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Departments of Medicine and Pediatrics, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637-1470
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Abstract |
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 Top Abstract I. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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The pilosebaceous unit (PSU) consists of a piliary component and a
sebaceous component. Each PSU has the capacity to differentiate into
either a terminal hair follicle (in which a large medullated hair
becomes the prominent structure) or a sebaceous follicle (in which the
sebaceous gland becomes prominent and the hair remains vellus) (Fig. 1a
). Androgens play a key role in the
development of the PSU in most areas of the body. In androgen-sensitive
areas before puberty, the hair is vellus and the sebaceous glands are
small. In response to increasing levels of androgens, PSUs become large
terminal hair follicles (sexual hairs) in sexual hair areas or they
become sebaceous follicles (sebaceous glands) in sebaceous areas.
Androgens appear to promote sexual hair growth by recruiting a
population of PSUs to switch from producing vellus hairs to initiating
terminal hair growth. PSU disorders, namely acne vulgaris, hirsutism,
and pattern alopecia, do not occur until after the processes of puberty
begin (5). However, it is clear that the pathogenesis of these
disorders involves more than androgen (1, 3). For one thing, although
the development of acne normally parallels the rise in androgen with
pubertal progression, acne wanes in the late teenage years while blood
androgen levels remain stable. For another, PSUs respond differently to
androgen depending on their location; e.g., sexual hairs
grow only in certain areas of the body, while hairs on the scalp
undergo regression from a terminal to a vellus type in genetically
susceptible individuals. In addition, acne, hirsutism, and alopecia are
variably expressed manifestations of androgen action, and the severity
of acne or hirsutism is quite variable for a given degree of androgen
excess. Furthermore, some women will develop acne or hirsutism at
normal levels of androgen (idiopathic acne or hirsutism), while at the
other extreme some women will have no manifestations of androgen excess
(cryptic hyperandrogenemia). All of these considerations indicate that
factors other than androgen play major roles in PSU development and in
PSU disorders.
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II. Embryology and Molecular Genetics of PSU Differentiation |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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PSU differentiation begins with formation of a dermal mesenchymal
condensation that sends a signal to the overlying embryonic epithelium
to "make an appendage here" (Fig. 2)
(6, 11). This results in downward growth of an epidermal plug to form a
skin appendage (6, 7). This initial message from the dermis to
epidermis is common to all classes of vertebrates. The epidermis
determines the type of appendage, directs its cephalo-caudal polarity,
and determines species specificity of keratin composition. For example,
mouse dermis can instruct the development of feather follicles in chick
epidermis. Some authors postulate that the epidermis sends the first
signal to the dermis and is responsible for the patterning of skin
appendages (12). Lymphoid-enhancing factor-1 (LEF-1), a DNA binding
molecule that acts by bringing together other DNA-bound transcription
factors, is expressed in the epidermis just before the formation of the
dermal mesenchymal condensations. Altering the expression of LEF-1 in
transgenic mice results in abnormal hair follicle distribution and
orientation (13, 14).
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The cells in the sebaceous anlagen are identical to those in the basal layer of the epidermis and the piliary canal. Most sebaceous glands arise in a cephalo-caudal sequence from hair follicles (15). The future common excretory duct, around which the acini of the sebaceous gland attach, begins as a solid cord. The cells composing the cord are filled with sebum, and eventually they lose their integrity, rupture, and form a channel that establishes the first pilosebaceous canal. Fetal sebaceous cells are quite large and functional and probably contribute to vernix caseosa.
Epithelial and mesenchymal cells appear to communicate during
morphogenesis, and these interactions seem to involve molecules or
"morphogens" that play a regulatory role in development. Likely
morphogens include growth factors, cell adhesion molecules,
extracellular matrix molecules, intracellular signaling molecules such
as ß-catenin and LEF-1, hormones, cytokines, enzymes and retinoids,
together with their receptors (16, 17). Growth factors such as
epidermal growth factor (EGF), transforming growth factor 
(TGF),
transforming growth factor ß (TGFß) and fibroblast growth factor
(FGF) affect the proliferation and differentiation of the cells of the
PSU during development (18). These growth factors appear to exert their
effects via autocrine or paracrine pathways between cell types. EGF was
the first growth factor to be implicated in hair development when it
was shown that its administration to newborn mice delayed hair follicle
development (19), and this effect occurred over the entire coat.
Furthermore, growth of the first coat of hair in newborn mice is
accelerated by the administration of antibodies to EGF (20). The EGF
peptide has been found in the outer root sheath and sebaceous gland in
later stages of follicular development in sheep skin (21). The EGF
receptor has been found in embryonic skin by autoradiography and
immunohistochemistry; however, it is present in the adjacent
interfollicular epidermis rather than the placode and hair germ (22, 23). In later development, the EGF receptors are expressed in the outer
root sheath and sebaceous epithelium, and in some species in the hair
bulb, but no EGF receptors have been demonstrated in the dermal papilla
(3). The specific distribution of EGF in skin and throughout follicle
morphogenesis suggests that this growth factor has a more important
role in differentiation than in proliferation (18). TGF, which is in
the EGF family and binds to the same receptor as EGF, has also been
found to inhibit murine hair growth (24). Several members of the TGFß
family (TGFß-1, ß-2, ß-3, bone morphogenetic protein-2, and bone
morphogenetic protein-4) have also been localized to various regions of
the developing PSU using in situ hybridization (25, 26). FGF
was also found to affect hair follicle initiation and development, but
the effects were confined to the area of treatment since FGF is not
readily diffusible in the skin (18). The FGF receptor 2 is likely to be
important in sebaceous gland development in humans, as a somatic
activating mutation of this receptor has been associated with localized
acne (27).
Cell adhesion molecules such as the cadherins, neural cell adhesion molecule (N-CAM), intercellular cell adhesion molecule (I-CAM), and tenascin are also thought to play a prominent role in PSU differentiation. Both E-cadherin and P-cadherin have been detected in developing follicles by immunohistochemistry (28). Whereas P-cadherin is expressed throughout the epithelium, E-cadherin is confined to cells in the presumptive matrix region. In studies of cultured lip skin, the addition of antibodies against E-cadherin and P-cadherin caused disruption of follicular development, and dispersal of the mesenchymal aggregate (3). Although both embryonic and fetal keratinocytes express E-cadherin, only embryonic keratinocytes express N-CAM, which is localized in the initial mesenchymal aggregate (6); N-CAM is probably important in cell adhesion and furthering cell aggregation. It is found in the dermal papilla and dermal sheath in the adult PSU (6). I-CAM is transiently expressed in the outer layer of the follicular cells, perhaps as a result of a signal from the condensing mesenchymal cells (6). Tenascin, an extracellular matrix protein, has been found to be expressed in the basement membrane underneath the hair germ, but not in the basement membrane between follicles (6). Tenascin is considered to be a marker for epithelial-mesenchymal interactions, but the exact function it plays in PSU development is not known.
Another molecule that may be important for PSU differentiation is epimorphin, which is a mesenchymal signal factor. Epimorphin is found in mesenchymal aggregates in embryonic rat skin and lung and may function in aggregative behavior of immature cells (29). Studies have shown that epimorphin can be detected in cell suspensions that have been aggregated by centrifugation, whereas it is not present in the same cells grown in monolayer. Other studies have shown that hair follicles fail to develop in embryonic skin cells cultured in the presence of antibodies to epimorphin (3). Other morphogens such as the wingless homolog Wnt and sonic hedgehog also seem important for the development and pattern of hair follicles (17, 30, 31).
Although more is being learned about the various molecules involved in cell-cell interaction within the PSU, these cells must be organized in a precise spatial and temporal order for proper function. The overall complexity of PSU morphogenesis indicates the involvement of multiple genes in a coordinated fashion, which suggests a role for homeobox (HOX) genes. HOX genes have been found to control the developmental fate of embryonic cells by encoding regulatory transcription factors that either induce or repress effector genes, which in turn are responsible for the position and development of each particular cell (32, 33).
The HOX genes are aligned in tandem as clusters arranged in a colinear
fashion on four different chromosomes (Fig. 3). They are transcribed in
"lock-step" with the first set of HOX genes being expressed
anteriorly (34). In humans, 39 HOX genes have been identified (33). The
HOX genes contain a homeobox, which is a highly conserved 180-bp DNA
sequence. Point mutations within the homeobox were discovered to be the
cause of "homeotic" malformations in fruit flies, i.e.,
malformations in which one body part develops looking like another. The
HOX genes encode monomer proteins with three -helices, with the
second and third helices being arranged in a helix-turn-helix
configuration. The homeobox encodes the highly conserved homeodomain,
which is thought to bind to specific areas of DNA of both HOX and
non-HOX genes to regulate transcription.
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Retinoic acid also plays an important role in PSU morphogenesis (see below), and the effects of retinoic acid on PSU development may be partly due to regulation of the pattern of expression of HOX genes by retinoic acid. Retinoic acid excess during a critical stage of mouse embryogenesis has been shown to cause abnormal development of hair follicles between the follicle peg and the bulbous follicle peg stage (38). Furthermore, retinoic acid stimulates sebaceous gland development and causes formation of a metaplastic branching tubular duct system from the developing follicle. Since retinoic acid alters the pattern of expression of HOX genes (34, 39), differential retinoic acid action on HOX gene expression within the PSU during embryogenesis may play a role in the subdivision of the PSU into its separate hair follicle and sebaceous gland components.
