-
cytes, the outer root sheath of the anagen hair follicle,
232
Horm Res 2000;54:230–242
Zouboulis
Fig. 2.
Synthesis of hormones in
human skin. ➀ Keratinocytes;
➁ hair follicles; ➂ cutaneous nerves;
➃ sebaceous glands; ➄ melanocytes;
➅ fibroblasts; ➆ endothelial cells.
ACTH = Adrenocorticotropic hor-
mone; ·-MSH = ·-melanocyte stim-
ulating hormone; CRH = cortico-
tropin releasing hormone; Vit. D =
vitamin D; atRA = all-trans retinoic
acid; IGF-I = insulin-like growth
factor I; IGFBP-3 = insulin-like
growth factor binding protein-3.
dermal fibroblasts and microvascular endothelial cells.
ß-Endorphin is mainly produced by the outer root sheath
of the anagen hair follicle and dermal fibroblasts.
The few data existing on prolactin synthesis in human
skin are controversial. While dermal fibroblasts in vitro
have been shown to synthesize prolactin [16], no prolactin
mRNA was detected in human skin in another study
[17].
Catecholamines – norepinephrine and epinephrine –
which are modified amino acids and natural activators of
cAMP pathway, are produced in human keratinocytes but
not in melanocytes [18]. Another type of modified amino
acid, the corticotropin releasing hormone (CRH), has
been detected in epidermal and follicular keratinocytes,
melanocytes, endothelial cells, and dermal nerves but not
in sebocytes or fibroblasts [4, 19].
Steroid hormones and vitamin D are derived from cho-
lesterol. The skin, especially the sebaceous glands, is capa-
ble of synthesizing cholesterol – from two-carbon frag-
ments such as acetate [20, 21] – which is utilized in cell
membranes, formation of the epidermal barrier, in se-
bum, and as substrate for steroid hormone synthesis [22].
Skin is also source of corticosteroids [23] and the unique
site of vitamin D
3
(cholecalciferol) production [24, 25].
Retinoids and eicosanoids, such as prostaglandins,
prostacyclins and leukotrienes, are fatty acid derivatives.
In humans, vitamin A (retinol) and natural retinoids are
derived from carotenoids in the diet that are modified by
the body; in the skin, excess retinol is mainly esterified
[26]. Human keratinocytes in vitro are able to produce
low amounts of the intracellularly active metabolite all-
trans retinoic acid (atRA) [27–29]. Eicosanoid synthesis
can also be induced in human keratinocytes by several
proinflammatory signals [30, 31].
Hormone Receptors in Human Skin
Hormones exert their biological effects on the skin
through interaction with high-affinity receptors, which
are, in turn, linked to one or more effector systems within
cells. These effectors involve many different components
of the cellular metabolic machinery, ranging from ion
transport at the cell surface to stimulation of the nuclear
transcriptional apparatus. In general, receptors for the
peptide hormones and neurotransmitters are aligned on
the cell surface, while those for the steroid and thyroid
hormones are found in the cytoplasmic or nuclear com-
partments.
Receptors for the Peptide Hormones and
Neurotransmitters
The peptide hormone and neurotransmitter receptors
fall into four major groups; three of them are represented
in human skin. The first includes the so-called serpentine
or ‘seven transmembrane domain’ receptors which con-
tain an amino terminal extracellular domain followed by
seven hydrophobic amino acid segments, each of which is
believed to span the membrane bilayer. The seventh seg-
ment is followed by a hydrophilic carboxyl terminal
Human Skin as Endocrine Organ
Horm Res 2000;54:230–242
233
domain that resides within the cytoplasmic compartment.
