ARTICLE
Inheritance
A genetic predisposition is a characteristic feature of AGA. The pattern
of inheritance is still considered by some authors to be consistent with
an autosomal dominant transmission [2]. However, the relatively strong
concordance of the degree of baldness in fathers and sons is not consistent
with a simple Mendelian trait and a polygenic basis is today considered
to be most likely [3, 4]. The predisposing genes are still unknown and
the genes for type 1 and type 2 5alpha-reductase (5alpha-R) are not associated
with the inheritance of AGA [3, 5]. Recently it has been postulated that
polycystic ovaries (PCO) in females and early onset AGA in brothers of
those women are associated with one allele of the steroid metabolism gene
CYP17 which affects androgen production or action [6, 7]. Another suceptibility
gene for PCO has been linked to a polymorphism of the insulin gene [8].
In man, mutations in the androgen receptor (AR) gene have clinical implications
and shorter so called CAG-repeat lengths within the AR gene may be associated
with the development of androgen-mediated skin disorders in men and women
[9]. However, the AR gene is located on the X chromosome and does not
explain father-to-son inheritance [3]. On the other hand, we recently
described individuals suffering from adrenoleukodystrophy which is an
X-chromosomal recessive trait. Although affected men tend to have low
T serum concentrations, one of the clinical hallmarks is a severe AGA-like
hair loss with early onset. We therefore hypothesized that one of the
AGA-predisposing genes might be the x-linked gene for adrenoleukodystrophy
[10].
Animal models
Several animal species have been reported to develop hair loss resembling
human AGA, including bears, lions, red deer and non-human primates. Most
of these models are rather impractical. A well-studied non-human baldness
model, however, is the stump-tailed macaque which represents a protected
species. These macaques have been used to assess the efficacy of several
compounds to treat androgenetic hair loss, such as minoxidil, systemic
5alpha-reductase (5alpha-R) inhibitors and topical androgen receptor blockers
[11]. In male Spraque-Dawley rats it has been shown that the hair growth
of the dorsal coat appears to be androgen-dependent. Castration of male
rats resulted in an accelerated entry into anagen III, whereas supplementation
of T inhibited this process. The hair shafts of castrated rats appeared
to be thicker and hair loss was not observed [12]. Transplanting miniaturized
HF from AGA (vellus hairs) onto nude mice has been tried in order to assess
the effect of several drugs on the hair cycle and on growth characteristics
of these hairs [13]. Another approach is to transplant HF from androgen-dependent
sites of the scalp (frontal hair) onto testosterone conditioned nude mice
and to measure the hair cycles of these HF [14].
The above mentioned experimental approaches rely on human hair affected
by AGA and transplanted onto nude mice. Other scientists investigate androgen-dependent
hair growth in rodents. Relevant mutations in rodents are genetically
transmitted and, thus, can be propagated. Mutant mice can be grown in
large colonies and are widely recognized as valuable animal models for
human disease. At present only one strain of mice has been described to
display an AGA-like hair loss. This hair loss can be aggravated by infusion
of testosterone or DHT and is on the other hand treatable with minoxidil
or cyproterone acetate [15, 16].
Pathogenesis
More than 50 years ago Hamilton observed that men who were castrated
did not develop AGA [17]. Therefore it was concluded that the growth of
hair follicles is in some areas androgen-dependent (Table
I). At present it is unknown how androgens exert their paradoxical
effect on the growth of HF at different body sites, and which genes are
involved. However, Hamilton already showed that AGA can be triggerd in
castrated men by injecting testosterone. The androgen-dependent nature
of AGA is furthermore demonstrated by the lack of frontal recession in
androgen-insensitive men who lack functional androgen receptors [18],
by the inducibility of AGA in the stump-tailed macaque by T [19], by hair
regrowth in women after removal of an androgen-secreting tumor [17], and
by the inhibition of ex vivo hair growth by T [20].
No or minimal beard growth or AGA is seen in pseudohermaphrodites who
lack 5alpha-R, indicating that DHT, the 5alpha-reduced metabolite of T
is the principal mediator of androgen-dependent hair loss. Interestingly,
5alpha-reduced metabolites of T are increased in balding areas of the
human scalp [22] as well as in the scalp of the stump-tailed macaques
[19]. It is not yet clear whether DHT is derived from the local metabolism
or from the circulation, but it can be assumed that under the influence
of DHT hair loss is characterized by a shortening of the anagen phase
and miniaturization of the hair follicle, which results in thinner and
shorter hair.
There is considerable support for the idea that the HF size is determined
by the size of its DP [23]. Van Scott [24] demonstrated a constant geometric
correlation between the proportions of the human HF, the DP and the hair
bulb matrix. They concluded that the size of the DP ultimately dictates
the size of the growing hair [25]. The size of the DP itself is dependent
on the total number of DP cells [26] and not on the volume of the extracellular
matrix. Hence, in AGA some DP cells will get lost. The most likely mechanism
is by apoptosis, but cell displacement might be an additional explanation.
Androgen metabolism (AM)
and hair growth
Androgens are required in males for the development of normal genitalia
in utero and with the beginning of puberty they become necessary
for the libido and secondary sexual characteristics as well as for maturation
and growth of the male muscle mass. Moreover, they are involved in the
pathogenesis of hair disorders such as hirsutism and AGA.