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III. Postnatal Growth and Development of the PSU |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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). The PSU at the telogen-anagen
transitional phase morphologically resembles the embryonic bulbous hair
peg. The dynamics of the hair growth cycle vary between species,
between different body sites in the same species, and between different
follicle types in the same body site (3). It is likely that hair
follicles have an intrinsic rhythmic behavior that is modulated by
systemic factors (3, 16). In man, these follicle cycles occur
independently, for the most part, with a superimposed modest summertime
peak of sexual and scalp hair growth, which may reflect changes in
androgen levels (42). The duration of anagen is the major determinant
of the length to which a hair grows, and it varies with the location of
the hair follicle. Mustache hairs grow for approximately 4 months and
scalp hairs for 3 yr. In contrast, the percentage of time scalp and
beard hairs spend in anagen only differs by about one-third. Other
factors influencing the amount of hair growth in various areas of the
body include the linear growth rate of the hair fiber, as well as the
diameter and density of the terminal hairs. Whereas shaving does not
induce hair growth, plucking a resting (telogen) hair causes an
advancement in the onset of anagen and thus induces hair regrowth (3, 43).
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There is evidence that PSU pluripotential stem cells reside in the bulge area of the outer root sheath, just beneath the sebaceous duct, and are capable of repopulating the hair matrix to the point where it will recapitulate ontogeny by reinducing the dermal papilla (47). This appears to be why the portion of the follicle about the sebaceous gland outlet is important for hair regeneration (48). Basal cells of the bulge form an outgrowth pointing away from the hair shaft and are therefore safeguarded against accidental loss due to plucking (41).
Changes take place in the dermal papilla during the hair growth cycle in terms of cell morphology, vascularization, and in composition and volume of the extracellular matrix (3). During late telogen the dermal papilla is pulled upward toward the bulge area. If the dermal papilla fails to ascend upward toward the bulge area during this phase, the follicle stops cycling and the hair is lost (49). This was deduced because mutations of the hairless gene, which encodes a transcription factor important for movement of the dermal papilla to the bulge area, results in permanent alopecia (50, 51). Stem cells of the bulge area are thought to be activated by dermal papilla cells, to which they respond by proliferating and growing down to push the dermal papilla away (41). Once the dermal papilla is pushed away, the bulge area becomes quiescent again. During anagen, the dermal papilla enlarges and develops an extensive extracellular matrix (3). At a given time, the anagen follicle receives a signal that terminates this phase and initiates catagen (see below). The catagen (regression) phase involves apoptosis (16, 52), which is associated with a decrease in volume of the extracellular matrix. In telogen the dermal papilla becomes a condensed ball of cells with almost nonexistent extracellular matrix located immediately below the lower pole of the follicular epithelium (3). There is a decline, and eventual cessation of mitotic activity in the extracellular matrix during telogen, and the matrix cells adjacent to the dermal papilla convert to lower outer root sheath cells. The hair becomes a club hair, which is eventually shed from the follicle to make room for new hair growth. The extracellular matrix becomes organized again around the papilla at the start of the next hair growth cycle (7). The dermal papilla has its own blood supply, and the capillary loops present in the dermal papilla in anagen are lost in telogen (3).
Multiple growth factors are ultimately involved with hair follicle growth and normal cycling including insulin-like growth factor-I (IGF-I), FGF-7 (also known as keratinocyte growth factor), FGF-5, and EGF. IGF expression is stimulated by androgen in dermal papilla cells, and IGF-I has been demonstrated to stimulate hair follicle growth in vitro (53). This suggests that some of the trophic effects of androgens on the hair follicle are mediated through growth factors such as IGF. IGF-I has also been shown to slow hair follicle entry into the catagen phase, which suggests that it is an important factor in control of the hair growth cycle (54). FGF-7 production has been found in the dermal papilla, and its receptor has been found in nearby matrix cells (55). When the FGF-7 receptor is disrupted in mice, the morphology of the hair follicles is abnormal and there are 60–80% fewer hair follicles present than in control mice (56). FGF-5 knock-out mice and mice with nonfunctional EGF receptors have long, fine angora-like hairs, due to an extended anagen phase, which suggests that these growth factors are potential signals that cause anagen to terminate and catagen to begin (43, 57, 58).
Hair grows through keratinocyte cell division, which takes place in the hair bulb close to the dermal papilla. The cells differentiate to form the various layers as they move up the follicle (59). Hair can thus be considered to be the holocrine secretion of the hair bulb. The mature hair consists of medulla, cortex, cuticle, inner root sheath (three layers), and outer root sheath. As matrix cells divide, they form keratin microfibrils, which mature in daughter cells in the upper bulb. At this point the keratin is 46–58 kDa in size. The hair shaft comes to consist essentially of solid packages of hard keratin fibrils embedded in an amorphous matrix. Accompanying this terminal differentiation of hair is the formation of larger keratins (53 and 63 kDa) in the shaft.
Keratins comprise more than 90% of hair proteins. Keratins are a group
of water-insoluble, cystine-containing proteins. Each hair fibril
consists of a bundle of coiled, low-sulfur keratins, which are in turn
bundled in an -helical pattern forming a coiled coil. The amorphous
matrix into which these bundles are imbedded contains high-sulfur,
lower molecular mass keratins. The molecular and biochemical
basis for the ultrastructural differences among the layers of hair is
unknown. Unlike scalp hairs, sexual hairs are curled around their axes.
Racial differences also affect such diverse features of hair as shape
and medullation. The concept of "donor dominance" was elucidated in
classic hair transplant studies (60), which indicated that these
structural differences were inherent in the PSU, i.e. hairs
retain the characteristics of their area of origin.
Before puberty, the androgen-dependent PSU consists of a prepubertal
vellus follicle, which consists of a virtually invisible hair and a
tiny sebaceous gland component (Fig. 1
) (1A ). Under the influence of
pubertal amounts of androgens, PSUs in sexual hair areas differentiate
in a distinctive pattern which depends on their location. Sexual hair
development is normally not seen before age 9 in girls (average age of
stage 3 sexual hair development, 12 yr) and age 10 in boys (average age
of stage 3 sexual hair development, 13 yr) (61). In the sexual hair
areas, a terminal hair follicle develops and the sebaceous gland
develops only moderately. In the balding-prone area of scalp, PSUs
respond to androgen in yet a different manner in individuals
predisposed to pattern alopecia. Terminal hair follicles that
previously grew without androgen gradually change with each growth
cycle to an intermediate kind of follicle in which the hair component
reverts to the vellus state, leaving an adult vellus follicle (Fig. 1).
These phenomena are reversed by antiandrogens: both types of
androgen-dependent PSUs revert toward the prepubertal state.
The most direct evidence that androgens are the principal hormones
controlling sexual hair growth is that androgens stimulate hair growth
in eunuchs and castration reduces it. The latter classic observation
illustrates the plastic nature of the PSU response to androgens,
i.e., the reversion from terminal to vellus follicles. The
sensitivity of sexual hair follicles to androgen is determined by their
pattern of distribution (1A ) and generally wanes from pubis to head
(Fig. 5), or from posterior to anterior
considering the embryogenesis of these PSUs. Thus, rising androgen
levels (such as occur either normally during puberty or abnormally in
hyperandrogenic states) recruit an increasing proportion of PSUs in a
given area to initiate the growth of terminal hair follicles, each in
accordance with its preset genetic sensitivity to androgen. The
apparent dose-response curve to androgen is fairly steep, with a
mustache typically appearing at plasma testosterone levels just
slightly above the upper limits of normal for women and the beard
requiring 10-fold higher levels for full growth. There is considerable
individual variability.
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In acne-prone areas, androgen causes the prepubertal vellus follicle to
develop into a sebaceous follicle in which the hair remains vellus and
the sebaceous gland enlarges tremendously. The sensitivity of sebaceous
glands to androgens seems to follow a different dose-response curve
than the hair follicle, with most sebaceous glands being highly and
similarly sensitive to testosterone. Sebum production is at its nadir
at about 4 yr of age and begins to increase at about 8 yr of age.
Microcomedones (1 mm or less in diameter), which form when desquamated
cornified cells of the upper canal of the sebaceous follicle become
exceptionally adherent and form a plug in the follicular canal, make
their appearance in about 40% of 8–10 yr olds. Thus, sebaceous gland
function begins before true puberty, at levels of testosterone below
those ordinarily required for the initiation of pubic hair growth (Fig. 6). This development corresponds with
adrenarche, the "adrenal puberty" marked by increasing production
of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-sulfate).
Seventy-five percent of the normal male amount of sebaceous gland
function is achieved at androgen levels normal for women. As for hair
growth, there is considerable individual variability in the degree of
sebum production to a given level of androgen. Although the apparent
dose-response curves above are given in terms of the major circulating
form of androgen, testosterone, other plasma androgens contribute to a
greater or lesser extent, as will be discussed.
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IV. Growth and Development of the PSU in Vitro |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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A. Organ culture
Organ culture has permitted the short-term study of growth and
development of hair follicles and sebaceous glands in vitro
without disturbing the natural close relationship between the stromal
and epithelial components of these structures (40, 67). Human hair
follicles isolated by microdissection have less stringent requirements
for maintenance and growth in culture than sebaceous glands (40).
