The Impact of Pyschological Stress on Acne

Abstract

Acne is one of the most common skin disorders. it is a mul-tifactorial and complex disease, originating in the pilosebaceous follicle where a hereditary background, androgens, skin lipids, disorders of keratinization, inflammatory signaling, and regulatory neuropeptides seem to be mainly involved. even though emotional stress has long been suspected to trigger or exacerbate acne, its influence on acne severity has been mostly underestimated until recently when studies have brought new data about the different mechanisms and possible factors involved in this interaction. A point to note is that there have been relatively few studies examining stress as a possible cause of acne or acne exacerbation; more studies have focused on stress and mental health problems occurring as a result of acne. in this review, we have tried to identify the underlying mechanisms that link stress to acne according to the latest scientific findings, and we summarize this perplexing connection. the basis for the association between emotional stress and the onset or exacerbation of acne is in several cutaneous neuro-genic factors which interact with a pathogenic cascade in acne. this bi-directional intimate relationship of the skin and the mind emphasizes the importance of a holistic and interdisciplinary approach to caring for patients with acne that involves not only dermatologists but also psychologists and psychiatrists.

Full text

The Impact of Pyschological Stress on Acne
Anamaria Jović, Branka Marinović, Krešimir Kostović, Romana Čeović,
Aleksandra Basta-Juzbašić, Zrinka Bukvić Mokos
University Hospital Centre Zagreb, Department of Dermatology and Venereology,
University of Zagreb School of Medicine, Zagreb, Croatia
Corresponding author:
Anamaria Jović, MD
University Hospital Centre Zagreb
Department of Dermatology and Venereology
University of Zagreb School of Medicine
Šalata 4
10000 Zagreb
Croatia
jovicanamaria@gmail.com
Acta Dermatovenerol Croat 2017;25(2):133-141 CLINICAL ARTICLE
ABSTRACT Acne is one of the most common skin disorders. It is a mul-
tifactorial and complex disease, originating in the pilosebaceous follicle
where a hereditary background, androgens, skin lipids, disorders of
keratinization, inammatory signaling, and regulatory neuropeptides
seem to be mainly involved. Even though emotional stress has long
been suspected to trigger or exacerbate acne, its inuence on acne
severity has been mostly underestimated until recently when studies
have brought new data about the dierent mechanisms and possible
factors involved in this interaction. A point to note is that there have
been relatively few studies examining stress as a possible cause of acne
or acne exacerbation; more studies have focused on stress and mental
health problems occurring as a result of acne. In this review, we have
tried to identify the underlying mechanisms that link stress to acne ac-
cording to the latest scientic ndings, and we summarize this perplex-
ing connection. The basis for the association between emotional stress
and the onset or exacerbation of acne is in several cutaneous neuro-
genic factors which interact with a pathogenic cascade in acne. This bi-
directional intimate relationship of the skin and the mind emphasizes
the importance of a holistic and interdisciplinary approach to caring
for patients with acne that involves not only dermatologists but also
psychologists and psychiatrists.
KEY WORDS: acne, psychological stress, sebaceous gland, neuroendo-
crinology
INTRODUCTION
Acne vulgaris is, along with eczema and psoriasis,
one of the most commonly seen chronic inamma-
tory skin diseases aecting individuals of all ages.
Eighty-ve percent of people between the ages of 12
and 24 will have some form of acne (1). Direct costs
related to acne, including loss of productivity and
related depression, exceed $2.2 billion annually in
the United States (2). It is a multifactorial and com-
plex disease, originating in the pilosebaceous follicle.
