0163-769X/00/$03.

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Endocrine Reviews 21(5): 457– 487
Copyright © 2000 by The Endocrine Society
Printed in U.S.A.

Neuroendocrinology of the Skin*

ANDRZEJ SLOMINSKI AND JACOBO WORTSMAN
Department of Pathology (A.S.), University of Tennessee, Memphis, Tennessee 38163; and Department
of Medicine (J.W.), Southern Illinois University, Springfield, Illinois

ABSTRACT
The classical observations of the skin as a target for melanotropins
have been complemented by the discovery of their actual production
at the local level. In fact, all of the elements controlling the activity
of the hypothalamus-pituitary-adrenal axis are expressed in the skin
including CRH, urocortin, and POMC, with its products ACTH,
␣-MSH, and ␤-endorphin. Demonstration of the corresponding recep-
tors in the same cells suggests para- or autocrine mechanisms of
action. These findings, together with the demonstration of cutaneous
production of numerous other hormones including vitamin D3, PTH-
related protein (PTHrP), catecholamines, and acetylcholine that
share regulation by environmental stressors such as UV light, un-
derlie a role for these agents in the skin response to stress. The
endocrine mediators with their receptors are organized into dermal
and epidermal units that allow precise control of their activity in a
field-restricted manner. The skin neuroendocrine system communi-
cates with itself and with the systemic level through humoral and
neural pathways to induce vascular, immune, or pigmentary changes,
to directly buffer noxious agents or neutralize the elicited local re-
actions. Therefore, we suggest that the skin neuroendocrine system
acts by preserving and maintaining the skin structural and functional
integrity and, by inference, systemic homeostasis. (Endocrine Re-
views 21: 457– 487, 2000)

I. Introduction B. Hypothalamic and pituitary hormones

II. Structure of the Skin C. Neuropeptides and neurotrophins
A. Developmental biology D. Neurotransmitters/neurohormones
B. Anatomy and histology E. Thyroid hormones
C. Physiology F. Sex steroid hormones
III. Skin as a Target for Neuroendocrine Signals G. Other steroid hormones
A. CRH and urocortin receptors (CRH-R) V. Molecular and Structural Basis for the Organizational
B. Melanocortin receptors (MC-R) Integration of Neuroendocrine Elements of the Skin
C. Opioid receptors VI. Regulation of Cutaneous Neuroendocrine System
D. GH receptor (GH-R) A. Solar radiation
E. PRL and LH/CG receptors (LH/CG-R) B. Hair cycle
F. Neurokinin receptors (NK-R) C. Cytokines
G. Calcitonin gene-related peptide receptor (CGRP-R) D. Degradation or inactivation of hormones and neu-
H. Vasoactive intestinal peptide receptor (VIP-R) rotransmitters
I. Neutrophin (NT) receptors VII. Regulation of Cutaneous Vitamin D Production
J. Miscellaneous neuropeptide receptors A. Vitamin D3 production
K. PTH and PTH-related protein (PTHrP) receptors B. Precutaneous regulation
L. Vitamin D receptor (VDR) C. Cutaneous regulation
M. Glucocorticoid and mineralocorticoid receptors D. Postcutaneous regulation
N. Androgen and estrogen receptors E. General comments
O. Thyroid hormone receptors VIII. Final Comments and Future Directions
P. Cholinergic receptors
Q. Adrenergic receptors
R. Glutamate receptors I. Introduction
S. Serotonin receptors
T. Histamine receptors
U. Miscellaneous receptors
T he skin is the largest body organ and functions as a
metabolically active biological barrier separating in-
ternal homeostasis from the external environment. Depend-
IV. Skin as a Source of Hormones and Neurotransmitters ing on anatomic localization and environmental influences,
A. PTHrP the skin shows remarkable functional and structural diver-
sity (1– 4), since it is continuously exposed to fluctuating
Address reprint requests to: Andrzej Slominski, M.D., Ph.D., Depart- external information represented by solar and thermal radi-
ment of Pathology, RM576-BMH Main, University of Tennessee, 899 Mad- ation, mechanical energy, changes in humidity, and/or
ison Avenue, Memphis, Tennessee 38163. E-mail: aslominski@utmem.edu chemical and biological insults. The maintenance of skin
* This work was supported by grants from National Science Foun-
dation (NSF) (IBN-9604364, IBN-9896030, and IBN-9405242), and Amer- structural integrity is therefore critical and must be served by
ican Cancer Society, Illinois Division (no. 99 –51) to A.S., and internal rapid mechanisms to restore the barrier properties of the
funding from the Department of Pathology, University of Tennessee. epidermis when disrupted by external trauma. Maintenance

457

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458 SLOMINSKI AND WORTSMAN
of organ, and hence systemic homeostasis, requires a special
cutaneous property, the capability to recognize and integrate
appropriate signals with a high degree of specificity. Such
sensory mechanism must be widely distributed, efficiently
self-regulated in intensity and field of activity, and endowed
with the capability of differentiating environmental noise
from biologically relevant signals (5, 6). To some extent, these
mechanisms are represented by the skin immune system,
activated by biological insults or trauma (7); and in humans,
by the pigmentary system, activated or modified by solar
radiation (8 –10). However, as presented in this work, the
main component in this critical skin function is the level of
activity of the local neuroendocrine system.
Over the last decade, it has become increasingly apparent
that the skin, particularly the epidermis, has powerful meta-
bolic and endocrine capabilities (11, 12). For example, the skin
synthesizes vitamin D, which enters the circulation and, upon
activation, exerts profound metabolic and endocrine effects (13,
14). Resident skin cells also synthesize and release the hormones
parathyroid hormone-related protein (PTHrP) (15), POMC-de-
rived MSH, ACTH, and ␤-endorphin peptides (5, 16, 17), the
CRH and urocortin peptides (18, 19), the neurotransmitters
catecholamines and acetylcholine (20, 21), and precursors to
biogenic amines (9, 21–23). While production of some of these
factors is not constitutive, it does respond to specific inductive
stimuli. The skin is also a site for activation of steroid hormones
such as the conversion of testosterone to 5␣-dihydrotestoster-
one or to estradiol, or the conversion of T4 to T3 (4, 11, 12). These
locally generated hormones and neurotransmitters can act in a
paracrine or autocrine fashion. Moreover, the presence of nu-
merous nerve endings and a rich vascular network provide
additional mechanisms for the expression of neuroendocrine
functions, e.g., transmission of regulatory signals to the global
or central systems via the vascular system, or through the af-
ferent neural network.
This emerging concept, of skin as a neuroendocrine organ,
is a relatively new addition to the field of cutaneous biology;
it combines concepts from immunology, endocrinology, and
neurobiology to unravel the multidirectional communica-
tions between brain, the endocrine and immune systems, and
peripheral organs (24 –28). In this regard, the skin has a
unique role because of its location, size, and relative func-
tional diversity. Moreover, cutaneous signals sent to neu-
roendocrine centers may play modulatory roles, although
peripheral intraorgan or intersystemic communications are
also necessary to maintain global and local homeostasis.
We will presently review evidence on the production of
hormones and neurotransmitters by the skin and on the ex-
pression of the corresponding receptors. Cutaneous regulation
of neuroendocrine communication will be analyzed and its
function discussed within the context of organ homeostasis.
Data on the experimental characterization of receptors for neu-
rohormones in skin cells will be reviewed, including regulation
of expression, ligand production, and characterization of signal
transduction pathways. Pertinent data will be included with the
understanding that the mere presence of a substance in a culture
system of skin cells does not necessarily imply that the sub-
stance has physiological relevance in vivo. Special attention will
be given to intraorgan communication and to the potential
systemic or central effects of skin-produced factors acting on
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Vol. 21, No. 5
sensory nerves, or skin-activated circulating cells, or through
direct release into the circulation as neurohormones or medi-
ators. This review will end by setting the stage for future basic
and clinical research.
II. Structure of the Skin
A. Developmental biology
The epithelial skin structures, e.g., epidermis, hair follicle,
and sebaceous, apocrine, and eccrine glands, all derive from
the embryonal outer epithelium, which originates from ec-
toderm (29). Nonkeratinocytic cells of the epidermis and hair
follicle that include melanocytes and Merkel cells are also of
ectodermal origin, but melanocytes migrate to the epidermis
from the neural crest (1, 3, 4, 29). Cell populations of meso-
dermal origin comprise the Langerhans cells and the T lym-
phocytes, which include the T␥␦ type expressed in mouse
epidermis and hair follicle and the sparse, mostly T␣␤ cells
expressed in human epidermis (7). All of the dermal com-
ponents are of mesodermal origin, with the exception of
nerves and specialized sensory receptors that develop from
the ectoderm (1, 3, 4, 7, 29). The dermal cellular populations
include fibroblasts/fibrocytes/myofibroblasts, adipocytes,
monocytes/macrophages, mast cells, Langerhans cells, T
lymphocytes, dendrocytes, smooth muscle cells, and vascu-
lar and lymphatic endothelial cells. Fibrocytes arise by dif-
ferentiation of stellate mesenchymal cells present in the pri-
mordial dermis, whereas adipocytes differentiate from
subdermal mesenchymal cells that surround newly formed
blood vessels. Macrophages, mast cells, Langerhans cells,
and dendrocytes migrate to the skin from the bone marrow.
Formation of the adnexal structures results from precise
mesenchymal epithelial interactions producing down
growth of primordial adnexal structures to reach the reticular
dermis and subcutis (1, 3, 4, 29 –31). The multidirectional
interaction between cells of ectodermal and mesodermal or-
igin results in a cohesive unified skin structure that, never-
theless, maintains a degree of heterogeneity expressed by
marked regional differences (1, 4, 29).
In the context of this review it must be noted that brain,
peripheral nervous system, retina, and medulla of adrenal
gland are also of ectodermal origin, whereas olfactory epi-
thelium and olfactory nerves, anterior lobe of hypophysis,
and epithelial elements of the mammary gland all derive
from the outer epithelium (29). Mesodermal structures in-
clude the immune system, endothelium of blood vessels,
adrenal cortex, and gonadal epithelium and stroma (7, 29).
These embryologic associations may determine the potential
capability for resident skin cells to produce molecules similar
to their close or distant relatives. Thus, cellular lineage may
predict neuroendocrine functional activity.
B. Anatomy and histology
The skin is composed of two main compartments: the
epidermis with the adnexal epithelial structures and the der-
mis with the nonepithelial elements of adnexa (1– 4). While
not a skin component, the subcutaneous fat is closely related
to the skin anatomically and functionally. Structure and
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
thickness of both epidermis and dermis vary according to
anatomic location; thus, the average thickness of the epider-
mis is 0.1 mm, but in the acral areas is up to 1.6 mm thick.
The latter regions contain thick cornified and granular layers
and numerous eccrine units and nerve endings but lack
folliculosebaceous-apocrine units. In contrast, facial skin
contains numerous vellus follicles with prominent sebaceous
glands; skin in the axilla and groins is characterized by nu-
merous apocrine glands, back skin has very thick reticular
dermis, and scalp skin contains large terminal hair follicles
routed deep into the subcutaneous fat. In furry animals,
terminal hair follicles cover most of the body, serving as
insulating cover and as touch organs (30 –32).
The basal membrane zone separates the epidermis and
epithelial adnexal structures from the dermis. Beneath the
basement membrane is a thin zone of adventitial dermis
that comprises the papillary dermis, between the epider-
mal folds and the periadnexal dermis surrounding ad-
nexal structures. The papillary dermis is characterized by
thin collagen bundles interspersed with elastic fibers, fre-
quent fibrocytes, abundant matrix, and a rich vascular
network composed predominantly of capillaries. The re-
ticular dermis is composed predominantly of thick colla-
gen bundles and elastic fibers and a lower concentration
of stromal matrix, with comparatively fewer fibrocytes;
there are also blood vessels, and adipocytes that extend
upward from the subcutaneous fat.
The skin immune system is composed of resident, re-
cruited, and recirculating cell populations (7). The resident
population is constitutively expressed in the skin under
physiological conditions. This is represented by keratino-
cytes, fibroblasts, vascular and lymphatic endothelial cells,
mast cells, tissue macrophages (histiocytes), T lymphocytes,
and dendritic cells. The recruited population comprises
monocytes, basophilic, neutrophilic, and eosinophilic gran-
ulocytes, as well as mast cells and T and B lymphocytes. The
recirculating cell population is represented by dendritic cells,
natural killer cells, and T lymphocytes. Recruited or recir-
culating cells reach the skin via circulation.
The vasculature is arranged into a superficial (subpapil-
lary) plexus, located in the upper reticular dermis, and a deep
plexus positioned in the lower reticular dermis (1– 4). These
plexuses are connected by communicating blood vessels,
which are most numerous in the upper dermis and around
folliculosebaceous and eccrine units. The vascular network
provides rich capillary supply for the dermal papillae and
periadnexal dermis. A lymphatic network accompanies the
vascular bed, although it is a functionally separate entity.
The skin contains an extensive neural network represented
by cholinergic and adrenergic nerves and by myelinated and
unmyelinated sensory fibers (1, 3, 4, 33, 34). The autonomic
nerves supply arterioles, glomus bodies, hair erector mus-
cles, and apocrine and eccrine glands. The terminal endings
of sensory fibers are either surrounded by histologically dis-
tinctive structures, such as Pacini and Meissner’s corpuscles,
Ruffini organs, Merkel disks, and mucocutaneous end or-
gans, or supply directly individual Merkel cells. A rich net-
work of free sensory endings surround and penetrate hair
follicles, pilosebaceous units, eccrine and apocrine glands,
papillary dermis, and epidermis. The sensory and autonomic
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459
networks do show regional differences according to ana-
tomic sites and also have topographical specificity by dis-
tributing into well defined areas called dermatomes. The
torso, extremities, posterior scalp, and neck are supplied by
sensory nerves arising from dorsal root ganglia of the spinal
cord, whereas face, most of the scalp, and upper anterior neck
are innervated by trigeminal nerve branches.
C. Physiology (1–22, 30 –35)
The most important function of the skin, determined by its
location at the interface between external and internal environ-
ments, is that of physical barrier. This is established in the
epidermis by a precisely regulated gradient of keratinocyte
differentiation stages, which forms a highly impermeable pro-
tein-lipid layer at the outer-most segment. This layer prevents
the destruction of living keratinocytes by environmental factors
and reduces or minimizes water evaporation, maintaining a
liquid environment to preserve skin structural integrity in the
face of frequent mechanical trauma. The epidermal pigmentary
system protects the skin against the damaging effect of solar
radiation in humans and, in conjunction with the follicular
pigmentary system, determines hair and skin color that play an
important role in social communication and camouflage in
many mammalian species. The epidermal and dermal immune
elements provide defense against biological insults, and they
are also involved in the integration of the response to foreign
and self-antigens through interactions with the central immune
system. Immune responses are involved in the reaction to viral
or microbial infections, or to cancer development; dysregulated
immune responses may be pathogenic in autoimmune diseases.
The adnexal organs are epidermally derived structures
that extend into dermis and subcutis. Their functional role is
pleiotropic by participating in the formation of hair shafts
from hair follicle, serving protective, thermoregulatory, and
sensory (touch) functions, as well as being involved in social
communication. The secretion of eccrine, apocrine, and se-
baceous glands is important for thermoregulation, for pres-
ervation of the integrity of the physical barrier, for regulation
of electrolyte balance, and for secretion of the pheromones
and odorant-affecting behavior. The dermis, in addition to its
structural role, is involved in mechanical protection and ther-
moregulation via its rich vascular network. The skin also
provides the sensory reception for touch, pressure, vibration,
temperature, pain, and pleasure through a neural network
comprised of specialized receptors and free nerve endings.
Finally, the skin, as a regulator of metabolism, transforms
various hormones and can also inactivate potentially harm-
ful substances of exogenous or endogenous origin.
III. Skin as a Target for Neuroendocrine Signals
Skin resident and circulating immune cells express recep-
tors for neuropeptides and neurotransmitters identical to
those expressed in the central neuroendocrine systems. Ex-
amples of those receptors and their expression sites are listed
in Table 1. Clinical observations made in diverse endocrine
disorders associated with cutaneous changes also confirm
that the skin is a target for hormones, neurohormones, and
neurotransmitters (3– 6, 12, 16 –21, 35–38). That the skin is
460 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

