The Aging Male, September/December 2005; 8(3/4): 166–174
Influence of physiological androgen levels on wound healing and
immune status in men
S. FIMMEL1 & C. C. ZOUBOULIS2
1
Department of Dermatology, Charité Universitaetsmedizin Berlin, Berlin, Germany, and 2Departments of Dermatology and
Immunology, Dessau Medical Center, Dessau, Germany
Abstract
Aging in men is associated with a progressive decline in the production of several hormones, including androgens. The extent
to which an age-dependent decline in androgen levels lead to health problems or can affect quality of life remains under
debate. Clinical results on replacement therapy do not yet provide a definitive clue on the benefit/risk balance. A sexual
dimorphism of the immune system is well established, and the differences between female and male immune responses under
normal, as well as pathological, conditions are generally attributed to the influence of estrogens, progestins, and androgens.
The suppressive effects of male sex hormones on immune functions have been observed in a wide variety of disease processes
and appear to be testosterone-mediated. Endogenous testosterone inhibits skin wound healing response in males and is
associated with an enhanced inflammatory response. Although there are no known gender-related differences in permeability
barrier function in adults, estrogens accelerates—whereas testosterone retards—barrier development in fetal skin, and male
fetuses demonstrate slower barrier development than female littermates.
Keywords: Aging, wound healing, androgens
Introduction
Male aging is associated with a progressive decline in
androgen production. The physiological causes for
this phenomenon seem to be multifactorial. Some
data exist on the magnitude of the decrease in adrenal
androgens with age and the prevalence of older male
individuals with low testosterone levels. Belanger et al.
[1] reported on a marked decrease in dehydroepiandrosterone (DHEA) formation by the adrenals, which
leads to a decrease of about 50% in total androgens in
men between the ages of 40 to 80 years. The extent to
which an age-dependent decline in androgen levels
leads to health problems, or can affect quality of life, is
under investigation [2–5]. In men older than middleage, total testosterone levels alone may be misleading
and the increased sex hormone-binding globulin
levels have to be considered in parallel. The mechanism of the age-associated decrease of the endocrine
testicular function is essentially due to primary
testicular failure, but important changes also occur
at the hypothalamopituitary level. The most prominent endocrinological alterations with regard to
male aging are related to the gonadal and the adrenal
hormones–DHEA/DHEA sulphate and androstenedione–but others, such as growth hormone, insulinlike growth factor 1, melatonin, cortisol, and
thyroxine are also affected [6–8]. In a subset of aging
male plasma testosterone, levels fall below a critical
level resulting in hypogonadism. This state of
testosterone deficiency has an impact on bone, muscle
and brain function, and is possibly a factor inducing
the accumulation of visceral fat associated with an
increased risk of non-insulin-dependent diabetes
mellitus [9] and cardiovascular diseases.
It is therefore probable that androgen replacement
to selected male individuals with proven androgen
deficiency may have beneficial effects. The major goal
of androgen substitution is to replace testosterone
at levels as close to physiological levels as possible.
For some androgen-dependent functions, testosterone is a pro-hormone, peripherally converted to 5adihydrotestosterone (DHT) and 17b-estradiol (E2),
of which the levels should preferably be within
physiological range. Natural testosterone is viewed
as the best androgen for substitution in hypogonadal
men. The reason behind this selection, however, is
that testosterone can be converted to DHT and E2,
thus developing the full spectrum of testosterone
activities in long-term substitution. Recent insights
imply that estrogens also fulfil a significant role in
men. A major disadvantage of natural testosterone
substitution is the strongly fluctuating levels of plasma
testosterone, which are not in the physiological range
at least 50% of the time. Also, the generated plasma
E2 is usually supraphysiological. Administration of
testosterone to young individuals has almost no
adverse effects. With increasing age the risk of adverse
Correspondence: C. C. Zouboulis, Departments of Dermatology and Immunology, Dessau Medical Center, Auchweg 38, 06847 Dessau, Germany.
Fax: 49 30 8445 2766.
