Treatment of Acne with Oral Contraceptives: Criteria for Pill Selection George T
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Treatment of Acne With Oral Contraceptives: Criteria for Pill Selection George T. Koulianos, MD, Mobile, Alabama Combination oral contraceptives (OCs) (those that actively promoted to the specialty. Thus, under- contain estrogen and progestin) are widely used in standing of these preparations may be limited and the treatment of acne because they modify an somewhat skewed. Marketing based on outdated excessively androgenic hormonal environment and animal bioassays has distorted clinicians’ apprecia- can decrease lesions. Dermatologists’ knowledge tion of OC options. Direct-to-consumer advertising of the most appropriate OC may be hampered by an has been another misleading factor; prominent incomplete understanding of these agents, mislead- claims about acne, which drive patients to request ing promotion, and confusion surrounding the new “the pill,” often overshadow more important health generation of OCs. Despite reports attributing sig- concerns and benefits. Finally, the recent develop- nificance to the degree of androgenicity of the prog- ment of a new generation of OCs containing prog- estin components of OCs, in vitro and animal estins, intended to be less androgenic than their bioassays of androgenicity have little clinical rele- earlier counterparts, may have further confused the vance. Because all of today’s low-dose combination issue. Although these progestins have proven no OCs are estrogen dominant, they are equally bene- better than the older ones, recent discussions of ficial in women with androgenic conditions such as their use in acne therapy have left many physicians acne. Use of the OC containing the lowest dose of and patients with the mistaken impression that only each hormone, consistent with the patient’s needs, certain OC formulations are appropriate to this can enhance compliance by preventing or limiting indication. common early-cycle side effects (eg, nausea/vomit- Accounting for different dosage strengths, there ing, breast tenderness, weight gain, headache), are currently more than 40 combination OCs avail- while providing acne improvement. able in the United States—from the older 50-µg estrogen preparations to the ultra-low 20-µg estrogen lthough oral contraceptives (OCs) are gener- formulations in the monophasic category, plus a ally reserved for severe cases of acne when variety of multiphasic pills, including the newest A other methods have failed, the use of combi- graduated-estrogen design. Review of the reproduc- nation OCs (those that contain estrogen and progestin) tive endocrinology literature reveals that all of them in the treatment of acne has become common practice. are essentially antiandrogenic and, thus, have anti- OCs are particularly valuable in patients with clinical acne potential. Therefore, selection of an optimal evidence of hyperandrogenism (hirsutism, irregular pe- agent rests on other considerations important to both riods). Both gynecologists and dermatologists recognize the clinician and patient—for example, low incidence the abilities of these agents to modify an excessively an- of side effects, high degree of patient acceptance, and drogenic hormonal environment and decrease acne ease of compliance. lesions in appropriately selected patients. Although management of the OC patient is For many dermatologists, familiarity with OCs is beyond the scope of dermatologic practice, a grasp of dominated by one or two agents that have been the principles underlying OC use in acne is essential. The following discussion seeks to provide the derma- From the Division of Reproductive Endocrinology and Infertility, tologist with a more complete understanding of the Mobile Infirmary and Medical Center, Mobile, Alabama. antiandrogenic properties of today’s “pill” formula- REPRINT REQUESTS to 3 Mobile Infirmary Circle, Suite 312, Mobile, AL 36607. tions, their universal potential for decreasing acne This paper has been supported by an unrestricted grant-in-aid lesions, and clinical criteria that determine the opti- from Parke-Davis Women’s Healthcare Division. mal OC choice. VOLUME 66, OCTOBER 2000 281 ORAL CONTRACEPTIVES Androgens and OCs press the ovarian production of total circulating T by Hormones and Acne—Acne can reflect multiple etiolo- direct gonadotropin suppression. gies, including such contributing factors as infection, Androgenicity of Progestins—All combination OCs abnormal keratinization, immunologic reaction, and consist of estrogen and progestin components. They hormonal influences. Generally, the mean serum may be monophasic, providing a uniform hormonal androgenic profile in acne is the same as in normal dose throughout the pill cycle, or multiphasic, gradu- patients. The exception is acne