TABLE 1. Selected hormone and neurotransmitter receptors expressed in keratinocytes and melanocytes

Cell type Receptor repertoire

Keratinocytes CRH-R1, MC1-R, ␮- and ␨-opioid-R, PRL-R, LH/CG-R, GH-R, CGRP-R, VIP-R, neurokinin-R, class II
PTH/PTHrP-R, vitamin D-R, androgen-R, estrogen-R, glucocorticoid-R, mineralocorticoid-R,
muscarinic-R, nicotinic-R, adrenoreceptors, glutamate-R, gastrin-releasing peptide-R, NPY-R,
purinoreceptors, H1 and H2 histamine-R, somatostatin-R (?), bombesin-R, (?)
Melanocytes CRH-R1, MC1-R, LH/CG-R, GH-R, CGRP-R, VIP-R, vitamin D-R, androgen-R estrogen-R, glucocorticoid-
R, adrenoreceptors, muscarinic-R, H2 histamine-R
R, Receptor; (?), possible expression.

also a target of neural responses is supported by studies
showing neural contributions to the etiology and clinical
manifestations of inflammatory skin diseases and vitiligo
(3, 4, 33, 34, 38, 39).
A. CRH and urocortin receptors (CRH-R)
This group comprises the G protein-coupled membrane-
bound CRH-R1 and CRH-R2 receptors (5, 40, 41), whose gene
expression was recently documented in human and rodent
skin (5, 18, 40, 42– 46). CRH-R1 expression has been detected
in epidermal and follicular keratinocytes, melanocytes, and
mast cells (5, 44, 46 – 49), and it is possible that these cells may
coexpress CRH-R2 (5, 44, 46, 50, 51). While specific CRH
binding sites were additionally seen in dermal fibroblasts,
endothelial cells, and smooth muscle of blood vessels (5, 40,
44, 46, 52–54), it remains to be tested whether these binding
sites represent CRH-R1, CRH-R2, or coexpression of both
receptors. Signal transduction through cutaneous CRH re-
ceptors is linked to stimulation of cAMP production and
increase of cytosolic Ca levels (46, 47, 50, 51). It remains to be
tested whether other pathways coupled to different receptor
subtypes specific for skin cells are also activated (46, 50).
CRH and urocortin have a recognized role in skin patho-
physiology through their actions on the skin immune system
(5, 40, 48, 55–59). Thus, in the periphery, CRH can act as a
proinflammatory agent (48, 55, 56) and, together with uro-
cortin, induces degranulation of mast cells (48, 57). However,
antiinflammatory effects have been also demonstrated in
models of tissue injury, e.g., in thermally injured skin where
local injection of CRH has an antiedema effect independent
of hypothalamus-pituitary-adrenal (HPA) axis function, and
in doxorubicin-induced eye lid inflammation that is reduced
in severity by pretreatment of the eyelid with CRH (58 – 60).
In addition, CRH has antinociceptive activity and accelerates
wound healing (58 – 60). CRH and urocortin also inhibit pro-
liferation of keratinocytes (51) and either stimulate or inhibit
melanoma cell proliferation depending on culture conditions
(Refs. 46 and 49 and A. Slominski and B. Zbytek, unpublished
data).
B. Melanocortin receptors (MC-R)
The membrane-bound G protein-coupled melanocortin re-
ceptors of type 1, 2, and 5 (MC1-R, MC2-R, MC5-R) have been
identified in the skin (5, 8, 17, 61– 69). MC1-R was detected
in melanocytes, keratinocytes, sebocytes, fibroblasts, endo-
thelial cells, Langerhans cells, and dermal immune cells,
while MC5-R was detected in the epithelial cells of eccrine,
apocrine, and sebaceous glands (5, 8, 17, 61– 64). Although
expression of the MC2-R gene has been detected in human
and mouse skin (65, 66), precise cell compartment(s) assign-
ment will require further testing; possible expression sites
include adipocytes, keratinocytes, and melanocytes (63– 66).
The MC receptors are activated by ACTH, and by ␣-, ␤-
and ␥-MSH; ligand affinity varies according to receptor type
and mammalian species (5, 8, 17, 61, 70). Signal transduction
through MC1-R, MC2-R, and MC5-R has been linked to ac-
tivation of adenylate cyclase (5, 8, 17, 61, 67– 69).
The best recognized phenotypic effect of the POMC-
derived ACTH and MSH peptides is the stimulation of mel-
anogenesis and its switching from pheo- to eumelanogenesis
(5, 8, 16, 17, 61, 67–72), which can also be documented clin-
ically (3–5, 8, 67, 72). There is a general agreement that ACTH,
␣-MSH, and ␤-MSH have the strongest melanogenic activity
(8, 16, 67– 69). ␥-MSH peptides have low intrinsic melano-
genic activity in human normal melanocytes and rodent ma-
lignant melanocytes (70, 71), similar to findings in frog and
lizard melanophores (8, 67, 68, 73). However, it is possible
that selected ␥-MSH peptides such as ␥2 and ␥3 could still
modulate pigmentation indirectly, modifying cellular re-
sponses to the other melanotropins (71). Studies in cultured
normal and malignant melanocytes show that MSH and
ACTH, acting via cAMP-dependent pathways (5, 8, 16, 17, 61,
67– 69, 72, 74 –79), stimulate the expression and activity of
enzymatic, structural, and regulatory proteins involved in
melanogenesis (5, 8, 67– 69). Depending on species and cel-
lular genotype, MSH and ACTH can inhibit or stimulate
proliferation of malignant melanocytes (8, 67– 69, 72, 74 –78).
However, most authors agree that in normal human mela-
nocytes, ACTH and MSH act as stimulators of cell prolifer-
ation (8, 69, 79), dendrite production (5, 8, 67– 69, 74), and
melanocyte migration (8) and decrease expression of inter-
cellular adhesion molecule-1 (ICAM-1) (80).
Epidermal, adnexal, vascular, and dermal structures rep-
resent additional targets for POMC peptides (5, 17, 35, 61–
64). Thus, ␣-MSH can modify proliferation and differentia-
tion of keratinocytes as well as their immune activity and
regulate activity of dermal fibroblast (5, 17, 64, 81, 82). In
endothelial cells, ␣-MSH may play a crucial role decreasing
their adherence and the transmigration of inflammatory
cells, a prerequisite step for immune and inflammatory re-
actions. ␣-MSH and ACTH have strong immunomodulating
activity in the skin that results in an overall immunosup-
pressive effect (5, 17, 64, 82). For example, ␣-MSH acts as
antagonist to interleukin-1 (IL-1) suppressing production of
proinflammatory cytokines while it induces production of
the immunosuppressive cytokine IL-10. ␣-MSH is also ca-
pable of suppressing accessory molecule expression on an-
tigen-presenting cells and may thereby serve as one of the