To this group belong the parathyroid hormone (PTH)/
parathyroid hormone-related peptide (PTHrP) receptor
which is expressed in dermal fibroblasts but not in epider-
mal keratinocytes [32, 33], the thyroid-stimulating hor-
mone (TSH) receptor which is present in dermal fibro-
blasts [34], the CRH receptors from which type 1 is
present in epidermal and follicular keratinocytes, melano-
cytes, and dermal fibroblasts, whereas sebocytes express
types 1 and 2 [4, 19], the melanocortin receptors (MCR),
among them MCR1 which presents high affinity for ·-
MSH and ACTH and is expressed in epidermal and follic-
ular keratinocytes, epidermal and follicular melanocytes,
sebocytes, sweat gland cells, endothelial cells, Langerhans
cells, monocytes, macrophages, lymphocytes and dermal
fibroblasts, MCR2 which is specific for ACTH and is
expressed in epidermal melanocytes and adipocytes, and
MCR5 which shows affinity for ·-MSH and ACTH and is
present in sebocytes, sweat gland cells and adipocytes [4,
12, 35, 36], the Ì-opiate receptors which bind with high
affinity ß-endorphin and are expressed in epidermal and
outer root sheat keratinocytes, undifferentiated sebocytes
and cells of the sweat gland secretory portion [4], the
vasoactive intestinal popypeptide (VIP) receptors which
are expressed in epidermal keratinocytes, sebocytes,
sweat gland cells, endothelial cells, mononuclear cells and
dermal nerve fibers [37–39], the neuropeptide Y receptor
which is present in sebocytes [38], and the calcitonin
gene-related peptide (CGRP) receptor which is expressed
in sebocytes and Langerhans cells [38, 40].
The second group includes the single-transmembrane
domain receptors that harbor intrinsic tyrosine kinase
activity. This includes the insulin/IGF-I receptor and the
epidermal growth factor receptor which are expressed in
epidermal keratinocytes [8, 41].
The third group, which is functionally similar to the
second group, is characterized by a large extracellular
binding domain followed by a single membrane spanning
segment and a cytoplasmic tail. These receptors do not
possess intrinsic tyrosine kinase activity but appear to
function through interaction with soluble transducer mol-
ecules which do possess such activity. In human skin, they
are represented by the GH receptor which is present in
melanocytes and dermal fibroblasts, epidermal and follic-
ular keratinocytes of the outer root sheath, especially the
basal ones, sebocytes, cells of the eccrine sweat gland
secretory duct, hair matrix cells of the dermal papillae,
endothelial cells, Schwann cells of peripheral nerve fasci-
cles, and adipocytes of the dermis [8, 42, 43].
Steroid Hormone and Thyroid Hormone Receptors
The nuclear receptors differ from the receptors of the
cell membrane in that they are soluble receptors with a
proclivity for employing transcriptional regulation as a
means of promoting their biological effects. Thus, though
some receptors are compartmentalized in the cytoplasm
while others are defined to the nucleus, they all operate
within the nucleus chromatin to initiate the signaling cas-
cade. They associate in the nucleus with DNA sequences
bearing a specific recognition element called ‘hormone
response element’. Hormone response elements have dif-
ferent canonical sequences for each hormone. These re-
ceptors are expressed in human skin and can be grouped
into two major subtypes based on shared structural and
functional properties.
The first group, the steroid receptor family, includes
the glucocorticoid receptor which is mainly expressed in
basal keratinocytes, Langerhans cells and dermal fibro-
blasts [44, 45], the androgen receptor which is present in
epidermal and follicular keratinocytes, sebocytes, sweat
gland cells, dermal papilla cells, dermal fibroblasts, endo-
thelial cells, and genital melanocytes [2, 46–48], and the
progesterone receptor which is expressed in basal epider-
mal keratinocytes only [49]. The glucocorticoid receptor
is down-regulated by its ligands in dermal fibroblasts but
is not affected by aging [50, 51]. Steroid receptors under
basal conditions exist as cytoplasmic, multimeric com-
plexes that include the heat shock proteins hsp 90, hsp 70,
and hsp 56. Association of the steroid ligand with the
receptor results in dissociation of the heat shock proteins.
This, in turn, exposes a nuclear translocation signal pre-
viously buried in the receptor structure and initiates
transport of the receptor to the nucleus.