The AM can be divided into glandular and extraglandular production,
transport, target cell metabolism and cellular response. The AM of adrenals
and gonads and the influence of the pituitary gland are beyond the scope
of this review and are described in detail elsewere [27]. The pathway
of AM begins with cholesterol which is converted to pregnenolone. Following
alpha-hydroxylation at the C17-position, the action of the enzyme C17-20
lyase cleaves distal carbon moities, leaving a C 19 carbon steroid with
a C-17 ketone in the distal ring. These "17-ketosteroids" make up a group
of relatively weak androgens, such as dehydroepiandrosterone (DHEA), defined
by their relatively low affinity to the AR. Approximately 75% of DHEA
and 95% of DHEA-S is derived from the adrenal gland. These weak androgens,
however, can be enzymatically converted to more potent androgens such
as T which is the major circulating androgen. In the HF the principial
pathways involved in conversion of weak to more potent androgens are through
activity of the enzymes 3beta-hydroxysteroid dehydrogena-se/DELTA5=>4-isomerase
(3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). In most
target organs T can be further metabolized to DHT via the action of 5alphaR
(Fig. 1). The affinity
of DHT to the AR is approximately five-fold higher than that of T. Potent
androgens such as T or DHT can be removed by conversion to weaker androgens,
or they can be metabolized via the aromatase to estrogens, or they can
be glucuronidated to form androgen conjugates that are more rapidly cleared
from the circulation. Remarkably, some target tissues show enhanced AM
and androgen sensitivity [27]. For the sebaceous glands in balding skin
it has been shown that they express increased 3beta-HSD activity when
compared to nonbalding scalp areas [28]. If target cells convert weak
androgens at an accelerated pace, then there will be enhanced conversion
of T to DHT. Another reason for the increased sensitivity of a target
to androgens is believed to involve an increase in the number of AR. Only
a small fraction of androgens exist as free steroids in the circulation,
with an equilibrium between free hormones and protein-bound androgens.
The most important protein for androgen binding is sex-hormone binding
globulin (SHBG). Normally approximately 70% of T is bound to SHBG, 19%
to albumin and only the remainder is unbound. Whether the bound fractions
are still metabolically active is a matter of controversy [29], but the
binding of androgens to SHBG is an important factor of AM because it acts
somehow as a "sink" for circulating T.
Like all steroid hormones, androgens exert their effects by binding
to an intracellular receptor, the AR. Binding of androgens to their AR
leads to conformational change of the AR-androgen complex (ARAC) which
is then transported into the nucleus where it can bind to DNA which has
distinctive binding sites: androgen-responsive elements (ARE). A rather
wide variety of proteins have this ARE encoded in their DNA. In this way
androgens are able to modulate the transcription of various genes, that
may be activated or suppressed.
The principal elements of the androgen metabolism can be summarized
as follows:
Androgen-dependent processes are not the result of the summation of
the activity of individual metabolites, but are solely due to the binding
of DHT and translocation of the receptor to the nucleus.
DHT-dependent cell functions will only be initated or will be amplified
if:
i: enough weak androgens are present for conversion;
ii: more potent androgens are formed via the action of 5alpha-R;
iii: the enzymatic activity of androgen inactivating enzymes is
rather low: e.g. aromatase;
iv: backconversion of weaker steroids to DHT takes places by e.g.
3alpha-HSD;
v: functionally active AR are present in high numbers.
That this simplified concept is valid is illustrated by mutations of
androgen metabolizing genes, where often a lack of potent androgens can
be observed leading to disturbed masculinization or to intersexuality.
Lessons to be learned
from steroidogenic enzyme mutations
The synthesis and regulation of steroidogenic enzymes requires an orchestrated
expression of biosynthetic enzymes in various tissues. Deficiency of one
of these enzymes results in disturbed synthesis of one or more classes
of hormones. The likely effects on health have been reviewed by White
[30]. Here, some genetic diseases affecting male sexual development and
hair growth will be described.
Steroid sulfatase (STS)
The skin is capable of synthesizing active androgens, such as DHT, from
the systemic precursor DHEA-S. The first step in this pathway is the desulfatation
of DHEA-S by the enzyme steroid sulfatase (STS). Because DHEA is further
metabolized to androstendione, T and in special target tissues eventually
to DHT, STS is an important enzyme for the conversion of the weak adrenal
androgens to more potent androgens in the periphery. DHEA-S is believed
to maintain axillary hair [31] and is thought to be involved in the pathogenesis
of hirsutism [32] in women. In women, however, excess of DHEA-S or the
STS metabolite is believed to be involved in several androgen-dependent
processes such as acne and AGA [33]. Remarkably, DHEA-S and DHEA plasma
levels seem to correlate with balding in young men [34].
3beta-hydroxysteroid dehydrogenase/delta5=>4-isomerase
(3beta-HSD)
The 3beta-HSD isoenzymes catalyze an obligatory step in the biosynthesis
of androgens, estrogens, mineralocorticoids and glucocorticoids. The enzyme
is expressed in the adrenal cortex and in steroidogenic cells of the gonads,
as well as in many other tissues, such as the liver and kidney. The two
3beta-HSD isoforms are expressed in a tissue-specific manner involving
separate mechanisms of regulation (Table
II).