Cortisol and insulin are necessary for optimal growth (72). Hair
follicles can be maintained in short-term organ culture while
maintaining their in situ morphology and growth at a normal
rate of about 0.3 mm/day (72, 73, 74). By day 14 in culture, the dermal
papilla rounds up and the follicle no longer produces a
keratinized hair fiber.
Human sebaceous glands isolated by microdissection can be maintained for up to 7 days in organ culture with full retention of their in situ morphology, rates of lipogenesis, and responses to steroid hormones (72, 75). Although they continue to form new cells at a normal rate until 14 days of culture, they do not differentiate normally after 7 days in culture unless phenol-red, an estrogen, is removed from the medium (67, 75). Insulin, cortisol, T3, and bovine pituitary extract are required for optimal maintenance of the human sebaceous gland in organ culture (72).
B. Monolayer culture
Monolayer culture has been used to study the specific factors
involved in the growth and development of hair and sebaceous epithelial
cells. However, monolayer culture is known to be incompatible with the
normal differentiation of skin epithelial cells (76). When epidermal
cells are grown in monolayer, they progress almost directly from basal
to a thin squamous cell layer without the intervening cell stages. On
the other hand, when epidermal cells are grown on an artificial dermis
(composed of 3T3 fibroblasts in a collagen lattice) lifted on a raft to
the air-liquid interface, development is virtually normal. The normal
balance between epidermal growth and differentiation in the lifted raft
system has been attributed to a retinoic acid gradient being
established at the epidermal-dermal junction (77). The nanomolar
concentration of retinoic acid in FCS inhibits normal orderly cell
maturation and the biochemical changes characteristic of terminal
differentiation in a submerged raft system. When rafts are lifted to
the surface of the medium, the level of retinoic acid falls in the
suprabasal layers, so differentiation progresses normally. If, however,
the retinoic acid concentration in the medium is raised in the lifted
raft system, epidermal differentiation becomes disturbed like that in
monolayer culture (78).
Hair and sebaceous epithelial cells are grown in epidermal type monolayer culture systems. Traditionally, this requires maintaining them in close contact with a stromal feeder layer consisting of 3T3-fibroblasts. For epidermal cells, the stromal growth factors have been identified and the requirements for growth in culture simplified: a collagen matrix or fibronectin are necessary for good plating efficiency, and insulin or IGF-I plus keratinocyte growth factor (FGF-7) are necessary for growth (79, 80). Hair and sebaceous epithelia have more stringent requirements for growth in primary monolayer culture. For sustained proliferation, most systems require a stromal support system and medium containing insulin, hydrocortisone, and cAMP-amplifying agent such as choleratoxin (72, 73, 81). Stromal support systems include 3T3 cells, nitrocellulose filters (72, 74), 3T3 cells mixed with collagen (76), and gelatin sponge supports (73). Although most previous studies have been done in the presence of serum, serum has been found to inhibit growth of hair follicles and to inhibit differentiation of sebaceous cells in culture (40, 73, 82). This may be due, in part, to inhibitory factors within serum such as TGFß (73). Only recently have chemically defined serum-free media become available that support growth of hair and epithelial cells.
Hair and sebaceous epithelial cells form typical polyhedral epithelial
cell colonies in culture, which resemble epidermal epithelial cell
colonies by light microscopy. Nevertheless, they can be identified as
unique epithelial cell populations by a variety of techniques. For
example, early-passage cells cultured from plucked anagen hairs have
the characteristics of outer root sheath cells according to
ultrastructural analysis and the pattern of expression of hair proteins
(83). They also have a pattern of testosterone metabolism that favors
androgen action (high ratio of 5-reductase to
17ß-hydroxysteroid dehydrogenase activities) compared with
epidermal cells (84). Dermal papilla cells, which themselves have a
distinctive profile in culture (85), are the only type of stroma known
to support the growth and early differentiation of putative hair germ
cells from epidermis (86). Fujie et al. (87) reported
recently that, by using specific growth medium containing bovine
pituitary extract, cells derived from human sebaceous glands could be
maintained in primary culture and serially cultured under serum free
conditions, without a biological feeder layer or specific matrices.
This effect was demonstrated in both explant culture and dispersed cell
culture. Sebocytes obtained from outgrowths (explants) from the
periphery of the gland lobules (88, 89) can be passaged twice in
monolayer culture without a stromal support system before rates of
sebocyte proliferation fall (72). Proliferation of these cells in
vitro has been found to depend inversely on the age of the donor
and also on the specific body site where the skin was isolated (88).
Recently, Zouboulis et al. (90) developed an aneuploid
immortalized human sebaceous gland cell line that maintains the
morphological and functional characteristics of normal differentiated
human sebocytes in the absence of a stromal matrix.
Our studies of sebocyte growth and development have used rat preputial sebocytes. The preputial glands of the rat are located on either side of the penis in the male, and the clitoris in the female. The secretions of the preputial gland are thought to play a role in both territorial marking and mating behavior. The preputial gland has been an attractive source of cells for the study of sebaceous cell growth and differentiation as the paired glands are easy to isolate because they are large and encapsulated, they are available on demand, and single cell suspensions at all stages of differentiation can be prepared for study (91). Although the preputial gland may have physiological functions beyond that of the human sebaceous glands, the gland is a holocrine organ, and preputial sebocytes resemble human sebocytes in many ways (81, 92, 93). Single cell suspensions are prepared from isolated preputial glands and plated on a mitomycin-C treated 3T3-J2 feeder layer. After attachment, sebocytes are cultured in a serum-free, chemically defined cell culture medium that permits definition of the factors regulating sebocyte proliferation and differentiation (82).
These sebaceous cells have been shown to exhibit a number of
differentiation characteristics in monolayer culture that are similar
to those of human sebocytes and distinguish them from epidermal cells.
Sebocytes form relatively slow-growing colonies (81, 94). They contain
a variety of keratins, including cytokeratin K4, which is localized to
suprabasal sebocytes and is constitutively expressed in culture (81, 88). Sebocytes also differ from epidermal cells by forming few
cornified envelopes in culture, as in vivo (Fig. 7, top panel) (81, 94). They
respond to ß-adrenergic treatment in vitro, as in
vivo, with a distinctive pattern of cAMP-regulatory subunit
predominance (95, 96). A striking difference between the behavior of
sebocytic and epidermal keratinocytes in culture is in their
differential response to the administration of
all-trans-retinoic acid (1A, 97). Retinoic acid causes
dose-dependent inhibition of sebocyte proliferation but does not have
an effect on epidermal cell growth (Fig. 7, bottom panel).
In contrast to its inhibitory effect on sebocytes, however, retinoic
acid appears to maintain the PSU duct (98). Sebocytes form
sebum-specific lipids such as squalene and wax esters (88). Although
fatty acid synthesis is greater in cultured sebocytes than in cultured
epidermal cells (88, 94), the amount of lipid is not enough to clearly
distinguish them from epidermal cells by light microscopy (99).
Electron microscopy reveals that sebocytes in monolayer culture form
abundant tiny lipid droplets, but they undergo only abortive
differentiation, with coalescence of these droplets in only a very few
cells at the center of colonies (Fig. 8) (1A ).
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V. Androgen Mechanism of Action in the PSU |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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) (105, 106, 107, 108). 3ß-Hydroxysteroid
dehydrogenase (HSD) is particularly prominent in sebaceous glands (109, 110). Type 2 17ß-HSD mRNA expression has been reported in outer root
sheath cells of cultured human hair, and type 3 17ß-HSD expression in
beard and axillary dermal papilla cells from both sexes (111). The
former favors inactivation of estrogen; the latter favors formation of
testosterone. The predominant 17ß-HSD isozyme expressed in human
sebaceous glands at both the mRNA and protein level is the type 2 form
(112). Furthermore, the oxidative activity (conversion of estrogen and
testosterone to less active precursors) of 17ß-HSD is greater in
sebaceous glands from non-acne-prone skin as compared with acne-prone
regions. A predominance of 5-reductase over 17ß-HSD activity
appears to favor DHT formation in sweat glands and in the outer root
sheath cells of pubic, as compared with scalp, hairs. In addition,
5-reductase is 2 to 4 times more active than 17ß-HSD in sebaceous
glands from facial skin (113). A summary of the localization of the
mediators of androgen signal transduction in the PSU is provided in
Table 2.
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-reductase, which is a
microsomal NADPH-dependent enzyme (114, 115, 116, 117). 5-Reductase was first
suspected to play a key role in androgen action when DHT was found to
be the predominant form of steroid bound to the androgen receptor in
prostate glands after the administration of testosterone (118, 119).
Testosterone and DHT stimulate 5-reductase mRNA and 5-reductase
activity, an effect mediated through the androgen receptor (116, 120, 121, 122). Two forms of 5-reductase exist, which are
differentially expressed in various tissues, likely as a result of
their respective promoters. They have different pH optima and
sensitivity to inhibitors. The two isozymes are approximately 46%
identical in sequence, have similar gene structures, are both
hydrophobic, and share similar substrate preferences (115, 116). The
type 2 isozyme is important for most androgen actions in sexual organs
(123), and a deficiency of 5-reductase type 2 in humans is a cause
of male pseudohermaphroditism (115, 124). However, the type 1 isozyme
is the major form of 5-reductase in skin.