ISSN 1368-5538 print/ISSN 1473-0790 online Ó 2005 Taylor & Francis
DOI: 10.1080/13685530500233847
Influence of androgen levels on wound healing and immune status
effects on the liver, lipid profile, cardiovascular
disease, prostate [10–12], sleep disorders [13–16]
and emotional behavior increases. The following
review will address the relevance of normal testosterone levels in aging males and the potential role of
androgen administration in wound healing, immune
status and epidermal permeability barrier homeostasis
of aging men.
Age-related decline of androgen levels
Terms like male menopause or andropause more or
less suggest that, similarly to women, all men go
through a profound decline of their androgen
production from middle age on. However, it should
be stressed that the age-related decline of androgens
in male follows a totally different pattern in comparison to the menopause. Several studies have shown
that plasma testosterone, and in particular free
testosterone, decreases with aging. Initially, crosssectional studies [17–19], but also more recent
longitudinal studies [20], have documented a statistical decline in plasma testosterone by approximately
30% in healthy men between the ages of 25–75 years.
Harman et al. [21] showed data indicating that as
many as 75% of all men are hypogonadal by the time
they reach the age of 80 years – and 50% of men over
the age of 65 years meet the endocrine criteria for
hypogonadism. Apart from the recommendations of
Morales and Lunenfeld [23], stringent criteria for
testosterone deficiency have not yet been formulated.
In a study of 300 healthy 20–100-year-old men,
Vermeulen et al. [19] defined the reference range of
testosterone to be between 11 nmol/l and 40 nmol/l.
The authors found only one man with subnormal
testosterone levels in the 20–40 year age group, but
found that more than 20% of participants over the
age of 60 and 15% of participants over the age of
80 still had testosterone levels above 20 nmol/l. The
implication of this is that the fall of testosterone levels
below normal is not universal in men, but affects only
a certain proportion. The term ‘‘partial androgen
deficiency of the aging male’’ (PADAM) has been
proposed to describe this phenomenon. The androgen deficiency is partial in two ways: (1) the decline
in androgen levels is not as profound as the decline of
estrogens in menopausal; and (2) it affects only a
proportion of aging men, increasing with age.
Wound healing
Aging and wound healing
Impaired wound healing leads to substantial morbidity and mortality of the elderly, as well as increased
costs to health services [24]. Although the process of
wound healing is a continuum, it is classically
separated into a series of overlapping phases. These
four phases (hemostasis, inflammation, proliferation
and resolution) have been studied in detail and
167
exhibit characteristic changes with aging. Decreased
levels of growth factors, diminished cell proliferation
and migration, and reduced extracellular matrix
secretion have been demonstrated [25]. Impaired
age-related wound healing states–involving both
acute wounds that fail to heal and chronic ulcers–
are characterized by excessive leukocytosis and
subsequently enhanced proteolytic degradation of
matrix constituents [26,27]. In addition to intrinsic
aging per se causing delayed healing, studies have
suggested marked gender differences in wound
repair. Reports have shown that men heal acute
wounds more slowly than women and also have an
altered inflammatory response. Older epidemiological studies have not reported any impact of gender on
wound repair; however, recent studies have demonstrated that the male genotype is a strongly positive
risk factor for impaired healing in the elderly [28–
30]. By analysis of acute wound tissue from health
status-defined subjects, Ashcroft et al. [31] showed
that collagen VII deposition was dramatically reduced with increasing age, particularly in elderly
men. In concordance with animal studies, wound
tumor necrosis factor (TNF)-a levels were shown to
increase with age on day 7 after wounding, with a
marked increase in macrophages staining positively
in the wounds of elderly males.
Whereas sustained systemic and local estrogen
levels in both young females and males may
contribute to reduced inflammation via direct effects
on cell adhesion molecule expression, the absence of
such protective anti-inflammatory action in the
elderly may correspond to increased inflammation
and TNF-a expression. Moreover, in elderly men,
reduced estrogens coupled with maintained levels of
bioactive testosterone results in a failure to dampen
the TNF-a response. Intriguingly, reversal of agerelated impaired healing can be achieved in both
animal and human models with topical and systemic
estrogens, associated with a downregulation of
neutrophil L-selectin and a dampened inflammatory
response [29]. Beyond the age-related modulation of
specific subsets of inflammatory cells, the responses
of individual cells also appear to alter with the age of
the donor. It has been reported that stimulated
mononuclear cell production of the pro-inflammatory interleukin (IL)- 6 and TNF-a and spontaneous
IL-6 production are increased in cells from human
donors [32].