The importance of the 3beta-HSD in male steroid hormone physiology is
underscored by a genetically determined deficiency that is transmitted
as an autosomal recessive trait and is characterized by varying degrees
of salt wasting. Fetal testicular 3beta-HSD deficiency causes undervirilized
male genitalia (pseudohermaphroditism); women exhibit either normal sexual
differentiation or mild virilization. 24 mutations have been identified
in 25 distinct families with 3beta-HSD deficiencies [36], leading to slightly
different clinical phenotypes. All mutations were detected in the type
II 3beta-HSD gene, which is expressed almost exclusively in the adrenals
and gonads. No mutation was detected in the type I 3beta-HSD gene, which
is expressed in peripheral tissues. Whether hair growth is affected in
these individuals has not been investigated so far, but because of the
importance of 3betaHSD in the AM and increased activity in AGA [28] this
question warrants further investigation.
17beta-hydroxysteroid dehydrogenases (17beta-HSD)
Isoenzymes of 17beta-HSD regulate levels of bioactive androgens and
estrogens in a variety of tissues. At present five isoenzymes of 17beta-HSD
that differ in tissue expression and requirements of cofactors such as
NADPH for type III 17beta-HSD, and NAD(+) for type 2 17beta-HSD are known
(Table III). The importance
of the type 3 enzyme in male steroid hormone physiology is underscored
by the genetic disease 17beta-HSD deficiency. Mutations in the type 3
17beta-HSD gene impair the formation of testosterone in the fetal testis
and give rise to genetic males with normal male Wolffian duct structures
but female external genitalia very similar to the abnormalities seen in
5alpha-R deficiency. These individuals are usually brought up as females,
but at puberty there is a striking rise in testosterone and they change
their social sex. To date, more than 18 recessive mutations have been
identified, giving rise to different clinical phenotypes. To our knowledge
the presence or absence of AGA has not been investigated so far. However,
potential significance of 17beta-HSD isoenzymes in AGA is underscored
by observations of Hodgins et al. [37] who plucked hair follicles
from young adults not yet expressing AGA but with a strong family history
of baldness and found two populations, one with high 17beta-HSD activity
and one with low enzyme activity. This study suggests that low enzyme
activity may be related to lesser degrees of balding. Therefore, linkage
of the genes coding for the 17beta-HSD isoenzymes and AGA warrants further
investigation.
5alpha-reductases (5alpha-R)
The microsomal enzyme steroid 5alpha-R is responsible for the conversion
of testosterone into the more potent androgen dihydrotestosterone and
the conversion of androstenedione to 5alpha-androstanedione (Fig.
1). 5alpha-R deficiency is a rare autosomal recessive trait that
was first described by Nowakowski and Lenz [39]. In 1974 it became clear
that these individuals lack functional 5alpha-R [40] and today we know
that the type 2 5alpha-R is lacking [41]. Several mutations of the gene
that encodes the type 2 5alpha-R have been described, but not every mutation
will result in complete deficiency of the enzyme. Therefore, the clinical
presentation of patients with 5alpha-R deficiency varies considerably
[42]. In typical cases, a 46, XY male who has testes, normal plasma T
and low DHT levels are observed. At birth a male ejaculatory system that
terminates in a blind-ending vagina can be recognized together with a
microphallus and a non-fused scrotum and maldescended testes. Therefore,
these individuals display a female phenotype and are usually brought up
as girls. However, many affected individuals who were brought up as females
undergo a dramatic change of social sex at the time of expected puberty.
They will have spermiogenesis, ejaculations and male-type sex drive. Interestingly,
no or minimal beard growth or AGA is seen in these men. These observations
together with the finding that both humans and stump-tailed macaques have
beard and frontal scalp HF with higher 5alphaR activity than HF from the
occiput [19, 43] indicates that the type 2 5alphaR is crucially involved
in the pathogenesis of androgen-dependent hair growth and therefore the
inhibition of this isoenzyme is a rational approach for treatment.
Today two distinct isoforms designated type 1 and type 2 have been cloned.
Subsequently it has been shown that both isoenzymes have distinct molecular,
biochemical and tissue expression characteristics (Table
IV). In humans mutations in the gene coding for the type 1 5alpha-R
have not been reported. In mice, however, a mutation in this gene will
cause early fetal death because of estrogen excess in utero [62,
63].
Aromatase
The cytochrome P450 aromatase enzyme is required for bioconversion of
androgens to estrogens. Only a single human gene encoding aromatase P450
(CYP19) has been isolated. Mutations in the CYP19 gene do occur rarely
and result in aromatase deficiency. Girls show pseudohermaphrodism at
birth. At puberty, they develop virilization, pubertal failure with no
signs of estrogen actions, hypergonadotropic hypogonadism, polycystic
ovaries on pelvic sonography, and a tall stature. Males are rather tall
with eunuchoid skeletal proportions. Their bone age is retarded and osteopenia
can be observed, indicating that estrogens are crucially important for
bone development. At puberty females will develop hirsutism due to an
androgen excess and in theory females and males might develop early onset
AGA.
