Adult female acne
INTRODUCTION
Acne affects an increasing number of adult females,
impairing quality of life, with significant negative psychological effect and
social impact. Adult female acne (AFA) is defined as one that affects women
over the age of 25 and may persist continuously or intermittently from
adolescence or manifest for the first time in this period. It is believed that
genetic and hormonal factors contribute to the pathogenesis of AFA,
characterized by chronic evolution, requiring maintenance treatment, in some
cases for years. Studies have confirmed
that persistent acne is more common than acne beginning in adulthood.
Other authors have confirmed that adult females are more
affected than men in all age groups and that acne can persist even after 50
years of age. In addition to persistent and late acne, more recently a third
type has been suggested, called recurrent acne, that is present in adolescence,
improves for a variable period of time, and returns in adulthood. There are few
publications regarding this, because current researches, despite questioning
the age of onset of acne, rarely ask the patient if acne recurred after a
period in adolescence. Some authors suggest two categories of AFA: 25 to 44
years of age and over 45 years of age in the period near menopause, but the
characteristics of each group still need to be better defined.
SPECIFIC CHARACTERISTICS OF ADULT FEMALE ACNE
The clinical characteristics of
adult female acne differ from those of adolescent acne; the key morphological
differences are listed in Figure 1 and Table 1. AFA lesions are located mainly on the lower
part of the face, including the mandibular region, the perioral region and the
chin, conferring a U-shape, in addition to the anterior cervical region. It is
characterized by inflammatory lesions, papules and pustules, with the presence
of few closed comedones or micro cysts. Acne on the
chin (deep‐seated, long‐lasting
small nodules (< 0.5 cm) and cysts in the U‐zone
alone) appears to be specific to women; however, mixed presentations with
inflammatory and non‐inflammatory lesions involving multiple areas of the face are
frequent. Localization of acne on the submandibular area is seen in only
11 % of adult females. Acne of the trunk is less common in this
population. Hyper seborrhea is present in about 70 % of adult females,
although acne is frequently mild to moderate in these patients. Flare‐ups before menstruation appear to be more common in older women,
and are observed in about half of adult patients with acne. These flares are
due to increased water content of the follicular wall in the last week of the
menstrual cycle, and may be more marked in patients using androgenic,
progesterone‐derived oral contraceptives (first and second generation) than
in patients using more recent formulations. Persistent, relapsing and new‐onset types of adult female acne are frequently associated with
inflammation (deep nodules), post‐inflammatory
pigmentation and a high frequency of scarring, with a significant negative
impact on the QoL. Overuse of cosmetics such as make‐up and peeling techniques to address these conditions may be an
issue. Post
inflammatory hyper pigmentation is more prevalent
in women with dark skin or phototype IV, and may be of greater concern than for
women with a lighter skin complexion. In addition, the skin may be more
sensitive than that of adolescents, with less tolerance to topical medications.
Adolescent acne that persists
and is transformed to adult acne often involves frequent relapses; adult female
acne therefore requires even more maintenance therapy for an extended period
than adolescent acne (in which the numerous pubertal lesions usually respond
quickly to treatment).
Although no clear difference in
pathogenesis between adult female acne and adolescent acne has been
demonstrated, adult female acne is dominated by three main pathophysiological
factors: (a) resistant strains of Propionibacterium acnes may
cause chronic stimulation of the innate immune system, initiating and
exacerbating inflammatory lesions; (b) levels of dihydroepiandrosterone sulfate
(DHEA‐S) in the upper range of normal stimulate IL‐2 production and enhance Th1 immune function; and (c) a genetic
predisposition in over half the patients (acne experienced by mother, father or
siblings). Increasing evidence suggests that levels of anti‐Müllerian hormone are elevated in adult females with acne,
further supporting a state of mild endocrine dysfunction. Increased serum
levels of insulin‐like growth factor 1 correlate positively with female acne
lesion counts, with evidence that a low‐glycemic‐load diet may significantly reduce acne severity and improve
insulin sensitivity. Obesity and insulin resistance are intrinsically linked to
acne and other systemic diseases. They can therefore be positively influenced
by low‐glycemic‐load dietary restrictions.
Figure 1.
Table 1: Clinical forms of adult female acne
Severity scales
It is believed that AFA is different from juvenile acne due
to its clinical evolution. Scales have been developed to validate a severity
score for each type of acne and thus ensure the best treatment. These include
the GEA (Global Evaluation Acne) scale and, more recently, the AFAST (Adult
Female Acne Scoring Tool), which includes the submandibular region evaluation,
as shown in Table 2.
Table 2: AFAST rating scale for adult female acne AFAST
SCALE (Adult Female Acne Scoring Tool)
Score 1: Assess the severity of acne on face (GEA SCORE)
ETIOPATHOGENESIS
The etiopathogenesis of acne vulgaris involves a complex
interaction between the main factors such as: genetic predisposition;
androgenic hormone stimulation leading to an increase in sebaceous secretion;
alteration of the lipid composition; follicular hyperkeratinization; bacterial
colonization mainly by Propionibacterium acnes (P. acnes) and periglandular
dermal inflammation. Currently, inflammation is considered a key component and
can be detected on histopathological and immunohistochemical examination in
apparently non-inflammatory acne lesions such as comedones and even in
perilesional areas, without lesions (subclinical).
The causes of AFA have not yet been fully elucidated.
Several other factors have been postulated as triggers or aggravating factors,
such as: exposure to ultraviolet radiation, stress, obesity, diet, smoking,
sleep disorders, cosmetics, medications, excessive skin washing, possible
resistance to P. acnes and endocrine deficiency diseases. Currently, the
deficiency of the epidermal barrier function has also been reported as a
relevant change. The damage of the barrier and the consequent increase in
transepidermal water loss may be responsible for the onset of the inflammatory
cascade that constitutes the central change in the onset of acne. Figure 1
presents the main etiopathogenical factors in AFA.