Four primary inter-related pathogenic factors of acne
have been recognized for decades: overproduction
of sebum, abnormal shedding of follicular epithelial
cells, Propionibacterium acnes follicular colonization,
and inammation (3-6). However, other endogenous
and exogenous factors like psychological stress, diet,
smoking, hormone concentrations, oxidative stress,
and genetic predisposition have been considered as
factors that can trigger or worsen acne (7-15). In the
past, most of the studies have focused on stress and
psychological consequences occurring as a result
133
Received: July 25, 2016
Accepted: May 25, 2017
ACTA DERMATOVENEROLOGICA CROATICA

134 ACTA DERMATOVENEROLOGICA CROATICA
of acne with only a few studies examining stress as
a possible cause of acne or acne exacerbation. Even
though emotional stress has long been suspected
to exacerbate acne, previous reports on its inuence
on acne severity have mostly been scientically un-
founded until the recent decade when psychoemo-
tional stress was conrmed as a pathogenetic aspect
in acne vulgaris (16,17). Additionally, studies have
shown that psychological stress can alter the immune
functions of the skin (18,19) and cutaneous barrier
function (20,21). The association between the mind
or mental health and dermatology has been claried
by the mounting evidence that microbial residents
and the functional integrity of the intestinal tract may
play an interceding role in both skin inammation
and emotional behavior (the gut-brain-skin theory).
The physiological association between intestinal mi-
crobiota, psychological symptoms such as depres-
sion, and inammatory skin conditions such as acne
was examined long ago and was recently validated
further by modern scientic investigations (22-26). It
has become evident that gut microbes and oral pro-
biotics may be related to the skin, specically acne
severity, through their ability to inuence systemic
inammation, oxidative stress, glycemic control, tis-
sue lipid content, and even mood (27-29).
Acne is undoubtedly a cause of anxiety and stress
in those who suer from it, and these patients suer
mainly from social limitations and reduced quality of
life (30-33). Psychological factors associate with acne
in at least three ways, described below.
First, emotional stress can exacerbate acne, as re-
ported by a high number of acne patients. Second,
as a consequence of acne, it is common for patients
to develop psychiatric problems like social phobias,
low self-esteem, or depression. Last but not least,
some mental diseases like psychosis and obsessive-
compulsive disorder may be dependent on an acne-
related issue (34).
The main diculty in evaluating the signicance
of acne on quality of life is resolving the chicken or the
egg dilemma: does acne cause psychiatric distress, or
do the stress and daily life changes exacerbate acne?
DOES STRESS EXACERBATE ACNE?
Yes, it seems to. Many patients report that emo-
tional stress makes their acne worse, and these
statements were conrmed in several studies by a
signicant percentage of aected adolescents and
adults (varying between 50-80%) (35-38). Griesemer
found that patients with acne reported a lag time
of two days between a stressful episode and the ex-
acerbation of acne (39). Lorenz et al. found that in-
tense anger also may aggravate acne severity (40).
An Australian survey that included 215 graduating
medical students, reported that 67% of them identi-
ed stress as one of the factors leading to acne ex-
acerbations (37). Two Korean epidemiological studies
found psychological stress to be the main triggering
or aggravating factor inuencing acne as reported by
the majority (80-82%) of patients (38). A prospective
cohort study, published in 2003, which comprised 22
university students, showed increased acne severity
during stressful exam periods by using previously
validated scales measuring acne severity and per-
ceived stress. Acne severity was signicantly associ-
ated with increased stress levels in comparison with
the period without exams despite adjusting for con-
founding factors such as lack of sleep and changes
in diet (17). Similar ndings have also been reported
by other, mostly questionnaire-based studies (41-44).
One study conducted with high school students also
found that increased stress correlated with increased
acne severity; there also did not seem to be any in-
creased sebum production during times of stress
(45). On the other hand, conicting ndings were
presented in a recent study consisting of 40 patients
with acne vulgaris (46). The authors concluded that
the intensity of stress does not correlate with the se-
verity of acne and they hypothesized that course of
the disease may depend on the tolerance to stress
and methods of coping with stress.