Localization of steroidogenic enzymes and the
androgen receptor within the hair follicle
Steroid sulfatase (STS)
A study implying that there is no STS activity in the hair follicle
was conducted with plucked follicles. However, the conversion of DHEA-S
to DHEA by human HF is now well documented by Dijkstra et al. [45]
but the exact localization within the HF is so far unknown.
3beta-hydroxysteroid dehydrogenase/delta5=>4-isomerase
(3beta-HSD/delta5=>4-i)
Homogenates of the isolated glands (ex vivo) exhibited besides
17beta-HSD and 5alpha-R activities also high 3beta-HSD/DELTA5=>4-i
activity which was highest in the sebaceous glands isolated from HF affected
by AGA [28]. Immunohistochemical studies confirmed these results showing
that 3beta-HSD/DELTA5=>4-i is located only in the sebaceous
gland and only the type 1 3beta-HSD/DELTA5=>4-i is believed
to be present in the skin [46]. However, plucked HF (without sebaceous
gland) ex vivo also exhibit marked 3beta-HSD/DELTA5=>4-i
activity [47,48] and detectable mRNA in outer root sheath keratinocytes
[49]. Therefore it can be assumed that this enzyme is present in the HF
as well. Which kind of HF cells express a specific type of 3beta-HSD/DELTA5=>4-i
isoenzyme is unknown.
17beta-hydroxysteroid dehydrogenases (17beta-HSD)
Very early it was shown that plucked human HF or HF from the stump-tailed
macaques express considerable 17beta-HSD activity [48, 50] because the
principle metabolite of T is androstenedione (Fig.
I). The isoenzyme-specific expression pattern in different parts
of the HF has not been investigated in detail mainly because of technical
problems. Only one study described the type 1 and 2 17beta-HSD in the
epithelial parts of the HF [49]. The authors did not find mRNA for 17betaHSD
in the DP.
5alpha-reductases
Early studies have revealed that plucked human hair follicles (HF) are
able to convert testosterone (T) to the more potent androgen dihydrotestosterone
(DHT) via the action of the enzyme 5alpha-R [47, 51-55]. Even in individuals
lacking type 2 5alpha-R some 5alpha-R activity can be measured in isolated
HF [56] indicating that an additional isoenzyme must be present. Recently,
the presence of both type 1 and type 2 5alpha-R within human HF has been
demonstrated [22] but the intrafollicular localization of both isoenzymes
remains controversial. Some authors were unable to find considerable 5alpha-R
activity in occipital scalp DP [57-60], whereas others found this enzyme
in the beard and occipital scalp DP [61, 62]. Recently we were able to
show that the main metabolic activity of type 2 5alpha-R can be detected
in intact occipital scalp and beard DP [63] (Fig.
2). These results are in contrast to the above mentioned results
measuring the testosterone consumption in DP cell cultures but are in
line with the observation of type 2 5alpha-R activity below the HF isthmus
[64] and with the detection of type 2 5alpha-R mRNA in DP cells [49].
In sum, provided the DP plays a crucial role during androgen-mediated
processes on the HF, our results suggest that the DP might amplify testosterone-driven
responses in the human HF via the action of type 2 5alpha-R. Provided
that the DP cell triggers and regulates the growth of HF, this physiological
role may be reflected by metabolic differences which could account for
differences in androgen sensitivity as observed in HF from different body
sites, and in conditions such as male pattern baldness. The observation
of type 2 5alpha-R could be a clue in the understanding of the regulation
of androgen action in the human hair follicle by local androgen modification
at the target cell level.
Aromatase
Immunohistochemical and PCR-based methods were used to examine the expression
of aromatase in male and female human skin specimens at various ages and
different body sites. Aromatase has been detected in the external root
sheath of anagen HF. The expression of aromatase did not vary with body
site or sex [65]. Localizing the aromatase in the external root sheath
of anagen HF suggests that aromatase may have a function in the intrafollicular
AM by converting potent androgens to less potent estrogens in order to
avoid potentially harmful androgen-mediated effects on androgen-dependent
HF. This concept is supported by the fact that women taking aromatase
inhibitors for the treatment of breast cancer will often experience AGA-like
hair loss [66]. Moreover, in both men and women aromatase activity has
been shown to be diminished in HF affected by AGA [43].
Androgen receptor (AR)
The AR´s within the HF are located in the sebaceous gland, the
dermal sheath and the outer root sheath of the HF [67], as well as the
matrix and hair DP [68], and in vitro it has been shown that DP
cells from an androgen sensitive body site contain more AR than DP cells
from androgen-insensitive HF [69].
Interaction of DHT with the androgen-receptor
(AR) and androgen-responsive elements (ARE)
DHT is a pivotal trigger of androgen-mediated effects on the hair follicle
and the principal signal transduction cascade: DHT- DHT/AR-ARE is similar
in all HF. However, DHT makes some hair follicles grow whereas others
will miniaturize. Something fundamentally different must be present in
beard versus frontal hair follicle target cells. This paradox is
at present not understood but an accumulating body of evidence indicates
that the AR or distinct ARE might be involved in this process.