Both 5-reductase isozymes are expressed at variable times in
development. Thigpen et al. (123) used immunoblotting to
demonstrate two waves of expression of the type 1 isozyme in human
skin, the first appearing at birth and lasting through age 2–3 yr and
the second beginning during puberty and continuing throughout life.
This suggested induction by androgens secreted perinatally and at
puberty. In contrast, there was just a single wave of expression of the
type 2 isozyme in skin, beginning at or just before birth and ending
around age 2–3 yr. Since they did not detect 5-reductase type 2
expression in adult skin, they postulated that the tendency to balding
may be programmed by the expression of the 5-reductase type 2 in
early life. However, the 5-reductase type 2 isozyme has been
localized by immunohistochemistry to hair follicles of human scalp;
specifically to the innermost portion of the outer root sheath and the
proximal inner root sheath (125). In addition, the 5-reductase
activity in the dermal papilla from beard resembles that of the type 2
isozyme in having an acidic pH optimum and a lower Michealis-Menten
constant than that of nonsexual hairs (101); this suggests that dermal
papillae of sexual hairs form more DHT than those of nonsexual hairs.
5-Reductase activity has been found in cultured fibroblasts from
sexual and nonsexual skin sites, in a distribution compatible with
regional specialization of mesenchymal cells with respect to this
important determinant of androgen action (1). 5-Reductase activity
is successively greater in fibroblasts cultured from nonsexual, pubic,
and genital skin (Table 3) (108). Further
studies found evidence for regional specialization of androgen
metabolism in sexual and nonsexual epithelial cell types. DHT formation
from testosterone in cells cultured from skin organelles increased in
the following order (%/mg DNA/min): epidermal (0.8%) < scalp
hair (2.8%) < pubic hair (8.1%) < foreskin fibroblasts
(71%) (84).
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-reductase has been found to be higher in sebaceous
glands of the scalp and facial skin than in other skin areas (106). The
type 1 isozyme is the major form of 5-reductase in the scalp, and
there are no obvious differences in type 1 isozyme expression between
balding vs. nonbalding areas of adult scalp according to
immunohistochemical studies (117, 123, 125). Within the scalp, the type
1 isozyme is localized primarily to the sebaceous glands, with lower
levels present in the hair follicle and dermis. Imperato-McGinley
et al. (126) found sebum production in patients with
5-reductase type 2 deficiency to equal that of normal males. This
suggested that either the male level of testosterone compensated for
the decreased DHT and was capable of sustaining sebum production or
that sebum production was under the control of the type 1 isozyme. The
type 1 isozyme is also the predominant isozyme in rat preputial
sebocytes (127). Androgens act after binding to the androgen receptor, which is a member of the subfamily of steroid hormone receptors that includes the progesterone, mineralocorticoid, and glucocorticoid receptors (128). At low concentrations, potent agonists of the androgen receptor facilitate interactions between the amino-terminal and carboxy-terminal regions of the androgen receptor, which stabilizes the receptor and likely causes a slowing of ligand dissociation from the receptor (129). Both testosterone and DHT bind to the same high-affinity androgen receptor, but they bind with different affinities and dissociation rate constants, have different efficacy in stabilizing the androgen receptor, and have different physiological roles (130). Once testosterone or DHT is bound to the androgen receptor, the substrate-receptor complex binds to the androgen receptor response element and regulates gene expression by acting as a transcription factor. The DHT-receptor complex appears to be the more effective complex at activating gene transcription (115) and may also be capable of activating genes that the testosterone-receptor complex cannot activate.
Androgen receptors in skin are primarily localized to dermal papilla,
sebaceous epithelium, and eccrine sweat epithelium according to
immunohistochemical analysis (131, 132, 133). They are also present in
lesser amounts in basal epidermal cells and scattered reticular dermal
fibroblasts. Successively greater numbers of androgen receptors have
been found in fibroblasts cultured from nonsexual, pubic, and genital
skin (Table 3) (108). It is unclear whether there is specific androgen
receptor immunoreactivity in the hair bulb or outer root sheath. In rat
preputial sebocytes, androgen receptor expression has been found to
increase with sebocyte differentiation (93). Androgen receptor mRNA
abundance seems to approach its maximum at the stage at which sebocytes
achieve competence for their specific pattern of lipid accumulation.
The dermal papilla cells are thought to be the primary target cells within the hair follicle that mediate the growth-stimulating signals of androgens, by releasing growth factors that act in a paracrine fashion on the other cells of the hair follicle (16, 134). Studies by Itami et al. (135) support this concept. These workers reported a stimulatory effect of androgen on the growth of beard hair epithelium in monolayer culture. However, as with outer root sheath cells grown from other sexual hairs (84), androgen did not directly stimulate the growth of outer root sheath cells, nor did androgen affect the growth of beard dermal papilla cells. However, when beard outer root sheath cells and beard dermal papilla cells were cocultured, androgen stimulated the growth of the beard epithelial cells, and antiandrogen countered this effect. Furthermore, dermal papilla cells cultured from androgen-sensitive (beard) hair follicles not only have more androgen receptor binding sites than do those from less androgen-sensitive (scalp) sites (134), but the dermal papilla are also larger (42). Saturation analysis revealed more androgen receptors in dermal papilla cells cultured from balding scalp, as compared with nonbalding scalp, which supports the hypothesis that androgens work via the dermal papilla cells (136).
The mode of androgen action on sebocyte proliferation is unclear. Akamatsu et al. (137, 138) reported a direct stimulatory effect of androgen on the growth of passaged human sebocytes in monolayer culture. In addition, there is evidence that the effect of testosterone and DHT on human sebaceous cell proliferation depends on the area of skin from which the glands are obtained. In one system, proliferation of sebaceous cells obtained from facial skin was stimulated up to 50% in a dose-dependent manner by both testosterone and DHT, whereas in sebaceous cells isolated from the extremity, testosterone had no effect at all, while DHT had only a small effect (137, 139). Furthermore, spironolactone, which exhibits antagonistic activity to androgens at a cellular level, inhibited sebocyte proliferation, thus supporting a receptor-mediated effect (139). In another system, the androgen effect on proliferation of facial sebaceous cells was maximized (50% increase) at about 10-9 M and lost at 10-7 M (87). On the other hand, androgen has an inhibitory effect on preputial sebocyte proliferation in primary monolayer culture (140). It is unclear whether these different effects are due to variances in culture technique or species differences.
Androgens have been shown to stimulate the differentiation of
sebocytes, although this effect is modest in vitro (75, 141). However, androgen augments the differentiative effect of
peroxisome proliferator activated receptor-
(PPAR). Recent
research also suggests important postreceptor interactions of androgen
with retinoic acid derivatives and GH.
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VI. Role of Peroxisome Proliferator-Activated Receptors in Sebocyte Development |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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We found that PPAR activators induced lipogenesis in rat sebocytes
in vitro (141), although in vivo studies had not
shown the systemic administration of the PPAR activators, clofibric
acid (144) or eicosatetraynoic acid (145), to stimulate sebum activity.
PPARs have been shown to regulate multiple lipid metabolic genes in
peroxisomes, microsomes, and mitochondria by acting on PPAR response
elements (146, 147). PPARs were originally identified as part of a
subfamily of "orphan receptors" within the nonsteroid receptor
family of nuclear hormone receptors (148). There are three PPAR
subtypes: , 
, and . Activation of PPAR and by their
respective specific ligands, the thiazolidinedione rosiglitazone and
the fibrate WY-14643, induced lipid droplet formation in sebocytes but
not in epidermal cells. Linoleic acid and carbaprostacyclin, both
PPAR and ligand-activators, were more effective but less
specific, stimulating lipid formation in both types of cells. Either
was more effective than the combination of PPAR and activation,
suggesting that PPAR is involved in this lipid formation. Linoleic
acid 0.1 mM stimulated significantly more
advanced sebocyte maturation than any other treatment, including
carbaprostacyclin, which was compatible with a distinct role of long
chain fatty acids in the final, terminally differentiated stage of
sebocyte maturation. When DHT was added with the PPAR activators, an
additive effect on lipid droplet formation in sebocytes was seen only
with the combination of DHT and a PPAR activator (Fig. 10). This suggests that PPAR
influences a step in sebocyte differentiation which is related but
distinct from that influenced by androgen.
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1 mRNA was demonstrated in sebocytes, but not in epidermal
cells; it was more strongly expressed in freshly dispersed than in
cultured sebocytes. In contrast, PPAR mRNA was expressed to a
similarly high extent before and after culture in both sebocytes and
epidermal cells. These findings are compatible with the concept that
androgen-enhanced PPAR1 gene expression plays a unique role in
initiating the differentiation of sebocytes, while activation of
constitutively expressed PPAR by long-chain fatty acids finalizes
sebocyte maturation. Since increased sebum production is an important element in the pathogenesis of acne vulgaris (149, 150), the finding that PPARs appear to mediate sebocyte cytoplasmic lipid accumulation may have implications for the treatment of acne. It may be feasible to develop PPAR antagonists that can interfere selectively with sebum formation without invoking the side-effects of currently available treatment modalities.