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
signals responsible for anergy or tolerance induction (17, 64,
82).
In addition to the regulation of hair pigmentation, ␣-MSH
and ACTH have other actions on adnexal structures (5, 17,
35, 62, 83, 84). For example, in mink and mice, ACTH acts as
inducer of anagen development (85, 86), whereas in mouse
anagen skin it induces premature onset of catagen (83).
ACTH and ␣-MSH also influence sebaceous gland function
(35, 84): ␣-MSH specifically stimulates sebum secretion and
lipogenesis in cutaneous sebaceous glands, enhancing wax
and sterol ester biosynthesis, and stimulating production
and release of female sex attractant odors and of male ag-
gression-promoting pheromones (by specialized preputial
glands) (35). ␣-MSH and perhaps ACTH may be important
in overall rodent skin thermoregulation, by preventing over-
wetting of hairs, and in behavior regulation through its ac-
tion on nonspecialized and specialized sebaceous glands (35,
84). It is likely that MSH and ACTH peptides also affect
function of human sebaceous glands.
C. Opioid receptors
␮-Opioid receptors, which bind with high-affinity ␤-
endorphin, were detected in cultured human epidermal ker-
atinocytes (87). Further investigations using in situ hybrid-
ization and immunocytochemistry on skin biopsy specimens
showed that the receptors are localized to keratinocytes in
the epidermis and outer root sheath of the hair follicles, to the
peripheral epithelial cells in sebaceous glands, and to the
secretory component in sweat glands (87). The related ␨-
opioid receptor that binds enkephalins with high affinity has
also been detected in human and mouse epidermal keratin-
ocytes (88). Met-enkephalin has been shown to inhibit pro-
liferation of mouse epidermal keratinocytes in vivo, in a cir-
cadian pattern (88), and both met- and leu-enkephalins can
inhibit differentiation of human keratinocytes in vitro (89). In
addition, ␤-endorphin and enkephalins have antinociceptive
and immunomodulatory properties (7, 24, 25, 27, 28).
D. GH receptor (GH-R)
The GH-R has been detected in human and rodent skin in
epidermis, hair follicle, eccrine glands, dermal fibroblasts,
adipocytes, and in Schwann and muscle cells (90 –93). Tran-
scription of the GH-R gene has also been detected in cultured
human melanocytes (91). These findings suggest that epi-
dermal, adnexal, and dermal cell populations can be direct
targets for GH. For example, GH can stimulate differentia-
tion of rat sebocytes and modify melanocyte proliferation
(94, 95). However, the phenotypic effects could also arise
from an indirect effect such as the stimulation of cutaneous
cells to produce insulin growth factor-1 (IGF-1).
The cutaneous phenotypic effects of GH have been thor-
oughly described in patients with acromegaly, whose skin
thickness increases considerably and acquires a doughy
texture (1–3, 36, 37, 68). This effect is accompanied by
increased fibroblasts activity and dermal glycosaminogly-
cans deposition that promotes water retention (96). Ad-
ditional cutaneous signs of acromegaly are acanthosis nig-
ricans, hypertrichosis with exception of the beard region,
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461
hyperpigmentation, eccrine and apocrine hyperhidrosis,
increased sebum secretion, growth of pedunculated fibro-
mas, and thickening and hardening of the nails (1–3, 36, 37,
68). Transgenic mice overexpresssing GH show skin over-
growth with increased dermal thickness, significant der-
mal fibrosis, and replacement of subcutaneous adipose
tissue by fibrous tissue (97).
E. PRL and LH/CG receptors (LH/CG-R)
Receptors for the pituitary hormones PRL, LH, and human
CG (hCG) are also expressed in the skin (98 –103). PRL re-
ceptors have been localized in rat epidermal and follicular
keratinocytes by in situ hybridization (98) and in ovine der-
mal papilla fibroblasts and follicular keratinocytes with a
radioligand binding assay (99). PRL binding sites exhibiting
high affinity for the ligand were identified in membrane
preparation from mink skin; the highest concentration of
binding sites was found during the winter fur growth cycle
(100). PRL stimulation of cultured human keratinocytes pro-
liferation has been linked to the expression of high-affinity
PRL binding sites on the cell surface (101). PRL can directly
and indirectly modulate the hair growth, shedding, and
molting cycle of furry animals, whereas in humans hyper-
prolactinemia has been associated with hirsutism (3, 31, 104 –
106). It has also been proposed that PRL participates in the
regulation of sebaceous gland activity, since acne vulgaris
can be associated with idiopathic hyperprolactinemia in the
absence of altered androgen concentrations (3, 106). PRL has
potent immunomodulatory properties (107), suggesting that
it can also regulate functions in the skin immune system.
Normal human skin also contains the mRNAs for the
LH/CG-R and a 66-kDa protein capable of binding 125I-hCG
(102). These receptors were detected in the epidermis, inner
and outer root sheaths of the anagen hair follicle, sebaceous
glands, and eccrine glands (103). Testing for expression of
FSH receptors in normal human skin found it to be below the
level of detectability (103).
F. Neurokinin receptors (NK-R)
Expression of the G protein-coupled neurokinin receptors
NK-1R, NK-2R, and NK-3R has been reported in human and
rodent skin (38, 108); however, others have detected only
NK1-R in extracts from human skin (109). Either substance
P (SP) or neurokinins A and B (NKA and NKB) could activate
these receptors, through signal transduction pathways in-
volving adenylate cyclase and phospholipases C and A2 (33,
34, 38). Human and rodent keratinocytes and endothelial
cells express NK-1R to NK-3R, and mast cells, fibroblasts,
and Langerhans cells express NK-1R (38). Activation of these
receptors stimulates proliferation of keratinocytes, fibro-
blasts, and endothelial cells and neovascularization (4, 7, 33,
34, 38, 108 –113). NKA and SP stimulate mast cells release of
histamine and tumor necrosis factor-␣ (TNF␣), and keratin-
ocyte and endothelial cell function with production and re-
lease of proinflammatory cytokines, and expression of ad-
hesion molecules (7, 33, 34, 38, 108 –115). SP stimulates hair
growth in rodents (116).
462 SLOMINSKI AND WORTSMAN
G. Calcitonin gene-related peptide receptor (CGRP-R)
There is functional evidence that the G protein-coupled
receptor CGRP-R is expressed in skin cells (3, 4, 7, 33, 38, 108,
110 –114, 117–120). CGRP is a potent vasodilator of small and
large vessels, at least partly through direct activation of ar-
teriolar smooth muscle cell receptors. CGRP also increases
vascular permeability, producing dermal edema through in-
direct activation of mast cells or through stimulation of nitric
oxide (NO) production by endothelial cells with consequent
vasodilatation (4, 33, 38, 108, 114). CGRP stimulates endo-
thelial cell, keratinocyte, and melanocyte proliferation (117,
119). Stimulation of keratinocyte proliferation has been
linked to direct activation of adenylyl cyclase activity (117),
and CGRP induces keratinocyte production and release of
promelanogenic factors (120). CGRP modifies the activity of
the skin immune system (7, 38, 110 –114, 118).
H. Vasoactive intestinal peptide receptor (VIP-R)
VIP-Rs are present in skin, and their activity is linked to
G protein-coupled stimulation of adenylyl cyclase activity
with cAMP production (3, 4, 7, 33, 38, 108, 110 –113, 117, 118).
VIP biding sites have been characterized in malignant human
melanocytes (121), where VIP stimulates cAMP production
(122).VIP also stimulates keratinocyte proliferation and
sweat production (4, 38, 117). Peptide histidine-methionine
(PHM) and GH releasing factor (GFR) have stimulatory ef-
fects on keratinocyte cAMP production and cell proliferation,
thought to be mediated through the VIP-R (38, 117). Indi-
rectly, VIP also participates in the wheal and flare reaction
through the activation of mast cells histamine release,
or through NO-induced vasodilatation (3, 4, 7, 33, 38, 108,
111, 112).
I. Neurotrophin (NT) receptors
Both human and rodent skin express transmembrane re-
ceptor proteins of the tyrosine kinase (Trk) and p75 pan-
neurotrophin (p75NTR) families, which show high and low
affinity for neuron growth factor (NGF), respectively (33, 38,
108, 123–131). The high-affinity receptors for NGF and NT4
include TrkA and TrkB; TrkC serves as a high-affinity re-
ceptor for NT3, which also binds, but with low affinity, to
TrkA and TrkB. The receptors for the Trk family and for
p75NTR are expressed in epidermal and follicular keratin-
ocytes, epidermal melanocytes, specialized dermal fibro-
blasts, mast cells, immunocytes, and cutaneous nerves (7, 33,
38, 108, 123–130). NGF stimulates melanocyte dendrite for-
mation and prolongs melanocyte survival after UV damage
(123, 124). NGF and other neurotrophins can regulate ker-
atinocyte proliferation and differentiation (123, 125, 128 –
130), functions that in the mouse appear to be coordinated
with the hair cycle (128). Lastly, NGF and other neurotro-
phins can act as mast cells secretagogs and can modulate
dermal fibroblasts and dermal immune cells function (7, 33,
38, 108, 123–130). NGF and neurotrophins may have a phys-
iological role in hair cycle and hair follicle morphogenesis
(128 –130, 132), whereas NGF may protect human keratino-
cytes from UVB-induced apoptosis (125).
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Vol. 21, No. 5
J. Miscellaneous neuropeptide receptors
Somatostatin is known to affect skin immune functions
and basal secretion of histamine and, thus, immune cells and
keratinocytes probably express the corresponding receptors
(38, 110 –112, 133). Similarly, the inhibition of cAMP pro-
duction by neuropeptide Y (NPY) in human keratinocytes,
the stimulation of keratinocyte DNA synthesis by bombesin,
and the acceleration of skin wound healing by TSH (12, 33,
38, 110 –112, 117) suggest that specific receptors for these
hormones may be also expressed in skin. There are, in fact,
data showing that the gene coding for the TSH receptor is
expressed in adipocytes and fibroblasts (134). Receptors for
bombesin and somatostatin have been shown in dermal fi-
broblasts (33, 38, 111, 112).
K. PTH and PTH-related protein (PTHrP) receptors
Dermal fibroblasts express class 1 PTH/PTHrP receptors,
which respond to PTH or the PTHrP signal by increasing
cAMP, production of cytokines and keratinocyte growth fac-
tor (KGF) (135, 136); however, the same receptor is not de-
tected in keratinocytes (135, 137–139). Nevertheless, PTHrP
has direct epidermal biological activity stimulating keratin-
ocyte proliferation and differentiation both in vitro and in
vivo, and hair follicle formation (15, 140, 141). The keratin-
ocyte intracellular activation pathway differs from that stim-
ulated by class I receptors; PTHrP, while producing intra-
cellular calcium accumulation and protein kinase C
stimulation, does not stimulate adenylate cyclase; instead it
activates the phospholipase C pathway (138, 139, 142, 143).
These PTH/PTHrP class II keratinocyte receptors have been
partially characterized and found to also respond to PTH
(138, 139, 143). PTHrP can indirectly regulate functional ac-
tivity of the epidermis through the stimulation of KGF pro-
duction by dermal fibroblasts (136). Furthermore, PTHrP can
play a role during wound healing, helping restore epidermal
homeostasis (144). Studies on the PTHrP knockout mouse
model, and in mice overexpressing the peptide in the skin,
document an important role of PTHrP on epidermal function
and hair formation (15, 141).
L. Vitamin D receptor (VDR)
Receptors for the active form of vitamin D [1,25-dihy-
droxyvitamin D (1,25-(OH)2D or calcitriol] are expressed in
human and rodent epidermal and follicular keratinocytes
(13, 145–151). In the mouse, hair cycle-dependent VDR ex-
pression has been reported: it is stronger in mid and late
anagen and in catagen and weaker in the telogen and early
anagen phases of hair growth (146). VDRs serve as targets
mediating calcitriol induction of keratinocyte differentiation
and inhibition of cell proliferation (13, 148). Because of these
properties, vitamin D derivatives are being used therapeu-
tically (topically) in psoriasis (3, 13, 14). The presence of
alopecia in some forms of vitamin D-resistant rickets with
decreased expression of VDR in dermal papilla cells indicates
a role in hair growth (13, 150). Some authors have identified
VDRs in human melanocytes and observed a modulatory
effect of 1,25-(OH) 2D on melanogenesis (8, 151). This ob-
servation has not been confirmed universally (152). Skin
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
immune cells may also express VDRs because of the finding
of constitutive immunosuppressive activity for 1,25-(OH) 2D
(153). Patients with mutations of VDR present with hypocal-
cemia, rickets, and significant cutaneous involvement ex-
pressed as sparse body hair and, sometimes, total alopecia
that includes the eyebrows and eyelashes (150). In the latter
subjects, VDR gene mutations result in premature stop sig-
nals or abnormal DNA binding and marked resistance to
calcitriol therapy (150). Experiments performed on mice
treated with topical calcitriol show normal hair regrowth
after chemotherapy-induced alopecia (147).
M. Glucocorticoid and mineralocorticoid receptors
Glucocorticoid receptors (GRs) are members of the super-
family of trans-acting transcriptional factors and are widely
expressed in all skin compartments (3, 4, 12, 31, 154 –157).
More specifically, GRs are expressed in epidermal and fol-
licular keratinocytes, epithelial cells of eccrine and apocrine
glands, sebocytes, melanocytes, immune cells of epidermis
and dermis, dermal fibroblasts, and smooth muscle (154 –
157); activation of these receptors regulates or modulates
specific functions in the corresponding cells. The role of
glucocorticoids is best emphasized by the skin changes as-
sociated with hypercortisolism (3, 36, 37). In such states there
are alterations in body fat distribution, general atrophy of the
skin, impairment of wound healing, easy bruisability, mild
acanthosis nigricans, acne, hirsutism, and alopecia. A glu-
cocorticoid direct inhibitory effect on hair growth has been
well documented in animal models (31). It must also be
emphasized that glucocorticoids, whether administered top-
ically or orally, are potent drugs used in the treatment of
inflammatory skin diseases (3).
Most recently, mineralocorticoid receptors (MRs) have
been detected in keratinocytes of the epidermis and hair
follicle and in sweat and sebaceous glands of human skin
(158). The same cutaneous structures also expressed 11␤-
hydroxysteroid dehydrogenase (11HSD), which converts
glucocorticoids to their inactive metabolites, thereby allow-
ing the binding of aldosterone to MRs at much lower pre-
vailing levels (158, 159).
N. Androgen and estrogen receptors
Sex steroid receptors belong to the superfamily of trans-
acting transcriptional factors, similar to glucocorticoid re-
ceptor (GR) and mineralocorticoid receptor (MR) (36, 68).
They are widely distributed in all skin compartments, and
their density and expression level vary depending on ana-
tomic site and gender (3, 4, 12, 160 –173). The well recognized
androgen effects on hair growth and sebaceous gland func-
tions are related to expression of the corresponding androgen
receptors (ARs) in epithelial cells of those adnexal structures
and in specialized dermal papilla fibroblasts that regulate
hair morphogenesis (161–165). ARs are also expressed in
other adnexal structures, in epidermal keratinocytes and me-
lanocytes, dermal fibroblasts, and resident and circulating
cells of the skin immune system (3, 4, 12, 31, 160 –165, 169).
Similar to ARs, estrogen receptors (ERs) are also expressed
in the epidermal, adnexal, and dermal compartments of the
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463
skin (3, 4, 12, 166 –168, 170 –173). ERs have been detected
variably, depending on the sensitivity method and presence
or absence of pathology, in epithelial cells of epidermis, hair
follicle, sebaceous, eccrine and apocrine glands, in melano-
cytes, and in dermal fibroblasts. Thus, both estrogens and
androgens regulate hair growth, sebaceous gland function,
proliferation and differentiation of epithelial cells of the epi-
dermis and adnexa, functional activity of dermal fibroblasts
and fibrocytes, wound healing, and skin immune cells ac-
tivity. There are also data showing that androgens and es-
trogens can modulate proliferation and melanogenesis in
cultured melanocytes (169 –171). Lastly, transgenic male
mice overexpressing GH show overgrowth of the skin that
is androgen dependent, e.g., it is not observed in females or
in castrated males (97).
Clinical signs of androgen excess include acne, hirsutism,
and androgenic alopecia (3, 36, 37, 163, 164). Acne results
from follicular hyperkeratinization, increased sebum pro-
duction, and from the release of lipases and proinflammatory
mediators by Propionicum acnes. In these conditions, an-
drogens [mainly dihydrotestosterone (DHT) and to a lesser
degree testosterone] mediate the increased sebum produc-
tion and follicular hyperkeratinization (3, 37, 163, 164). Hir-
sutism and androgenic alopecia are associated with in-
creased production of DHT within the dermal papilla of
androgen-responsive hair follicles of the face, chest, genital
skin, and scalp (3, 12, 31, 37, 163). Conversely, in males with
androgen deficiency, the skin remains thin and fine; seba-
ceous and apocrine glands and sexual hair follicles remain
dormant; beard, axillary, and pubic hair do not develop and
neither does androgenic alopecia; and there is also a general
decrease in skin pigmentation (3, 37, 163). Increased estrogen
levels, for example during pregnancy, can lead to hyperpig-
mentation of nipples, areolae, genital skin, and facial skin (3).
The latter, known as melasma, is exacerbated by sun expo-
sure (3). In addition, preexisting nevi and ephelides darken,
and telangiectasia, spider angioma, and palmar erythema
may develop (3, 37).
The presence of actual ERs in malignant melanocytes has
been questioned (174). However, studies with normal cul-
tured melanocytes have demonstrated both the presence of
receptors and phenotypic effects on cell proliferation (171).
Nevertheless, the reports are truly conflicting as regards the
estrogen effect on melanogenesis. Thus, while some have
reported stimulation of tyrosinase activity and melanin syn-
thesis by estrogens (170), others have shown an opposite
inhibitory effect (171). These contradictory results indicate
the need for additional work on the role of estrogens in
melanocyte functions.
O. Thyroid hormone receptors
The skin is a recognized target for T3 (3, 4, 12, 31, 36, 37,
157, 164, 175, 176). This hormone is involved in the process
of epidermal differentiation and increases its responsiveness
to growth factors. It also participates in the function of se-
baceous, eccrine, and apocrine glands, in hair growth, and in
the production of proteo- and glycosaminoglycans by dermal
fibroblasts. All of these effects are probably mediated by
interactions with the specific thyroid hormone receptors
464 SLOMINSKI AND WORTSMAN
(TRs) that serve as transcriptional regulators. In fact, thyroid
hormone receptors (c-erb-A) were detected by RT-PCR in
human skin (177), and c-erbA␤ and c-erbA␣ mRNAs were
detected in dermal fibroblasts, consistent with T3 binding to
fibroblast nuclear extracts (178). Since T3 may have an in-
hibitory effect on melanogenesis in malignant melanocytes,
it is likely that TR is also expressed in melanocytes (179).
A potential role for thyroid hormones in the regulation
of skin function is suggested by its changes in hyper- and
hypothyroidism (3, 36, 37). In the former, the skin changes
include erythema, palmoplantar hyperhidrosis, acropathy,
and infiltrative dermopathy. Graves’ disease also may be
associated with generalized pruritus, chronic urticaria, alo-
pecia areata, vitiligo, and diffuse skin pigmentation. In hy-
pothyroidism, the skin is cool, dry with pasty appearance;
the epidermis is thin and hyperkeratotic; alopecia may de-
velop, and there is diffuse myxedema. In contrast to the
pretibial myxedema present in hyperthyroidism, the gener-
alized myxedema of hypothyroidism is reversible with thy-
roid hormone therapy (37).
P. Cholinergic receptors
Grando and associates (20, 180 –182) found that human
keratinocytes express both nicotinic and muscarinic recep-
tors in a differentiation-dependent manner. Specifically, hu-
man keratinocytes were found to express the ␣3, ␣5, ␣6, ␣7,
␤1, ␤2, and ␤4 nicotinic receptor subunits (20, 180, 181).
Immunocytochemistry studies further showed that the num-
ber and subunit composition varies according to stage of
epidermal keratinocyte differentiation (20, 181). The nicotinic
receptors on keratinocytes represent functional ion channels
mediating the influx of Na⫹ and Ca⫹2, and the efflux of K⫹,
being thus essential for keratinocyte viability (20, 180, 181).
Activation of nicotinic receptors stimulates keratinocyte mo-
tility and differentiation (20, 180, 181).
Muscarinic receptors of several subtypes have been de-
tected in vitro and in vivo in epidermal keratinocytes (20, 181,
182). The subtypes expressed include the m1, m3, m4, and m5
types, with both timing and level of expression being de-
pendent on keratinocyte differentiation stage (20, 181, 182).
Muscarinic receptors have been characterized also in malig-
nant human melanocytes (183, 184), and there is strong ev-
idence for their expression in normal melanocytes (Grando
et al., unpublished observation).
Q. Adrenergic receptors
Radioligand binding studies have shown cutaneous ad-
renergic receptors, with epidermal keratinocytes and eccrine
epithelial cells expressing predominantly the ␤2 adrenore-
ceptors (4, 21, 185–187). In situ binding assays have further
identified ␣1- adrenoreceptors in the epidermis (188). Stim-
ulation of ␤-adrenergic receptors in epidermal keratinocytes
results in increased cAMP production, calcium influx, and
stimulation of keratinocyte differentiation (3, 4, 21, 187).
␤-Receptors are expressed in inflammatory cells of the der-
mis (185), thus explaining the ␤2-adrenoreceptor agonists
inhibition of proinflammatory TNF␣ release (189). ␣- And
␤-adrenoreceptors are expressed in dermal blood vessels,
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Vol. 21, No. 5
and their activation induces vasoconstriction and decreases
vascular permeability (4, 190, 191). Since the melanoma cell
phenotype can be modified by adrenergic agonists, it is pos-
sible that normal mammalian melanocytes may express ad-
renergic receptors, similar to pigment cells of other verte-
brates (8, 66, 192). The ␤1, ␤2, and ␤3 adrenoceptors are also
present on adipocytes (193).
R. Glutamate receptors
Immunocytochemical studies performed on rat skin dem-
onstrated the presence of the G protein-coupled metabotropic
receptors of the ionotropic glutamate-gated ion channels such
as the N-methyl-d-aspartate (NMDA) and ␣-amino-3-hydroxy-
5-methyl-4-isoxazole propionate (AMPA) types of glutamate
receptors in basal epidermal keratinocytes (194). In addition to
receptor expression, the specific glutamate transporters have
been also detected. Thus, EAAC1 was found in basal keratin-
ocytes, GLT-1 in suprabasal keratinocytes, and the AMPA-type
receptor clustering protein, GRIP, in basal keratinocytes (194).
In the same rat model, epidermal expression levels of the
NMAD receptor and the EAAC1 glutamate transporter were
significantly related to wound healing and embryogenesis. Cul-
tured human keratinocytes have shown expression of mRNAs
for the NMDAR1 subunit and for GRIP (194).
S. Serotonin receptors
The potential presence of serotonin receptors in the skin is
suggested by the local effects of serotonin, e.g., pro-edema,
vasodilatory, proinflammatory, and pruritogenic (3, 4, 34,
115, 195, 196). In mouse skin, serotonin-induced vascular
permeability is mediated by the activation of 5-hydroxytryp-
tamine type 1 (HT1) and HT2 receptors (197). The prurito-
genic effect of serotonin may be mediated through direct
activation of HT3 receptors or indirectly through mast cells
(7, 27, 34, 198). Cutaneous expression of 5-HT2A receptors
was detected in unmyelinated axons at the dermal-epider-
mal junction and in the nerve endings of Pacinian corpuscles
(199). Because of serotonin proinflammatory activity, it is
likely that cells of the skin immune system will also express
the HT receptors generally found in the immune cells (7, 27).
Such mechanism would explain the initiation of T cell-
dependent contact sensitivity by serotonin released from
human platelets (200), and also the release of prostaglandin
E2 from rat skin in vitro (201). Since serotonin can stimulate
epidermal keratinocyte proliferation in organ culture, these
cells may also express HT receptors (202).
T. Histamine receptors
After its release from mast cells, basophils, and platelets,
histamine has pleiotropic phenotypic effects in the skin
through interactions with H1, H2, and H3 receptors (3, 7, 115,
203). Histamine’s most prominent cutaneous effects are on
the local vascular and immune systems, supporting the use
of antihistamine drugs for the treatment of pruritus, urti-
caria, and angioedema (3, 7, 115, 195). Histamine receptors
are expressed in the dermal compartment on immunocytes,
endothelial cells, blood vessels, smooth muscle, fibroblasts,
and nerve endings (3, 7, 115, 195, 203), whereas in the epi-
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 465