Androgen receptor (AR)
Without functionally active AR a genetically male fetus will not undergo
normal male development in utero and a phenotypically female child
is born. This is demonstrated by the various forms of androgen insensitivity
syndrome (AIS). Several mutations in the gene for the AR may lead to AIS,
but not every mutation will result in complete absence of functional AR.
Interestingly complete AIS (grade 8) is characterized by a female phenotype
despite a male genotype and lack of pubic hair, whereas in complete AIS
(grade 7) pubic hair is present. To our knowledge defined mutations of
the AR and their effect on AGA have not been looked for systemically,
but it is conceivable that some mutations may prevent balding.
Androgen-responsive genes
After forming the DHT/AR complex and transport into the nucleus, this
complex will bind to distinct DNA binding sites of androgen-susceptible
genes. In the prostate DHT affects genes such as the prostate steroid-binding
protein (PSBD) or testosterone-repressed prostate message (TRPM) [70].
In the prostate DHT induces 5alpha-R activity in an autocrine manner [71].
TGF-beta1 has been shown to inhibit 5alpha-R in genital skin fibroblasts
[72]. Conflicting results exist for IGF-1. This protein has been shown
to induce 5alpha-R activity [73], but other groups were unable to confirm
these data [74].
In vitro, DP cells respond differently to exogenous T, DHT, or
estradiole [75]. Proliferation is inhibited by T and DHT but not by estradiole.
DP cells in vitro retain some of their in vivo parameters,
and it has been shown that nexin-1 is not only present in the anagen hair
bulb [76], but also that this gene is regulated by androgens [77] which
might indicate a role during the pathogenesis of AGA. Androgen-dependent
HF secrete soluble factors in response to T such as IGF-1 that stimulate
the growth of follicular epithelial cells [78] or inhibit the growth of
complete HF [20]. Other groups reported the secretion of stem cell factor
[79, 80] upon stimulation with T. Whether this is of pathophysiological
importance in AGA is unknown so far.
Summary and future perspectives
AGA can be defined as a DHT-dependent process with continuous miniaturization
of sensitive HF. The type 2 5alphaR plays a central role by the intrafollicular
conversion of T to DHT. So far the predisposing genes for AGA are unknown
and we do not understand the molecular steps involved in androgen-dependent
beard growth versus androgen-dependent hair loss. However, with
the cloning of the entire human gene within the next few years, we may
have new tools to explore the etiopathogenesis of AGA in more detail.
Article accepted on 10/12/99
REFERENCES
1. Braun-Falco O, Bergner T. Die androgenetische Alopezie des
Mannes. Neuere Entwicklungen. Hautarzt 1989; 40: 669-78.
2. Bergfeld WF. Androgenetic alopecia: an autosomal dominant
disorder. Am J Med 1995; 98: 95S-8S.
3. Ellis JA, Stebbing M, Harrap SB. Genetic analysis of male
pattern baldness and the 5alpha-reductase genes. J Invest Dermatol
1998; 110: 849-53.
4. Kuster W, Happle R. The inheritance of common baldness: two
B or not two B? J Am Acad Dermatol 1984; 11: 921-26.
5. Sreekumar GP, Pardinas J, Wong CQ, Whiting D, Katz HI, Price
V, Zlotogorski A, Roberts J, Clark BC, Stenn K, Parimoo S. Serum androgens
and genetic linkage analysis in early onset androgenetic alopecia. J
Invest Dermatol 1999; 113: 277-9.
6. Carey AH, Chan KL, Short F, White D, Williamson R, Franks
S. Evidence for a single gene effect causing polycystic ovaries and male
pattern baldness. Clin Endocrinol (Oxf) 1993; 38: 653-58.
7. Ferriman D, Purdie AW. The inheritance of polycystic ovarian
disease and a possible relationship to premature balding. Clin Endocrinol
(Oxf) 1979; 11: 291-300.
8. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S,
Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R. Linkage
and association of insulin gene VNTR regulatory polymorphism with polycystic
ovary syndrome. Lancet 1997; 349: 986-90.
9. Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG
repeat lengths) in androgenetic alopecia, hirsutism, and acne [In Process
Citation]. J Cutan Med Surg 1998; 3: 9-15.
10. König A, Happle R, Tchicherina E, Schäfer JR, Sokolowski
P, Köhler W, Hoffmann R. An X-linked gene involved in androgenetic
alopecia: a lesson to be learned from adernoleukodystrophy. Dermatology
(in press) 2000.
11. Rhodes L, Harper J, Uno H, Gaito G, Audette-Arruda J, Kurata
S, Berman C, Primka R, Pikounis B. The effects of finasteride (Proscar)
on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone
in adult male and female stumptail macaques (Macaca arctoides). J Clin
Endocrinol Metab 1994; 79: 991-6.
12. Ohuchi A, Mitsui S, Hotta M, Hattori M, Tsuboi R, Ogawa H.
Involvement of androgens in vivo and in vitro during the
dorsal hair growth of castrated rat, in Neste va D, Randall V (eds): Hair
research for the next millennium. Amsterdam, Elsevier, 1996, p. 293-6.