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VII. Retinoid Effects on the PSU |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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Retinoids have profound effects on sebaceous gland activity. Whereas trace amounts promote sebocyte growth and differentiation, larger doses cause atrophy of sebaceous glands and a decrease in sebum secretion in both animals and humans (64, 65, 69, 154). Retinoids have been postulated to inhibit lipid synthesis in sebocytes either directly, through an inhibition of lipogenic enzymes, or indirectly, by decreased cell proliferation (155). Retinoids have been used for the treatment of acne vulgaris for a long time although the precise mechanism for their efficacy has not been completely elucidated.
Retinoids act via specific nuclear receptors that belong to the
superfamily of nuclear receptors (which include steroid receptors and
PPARs) and act as ligand-dependent transcriptional regulators (128, 148). There are two classes of retinoid receptors, the retinoic acid
receptor (RAR) and the retinoid X receptor (RXR) (156, 157). Each class
of receptor contains three subtypes: , ß, and (128, 158). The
expression of retinoid receptors is tissue-specific. Whereas sebaceous
glands express predominantly RXR and RAR in mice and humans
(159, 160, 161), RARß is highly expressed in cultured dermal papilla cells
from human scalp hair follicles (162).
Two distinct cellular retinoic acid binding proteins (cRABPs) have been found, which may serve to regulate the intracellular level of retinoic acid and thus further regulate retinoid action (152). cRABP-I is postulated to enhance the metabolism of retinoic acid to inactive derivatives and thus limit the retinoic acid-specific action that hinders cell differentiation, and cRABP-II may facilitate retinoic acid signal transduction (152).
All-trans-retinoic acid, the natural ligand of RAR, acts after binding to RAR and also acts via its metabolism to 9-cis-retinoic acid, which is the natural ligand for RXR (128, 163, 164, 165). Activation of these selective receptors shows distinct biological effects on different cell types. However, the mechanisms underlying the divergent effects of RAR and RXR activation are unclear (166, 167). It has been suggested that they activate different signaling pathways, regulate the expression of distinct target genes, and/or have opposing effects on the same target gene (147, 168, 169, 170). Unlike RAR, which functions only when heterodimerized with RXR, RXR functions by forming either homodimers or heterodimers with other ligand-regulated receptors including PPARs, thyroid hormone receptor, and vitamin D receptor (171, 172, 173, 174, 175). RXR thus has been termed a master regulator since it functions as a key regulator of the activity of several nuclear receptors. The heterodimerization of RXR with one nuclear receptor may limit its ability to heterodimerize with other receptors if the quantity of RXR is limited. Homo- or heterodimers bind to retinoic acid response elements on DNA, typically in the promoter regions of susceptible genes, and thus control the transcription of specific genes. The characterization of retinoic acid response elements has revealed a complex pattern of retinoid recognition and activation (128, 148). Potential retinoid receptor-dependent signaling pathways that mediate cell proliferation and differentiation include those pathways involved in the induction of apoptosis and regulation of multiple growth factors and metabolic enzymes (147, 166, 167, 168, 169, 170, 176, 177, 178).
Previous studies using all-trans-retinoic acid have not been
able to discern the individual actions of each receptor as
all-trans-retinoic acid acts on both RAR and RXR receptors.
It has not been entirely clear which of the retinoid receptor pathways
is involved in the specific processes of sebocyte growth and
development. Recently, however, we tested selective RAR and RXR
ligand-activators and their antagonists for their effects on preputial
sebocyte growth and development (179). RARs (especially the ß - or
-subtypes) mediate both the antiproliferative and
antidifferentiative effects of retinoids. However, RXRs had prominent
differentiative and weak proliferative effects. Therefore, the
antiproliferative and antidifferentiative effects of
all-trans-retinoic acid are probably mediated by RARs,
whereas its differentiative effect at high dose may be mediated by RXRs
via all-trans-retinoic acid metabolism to
9-cis-retinoic acid. The stimulatory effects of the specific
RXR ligand on sebaceous cells suggested that the RXR effect may be
related to the ability of RXR to heterodimerize with PPARs (141).
Indeed, our preliminary data suggest that a low dose of RXR ligand
augments the sebocyte response to activating ligands of PPARs (180).
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VIII. Roles of Nonandrogenic Hormones in PSU Development |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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Several observations suggest that GH and IGF play a role in PSU growth
and development. GH replacement augments the amount of sexual hair
growth in response to testosterone in panhypopituitary children (Fig. 11) (181). In addition, GH substitution
in adult GH-deficient men has been found to enhance androgen effects on
hair growth (182). Furthermore, there may be a positive association
between high IGF-I levels and the likelihood of vertex baldness in men
(183). Acne vulgaris, a sebaceous gland disorder, increases at puberty
when GH as well as androgen levels are rising (1). However, acne peaks
in midadolescence and then normally wanes while androgen levels remain
high. This course corresponds less closely to plasma androgen levels
than it does to GH and IGF-I levels (184), suggesting an effect of GH
and IGFs on sebaceous gland development. In addition, the GH excess of
acromegaly is known to be associated with excess output of sebum
(seborrhea) (185).
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GH is an important factor for organ growth and cell differentiation (189). After binding to the GH receptor, it has both direct effects as well as indirect effects through IGF production (190, 191, 192). The IGFs make up a family of peptides that are partly GH dependent and mediate many of the mitogenic and anabolic actions of GH (190, 192).
The GH receptor has been found in hair follicles and the acini of sebaceous glands by immunohistochemistry (193, 194, 195, 196). IGF-I has also been detected in hair follicles (197), with the IGF-I receptor being localized to the outer root sheath and matrix cells of the hair bulb (198). IGF-I has been localized to the peripheral cells of the sebaceous gland in normal rat skin by immunohistochemistry (197). This location of IGF-I corresponds with the position of the basal, highly mitotic cells of the gland. These observations support the possibility that GH and IGFs are trophic factors acting directly on hair follicles and sebaceous epithelium.
IGF-I at physiological doses is essential for hair follicle growth
in vitro (54, 73). IGF-I prevents hair follicles from
entering catagen and thus may be an important physiological regulator
of hair follicle growth and the hair growth cycle (73). During the rat
hair growth cycle, a marked decrease in IGF-I receptor expression is
found during late anagen and early catagen (199), suggesting that a
potential signal for hair follicles to enter catagen is a decrease in
IGF-I receptor expression. Furthermore, IGF-I may mediate some of the
androgen effects on PSUs, by inducing the up-regulation of
5-reductase by DHT in genital skin fibroblasts (200). IGF-I is 10
times more potent than IGF-II in stimulating hair follicle growth (54).
Insulin may be directly involved in hair growth as hair growth can be retarded in diabetes mellitus and accelerated by insulin treatment (201). Insulin is one of many additives required for optimal growth of many epithelial cell types in culture (72, 81, 202); in high doses it has been found to be necessary for fat cell differentiation, where it likely serves as a key regulator of lipid biosynthetic enzymes (203, 204). Insulin may act as an IGF-I surrogate as it has approximately 50% amino acid homology to the IGFs (205, 206, 207), and it binds to the IGF-I receptor at high concentrations (208). Insulin at supraphysiological doses is essential for hair follicle growth in vitro (54, 73), and in the absence of insulin, hair follicles prematurely enter into a catagen-like state in vitro (54, 209). Insulin in high dosage stimulates sebocyte proliferation in culture (140, 210).
Our data in preputial sebocytes indicate that GH, IGFs, and insulin
have distinct effects on sebaceous cell growth and differentiation
in vitro (140). GH stimulates differentiation of sebocytes
yet surprisingly has no effect on DNA synthesis (Fig. 12). GH also augments the effect of DHT
on sebocyte differentiation, an effect that is beyond that found with
IGFs or insulin (Fig. 13). In contrast,
IGF-I exerts its major effect on proliferation, while having an effect
similar to insulin on differentiation (Fig. 12). Insulin in
supraphysiological doses is an important factor in sebocyte
differentiation, and dose-response considerations suggest that its
effect of potentiating the GH induction of differentiation exceeds that
expected from its action as an IGF-I surrogate (Fig. 14). These data indicate that GH may in
part exert its metabolic effects on sebocytes directly rather than
indirectly through IGF production. These data are consistent with the
concept that increases in GH and IGF production contribute in
complementary ways to the increase in sebum production during puberty
and in acromegaly. The exact mechanism by which GH affects sebocyte
differentiation is not completely understood, and much remains to be
clarified in the chain of events after GH stimulation.
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Estrogen prolongs the growth period of scalp hair by increasing cell proliferation rates and postponing the anagen-telogen transition (214). Estrogen in low dosage stimulates pubic and axillary hair growth slightly. This is clear from observations that pubic hair increases upon inducing puberty in hypogonadal patients with physiological doses of estradiol alone (215). This occurs without a detectable increase in plasma androgens. It is possible that this effect of estrogen on hair growth is mediated in part by induction of androgen receptors (216), or by increase in IGF-I (217). In late pregnancy, when estrogen levels are high, a high proportion of scalp hair follicles remain in anagen (218). Postpartum, a large number of hair follicles simultaneously advance into telogen, causing loss of a large number of hairs. This postpartum telogen effluvium has been postulated to be caused by the rapid decrease of estrogen at the time of delivery (219). On the other hand, estrogen directly suppresses sebaceous gland function (1, 3, 75, 220, 221). An estrogen effect is clear at ethinyl estradiol doses of 35 µg/day or more (222).