dermis, H1 and H2 receptors are expressed on keratinocytes
(204 –207). Epidermal melanocytes express H2 receptors
(208). Activation of keratinocyte H2 receptors affect prolif-
eration and differentiation via activation of the adenylate
cyclase/phospholipase C pathway with associated increases
in intracellular calcium levels (204, 205). In the same cell
system, activation of the H1 receptor enhances UVB-induced
IL-6 production (206), whereas H1 receptor antagonists in-
hibit ICAM-1 expression (207). Activation of the H2 receptors
on melanocytes stimulates melanogenesis (208). Thus, both
the dermal and epidermal compartments are clear targets for
histamine, regulating cellular functions not directly con-
nected with the previously described proinflammatory ef-
fects of this mediator. Of great interest is the proposed role
for the mast cell as a coordinator of immune, neural, and
endocrine activity on the central level and peripheral organs
(115, 203); in this context the cutaneous actions of histamine
through specific receptors would also be addressed at coor-
dinating the local cutaneous neuroendocrine system re-
sponses (203).
U. Miscellaneous receptors
A number of studies suggest that epidermal keratinocytes
express purinoreceptors that, when activated by adenosine
or adenine nucleotides, will stimulate cAMP and IP3 pro-
duction, respectively (209, 210). Purinoreceptor activation
inhibits keratinocyte proliferation (211). Functionally active
adrenomedullin receptors (AM-R), which are G-protein
linked and coupled to adenylyl cyclase activity, have been
identified in epithelial cells of epidermis, hair follicle, seba-
ceous and eccrine glands, and in melanoma cells (212). AM
binding sites have been characterized in cultured keratino-
cytes and in melanoma cells; in the latter system AM stim-
ulates DNA synthesis (212). Calcium sensing receptors iden-
tical to those found in the parathyroid glands have been
identified in cultured normal human keratinocytes (213).
There is also experimental data suggesting the existence of
receptors for l-tyrosine and l-DOPA (214), since both l-
tyrosine and l-DOPA can act as regulators of melanogenesis
(10, 23), and l-DOPA can suppress lymphocyte activity (215).
Finally, the modulatory effect of melatonin on keratinocyte
proliferation and inhibition of melanogenesis suggests that
melatonin receptors are expressed also in mammalian skin
(216 –218). Nevertheless, the evidence is based solely on the
detection of melatonin binding sites, while specific receptors
for melatonin remain to be characterized. In lower verte-
brates, skin melatonin receptors are well characterized, and
melatonin is recognized to play an important role in skin
pigmentation, acting as a lightening agent (8, 67, 68).
IV. Skin as a Source of Hormones and
Neurotransmitters
Hormones and neurotransmitters produced by epidermal
and adnexal structures and dermal cells are listed in Table 2.
Neuropeptides released by cutaneous nerve endings or pro-
duced by skin are listed in Table 3. The production of vitamin
D is covered separately because it is synthesized in the skin,
and its systemic effects have been well characterized.
A. PTHrP
PTHrP is a protein made ubiquitously throughout the
body and expressed most intensely in embryonal and fetal
tissues (15). Its gene is encoded in chromosome 12 and, when
expressed and processed in human keratinocytes, yields
three or more isoforms (5, 137). Three transcripts that have
been best characterized are 139, 141, and 173 amino acids
long (137). The N-terminal region of PTHrP shows a high
degree of homology with PTH, with which it shares 8 or 9 of
the first residues. Likewise, PTHrP can bind to the classic
bone and renal receptors for PTH (type I), producing hy-
percalcemia (219).
In the skin, PTHrP is highly expressed in the granular layer
of the epidermis and outer root sheath of the hair follicle and
at much lower levels in basal keratinocytes and melanocytes
(15, 220). Pathologically, PTHrP is frequently expressed in
squamous carcinomas and in their corresponding cutaneous
form (15, 143). Expression of PTHrP has also been reported
in metastatic melanoma (221, 222). In addition, during
wound healing PTHrP is produced by granulation tissue
cells that include myofibroblasts and infiltrating macro-
phages (144). It is of interest that PTHrP is the main cause for
the syndrome of humoral hypercalcemia of malignancy
(HHM) and that it is produced predominantly by squamous
cell tumors (223). However, cutaneous squamous cell carci-
nomas, which have a high incidence of about 39/100,000,
may have resulted in only a few documented cases of HHM
(223). The reason for this discrepancy is unclear but may be
related to lower levels of expression, release of mostly inac-
tive fragments, or of inability of PTHrP molecules to cross the
basement membranes and reach the systemic circulation
(219). Presumably, such a barrier is broken in some cases of
advanced squamous cell carcinoma of the skin that develop
hypercalcemia. HHM associated with increased serum levels
of PTHrP has also been described in metastatic human mel-
anoma (221); and, in at least one case, clear evidence is
provided that melanoma cells themselves have been the
source of PTHrP (222). The reported patient had no signs of
bone metastases, and PTHrP immunoreactivity was detected
in melanoma cells on autopsy specimens but not in a biopsy

TABLE 2. Selected hormones and neurotransmitters produced in the skin

Compartment Hormones and neurotransmitter repertoire

Epidermis Vitamin D, PTHrP, androgens, T3, L-DOPA, catecholamines, acetylcholine, serotonin,
glutamate, aspartate, CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, TRH
Dermis and adnexal structures Vitamin D, PTHrP, estrogens, androgens, L-DOPA, serotonin, glutamate, aspartate, CRH,
urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, GH, histamine catecholamines,a
acetylcholinea
a
In the dermis, catecholamines and acetylcholine originate predominantly from cutaneous nerve endings.

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466 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

TABLE 3. Selected neuropeptides generated in the skin

Source Neuropeptide
Resident and circulating skin cells Gastrin-releasing peptide, somatostatin, NPY, atrial natriuretic peptide, PHM/PHI, galanin,
neurokinins, substance P, neurotensin, CGRP, VIP, bradikinin, cholecystokinin, endothelins,
CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins
Nerve endings Substance P, neurokinins, neurotensin, CGRP, VIP, somatostatin, NPY, atrial natriuretic
peptide, gastrin-releasing peptide PHM/PHI, bradikinin, galanin, cholecystokinin,
endothelins, ␣-, ␥-MSH, ␤-endorphin, CRH, urocortin, dynorphin, enkephalins

specimen of the melanoma obtained before onset of hyper-
calcemia (222).
B. Hypothalamic and pituitary hormones
1. CRH and related urocortin peptide. The skin is one of the
organs producing all the peptides hormones that are central
components of the HPA, the main mediator of the systemic
response to stress (5, 6, 9, 16 –19, 25, 28, 36, 56). Among the
hormones involved in this classic neuroendocrine pathway
are hypothalamic CRH and, more recently, the related pep-
tide urocortin (18, 19). In the skin, CRH gene expression has
been detected in cultured human keratinocytes and mela-
nocytes with actual production of the peptide, as shown by
RIA and RP-HPLC; furthermore, the CRH antigen has been
localized in situ to epidermis, hair follicle, nerve bundles, and
dermal blood vessels (18, 42– 44, 46, 49). In mouse skin, which
does not express the CRH gene, high concentrations of CRH
have been detected by RIA, and chemical identification of
CRH was documented by RP-HPLC analysis (44, 46). Since
the CRH immunoreactivity was localized to epidermal and
follicular keratinocytes and in nerve bundles (43, 44), it was
postulated that CRH is imported to the mouse skin by cu-
taneous nerve endings (43, 44, 46); alternatively, mouse skin
could express a related gene, with high homology to CRH
(46).
We recently observed expression of the urocortin gene in
mouse skin and also detected the actual urocortin peptide
(19). Urocortin tissue levels were highest in telogen skin and
decreased progressively during hair cycle to the lowest level
in late anagen (19). This pattern is opposite to the hair cycle-
associated production of CRH as determined in the same
model (44). Expression of the urocortin gene has also been
documented in whole human skin, human keratinocytes,
human melanocytes, and in hamster melanoma cells (19).
Similar to CRH, expression of urocortin peptide was detected
in situ in the epidermis, hair follicle, sweat glands, melano-
cytic nevi, smooth muscle, and wall of blood vessels (19). The
reported expression of CRH and urocortin in lymphocytes
(224, 225) strongly suggests that cells of the skin immune
system may also contribute to the cutaneous pool of those
peptides. Therefore, the hormone products that initiate HPA
activation at the central level are also readily available in the
skin.
2. POMC. There is a large body of data documenting ex-
pression of POMC gene in whole human and rodent skin and
in cultured skin cells that include keratinocytes, melanocytes,
dermal fibroblasts, and endothelial cells, Langerhans cells,
monocytes/macrophages, T lymphocytes, and leukocytes
(5, 16, 17, 64, 83).
a. Human skin. The POMC peptides ACTH, ␣-MSH, and
␤-MSH and ␤-endorphin peptides have been detected by
immunocytochemistry in normal and pathological melano-
cytes, keratinocytes, Langerhans cells, and mononuclear der-
mal inflammatory cells (5, 17, 226, 227). Studies with RP-
HPLC and Western blotting in cultured human melanocytes
and keratinocytes showed multiple forms of those peptides
such as ACTH 1–10, acetyl-ACTH 1–10, ACTH 1–17, ACTH
1–39, desacetyl-␣-MSH, ␣-MSH, and ␤-endorphin (5, 17,
228 –230). Human dermal endothelial cells and fibroblasts
did not only produce, but also released, ␣-MSH and ACTH
immunoreactivity into the medium (17, 64, 82, 108, 231). The
other POMC peptide, ␤-MSH, was detected by immunocy-
tochemistry in human skin in epidermal and follicular ker-
atinocytes, malignant keratinocytes, melanoma cells, and
dermal inflammatory mononuclear cells (5). ␥3-MSH has
also been detected in keratinocytes, melanoma cells, neutro-
phils, and in nerve endings (5, 232).
b. Rodent skin. ACTH, ␣-MSH, and ␤-MSH antigens were
detected in epidermal and follicular keratinocytes of mouse
skin (5, 17, 83), and ACTH and ␣-MSH were also detected in
nerve bundles and smooth muscle; ␤-endorphin has been
identified only in the sebaceous glands (5, 83). Cultured
murine and hamster melanoma cells expressed the ACTH,
␣-MSH, ␤-endorphin, and ␥3-MSH antigens (5, 16).
As regards the POMC gene expression, the transcription
of shorter and longer POMC mRNA forms has been iden-
tified in epidermal and dermal cells (5, 17). This pattern was
accompanied by translation of a 30-kDa POMC precursor
and its subsequent processing to ACTH, ␣-MSH, ␤-MSH,
␤-endorphin, and ␥3-MSH peptides (5, 17). Detection of the
processing enzymes PC1 and PC2 convertases in human and
rodent skin indicates that processing of POMC in skin is
similar to that in the hypothalamus and pituitary (17, 108,
232a). It must be noted that one group has reported only 80%
homology between the human cutaneous POMC mRNA and
its pituitary counterpart (233); however, subsequent analysis
of the reported sequence by others showed contamination
with murine pituitary POMC cDNA (234).
Therefore, the information above is convincing evidence of
POMC peptide production in the skin and its processing to
␣-MSH, ACTH, and ␤-endorphin-related peptides. Defini-
tion of local production of other products of POMC process-
ing will require additional research.
3. Other pituitary hormones. Studies with in vitro systems have
shown that human dermal fibroblasts express PRL mRNA
150 kb longer than the pituitary form (235). However, the
fibroblasts synthesized and secreted PRL peptide, immuno-
logically and electrophoretically identical to pituitary PRL

