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A gynecologist's guide to acne 

By Helen R. Deitch, MD, and Paula J. Adams Hillard, MD 

Acne is among the most common of all dermatologic conditions, plaguing 85% of people aged 15 to 24.¹ It is the most common reason for visits to the dermatologist in the United States for the 15- to 49-year- old age group, at a total cost of $1 billion a year. Teenagers bear an additional emotional cost, as acne occurs during an important period of psychosocial development, and can lead to significant impairment in self-esteem. Psychological reactions to acne can include withdrawal, problems with social functioning, depression, anxiety, and anger. Adolescent girls may be more vulnerable than boys to the negative psychological effects.²
 
 

LEARNING OBJECTIVES  Upon completion of this article, participants will be able to:  Understand the various factors that influence the development of acne.  Describe the role of topical and systemic therapy in the treatment of acne.  Identify the effect of low-dose oral contraceptives on the management of acne.  Recognize the risks and precautions that treating acne may involve.

 
 

Key points

• Rule out systemic disease in a patient who has very severe acne or very early onset of the condition, and PCOS if the woman has hyperandrogenism and is anovulatory or oligomenorrheic.  • Consider switching a patient to a different pill formulation if her mild-to-moderate acne does not respond to the first combined you prescribe.  • Ensure that all patients on spironolactone or isotretinoin have reliable contraception, given the known teratogenic potential of these drugs.

 

Acne can also be physically destructive by leaving permanent and often disfiguring scars.³ The gynecologist may be the only physician seen by older teens and young adults, and as a primary clinician, is in an excellent position to treat mild-to-moderate acne using an armamentarium consisting of both hormonal and nonhormonal medications.

Acne pathophysiology 

Eighty percent of testosterone is bound to sex hormone-binding globulin (SHBG) in women, with an additional 19% bound to albumin. The liver produces SHBG and its levels are increased by estrogens and thyroid hormone, and decreased by androgens and insulin. The remaining 1% of testosterone, along with a contribution from the albumin bound portion, is biologically active.⁴

It has been suggested that girls who develop severe acne at a young age are at increased risk for the development of scarring and more severe disease later in life.⁵ Serum levels of DHEAS and early onset of comedones are the best predictors of severe acne.⁶ Androgens increase sebum production, which creates an environment for the proliferation of the bacterium Propionibacterium acnes (P acnes) within the pilosebaceous unit.⁷ Testosterone is converted to dihydrotestosterone (DHT) in the skin, and acts directly on the sebaceous gland to increase its size and metabolic rate.⁸ Abnormal keritanization of the follicle leads to plugging and accumulation of sebum, keratin, and bacteria. P acnes generates substances within the sebum that create inflammation, including lipases and proteases, and free fatty acids derived from the sebum are primary irritants.⁸ 

Chemotactic factors attract neutrophils to the follicular wall, which cause weakening and inflammation. All of these factors lead to the development of the comedone, a plugged pilosebaceous unit and precursor to inflammatory acne.

Classifying degrees of severity 

Mild acne comprises comedones, few to several papules or pustules, and no nodules. Comedones, several to many papules and pustules, and few to several nodules define moderate acne. Severe acne consists of comedones, numerous or extensive papules, pustules, and nodules.^8,9 Acne variants include acne induced by cosmetics or medications such as systemic corticosteroids or anabolic steroids, lithium, or isoniazid. 

Systemic diseases may be the underlying cause for acne in patients with very severe acne or onset of acne at a young age, and other clinical evidence of hyperandrogenism such as hirsutism should also raise suspicion for potentially serious underlying diseases. Testosterone producing tumors, late-onset congenital adrenal hyperplasia, and Cushing's disease are rare conditions that can result in acne and hirsutism. 

