therapy for acne using oral contraceptive pills
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Therapy for Acne Using Oral Contraceptive Pills
The etiology of acne vulgaris is multifactorial and
complex. The four
key factors involved in the development of acne
include follicular
plugging, inflammation, the presence and activity
of Propionibacterium
acnes, and sebum. Androgen hormones stimulate
the sebaceous gland and
promote sebum excretion. Therefore, therapies
that have an overallantiandrogen effect, like combination oral
contraceptive pills, may be
useful in the management of acne vulgaris.
Numerous combination oral
contraceptive pills have been evaluated in the
treatment of acne
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vulgaris and have been found to be effective.
With a thorough
understanding of their proper use and potentialassociated risks,
these hormonal treatments may be prescribed
safely and effectively to
women with acne.
Acne vulgaris is a multifactorial, complex process.
Four key
pathogenetic factors contribute to the
development of acne lesions:
follicular epidermal hyperproliferation, excesssebum, the presence
and activity of Propionibacterium acnes, and
inflammation. A single,
primary cause of acne vulgaris has not been
identified, but there is
evidence to suggest that androgenic hormones
play a central role.
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First, comedonal acne lesions first appear
coincident with adrenal
production of androgen hormones, andcirculating levels of the adrenal
androgen dehydroepiandrosterone (DHEA)
correlate with the development
of acne in premenarchal girls.1
Second, individuals who are androgen insensitive
do not develop acne.2
Androgen production and circulating levels of
androgens are within the
normal range in affected individuals, but theandrogen receptor does
not respond to these androgens. Androgen
receptors normally are
present in the follicle where the earliest acne
lesions develop and in
the sebaceous gland.3 Third, disease states
associated with
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hyperandrogenism, such as polycystic ovarian
syndrome or androgen-
secreting tumors, may be associated with acnevulgaris.4
Fourth, medications that have an overall
antiandrogen effect, such as
combination oral contraceptive pills, improve
acne.5
As outlined above, there are 4 important
pathogenetic factors at play
in the development of acne. Androgen hormones
may promote both
follicular epidermal hyperproliferation and
plugging as well as sebum
production, 2 of the 4 key acne triggers.
Testosterone and
dihydrotestosterone bind the androgen receptorand induce sebocyte
differentiation and sebum production by altering
gene transcription in
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the cell nucleus. Sebum production does increase
after systemic
administration of androgen hormones, and acnevulgaris is more common
in individuals who produce more sebum.6
Evidence to suggest a role of androgen hormones
in follicular plugging
is indirect. Androgen receptors and androgen
biosynthetic machinery
is present in the portion of the follicle where
comedonal acne
develops. Acne treatments that theoreticallytarget only androgen
hormones, such as combination oral
contraceptive pills, improve
comedonal acne lesion counts suggesting that
these androgen hormones
may contribute to follicular plugging.7
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Androgen hormones are produced in the gonads
and the adrenal gland.
Androgens produced in the ovaries includeandrostenedione, DHEA, and
testosterone. DHEA and androstenedione also are
synthesized in the
adrenal gland. The enzymatic machinery
necessary to convert
androstenedione and DHEA to testosterone is
present in peripheral
tissues, including the skin. Additionally, the
enzyme 5 reductase type
1, which converts testosterone to the more
potent dihydrotestosterone
(DHT), also is present in the sebaceous
follicle.8,9
Both testosterone and DHT are capable ofbinding the androgen
receptor, activating sebocyte differentiation and
sebum production,
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and contributing to the development of acne
vulgaris.
Although androgen hormones do play an integralrole in the
pathogenesis of acne vulgaris, circulating levels
of androgen hormones
usually are within the normal range in women
with acne. Women with
acne and elevated circulating androgens most
often have other signs of
virilism, such as hirsutism, deepening voice, and
irregular menstrual
periods.
Women with virilism and acne should undergo a
hormonal workup to
screen for ovarian or adrenal sources of excess
androgen production.
Adrenal tumors and late-onset congenital adrenal
hyperplasia will
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result in increases in DHEA-S and ovarian tumors,
whereas polycystic
ovarian syndrome will result in increases in freetestosterone. A full
hormonal workup therefore should include free
and total testosterone,
DHEA-S, and sex-hormone binding globulin
(SHBG).
Luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) also
may be measured ,a ratio greater than 2
indicates polycystic ovari.
LH:FSH an syndrome. Even in the presence of a
completely normal
hormonal workup or in women with no other
signs of virilism,
medications that target androgen hormones maybe prescribed safely and
effectively to treat acne.
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There are several ways that a drug can block the
androgen effect in
acne. First, testosterone production in the gonadsor adrenal gland
can be reduced. Second, the enzymes needed to
convert weak to potent
androgens may be inhibited Third, the androgen
receptor can be
blocked. Finally, the amount of free, unbound,
and biologically active
androgen in the circulation can be diminished.