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
(235). The data are also consistent with earlier observations
of PRL production by normal human connective tissue (236),
and with detection of PRL immunoreactivity in sweat glands
(237, 238). Expression of the human GH gene has also been
detected by RT-PCR in cultured dermal fibroblasts (239);
human endothelial cells express the PRL gene (240); and
human immune cells produce both PRL and GH (25, 241–
243). Our most recent studies indicate restricted expression
of GH gene in the dermal compartment, that failed to detect
production of PRL mRNA in whole human skin (243a).
Therefore, actual GH and PRL production by the main cu-
taneous cell compartments has yet to be determined.
C. Neuropeptides and neurotrophins
1. Enkephalins. Met-enkephalins (Met-E) and leu-enkephalins
(Leu-E), which are products of the larger protein precursor
proenkephalin A (PEA) (36, 68), are also produced by mam-
malian skin (88, 244 –249). Met-E immunoreactivity has been
detected in normal human skin and is increased in areas
affected by psoriasis (88, 244, 245). The corresponding anti-
gen is located in epidermal keratinocytes and in inflamma-
tory infiltrate components such as T lymphocytes, macro-
phages, and leukocytes. Met-E has been also detected in the
keratinocytes of basal, spinous, and granular layers of hu-
man and murine epidermis (88, 245, 250). The detection of
PEA mRNA in lesional psoriatic skin further supports local
production of the Met-E peptide (244). The cellular source
expressing PEA could be mesenchymal dermal cells (248,
249) or immune cells including mast cells (24, 25), since
regulated PEA mRNA expression and production of final
enkephalin peptides has been detected in rodent skin mes-
enchymal cells (249), and circulating immune cells express
the PEA gene (251). The Met-E peptide has been also detected
in epidermal Merkel cells and Langerhans cells (246, 247).
Upon further review of the data, it appears that cell type and
conditions necessary for expression of the PEA gene remain
to be determined. Similar research is needed to determine the
cellular source of pro-dynorphin-related peptides, the pres-
ence of which has been reported in mammalian skin (252).
2. Nonopioid neuropeptides. Mammalian skin expresses a va-
riety of neuropeptides that include tachykinins SP and NKA,
CGRP, VIP, NPY, somatostatin (SOM), galanin, atrial natri-
uretic peptide (ANP), peptide histidine methionine/peptide
histidine-isoleucinamide (PHM/PHI), bradykinin, cholecys-
tokinin (CKK), and gastrin-releasing peptide (GRP) (4, 7, 33,
34, 38, 108 –114). In normal human skin, the most abundant
of these peptides are SP, CGRP, VIP, and NPY, although
detectable but lower levels of NKA, SOM, and ANP are also
present. Neuropeptides are synthesized by nerve cells and
released predominantly by unmyelinated afferent C fibers
characterized as C-polymodal nociceptors (C-PNN) and by
small myelinated A␦-fibers (33, 34, 38, 108). To a lesser extent,
autonomic efferent nerves also release the neuropeptides (4,
33, 34). In general, nerves penetrating into the epidermis
contain SP, NKA, and CGRP, whereas those innervating
dermal structures contain SP, CGRP, VIP, and NKA (33). The
neuropeptides are synthesized in dorsal root ganglia, where
they are processed and sorted in the Golgi network and then
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467
migrate, within dense core vesicles through retrograde ax-
onal transport, to nerve endings in the skin (34). The skin
concentration of neuropeptides varies by anatomical site,
reflecting, probably, regional differences in innervation (4,
33, 253). It is generally accepted that afferent or efferent
nerves are the main source for the cutaneous neuropeptides
listed above.
An additional source of cutaneous neuropeptides is their
synthesis and secretion by resident and circulating skin cells,
present in inflamed or even normal skin (4, 7, 24, 25, 27, 28,
38, 110, 111, 115, 254, 255). For example, Merkel cells express
antigens that are recognized by antibodies against CGRP, SP,
NKA, VIP, PHI, NPY, SOM, and galanin (38, 111, 112, 255).
Likewise, Langerhans cells express CGRP, SP, GRP, VIP,
SOM, and NKA antigens (110, 254). It remains to be tested
whether expression of those antigens is connected to actual
transcription and translation of the corresponding genes.
Several immunocytochemical studies have reported the
presence of VIP, SOM, SP, CGRP, NPY, and NKA in dermal
and epidermal immune cells from skin affected with psori-
asis, urticaria pigmentosa, allergic dermatitis, and, in some
cases, uninvolved normal skin (4, 7, 38, 110, 111, 254, 255).
NPY has been additionally detected in epidermal and fol-
licular keratinocytes of normal skin and SOM in basal epi-
dermal keratinocytes of atopic dermatitis skin (38, 133, 254).
Thus, skin cells definitively can produce neuropeptides;
however, the conditions necessary for such production and
the precise identity of the producing cells remain to be de-
fined.
3. Neurotrophins. The skin can produce the neurotrophins
NGF, NT-3, NT-4, and brain-derived neurotrophic factor
(BDNF) (7, 123–125, 128 –130, 256 –258). NGF is synthesized
and secreted by keratinocytes, Merkel cells, and dermal fi-
broblasts and mast cells (7, 123, 128, 256 –258). In human skin,
production of NT3 has been detected in dermal fibroblasts
(124), whereas in the mouse it is more widely expressed since
NT3 is found in epidermal and follicular keratinocytes of
developing skin, and in adult animals it is detected in ker-
atinocytes of hair follicle and DP fibroblasts (128 –130). Hair
follicle keratinocytes can synthesize NT4 and NGF (128 –130),
and dermal Schwann cells can synthesize NGF, NT-3, and
NT-4. Locally produced neurotensin can induce mast cell
degranulation (203). It may be speculated that the pleomor-
phism of neurotrophin cutaneous expression could be re-
lated to their significance in regeneration, a functional ca-
pability vital for the maintenance of homeostasis.
D. Neurotransmitters/neurohormones
1. Acetylcholine. Cultured human keratinocytes can synthe-
size, secrete, and degrade acetylcholine (180, 181, 259).
Keratinocyte acetylcholine is synthesized by choline acetyl-
transferase from acetyl coenzyme A and choline; in turn,
acetylcholine is hydrolyzed by acetylcholinesterase to acetate
and choline. Activities of both enzymes, choline acetyltrans-
ferase and acetylcholinenesterase, have been detected and
characterized in homogenates of cultured keratinocytes.
Immunolocalization studies have shown that choline acetyl-
transferase is consistently present in all layers of the human
468 SLOMINSKI AND WORTSMAN
epidermis, while acetylcholinesterase is restricted to basal
keratinocytes (180, 181, 259). Acetylcholinesterase activity
has been also detected in situ in epidermal melanocytes
(260). In addition to local synthesis, acetylcholine is also
released by cholinergic nerve endings supplying dermal
structures (34).
2. Catecholamines. The human epidermis has the capability
to synthesize the catecholamines dopamine, norepineph-
rine, and epinephrine (21, 22, 187, 261–263), which is con-
sistent with previous findings of phenylethanolamine-N-
methyl transferase immunoreactivity in human epidermal
keratinocytes (264). The synthetic activity of cutaneous
catecholamines resides predominantly in keratinocytes
that express biopterin-dependent tyrosine hydroxylase
and phenylethanolamine-N-methyl transferase (21, 187,
261, 262). Catecholamine production takes place in human
and rodent melanoma cells (265, 266), which suggests that
normal melanocytes may also produce catecholamines
(267). Catecholamines can be inactivated directly in the
epidermis by the enzymes monoamine oxidase (MAO) and
by catechol-methyl transferase, the enzyme already char-
acterized in keratinocytes and melanocytes (187, 268, 269).
l-Tyrosine, a precursor for both catecholamines and for
melanin, is also synthesized in human keratinocytes and me-
lanocytes from l-phenylalanine by phenylalanine hydroxylase
(20, 21, 187, 262, 270). Moreover, phenylalanine hydroxylase
and tyrosine hydroxylase activities are dependent on the co-
factor 6BH4, which is also synthesized and recycled by human
keratinocytes and melanocytes (21, 22, 187, 261). Lymphocytes
may also represent an additional source of catecholamines
(271). It has been proposed that l-tyrosine and its hydroxylation
product l-DOPA would have hormone- and neurotransmitter-
like roles (23, 214, 272), with melanocytes being the main site of
cutaneous l-DOPA production through the tyrosine hydroxy-
lase activity of tyrosinase (8, 273). l-DOPA produced by me-
lanocytes can, in fact, be released into the extracellular envi-
ronment. As for norepinephrine, an important cutaneous
source is its dermal release from adrenergic nerve fibers (4, 33,
34).
3. Other neurohormones. Serotonin may be also synthesized in
the mammalian skin, since rodent mast cells can synthesize
serotonin, although this property is not shared by human
mast cells (7, 27, 115, 195). Serotonin has also been detected
in Merkel cells and human melanocytes and melanoma cells
(266, 274, 275). In rodent skin serotonin can be transformed
into N-acetylserotonin (NAS), and the responsible enzyme
arylalkylamine N-acetyltransferase, together with its gene,
are correspondingly expressed (196, 276, 277). In hamster
skin NAS can be further metabolized to melatonin and 5-
methoxytryptamine (278). Finally, the neurotransmitters glu-
tamate and aspartate have been detected by immunocyto-
chemistry in epidermal keratinocytes and in dermal and
epidermal dendritic immunocytes (279).
E. Thyroid hormones
Human skin may be an extrathyroid site of conversion of
T4 into the more active T3 (12, 280 –282). This metabolic trans-
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Vol. 21, No. 5
formation would occur in the epidermal keratinocytes
through the action of type 2 deiodination pathway (280, 281),
with efficiency inversely related to the serum T4 (12). The
human epidermis is also the site of T3 deiodination to 3,3⬘-
diiodothyronine (12). More recent data suggest, however,
that at least rodent skin expresses only deiodinase type 3,
which catalyzes the 5-deiodination of thyroid hormones
(283–285). Since the cutaneous expression of three deiodi-
nases in rodent skin changes during embryonal develop-
ment, this area needs to be reexamined with modern meth-
ods, as it applies to human skin (284, 285).
F. Sex steroid hormones
The skin can transform the steroids dehydroepiandros-
terone (DHEA) and its sulfate (DHEA-S) into active andro-
gens and estrogens (4, 160, 286 –288). Specifically, enzymatic
activity corresponding to 3␤-hydroxysteroid dehydroge-
nase/⌬5–⌬4 isomerase (3␤-HSD) has been localized to the
sebaceous glands and, to a lesser degree, in hair follicles,
epidermis, and eccrine glands, while 17␤-hydroxysteroid de-
hydrogenase (17␤-HSD) has been localized to follicular and
epidermal keratinocytes (287–291). 3␤-HSD converts DHEA
into 4-androstenedione, and 5-androstene-3␤,17␤-diol into
testosterone, while 17␤-HSD converts DHEA into 5-andro-
stene-3␤,17␤-diol, 4-androstenedione into testosterone, and
androstanedione into DHT (4, 36, 160). Testosterone is also
converted into DHT through the action of a 5␣-reductase,
detected in dermal and dermal papilla fibroblasts, follicular
and epidermal keratinocytes, and sebaceous and apocrine
glands (4, 160, 164, 286, 289 –297). There are two isozymic
forms of the 5␣-reductase, but the skin expresses predomi-
nantly the type I in a highly specific cellular and regional
distribution (290 –296). Nevertheless, cutaneous expression
of 5␣-reductase type 2 has been also reported, but at much
lower levels; this form has been immunodetected in hair
follicles of human scalp (295, 296). The skin immune system
can also convert DHEA into 5-androstene-3␤,17␤-diol and
into 5-androstene-3␤,7␤,17␤-triol. Cutaneous conversion of
testosterone into estradiol is mediated by an aromatase ex-
pressed in dermal fibroblasts and adipocytes, but not in
keratinocytes (4). However, in keratinocytes 17␤-HSD can
transform 17␤-estradiol into estrone or estrone into 17␤-
estradiol (286).
G. Other steroid hormones
The presence of 17␤-HSD indicates that skin can dehy-
drogenate pregnenolone into progesterone, although the re-
action does not proceed in cultured keratinocytes (286). The
skin expresses genes for cytochromes P450SCC, P450c17, and
P450c21 (66). Immunocytochemistry localization of the an-
tigens for cytochrome P450SCC and P450C17 showed the
former in epidermal keratinocytes and eccrine glands and the
latter in epidermal and follicular keratinocytes, and in se-
baceous and eccrine glands (102). These findings, together
with the expression of the ACTH and of the MC2-R gene,
suggest that the skin could potentially synthesize glucocor-
ticoids (66). In fact, early studies have shown that whole
human skin can metabolize progesterone (PROG) (4), while
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
human keratinocytes can transform DOC into 5␣-dihydro-
DOC (286). We have recently reported that skin-derived ma-
lignant melanocytes can indeed metabolize exogenous
PROG to DOC, corticosterone, and 18OHDOC, and that it
can also metabolize DOC to corticosterone and 18OHDOC
(Fig. 1) (298). A more physiological preparation, whole skin
from the rat, can transform PROG into DOC and metabolize
DOC to corticosterone-like and to 11-dehydrocorticosterone-
like molecular species (Fig. 2) (299).
V. Molecular and Structural Basis for the
Organizational Integration of Neuroendocrine
Elements of the Skin
It is apparent from the massive amount of data summa-
rized in this work that the skin function extends beyond that
of static barrier organ. Thus, in addition to separating the
external environment from internal homeostasis, the skin
also exerts important endocrine and exocrine activities (cf.
Fig. 3). The well characterized exocrine function is performed
by the adnexal structures that comprise eccrine, apocrine,
and sebaceous glands and hair follicles. These are important
in strengthening the epidermal barrier, in thermoregulation,
and in the defense against microorganisms (3, 4, 7, 11). For-
mation of the hair shaft together with the secretions of ec-
crine, apocrine, and sebaceous glands also plays an impor-
tant role in social communication. Furthermore, at least in
furry animals, the skin plays an important role in behavioral
regulation, ascribed to the exocrine activity of the specialized
and nonspecialized sebaceous glands that produce and se-
crete odorants and pheromones (35).
As regards the newly recognized endocrine function of the
skin, this is performed by cells compartmentally arranged
into endocrine units (Fig. 4). These units are composed of
cells of epithelial, neural crest, mesenchymal, and bone mar-
row origin that form the epidermal, dermal, and adnexal
structures (cf. Figure 3). As listed in Tables 1 and 2, these
cutaneous cells and adnexal structures can concomitantly
produce hormones and express the corresponding receptors
(see Section III), indicating that the predominant mechanisms
of interaction within the different cutaneous compartments
are auto- and paracrine in nature. For example, the common
skin stressor, UV radiation, stimulates epidermal production
and secretion of the POMC-derived MSH and ACTH pep-
tides. In turn, these peptides interact with MC receptors on
melanocytes, keratinocytes, and Langerhans cells (LC) to
modify their functional activity and increase cutaneous mel-
anin pigmentation (5, 9, 17, 64) and also generate local an-
tiinflammatory and immunosuppressive effects (17, 64, 108).
Immunosuppression, mediated predominantly by ␣-MSH, is
expressed as functional antagonism to IL-1, down-regulation
of accessory molecules expression on antigen presenting
cells, and stimulation of IL-10 secretion (17, 64, 82, 108). At
the dermal level these immunosuppressive effects include
modulation of local cytokine production, and inhibition of
endothelial cells expression of adhesion molecules necessary
for inflammatory cells transmigration through the capillary
network (7, 17, 64, 82, 108). Dermally produced ␣-MSH and
ACTH modify hair pigmentation and sebaceous gland func-
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469
tion, whereas ACTH modifies hair growth (5, 16, 35, 61, 83,
86). Cutaneously produced CRH and urocortin affect epi-
dermal proliferation of keratinocytes and melanocytes (18,
19, 46, 51), and in the dermis these peptides can modify local
immune responses and act as vasodilators and mast cell
segregators (40, 48, 56 – 60, 203).
There is important neural representation in the skin, and
one of its components is the epidermal cholinergic system
(20). Its neurotransmitter, acetylcholine, is produced by the
keratinocytes in which, through interactions with muscarinic
and nicotinic receptors expressed predominantly in the basal
or suprabasal epidermal layers, keratinocyte proliferation,
migration, and differentiation are regulated (20, 181, 259).
Acetylcholine availability is determined by the local concen-
tration of acetylcholinesterase, which is highest in the basal
layer and decreases gradually along the vertical axis to reach
its lowest levels below the stratum corneum (20, 181). The
adrenergic system, represented by the catecholamines pro-
duced by keratinocytes, interacts with adrenergic receptors
expressed on the same cells to regulate their phenotype (21,
187, 300). The local production of the nonessential amino acid
l-tyrosine from l-phenylalanine by melanocytes and kera-
tinocytes ensures its availability for catecholamine synthesis
and melanogenesis in the epidermal unit, independent of
systemic supply (21, 22, 261). Both l-DOPA, a product of
local l-tyrosine hydroxylation, and catecholamines can po-
tentially modify cutaneous immune responses (215, 271).
As regards sex hormones actions, testosterone by itself, or
after conversion to DHT in keratinocytes and dermal fibro-
blasts modifies hair growth and sebaceous glands function
(4, 163, 164). Dermally produced estradiol (4) can affect func-
tion of adnexal structures and the wound healing process
(172, 173).
As discussed in the section on the vitamin D receptor, the
active vitamin D3 metabolite 1,25-(OH)2D3 inhibits keratin-
ocytes proliferation and stimulates their differentiation via
interaction with the VDR (13, 14). Evidence for the epidermal
conversion of vitamin D into 1,25-(OH) 2D3 (301) would
further support local (auto- and paracrine) mechanisms of
action. PTHrP produced in the epidermis and hair follicle has
a similar effect on keratinocytes through interaction with a
receptor different from the classic class 1 PTH/PTHrP re-
ceptor (15, 302). Both vitamin 1,25-(OH) 2D3 and PTHrP can
affect hair growth (13–15, 302).
Notwithstanding their overwhelming local action, hor-
mones produced in the skin can also enter superficial and
deep vascular dermal plexuses, or vessels supplying adnexal
structures, with long distance effects. Such a true endocrine
role is most apparent in the case of hormones and cytokines
produced in the dermis that have rather free access, by dif-
fusion to local capillary vessels. Limiting factors for this
diffusion are the distance between production site and vas-
culature, adhesiveness to the extracellular matrix, and local
rate of degradation. In contrast, epidermally produced hor-
mones and cytokines must penetrate the basement mem-
brane (BM) before traversing the extracellular matrix (EM) of
the papillary dermis; therefore, the permeability barrier and
the adhesiveness to the BM and EM limit their access to the
most superficial capillary vessels. An example of the relative
restriction posed by the dermal-epidermal junction is the
470 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