Polycystic ovary syndrome (PCOS) should be considered in women with evidence of hyperandrogenism and oligomenorrhea or anovulatory cycles. The confirmation of PCOS, with an incidence among adult women of approximately 7% to 10%, has important health consequences beyond the typical reproductive issues, and once oral contraceptives have been initiated, their beneficial effects will often mask mild hyperandrogenism, precluding the ability to confirm the diagnosis. The laboratory evaluation for these diseases is beyond the scope of this article, but is recommended prior to the initiation of OC treatment. 

The gynecologist is in an ideal position not only to treat acne, but also to diagnose and manage hyperandrogenic states. This provides the potential to minimize long-term sequelae, including not only hirsutism and scarring acne, but also the medically serious conditions of cardiovascular disease, type 2 diabetes, and endometrial carcinoma. 

Topical and oral treatment 

Topical retinoids. Comedonal acne usually responds well to topical tretinoin, available in varying strengths and as cream, gel, and solution. Topical tretinoin promotes cell turnover and decreases adhesiveness between keritanized cells. It acts specifically on microcomedones, the precursor to acne, to prevent the development of new lesions and has an indirect antimicrobial effect.¹⁰ It promotes the conversion of closed comedones to open comedones and accelerates the protrusion of existing comedones.

Tretinoin has also been shown to enhance the absorption of other topical medications such as benzoyl peroxide and antibiotics. Side effects include redness, burning, and peeling, which can be minimized by application every other day, beginning with a lower concentration (0.025%) until tolerance develops.¹⁰ The gel may be less irritating than the liquid.

Other topical retinoids that may be tolerated more or less well than topical tretinoin include the new retinoid, adapalene (Differen). Salicylic acid is also comedeolytic, and available as topical therapy in both over-the-counter formulations and by prescription.

Benzoyl peroxide. Benzoyl peroxide and topical antibiotics are effective against inflammatory acne. Benzoyl peroxide acts as both an anti-inflammatory agent by decreasing the colonization with P acnes, and as a drying agent. Benzoyl peroxide topical therapy is available in multiple brands and as a generic drug, in strengths ranging from 2.5% to 20%, and as lotion, cream, gel, mask, bar, and liquid. Most adolescents have tried some of the over-the-counter formulations, although they may not have used them consistently or attained a maximum benefit from the appropriate concentration. Benzoyl peroxide is applied twice a day, and patients should be cautioned that it could bleach clothing and hair. 

Topical antibiotics. Erythromycin, clindamycin, and tetracycline are examples of topical antibiotics that decrease colonization with P acnes and have minimal side effects. However, there has been an increase in bacterial resistance to these medications over the past 20 years.¹⁰ Benzoyl peroxide and topical antibiotics work well in combination, and have been found to reduce the risk of resistance. The topical medication Benzamycin (benzoyl peroxide 5%, erythromycin 3% gel) has been proven to decrease resistant P acnes and both erythromycin and clindamycin are more efficacious when combined with benzoyl peroxide.^10,11

Systemic therapy 

Spironolactone. This diuretic with antiandrogenic effects works by decreasing androgen production from both adrenal and ovarian sources, as well as blocking DHT receptors in the sebaceous gland.¹² Spironolactone is effective in treating acne in doses of 100 to 200 mg/day, with side effects including menstrual irregularities, breast tenderness, and hyperkalemia.¹² Starting with a low dose (25 to 50 mg) and slowly increasing the dose can help to reduce side effects.¹² Spironolactone can be given in conjunction with antibiotics and OCs; the latter have the added benefit of offsetting any menstrual irregularities. Due to its antiandrogenic effects, spironolactone is a potential teratogen to the male fetus, and reliable contraception is recommended.¹³

Combined OCs. Therapy with combined OCs may well be preferable to spironolactone as an initial systemic therapy. Approximately 50% of 17-year-olds have had intercourse.¹⁴ Typically adolescents wait 1 year or more after first intercourse before they seek medical advice for contraception, and may be unable or unwilling to divulge their current or planned sexual debut, particularly if they are not aware that they can do so confidentially.¹⁵ Thus, even an adolescent who denies sexual activity may require effective contraception, and an adolescent who is currently choosing to postpone sexual intercourse may become sexually active prior to seeking effective contraception. OCs as therapy for acne will thus provide both effective contraception if needed and be therapeutic for acne.