Prolactin plays a role in PSU function as indicated by the development of hirsutism and seborrhea in hyperprolactinemia in women. To a great extent this PRL effect is mediated by its stimulation of adrenal androgen production (223). However, Wielgosz and Armstrong (224) reported in 1977 that PRL caused a significant increase in preputial gland weight in hypophysectomized, ovariectomized immature rats, suggesting that PRL acts directly as a sebotropic hormone. This may be a somatotrophic effect. However, PRL receptors have been localized to the dermal papilla and sebaceous glands in sheep skin (225).
Other hormones thought to be important in PSU growth and development include thyroid hormone and catecholamines. Thyroid disturbances lead to changes in hair character and growth. Hypothyroidism causes scalp hair to become dull and brittle. A diffuse alopecia occurs with a greater proportion of hair follicles in telogen (226, 227). Replacement treatment typically reestablishes the normal anagen/telogen ratio (227). Hyperthyroidism can also lead to diffuse hair loss (201). Thyroid hormone has also been shown to stimulate sebum secretion in hypophysectomized/castrated rats (228). Thyroid hormone receptors have recently been localized to the outer root sheath, dermal papilla, and sebaceous gland in human PSUs by immunohistochemistry (229, 230). Studies using RT-PCR have indicated that the ß1 isoform is the major isoform expressed in the adult human PSU (230). Furthermore, the addition of T3 to culture media causes the proliferation of outer root sheath and dermal papilla cells (229). Catechols are leading candidates as important natural activators of cAMP pathways. Epinephrine has been reported to rapidly stimulate sebocyte lipogenesis (96), so it may be involved in the aggravation of acne by stress.
The PTH-related protein (PTHrP), the vitamin D receptor, and melanocortin-5 receptor also play roles in PSU development. PTHrP is produced by cells of the inner root sheath of the hair follicle, and treatment of mice with an antagonist of this protein increases the number of hair follicles in the anagen phase (231). Furthermore, PTHrP knockout mice have shaggy hair and hypoplastic sebaceous glands (232), while mice with PTHrP overexpression in skin fail to initiate or have a delay in hair follicle development and have hyperplastic sebaceous glands (232, 233). The vitamin D receptor has been found to be expressed in the outer root sheath and dermal papilla of hair follicles and in sebaceous glands (234, 235). Mutations of the vitamin D receptor have been associated with alopecia in humans (236). Furthermore, vitamin D receptor knock-out mice also develop alopecia starting at 1 month of age (237). Histology of the skin of these knock-out mice reveals dilatation of the hair follicles and development of dermoid cysts. When the mineral status of these mice is normalized by dietary supplements, alopecia still occurred, which suggests that the abnormality in the vitamin D receptor mediates the alopecia (238). The melanocortin-5 receptor is a widely distributed receptor for ACTH and melanocortin peptides. Targeted disruption of this receptor leads to a decrease in sebaceous lipid production and a defect in water repulsion in mice, indicating the importance of the melanocortin-5 receptor in sebaceous gland function (239).
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IX. PSU Pathophysiology in Hirsutism, Acne Vulgaris, and Pattern Alopecia |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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A. Hirsutism
Hirsutism is typically defined as excessive male-pattern hair
growth in women. This definition distinguishes hirsutism from
hypertrichosis, which is the term reserved to describe the
androgen-independent growth of body hair which is vellus, prominent in
nonsexual areas and most commonly familial or caused by metabolic
disorders (e.g., thyroid disturbances, anorexia nervosa,
porphyria) or medications (e.g., phenytoin, minoxidil, or
cyclosporine). The degree of hirsutism can be graded by the method of
Ferriman and Gallwey (Fig. 15), whereby
each of the nine body areas that are most hormonally sensitive are
assigned a score from 0 (no hair) to 4 (frankly virile) and the scores
are summed. A total score of 8 or more is abnormal for adult Caucasian
women. Thus, it is normal for women to have a few terminal hairs in
most of the "male" areas. Although the Ferriman-Gallwey scale is a
useful clinical scoring systems, it does have its limitations. It does
not take into account the fact that clearly abnormal amounts of hair
growth may be confined to only one or two areas without raising the
total hirsutism score, it does not weight the face appropriately to its
cosmetic importance, and it does not allow one to grade the sideburn or
neck areas, although these are the areas that are usually worrisome
cosmetically. Furthermore, it omits grading of hair on the perineal and
buttock area, which can be a source of embarrassment to affected women.
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To better delineate the relationship between hirsutism and androgen
levels, we have related hirsutism score to plasma free testosterone
(Fig. 16) (242). Influences of race and
age were minimized by confining the study to Caucasian females 18–21
yr of age. There was a striking variability of the relationship between
hirsutism score and the plasma free testosterone concentration.
Although plasma free testosterone was significantly elevated in those
with mild hirsutism (hirsutism score 8–16), it was normal in half the
subjects. To look at it another way, among women with modest elevations
of plasma free testosterone (up to 2-fold), 22% had moderate hirsutism
(hirsutism score 17–25), 43% had mild hirsutism, and 35% had none.
All four moderately hirsute women in this study had elevated plasma
free testosterone. The variation in the plasma free testosterone
concentration within the mildly hirsute group was twice as great as
could be accounted for by the normal episodic, diurnal, and cyclic
variations in plasma free testosterone. This suggested that more than
half of the variability in the response of the population to androgen
was independent of the plasma free testosterone concentration. It is
possible that differences among individuals with respect to other
plasma androgens could make the difference. However, only one of the
seven hirsute women with a normal plasma free testosterone had an
elevated plasma DHT level and that was minimally abnormal. This
supports the theoretical consideration which suggested that the
contribution of other plasma androgenic steroids to hirsutism appears
to be relatively low (108). These data illustrate the marked
variability in the relationship of hirsutism to plasma free
testosterone. We concluded that mild hirsutism is associated with
hyperandrogenemia in half of cases, and that the great majority of
women with moderately severe hirsutism are hyperandrogenic.
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The pathogenesis of acne is thought by most to commence with plugging of the outlet of the sebaceous gland with desquamated cornified cells of the upper canal of the follicle. These cells become abnormally adherent, thus interrupting the normal process of shedding and discharge through the follicular orifice, and a hyperkeratotic plug is formed. The more severe stages of acne are the consequences of obstruction and impaction, with bacterial secondary infection of static sebum occurring in an anaerobic environment. P. acnes is an anaerobic diphtheroid that is a normal constituent of the cutaneous flora and populates the androgen-stimulated sebaceous follicle. It is not present on the skin in an appreciable amount until the onset of puberty (244), and skin of acne-prone patients has a greater population of this bacteria than those without acne (245). P. acnes causes hydrolysis of triglycerides to liberate FFA as irritants, as well as releasing chemotactic factors that attract neutrophils, which cause further damage and eventual rupture of the follicular wall (246).
A closed comedone takes 2 months to form from its precursor lesion, the
microcomedone (149). Inflammatory acne, consisting of papules,
pustules, nodules, and cysts, is a later phenomenon that develops from
comedonal acne. Although inflammatory lesions may be fewer in number
compared with comedones, these are what usually lead patients to seek
treatment (247). Inflammatory acne may leave deep physical and
psychological scars. A clinically useful acne grading system is shown
in Table 4.
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) (242). Furthermore, acne severity did
not correlate with free testosterone levels.
DHEA-sulfate also plays a role in acne through its conversion to more
potent androgens that stimulate sebum production. Prominence of
3ß-hydroxysteroid dehydrogenase in sebocytes (109, 110) permits DHEA
to be a prominent prohormone for DHT formation within skin. Plasma
DHEA-sulfate is likely the most important androgen for the initiation
of comedonal acne in early puberty, as it rises first (4). Marynick
et al. (250) found that DHEA-sulfate plasma concentrations
correlated specifically with cystic acne. Excessive DHT formation in
skin has also been implicated in the pathogenesis of acne vulgaris
(100, 251), suggesting that activity of 5-reductase may also play an
important role.
When the onset of inflammatory acne is early (before age 8) or late (in the third decade), persists beyond the teen years, is resistant to appropriate therapy, flares severely with the menstrual cycle, or is accompanied by hirsutism or oligomenorrhea, underlying hyperandrogenism should be suspected (242, 252). However, acne alone, even comedonal acne alone, may be due to androgen excess (242, 248). Thus, minor or mild acne can be the sole manifestation of hyperandrogenemia.
C. Pattern alopecia
Pattern alopecia is the androgen-dependent thinning of hair that
occurs progressively with advancing age in genetically susceptible men
and women. However, it can begin as soon as the early teenage years.
The process is mainly the result of miniaturization of terminal to
vellus hair follicles (Fig. 1). There is also moderate loss of PSUs
with time and often moderate inflammatory changes with perifollicular
lymphocytic infiltration (253). The androgen dependency of pattern
alopecia was initially deduced on the basis of eunuchs not suffering
from male pattern hair loss unless they are given replacement
testosterone (254). Pattern alopecia is generally thought to be
distinct from the diffuse thinning of scalp hair associated with aging.