FIG. 1. Metabolism of progesterone to DOC, corticosterone, and 18OHDOC in malignant melanocytes. A, TLC separation of 14C-progesterone
metabolites produced by melanoma cells. B, RP-HPLC identification of 3H-18OHDOC as a metabolite of 3H-DOC. Upper panel, UV detection
of 18OHDOC standard; lower panel, radioactivity in eluted fractions with arrow indicating 3H-18OHDOC peak. C, Enzyme-linked immu-
nosorbent assay (ELISA) identification of corticosterone (B) in RP-HPLC-separated fractions. Upper panel, UV detection of corticosterone (B)
standard; lower panel, immunoreactive corticosterone (arrow) in media from human melanoma cells incubated with progesterone. Control
represents media from cells cultured without progesterone added. DOC, 11-Deoxycorticosterone; B, corticosterone; Aldo, aldosterone; 11-
dehydro-B, 11-dehydrocorticosterone; 18ODOC, 18-hydroxycorticosterone. [Reproduced with permission from A. Slominski et al.: FEBS Lett
445:364 –366, 1999 (298). Experimental conditions are detailed in Ref. 298.]

rarity of patients showing systemic effect (hypercalcemia)
from cutaneous PTHrP, a hormone produced abundantly in
the epidermis (15, 302). Still, epidermally produced vitamin
D (14), urocanic acid (303, 304), and, perhaps, PTHrP do enter
the systemic circulation and are able to modify the functional
activity of distant organs, providing evidence for endocrine
effects by factors produced in the epidermis. Urocanic acid
produced in the stratum corneum of the epidermis can also
enter the systemic circulation and have immunosuppressive
effects (4, 123, 303, 304). As mentioned above, epidermal

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 471

FIG. 2. Active steroidogenesis in normal rat skin. Both panels show TLC separation of steroid products. The right lanes marked 14C-PROG (A)
or 14C-DOC (B) show radioactive steroid intermediates generated in rat skin. The left lanes marked controls represent nonenzymatic trans-
formation of 14C-PROG (A) or 14C-DOC (B) incubated in culture media only. Experimental conditions are detailed in Ref. 299. PROG,
Progesterone; DOC, 11-deoxycorticosterone; B, corticosterone; Aldo, aldosterone; A, 11-dehydrocorticosterone; 18OHB, 18-hydroxycorticoste-
rone. [Reproduced with permission from: A. Slominski et al.: Biochim Biophys Acta 1474:1– 4, 2000 (299). © Elsevier Science.]

PTHrP may play predominantly para- or autocrine roles (15,
141). It could, however, have a distant effect after release by
pathological conditions (skin cancer) (222, 223).
Cutaneous neuroendocrine elements are therefore tightly
organized and arranged into epidermal and dermal endo-
crine units, as determined by the physical separation be-
tween those compartments (Figs. 4 and 5). These units, which
become fully expressed in a field-restricted stress-dependent
manner, have broad bidirectional communications. This is
accomplished through soluble factors able to penetrate the
basement membrane and, also, through sensory nerve end-
ings connecting epidermis and dermal structures (Figs. 4 and
5). Sensory nerve fibers provide anterograde or retrograde
transmission of impulses through axon reflexes with release
of neuropeptides at epidermal or dermal nerve endings (33,
34, 38). The latter intracutaneous communication mechanism
represents therefore a high-speed and extremely specific con-
nection for the transfer of information, sensed externally or
internally, to specific target cells. Target cell activation may
then be mediated by neuropeptides (cf. Table 3 and Section
IV.C) synthesized and released predominantly by the un-
myelinated C fibers described as C-polymodal nociceptors
(C-PNN), or by myelinated A␦-fibers (33, 34, 38). There are
specific roles for each of the different neuropeptides released
by afferent nerve endings in the functional regulation of
epidermal barrier properties, skin immune activity, vascular
activity, hair growth, and adnexal functions. Those topics, as
well as their mechanism of action, have been discussed in
comprehensive reviews on the subject (5, 7, 33, 34, 38, 56,
110 –112, 128, 203). It is apparent from neuroimmunocyto-
chemistry studies that nerve subpopulations containing dif-
ferent neuropeptides, such as SP, NKA, CGRP, VIP, SOM,