secondary to masculin- ating the progestin or, more recently, the estrogen izing disorders such as polycystic ovary syndrome, in dose in stages. which circulating androgen levels are abnormally high. Since the introduction of OCs almost 4 decades Nevertheless, androgens acting peripherally at the ago, the dose of both hormones has been significantly sebaceous follicle are a prerequisite for acne in all reduced, resulting in safer formulations with compara- patients. These hormones promote development of the ble efficacy. In the low-dose OCs (<50 µg estrogen) condition by causing an increase in sebum production available in the United States today, the estrogen com- and, possibly, by enhancing follicular hyperkeratosis. ponent is exclusively ethinyl estradiol (EE), while the The 3 major sources of androgens are the ovary, the progestin may be norethindrone; norethindrone adrenal gland, and the skin. Under the influence of acetate (NA); ethynodiol diacetate; norgestrel; levo- luteinizing hormone, the ovary contributes approxi- norgestrel (LNG); or the 2 new progestins, norgesti- mately 50% of circulating androgens—it secretes mate and desogestrel (DSG). All of the progestogens testosterone (T) and androstenedione, with much of are derivatives of 19-nortestosterone and ethisterone, the latter being peripherally converted to T. The adre- the first orally active synthetic T. nal gland contributes the other 50% of T, also largely There has been a great deal of discussion concern- from conversion of secreted androstenedione. Via the ing the purported androgenicity (or its relative lack) enzyme 5-alpha-reductase, the skin has the ability to of certain progestins. LNG has had a reputation for metabolize androgens into more potent metabolites being significantly androgenic, whereas the new (eg, dihydrotestosterone). In addition, relatively progestins are reported to minimize this property. nonandrogenic adrenal androgens, such as dehy- Tables listing these OC components and their andro- droepiandrosterone, can be converted to more potent genicity indexes have emerged in papers, handbooks, androgens, including T. Thus, patients with normal and even respected medical textbooks. But the liter- T levels can have acne secondary to enhanced 5-alpha- ature on the subject can be misleading in several reductase activity, which varies from individual to indi- respects. Early estimates of androgenic potency were vidual and cannot be measured in the clinical setting. based on progestin doses much higher than those Like other steroid hormones, T circulates in the used today. In addition, early estimates were calculat- bloodstream either bound or unbound to plasma pro- ed primarily from in vitro androgen-receptor binding teins. The principal specific steroid-binding protein for tests and bioassays.3 Today, researchers emphasize the T is sex hormone–binding globulin (SHBG), which inadequacies of these methods for assessing clinical accounts for 80% to 85% of the total circulating quan- effects. Source and type of tissue, choice and purity of tity of this substance.1 Because of the high affinity of T reference steroid, purity of test substance, incubation for SHBG, bound T is biologically inactive. As the time and temperature, and technique for separating concentration of SHBG decreases (eg, in polycystic receptor-bound from unbound steroid can all skew ovary syndrome or obesity), the amount of unbound or receptor-binding results. Comparable methodologic free T increases, resulting in increased biologic activity. deficiencies apply to bioassays, complicated further Conversion of as little as 1% of T from bound to by the fact that animal data are of limited utility for unbound can precipitate a hyperandrogenic state and extrapolation to human clinical situations.3,4 Activity possible acne pathogenesis. Conversely, an increase in in animals is unlikely to have a clinical correlate.4 SHBG produces an accompanying increase in uptake Further confounding the significance of the early of T and a subsequent reduction in concentration of findings is that a single substance may, in addition to free, biologically active hormone. A number of factors its androgenic effect, have antiandrogenic, estro- affect production of SHBG in the liver—of greatest genic, and antiestrogenic properties, none of which is clinical relevance is that androgens decrease SHBG measured by a test specific for androgen activity. and estrogens increase it. Finally, it is impossible to predict the clinical effect of OCs help to relieve acne precisely because they a combination agent from the findings for individual reduce excessive androgens from any source.2 They components.5,6 The nature and proportion of the 2 stimulate the production of SHBG, thus reducing constituents in a mixture may have a major influence free and biologically active