However, Whiting found a 10% loss of hair follicles in the
transitional zone of balding in men with pattern alopecia (personal
communication). Thus, it remains possible that pattern alopecia may
partially be due to an accentuation of the normal process of hair loss
associated with aging. In men, pattern alopecia typically presents as
temporo-occipital pattern (male-pattern) balding (Fig. 17) (255). In female pattern alopecia,
the thinning typically begins with involvement of the crown of the
scalp (rather than the vertex and bifrontal areas as in men) and may
become fairly diffuse (Fig. 18) (256).
Women can have isolated pattern alopecia or seborrhea with neither
hirsutism nor acne, with a clear elevation of plasma free testosterone
(257). Pattern alopecia can be psychologically devastating in both
sexes.
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D. PSU sensitivity to androgen
We have devised a model for the interaction between intrinsic PSU
sensitivity to androgen and plasma androgen levels in the pathogenesis
of hirsutism, acne, or pattern alopecia (Fig. 19) (1). In this model, the apparent
sensitivity of the skin to androgens is as great a factor, if not
greater, than the plasma androgen level in determining the skin
manifestations of androgen excess. The variability in the response to
androgen may be both quantitative (severity) or qualitative (hirsutism
and/or acne and/or alopecia). Indeed, in some women, hyperhidrosis
(i.e., excessive sweat gland function) may be the only skin
manifestation of androgen excess (264). At a normal plasma free
testosterone concentration, only a small percentage of women will have
hirsutism or acne, those with a high apparent skin sensitivity to
androgen being identified clinically as having idiopathic hirsutism or
acne. We advocate reserving the term "idiopathic hirsutism" for
those patients in whom excessive growth of terminal hair is not
explained by androgen excess. In this sense, we believe that hirsutism
is either hyperandrogenic or idiopathic. (Parenthetically, this
terminology distinguishes idiopathic hirsutism from "idiopathic
hyperandrogenism," in which the source of androgen excess can not be
localized to the ovaries or adrenal glands (265), an entity that is
often confused with idiopathic hirsutism). At a modestly elevated
plasma free testosterone concentration (up to 2-fold), most women will
have hirsutism or acne, but in a few cases there will be no skin
manifestations. This variability would seem to be the basis of the
cryptic hyperandrogenemia reported to occur with mild hyperandrogenic
states, such as polycystic ovary syndrome and nonclassic congenital
adrenal hyperplasia (266, 267, 268). At moderate elevations of free
testosterone (over 2-fold), virtually all women will have some degree
of hirsutism and/or acne.
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-reductase activity and 5-reduced testosterone metabolites are
related to hair growth (269), and increased 5-reductase activity has
been demonstrated in skin of hirsute women (as compared with nonhirsute
women) (270), as well as in sebaceous glands of acne-prone skin (271).
In addition, greater 3ß-hydroxysteroid dehydrogenase activity has
been found in sebaceous glands from balding scalp than nonbalding scalp
(102). Furthermore, many authors have postulated that androstanediol
glucuronide and other androgen conjugates are biochemical markers of
cutaneous androgen metabolism and action (272, 273), and these levels
are elevated in hirsute women (273, 274). Toscano et al.
(274) found variations in androgen metabolism in patients with
hirsutism as compared to those with acne. Hirsute women had higher
levels of 3-androstanediol and its glucuronide, whereas women with
acne alone had levels similar to the control group. This suggested that
the presentation of hirsutism or acne was dependent on differential
skin metabolism of androgens. However, Rittmaster (275, 276) has
reviewed evidence that counters this hypothesis and strongly suggests
that androgen conjugates are more likely to be markers of adrenal
steroid production and metabolism than of skin metabolism. This
controversy is still under debate. In summary, the expression of two
separate clinical manifestations of PSU disorders may be due to
different metabolic fates of DHT itself. Alternatively, these findings
may simply be explained by the fact that sebaceous and sweat glands are
the skin organelles with the highest 5-reductase activity and that
they undergo varying degrees of hypertrophy in hyperandrogenic states. There are associations of hirsutism and acne with hyperprolactinemia (223), acromegaly (277), and insulin-resistant states (278, 279, 280, 281). The hirsutism in these states has been generally thought to be mediated by hyperandrogenism. Two considerations suggest that insulin-like growth factors also likely play a direct role. First, GH and IGF-I directly promote PSU growth and/or differentiation. Second, hirsute patients with adrenal hyperandrogenism reportedly have an increase in IGF-I levels, while those with ovarian hyperandrogenism have decreased levels of IGF binding protein-3, which would seem to enhance IGF-I bioavailability (282).
The possibility that variations in androgen receptor expression are related to PSU responsiveness seemed unlikely from early studies (283). However, recent investigations have reopened the question by examining the length of the polymorphic CAG repeat in exon 1 of the androgen receptor (which can affect receptor activity) and the imprinting status of the androgen receptor (as the androgen receptor is subject to X chromosome inactivation) in hirsute and nonhirsute females (284, 285, 286). No correlation was found between the number of CAG repeats and the presence or absence of hirsutism (284, 285, 286). Whereas Vottero et al. (285) reported that hirsute patients had skewing of X chromosome inactivation with the shorter of the two alleles of the androgen receptor (the most active) being significantly less methylated, a recent larger study by Calvo et al. (286) showed no evidence of skewed X chromosome inactivation in hirsute women. Thus, neither the number of CAG repeats in the androgen receptor gene nor skewed X chromosome inactivation is likely to play a role in variable PSU responsiveness to androgens.
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X. The Role of Hormonal Treatment in PSU Disorders |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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).
Typically, 9–12 months of treatment are needed to judge the efficacy
of a given treatment on hair growth, because of the long duration of
the hair growth cycle, and 2–3 months may be needed to see the full
effect of treatment on acne.
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The estrogenic component of most oral contraceptives currently in use is either ethinyl estradiol or mestranol. The choice of a specific oral contraceptive should be predicated on the progestational component as many progestins have some androgenic potential. Ethynodiol diacetate has a relatively low androgenic potential, while progestins such as norethindrone, norgestrel, and levonorgestrel are particularly androgenic (291), as can be judged from their attenuation of the estrogen-induced increase in SHBG level (292). Norgestimate exemplifies the newer generation of progestins that are virtually nonandrogenic (293) and seems to be the progestin of choice for treatment of hyperandrogenic women (222).
In clinical trials of estrogen-progestin therapy, the extent of hair growth, based on shaving frequency, is improved in half of women (294). This treatment can be expected to arrest progression of hair growth and reduce the need for depilation procedures.
Estrogens also have a direct, dose-dependent suppressive effect on sebaceous cell function, with a uniform effect on acne at a dose of 100 µg/day. Recent studies have demonstrated that treatment of women with moderate acne with oral contraceptives containing 35 µg of ethinyl estradiol in combination with norgestimate improves the extent of acne by 50–70% (222, 295). Indeed, an oral contraceptive pill combining these agents (Ortho-Tri-Cyclen, Ortho Pharmaceutical Corp., Raritan, NJ) has recently been approved for the treatment of acne in women by the Food and Drug Administration.
Chronic administration of GnRH agonists suppresses pituitary-ovarian function, thus inhibiting both ovarian androgen and estrogen secretion. These agonists have been reported to be effective in the treatment of hirsutism (296, 297). However, because of the concomitant reduction of serum estrogen levels and reductions in bone mineral density observed when GnRH agonists are used alone (298, 299), it is unwise to use these agents for longer than 6 months. It has been suggested that "add back" therapy in which estrogen and progestin replacement is prescribed in conjunction with a GnRH agonist may be effective in treating androgen excess without the side effects of hypoestrogenemia (300). This therapy would seem to be useful as an alternative to oral contraceptives in women who cannot tolerate the high estrogen dose of a contraceptive pill.
Ketoconazole, a synthetic imidazole antifungal agent, inhibits multiple steps in the biosynthesis of testosterone (301, 302). In doses of 400 mg per day for 6 months it has been demonstrated to have a moderate salutary effect on acne and hirsutism. However, side effects are relatively frequent and include nausea, dry skin, pruritis, and transaminase elevation (303).
Glucocorticoid therapy can be helpful in those women with hyperandrogenism from an adrenal source, as adrenal androgens are more sensitive than cortisol to the suppressive effects of glucocorticoids (304). Glucocorticoids are the mainstay of treatment of the adrenal androgen excess of CAH, but appear to be less effective in other forms of functional adrenal androgen excess (305, 306). Prednisone in doses of 5–10 mg at bedtime is usually effective in suppressing adrenal androgens while posing minimal risk of the sequelae of glucocorticoid excess such as adrenal atrophy, weight gain, and decreased bone mineral density. We do not advocate the use of dexamethasone because it is difficult to prevent long-lasting Cushingoid striae even with doses as low as 0.5 mg daily. DHEA-sulfate levels are used to indicate the degree of adrenal suppression; the target is a level of approximately 70 µg/dl. It has been suggested by some that antiandrogen therapy in the form of cyproterone acetate (307) or spironolactone (306) is at least as effective as glucocorticoid for the treatment of hirsutism due to adrenal androgen excess (see below).
A number of therapies are available to interfere with the action of
androgens at the target organ level. This is accomplished by either
inhibiting the binding of testosterone or DHT to the androgen receptor
or by inhibiting the conversion of testosterone to DHT by
5-reductase. Antiandrogens currently available include cyproterone
acetate, spironolactone, and flutamide, while finasteride is available
as a 5-reductase inhibitor. These agents can be expected to reduce
the Ferriman-Gallwey score by approximately 15–40% in 6 months with
considerable variations between studies and between individuals (308, 309). All of these agents must be used with adequate contraception in
women to prevent the possibility of genital ambiguity in a male fetus.