Wound healing and estrogens
The skin appears to act as an end-organ target for
estrogenic action. Marked structural and functional
skin changes occurring after the menopause can be
related to altered hormonal profiles. One of the most
important consequences of such hormonal changes is
the age-related delay in cutaneous wound healing.
Reduced estrogen levels have major downstream
effects on cellular and tissue responses to injury; such
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S. Fimmel & C. C. Zouboulis
downstream effects include impaired cytokine signal
transduction, unchecked inflammation and altered
protein balance, and have a major impact on the rate
of wound healing. Local levels of bioavailable
estrogens are altered in the elderly due to a
combination of decreased circulating gonadal estrogens (particularly important in postmenopausal
females) and markedly reduced levels of the adrenal
sex steroid precursor DHEA, resulting in a parallel
decrease in androgen and estrogen formation from
DHEA aromatization in peripheral tissues [33–35].
Estrogens can reverse age-related impaired healing in
females when applied topically or given systemically,
and is associated with reduced local inflammation
and enhanced matrix deposition. In 1997, Ashcroft
et al. showed that ovariectomized young female
rodents exhibited a marked delay in repair of acute
incisional wounds, which was reversed by the topical
application of estrogens. The cellular mechanism
underlying these changes involved an estrogeninduced increase in latent tumor growth factor-ß1
secretion by dermal fibroblasts [36]. Ashcroft et al.
have investigated the effects of topical estrogens on
cutaneous wound healing in healthy elderly men and
women, and related these effects to the inflammatory
responses and local elastase levels, an enzyme known
to be upregulated in impaired wound healing states.
Eighteen health status-defined females (mean age
74.4 years) and 18 males (mean age 70.7 years) were
randomized in a double-blind study to either active
estrogen patch or identical placebo patch attached for
24 hours to the inner upper arm, through which two
4-mm punch biopsies were made. The wounds were
excised at either day 7 or day 80 postwounding.
Compared to placebo, estrogen treatment increased
the extent of wound healing in both males and
females, with a decrease in wound size at day 7,
increased collagen levels at days 7 and 80, and
increased day 7 fibronectin levels. Estrogen treatment
was associated with a decrease in wound elastase
levels secondary to reduced neutrophil numbers, and
decreased fibronectin degradation. In vitro studies
using isolated human neutrophils indicated that one
mechanism underlying the altered inflammatory response involves both a direct inhibition of neutrophil
chemotaxis by estrogens and an altered expression of
neutrophil adhesion molecules [29].
Estrogens can reverse age-related impaired wound
healing in human and animal models, characterized
by a dampened inflammatory response and increased
matrix deposited at the wound site. Macrophage
migration inhibitory factor (MIF) is a candidate
proinflammatory cytokine involved in the hormonal
regulation of inflammation. Ashcroft and colleagues
demonstrated that MIF is upregulated in a distinct
spatial and temporal pattern during wound healing,
and its expression is markedly elevated in wounds of
estrogen-deficient mice as compared with intact
animals. Wound-healing studies in mice rendered
null for the MIF gene have demonstrated that in the
absence of MIF, the excessive inflammation and
delayed-healing phenotype associated with reduced
estrogens is reversed. Moreover, in vitro assays have
shown a striking estrogen-mediated decrease in MIF
production by activated murine macrophages, a
process involving the estrogen receptor [37].
Wound healing and androgens
In elderly males, the response to estrogen is significantly reduced compared with that in females,
suggesting that other, unknown, factors are involved
beyond the effects of reduced estrogens. One factor
that has not been investigated to date is the potential
role of androgens in wound repair and local
cutaneous inflammation. Elderly men generally
maintain testosterone levels, albeit with a gradual
reduction with increasing age, and androgens have
been reported to be pivotal mediators of local and
humoral immune responses in other pathophysiological processes.