The second group, the thyroid receptor family, includes
the thyroid hormone receptors (isotypes ·1 and ß1), where-
as the isotype ß1 is present in epidermal keratinocytes, out-
er root sheat cells, cebocytes, dermal papilla cells, and der-
mal fibroblasts [6, 52, 53], the estrogen receptor-ß (but not
the estrogen receptor-·) which is expressed in dermal
papilla cells and dermal fibroblasts, sebocytes, adipocytes,
melanocytes, and keratinocytes of the outer root sheath
[48, 54–56], the retinoic acid receptors (RAR; isotypes ·
and Á) and retinoid X receptors (RXR; isotypes ·, ß, Á)
which are expressed in epidermal keratinocytes of the stra-
tum granulosum, follicular keratinocytes, sebocytes, and
endothelial cells, while only the RXR· isotype is present in
melanocytes, fibroblasts, and inflammatory cells [57–61],
the vitamin D receptor which is present in keratinocytes
of all epidermal layers except those of the stratum cor-
neum, epithelial cells of the epidermal appendages, mela-
234
Horm Res 2000;54:230–242
Zouboulis
nocytes, Langerhans cells, CD11b+ macrophages and
CD3+ T-lymphocytes [62, 63], and the peroxisome pro-
liferator-related receptors (PPAR) which are expressed in
epidermal and follicular keratinocytes, sebocytes, sweat
gland cells, endothelial cells, and adipocytes (isotype Á),
whereas isotypes · and ‰ are also expressed in keratino-
cytes and sebocytes [64]. The members of the thyroid
receptor family share a high degree of homology to the
proto-oncogene c-erbA and high affinity for a common
DNA recognition site. With the exception of the estrogen
receptor they do not associate with the heat shock proteins
and they are constitutively bound to chromatin in the
nucleus. The estrogen receptor, though demonstrating an
association with heat shock proteins, is largely confined to
the nuclear compartment. The estrogen receptor binds to
its regulatory element as a homodimer, while the other
receptors prefer binding as heterodimers together with a
RXR molecule. The latter amplifies both the DNA bind-
ing and the functional activity of the receptor.
Activation and Inactivation of Hormones in
Human Skin
In addition to its capacity to produce hormones and
express receptors for binding of distant, paracrine, juxta-
crine, autocrine, and intracrine hormones, the human
skin is able to metabolize hormones in order to activate
and inactivate them. These steps are overtaken in most
cases by different skin cell populations in a coordinated
way indicating the endocrine autonomy of the skin. Char-
acteristic examples for this kind of endocrine skin func-
tion are the metabolic pathways of the CRH/POMC axis,
sex steroids, vitamin D, and retinoids.
The CRH/POMC Axis
The skin is strategically located as a barrier between
the external and internal environments being permanent-
ly exposed to noxious stressors. To effectively deal with
such damaging signals the skin exhibits a highly organized
CRH/POMC system which is analogous to the hypothala-
mus/pituitary/adrenal axis [4]. Activation of this pathway
by stress-sensoring cutaneous signals, mainly proinflam-
matory cytokines, proceeds through the production and
release of CRH from keratinocytes, melanocytes, endo-
thelial cells, and dermal nerves which stimulates skin cell
CRH receptors in paracrine and autocrine manners. CRH
synthesis in melanocytes is up-regulated by ultraviolet
radiation B and down-regulated by dexamethasone [4].
Interestingly, CRH receptors in human sebocytes can be
regulated by several downstream hormones, mainly by
testosterone, estrogens, and GH [19]. CRH enhances the
production and secretion of the POMC peptides ·-MSH,
ACTH, and ß-endorphin, especially in keratinocytes, me-
lanocytes, endothelial cells and cutaneous nerves [12, 13,
15] by a complex multistep process that requires POMC
processing by prohormone convertases [4]. These en-
zymes are expressed in keratinocytes, melanocytes, and
endothelial cells. Production of ·-MSH and ACTH can be
significantly up-regulated by ultraviolet light and interleu-
kin (IL)-1 and down-regulated by tumor growth factor-ß
and dexamethasone. ACTH activates the steroidogenic
acute regulatory protein and thereof the MCR inducing
thereby the production and secretion of cortisol [65], a
powerful natural anti-inflammatory factor that counter-
acts the effect of stress signals and buffers tissue damage.
