Therapy for Acne Using Oral Contraceptive Pills

7/30/2019 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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1. Lucky A, Biro FM, Huster GA, et al: Acne

vulgaris in premenarchal girls.

Arch Dermatol 130:308-314, 1994

2. Imperato-McGinley J, Gautier T, Cai LQ, et al:

The androgen control of

sebum production: Studies of subjects with

dihydrotestosterone deficiency

and complete androgen insensitivity. J Clin

Endocrinol Metab

76:524-528, 1993

3. Choudhry R, Hodgins M, Van der Kwast T, et

al: Localization ofandrocyproterone

acetate compared with minocycline in the

treatment of acne

vulgaris. Clin Exp Dermatol 12:319-322, 1987

19. Van Vloten W, van Haselen C, van Zuuren E,

et al: The effect of two


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combined oral contraceptives containing either

drospirenone or cyproterone

acetate on acne and seborrhea. Cutis 69:2-15,2002

20. Charoenvisal C, Thaipisuttikul Y, Pinjaroen S,

et al: Effects on acne of

two oral contraceptives containing desogestrel

and cyproterone acetate.

Int J Fertil 41:423-429, 1996

21. Mango D, Ricci S, Manna P, et al: Clinical and

hormonal effects of

ethinyl estradiol combined with gestodene anddesogestrel in young

women with acne vulgaris. Contraception 53:163-

170, 1996

22. Halbe HW, deMelo NR, Bahamondes L, et al:

Efficacy and acceptability

of 2 monophasic oral contraceptives containing

ethinyl estradiol and


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either desogestrel or gestodene. Eur J Contracept

Reprod Health Care

3:113-120, 1998

23. Koetsawang S, Charoenvisal C,

Banharnsupawat L, et al: Multicenter

trial of 2 monophasic oral contraceptives

containing 30 mcg ethinyl

estradiol and either desogestrel or gestodene in

Thai women. Contraception

51:225-229, 1995

24. Thorneycroft I, Stanczyk F, Bradshaw K, et al:

Effect of low-dose oralcontraceptives on androgenic markers and acne.

Contraception 60:

255-262, 1999

25. Palatsi R, Hirvensalo E, Liukko P, et al: Serum

total and unbound

testosterone and SHBG in female acne patients

treated with 2 different


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oral contraceptives. Acta Derm Venereol 64:517-

523, 1984

26. Rosen MP, Breitkopf DM, Nagamani M: arandomized controlled trial

of second and third generation oral

contraceptives in the treatment of

acne vulgaris. Am J Obstet Gynecol 188:1158-

1160, 2003

27. Burkman RT: Oral Contraceptives: Current

status. Clinical Obstet Gynecol

44:62-72, 2001

28. WHO Working Group: Cardiovascular Diseaseand Steroid Hormone

Contraception. Geneva, World Health

Organization, 1998.

29. Cancer CGoHFiB. Breast cancer and hormonal

contraceptives: Collaborative

reanalysis of individual data on 53,297 women

with breast


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cancer and 100,239 women without breast

cancer from 54 epidemiological

studies. Lancet 347:1713-1727, 1996

30. Schlesselman JJ: Risk of endometrial cancer

in relation to use of combined

oral contraceptives. A practitioners guide to

meta-analysis. Hum

Reprod 12:1851-1863, 1997

31. Hankinson SE, Colditz GA, Hunter DJ, et al: A

quantitative assessment

of oral contraceptive use and risk of ovarian

cancer. Obstet Gynecol80:708-714, 1992

32. Hersh E: Adverse drug interactions in dental

practice:

Interactions involving

antibiotics. J Am Dental Assoc 130:236-251, 1999

33. London BM, Lookingbill DP. Frequency of

pregnancy in acne patients


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taking oral antibiotics and oral contraceptives.

Arch Dermatol 130:392-

393, 1994

34. Helms SE, Bredle DL, Zajic J, et al: Oral

contraceptive failure rates and

oral antibiotics. J Am Acad Dermatol 36:705-710,

1997

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Therapy for Acne Using Oral Contraceptive Pills