In this context, several reports indicate that
androgens play a critical role in the immune response
and account for differences in outcome based on sex,
including susceptibility to sepsis, parasitic infections,
and atherosclerosis related to enhanced monocyte
adhesion to endothelium [38–40]. Androgens have
been related to both pro- and anti-inflammatory
states at both the systemic level [41] and the cellular
level, modulating IL-1, IL-2, and IL-6 in a variety of
cell types including fibroblasts, macrophages (increasing IL-6), Kupffer cells (decreasing IL-6),
splenocytes and osteoblasts [42–45]. Moreover,
recent in vivo studies have suggested that castration
of rats following burn injury significantly reduces
systemic levels of proinflammatory TNF-a, and that
the in vitro macrophage production of IL-1 and
TNF-a is inhibited by androstenediol [46,47]. Taken
together, these reports suggest that androgens may
exert both anti- and proinflammatory effects that
depend on the cell type, animal model and dose of
treatment administered. In this regard, the role of
androgens in the cutaneous wound healing response
and the effects on local inflammation have not been
thoroughly investigated.
Corroborative evidence for an inhibitory role for
testosterone in the healing response came from an
investigation concerning the relationship between
wound area and systemic testosterone levels. In
elderly men, there was a significant delay in repair
with increasing testosterone levels, strongly implicating this hormone as a direct or indirect modulator of
age-related wound repair. Systemic testosterone
levels in elderly health status-defined human males
strongly correlates with impaired healing of acute
wounds. Gilliver et al. [48] reported that castration of
male mice resulted in a striking acceleration of local
cutaneous wound healing, which was also associated
with a reduced inflammatory response and increased
hair growth. Using a hairless mouse model, they
Influence of androgen levels on wound healing and immune status
demonstrated that testosterone reduction stimulated
the healing response, not through hair follicle
epithelial/mesenchymal cell proliferation, but directly
via effects on wound cell populations. The mechanisms underlying the observed effects involved a direct
effect of testosterone on murine macrophage, TNFa, production via the androgen receptor (AR) in
parallel to the in vivo downregulation of TNF-a
following castration or AR antagonism. Blockade of
androgen action systemically, via AR antagonism,
accelerates healing significantly, suggesting a specific
target for future therapeutic intervention in impaired
wound healing states in elderly males.
The sexual dimorphism of the immune
response
Both experimental [49–56] and clinical epidemiological studies [57–63] have demonstrated the presence
of a naturally occurring sexual dimorphism in the
immune response to trauma, hemorrhage and sepsis,
with significant advantages for women. During their
reproductive years, females have a more vigorous
cellular and humoral immune response than males as
evidenced by a more developed thymus, higher
immunoglobulin concentrations, and a greater ability
to reject tumors and homografts and a better outcome
from sepsis. Furthermore, evidence suggests that
physiological levels of estrogens stimulate humoral
and cell-mediated immune responses, while the
male hormone testosterone does the opposite [64–
66]. Whereas several studies have demonstrated the
presence of AR in human and murine immune cells
[67,68], recent findings also indicate that immune
cells have the ability to directly metabolize sex
steroids [69].
Investigation of Offner et al. [59] have shown that
depressed cell-mediated immunity is reversed by
castration or pharmacologic testosterone receptor
blockade. Female rats, in contrast, showed enhanced
immune function that was reduced to male levels by
testosterone administration. This sexual dimorphism
is believed to be responsible for the improved
outcome in female mice following septic challenge.
A five-year prospective cohort study confirmed that
male gender is an independent risk for major
infection after controlling for age and Injury Severity
Score. Males had a 58% greater risk of developing a
major infection. The authors concluded that male
gender is associated with a dramatically increased
risk of major infections following trauma.