Steroidogenesis
Human sebocytes and keratinocytes express the ste-
roidogenic acute regulatory protein which is essential for
cholesterol translocation from the outer to the inner mito-
chondrial membrane and thus the initiation of steroido-
genesis [22] (fig. 3). They also express the P450 side chain
cleavage enzyme which catalyses the conversion of choles-
terol into pregnenolone, the cytochrome P450 17-hydrox-
ylase that leads to precursors of cortisol and DHEA, and
the steroidogenic factor-1 which maintains these reac-
tions. DHEA can be further converted into androstene-
dione and the tissue potent androgen testosterone by
sebocytes only, since only sebocytes express 3ß-hydroxy-
steroid dehydrogenase-¢
5-4
isomerase [2]. Further activa-
tion of testosterone by its conversion into 5·-DHT is cata-
lyzed by 5·-reductase type 1 which is expressed in almost
all skin cells but especially in sebocytes [66], while fibro-
blasts and dermal papilla cells also express 5·-reductase
type 2 [48]. Sebocytes are also able to regulate the balance
of testosterone and androstenedione bidirectionally by
expressing the 17ß-hydroxysteroid dehydrogenase iso-
types 2 and 3 [2]. Androgen conversion to estrogens in the
skin takes place in dermal fibroblasts which express the
responsible enzyme cytochrome P450 19 (aromatase) and
androgen inactivation to androsterone or 3·-androstane-
diol in epidermal keratinocytes which strongly express the
responsible enzyme 3·-hydroxysteroid dehydrogenase [2,
67]. In contrast to this skin-related pathway, conversion
of the adrenal DHEA sulfate – which reaches the skin
through the circulation – to DHEA only occurs with the
assistance of monocytes which exhibit steroid sulfatase
activity [68]. Therefore, the skin is a steroidogenic tissue
and different skin cell types overtake distinct duties in the
Human Skin as Endocrine Organ
Horm Res 2000;54:230–242
235
Fig. 3.
Steroidogenesis in human skin. Left panel: The complete pathway of sex hormone synthesis from cholesterine.
StAR = steroidogenic acute regulatory protein, P450scc = cytochrome P450 side chain cleavage enzyme, 5·-DHT =
5·-dihydrotestosterone, ER = estrogen receptor. Middle panel: Sebocytes (S) but neither keratinocytes (K) nor mela-
nocytes (M) express 3ß-hydroxysteroid dehydrogenase-¢
5–4
-isomerase (¢5–3ß-HSD), the enzyme converting dehy-
droepiandrosterone and androstenedione to testosterone at the mRNA level (RT-PCR). Right pannel: Sebocytes but
not keratinocytes are able to metabolize
3
H-dehydroepiandrosterone ([
3
H-]DHEA) to downstream androgen com-
pounds.
synthesis of tissue active androgens and their inactivation
leading to androgen and estrogen homeostasis. Adrenal
androgens may only be activated in the skin in pathologic
conditions which require the presence of inflammatory
cells in the skin.
In addition, evaluation of skin layer-specific predni-
carbate biotransformation has shown that epidermal ker-
atinocytes can hydrolyze the double ester prednicarbate at
position 21 to the monoester prednisolone 17-ethylcar-
bonate which nonenzymatically transforms to predniso-
lone 21-ethylcarbonate. This metabolite is enzymatically
cleaved to prednisolone, the main biotransformation cor-
ticosteroid product. Fibroblasts show a distinctively lower
enzyme activity [23]. Prednicarbate, prednisolone 17-
ethylcarbonate and prednisolone 21-ethylcarbonate are
hydrolyzed to a minor extent only. Therefore, epidermal
keratinocytes are likely to be responsible for the conver-
sion of potent corticosteroids to less potent ones in human
skin, while dermal fibroblasts are barely able to metabo-
lize the steroids.
The Vitamin D Pathway
Skin is the unique site of vitamin D
3
production
and liver is thought to be the main site of conversion
to 25(OH)D
3
. Skin is further capable of activating
25(OH)D
3
via 1·-hydroxylation and the resulting
1·,25(OH)
2
D
3
(calcitriol) plays a role in epidermal ho-
meostasis in normal and diseased skin. Human keratino-
cytes have been shown to substantially but slowly convert
3
H-D
3
to
3
H-25(OH)-D
3
[24]. In addition, they were
found to slowly but constantly form calcitriol from a large
reservoir of D
3
. Interestingly, physiological doses of ul-
traviolet light B radiation at 300 nm induce the conver-
sion of 7-dehydrocholesterol via pre-D
3
and D
3
into calci-
triol in the picomolar range in epidermal keratinocytes
[25]. Skin can further degrade vitamin D
3
: Cytochrome
P450 27 in epidermis completes the set of essential vita-
min D
3
hydroxylases [24]. Thus, by orchestrating the
entire system of production, activation and inactivation,
skin is an autonomous source of hormonally active calci-
triol.