Genetics
Genetic predisposition has been considered an important
predisposing factor, influencing the number, size and activity of the sebaceous
glands. Its influence on hormonal control has also been observed, as well as on
the process of follicular hyperkeratinization and on innate immunity. In one
study, adult women with acne reported first-degree relatives with acne in
adulthood.
Hormones
The role of androgens in the etiopathogenesis of acne
vulgaris is well established. Testosterone, Dehydroepiandrosterone Sulfate
(SDHEA) and Dihydrotestosterone (DHT) stimulate sebaceous gland growth and
sebum production. Estrogens have the opposite effect, that is, they inhibit the
secretion of androgens, modulate genes involved in the growth of the sebaceous
gland and inhibit their function.
The activity of the sebaceous gland therefore depends on
the estrogen/androgen ratio.
In relation to AFA and hormones, the following are
outstanding:
1) Increased sensitivity of the sebaceous gland to
androgenic hormones: As in acne vulgaris, in AFA there is an increase in the
number and sensitivity of the receptors located in sebocytes and keratinocytes
to circulating androgenic hormones.
2) Increased peripheral hormonal conversion: sebocytes
and keratinocytes present an enzymatic system capable of locally producing
testosterone and DHT. Hyperactivity and abnormal activity of enzymes related to
the metabolism of androgenic hormones such as 5-alpha reductase,
3-beta-hydroxysteroid dehydrogenase and 17-hydroxysteroid dehydrogenase, with increased
pre-hormone peripheral conversion (SDHEA, androstenedione and testosterone)
into more potent androgenic hormones (testosterone and DHT). DHT is 5 to 10
times more potent than its precursor testosterone, and less likely to be
metabolized by aromatase into estrogen.
3) Worsening of the disease in the premenstrual period in
60 to 70% of women, as well as in premenopausal, pregnancy and during the use
of progestin-only contraceptives. In these periods there is a relative increase
of the hormones with greater androgenic activity, in relation to estradiol.
4) Other hormones, besides androgens and estrogens,
regulate the production of sebum: the sebaceous gland is a neuroendocrine organ
and the production of sebum can also be stimulated, in periods of stress, by
neuropeptides and hormones such as melanocortins and corticotropin-releasing
hormone (CRH). CRH increases the expression of 3β-hydroxy-steroid dehydrogenase
mRNA, the enzyme responsible for the conversion of dihydroepiandrosterone
(DHEA) to testosterone. Also neuropeptides, histamine, retinoids, vitamin D and
insulin-like growth factor 1 (IGF-1) have been described as regulators of sebum
production.
Changes in sebum
Qualitative changes were verified in the components of
sebum in the skin with acne. There is a relative decrease of Linoleic Acid
(AL), an Essential Fatty Acid (EFA), and protector of the glandular epithelial
wall. There is also the peroxidation of squalene by the combined action of P.
acnes and ultraviolet radiation. These alterations and the presence of free
fatty acids resulting from the hydrolysis of triglycerides, through the action
of lipases released by P. acnes, cause damage the epithelium, increasing
infundibular keratinization and dermal inflammation.
Follicular hyperkeratinization
There is an abnormal proliferation of keratinocytes,
stimulated by pro-inflammatory cytokines, such as interleukin-1 alpha (IL-1
alpha). This cytokine is triggered by the activation of Toll-like receptors TLR
2 and 4, related to innate immunity, which recognize molecular patterns present
in P. acnes, as well as sebaceous hyper-secretion and squalene peroxidation.
The formation of the micro-comedone is also preceded by a mononuclear
infiltrate formed mainly by CD4+ T lymphocytes and CD68+ macrophages, which
corroborates to the hypothesis of the participation of the inflammatory process
in the early stages of acne.
Bacterial colonization
The main bacterium involved in the pathogenesis of acne
is P. acnes. It is a Gram-positive anaerobic bacterium that makes up the
microbiome of the skin, being located preferably in the seborrheic areas. In
skin with acne there is an exaggerated growth of the population of P. acnes. P. acnes is involved in several mechanisms:
stimulation of follicular hyper-keratinization; alteration of the sebaceous
composition; and inflammatory response through TLR activation. In addition, it
produces several enzymes, such as lipases, proteases, hyaluronidases,
endoglyceramidase, sialidase/neuroaminidase, proteinase and 5 cAMP factors, which
contribute to follicular rupture and tissue degradation.
Immuno-inflammatory processes
Upon recognition of the P. acnes molecular patterns, TLR
2 and 4 are activated, triggering an inflammatory cascade through the nuclear
pathway NFk β, with production of pro-inflammatory cytokines or interleukins
and tumor necrosis factor alpha (TNF-alpha) that recruit neutrophils and
macrophages, maintaining the inflammatory cycle. Activation of TLR leads to the
release of antimicrobial peptides such as beta-defensins 1 and 2, cathelecidins
and granulolysins. A second nuclear pathway is also activated - pathway AP1,
with release of metalloproteinases 1, 3 and 9 that degrade the extracellular
dermal matrix and are associated with the formation of scars.
Other factors
Diet
Studies have shown that consumption of high glycemic and
dairy foods increases insulin and IGF1 levels. The gonads and sebaceous glands
have receptors for both hormones which stimulate the production of androgens,
such as testosterone, and inhibit the action of aromatase that converts
testosterone to estradiol. The nutritional status of the cell is recognized
initially by the transcription factors FOX01 and the signaling pathway mTORC1.
High glycemic load foods, dairy products, increased insulin and IGF1 stimulate
mTORC1, triggering processes such as: increased protein and lipid synthesis,
cell proliferation, cell differentiation with acroinfundibular
hyper-proliferation of keratinocytes, sebaceous gland hyperplasia, increased
sebaceous lipogenesis, insulin resistance and increased body mass index. In
addition to the diet rich in foods with a high glycemic load and the
consumption of dairy products, worsening of acne by the use of dietary
supplements for muscle mass gains that are rich in branched-chain amino acids
and peptides derived from whey is observed in daily practice.