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472 SLOMINSKI AND WORTSMAN
FIG. 3. Localization of the cellular com-
ponents of the exocrine and endocrine
skin units. The epidermis is repre-
sented by the upper layer, separated
from the dermis by the basement mem-
brane. The listed cell types have the
capability to produce hormones, neural
mediators, and cytokines; they also ex-
press the corresponding receptors indi-
cating auto- and paracrine mechanisms
of action.
NPY, PHM, enkephalins, CRH, and ␥- and ␣-MSH, do enter
cutaneous structures. The presence of this neural network
with fibers penetrating all the vital layers of the epidermis
and branching into dermal structures, adnexa, Merkel cells,
epidermal Langerhans cells, melanocytes, and dermal mast
cells provides, therefore, the support for a dual role for those
cells, as effectors and regulators (33, 34, 38, 110, 114, 115, 118,
119, 128, 203, 300, 305–313). Within this local branching neu-
ral network, disturbances of local homeostasis expressed as
production of chemical mediators can be sensed in a specific
manner and transmitted to local subunits to counteract nox-
ious stimuli or protect against further damage. The neural
branches can be also activated directly by neurohormones
and bioactive peptides produced locally, such as histamine,
eicosanoids, or NO (33, 34, 38, 112, 203, 312, 314); or, by
physicochemical agents such as changes in pH, cation, and
free radical concentration (cf. Ref. 34). Indirect neural mod-
ulation may be provided by the cytokine networks that mod-
ify the chemical environment surrounding the nerve end-
ings. As compared with this neural mechanism, humoral
communication, dependent on local diffusion, results in a
much slower response.
The special role of autonomic nerves in the cutaneous
neuroendocrine organization is limited by the predominant
dermal ending of their fibers. Thus, they can only regulate
function in the dermal endocrine unit although neurotrans-
mitters released in the proximity of the basement membrane
could potentially diffuse into the epidermal compartment. It
is also possible that autonomic nerves could enter the epi-
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Vol. 21, No. 5
dermis; however, this hypothesis still requires experimental
investigation.
The bidirectional interaction between skin elements and
local neural network is perhaps best illustrated by the
changes in murine skin during the hair cycle, which are
dependent on appropriate dermal and adnexal innervation
(128, 300, 311). In this process, the hair cycle-associated tissue
remodeling is accompanied by a tightly regulated sprouting
and regression of specific afferent and efferent nerve fibers
that form a neural and neurotransmitter network. Its cuta-
neous expression is highly specific and tightly determined by
the actual phase of the hair cycle (128, 300, 311).
The epidermal and dermal endocrine units with their bi-
directional communication pathways, which proceed via sol-
uble mediators or via antidromic axon reflexes through the
nerve branches that link both compartments, combine to
form the skin neuroendocrine organization (Fig. 5). In gen-
eral, this neuroendocrine organization functions to coordi-
nate the epidermal and dermal changes necessary for rein-
forcing the physical barrier and maintaining its structural
integrity. To implement these objectives, it modulates sen-
sory reception, melanin pigment production and distribu-
tion, activity of the local immune system, vascular functions,
thermoregulation, exocrine secretion, and metabolic trans-
formation of prohormones or hormones into other molecules
of different biological activity.
The skin neuroendocrine system is thus continuously
sensing environmental components and, when activation
threshold levels are reached, a reaction is triggered with
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
FIG. 4. Diagram demonstrating the proposed flow of information
between dermal and epidermal endocrine units and their systemic
connections. For functional purposes, cells with endocrine capability
become activated in response to environmental stimuli in a stress-
dependent manner, organized according to anatomic compartment of
residence. They communicate by humoral signals (central arrows) and
sensory nerve endings (arrows on the left). The efferent neural
regulation is provided by the autonomic nerves (right), and also by
sensory nerves (left) via antidromic conduction.
production of specific biological factors. Some of these fac-
tors may be released to the extracellular compartment to
activate sensory nerve endings, directly enter the circulation,
or activate circulating immune cells. The sum of these actions
sets the optimal mode for dealing with deleterious environ-
mental changes (Fig. 6). Humoral signals that could directly
enter the circulation include cytokines and hormones and
vitamin D3. The latter represents a marker for a cutaneous
action in response to an environmental component (UV-B),
which results in well defined systemic effects on calcium
homeostasis (14). An analogous example in amphibians is the
skin regulation of pituitary function through TRH and skin
peptide tyrosine-tyrosine (SPPY) (315, 316). Environmental
factor(s) determine concentrations of TRH and SPPY in frog
skin, which are higher than in any neuroendocrine organ;
skin TRH reaches the pituitary to stimulate production and
release of PRL and ␣-MSH, while SPPY inhibits production
of ␣-MSH (315, 316). In mammals, there are other local
hormonal factors that could potentially enter systemic cir-
culation after UV radiation exposure or in pathological con-
ditions. Among those are POMC-derived ␣-MSH and ␤-
endorphin (5, 9, 108, 230), met-enkephalin (245), PTHrP (15,
302), or DHT, estradiol, and T3 (4, 11, 12). Skin cytokines can
also directly affect the functional activity of distant immune
and nonimmune organs (7, 11, 17, 27, 108), whereas circu-
lating cytokines are known to affect hypothalamo-pituitary
axis function (24 –28). Thus, IL-1, IL-6, interferons, and TNF␣
can access brain and pituitary to up-regulate production and
release of selected hypothalamic and pituitary hormones.
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473
FIG. 5. Organization and function of the skin neuroendocrine system.
The epidermal and dermal endocrine units modulate functional ac-
tivity of epidermal and dermal compartments. Endocrine units coor-
dinate their actions by humoral signals (central arrows) and/or by the
local neural network (connecting arrow on the left).
Cytokines may have similar action on the regulation of
adrenal gland function (28, 317). Intermediates of melano-
genesis l-DOPA and products of its metabolism in the me-
lanocytes might also have systemic effects when, under
pathological conditions, they are released into the circulation
(10, 23, 318).
Many epidermally or dermally derived molecules are in-
capable of migrating because of insignificant concentration
in the vicinity of blood vessels; however, a systemic effect is
still theoretically possible. Thus, direct stimulation of dermal,
adnexal, or subcutaneous cellular components could second-
arily result in the production of biological mediators with
definite systemic effects. An example of this amplification
mechanism is represented by the cytokines IL-1 and TNF␣,
which can stimulate leptin production by adipose tissue in
the deep dermis and/or subcutis (319, 320). In this manner,
small amounts of cutaneous cytokines could affect feeding
behavior and energy balance (319). Another example is the
activation of skin immune cells that can enter the circulation
and have distant immunological or regulatory effect (7, 27).
Similar to the humoral model of communication in the
cutaneous endocrine system, with potential cytokine-medi-
ated stimulation of the HPA axis, the cutaneous neural sig-
naling system could also activate central nervous system
pathways. The latter connections have the advantages of
being more rapid with higher specificity (Fig. 6). Thus,
changes in the skin physicochemical environment generated
by physical, chemical, or biological trauma, UV radiation, or
local disease processes could be sensed by afferent nerve
ending, and thence transmitted via the spinal cord to the
brain. However, before the information is sent to the brain,
474 SLOMINSKI AND WORTSMAN
FIG. 6. Systemic effects of skin neuroendocrine system products. In
response to noxious stimuli, the skin endocrine system mounts a
progressive, intensity-dependent, highly coordinated response. In the
case of high-magnitude stimuli, the generated signals travel through
humoral or neural pathways to reach the central nervous system,
immune system, and other organs.
it may be modulated by the local cutaneous neuroendocrine
units through the direct activation of nerve receptors by
neurohormones and neurotransmitters, or by neuropeptides
(cf. Tables 2 and 3), histamine, eicosanoids, NO, and other
proinflammatory mediators (5, 7, 27, 33, 34, 108, 113, 203,
314). Alternatively, stress released cytokines and proinflam-
matory biological modifiers could affect signal type and neu-
ral sensor availability through indirect mechanisms, e.g., ac-
tivation of other cells to produce and release factors
activating afferent receptors. In this context, mast cells, me-
lanocytes, Langerhans cells, and Merkel cells could be par-
ticularly important because of their close contact with nerve
endings (33, 34, 110, 111, 119, 203, 305–308). Secondary
changes in hydrogen ions, cations, free radical and NO con-
centrations or eicosanoids produced by cytokine-activated
keratinocytes or immune cells could have similar effects on
sensory nerve endings. In the visceral organs the cytokine
IL-1, IL-6, and TNF␣ signals can be potentially transmitted
through an indirect mechanism via the vagus nerve to the
central nervous system (26, 28, 321). Lastly, upon leaving the
skin, some afferent neural signals may also be relayed from
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Vol. 21, No. 5
the spinal cord to other organs without ever reaching the
higher centers. To summarize, the skin can generate rapid
(neural) or slow (humoral) moving signals to induce re-
sponses at the general or systemic level or at the organ-
specific level. These responses are designed to counteract the
damaging effect of environmental insults or to adjust the
homeostatic system to the optimal mode that would buffer
environmental noxious agents most efficiently.
VI. Regulation of Cutaneous Neuroendocrine System
There are number of environmental and intrinsic factors
that regulate the cutaneous neuroendocrine system activity
level. The most prominent environmental factor affecting the
skin is solar radiation, particularly within the UVA and UVB
wavelengths. Temperature, humidity, and concentrations of
chemical and biological agents represent other factors. Some
internal factors affecting the skin neuroendocrine system are
changes in the physicochemical microenvironment or in bi-
ological modifiers; these may be generated in reaction to
environmental signals or result from local cyclic biological
rhythm associated with hair cycling, or from local or general
disease processes. Of the endocrine factors produced by the
skin the most important is vitamin D, which is not only a
regulator of the calcium metabolism but has other systemic
effects (13, 14, 145). For example, epidemiological evidence
suggests that sunlight deprivation with associated reduction
in the circulating levels of vitamin D3 derivatives may result
in increased incidence of the carcinomas of breast, colon, and
prostate (145).
A. Solar radiation
UV light is a form of electromagnetic energy that includes
the wavelength between 100 to 400 nm of the solar spectrum.
Although it includes vacuum UV, UVC, UVB, and UVA, only
the 290 – 400 nm wavelengths that comprise UVA and UVB
reach the surface of the earth, because of the partial absorp-
tion by atmosphere. UVB (290 –320 nm) interacts very effi-
ciently with the skin, inducing sunburn and pigmentation (3,
4, 9). UVA (320 – 400 nm) has better penetration through the
atmosphere but lower efficiency in inducing erythema and
melanogenesis. It is classified as UVA1 (320 –340 nm) and
UVA2 (340 – 400 nm), and it has been proposed that the
photobiological mechanism of action for UVA1 is similar to
that of UVB; the effects of UVA2 would involve distinctive
oxygen-dependent photochemistry. The cutaneous effects of
UV radiation are dependent on the penetration and absorp-
tion of the particular wavelength. In human skin UVB is
absorbed predominantly by stratum corneum and to a lesser
degree by the epidermis. The very small fraction of UVB that
reaches the dermis, however, has significant biological ef-
fects inducing immediate and delayed erythema (3, 4, 9).
Transmission of UVA through epidermis of white skin is
high, resulting in approximately 50% of energy reaching the
dermis. UVA has only 1/1,000 of UVB biological activity, but
it also contributes to the cutaneous actions of solar radiation
(3, 4, 9). Thus, it has a major effect in aging of the skin, it has
a more limited role in the induction of skin cancer, and it does
not produce burning of the skin. In general, the biological
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
responses to solar radiation are dependent on individual
susceptibility determined by skin pigmentation, prior expo-
sure to UV radiation (decreases the threshold for subsequent
responses), region affected, radiation field size, and envi-
ronmental conditions (3, 4, 9). There is, nevertheless, a high
degree of precision and predictability of the cutaneous re-
sponse to UV, demonstrating that mechanisms have evolved
to transform some of the solar energy into a catalyst acti-
vating a recording system (9). Such a recording role could be
served by the local neuroendocrine system, whose activation
is designed to buffer or counteract the damaging effect of UV.
1. CRH-POMC system. UVB stimulates production of CRH
peptide in normal melanocytes without noticeable changes
in CRH mRNA levels, suggesting posttranscriptional regu-
lation (322). UVR can stimulate/induce POMC gene expres-
sion in the skin in human and rodent normal and malignant
keratinocytes and melanocytes maintained in cell culture (5,
9, 17, 64, 108, 230, 323). The stimulation of ACTH, ␣-MSH,
␤-LPH, and ␤-endorphin production and secretion in re-
sponse to UVB is dose dependent in normal and malignant
epidermal cells, and in dermal endothelial cells; POMC
mRNA production is correspondingly increased (17, 64, 108,
323). UVA can also stimulate POMC gene expression with
subsequent MSH and ACTH production in human keratin-
ocytes and endothelial cells (17, 64, 108). This stimulation of
POMC gene expression and production of POMC peptides
are observed after a 10-h latency period; production becomes
significant at 10 –24 h (17). Of interest, humans and horses
exposed to sunlight exhibit increases in the circulating levels
of ␣-MSH and ACTH, and experimental whole-body expo-
sure to UVR in humans increases ␤-LPH and ␤-endorphin
serum levels (5). In the case of ␤-LPH the response is abro-
gated by UV-absorbing topical sun blockers, implicating me-
diation by a photoreaction (324).
UVB can also up-regulate expression of MC1-R on normal
and malignant cultured melanocytes and keratinocytes (5,
17, 323). This UVB up-regulation of MSH receptors expres-
sion is associated in melanocytes, with increased respon-
siveness to MSH in terms of stimulation of melanogenesis, as
shown in both cell culture and in vivo conditions (75, 323,
325). These experimental findings are consistent with the
effects of exogenous MSH and ACTH in humans, which
cause increased skin pigmentation affecting predominantly
the sun-exposed areas. Clinically, the similarly increased
skin pigmentation of patients with Addison’s disease is most
striking in the sun-exposed areas. These experimental and
clinical observations led Pawelek and colleagues (9, 75, 325)
to propose that the effects of UVB on cutaneous melanogen-
esis do not represent random (unrelated) events but, instead,
a highly coordinated sequence in which expression of MSH
receptors and local production of POMC-derived MSH and
ACTH peptides are important intermediate steps.
2. Immunoregulatory molecules. UV radiation influences the
immune system at both local and systemic levels with the net
effect being immunosuppressive (7, 17, 64, 82, 108, 114, 326,
327). The mechanism for this action can be either direct
absorption of light energy by cells of skin immune system
that include resident and nonresident (circulating cells) or
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475
indirect through UV-induced activation of nonimmune cells
in epidermis and dermis with release of cytokines and chem-
ical mediators (7, 9, 17, 64, 82, 108, 114, 326 –333). Important
in this regard is trans-urocanic acid (UCA) which, after ab-
sorption of UVB, or to lesser degree of UVA energy, isomer-
izes into cis-UCA in the stratum corneum (303, 304). cis-UCA
acts as a potent local and systemic immunomodulator and
immunosuppressor (7, 303, 304).
Keratinocytes stimulated by UVR can produce and secrete
the cytokines IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF␣, and
macrophage inhibitory factor (MIF), eicosanoids, basic fibro-
blast growth factor (bFGF), IGF-I, transforming growth fac-
tor (TGF-␣), and endothelins (7, 17, 108, 114, 326 –333). This
effect is rapid (within 1–3 h) and predominantly mediated by
UVB, although UVA also stimulates IL-10 and, to a lesser
degree, IL-6 production. UVR also switches the local cyto-
kines and mediators release profile of nonepithelial compo-
nents of epidermis and dermis including lymphocytes, mac-
rophages, mast cells, endothelial cells, and melanocytes. The
cytokines IL-1, IL-6, TNF␣, and MIF exert local activity,
which does not preclude systemic effects upon entering the
circulation.
3. Neuropeptides, neurotrophins, and neurotransmitters. UVA,
but not UVB, irradiation increases the skin levels of met-
enkephalin, and multiple whole-body UVA exposure can
also increase the plasma level of the peptide (245). For its
part, UVB induces release of CGRP, SP, and NKA from
cutaneous sensory nerves (38, 108). CGRP appears to have
immunosuppressive properties, while SP and NKA enhance
cutaneous neuroinflammation (38, 108, 114). UVB also stim-
ulates NO production by keratinocytes, melanocytes, and
NO release from sensory nerve endings (9, 108, 314). Also,
UVB induces production and release of the neutrophin NGF
by epidermal keratinocytes (123, 256).
Schallreuter et al. (334, 335) have shown that UVB enhances
tetrahydrobiopterin production and phenylalanine hydrox-
ylase activity, with net increase in the epidermal supply of
l-tyrosine. l-Tyrosine is a precursor for both catecholamine
biosynthesis and melanogenesis. Stimulation of melanogen-
esis by UVB is associated with increased production of the
biologically active products l-DOPA, dihydroxyindole
(DHI), and DHI carboxylic acid (9, 123).
B. Hair cycle
Hair growth and the cyclic activity of the hair follicle are
timed by a “biological clock,” which in rodents changes
periodically the physiology and morphology of the entire
skin (30, 31). In mice, the expression of POMC gene and
production of the POMC peptides ␤-endorphin, ACTH, and
␣-MSH are synchronized with hair follicle cycle (5). POMC
production is lowest in telogen (resting phase), increases
during anagen (growing phase), and decreases in catagen
(involution phase). These changes correlate closely with the
local expression of the MC1 gene (65). The intracutaneous
concentration of CRH and expression of CRH-R1 exhibit
similar changes coupled with the hair cycle, being highest
during anagen and lowest during the catagen and telogen
phases (44). A similar phenomenon has been described for
476 SLOMINSKI AND WORTSMAN
SP, with maximal levels occurring in early anagen and min-
imal levels occurring in catagen skin (116). Thus, the bio-
logical clock regulating the cyclic activity of hair follicles
appears to regulate simultaneously the local production or
release of neuropeptides and the expression of the corre-
sponding receptors.
The hair cycle is associated with striking changes, which
are qualitative in distribution and quantitative in expression
levels of the neutrophins NT-3 and NGF and their corre-
sponding receptors in the skin of the C57 BL/6 mouse (128 –
132). Furthermore, the pattern of sensory and sympathetic
innervation of different cutaneous structures including the
hair follicle itself, shows significant hair cycle-dependent
changes (128, 300, 311). The changes in adrenergic innerva-
tion are accompanied by specific patterns of follicular ␤2-
adrenergic receptor expression. Therefore, the whole cuta-
neous neural network involved in the regulation of hair
growth undergoes cyclic changes (128, 300, 311), which can
potentially affect the function of other cutaneous structures,
sensory skin responsiveness, and transmission of afferent
signals to the spinal cord. Because of the extent and magni-
tude of the hair cycle-dependent changes, it is likely that
these are regulated within the skin itself, under the control
of the “biological clock” governing hair cycle.
C. Cytokines
Similar to its effects at the central level, the proinflamma-
tory IL-1 has significant local stimulatory/inductory effects
on POMC gene expression and production of POMC pep-
tides in normal and malignant epidermal melanocytes and
keratinocytes, dermal endothelial cells, and circulating im-
mune cells that include macrophages (5, 17, 64, 108, 230).
Another cytokine, TNF␣, stimulates production of POMC
mRNA in normal dermal fibroblasts, while TGF-␤ inhibits it
in keratinocytes and normal dermal fibroblasts, but not in
keloid fibroblasts (231). TNF␣ also stimulates production of
the POMC products ␤-endorphin and ACTH peptides (336).
Many cytokines can up-regulate expression of the MC-1 gene
and of functional cell surface MSH receptors in normal and
malignant melanocytes (5, 17, 64, 323). Those include Il-1␣,
IL-1␤, endothelin-1 (ET-1), adult T cell leukemia-derived
factor/thioredoxin (ADF/TRX), INF-␣, INF-␤, INF-␥,
(Bu)2cAMP, and the hormones ␣-MSH, ␤-MSH, and ACTH.
IL-1 can also stimulate MC-1 receptor expression in normal
and malignant human keratinocytes and in human dermal
microvascular endothelial cells (HDMEC) (17, 64, 230). Con-
versely, TNF␣ inhibits MC1 expression in melanocytes.
Thus, selected cytokines regulate precisely (“fine-tuning”)
the level of expression of POMC and MC1-R. The roles of
cytokines in the cutaneous regulation of epidermal cholin-
ergic system, production of catecholamines, steroid synthesis
and metabolism, and synthesis of neuropeptides CRH, uro-
cortin, and enkephalins remain to be investigated.
D. Degradation or inactivation of hormones and
neurotransmitters
One important mechanism regulating the availability of
locally produced hormones is their degradation in situ. In this
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Vol. 21, No. 5
context peptide hormones and neuropeptides can be degra-
dated by neutral endopeptidases (NEP) and angiotensin con-
verting enzyme (ACE), which are present in dermal fibro-
blasts, endothelial cells, and keratinocytes (34, 38, 108, 337).
NEP activity is not static, but can be stimulated by proin-
flammatory cytokines, by factors raising intracellular cAMP,
and glucocorticoids (38); in addition, its cutaneous pattern of
expression changes during wound healing (337). Other pro-
teolytic enzymes such as mast cells-derived tryptase or chy-
mase can degrade neuropeptides, effectively attenuating
their activity (7, 34, 38, 108, 115, 203).
Catecholamines and other biogenic amines can be inacti-
vated directly in the epidermis, by the action of MAO and/or
by catechol-methyl transferase (21, 268, 269); the latter en-
zyme has been already characterized in keratinocytes and
melanocytes. Acetylcholine is degraded to acetate and cho-
line by epidermal acetylcholinesterase (20, 259). The skin is,
in addition, a well recognized site for the transformation of
glucocorticoids and sex hormones to molecular forms with
higher or lower hormonal activity, or overtly inactive (4, 11,
160, 297).
VII. Regulation of Cutaneous Vitamin D Production
A. Vitamin D3 production
The recognition that the skin could react with an invisible
component of sunlight to make a factor indispensable for the
mineralization of bone vitamin D represents a remarkable
scientific accomplishment (14). Vitamin D3, or cholecalcif-
erol, is formed from the precursor steroid 7-dehydrocholes-
terol (7-DHC), which is normally concentrated to the plasma
membrane of basal epidermal keratinocytes (80% of skin
content). Upon stimulation with sunlight photons of UVB
light (290 –310 nm wavelength), 7-DHC undergoes photo-
lysis with breakage of the 9,10-carbon bond generating the
thermolabile intermediate previtamin D3. At normal skin
temperature previtamin D3 molecules convert into vitamin
D3 through internal rearrangement (Fig. 7). Vitamin D3 en-
ters the circulation bound with high specificity to vitamin D
binding protein (DBP) to exert its systemic actions (338).
When newly formed previtamin D3 and vitamin D3 continue
to be irradiated, they convert into additional steroids such as
lumisterol, pyrocalciferol, and tachysterol, which are prac-
tically devoid of vitamin D3 activity (14). Although light and
temperature are the only variables involved in the biosyn-
thetic process, they do not account entirely for the rates of
biosynthesis observed in tissues. Thus, irradiation of 7-DHC
dissolved in isotropic organic solvents such as hexane gen-
erates only one tenth of the amount observed in similarly
irradiated skin (14). The explanation for this discrepancy was
obtained in experiments with artificial liposomes, which un-
covered the crucial role played by plasma membrane phos-
pholipids in the kinetics of the reaction. Thus, through am-
phipatic interactions, previtamin D3 remains stabilized in its
“cholesterol like” cZc– conformation, the only one leading to
conversion to vitamin D3. Furthermore, the fastest rate of
previtamin D3 isomerization was seen in association with
phospholipids containing 18 carbon atoms in the hydrocar-
bon chain (339).
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 477

FIG. 7. Cutaneous synthesis of vitamin D3. Under exposure to UVB, cutaneous 7-dehydrocholesterol molecules undergo photolysis to the
secosteroid product cZc-previtamin D3 (this cis-conformer is the only form that can be converted into vitamin D3). Thermal energy produces
intramolecular rearrangement of cZc-previtamin D3 with a 1,7-sigmatropic hydrogen transfer from C-19 to C-9, to yield vitamin D3. [Modified
from X. Q. Tian and M. F. Holick: J Biol Chem 274:4174 – 4179, 1999 (339), by permission from the Journal of Biological Chemistry. © The
American Society for Biochemistry and Molecular Biology.]