ADULT FEMALE ACNE
Over the last few years, there has been more and
more discussion on adult acne, specically adult fe-
male acne that dierentiates itself from adolescent
acne by its specic clinical aspects, its evolution, and
dierent physiopathological mechanisms (47). Fre-
quently, stress is reported as a factor triggering fe-
male acne. For Dumont-Wallon, it is part of the four
most often described factors promoting acne (48).
Dreno et al. conducted a large-scale prospective ob-
servational international study evaluating clinical
characteristics of acne and lifestyle in adult women
(≥25 years). There was an association between job
stress and acne severity, which could bolster the re-
lationship between stress and acne. The signicant
majority of subjects (83.2%) reported at least moder-
ate stress, including 15.5% who reported high-stress
levels. A total of 23.0% examinees reported that their
jobs were psychologically stressful, and job stress
was correlated with more severe acne in women. It
has also been shown that compared to women with-
out localized acne, those with mandibular acne were
more likely to be employed, reported greater daily
stress levels (5.8% vs. 5.1%), and were more likely to
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Impact of psychological stress on acne 2017;25(2):133-141

ACTA DERMATOVENEROLOGICA CROATICA 135
dene their jobs psychologically stressful (71.4% vs.
57.5%) (49). Similar ndings were published by Poli
et al. who reported that stress was recorded as causal
factor for acne in 50% of women aged 25-40 years
who completed a self-administered questionnaire
(36).
Adult female acne has increased in prevalence in
recent years, reaching up to a reported percentage of
41-54% (47); this can be partly explained by the fact
that social pressure is high for adult women, speci-
cally the demands of work or a career in addition to
the duties of a mother and wife. Women also have a
greater risk of developing psychiatric disorders such
as depression and anxiety (50,51). Moreover, large
cities demand a lifestyle which requires sleep depri-
vation, an intrinsic stressor which is increased in the
modern lifestyle and has several negative conse-
quences on health, including hormonal secretion and
the immune system (21,52). Thus, the stress caused by
worsened sleep quality may exercise a relevant role in
adult female acne, as this disease has increased sig-
nicantly in the last decade (53).
HOW STRESS GETS UNDER THE SKIN
Stress is a term we are faced with in everyday life,
being a stimulant for some but pressure for many
others. Psychological stress is an accepted fact of life,
usually triggered by a stimulus that induces a reac-
tion in the brain. As a consequence, additional physi-
ological systems are activated in the body, including
the immune, endocrine, and nervous systems (54,55).
The concept of the skin neuro-endocrine was formu-
lated twenty years ago, and recent advances in this
eld additionally strengthened evidence of its role.
We may say that skin is a bi-directional platform for
a signal exchange with other peripheral organs, such
as endocrine and immune system (56). Skin cells and
appendages not only respond to neuropeptides, ste-
roids, and other regulatory signals but also actively
synthesize a variety of hormones (57). The skin repre-
sents the rst line of defense against many noxious en-
vironmental inputs. Some researchers have indicated
that the skin is especially sensitive to psychological
stress. Experimental ndings demonstrate that stress-
ors aect cutaneous and adaptive immunity (18); fur-
thermore, psychological stress alters cutaneous bar-
rier homeostasis (20,21,58). For example, it has been
shown that the recovery time of the stratum corneum
barrier is reduced after elimination of psychological
stress (innate immunity) (59). Antigen presentation
by epidermal Langerhans cells (adaptive immunity)
was also altered (60). Moreover, psychological stress
may trigger or exacerbate immune-mediated der-
matological disorders. As an evolutionary adaptation
to the ght-or-ight response, psychological stress
generates some responses that can be detrimental in
some states. Stress signals initiate the hypothalamus-
pituitary-adrenal (HPA) axis and the sympathetic ner-
vous system, while also inducing secretion of dier-
ent neurotransmitters, cytokines, and hormones that
possess skin receptors and can aggravate several skin
diseases, including acne (24-27). The exact mecha-
nisms of stress-induced triggering or aggravation of
acne have not yet been completely understood; how-
ever, various mechanisms have been proposed. Some
believe that glucocorticosteroids and adrenal andro-
gens are released during emotionally stressful peri-
ods and lead to acne worsening. The skin expresses
specic genes involved in pathways associated with
inammation and extracellular matrix remodelling
at higher rates in acne-aected parts compared to
acne-unaected skin, including genes encoding for
matrix metalloproteinases 1 and 3, interleukin-8, hu-
man β-defensin 4, and granzyme B (61). Facial skin
from patients with acne is characterized by rich inner-
vation, by increased numbers of substance P-contain-
ing nerves and mast cells, and by high expression of
neutral endopeptidase in the sebaceous glands (SG)
compared with healthy skin (62).