Drugs
Certain medications are associated with the development
of acne, such as benzodiazepines, lithium, cyclosporin, ramipril, isoniazid,
iodides, bromides, vitamin B-type complexes, serotonin uptake inhibitors,
epidermal growth receptor inhibitors and progestin contraceptives.
First-generation progestins such as norgestrel and levonorgestrel have
androgenic effect similar to testosterone. Corticosteroids stimulate hyperkeratinization
and increase the expression of TLR 2.
Authors have noted that levonorgestrel intrauterine
devices, subcutaneous etonorgestrel and levonorgestrel implants, and
long-acting methods with progestin alone may have a negative effect on acne or
may trigger acne in predisposed women. A prospective study showed that 10% of
80 women who used subcutaneous implants with etonorgestrel had acne. Another
multicenter, randomized, controlled study of subcutaneous implants with
etonorgestrel or levonorgestrel compared to copper intrauterine devices showed
that acne was more frequent in the group with implants. However, it is
important to consider other causes for the appearance of acne in these cases,
such as the suspension of estrogen-containing oral contraceptives.
Stress
Stress stimulates the release of pro-inflammatory
cytokines and CRH, leading to increased levels of cortisol. Recent studies show
that sleep deprivation associated with women’s modern lifestyle and stress have
an important impact on the hypothalamic-pituitary-adrenal axis and in increased
secretion of stress-related hormones, and may also be an aggravating factor for
acne. Goulden et al and Poli et al reported stress as a worsening factor for
acne in 71% and 50% of women, respectively.
Tobacco
There is a close relationship between smoking and the
occurrence of AFA. Studies show that tobacco is the main factor responsible for
the appearance of non-inflammatory acne in this age group, with a significant
difference between female smokers and nonsmokers. The comedonal form
predominates in smokers and is characterized by the presence of micro and
macro-comedones and few inflammatory lesions, which led the authors to describe
this clinical form as “smoker’s face.” The sebaceous gland is sensitive to
acetylcholine that is stimulated by nicotine. Acetylcholine leads to cellular
modulation and differentiation, inducing hyper-keratinization and influencing
sebum production and composition, as well as reducing antioxidant agents and
increasing peroxidation of sebum components, such as squalene.
Endocrine diseases
The association of acne with an endocrinopathy
characterized by hyper-androgenism usually presents other clinical signs such
as: hirsutism, seborrhoea, alopecia, menstrual disorders, ovulatory
dysfunction, infertility, early puberty, metabolic syndrome and virilization.
The main endocrinopathies that occur with hyper-androgenism are: Polycystic
ovary syndrome POS, late congenital adrenal hyperplasia or dysfunction and,
more rarely, ovarian, adrenal, pituitary and hypothalamic tumors.
Hyperinsulinemia and peripheral insulin resistance occur frequently in women
with POS.
Hyperinsulinemia influences the concentration of plasma
IGF-1 and Insulin Growth Factor Binding Protein-Like 3 binding protein
(IGFBP-3), which act directly on keratinocyte proliferation and apoptosis. In a
hyperinsulinemic state, the rate of IGF-1 is elevated and IGFBP-3 is lowered,
leading to an imbalance that culminates in hyperproliferation of keratinocytes.
Increased IGF-1 also inhibits aromatase and prevents the conversion of
testosterone to estrogen. In this hyperinsulinemia, there is still a decrease
in the hepatic production of SHBG, favoring the elevation of the free androgens
that constitute its active form. In adult women with acne and POS, it is
important to evaluate the possibility of glucose intolerance. In POS, total
cholesterol is increased at the expense of increasing the low density
lipoprotein (LDL) fraction and decreasing the high density lipoprotein (HDL).
Triglycerides are also increased as the plasminogen activator inhibitor (PAI)
is. These changes in lipids and the increase in PAI favor arterial
hypertension, coronary disease and thrombosis. In women with acne, obesity and
PCOS, metabolic syndrome is very common, characterized by: 1) abdominal obesity
(circumference of the waist)> 88cm; 2) triglycerides> 150mg / dL; 3) HDL
130 /> 85mm Hg; 5) high glycemia = 110-126mg / dL; and glycemia two hours
after the glucose tolerance test = 140-199mg / dL.
LABORATORY
INVESTIGATIONS
In the presence of other clinical signs of
hyperandrogenism, most authors suggest plasma concentrations of free and total
testosterone, S-DHEA, Luteinizing Hormone (LH), Follicle Stimulating Hormone
(FSH) and, in some cases, when suspecting POS, transvaginal ultrasound for
visualization of the ovaries. These tests should always be performed in the
follicular phase, preferably between the first and fifth day of the menstrual
cycle and the collection should be done in the morning, between 8 and 10 am. In
this way, the hormonal variations of the menstrual cycle interfere less with
blood analysis. It is not recommended to perform exams when hormonal
contraceptives are in use.
POS is the most frequently diagnosed cause. In suspected
POS, the following criteria should be checked: presence of menstrual
alterations (amenorrhea or oligomenorrhea), clinical and/or biochemical and/or
hyperandrogenism, as well as ultrasonographic changes (presence of 12 or more
follicles with 2 and 9 mm of diameter or increase in ovarian volume >
10cm3). In the revised consensus of 2004, the presence of two of the three
criteria confirmed the diagnosis.
Figure 2 presents a scheme for laboratory investigation
of AFA.
Although most AFA patients show no signs of clinical or
laboratory hyperandrogenism, slightly elevated levels of S-DHEA have been
observed.
DHT could be useful as a primary marker of peripheral
androgen production, but its dosage is not recommended in clinical practice,
since it is rapidly metabolized and has high affinity for SHBG.
