Therapy for Acne Using Oral Contraceptive Pills
Content
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 overall antiandrogen 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
vulgaris and have been found to be effective. With a thorough understanding of their proper use and potential associated 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, excess sebum, 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.
First, comedonal acne lesions first appear coincident with adrenal production of androgen hormones, and circulating 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 the androgen 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
hyperandrogenism, such as polycystic ovarian syndrome or androgensecreting tumors, may be associated with acne vulgaris.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 receptor and induce sebocyte differentiation and sebum production by altering gene transcription in
the cell nucleus. Sebum production does increase after systemic administration of androgen hormones, and acne vulgaris 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 theoretically target 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
Androgen hormones are produced in the gonads and the adrenal gland. Androgens produced in the ovaries include androstenedione, 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 of binding the androgen receptor, activating sebocyte differentiation and sebum production,
and contributing to the development of acne vulgaris. Although androgen hormones do play an integral role 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
result in increases in DHEA-S and ovarian tumors, whereas polycystic ovarian syndrome will result in increases in free testosterone. 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 may be prescribed safely and effectively to treat acne.
There are several ways that a drug can block the androgen effect in acne. First, testosterone production in the gonads or 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 Contraceptives Combination 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
have been associated with a higher risk of venous thromboembolism than doses less than 50 g.10 Ethinyl estradiol is capable 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 of the pituitary gonadotrophins, LH, and FSH. The net result is less circulating, unbound testosterone available to interact with the androgen receptor .
The progestins contained in combination oral contraceptives vary greatly from pill to pill. The earliest progestins were 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
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 in worsening 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
developed on average 5% of the time.13 The OCPs in this study combined ethinyl estradiol with the progestins norethindrone 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 and acne 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
contraceptives and antibiotics. The reviewers’ conclusions were that OCPs containing either cyproterone acetate or chlormadinone 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
g/ethinyl estradiol 20 g Alesse®) versus placebo.14,15 Acne lesion counts were lower in those receiving oral contraceptives 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 compared norgestimate 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
antibiotics. This was performed by Monk and coworkers and compared cyproterone acetate 2 mg/ethinyl estradiol 50 g to 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 metaanalysis, 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
included in the analysis. Cyproterone acetatecontaining OCPs also were compared with formulations containing the progestins 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 OCP’s containing the progestins desogestrel and gestodene. 21-23 Pooled data from these studies showed no significant 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/
ethinyl estradiol to desogestrel/ethinyl estradiol.,25,26 One of the two found a small difference in mean acne 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 users of 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
estradiol are prescribed. The risk of ischemic stroke also is associated with OCP use. Again, this risk is increased 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 cigarettes or 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
addressed the issue of breast cancer risks in OCP users. It included a total of 53,297 women with breast cancer and 100,239 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 endometrial cancer is lessened by as much as 50%.30 This protective effect begins after 1 year of OCP use
and increases with duration of use. The risk of ovarian cancer is also reduced by 40% to 80% in OCP users. The risk is lessened 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 include nausea, breast tenderness, bbloating, weight gain, and break-through menstrual bleeding. With the exception of breakthrough menstrual bleeding, these side effects are lessened when lower doses of ethinyl
estradiol are prescribed. For years, prescriptions of oral contraceptives have been written and dispensed in 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 that target all of the causes of acne vulgaris. A common approach to treating acne in women
is to combine a topical retinoid, a systemic antibiotic, and an OCP. Antibiotics have been incriminated in lessening the 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
published in the dermatology literature evaluating the potential interaction between OCPs and antibiotics commonly 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%. The OCP 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
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 3035g/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
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 of androcyproterone 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
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 and desogestrel in young women with acne vulgaris. Contraception 53:163170, 1996 22. Halbe HW, deMelo NR, Bahamondes L, et al: Efficacy and acceptability of 2 monophasic oral contraceptives containing ethinyl estradiol and
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 oral contraceptives 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
oral contraceptives. Acta Derm Venereol 64:517523, 1984 26. Rosen MP, Breitkopf DM, Nagamani M: a randomized controlled trial of second and third generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol 188:11581160, 2003 27. Burkman RT: Oral Contraceptives: Current status. Clinical Obstet Gynecol 44:62-72, 2001 28. WHO Working Group: Cardiovascular Disease and 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
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 practitioner’s 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 Gynecol 80:708-714, 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
taking oral antibiotics and oral contraceptives. Arch Dermatol 130:392393, 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
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 overall antiandrogen 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
vulgaris and have been found to be effective. With a thorough understanding of their proper use and potential associated 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, excess sebum, 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.