New data regarding the physiology of SG indi-
cate that SG have receptors for numerous neuropep-
tides (β-endorphin, corticotropin-releasing hormone
(CRH), urocortin, proopiomelanocortin, vasoactive in-
testinal polypeptide, neuropeptide Y, and calcitonin
gene-related peptide), and these receptors modulate
inammation, proliferation, and sebum production
and composition, as well as androgen metabolism in
human sebocytes. These neuroendocrine factors with
their autocrine, paracrine, and endocrine actions ap-
pear to mediate centrally and topically induced stress
towards the SG resulting in the clinical course of acne
(16).
Corticotropin-releasing hormone (CRH)
As acne is apparently exacerbated by acute or
chronic psychological stress, the corticotropin-releas-
ing hormone (CRH) appears to be an important as-
pect in the development of acne lesions (63,64). CRH
is a 41-amino acid polypeptide; the innate eect of
CRH and related peptides involves interactions with
membrane-bound CRH receptor type 1 (CRHR-1) and
type 2 (CRHR-2), and it can be modied by its binding
protein (CRH-BP) at the central, local, or systemic lev-
els (65). Pro-CRH processing into CRH appears to be
similar at the central and peripheral levels, including
the skin (66). CRHR-1 is said to be the predominant
form of CRHR expressed in the human skin and pos-
sibly plays a signicant role in coordinating responses
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136
to external stress in analogy to the central response.
CRHR-2 expression was fully documented in cells of
adnexal structures, smooth muscle, blood vessels,
and selected cells of immune origin, and rather plays
a modulatory role. CRH is one of the main compo-
nents of the stress system, the HPA axis, acting to
stimulate attention, inhibit appetite, and promote
secretion of adrenocorticotrophic hormone (ACTH),
α-melanocyte-stimulating hormone, other proopi-
omelanocortin (POMC) derived peptides, and β-en-
dorphin in the pituitary gland via the activation of
CRHR-1 (67). ACTH, in turn, stimulates the production
and secretion of cortisol or corticosterone by the ad-
renal cortex through the activation of melanocortin
receptor type 2 (MC2R). CRH is synthesized among
others by keratinocytes, immune cells, and human
mast cells under the inuence of stress. Propioni-
bacterium acnes, a commensal bacteria of the skin
whose proliferation is linked to acne, can stimulate
the production of CRH by keratinocytes (68). CRH is
also reported to act as a growth factor in the skin by
activating CRHR-1. It plays a role in the regulation of
keratinocyte proliferation and dierentiation, repre-
senting an important step in the early stages of the
development of acne lesions (69). It is also an inhibi-
tor of the early and late apoptosis of many skin cell
types such as keratinocytes, dermal broblasts, and
melanocytes (70). Moreover, CRH is known to act on
inammation by inducing the degranulation of mast
cells (71), the release of inammatory cytokines, and
the modulation of immune cells; CRH enhances inter-
leukin-6 and inhibits IL-1β production in human kera-
tinocytes (72). On the other hand, a study examining
the concentrations of cortisol, 11-deoxycortisol, and
adrenal androgen in women aged 19-39 years with
idiopathic acne before and after inducing prolonged
adrenal stimulation via ACTH infusion reported there
were no signicant dierences in the levels of these
hormones among women with acne and controls
(73). However, this does not undermine the impor-
tance of these hormones in acne development but
rather leads us to the ndings that acne development
and its clinical course depend on the neuroendocrine
factors that mediate stress towards the SG (17,74).