A distal metabolite of DHT, produced in
androgen-responsive tissues, is 3-alpha, 17-beta-androstanediol glucuronate. In
the final phase of metabolization, the enzyme 3α-hydroxy dehydrogenase converts
DHT to 3α-androstenediol which undergoes glucuronidation. This modification
decreases its affinity for binding proteins, increases its hydrophilicity and
facilitates renal excretion. This metabolite can be used as a marker of
hyperandrogenism, especially in women with idiopathic hirsutism, but is not
useful in AFA.
Another androgenic metabolite of interest is Androsterone
Glucuronate (ADT-G), which corresponds to 93% of all metabolites. Currently the
use of sensitive and specific laboratory techniques, such as liquid
chromatography associated with mass spectrometry, for the dosages of this
metabolite, allows evaluation of the total androgenic activity of the organism,
with great accuracy, showing correlation with the clinical findings.
TREATMENT OF ADULT
FEMALE ACNE
Physicians should be
encouraged to take a holistic approach to managing women with acne, considering
the distinctive features and circumstances of each individual. These include:
extent, severity and duration of disease; response to previous treatments;
predisposition to scarring and post‐inflammatory hyper pigmentation (PIH), as well
as patient preference, psychosocial impact, possibility of
pregnancy, slow response to treatment and increased risk of sensitive skin
irritation.
AFA is a therapeutic challenge because it presents a
tendency to relapse, even after cycles of oral antibiotics or isotretinoin. The
typical evolution of AFA, with frequent relapses, makes maintenance treatment
essential.
Figure 3 presents an algorithm for treating AFA.
ACNE
MANAGEMENT GUIDELINES BY THE DERMATOLOGICAL SOCIETY OF SINGAPORE, JULY 1, 2019
Recommendations for therapy of female acne, regardless of type
or severity
|
Recommendations |
|
|
General skin care |
‐ Gentle, non‐soap cleanser (pH
around 5.5) ‐Non‐comedogenic, oil‐free moisturizer ‐ Limited use of facial
treatments ‐ Cosmetic concealers
(make‐up and camouflage cream) of good quality (non‐comedogenic, oil‐free) ‐Ultraviolet‐blocking photo protection
(light, non‐comedogenic) |
|
Post‐inflammatory hyper pigmentation |
First line: ‐ Topical azelaic acid
(15 % gel; 20 % cream) ‐ Topical retinoids ‐ BPO + topical
retinoids Second line: ‐ Hydroquinone ‐ Hydroquinone +
retinoic acid + corticosteroid ‐ Adjunctive
therapies: ‐ Non‐ablative fractional
photochemolysis ‐ Superficial chemical
peels |
|
Scarring |
First line: ‐ Topical retinoids Adjunctive therapies: ‐ Cryosurgery ‐ Dermabrasion,
microneedling, chemical peels ‐ Laser therapy ‐ Punch excision and
punch elevation/grafting of deep scars ‐ Subcision and fillers |
|
Maintenance therapy |
‐ Azelaic acid ‐ Topical retinoids
(e.g. adapalene) |
|
Psychological support |
‐ Empathy and
understanding of the impact of disease on quality of life (personal and
professional factors) ‐ Self‐perceptions of acne
severity vary and can be misjudged ‐ Assess stress and
sleep patterns |
TOPICAL TREATMENT
Topical agents are usually
sufficient to manage mild disease; however, for adult females (who often have a
longer duration of disease), a fixed combination of topical agents or a topical
agent plus a systemic treatment may be required.
Retinoids are a first‐line choice for most mild‐to‐moderate types
of adult acne. They are comedolytic, anti‐comedogenic and anti‐inflammatory. They reduce hyper pigmentation and are pro‐collagenic, assisting rebuilding of the papillary matrix. Third‐generation agents such as adapalene 0.1 % and
microcrystalline solutions of tretinoin (< 10 microns) are better
tolerated than older retinoid generations and formulations. However, women
should avoid retinoids, at least during the first trimester of pregnancy, due
to their teratogenicity.
Azelaic acid (20 % cream or 15 %
gel) is also a first‐line choice
for mild‐to‐moderate adult acne in females; it has good efficacy and a
favorable safety profile, even in pregnant women and breastfeeding demonstrates anti‐tyrosinase activity (useful for PIH) and antibacterial and
anticomedogenic activity. Azelaic acid thus represents an
important option for women of childbearing age and with a desire to become
pregnant as it is considered safe by the Food and Drug Administration (FDA).
Benzoyl peroxide (BPO) has strong
bactericidal properties and can be used in pregnancy, but may cause irritant
contact dermatitis and dryness of the skin,
the extent of which is related to the amount and type of product,
concentration, and vehicle. Therefore, concentrations of benzoyl
peroxide above 5% are not recommended for use in adult women. It can also cause
photosensitivity and bleaching of clothing.
Topical antibiotics have a direct
anti-inflammatory action reducing perifollicular lymphocytic infiltrate. Topical antibiotics should not be considered for
monotherapy or alongside systemic antibiotics, due to the long duration of
female acne and high prevalence of bacterial resistance; however, they can be
combined with a retinoid or BPO.
Dapsone 5% gel is used as treatment twice daily in adult
females with good efficacy and tolerance. In patients with acne vulgaris, it
has been shown to be useful when combined with doxycycline and then alone as
maintenance for long periods, with the advantage of having no risk for
bacterial resistance.
With mild inflammatory acne, topical
retinoids can be combined with BPO, azelaic acid, or clindamycin phosphate in
fixed formulations according to the prevalence of retentional or inflammatory
lesions; with moderate disease, these agents can be prescribed along-side
systemic treatments (e.g. cyclins, anti‐androgens
or zinc salts). However, no topical antibiotics are recommended with systemic
antibiotics.