236
Horm Res 2000;54:230–242
Zouboulis
The Retinoid Pathway
Epidermal keratinocytes in vivo regulate the levels of
the intracellularly active all-trans retinoic acid (atRA) by
induction of retinoic acid 4-hydroxylase [69]. atRA inac-
tivation by 4-hydroxylation prevents endogenous and ex-
ogenous atRA accumulation in the epidermis. In contrast
to atRA, retinol, retinaldehyde, 9-cis retinoic acid, and
13-cis retinoic acid are not able to regulate their own
hydroxylation. On the other hand, human keratinocytes
in vitro rapidly take up and initially convert retinol to
retinyl esters and then with time to low amounts of the
intracellularly active metabolite atRA [27–29]. 3,4-Dide-
hydro-retinol can also be detected [27, 70]. However,
ester formation, especially of retinyl oleate (18:1) and
retinyl palmitate (16:0), remains the main root by which
excess retinol is also handled by human keratinocytes in
vitro [27–29, 70]. Retinoid metabolism in human skin is
likely to be a cell-specific event, since sebocytes exhibit a
distinct metabolic pattern compared to epidermal kerati-
nocytes [60].
Biological Activity of Hormones in Human Skin
GH and IGF-I
The effects of the GH/IGF-I axis are addressed to-
wards a homeostatic regulation of cell proliferation and
differentiation. GH activity is mainly mediated by the
IGFs but GH has also direct effects on human skin cells
[6]. GH enhances androgen effects on hair growth and is
likely to be involved in sebaceous gland development. It
stimulates sebocyte differentiation and also augments the
effect of 5·-DHT on sebaceous lipid synthesis [71]. On
the other hand, GH does not affect keratinocyte or sebo-
cyte proliferation but it enhances the proliferation of der-
mal fibroblasts in vitro [8, 71]. IGF molecules circulate
mostly bound to IGFBPs. GH and IGF-I induce increases
in skin IGFBP-3 mRNA abundance [11], with a magni-
tude dependent on the presence of Ca
2+
. IGF-I at physio-
logical levels is essential for hair follicle growth by pre-
venting them from entering the catagen phase [72]. IGF-I
and insulin have been shown to significantly stimulate
sebocyte proliferation but also influence sebocyte differ-
entiation, especially in combination with GH, in vitro
[71, 73]. Insulin may act as an IGF-I surrogate as it exhib-
its marked homology to the IGFs and binds the IGF-I
receptor at high concentrations. IGF-I was also shown to
promote clonal proliferation of cultured keratinocytes [8]
and to upregulate hyaluroran synthesis in dermal fibro-
blasts exhibiting a similar effect to basal fibroblast growth
factors [74]. The IGF-I/IGF-I receptor loop was found to
be critically involved in maintenance of human skin
organ cultures ex vivo [41]; IGF-I locally produced by der-
mal fibroblasts interacted in a paracrine manner with its
receptor, predominantly expressed in basal keratinocytes,
to maintain tissue homeostasis. The GH/IGF-I axis shows
an age-related decreased hormone production concomi-
tant with symptoms similar to those of GH-deficient
adults [75]. At last, GH is able to switch the predominant
CRH receptor-1 mRNA expression to a sole CRH recep-
tor-2 expression in human sebocytes [19] indicating a pos-
sible interaction of the GH/IGF-I axis with the hypothala-
mus/pituitary-like axis in human skin.