It has become apparent that SG is an organ with
an independent peripheral endocrine function
which, together with the sweat glands, encompasses
the vast majority of androgen metabolism in the skin.
The presence of a complete CRH system in human
sebocytes has been conrmed in vitro and in vivo
(75,76). CRH is a major autocrine hormone in these
cell types with homeostatic dierentiation activity. It
directly induces lipid synthesis and steroidogenesis
and enhances mRNA expression of 5-3β-hydroxys-
teroid dehydrogenase, independently from the HPA
axis (16,76). CRH regulates the lipid synthesis in hu-
man sebocytes, promoting up-regulation at lower
concentrations of lipid content and inducing a de-
crease when the levels are higher (76). Testosterone
and growth hormone, which also enhance sebaceous
lipid synthesis, were found to antagonize CRH activ-
ity and CRHR expression; precisely, testosterone sup-
presses CRHR-1 and CRHR-2 mRNA expression in SZ95
sebocytes while growth hormone switches CRHR-1
mRNA expression to CRHR-2 (76). These ndings im-
plicate the involvement of CRH in the clinical devel-
opment of acne and seborrhea, as well as in further
skin diseases associated with alterations in the forma-
tion of sebaceous lipids. Ganceviciene et al. analyzed
CRHRs by immunohistochemistry in three groups of
biopsies; the facial skin biopsies of 33 acne patients,
non-involved thigh skin of these patients, and nor-
mal skin of eight age-matched healthy volunteers
(74). There was a denite positive reaction for CRH
in acne-involved skin in all types of SG cells, regard-
less of their dierentiation stage. The results diered
in noninvolved and healthy skin biopsies where SG
exhibited a weaker CRH staining depending upon the
dierentiation stage of sebocytes. The most positive
reaction for CRH-BP in acne-involved SG was in dier-
entiating sebocytes. CRHR-1 and CRHR-2 showed the
strongest expression in sweat glands and SG, respec-
tively. They concluded that expression of the com-
plete CRH system is abundant in acne-involved skin,
especially in SG, possibly activating pathways that af-
fect immune and inammatory processes leading to
the development and stress-induced exacerbation of
acne. Concerning the clinical perspectives of CRH and
its receptors in the pathogenesis and the course of
acne, CRHR antagonists could soon arise as possible
therapeutics. At this time, there have already been
some studies demonstrating this eect (77).
Melanocortins
Melanocortin (MC) peptides can also directly af-
fect the function of human sebocytes via MC recep-
tors. Alpha-melanocyte-stimulating hormone (α-
MSH) has been demonstrated to act as a modulator
of the preputial rat gland, a specialized sebaceous
gland-like structure of rodents. The eect of α-MSH is
mediated through binding to G-protein-coupled MC
receptors (MC-R) on the cell surface of the target cell.
To this point, ve dierent MC-Rs have been cloned
(78). The presence of both MC-R, specically MC-1R
and MC-5R, which bind α-MSH, were detected in hu-
man sebocyte cultures established from the facial
skin as well as in immortal human sebocyte cell line
– SZ95 (79-81). In SZ95 sebocytes, α-MSH partially
ACTA DERMATOVENEROLOGICA CROATICA
Jović et al. Acta Dermatovenerol Croat
Impact of psychological stress on acne 2017;25(2):133-141

137
ACTA DERMATOVENEROLOGICA CROATICA
prohibited the inductive eect of IL-1β on the se-
cretion of IL-8, an important chemokine that directs
neutrophils to inammatory sites including SG (79).