13. Kondo S, Hozumi Y: Transplantation of vellus hair in male
pattern baldness to nude mice., in Neste va D, Randall V, eds. Hair research
for the next millennium. Amsterdam, Elsevier, 1996, p. 315-8.
14. Van Neste D, de Brouwer B, Tételin C, Bonfils A: Testosterone
conditioned nude mice: an improved model for experimental monitoring of
human hair production by androgen dependent balding scalp grafts., in
Neste va D, Randall V, eds., Hair research for the next millennium. Amsterdam,
Elsevier, 1996, p. 319-22.
15. Matias JR, Orentreich N. The effect of testosterone, cyproterone
acetate, and minoxidil on hair loss in the androchronogenetic alopecia
mouse. Clin Dermatol 1988; 6: 169-76.
16. Matias JR, Malloy V, Orentreich N. Animal models of androgen-dependent
disorders of the pilosebaceous apparatus. 1. The androchronogenetic alopecia
(AGA) mouse as a model for male-pattern baldness. Arch Dermatol Res
1989; 281: 247-53.
17. Hamilton JB. Male hormone stimulation as a prerequisite and
an incitement in common baldness. Am J Anat 1942; 71: 451-3.
18. Balducci R, Ghirri P, Brown TR, Bradford S, Boldrini A, Boscherini
B, Sciarra F, Toscano V. A clinician looks at androgen resistance. Steroids
1996; 61: 205-11.
19. Takashima I, Montagna W. Studies of common baldness of the
stump-tailed macaque (Macaca speciosa). VI. The effect of testosterone
on common baldness. Arch Dermatol 1971; 103: 527-34.
20. Obana N, Chang C, Uno H. Inhibition of hair growth by testosterone
in the presence of dermal papilla cells from the frontal bald scalp of
the postpubertal stumptailed macaque. Endocrinology 1997; 138:
356-61.
21. Metcalf BW, Levy MA, Holt DA. Inhibitors of steroid 5 alpha-reductase
in benign prostatic hyperplasia, male pattern baldness and acne. Trends
Pharmacol Sci 1989; 10: 491-5.
22. Sawaya ME, Price VH. Different levels of 5alpha-reductase
type I and II, aromatase, and androgen receptor in hair follicles of women
and men with androgenetic alopecia. J Invest Dermatol 1997; 109:
296-300.
23. Jahoda CA. Cellular and developmental aspects of androgenetic
alopecia. Exp Dermatol 1998; 7: 235-48.
24. Van Scott EJ, Ekel TM. Goemetric relationships between the
matrix of the hair bulb and its dermal papilla in normal and alopecic
scalp. J Invest Dermatol 1958; 31: 281-7.
25. Van Scott EJ, Ekel TM, Auerbach R. Determinants of rate and
kinetics of cell division in human scalp hair. J Invest Dermatol
1963; 41: 281-7.
26. Elliot K, Stephenson TJ, Messenger AG. Differences in hair
follicle dermal papilla volume are due to extracellular matrix volume
and cell number: implications for the control of hair follicle size and
androgen responses. J Invest Dermatol 1999; 113: 873-7.
27. Sperling LC, Heimer WL. Androgen biology as a basis for the
diagnosis and treatment of androgenic disorders in women. I. J Am Acad
Dermatol 1993; 28: 669-83.
28. Sawaya ME, Honig LS, Garland LD, Hsia SL. delta 5-3 beta-hydroxysteroid
dehydrogenase activity in sebaceous glands of scalp in male-pattern baldness.
J Invest Dermatol 1988; 91: 101-5.
29. Ehrmann DA, Rosenfield RL. Clinical review 10: An endocrinologic
approach to the patient with hirsutism. J Clin Endocrinol Metab
1990; 71: 1-4.
30. White PC. Genetic diseases of steroid metabolism. Vitam
Horm 1994; 49: 131-95.
31. Ishihara F, Komatsu M, Yamada T, Aizawa T, Ichikawa K, Takasu
N, Komiya I. Role of dehydroepiandrosterone and dehydroepiandrosterone
sulfate for the maintenance of axillary hair in women. Horm Metab Res
1993; 25: 34-6.
32. Steinberger E, Smith KD, Rodriguez-Rigau LJ. Testosterone,
dehydroepiandrosterone, and dehydroepiandrosterone sulfate in hyperandrogenic
women. J Clin Endocrinol Metab 1984; 59: 471-7.
33. Kasick JM, Bergfeld WF, Steck WD, Gupta MK. Adrenal androgenic
female-pattern alopecia: sex hormones and the balding woman. Cleve
Clin Q 1983; 50: 111-22.
34. Pitts RL. Serum elevation of dehydroepiandrosterone sulfate
associated with male pattern baldness in young men. J Am Acad Dermatol
1987; 16: 571-3.
35. Rheaume E, Simard J, Morel Y, Mebarki F, Zachmann M, Forest
MG, New MI, Labrie F. Congenital adrenal hyperplasia due to point mutations
in the type II 3 beta-hydroxysteroid dehydrogenase gene. Nat Genet
1992; 1: 239-45.