Combination Oral ContraceptivesCombination oral contraceptive pills (OCPs)
combine an estrogen,
ethinyl estradiol, and a progestin. Most OCPs
available today contain
35 g of ethinyl estradiol or less. Estrogen dosages
greater than 50 g
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have been associated with a higher risk of venous
thromboembolism than
doses less than 50 g.10 Ethinyl estradiol iscapable of increasing
hepatic synthesis of SHBG, which binds
circulating testosterone,
rendering it biologically inactive.
Ethinyl estradiol also lessens ovarian hormone
production, including
the production of androgens and their precursors,
via a negative
feedback loop involving production and release ofthe pituitary
gonadotrophins, LH, and FSH. The net result is
less circulating,
unbound testosterone available to interact with
the androgen receptor
.
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The progestins contained in combination oral
contraceptives vary
greatly from pill to pill. The earliest progestinswere synthesized
directly from testosterone and exhibited both
androgenic and
progestational activity.11 Gradually, the structure
of these
progestins was further modified to educe
androgenicity and enhance
progestational activity. Nonetheless, progestins
taken alone decrease
the plasma SHBG and therefore increase free,
circulating testosterone.
Cyproterone acetate and drospirenone are two
progestins that are truly
antiandrogenic.
These progestins block the androgen receptor
and inhibit production of
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DHT in the peripheral tissues by blocking the
enzyme 5 reductase type
I.
Regardles, when any progestin is combined with
ethinyl estradiol in a
combination oral ontraceptive, the net result is
an increase in SHBG
and a decrease in free estosterone.11,12
Efficacy
Anecdotal reports of the influence of OCPs on
acne are rampant and
often conflicting. Some reports implicate OCPs inworsening acne
vulgaris, whereas others suggest that they are
responsible for
clearing acne.
One study published in 1990 compared 4
different OCP formulations and
found that acne
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developed on average 5% of the time.13 The
OCPs in this study combined
ethinyl estradiol with the progestinsnorethindrone acetate,
norethindrone or levonorgestrel.
More recent studies have focused on the role of
OCPs in improving
acne. A large meta-analysis has recently been
published evaluating the
role of oral contraceptives in the treatment of
acne.5 Twenty-one
clinical trials assessing oral contraceptives andacne were included
in the analysis. A total of 4981 participants were
analyzed in these
trials. In these studies, comparisons were made
between 2 different
oral ontraceptives, oral contraceptives and
placebo, or between oral
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contraceptives and antibiotics. The reviewers
conclusions were that
OCPs containing either cyproterone acetate orchlormadinone acetate,
neither of which is available in the USA, appeared
more effective in
clearing acne than those containing the progestin
levonorgestrel, but
studies were limited. There was not enough
evidence to compare
meaningfully other oral contraceptives in the
treatment of acne
vulgaris
Five clinical trials included in the meta-analysis
compared a
combination OCP to placebo in the treatment of
acne vulgaris.
Two trials compared a combination pill containing
levonorgestrel 100
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g/ethinyl estradiol 20 g Alesse) versus
placebo.14,15 Acne lesion
counts were lower in those receiving oralcontraceptives than in those
receiving placebo.
Another study compared norethindrone acetate
1000 g/ ethinyl estradiol
20 to 30-35 g Estrostep) with placebo.
Global assessments of acne were reported to be
better in those on the
OCP than in those receiving placebo. Two
additional studies comparednorgestimate 180 to 215-250 g/ ethinyl estradiol
35 g
(Ortho-Tricyclen) and found fewer acne lesions
in those receiving the
combination OCP versus placebo.16,17
Only one trial compared a combination oral
contraceptive to
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antibiotics. This was performed by Monk and
coworkers and compared
cyproterone acetate 2 mg/ethinyl estradiol 50 gto minocycline 50
mg.18 Ninety-eight women were enrolled in the
study, but 20 women
discontinued the study early. Acne outcomes
were measured by patient
self-assessment, and no difference was identified
between the two
groups.
Of the 15 remaining trials included in the meta-analysis, 9 compared
cyproterone acetate or hlormadinone acetate
containing formulations
to other OCPs. OCPs containing these 2
progestins did improve acne
more than OCPs containing levonorgestrel in the
limited studies
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included in the analysis. Cyproterone acetate-
containing OCPs also
were compared with formulations containing theprogestins drospirenone
and desogestrel, and no significant differences
were seen in acne
lesion counts or acne grading between the
groups.19,20 Three of the 6
remaining analyzed studies compared OCPs
containing the progestins
desogestrel and gestodene. 21-23
Pooled data from these studies showed nosignificant differences in
acne outcomes. One study comparing OCPs
containing the progestins
levonorgestrel versus norethindrone acetate
again found no differences
in acne outcomes.24 Two remaining studies
compared levonorgestrel/
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ethinyl estradiol to desogestrel/ethinyl
estradiol.,25,26
One of the two found a small difference in meanacne severity whereas
the other study showed no significant difference
between the two
groups
Safety
Adverse events, including cardiovascular risks,
have been associated
with OCP use. The risk of venous
thromboembolism is tripled in usersof OCPs compared with nonusers.