Associations
Retinoids + Benzoyl peroxide
The efficacy and safety of adapalene 0.1% combined with
2.5% benzoyl peroxide gel compared to the vehicle in women 25 years of age or
older were analyzed by meta-analysis of data extracted from subgroups from
three multi-center, phase 2 and 3, randomized, parallel and double-blind
studies. A rapid onset of action was demonstrated, with a significant reduction
in lesions from the first week of use; the combination was considered
effective, safe and tolerated well in both the population less than 18 years
and over 25 years, with similar indices.
Retinoids + Antibiotics
The tretinoin-clindamicyn combination has been studied
for the treatment of acne; a later analysis included only data from adult
females. The combination proved to be more effective in reducing inflammatory
and non-inflammatory lesions than the isolated tretinoin or clindamycin.
Antibiotics + Benzoyl peroxide
The combination of benzoyl peroxide 3.75% + clindamycin
1.2% was studied for long-term use (up to 24 weeks) in 20 adult females. At
week 12, inflammatory lesions decreased by 70% and non-inflammatory lesions
decreased by 58%. In the 24th week, the improvement was 93% and 90%,
respectively. There were no serious adverse events. This study allowed to
evaluate the safety of long term use as well as demonstrated continuous
improvement.
SYSTEMIC TREATMENT
Systemic treatments are
usually required for moderate to severe acne as well as for mild forms (mainly
mandibular acne) associated with scarring, long duration or failure to respond
to topical therapies. Combination with fixed‐dose topical therapies is useful in moderate to
severe disease and may be more convenient than multiple individual agents. Zinc
salts may be useful for general inflammation and during pregnancy.
Antibiotics
Adult women with facial acne have a good response to
antibiotics; however, relapses are common after discontinuation of treatment. Systemic antibiotics should not be used
alone, but may show synergistic efficacy combined with topical therapies
(except topical antibiotics). These can be combined with BPO, retinoid or
azelaic acid, but tetracyclines and retinoids need to be avoided during
pregnancy. Adding benzoyl
peroxide in the concentration of 2.5 to 5% has synergistic action to
antibiotics, accelerating the response, besides preventing the development of
resistance, while retinoids can
target most pathogenic factors more effectively than anti‐microbial
therapy alone. Doxycycline and lymecycline are preferred choices (once‐daily
formulations with few food interactions and good patient adherence). Erythromycin is associated with greater
bacterial resistance than other antibiotics, but is the first choice for
pregnant women.
Hormones
Hormonal therapies,
including anti‐androgens and 3rd/4th generation OCs are
highly effective for AFA, even in patients without serum hormone changes, they
are suitable for long-term therapy because they have no potential to induce
bacterial resistance and represent an alternative to systemic antibiotics. In
adult females, hormonal agents are recommended in the following situations:
presence of severe seborrhea; worsening in the premenstrual period; presence of
endocrine changes; persistent recalcitrant inflammatory acne in which standard
treatments have failed, including repeated cycles of isotretinoin; late onset
acne and when oral contraception is required or desired. As hormone treatments
reduce excess sebum production, it is recommended that they are combined with
agents that act on other pathogenic factors, such as antibiotics, benzoyl
peroxide, retinoids, and azelaic acid.
Androgen receptor blockers (antiandrogens)
The most prominent are: cyproterone acetate,
spironolactone, and drospirenone.
Ciproterone acetate: Combined with ethinyl estradiol, it
is recommended for the treatment of mild to moderate AFA. Side effects include
menstrual changes, tenderness and enlargement of the breast, nausea, vomiting,
fluid retention, edema, headache, and melasma.
SPIRONOLACTONE
Spironolactone as low‐dose
monotherapy (50–150 mg/day) or combined with topical therapy can be used
for acne resistant to standard treatment (a 3rd/4th generation
OC may be added for menstrual irregularity as 80% of the patients
present menstrual irregularity);
however, its use in acne is currently off‐label in Europe and the US (where clinical
trials are ongoing) and should be avoided in pregnancy.
A retrospective study of spironolactone found that there
is no need for periodic control of potassium levels in young women, who do not
have nephropathies, and are not users of other medications that may increase
potassium levels. A systematic review
published in 2017 concluded that the evidence for its use in the treatment of
AFA is still poor, its recommendation is still based on expert opinion or
consensus, and randomized, controlled, double-blind trials for the proof of effectiveness
are still lacking.
Inhibitors of ovarian androgen production
OCPs containing ethinyl estradiol combined with
progestins with antiandrogenic activity are recommended for the treatment of
mild to moderate AFA. Although the evidence is limited and somewhat
conflicting, combinations containing cyproterone acetate may be slightly more
effective than those containing newer progestins, such as desogestrel,
gestodene, levonorgestrel, or norgestimate. Drospirenone-containing OCPs are
effective in reducing inflammatory and non-inflammatory acne lesions.
Clinicians should be aware of the absolute and relative contra-indications of
OCPs prior to prescription. According to a systematic review in 2014, the risk
of thromboembolism with OCPs is related to both estrogen and progestin type.
Thus, the higher the estrogen concentration the greater the risk, and for the
progestins it was concluded that the second generation (more androgenic) have a
lower risk than those of the third and fourth generations.
Inhibitors of adrenal androgen production
Low doses of corticosteroids, such as prednisone (2.5 or
5mg), can suppress adrenal androgen production and are recommended in late
congenital adrenal hyperplasia, acute inflammatory lesions in AFA, and
short-term treatment of very severe acne.
ISOTRETINOIN
Isotretinoin is a highly
effective oral treatment, specifically indicated for use after failure of other
therapies; however, in women it may be used as first‐line treatment
for severe nodular acne or second‐line treatment for severe papulopustular acne
unresponsive to courses of oral antibiotic along with topical
medications and frequent recurrences, tendency to scars and negative
psychosocial impact.
Combining isotretinoin
with OCs when contraception is required offers synergistic effects, and
concomitant use of oral antihistamine (off label) reduces the degree of side
effects. Isotretinoin is more often associated with relapses when an androgen
excess is present.