Combined OCs have been extensively studied as a treatment for acne, and are effective alone or in combination with other oral or topical treatments. They act on multiple sites to decrease the total and free androgen levels, ultimately leading to a reduction in sebum production.¹⁶ The estrogen component stimulates the production of SHBG by the liver, which leads to a reduction in free testosterone. OCs directly suppress the production of both ovarian and adrenal androgens and competitively inhibit 5-reductase, which converts testosterone into the more biologically active DHT. Two randomized, placebo-controlled trials have demonstrated effectiveness in improving acne as judged by both lesion counts and clinical and subjective assessment of improvement.^7,17 These studies also showed a significant increase in SHBG and a decrease in free testosterone.^7,17 

Although concern has been expressed about OC formulations containing the so-called "androgenic" progestogens, direct comparisons between levonorgestrel- and norethindrone acetate-containing OCs revealed a similar improvement in acne lesions.¹⁶ Interestingly, these particular pill formulations appeared to have the same end result—a decrease in free testosterone—although they appear to do so through slightly different actions or sites. 

The levonorgestrel-containing pill decreased androgen levels in the peripheral (3-androstanediol glucuronide, a metabolite of DHT that correlates highly with 5-reductase activity), ovarian (total testosterone), and adrenal (DHEAS) compartments. Norethindrone acetate decreased androgen levels in the adrenal and peripheral compartments only, but showed a 2.2-fold greater increase in SHBG than levonorgestrel. Both formulations decreased free testosterone by a similar percentage. The end result was a comparable improvement in acne. 

There has been concern that the progestogen component in combined OCs has the potential for "androgenic" side effects, such as deepening of the voice, clitoromegaly, weight gain, and decreased breast size. These effects do not occur with the low progestin doses used in OCs. Studies with levonorgestrel have shown that a tenfold higher level is needed to produce androgenic effects versus antiovulatory effects. ¹⁸ 

van der Vange and colleagues found elevations in SHBG and decreases in free testosterone levels in seven different OC preparations.¹⁹ Levonorgestrel norethindrone, desogestrel, gestodene, and norgestimate all have been shown to improve serum androgen levels.^{16, 20, 21} 

There are few trials directly comparing different OCs as acne treatment, and currently there is little basis to assume that one preparation is superior to another as acne therapy. The fact that one brand of OC has been able to position itself in the market as "the acne pill" relates to the efforts and money expended to gain FDA approval for this indication. The patient-package labeling states that the formulation "is indicated for the treatment of moderate acne vulgaris in females, 15 years of age or older, who have no known contraindications to oral contraceptive therapy, a desire for contraception, have achieved menarche, and are unresponsive to topical anti-acne medications." These efforts appear to have resulted in a marked increase in public awareness of this particular noncontraceptive benefit of oral contraceptives. Other manufacturers have submitted data to the FDA to earn the acne indication. 

Many gynecologists and some dermatologists are using OCs as treatment for moderate-to-severe acne, even in teens younger than age 15 and those who are not sexually active. In this regard, clinicians are making judgments about the preponderance of benefits over potential medical risks, particularly among otherwise healthy adolescents. Similar judgments are made for the use of OCs for treating other medical conditions such as dysmenorrhea or menorrhagia. 

Adolescents and young adult women should be informed of the potential risks of OCs—the increased risk of venous thromboembolism, as well as the incidence of other "nuisance" side effects that may affect OC compliance: breakthrough bleeding, nausea, mood changes, breast tenderness, headaches. In addition, the other noncontraceptive benefits can be discussed, including a decrease in dysmenorrhea and menorrhagia. Contrary to the hope of many patients, the beneficial effects of OCs on acne do not occur overnight, and it is important to counsel that an appropriate trial of approximately 3 months is necessary to assess the effect on acne. While most OC formulations benefit most women with acne, it may be true that there is some interindividual variation in response. If a response is not seen (or if the individual believes that there has been a detrimental effect on acne), a switch to a different pill formulation may be appropriate. 