Angele et al. [70] have implicated high testosterone and low E2 levels in the pathogenesis of immune
suppression following trauma and hemorrhage using
their well-established rodent model. Most recently,
Schröder et al. [42] observed a marked reduction in
hospital mortality among female patients with surgical sepsis (26% versus 70% in males). Cell-mediated
immune response appears to exhibit sexual dimorphism. A century ago, it was observed that castration in
169
adult male rabbits increased thymic mass, suggesting
that sex hormones influenced the immune system. It
has been proposed that maintenance of immune
integrity in females following injury is due, at least in
part, to the absence of immunosuppressive effects by
androgens [71]. In a murine model of traumahemorrhage, Wichmann et al. [51] demonstrated
that castration prior to injury prevented post-trauma
immune depression. Castration two weeks prior to
trauma-hemorrhage reduced plasma testosterone
levels and preserved splenocyte IL-2 and IL-3 release
compared with sham-operated animals. This laboratory also observed that pretreatment of female mice
with DHT resulted in immunosuppression following
trauma-hemorrhage similar to that occurring in
males. The authors proposed that the balance
between testosterone and E2 might be responsible
for the immune depression seen in male mice post
injury. Androgen has been shown to be responsible
for producing immunosuppression in male mice
[52,54]. Support for this notion comes from studies
[40,52] that illustrated that depletion of male sex
steroids by castration two weeks before trauma and
hemorrhage prevented the depression of immune
responses typically observed in normal males under
those conditions. Similarly, administration of an
androgen receptor blocker, e.g., flutamide, restored
depressed immune responses and increased the
survival rate of hemorrhaged animals subjected to
subsequent sepsis [73,80]. Conversely, administration of physiological levels of androgen in female
mice resulted in depressed splenic and peritoneal
macrophage immune response following trauma
and hemorrhage to levels comparable to those of
males under those conditions [70]. Therefore, physiological levels of androgens suppress systemic cellmediated immune responses in male mice following trauma and hemorrhage. Furthermore, this
impairment has been associated with an increased
release of proinflammatory cytokines and a decreased
production of tumor growth factor-b at the wound
site [81].
Both immunologic and physiologic parameters in
animal models of trauma and hemorrhage have been
examined, and a high estrogen-to-androgen ratio
appears to be associated with an improved outcome
[50–52,57,58,71,73–79]. Estrogen treatment restored
the delayed-type hypersensitivity and splenocyteproliferative responses, reduced macrophage IL-6
and increased survival after bacterial challenge. These
studies suggested that estrogen treatment of injured
male mice improves cellular immunity through direct
modulation of NF-B activation [72]. In the laboratory,
an increase in the ratio of estrogen to androgen, by
either the appropriate receptor agonist or antagonist,
has advantageous immunologic and physiologic effects. For example, male animals subjected to trauma
and hemorrhage and then treated with E2 exhibit a
restitution of immune and cardiovascular functions
[74,75]. In addition, flutamide provided immune
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S. Fimmel & C. C. Zouboulis
and cardiovascular protective effects in male rodents
subjected to trauma and hemorrhage, and conferred
a survival advantage for male mice in which sepsis
was induced 48 hours after hemorrhage [73,80]. In
support of these data, improved immunologic and
physiologic parameters have been reported for
females in animal models of trauma and hemorrhage.
The role of 5a–dehydrotestosterone (DHT)
Several studies in mice indicated that, in particular,
the most potent androgen DHT, suppress cytokine
release by T cells and alter their cytokine profile
[54,70,82,83]. Nitsch et al. [84] showed that
precastration of mice prevented the significantly
suppressed capacity of wound immune cells to
release IL-1b and IL-6. In addition, precastration
normalized the elevated IL-6 expression at the
wound site in the trauma-hemorrhage mouse model.