It acts by reducing the size and activity of the
sebaceous glands by apoptosis of sebocytes; exhibits anti-inflammatory
properties by modulating TLR 2 expression and gene transcription mediated by
Fox O or Forkhead Box Class O.
Isotretinoin is associated
with significant dose‐related side effects and is contraindicated in
pregnancy. The most common are mucocutaneous: cheilitis,
xerophthalmia, conjunctivitis, nasal dryness, epistaxis and irritative
dermatitis. Laboratory abnormalities may include elevation of liver enzymes,
increase in triglyceride and cholesterol levels, elevation of LDL fraction, and
decrease in HDL fraction. Teratogenicity is the most serious and irreversible
adverse effect. Fetal exposure to isotretinoin, regardless of dose, at any time
during gestation, but especially in the first trimester, can cause serious
defects, with an incidence of approximately 28%.
The occurrence of depression, suicidal ideation or
attempted suicide associated with isotretinoin in the treatment of acne
vulgaris has been reported in the literature of case reports and case-control
studies. The observed incidence ranges from less than 1% to 3%, while in the
general population it is estimated to be between 1.6 and 7.5%, with an average
of 3%. Numerous studies have concluded that the drug more often determines
improvement or cure of depressive symptoms that have been proven to be related
to acne and cause depression. Population studies have not confirmed this
association. However, the recommendation remains to monitor symptoms and, if
necessary, request psychiatric evaluation and treatment. It is worth
remembering that in adult females, emotional and psychic disorders, stress,
insomnia, and other symptoms are common.
The development of Inflammatory Bowel Disease (IBD),
particularly ulcerative colitis was related to isotretinoin. However, several
population-based, case-control studies have concluded that this association
does not exist. On the other hand, Crohn’s disease has been reported with the
use of tetracycline-class antibiotics, particularly doxycycline and even
topical treatments for acne, evidencing that the causal factor is the disease and
not the therapeutic option. There seems to be a misconception about the true
triggering factor. A recent meta-analysis has shown that there is no increased
risk of developing IBD after exposure to isotretinoin.
Clinical and laboratory monitoring includes detailed
history, complete physical examination, and complementary examinations.
Reassessments of hepatic transaminases and lipids were performed monthly in the
past. Considering that the proportion of patients with laboratory abnormalities
is low, particularly adolescents, it is currently recommended to repeat the
tests 4 to 6 weeks after starting treatment and reassessments only for those
who have changed. The recommended daily dose is 0.5 to 1.0mg / kg, after meals
(preferably fatty), for a period of 6 to 12 months, up to a total dose of 120
to 150mg/kg.
There are reports of use of lower daily doses, without
the need to reach the total dose of 120mg/kg body weight. The benefits of
regimens with 0.3 to 0.4mg/kg/day, 20mg/day, 20mg every other day, 5mg/day, in
the treatment of moderate acne, with the same efficacy, fewer side effects and
greater adherence to treatment. However, this is not recommended for use in
leaflets. These regimens may be a useful option for AFA resistant to topical
and hormonal treatments by reducing adverse events. However, effective
prevention of pregnancy is necessary since these women may be of childbearing
age and the risk of teratogenicity is equal to the use at usual doses. To begin
treatment in women of childbearing age, it is necessary to inform of the risks,
the need for two contraceptive methods, pregnancy tests and to wait for
menstruation. In adult females, particularly those with overweight tendency or
obese, or with hormonal changes, more frequent laboratory monitoring becomes
essential. There has been an increased risk of elevated cholesterol and triglycerides
and weight gain. No changes were detected in serum androgens and insulin.
Adult women with hyperandrogenism often require more than
one course of treatment with isotretinoin, in addition to hormones. One measure
that may contribute to avoid recurrence is maintenance therapy with adapalene,
benzoyl peroxide, or azelaic acid for 6 months to 2 years. A risk of relapse
that is 3.5 times greater has been reported in women who did not use concomitant
anti-androgen therapy.
Maintenance treatment
The pathophysiology of adult
female acne is not yet fully explored, but persistence and relapse are a
typical course. Therefore, treatment duration and appropriate long‐term patient support should be management considerations.
Maintenance therapy is required to minimize the risk of relapse after acute
treatment and where recurrences are frequent.
Topical retinoids (e.g. 0.1% adapalene) and 15 or 20% azelaic
acid are good candidates for maintenance therapy. The effect of adapalene has
been shown to persist after cessation of active treatment, and azelaic acid has
demonstrated non‐inferiority to adapalene, with a favorable safety profile for
maintenance therapy of adult female acne.
Adjuvant treatments
Cosmeceuticals and cosmetics
The topical and systemic treatment for acne can cause
dryness, irritation, damage to the epidermal barrier, increased transepidermal
water loss and inflammation, and may reduce adhesion. Moisturizers may
contribute to reduce these adverse events of topical products and oral
isotretinoin by avoiding the impairment of the epidermal barrier that is
essential to prevent or reduce inflammation.
Many authors consider that because cosmeceuticals are
available without prescription and medical supervision, there may be harm in
educating patients about their dermatoses (such as acne). Intensive advertising
is highly targeted at adult females and may induce them to self-medication with
ineffective and skin-irritating products, as well as causing delay in seeking
suitable dermatological care, increasing the risk of continuation. In addition,
data on acne efficacy is limited and information presented by companies is much
more based on in vitro research than in randomized controlled trials of
finished products.
Acne cosmeceuticals include cleansing agents for oily or
sensitive skin, sebaceous secretion regulators, anti-inflammatory drugs,
moisturizers and sunscreens (useful for preventing post-inflammatory hyper pigmentation).