Oral isotretinoin. Severe, recalcitrant cystic or nodular acne, and moderate acne that is unresponsive to conventional therapy should be treated with oral isotretinoin to prevent scarring. Isotretinoin is a vitamin A analog that affects all of the factors related to acne formation by decreasing sebum production, follicular keritanization, and P acnes counts. Accutane is a known teratogen that causes defects including hydrocephalus, cortical blindness, facial dysmorphism, and cardiac anomalies. FDA labeling requires females to use two effective forms of birth control starting 1 month before initiating treatment and while undergoing therapy.²²

The gynecologist who evaluates a patient who may be a candidate for oral isotretinoin is in an excellent position to initiate OCs prior to referral to the dermatologist. This provides one form of the requisite contraception (which would be combined with the recommendation of condom use in sexually active teens), and in addition, may result in sufficient benefit as acne therapy that isotretinoin may not be required. 

Isotretinoin requires careful monitoring due to possible hepatotoxicity, and generally should be prescribed by a dermatologist who is familiar with its use and side effects. In fact, some dermatologists are starting to "position" OCs for use prior to the initiation of isotretinoin in their therapeutic armamentarium. If OCs do not provide sufficient benefit for severe acne, they can be continued to provide some additional therapeutic benefit, as well as the contraception that is necessary during isotretinoin therapy.

Conclusion 

REFERENCES

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6. Lucky AW. A review of infantile and pediatric acne. Dermatology. 1998;196:95-97. 

7. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol. 1997;37:746-754. 

8. Habif TP. Acne, rosacea and related disorders. In: Clinical Dermatology: A Color Guide to Diagnosis and Therapy. St. Louis, Mo: Mosby-Year Book, Inc., 1996. 

9. Lucky AW. Hormonal correlates of acne and hirsutism. Am J Med. 1995;98:89S-94S. 

10. Gollnick H, Schramm M. Topical therapy in acne. J Eur Acad Dermatol Venereol. 1998;11:S8-S12. 

11. Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol. 1994;131:331-336. 

12. Shaw JC. Antiandrogen and hormonal treatment of acne. Dermatol Clin. 1996;14:803-811. 

13. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Lactation. Baltimore, Md: Williams and Wilkins; 1997. 

14. Singh S, Darroch JE. Trends in sexual activity among adolescent American women: 1982-1995. Fam Plann Perspect. 1999;31:212-219. 

15. Sex and America's Teenagers. New York, NY: Alan Guttmacher Institute; 1994. 

16. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception. 1999;60:255-262. 

17. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol. 1997;89:615-622. 

18. Upton GV, Corbin A. The relevance of the pharmacologic properties of a progestational agent to its clinical effects as a combination oral contraceptive. Yale J Biol Med. 1989;62:445-457. 

19. van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception. 1990;41:345-352. 

20. Murphy A, Cropp CS, Smith BS, et al. Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women. Fertil Steril. 1990;53:35-39. 

21. Coenen CM, Thomas CM, Borm GF, et al. Changes in androgens during treatment with four low-dose contraceptives. Contraception. 1996;53:171-176. 

22. Perlman SE, Leach EE, Dominguez L, et al. "Be smart, be safe, be sure". The revised Pregnancy Prevention Program for women on isotretinoin. J Reprod Med. 2001;46:179-185. 

Dr. Deitch is a Clinical Fellow in Pediatric and Adolescent Gynecology at Children's Hospital Medical Center, Cincinnati, Ohio. Dr. Adams Hillard is a Professor in the Department of Obstetrics/Gynecology and Department of Pediatrics and Director of Women's Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.