Moreover, wound-breaking strength was improved
in castrated mice 10 days after trauma and hemorrhage. Because the percentage of macrophages and
polymorphonuclear leukocytes within the wound
immune cells was unaffected by trauma-hemorrhage
or castration, the improvement in cytokine release in
castrated animals was independent of distribution of
wound immune cells. Similarly, depletion of DHT
by castration restored the depressed cytokine release
capacity of splenic and peritoneal macrophages
following trauma-hemorrhage, whereas cell-mediated
immune response in sham mice was not affected
[50,52]. These findings suggested that physiological
levels of testosterone were only harmful in an
immunologically compromized host, not in normal
animals. In this respect, it has been illustrated that
steroid synthesis had been altered following hemorrhage [85,86]. Those studies demonstrated an
increased DHT synthesis and a decreased catabolism
of this steroid hormone following trauma-hemorrhage due to changes in the activity of enzymes
involved in steroid synthesis. In particular, 5areductase activity was increased, whereas 17b-hydroxysteroid dehydrogenase activity was decreased
following trauma-hemorrhage in lymphocytes and
splenic macrophages harvested from male mice.
Although steroid synthesis pathways in wound
fibroblasts following hemorrhage have not been
studied, the existing findings suggest that an enhanced intracellular DHT synthesis following
trauma-hemorrhage may explain the immunodepressive effects of physiological DHT plasma levels. In
this respect, suppressed wound immune cell cytokine
release capacities following hemorrhage correlated
with increased rates of wound infection [87]. Moreover, normalization of suppressed cell-mediated
immune responses by androgen depletion decreased
the susceptibility to subsequent polymicrobial sepsis
[88]. Schneider et al. [89] supported the concept that
androgens directly regulate macrophage functions
after trauma and hemorrhagic shock. Both Kupffer
cells and splenic macrophages possess intrinsic sex
steroid synthesis capacity, because the 5a-reductase
inhibitor 4-hydroxyandrostenedione (4-OHA) directly inhibited the effects of testosterone, but not
DHT, on cytokine production. Moreover, inhibition
of 5a-reductase enzyme activity, which converts
testosterone to DHT, restored in vitro, as well as in
vivo, macrophage immune responses after traumatic
injury, indicating that DHT represents the crucial
androgen that regulates macrophage cytokine release
after traumatic injury [89–91].
Epidermal permeability barrier homeostasis
Sex hormones exert important influence on the late
stages of permeability barrier development in utero
[92]. Although there are no known gender-related
differences in permeability barrier function in adults,
estrogens accelerate whereas testosterone retards
barrier development in fetal skin, and male fetuses
demonstrate slower barrier development than female
littermates. Moreover, prenatal administration of
flutamide equalizes developmental rates in male and
female fetuses [93]. A negative influence of androgens
on skin development could explain ongoing outcome
differences in premature human male versus female
infants, even when treated with surfactant replacement
therapy [94,95]. Kao et al. [96] evaluated the effects
of changes in testosterone on barrier homeostasis in
adult murine and human skin. Hypogonadal mice
(whether by castration or by treatment with systemic
flutamide) displayed significantly faster barrier recovery at 3, 6 and 12 hours than controls did, and
testosterone replacement slowed barrier recovery in
castrated mice. Moreover, testosterone directly
affected the skin, as topical flutamide also accelerated
barrier recovery in normal male mice. These findings
appear to be of physiological significance, since
prepubertal male mice (age 5 weeks) displayed
accelerated barrier recovery in comparison with adult
postpubertal (age 11 weeks) males. These studies
also appear to be relevant to humans, as a hypopituitary human subject demonstrated repeated
changes in barrier recovery in parallel with peaks
and nadirs in serum testosterone levels during
intermittent testosterone replacement [97]. Mechanistic studies showed that differences in epidermal
lipid synthesis do not account for the testosteroneinduced functional alterations. Instead, epidermal
lamellar body formation and secretion both decrease,
resulting in decreased extracellular lamellar bilayers
in testosterone-replete animals. These studies demonstrate that fluctuations in testosterone modulate
barrier function can have negative consequences for
permeability barrier homeostasis. In addition, testosterone repletion affected adversely the kinetics of
barrier recovery versus sham-operated controls [93].
Androgen depletion accelerated barrier recovery, and
barrier function was enhanced significantly by either
surgical or medical castration, indicating that these
Influence of androgen levels on wound healing and immune status
observations were independent of the method of
androgen depletion [93]. Androgen influenced not
only barrier function, but also stratum corneum
integrity, a measure of tissue cohesiveness. The
functional differences in castrated versus shamoperated animals reflect changes in hormone levels
that are within the normal-to-subnormal (hypogonadal) range. The physiologic relevance of these
opposing outcomes in permeability barrier homeostasis was shown not only in prepubertal versus
pubertal rodents, but also in humans.