Antiandrogens act by competitively inhibiting binding of androgen to the androgen receptor. Ebling et al. (310) examined several hair parameters to ascertain which might best shed light on the effect of antiandrogen given in combination with ethinyl estradiol. Shaved thigh hairs were examined in one hirsute woman. Their diameter decreased by 33%, length by 50%, and medullation by 90%. In contrast, the linear growth rate decreased by only 10%. Subsequent studies confirmed a modest decrease in the diameter of sexual hairs (311, 312) and indicated that antiandrogens act primarily by decreasing the density of anagen hairs (312). In response to antiandrogen treatment a marked (65–75%) decrease in the density of anagen hairs accounted for a decrease in the overall density of plucked hairs by 24%. Thus, these data indicate that antiandrogens reverse hirsutism primarily by inhibiting the initiation of the growth of sexual hair follicles, with the result that the remaining PSUs revert toward the vellus type.
Cyproterone acetate is the prototypic antiandrogen. It was developed as a potent progestin and was found to be a moderately potent antiandrogen and a weak glucocorticoid. It acts mainly by competitive inhibition of the binding of testosterone and DHT to the androgen receptor (313). It has the added benefit of suppressing ovarian androgen secretion and subsequently lowering serum testosterone, and, in addition, it may act to enhance the metabolic clearance of testosterone by inducing hepatic enzymes. It is an effective treatment for hirsutism and acne (314, 315, 316). Although not available for use in the United States, it is widely used throughout Canada, Mexico, and Europe. Because of its potent progestational activity and its prolonged half-time, it is administered in a "reverse sequential" manner: cyproterone acetate, 50–100 mg per day, from day 5 to 15 of the cycle with ethinyl estradiol in a dose of 35–50 µg per day from day 5 to 26 of the cycle (315). The dose of cyproterone acetate may be reduced incrementally at 6- month intervals. Diane (2 mg of cyproterone acetate with 50 µg of ethinyl estradiol) is effective in maintaining improvement in milder cases of hirsutism, and Dianette (2 mg of cyproterone acetate with 35 µg of ethinyl estradiol) (Schering, Berlin, Germany) is a leading therapy for the treatment of acne in women. Side effects of cyproterone acetate include irregular uterine bleeding, nausea, headache, fatigue, weight gain, and decreased libido.
The spironolactone metabolite canrenone binds competitively to the androgen receptor with 67% the affinity of DHT (317). It also works as a weak inhibitor of testosterone biosynthesis and a weak progestin, especially at higher doses. The antiandrogen properties are seen when the drug is given at high doses of (100–200 mg daily, in two divided doses). Several studies have demonstrated the efficacy of spironolactone in the treatment of hirsutism and acne (318, 319, 320, 321, 322) and a potential benefit in pattern alopecia (323). It may be possible to reduce the maintenance dose after the maximal effect has been achieved. The side effects of spironolactone tend to be dose-related (308), possibly because of its structural relationship to progesterone (324). The most common side effect is menstrual irregularity; thus, it is often helpful to use an oral contraceptive along with spironolactone to regulate the menstrual cycles. Other less common side effects of spironolactone include nausea, dyspepsia, fatigue, and breast tenderness. Patients should be monitored for hyperkalemia, hypotension, and liver dysfunction.
Flutamide is a potent nonsteroidal antiandrogen marketed for prostate cancer. It has no progestational, estrogenic, corticoid, antigonadotropic, or androgenic activity (325). Flutamide is typically used at a dose of 125–250 mg twice daily with or without the addition of an oral contraceptive. Its clinical efficacy has been shown to be similar to spironolactone (320). Trials using flutamide in women with hirsutism and acne have demonstrated a marked improvement in hirsutism and complete clearing of acne (326, 327). Flutamide is not extensively used for the treatment of hirsutism because of its expense and the possible side effect of hepatocellular toxicity (328). However, it must be noted that a recent prospective, randomized trial comparing low-dose flutamide, finasteride, ketoconazole, and combination cyproterone acetate-ethinyl estradiol demonstrated relative superiority of flutamide and cyproterone acetate-ethinyl estradiol in the treatment of hirsutism (329).
Finasteride, a 4-aza-steroid, is an inhibitor of the type 2
5-reductase that converts testosterone to DHT. Many studies have
demonstrated some degree of efficacy of finasteride in treating
hirsutism (309, 321, 322, 330, 331). It has recently received Food and
Drug Administration approval for the treatment of pattern alopecia in
young men. Kaufman et al. (332) showed that an oral dose of
1 mg daily leads to a gradual 16% increase in scalp hair count and
slowing of the progression of hair loss over 2 yr in most men with
male-pattern hair loss. However, 14% of treated men had no response.
Finasteride at this dosage has been shown to have no effect on
spermatogenesis or semen production in young men (333). This low-dose
finasteride treatment has been shown to decrease both scalp skin and
serum DHT levels (334). Preliminary studies in postmenopausal women
show little benefit of low-dose finasteride treatment on pattern
alopecia (335).
There is considerable current interest in the possible role of insulin-lowering agents in the therapy of hyperandrogenism because of the evidence that hyperinsulinemia may play a critical role in the pathogenesis of the hyperandrogenism of polycystic ovary syndrome (PCOS), the most common cause of female hyperandrogenism. The insulin excess produced by resistance to the glucose-metabolic effects of insulin seems to amplify the androgen response to trophic hormones in the ovary and adrenal cortex and to cause acanthosis nigricans (336, 337). It is also possible that the insulin-IGF-I system acts in concert with androgen to stimulate PSU development, as reviewed above.
Several different modalities have been used to lower insulin levels in PCOS. These include weight loss (338), metformin (339, 340, 341, 342, 343, 344, 345, 346, 347, 348), thiazolidinediones (349, 350, 351), and D-chiro-inositol (352). To a greater or lesser degree, all of these insulin-lowering maneuvers lower plasma androgen levels. The extent to which these effects are translated into improvement in hirsutism or acne remains to be determined.
Metformin is a disubstituted biguanide that improves glucose tolerance usually in association with moderate reductions of serum insulin levels (353, 354). Although there is modest improvement in glucose disposal rate with metformin, the primary mechanism of action appears to be in its effect on reducing hepatic glucose output (355). A number of studies that examine the effects of metformin in women with PCOS have been published (339, 340, 341, 342, 343, 344, 345, 346, 347, 348). These studies vary widely in design (dose of metformin, duration of treatment, methods of assessment of insulin resistance, etc.). While there is an inconsistent effect of metformin on carbohydrate metabolism and androgen secretion across these studies, on balance there does appear to be a modest benefit from metformin treatment in PCOS, particularly when weight loss can be achieved.
Thiazolidinediones are a class of antidiabetic drugs that improve the
action of insulin in the liver, skeletal muscle, and adipose tissue
(356). The first of these to become available for clinical use was
troglitazone (which has recently been replaced in the market by
rosiglitazone and pioglitazone). In contrast to the effects observed
with metformin, troglitazone has a major impact on glucose disposal
rate, with a modest effect on hepatic glucose output (355). As such,
thiazolidinediones are most appropriately viewed as a true insulin
sensitizing agents. There is a high degree of concordance in the
findings of the published studies in which troglitazone was
administered to women with PCOS (349, 350, 351). Importantly, the metabolic
profile was improved in such a way as to lower cardiovascular risk
factors. Furthermore, troglitazone has also been recently shown to
enhance ovulatory function in PCOS (350). The attenuation of
hyperinsulinemia is associated with improvement of hyperandrogenemia in
obese women with PCOS. The effect on acne will be of particular
interest since this class of agents would seem to have potentially
counterbalancing effects on sebaceous cell function, with suppression
of insulin and androgen levels tending to lower sebum output and direct
PPAR activation tending to increase it.
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XI. Conclusions |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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, and less directly with many other
factors, to stimulate sebocyte differentiation (Fig. 20). Retinoids are important factors in
PSU development. They not only regulate aspects of embryonic
development through regulation of homeobox genes, but they exert
ongoing effects on the PSU. In sebocytes, RARs appear to mediate the
suppression of growth, while the RXRs appear to stimulate
differentiation via their interaction with PPARs. IGFs and insulin play
important roles in PSU development. IGF-I is essential for hair
follicle growth and sebocyte growth in vitro. Insulin in
high doses substitutes for IGF-I and seems to exert effects on sebocyte
differentiation beyond its effect as an IGF-I surrogate. GH promotes
both sexual hair growth and sebocyte differentiation in response to
androgen, and its effect in the latter regard seems to be direct, not
mediated by IGF-I. Many other hormones, such as glucocorticoids,
estrogen, and thyroid hormone, play roles in PSU growth and
development, but their exact roles remain to be elucidated.
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Footnotes |
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References |
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TopAbstractI. IntroductionII. Embryology and Molecular...III. Postnatal Growth and...IV. Growth and Development...V. Androgen Mechanism of...VI. Role of Peroxisome...VII. Retinoid Effects on...VIII. Roles of Nonandrogenic...IX. PSU Pathophysiology in...X. The Role of...XI. ConclusionsReferences |
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