Once formed in the skin, vitamin D is translocated to the
circulation over a period of 30 h or longer. It reaches pe-
ripheral tissues bound with high specificity (98%) to vitamin
D binding protein (also known as group-specific component
or GC). This is in contrast to orally derived vitamin D2 (er-
gocholecalciferol), which circulates only 50% bound to vita-
min D binding protein, with the remaining fraction being
bound to cholesterol containing lipoproteins (14). Vitamin D
is metabolized (activated) to 25-hydroxyvitamin D (in the
liver) and to 1,25 dihydroxyvitamin D (in the kidney) (14).
According to the level of action, the physiological and patho-
logical factors that modify the systemic supply of cutaneous
vitamin D3 can be classified into precutaneous, cutaneous,
and postcutaneous.
B. Precutaneous regulation
1. Environment dependent. This category includes geographic
latitude. Thus, as the earth experiences its seasonal tilting
during fall and winter, sunlight arrives at an angle at the
more polar latitudes crossing the atmosphere almost tan-
gentially during winter, and lessening transmission of UVB
wavelengths. For example, during winter in Boston, Massa-
chusetts (latitude 42.2 oN) these wavelengths disappear
(339), and a similar situation is observed in the Southern
Hemisphere, where vitamin D3 photosynthesis is extremely
low during winter in Cape Town, South Africa (latitude
35oS), but almost unchanged throughout the year in Johan-
nesburg (26oS)(340). Another environmental variable is the
time of day, since vitamin D3 synthesis is maximal at midday,
with only very small amounts being formed before 0800 h or
after 1700 h. In fact, in Cape Town, only negligible amounts
of previtamin D3 are formed in the winter before 0010 h and
after 1500 h. In general, latitude, season of the year, and time
of day affect the cutaneous photosynthetic process in a highly
coordinated, mutually dependent manner (14).
2. Environment independent.
a. Clothing. Garments provide significant protection
against the damaging effects of solar light that include ery-
thema, accelerated aging, and development of skin cancer.
Experiments on transmission of UVB light through different
fabrics showed significant effects on the photosynthesis of
vitamin D3 (341). Of fabrics with similar thread density, black
wool had the highest light absorption coefficient followed,
respectively, by black polyester, black cotton, white cotton,
white wool, and white polyester. All of the fabrics produced
significant attenuation of the shorter wavelengths (UVB),
and studies in volunteers wearing garments made of the
same materials showed complete obliteration of the normal
serum vitamin D3 photosynthetic response to one MED (min-
imal erythema dose) of UVB (341). This absence of vitamin
D serum response persisted after whole-body irradiation was
increased to the equivalent of 6 MEDs. In addition, regular
street clothing, even that worn during summer, also pro-
duced significant suppression of the vitamin D3 response to
UVB (341).
b. Sunscreens. These agents prevent skin penetration of
solar radiation. Thus, PABA (para-aminobenzoic acid), the
common active ingredient of sunscreens, has an absorption
spectrum that overlaps the spectrum responsible for the pho-
tosynthesis of vitamin D3 (342). As would be expected, ap-
plication of PABA to skin pieces blocked the conversion of
7-DHC to previtamin D3 that normally follows exposure to
simulated sunlight. Moreover, in healthy volunteers, cover-
age of the whole body with sunscreens abolished the serum
vitamin D3 response to UVB light delivered in a photother-
apy unit (342). Also patients with photodependent cutaneous
disorders such as skin cancer, who must use sunscreen
chronically, have lower serum levels of 25-hydroxyvitamin
D as compared with matched controls (343). Nevertheless, it
must be noted that these lower 25-hydroxyvitamin D levels
have not been associated with secondary hyperparathyroid-
ism or metabolic bone disease (344).
C. Cutaneous regulation
1. Regional (anatomical) activity of solar radiation. The segmen-
tal body contributions to the supply of vitamin D3 were
evaluated in healthy individuals who had sunscreens ap-
plied to selected areas of the body before UVB irradiation
(345). Significant and almost equivalent serum vitamin D3
increases occurred after selective irradiation of either trunk,
legs, or the entire body. UVB exposure of only the head and
neck or arms produced a lesser rise in vitamin D3 serum
levels, which did not reach statistical significance (345).
2. Race-related skin pigmentation. Melanin is not a “neutral
density” light filter, but exhibits varying absorption coeffi-
cients, with maximal absorption for the shorter wavelengths

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478 SLOMINSKI AND WORTSMAN
of the spectrum (⬃ 300 nm) (346). Thus, melanin has a sig-
nificant effect on the synthesis of vitamin D3. As would be
expected, the highest vitamin D3 response to UVB is seen in
white individuals, followed by Orientals (East Asians) and
Indians (South Asians) and is extremely attenuated in blacks
(African Americans) (347). This race effect is also associated
with lower prevailing levels of 25-hydroxyvitamin D, al-
though the serum concentrations of 1,25-dihydroxyvitamin
D are similar among race groups. The latter results from the
intrinsic properties of the renal enzyme l␣-hydroxylase,
which can compensate for wide differences in availability of
25-hydroxyvitamin D (348). Asian Indian individuals, who
have additional peculiarities in their vitamin D metabolism,
are particularly sensitive to the development of clinical
vitamin D deficiency, rickets and osteomalacia, when living
in areas with low levels of ambient sunlight (349).
The UVB light threshold that produced measurable syn-
thesis of vitamin D3 was 18 mjoules/cm2 in a population of
white subjects with similar cutaneous photosensitivity (skin
type III of the Fitzpatrick-Pathak classification; 1 MED⫽30
mjoules/cm2), although every dose tested was associated
with blood levels higher than baseline (350). Serum GC is
another factor involved in the availability of vitamin D3 that
could be race dependent. Thus, anthropologists have iden-
tified a large number of variants, each related to different
human populations. By isoelectric focusing, the observed GC
suballele frequencies appear to correlate with skin pigmen-
tation, but electrophoretically identical variants were also
found in populations widely differing genetically and geo-
graphically (351). From the functional point of view, there is
no evidence for differences in vitamin D binding among
those variants. Moreover, the serum concentration of GC is
similar across race groups that include blacks, whites, Ori-
entals, and Asian Indians (347).
3. Suntanning. In the setting of suntanning, vitamin D3 for-
mation is affected in a complex manner. As already men-
tioned, both previtamin D3 and vitamin D3 are photosensi-
tive substrates that, if irradiated continuously, undergo
further conversion to inactive metabolites while still in the
skin (14). Nevertheless, measurements performed in tanned
white subjects showed elevated vitamin D3 serum levels with
correspondingly higher serum 25-hydroxyvitamin D con-
centration (352). Acute exposure to UVB radiation resulted,
however, in attenuated serum vitamin D3 response, presum-
ably the result of acquired cutaneous melanization (352).
4. Aging. Elderly individuals have lower serum levels of
25-hydroxyvitamin D as compared with their younger coun-
terparts. This aging effect is due to progressive decrease in
epidermal 7– dehydrocholesterol substrate content (353). As
would be expected, acute irradiation with UVB in older sub-
jects results in blunted serum vitamin D3 responses (354).
5. Cutaneous disease. The only cutaneous disorders in which
vitamin D3 formation has been systematically studied are the
epidermal disease, psoriasis (355), and the connective tissue
disease, progressive systemic sclerosis (356). The latter, al-
though predominantly a dermal disorder, is often associated
with epidermal atrophy. Acute irradiation experiments in
these two groups of patients did show similar vitamin D3
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Vol. 21, No. 5
responses in patients and controls. Moreover, the responses
were unrelated to the extent of cutaneous involvement.
These results probably reflect the small fraction of irradiated
body surface required to sustain the normal vitamin D3 re-
quirements. A small fraction of vitamin D3 formation does
occur in the dermis (⬍10%), which has a much lower 7-DHC
content than the epidermis and is less exposed to the low-
penetrance shorter light wavelengths responsible for vitamin
D3 formation. As mentioned above, the dermal disease, pro-
gressive systemic sclerosis, even when widespread, does not
interfere with the vitamin D3 response to UVB (356).
D. Postcutaneous regulation
1. Obesity. Overweight appears to represent the only post-
cutaneous factor interfering with vitamin D3 photosynthesis.
Obese individuals have lower serum 25-hydroxyvitamin D
levels than lean controls and also have blunted response to
UVB. Oral absorption of vitamin D2 is also decreased in
obesity. In vitro experiments of irradiation of skin pieces from
obese and lean individuals showed similar epidermal 7-DHC
content and in vitro response to UVB. These results are sug-
gestive of defective translocation of the vitamin into the
circulation, or defective plasma transport (357). Of note, obe-
sity is also associated with increases in plasma FFA, which
can displace vitamin D3 from plasma vitamin D binding
protein (358).
E. General comments
An important consideration on the physiology of vitamin
D3 synthesis is that it represents a mostly biophysical reac-
tion. Thus, the serum vitamin D3 response to UVB is not
altered by the oral administration of pharmacological doses
of vitamin D2 (359) or of 1,25-dihydroxyvitamin D (360).
There are nevertheless local regulatory mechanisms that can
influence the process. When exposure to sunlight is exces-
sive, inactivation of previtamin D3 and vitamin D3 itself are
well known consequences. Moreover, when high irradiance
levels are sustained, melanocyte activity is enhanced, result-
ing in tanning and blunted response to acute UVB exposure.
The opposite situation, decreased exposure to UVB with
reduced vitamin D3 production, can be compensated, at least
partly, by enhanced activity of the renal 1␣-hydroxylase en-
zyme (348).
Lastly, there has been some controversy regarding the
significance of findings in acute vs. chronic studies evaluat-
ing the vitamin D response to UVB. Within this context, it
must be noted that acute studies are performed under more
stringent conditions, i.e., mostly during the winter, to prevent
the interference of ambient sunlight, which involves expo-
sure of the whole body to UVB, and require a phototherapy
unit that must be continuously calibrated. It is then apparent
that biological significance is better evaluated in larger pop-
ulations. Thus, small acute responses that do not reach sta-
tistical significance, such as those observed after selective
irradiance of the upper extremities or head and neck, or after
subthreshold doses of UVB, may still result in normal vita-
min D3 levels, when irradiation is continued through much
longer periods. A similar explanation would be operative in
October, 2000 NEUROENDOCRINOLOGY OF THE SKIN
black individuals, who show lack of response to acute UVB
irradiance, yet also exhibit the normal seasonal variance
(UVB dependent) in 25-hydroxyvitamin D serum levels
(361).
VIII. Final Comments and Future Directions
The present work provides a conceptual framework for the
organization of the cutaneous neuroendocrine system into
epidermal and dermal units. Further, it develops an under-
standing of the integrated pattern of regulation of those
endocrine units, and of the exquisite coordination in expres-
sion of their functional effects to achieve the best strategy for
dealing with the continuous interactions between skin and
environmental agents. Among the recently uncovered reg-
ulatory mechanisms are a myriad of precise interactions with
receptors for hormones, neurotransmitters, and neuropep-
tides, e.g., hypothalamic, pituitary, and steroid hormones,
PTH and PTHrP, vitamin D, neuropeptides, neurotrophins,
and with nicotinic, muscarinic, adrenergic, serotonin, and
glutamate neurotransmitter receptors, all widely expressed
in cutaneous compartments. Surprisingly, the source of li-
gands for these receptors is the skin itself, sometimes the
same histological compartment, or even the same cells. Thus,
the conclusive documentation now available demonstrates
that in addition to vitamin D3, the skin produces PTHrP,
CRH, urocortin, POMC-derived peptides, enkephalins, cat-
echolamines, acetylcholine, and neurotrophins. The skin is
also involved in steroidogenesis and sex hormone conver-
sion. Intriguing experimental data showing interconversion
of thyroid hormones, however, require further confirmation.
Existing data also justify further studies on cutaneous pro-
duction and metabolism of neurohormones serotonin and
melatonin and the neurotransmitters aspartate and gluta-
mate. Rapid and efficient communication between the dif-
ferent cutaneous compartments is provided by the existing
rich sensory innervation with its reservoir of neuropeptides
and neurotransmitters, affording a high degree of specificity.
A physiological role for this system is underscored by its
effects on systemic immunity, by the production of vitamin
D3 with its action on calcium homeostasis and bone miner-
alization, and by the generation of afferent neurogenic sig-
nals connecting the skin with the rest of the body. Concom-
itant functional studies have helped further clarify its
function by disclosing that cutaneous neuroendocrine sys-
tem activity can be effectively modified by exposure to com-
mon environmental factors such as solar radiation, by in-
trinsic signals such as those associated with hair cycling, by
biological modifiers (cytokines/chemokines), or by local or
systemic pathological conditions.
This field represents, therefore, a fertile ground for future
studies on cutaneous biology, including the application of
more advanced methodology to confirm previous findings;
the determination of other hormonal factors that could be
produced by the skin; and the further definition of existent
or yet-to-be-discovered regulatory pathways. Moreover, the
potential clinical implications cannot be overlooked, as this
area opens the possibility for multiple points of interaction
on ongoing pathological processes. Possible pathological tar-
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479
get conditions include not only inflammatory diseases, but
benign hyperproliferative skin disorders, vasculopathic and
autoimmune reactions, disorders of pigmentation and hair
cycling, and malignant processes such as melanoma devel-
opment and epidermal carcinogenesis. Specifically, locally
produced POMC peptides ACTH and ␣-MSH can affect skin
functions by enhancing melanogenesis, stimulating hair
growth and sebaceous gland functions, and attenuating in-
flammatory responses. CRH, in addition to its local vasodi-
latory and proinflammatory effects, may also inhibit prolif-
eration of epidermal keratinocytes. Vitamin D is already
used in the therapy of psoriasis, and glucocorticoids are
drugs of choice in the treatment of inflammatory skin dis-
orders. Finally, the multidirectional communication between
skin, endocrine, immune, and central nervous systems sug-
gests that the skin may be an important regulator of global
homeostasis acting as a sensor for external or internal dis-
turbances, and as an effector/producer of humoral or neural
signals sent to other coordinating centers. In this context, the
possibility of pathological consequences for dysregulation in
this cutaneous neuroendocrine system poses a powerful
challenge that can only be addressed with a strong, coordi-
nated, and multidisciplinary approach.
Acknowledgments
We thank Drs. C. Gomez-Sanchez, O. Johansson, W. B. Malarkey, J.
Orloff, M. F. Holick, S. Asa, D. L. St. Germain, S. Grando, T. Smith, E.
Wei, and L. Y. Matsuoka for their help in the preparation of the manu-
script. The excellent secretarial work of Ms. LuEllen Giera is acknowl-
edged.
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