Neuropeptides
POMC peptides are likely to play a major role in the
regulation of skin pigmentary system [3, 76] and of cuta-
neous inflammation [12, 13]. ACTH and ·-MSH exhibit
the most significant melanogenic activity via cAMP-
dependent pathways and tyrosinase activation, which is
enhanced by ultraviolet light [4]. Melanogenesis is a high-
ly regulated process modified by postranslational, transla-
tional, or transcriptional mechanisms. In addition, den-
drite formation and stimulation of melanocyte prolifera-
tion by POMC peptides have been reported. ·-MSH can
also stimulate attachment of melanocytes to laminin and
fibronectin and inhibit tumor necrosis factor (TNF)-·-
stimulated expression of the intracellular adhesion mole-
cule-1. In keratinocytes, ·-MSH stimulates cell prolifera-
tion and down-regulates expression of hsp 70 [77] and
modulates cytokine production with up-regulation of IL-
10 and inhibition of the IL-1-induced production and
secretion of IL-8 [12, 13]. The latter effect was also
detected in sebocytes and fibroblasts, where it may be
mediated by NF-kB and AP-1 [35, 78]. ß-Endorphin was
shown to stimulate cytokeratin 16 expression and down-
regulate Ì-opiate receptor expression in human epidermis
[79]. VIP, in the presence of lethally treated 3T3 fibro-
blast feeder cells and epidermal growth factor, stimulated
proliferation of keratinocytes, whereas substance P and
CGRP were ineffective. VIP stimulated adenylate cyclase
activity in membranes obtained from cultured keratino-
cytes, indicating an involvement of cAMP as second mes-
senger in this reaction [80]. On the other hand, it is likely
that overproduction of ACTH may prolong the anagen
phase of hair cycle [4]. ·-MSH also stimulates synthesis
and activity of collagenase/matrix metalloproteinase-1 in
dermal fibroblasts [81]. TNF-· addition resulted in in-
creased ß-endorphin and ACTH levels [14]. In contrast,
tumor growth factor-ß-stimulated fibroblasts showed no
Human Skin as Endocrine Organ
Horm Res 2000;54:230–242
237
alteration in ß-endorphin and ·-MSH levels, whereas
ACTH release was significantly enhanced. ·-MSH may
play a crutial role on endothelial cell function by decreas-
ing the adherence and transmigration of inflammatory
cells, a prerequisite for immune and inflammatory reac-
tions [4]. The POMC peptides have strong immunomo-
dulatory potential resulting in an overall immunosuppres-
sive effect with ·-MSH presenting the widest spectrum of
activities [12], such as suppression of the contact hyper-
sensitivity reaction to nickel by systemic or topical appli-
cation [4]. Both ·-MSH and ß-endorphin induced hista-
mine release from human foreskin mast cells in vitro
[14].
Sex Steroids
The local formation of sex steroids provides autono-
mous control to human skin which is thus able to adjust
the formation and metabolism of sex steroids according to
local needs [2, 82]. The situation of a high secretion rate of
adrenal precursor sex steroids in men and women is com-
pletely different from the animal models used in the labo-
ratory (except monkeys) where the secretion of sex ste-
roids takes place exclusively in the gonads. In these lower
animal species, no significant amounts of androgens or
estrogens are made outside the testes or ovaries and no sex
steroid is left after castration. Sex steroids in human skin
are activated intracellularly and exert their action on the
cells themselves without release in the extracellular space
and in the general circulation (intracrine function). The
rate of formation of each sex steroid thus depends upon
the level of expression of each of the specific androgen-
and estrogen-synthesizing enzymes in each cell type. Se-
baceous glands and sweat glands account for the vast
majority of androgen metabolism in skin [2, 6].
The biological activity of testosterone on the skin is
effected in large part by its conversion to 5·-DHT by 5·-
reductase [83]. Testosterone and 5·-DHT, being the tis-
sue active androgens, stimulate 5·-reductase mRNA and
5·-reductase activity, and their effects are mediated
through their binding to the androgen receptor. They
stimulate proliferation of target cells, such as sebocytes
and dermal papilla cells [84–87]. In addition, there is evi-
dence that the effect of androgens on human sebocyte pro-
liferation depends on the area of skin from which the
sebaceous glands are obtained; facial sebocytes are mostly
affected [84, 88]. Androgens have also been shown to
stimulate sebocyte differentiation [89] which is aug-
mented by co-incubation with PPARÁ ligands [90]. Der-
mal papilla cells mediate the growth-stimulating signals of
androgens by releasing growth factors that act in a para-
crine fashion on the other cells of the follicle [6, 87].
Excessive amounts of tissue active androgens were shown
to induce apoptosis of dermal papilla cells through the
bcl-2 pathway [91]. In aged skin, lower serum levels of
testosterone and gradual decline in DHEA and DHEA
sulfate are detected, at least in males [75].