Obesity and age increase the risk of venous
thromboembolism and
associated mortality doubles in women age 35 to
44 compared with
younger women.27 This risk is higher when
higher doses of ethinyl
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estradiol are prescribed. The risk of ischemic
stroke also is
associated with OCP use. Again, this risk isincreased with higher
doses of ethinyl estradiol. The risk of ischemic
stroke in users of
OCPs is greater in women who also have
hypertension, smoke igarettes,
or have migraine headaches.27,28
Similarly, the risk of myocardial infarction in OCP
users is greater
in women who smoke cigarettesor who have hypertension or diabetes. In fact, in
the absence of these
additional risk factors, there is no increase in
myocardial infarction
in users of OCPs versus nonusers.27,28
A large World Health Organization meta-analysis
performed in 1996
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addressed the issue of breast cancer risks in OCP
users. It included a
total of 53,297 women with breast cancer and100,239 controls. The
relative risk of developing breast cancer in a
current user of an OCP
was 1.24 compared with women who had never
taken an OCP. Breast cancer
was more often localized at the time of diagnosis
in OCP users than in
nonusers. Family history of breast cancer, dosage
or formulation of
the OCP, and duration of use did not correlate
with risk.27,29
Conversely, OCPs may play a protective role
against some benign and
malignant neoplasms. The risk of endometrialcancer is lessened by as
much as 50%.30 This protective effect begins
after 1 year of OCP use
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and increases with duration of use. The risk of
ovarian cancer is also
reduced by 40% to 80% in OCP users. The risk islessened after just 1
year of use and is maintained even after the OCP
has been
discontinued.31
There is also some protection against uterine
leiomyomas and pelvic
inflammatory disease.27
Common side effects associated with oral
contraceptives includenausea, breast tenderness, bbloating, weight
gain, and break-through
menstrual bleeding. With the exception of break-
through menstrual
bleeding, these side effects are lessened when
lower doses of ethinyl
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estradiol are prescribed. For years, prescriptions
of oral
contraceptives have been written and dispensedin conjunction with an
annual gynecologic examination. Annual well
woman examinations are an
important component of health maintenance for
women and should be
encouraged for all women, whether taking an
oral contraceptive or not
Androgen hormones play an integral role in the
development of acne
vulgaris and thus offer an important target when
treating acne.
However, acne vulgaris is a complex,
multifactorial process. The most
successful treatments combine medications thattarget all of the
causes of acne vulgaris. A common approach to
treating acne in women
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is to combine a topical retinoid, a systemic
antibiotic, and an OCP.
Antibiotics have been incriminated in lesseningthe effectiveness of
OCPs when used in combination. However, of all
alleged antibiotic
oral contraceptive interactions, 76% involve
rifampin. 32
Rifampin is a potent inducer of cytochrome p450
and increases the
metabolism of OCPs and other medications. It
has been hypothesized
that other antibiotics decrease the gut flora that
are needed to
degrade inactive metabolites of OCPs to active
drug during
enterohepatic recirculation.
Evidence to support this claim is lacking. Two
studies have been
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published in the dermatology literature evaluating
the potential
interaction between OCPs and antibioticscommonly prescribed for acne
vulgaris.
One study surveyed 281 women and found that
34 had used low-estrogen
containing OCPs and antibiotics for a combined
total of 71 years. One
woman on tetracycline and OCPs for twelve
months became pregnant
yielding an overall pregnancy rate of 1.4%. TheOCP failure rate with
typical use is 3%.33 Another study
evaluated 356 women on OCPs and antibiotics
compared with 425 women on
OCPs alone and found that the pregnancy rate
was not statistically
different in the two groups.34
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Summary
Combination OCPs offer an additional tool in the
management of acne
but do not represent first-line therapy or
monotherapy.
Two OCPs, ethinyl estradiol 20 to 30-
35g/norethindrone acetate 1mg
(Estrostep) and ethinyl estradiol 35
g/norgestimate 0.18 to 0.215
0.25 mg (Ortho-tricyclen), now have approval
by the Food and Drug
Administration for the treatment of acne vulgaris.However, the
decrease in free testosterone observed with all
combination oral
contraceptive pills suggests that they all have the
capability to
improve acne ulgaris.11,12
References
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