First, comedonal acne lesions first appear coincident with adrenal production of androgen hormones, and circulating 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 the androgen 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
hyperandrogenism, such as polycystic ovarian syndrome or androgensecreting tumors, may be associated with acne vulgaris.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 receptor and induce sebocyte differentiation and sebum production by altering gene transcription in
the cell nucleus. Sebum production does increase after systemic administration of androgen hormones, and acne vulgaris 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 theoretically target 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
Androgen hormones are produced in the gonads and the adrenal gland. Androgens produced in the ovaries include androstenedione, 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 of binding the androgen receptor, activating sebocyte differentiation and sebum production,
and contributing to the development of acne vulgaris. Although androgen hormones do play an integral role 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
result in increases in DHEA-S and ovarian tumors, whereas polycystic ovarian syndrome will result in increases in free testosterone. 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 may be prescribed safely and effectively to treat acne.
There are several ways that a drug can block the androgen effect in acne. First, testosterone production in the gonads or 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 Contraceptives Combination 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
have been associated with a higher risk of venous thromboembolism than doses less than 50 g.10 Ethinyl estradiol is capable 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 of the pituitary gonadotrophins, LH, and FSH. The net result is less circulating, unbound testosterone available to interact with the androgen receptor .
The progestins contained in combination oral contraceptives vary greatly from pill to pill. The earliest progestins were 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
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 in worsening 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
developed on average 5% of the time.13 The OCPs in this study combined ethinyl estradiol with the progestins norethindrone 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 and acne 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
contraceptives and antibiotics. The reviewers’ conclusions were that OCPs containing either cyproterone acetate or chlormadinone 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
g/ethinyl estradiol 20 g Alesse®) versus placebo.14,15 Acne lesion counts were lower in those receiving oral contraceptives 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 compared norgestimate 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
antibiotics. This was performed by Monk and coworkers and compared cyproterone acetate 2 mg/ethinyl estradiol 50 g to 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 metaanalysis, 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
included in the analysis. Cyproterone acetatecontaining OCPs also were compared with formulations containing the progestins 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 OCP’s containing the progestins desogestrel and gestodene. 21-23 Pooled data from these studies showed no significant 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/
ethinyl estradiol to desogestrel/ethinyl estradiol.,25,26 One of the two found a small difference in mean acne 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 users of 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
estradiol are prescribed. The risk of ischemic stroke also is associated with OCP use. Again, this risk is increased 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 cigarettes or 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
addressed the issue of breast cancer risks in OCP users. It included a total of 53,297 women with breast cancer and 100,239 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 endometrial cancer is lessened by as much as 50%.30 This protective effect begins after 1 year of OCP use
and increases with duration of use. The risk of ovarian cancer is also reduced by 40% to 80% in OCP users. The risk is lessened 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 include nausea, breast tenderness, bbloating, weight gain, and break-through menstrual bleeding. With the exception of breakthrough menstrual bleeding, these side effects are lessened when lower doses of ethinyl
estradiol are prescribed. For years, prescriptions of oral contraceptives have been written and dispensed in 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 that target all of the causes of acne vulgaris. A common approach to treating acne in women
is to combine a topical retinoid, a systemic antibiotic, and an OCP. Antibiotics have been incriminated in lessening the 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
published in the dermatology literature evaluating the potential interaction between OCPs and antibiotics commonly 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%. The OCP 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
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 3035g/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
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 of androcyproterone 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
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 and desogestrel in young women with acne vulgaris. Contraception 53:163170, 1996 22. Halbe HW, deMelo NR, Bahamondes L, et al: Efficacy and acceptability of 2 monophasic oral contraceptives containing ethinyl estradiol and
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 oral contraceptives 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
oral contraceptives. Acta Derm Venereol 64:517523, 1984 26. Rosen MP, Breitkopf DM, Nagamani M: a randomized controlled trial of second and third generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol 188:11581160, 2003 27. Burkman RT: Oral Contraceptives: Current status. Clinical Obstet Gynecol 44:62-72, 2001 28. WHO Working Group: Cardiovascular Disease and 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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