Estrogens prolong the growth period of scalp hair by
increasing cell proliferation rates and postponing the
anagen-telogen transition [87]. On the other hand, they
directly suppress an enhanced sebaceous gland function
[4, 89]. Estradiol has also been shown to increase prolifer-
ation of melanocytes but decrease both the melanin con-
tent and the tyrosinase activity [56]. Inhibition of 5·-
reductase and of androgen receptor activity resulted in a
great stimulation of vascular endothelial growth factor
(VEGF) and aromatase expression in dermal papilla cells.
Strong stimulation of VEGF protein and gene expression
was also observed in the presence of 17ß-estradiol [48].
Both testosterone and estradiol are able to regulate CRH
receptor mRNA levels, whereby in an opposite way [19].
Glucocorticoids
Glucocorticoids induce hair growth [92], stimulate se-
bocyte proliferation [73], and induce skin atrophy proba-
bly due to an effect on dermal fibroblasts [23]. The
aggravation of sebaceous gland diseases by glucocorti-
coids may be due to their stimulatory effects on prolifera-
tion and differentiation in the presence of other growth
factors [4]. Glucocorticoids can regulate keratinocyte dif-
ferentiation by repressing the expression of the basal cell
specific keratins K5 and K14 and disease-associated kera-
tins K6, K16, and K17, an effect induced directly,
through interactions of keratin response elements with
glucocorticoids and indirectly, by blocking the AP-1 in-
duction of keratin gene expression [93].
Retinoids
Retinoic acids exhibit earlier and stronger biological
effects on the keratinocytes than retinol, probably due to
their early high cellular accumulation and their less rapid
metabolism [29, 94]. These findings support the assump-
tion that the intensity of retinoid signaling is dependent,
in part, on the quantity of cellular retinoic acid. This
assumption is supported by the tight autoregulatory
mechanism in human keratinocytes offering protection
against excessive accumulation of cellular retinoic acid
[58]. atRA binds to and induces cellular retinoic acid-
binding protein II (CRABP II) as well as binds to and acti-
vates nuclear RARs [95]. Most actions of atRA are now
recognized to be mediated through activation of RARs,
238
Horm Res 2000;54:230–242
Zouboulis
whereas, in epithelial skin cells RAR modulate cell prolif-
eration and RXR rather influence cell differentiation
[60]. Retinoids regulate proliferation and differentiation
of skin epithelial cells towards an homeostatic status [94],
especially inhibit enhanced proliferation and lipogenesis
in human sebocytes but are also able to enhance them
under vitamin A deficient conditions [96, 97].
Vitamin D
Calcitriol, like retinoids, rapidly up-regulates the ma-
jor vitamin D
3
metabolizing enzyme 24-hydroxylase at
the mRNA level, which is an established indicator for cal-
citriol presence [24]. It enhances the growth-promoting
activity of autocrine epidermal growth factor receptor
ligands in keratinocytes [98] and can also rapidly increase
the activity of 17ß-hydroxysteroid dehydrogenase (iso-
type 2), which leads predominantly in conversion of estra-
diol to estrone [99]. This estradiol inactivation increases
with increased calcitriol levels, especially those who ex-
hibit antiproliferative effects on keratinocytes. In addi-
tion, keratinocytes produce abundant PTHrP which is
down-regulated by calcitriol suggesting a physiological
role [100]. The antiproliferative and anti-inflammatory
effects of calcitriol on the skin were shown to be mediated,
at least in part, by a complex tumor growth factor-ß regu-
lation in dermal fibroblasts [101].
Thyroid Hormones
Hypothyroidism causes disturbances of skin quality
and hair character and growth with an increased telogen
rate and diffuse alopecia [6, 7]. Replacement reestablishes
the normal anagen/telogen ratio. L-Triiodothyronine was
shown to stimulate proliferation of outer root sheath kera-
tinocytes and dermal papilla cells [102].
PTHrP
Regulation of the PTH/PTHrP receptor on dermal
fibroblasts increases the membrane-associated protein ki-
nase C activity modulating proliferation of epidermal ker-
atinocytes in a paracrine manner [32].
PPAR Ligands
PPARs are pleiotropic regulators of growth and differ-
entiation of many cell types, including skin cells. PPAR·
seems to contribute to skin barrier function and to regula-
tion of inflammation, PPARÁ is necessary for sebocyte
differentiation, and PPAR‰ can ameliorate inflammatory
responses in the skin [64]. PPAR‰ is the predominant sub-
type in human keratinocytes and is highly expressed in
basal and suprabasal cells [103, 104]. Induction of PPAR·
and PPARÁ expression is linked to differentiation, and
accordingly, is confined to suprabasal keratinocytes.