36. Morel Y, Mebarki F, Rheaume E, Sanchez R, Forest MG, Simard
J. Structure-function relationships of 3 beta-hydroxysteroid dehydrogenase:
contribution made by the molecular genetics of 3 beta- hydroxysteroid
dehydrogenase deficiency. Steroids 1997; 62: 176-84.
37. Hodgins MB, Murad S, Simpson NB. A search for variation in
hair follicle androgen metabolism which might be linked to male pattern
baldness. Br J Dermatol 1985; 113: 794 (abstr.).
38. Andersson S, Moghrabi N. Physiology and molecular genetics
of 17 beta-hydroxysteroid dehydrogenases. Steroids 1997; 62: 143-7.
39. Nowakowski H, Lenz W. Genetic aspects of male hypogonadism.
Prog Horm REs 1961; 17: 53-89.
40. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE.
Steroid 5alpha-reductase deficiency in man: an inherited form of male
pseudohermaphroditism. Science 1974; 186: 1213-5.
41. Thigpen AE, Davis DL, Milatovich A, Mendonca BB, Imperato-McGinley
J, Griffin JE, Francke U, Wilson JD, Russell DW. Molecular genetics of
steroid 5 alpha-reductase 2 deficiency. J Clin Invest 1992; 90:
799-809.
42. Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dorr HG, Hauss
H, Heinrich U, Hemminghaus M, Hoepffner W, Holder M, Schnabel D, Kruse
K. Phenotypic classification of male pseudohermaphroditism due to steroid
5 alpha-reductase 2 deficiency. Am J Med Genet 1996; 63: 223-30.
43. Sawaya ME. Steroid chemistry and hormone controls during
the hair follicle cycle. Ann N Y Acad Sci 1991; 642: 376-83; discussion
383-74.
44. Chen W, Zouboulis CC, Orfanos CE. The 5 alpha-reductase system
and its inhibitors. Recent development and its perspective in treating
androgen-dependent skin disorders. Dermatology 1996; 193: 177-84.
45. Dijkstra AC, Vermeesch-Markslag AM, Vromans EW, Happle R,
van de Kerkhof PC, Zwanenburg B, Vos F, Vermorken AJ. Substrate specific
sulfatase activity from hair follicles in recessive X-linked ichthyosis.
Acta Derm Venereol 1987; 67: 369-76.
46. Dumont M, Van LT, Dupont E, Pelletier G, Labrie F. Characterization,
expression, and immunohistochemical localization of 3 beta-hydroxysteroid
dehydrogenase/delta 5-delta 4 isomerase in human skin. J Invest Dermatol
1992; 99: 415-21.
47. Fazekas AG, Lanthier A. Metabolism of androgens by isolated
human beard hair follicles. Steroids 1971; 18: 367-79.
48. Hay JB, Hodgins MB. Distribution of androgen metabolizing
enzymes in isolated tissues of human forehead and axillary skin.
J Endocrinol 1978; 79: 29-39.
49. Courchay G, Boyera N, Bernard BA, Mahe Y. Messenger RNA expression
of steroidogenesis enzyme subtypes in the human pilosebaceous unit. Skin
Pharmacol 1996; 9: 169-76.
50. Takashima I, Adachi K, Montagna W. Studies of common baldness
in the stumptailed macaque. IV. In vitro metabolism of testosterone
in the hair follicles. J Invest Dermatol 1970; 55: 329-34.
51. Schweikert HU, Wilson JD. Regulation of human hair growth
by steroid hormones. I. Testerone metabolism in isolated hairs. J Clin
Endocrinol Metab 1974; 38: 811-9.
52. Schweikert HU, Wilson JD. Regulation of human hair growth
by steroid hormones. II. Androstenedione metabolism in isolated hairs.
J Clin Endocrinol Metab 1974; 39: 1012-9.
53. Takayasu S, Adachi K. The conversion of testosterone to 17-hydroxy-5-androstan-3-one
(dihydrotestosterone) by human hair follicles. J Clin Endocrinol Metab
1972; 34: 1098-101.
54. Takayasu S, Wakimoto H, Itami S, Sano S. Activity of testosterone
5 alpha-reductase in various tissues of human skin. J Invest Dermatol
1980; 74: 187-91.
55. Fazekas AG, Sandor T. Metabolism of androgens by isolated
human hair follicles. J Steroid Biochem 1972; 3: 485-91.
56. Schmidt JA, Schweikert HU. Testosterone and epitestosterone
metabolism of single hairs in 5 patients with 5 alpha-reductase-deficiency.
Acta Endocrinol (Copenh) 1986; 113: 588-92.
57. Thornton MJ, Hamada K, Laing I, Messenger AG, Randall VA.
Metabolism of testosterone by cultured dermal papilla cells from human
beard, pubic, and scalp hair follicles. Ann N Y Acad Sci 1991;
642: 452-3.
58. Thornton MJ, Laing I, Hamada K, Messenger AG, Randall VA.
Differences in testosterone metabolism by beard and scalp hair follicle
dermal papilla cells. Clin Endocrinol (Oxf) 1993; 39: 633-9.