Clinical data on retinoids retinol, retinaldehyde, retinyl ester, adapalene
0.1%, niacinamide (active form, amide, niacin or nicotinic acid or vitamin B3)
and glycolic acid in concentrations of 5 to 20% indicate that they may be
useful in the initial, mild to moderate forms of acne, particularly comedonal
and accompanied by increased seborrhea. They are not superior to medicines for
these forms and there is no data for severe acne. Niacinamide may be useful for
antimicrobial, sebostatic, anti-inflammatory effects, inhibition of melanosome transfer,
increased synthesis of ceramides, inhibition of nitric oxide and consequent
changes in capillary permeability.
As some anti-acne agents may cause skin dryness, erythema
and discomfort, moisturizers and cleansing agents (preferably soap free and near-skin
pH) are recommended as an essential part of the therapeutic regimen in AFA. It
is necessary to add photo-protection with non-comedogenic products capable of
also providing comfort and hydration. In certain climatic conditions the use of
moisturizer may be crucial for adherence to treatment, counteracting dryness
and improving the barrier function of the stratum corneum.
Glycolic acid is the alpha-hydroxy acid most used in the
treatment of acne and hyper pigmentation, as it quickly crosses the stratum
corneum, reaches the lower layers of the epidermis and the hair follicles
reducing the cohesion between the keratinocytes. It is considered useful in
reducing the size of follicular ostia and in removing comedones. A topical
combination containing 10.4% L-lactic acid, 2% salicylic acid and alpha-hydroxy
acid/retinoate conjugate (ethyl lactyl retinoate) was used in the topical
treatment of females of ages 20 to 58. After 4 weeks, improvement was achieved,
which remained continuous and cumulative in the eighth week.
A formulation containing 0.1% retinaldehyde and 6%
glycolic acid was studied for concomitant use with other acne treatments
(except retinoids) and has been shown to be tolerable. Authors commented on the
possibility of using this formulation as monotherapy in mild to moderate acne.
Among cosmetics, corrective makeup and camouflage are
useful and should be part of the therapeutic regimen as they improve the
quality of life, contribute to sun protection and reduce the habit of
inconsistency, very common in females. Obvious facial injuries are a very
important problem for women. Well-targeted use of cosmeceuticals and cosmetics
can benefit drug treatment by reducing side effects, reducing the need for
topical antibiotics, and improving adherence to the therapeutic regimen.
Mechanical procedures
Indications of
procedures
· Comedonal
acne
· Recalcitrant
acne
· Nodulocystic
acne
· Flare
up of acne after isotretinoin
· When
isotretinoin is contraindicated or needs to be avoided
· Patients
with tendency to hypertrophic and keloidal scarring
· Need
for quick response for psychological and social reasons
Intralesional infiltration with corticosteroid: The
corticosteroid of choice for this minimally invasive procedure is triamcinolone
acetonide. It is indicated in nodulocystic acne, in a concentration of
2.5mg/mL, diluted in distilled water, in single application, with improvement
in 48 to 72 hours. In the presence of multiple lesions, 5mg per application
should not be exceeded to avoid systemic absorption. It is useful in the
treatment of inflammatory nodules, even during the use of oral isotretinoin,
since it accelerates regression and relieves pain rapidly in these lesions. It
is also indicated in the approach of hypertrophic and keloid scars, with total
or partial regression.
Manual extraction of comedones: Removal of comedones,
particularly open ones, may be useful by unclogging the follicular opening,
facilitating the penetration of topical keratolytic products and contributing
to the reduction of inflammation. In addition, it provides a positive impact on
the quality of life, prevents the manipulation of the lesions in an inadequate
way by the patient and/ or laymen.
Eletrocauterization of macro-comedones: The
electrocautery of closed macro-comedones should be performed with great care
not to reach excessive depth and cause scarring. It is useful since
macro-comedones frequently evolve to inflammatory lesions. In addition, it
avoids manipulation that causes exulcerations and inflammation.
Draining of cysts and abscesses: It is a necessary
procedure when there is fluctuation in these lesions, associated with the use
of oral antibiotics, because it reduces the period of evolution and the
scarring development.
Microdermabrasion: Microdermabrasion is a very
superficial exfoliation method equivalent to a superficial peeling. It is based
on the blasting of aluminum crystals until the appearance of mild erythema.
After 2 to 3 days there is a fine peeling. The advantage over chemical peels is
lack of burning, but the result may be poorer. It is most indicated in the
preparation of the skin for the treatment of superficial atrophic scars. It is
a simple, safe procedure and when carried out serially in several weekly
sessions can induce reorganization and increase the density of dermal collagen.
Chemical peels, lights and lasers
The superficial chemical peels have keratolytic action,
causing superficial exfoliation due to its epidermal effects that are useful
for comedonal and mild inflammatory forms. The most commonly used agents in the
treatment of active acne are Jessner’s solution, 10% trichloroacetic acid (TCA)
or 20% in aqueous solution, 30% salicylic in hydro-alcoholic solution or
polyethylene glycol, 70% glycolic or other gel concentrations of natrosol, with
partially buffered pH and 50% pyruvic acid. Salicylic and pyruvic acids have
demonstrated a significant reduction in sebum content in the skin with acne
through sebummetry. Several comparative studies have shown similar efficacy
among the agents, with varying differences in tolerability. All can cause
burning, erythema and desquamation after 3 to 5 days, lasting from 7 to 15
days. Unpredictable immediate reactions may occur, particularly with glycolic
acid, which requires more care and observation of symptoms and signs until
their removal. Such reactions include edema, vesiculation and undesirable
bleaching due to epidermolysis. In this situation, immediate neutralization
with 10% sodium bicarbonate in aqueous solution and removal of the agent should
be performed. In general, they are safe procedures, without late complications;
except when exaggerated, unpredictable immediate reactions occur that may cause
post-inflammatory hyper pigmentation.