In acne-involved skin, sebocytes and keratinocytes of
the ductus seboglandularis showed MC-1R expres-
sion to a high degree in contrast with less intense
dispersed immunoreactivity in normal skin samples,
suggesting that this receptor is involved in the initia-
tion of acne. It has been shown that proinammatory
signals up-regulate MC-1R (82). Since proinamma-
tory cytokines are upregulated in acne lesions (83),
based on the previously mentioned data, sebocytes
would respond to these cytokines with increased
MC-1R expression, thereby generating a negative
feedback mechanism for α-MSH which exerts direct
anti-inammatory actions as it inhibits IL-1β-medi-
ated IL-8 secretion.
The expression of MC-5R is weaker than that
of MC1-R, but it has been shown to be a marker of
human sebocyte dierentiation, since it is only ex-
pressed in dierentiated, lipid-containing sebocytes.
The targeted disruption of MC-5R in mice resulted in
reduced sebaceous lipid production and a severe de-
fect in water repulsion (81). These ndings of Zhang
et al. stimulated a search for MC-5R antagonists as
potential sebum-suppressive agents. As anticipated,
an antagonist-inhibited sebocyte dierentiation in
vitro and reduced sebum production in human skin
transplanted onto immunodecient mice. These data
suggest that antagonists of MC-1R and MC-5R could
be active sebum-suppressive agents, clinically useful
for the treatment of disorders with excessive sebum
production, such as acne (81,84). Clinical trials with
MC-5R antagonists, like topical gel MTC896, have
been initiated for the treatment of excessive sebum
production in subjects with acne and other skin con-
ditions. MTC896 has completed Phase II clinical trials
(85).
Substance P
There have been various reports that demon-
strate an association between human sebocytes and
neurogenic stress axes. Nerve bers release neuro-
genic neuromediators, neuropeptides (NEP), that
exert proinammatory responses on immune system
cells and/or cells of many peripheral tissues as well as
the skin (86,87). Substance P (SP), an important neu-
ropeptide related to stress response and pain, also
plays a fundamental role in acne (88). The sebaceous
gland of patients with acne expresses SP (6,62). In
2002, Toyoda et al. demonstrated for the rst time in
cultured sebocytes that SP stimulates NEP expression
by sebaceous cells in a dose-dependent manner, in
addition to the fact that more numerous SP-contain-
ing nerve bers were present around SG of the facial
skin in patients with acne compared with controls
(62). Later, Lee et al. demonstrated that the addition
of SP induced less proliferation and dierentiation.
Furthermore, the addition of SP increased immunore-
activity to interleukin-1 (IL-1), interleukin-6 (IL-6), and
tumor necrosis factor-α (TNF-α), demonstrating the
inuence of SP on the production of inammatory
mediators (89). Since these ndings, the active patho-
genic role of SP as a potential mediator of neurogenic
inammation in acne has been acknowledged. These
results indicate a connection of neurogenic factors
such as neuropeptides with the pathogenesis of acne
and represent a plausible mechanism for the exacer-
bation of acne from a neurological point of view (90).
CONCLUSION
There is increasing evidence that psychological
stress is an important factor in acne pathogenesis.
Emotional stress associated with the production of
hormones, neuropeptides, and inammatory cyto-
kines inuences the chronic course and exacerbation
of acne by altering the activity of the pilosebaceous
unit. These mechanisms involve the HPA axis and
the neuro-immuno-cutaneous system where neu-
ropeptides and hormones such as CRH, melanocor-
tins, and substance P play a substantial role. On the
other hand, great emotional distress and dysmorphic
tendencies may develop as the consequence of this
disease. Therefore, dermatologists should be capable
of recognizing the psychological factors which either
contribute to the exacerbation of acne or inuence
the self-perception of patients with acne. Addition-
ally, an interdisciplinary therapeutic approach should
be employed in qualifying patients, involving not
only dermatologists but also psychologists and psy-
chiatrists.
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