Androgens also seem to be responsible for the
detected gender-associated differences in cutaneous
barrier function. Hanley et al. [93] demonstrated that
cutaneous barrier formation, measured as transepidermal water loss, is delayed in male fetal rats.
Administration of estrogen to pregnant mothers
accelerated fetal barrier development both morphologically and functionally. In contrast, administration
of DHT delayed barrier formation both in vivo and in
vitro. Finally, treatment of pregnant rats with the
androgen antagonist flutamide eliminated the gender
difference in barrier formation. These studies indicated that: (a) estrogens accelerate and androgens
delay cutaneous barrier formation; (b) these hormones exert their effects directly on the skin; and (c)
sex differences in rates of barrier development in vivo
may be mediated by testosterone.
Androgens are also more likely to be the mediators
of gender differences in skin maturation. To determine if DHT, like estrogens, glucocorticoids, and
thyroid hormone, directly affects the skin, fetal skin
explants were incubated in the presence or absence
of DHT. Epidermal water loss in treated explants
was increased by *25% after 3 or 4 days in culture
[93]. Electron microscopy data revealed disorganized, unprocessed lamellar material in multiple
layers of the stratum corneum interstices in explants
incubated for 4 days with DHT. In contrast, control
explants exhibited mature bilayers throughout the
extracellular spaces of the stratum corneum, and
unprocessed material was limited to the stratum
granulosum–stratum corneum interface. Testosterone levels began to rise in the male fetal rats on day
16 of estimated gestational age [98], close to the time
of onset of epidermal stratification. Hanley et al. [93]
have demonstrated that the male fetus displayed a
less competent barrier than the female on day 20 of
estimated gestational age. Moreover, maternal administration of DHT caused a significant delay in
barrier formation, suggesting that this gender difference is due to inhibitory effects by androgens. DHT,
which did not aromatize to E2, appeared to have a
direct effect on the skin, since the addition of DHT
to fetal skin explants in vitro also delayed barrier
maturation.
Moreover, gender may also influence the severity
of diseases with abnormalities in skin barrier function. It is mentioned that severe atopic dermatitis and
severe psoriasis occur more commonly in males than
171
in females. Yet, the exact impact of gender on the
severity of skin disease has not been studied systematically [99].
Conclusions
A sexual dimorphism of the immune system is well
established, and the differences between female and
male immune responses under normal, as well as
pathological, conditions are generally attributed to
the influence of estrogens, progestins, and androgens. The suppressive effects of male sex hormones
on immune functions have been observed in a wide
variety of disease processes and appear to be
testosterone-mediated, as illustrated by numerous
animal studies.
Endogenous testosterone inhibits the cutaneous
wound healing response in males and is associated
with an enhanced inflammatory response. Because
decreasing androgen levels resulted in improved
wound healing, the short-term treatment with flutamide following trauma-hemorrhage may similarly
beneficially affect local wound immune cell function.
Therefore, attempts to improve wound immune cell
function at the wound site by treatment with AR
blockers may represent a useful adjunct for improving
wound healing and decreasing the incidence of
wound infections in critically ill patients.
Estrogens are also critical mediators of wound
healing accelerating repair in both human and animal
models. The existing data demonstrate that topically
applied estrogens, in both male and female subjects,
can significantly diminish delay in wound healing in
the elderly. There is convincing evidence to show
that aromatization of androgens to estrogens is an
important pathway for mediating the action of
testosterone on skin physiology. Aromatase, localized
to sebaceous glands and to both outer as well as inner
root sheath cells of anagen terminal hair follicles, may
play a ‘‘detoxifying’’ role by removing excess androgens [101]. Kung proposes that the major action of
testosterone is mediated through aromatization to E2
and binding to the estrogen receptors and the
balance between testosterone and E2 may be
responsible for the immune depression seen in male
mice after injury [101].
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