The average peels are performed with the combination of a
keratolytic agent - Jessner’s solution (no removal) or 70% glycolic acid
(removed as soon as there is mild burning or the appearance of erythema) - and
TCA 35% in aqueous solution applied immediately after. They are indicated for
the treatment of superficial atrophic scars in isolated semi-annual
applications or associated with other procedures at different times,
particularly when they are deep. In this situation, the peel acts as a
preparation of the skin, making its surface more homogeneous.
The application of blue or red light emitting diodes
(LEDs) has an anti-inflammatory effect faster than topical and/or systemic
treatments. One study showed that this effect was similar to salicylic acid
peel. The associated lights in the early stages of treatment improved
inflammation and adhesion. No adverse event has been recorded. Photodynamic
Therapy (PDT), as it is better known, has been proposed as a therapeutic option
for acne, although with many doubts and scanty evidence.
A review of randomized, controlled studies of light-based
therapies for acne treatment concluded that none of the studies demonstrated
efficacy; it is necessary to carry out well-designed studies that employ
standardized outcome measures as well as comparison with usual drug treatments.
At the moment there is no laser technology whose target
is the sebaceous gland and that can destroy it, leading to healing. Two
suggestions have been discussed. One associates an integrated cooling and
vacuum system applied to the skin followed by the application of 3 to 4 pulses
of the 1540-nm medium-erbium: glass infrared laser. An open, uncontrolled study
including 12 patients with mild to moderate acne used this method in 4 to 6
sessions, with a 2-week interval. The improvement scores were 3.6 and 2.0, on a
scale of 0 to 4, after one and 3 months of the last session, without adverse
events. Another recently developed method is the use of a suspension of inert
gold micro-particles with silica center applied with 8-minute massage on the
face followed by 800nm laser application. There are 3 sessions, with intervals
of 2 weeks. There are reports of improvement of up to 61% of inflammatory
lesions.
Scars
Acute atrophic acne scars can be treated with minimally
invasive procedures such as medium chemical peels, hyaluronic acid and
L-poly-lactic acid fillers, and non-ablative radiofrequency. The most severe, that
may be persistent, have a negative impact on the quality of life and pose a
therapeutic challenge. The treatment is always prolonged and requires an
association of techniques, including surgical removal of areas with intense
atrophy, in several sessions. The most invasive procedures include:
sub-incision, punch lift, dermabrasion, fractional CO2 laser or Erbium: Yag, ablative
or non-ablative, microneedling, and radiofrequency, among others. The most
commonly mentioned are the medium peels, various types of lasers and, more
recently, microneedling. Studies with histological evaluation after
fractionated CO2 laser treatment showed thickening of the epidermis,
disappearance of degenerated elastic fibers, increased elastic fiber density
and dermal collagen. These effects, in addition to treating scars, improve the
general appearance of the skin and the signs of photo-aging, constituting
interesting results for adult females. The combination of techniques is the
most effective option for acne scars. A retrospective, non-blind, uncontrolled
study evaluated in 114 patients the results of the combination, under tumescent
anesthesia, in a single session, of 20% TCA superficial peel, extensive
sub-incision and fractionated CO2 laser. There was improvement of 2.9 on a
scale of 1 to 4 and few complications; 90% of the patients were satisfied. A
recent systematic review concluded that there is no evidence of high quality
for the various interventions proposed for the treatment of acne scars due to
poor methodology, lack of statistical power, lack of standardization of
efficacy data and variables evaluated before the interventions. There is
moderate evidence for fillers, but there is a lack of studies with prolonged
follow-up (the largest was 48 weeks) and comparative with placebo or false
intervention. This review was not able to establish any intervention as a first
line for the treatment of acne scars.
QUALITY OF LIFE
The term quality of life (QoL) can be characterized, in a
subjective way, as the patient’s perception about their illness and treatment,
whereas in the technical concept it covers a series of components related to
mental health, physical, functional and social dimensions. In dermatological
diseases, studies suggest that psychometric tools may help the physician better
choose the therapeutic proposal and detect patients psychologically affected,
even with a clinical condition considered to be mild. The development of
indicators, instruments or questionnaires is based on evidence that there is
disagreement between the evaluation of the physician or health professional and
that of the patient regarding the severity of the disease and treatment
success, as well as different responses to the established therapy and
different levels of satisfaction between patients with the same clinical
condition.
Studies related to acne point to a negative influence on
quality of life, including the presence of signs and symptoms of depression and
anxiety, such as anger and low self-esteem. The use of disease-specific
questionnaires, such as Quality of Life in Acne (Acne-QoL), already translated
and validated for Brazilian Portuguese, quantifies the impact of acne on
quality of life.
The literature shows that the impact on quality of life
does not always correlate with the severity of acne. In some cases, females
with mild clinical conditions have a high impact on quality of life. Studies
have also shown that the psychological impact of acne appears to affect more
females than males. In any case, the physician’s attention, good relationship
with the patient and adequate treatment, topical and/or systemic, although not
completely effective demonstrates a positive impact on quality of life.
CONCLUSION
AFA has been considered a particular subtype
of acne, distinct from acne vulgaris or adolescent acne, not only for
differences in clinical status and etiopathogenesis, but also for its
chronicity, which may last until the postmenopausal period. Some characteristics
such as more sensitive and less oily skin, and multiple etiopathogenic factors,
such as new work rate in women’s lives, stress, sleep disorders, dietary
supplements and certain types of contraceptive methods make management more
complex. The psychological impact of acne can be
significant, varying between individuals, but may have a particular impact on
women due to their greater susceptibility to stress and gender‐specific triggers for it. Stress has a reciprocal
pathophysiological link to acne susceptibility and severity, and should be
actively managed as part of a comprehensive, holistic treatment plan. The
therapy plan that is chosen should aim not only to improve the clinical
symptoms of disease, but also to reduce psychological distress and improve the
quality of life, including appropriate use of selected cosmetics to raise self‐esteem.
For all these issues, AFA is a challenge in clinical practices and should be
further understood.