59. Randall VA, Thornton MJ, Hamada K, Messenger AG. Mechanism
of androgen action in cultured dermal papilla cells derived from human
hair follicles with varying responses to androgens in vivo. J
Invest Dermatol 1992; 98: 86S-91S.
60. Randall VA, Thornton MJ, Hamada K, Messenger AG. Androgen
action in cultured dermal papilla cells from human hair follicles. Skin
Pharmacol 1994; 7: 20-6.
61. Itami S, Kurata S, Sonoda T, Takayasu S. Mechanism of action
of androgen in dermal papilla cells. Ann N Y Acad Sci 1991; 642:
385-95.
62. Itami S, Kurata S, Sonoda T, Takayasu S. Characterization
of 5 alpha-reductase in cultured human dermal papilla cells from beard
and occipital scalp hair. J Invest Dermatol 1991; 96: 57-60.
63. Hoffmann R, Happle R. Finasteride is the main inhibitor of
5a-reductase activity in microdissected dermal papillae from human hair
follicles. Arch Dermatol Res 1999; 100-3.
64. Thiboutot DM, Knaggs H, Gilliland K, Hagari S. Activity of
type 1 5 alpha-reductase is greater in the follicular infrainfundibulum
compared with the epidermis. Br J Dermatol 1997; 136: 166-71.
65. Sawaya ME, Penneys NS. Immunohistochemical distribution of
aromatase and 3B-hydroxysteroid dehydrogenase in human hair follicle and
sebaceous gland. J Cutan Pathol 1992; 19: 309-14.
66. Ayoub JP, Valero V, Hortobagyi GN. Tamoxifen-induced female
androgenetic alopecia in a patient with breast cancer. Ann Intern Med
1997; 126: 745-6.
67. Blauer M, Vaalasti A, Pauli SL, Ylikomi T, Joensuu T, Tuohimaa
P. Location of androgen receptor in human skin. J Invest Dermatol
1991; 97: 264-8.
68. Diani AR, Mills CJ. Immunocytochemical localization of androgen
receptors in the scalp of the stumptail macaque monkey, a model of androgenetic
alopecia. J Invest Dermatol 1994; 102: 511-4.
69. Hibberts NA, Howell AE, Randall VA. Balding hair follicle
dermal papilla cells contain higher levels of androgen receptors than
those from non-balding scalp. J Endocrinol 1998; 156: 59-65.
70. Rittmaster RS, Magor KE, Manning AP, Norman RW, Lazier CB.
Differential effect of 5 alpha-reductase inhibition and castration on
androgen-regulated gene expression in rat prostate. Mol Endocrinol
1991; 5: 1023-9.
71. George FW, Russell DW, Wilson JD. Feed-forward control of
prostate growth: dihydrotestosterone induces expression of its own biosynthetic
enzyme, steroid 5 alpha-reductase. Proc Natl Acad Sci U S A 1991;
88: 8044-7.
72. Wahe M, Antonipillai I, Horton R. Effects of transforming
growth factor beta and epidermal growth factor on steroid 5 alpha-reductase
activity in genital skin fibroblasts. Mol Cell Endocrinol 1993;
98: 55-9.
73. Horton R, Pasupuletti V, Antonipillai I. Androgen induction
of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I.
Endocrinology 1993; 133: 447-51.
74. Dykstra KD, Payne AM, Abdelrahim M, Francis GL. Insulin-like
growth factor 1, but not growth hormone, has in vitro proliferative
effects on neonatal foreskin fibroblasts without affecting 5-alpha-reductase
or androgen receptor activity. J Androl 1993; 14: 73-8.
75. Arai A, von Hintzenstern J, Kiesewetter F, Schell H, Hornstein
OP. In vitro effects of testosterone, dihydrotestosterone and estradiol
on cell growth of human hair bulb papilla cells and hair root sheath fibroblasts.
Acta Derm Venereol 1990; 70: 338-41.
76. Yu DW, Yang T, Sonoda T, Gaffney K, Jensen PJ, Dooley T,
Ledbetter S, Freedberg IM, Lavker R, Sun TT. Message of nexin 1, a serine
protease inhibitor, is accumulated in the follicular papilla during anagen
of the hair cycle. J Cell Sci 1995; 108: 3867-74.
77. Sonoda T, Kurata S, Asada Y, Takayasu S. Message of protease
nexin-1 is expressed in human dermal papilla cells and is affected by
androgens. J Invest Dermatol 1998; 100: 612 (abstr.).
78. Itami S, Sonoda T, Kurata S, Takayasu S. Mechanism of action
of androgen in hair follicles. J Dermatol Sci 1994; 7 (suppl.)l:
S98-103.
79. Thornton MJ, Hamada K, Messenger AG, Randall VA. Androgen-dependent
beard dermal papilla cells secrete autocrine growth factor(s) in response
to testosterone unlike scalp cells. J Invest Dermatol 1998; 111:
727-32.
80. Hibberts NA, Messenger AG, Randall VA. Dermal papilla cells
derived from beard hair follicles secrete more stem cell factor (SCF)
in culture than scalp cells or dermal fibroblasts. Biochem Biophys
Res Commun 1996; 222: 401-5.
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