PPAR‰ and PPARÁ inhibition resulted in a dramatic
decrease in proliferation and a robust up-regulation of the
expression of involucrin and transglutaminase [104, 105].
Preliminary results have shown expression of PPAR‰ and
PPARÁ in the human sebaceous gland [106, 107]. Linole-
ic acid, a natural PPAR‰ ligand, induces accumulation of
neutral lipids in undifferentiated human sebocytes and
reduces spontaneous IL-8 secretion [108]. Estradiol me-
tabolizes prostaglandin D2 to ¢12-prostaglandin J2, a
natural ligand for PPARÁ [109].
Eicosanoids
Proinflammatory cytokines, such as IL-1ß and TNF-·,
induce cytosolic phospholipase A
2
expression in keratino-
cytes and are able to increase the extracellular release of
arachidonic acid and stimulate eicosanoid synthesis [31]
(fig. 4). Enhanced keratinocyte prostaglandin synthesis af-
ter ultraviolet light injury is also due to increased phos-
pholipase activity [30]. The major arachidonic acid me-
tabolites after stimulation with interleukin 1ß are prosta-
glandin E
2
and leukotriene B
4
(LTB
4
), while TNF-· stim-
ulates hydroxyeicosatetraenoic acid (HETE) production.
IL1· expression has been detected in follicular keratino-
cytes and sebocytes in vivo and in vitro [73, 110–112].
Interestingly, LTB
4
is a natural ligand for PPAR· [113,
114], soluble 15-HETE, which is a natural ligand for
PPAR-Á [115], is synthesized in human sebaceous glands
[116], and PPARs can regulate lipid and lipoprotein
metabolism, cell proliferation, differentiation and apop-
tosis of various cell types including sebocytes [90]. The
axis IL-1/LTB
4
/PPAR·/lipid synthesis and inflammation
was confirmed by a current clinical study; treatment of
acne patients with a specific 5-lipoxygenase inhibitor
administered systemically led to a 70% reduction in
inflammatory acne lesions at 3 months, an approximately
65% reduction in total sebum lipids as well as a substan-
tial decrease in proinflammatory lipids [117].
Release of Skin-Produced Hormones in the
Circulation
There is increasing evidence that human skin produces
hormones which are released in the circulation and are
important for functions of the entire organism. Major
examples include sex steroids where a large proportion of
androgens and estrogens in men and women are synthe-
sized locally in peripheral target tissues from the inactive
Human Skin as Endocrine Organ
Horm Res 2000;54:230–242
239
Fig. 4.
The cascade of eicosanoid synthesis
in the skin. IL-1ß = Interleukin-1ß; TNF-· =
tumor necrosis factor-·; LTB4 = leucotriene
B4; 15-HETE = 15-hydroxyeicosatetraenoic
acid; PPAR· = peroxisome proliferator-acti-
vated receptor-·; PPARÁ = peroxisome pro-
liferator-activated receptor-Á.
adrenal precursors DHEA and androstenedione. DHEA
and androstenedione are converted to testosterone and
further to 5·-DHT by the intracellular enzyme 5·-reduc-
tase in the periphery, thus making the skin responsible for
large amounts of the circulating testosterone and 5·-DHT
levels. Up to 50% of the total circulating testosterone is
produced in the skin and in other peripheral organs [5].
The best estimate of the intracrine formation of estrogens
in peripheral tissues in women is in the order of 75%
before menopause and close to 100% after menopause,
except for a small contribution from ovarian and/or adre-
nal testosterone and androstenedione [82]. Thus, in post-
menopausal women, almost all active sex steroids are
made in target tissues by an intracrine mechanism.
On the other hand, IGFBP-3 message abundance is
greater in the skin that in the liver and circulating IGFBP-3
concentrations are significantly increased by GH and IGF-
I [11]. GH has a direct function in the regulation of IGFBP-
3 synthesis, and the response of skin IGFBP-3 mRNA lev-
els to both GH and IGF-I suggests that dermal fibroblasts
could be more important than the liver in the regulation of
circulating reservoir IGFBP-3 in certain circumstances.
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