Acne vulgaris is a hormonal disease succinctly

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2 Key to successful acne management is understanding and targeting the hormonal factors that mediate the disease process. BY WILLIAM DANBY, MD Acne vulgaris is a hormonal disease succinctly described in four words: No hormones, no acne. Attempting to manage acne by attending only to the plugged pores and the attendant inflammatory component without regard to the underlying hormonal stimuli is an exercise in chronic frustration. It is also expensive for the patient, who is being asked to pay for incomplete treatment. Instead, dermatologists must evaluate the hormonal factors that contribute to acne vulgaris and target these. Hormonal Sources Looking to management, one must consider first the sources of these hormones, of which there are four. The first and most obvious is the gonads. In males, no therapeutic manipulation of these hormones is acceptable. In females, several options are available. The second source is the adrenals. It has been shown that acne in girls and boys is related first to new adrenal activity. It is also fairly well accepted that stress worsens acne, and recently it has been shown that overproduction of adrenal androgens in delayed onset congenital adrenal hyperplasia is occasionally related to acne in the adolescent and even in the post-adolescent period. Ultimately the circulating gonadal and adrenal testosterone arrives at the pilosebaceous units where it meets the enzyme 5α-reductase and becomes dihydrotestosterone. The third source is exogenous androgens, which have been known for decades to cause acne. This observation was derived from the sometimes legal, but more often illicit use of androgenic anabolic steroids. The presence of exogenous androgen in dairy products was described as early as the 1970s, 1 and the clinical correlation of dairy intake with acne was described as far back as the 1930s. But acne is a very common disorder and dairy products are consumed by a high percentage of our population, so proving an association between acne and dairy was no mean epidemiological and statistical feat. Nevertheless, this association is now well-documented, although more work needs to be done on the causal relationship between the two on a molecular basis. 2 But even defining this third source does not provide the whole story. Within the germinative epithelium of the sebaceous unit itself, as detailed as early as 1970 by Calman and as further elucidated by Thiboutot in the last few years, there exists a system of enzymes that are capable of taking precursor molecules from the blood and turning them into dihydrotestosterone. 3 So the fourth source is deep within and uses raw materials supplied not only by the adrenals and gonads but also by diet. This is the intracrine system. By some estimates, 50 percent of the body s androgens are processed in the pilosebaceous units. Returning to dairy products, we know that milk contains progesterone, testosterone, and two chemicals that have already been acted upon by 5α-reductase, 5α-androstane- June 2007 Practical Dermatology 33

3 Hormones and Acne dione and 5α-pregnanedione. Importantly, all four of these are precursors for dihydrotestosterone, manufactured on site in the pilosebaceous unit. Hormonal Dynamics For many years, attempts have been made to relate the activity of acne or the output of sebaceous glands to serum levels of dihydrotestosterone. Only rarely is a rough correlation achieved, which should probably have sent us some sort of message. Importantly, high levels are usually achieved only rarely, e.g. in severe metabolic abnormalities or with adrenal, ovarian, or testicular tumors. The problem in normal individuals and those with regular acne is that individual hormone molecules appear in the blood from various sources, at various speeds, and are either free or bound to various proteins. Individual hormone molecules disappear from the blood at a speed related to their affinity to receptors (the fit), number of receptors, the avidity with which they are bound (the grip), and whether they are metabolized at the receptor site or reach a steady state in equilibrium with the blood level of identical or similar molecules. Thus, measuring the concentration of a hormone in blood at a single point in time gives relatively little information about the pharmacokinetics of the molecule. If the hormone is produced by the body (or absorbed from the gut) quickly and then removed swiftly, the blood level will be low. It has been suggested that androgens will be removed in as few as two passes through the circulation, leaving little circulating in the blood for measurement. In essence, these hormones disappear into the intracrine system from which they emerge only as a component of sebum, in which such hormones have been known to be resident for decades. Managing acne, therefore, becomes primarily an exercise in managing hormones. Concurrent management of the epiphenomena of inflammation and infection is of course essential, but the need should fade once the drivers of the disordered intrafollicular keratinization are brought under control. Controlling Gonadal Hormones Therapy directed at testicular testosterone, unless one could specifically block its effect on pilosebaceous units, is out of the question. Blockade could be managed by use of dutasteride, which has the capacity to block both isoenzymes I and II of 5α-reductase. However, no published investigations of the use of this drug in this disorder have appeared. Ovarian-source hormones, on the other hand, are amenable to manipulation. The older preparations of oral contraceptives (OCs), containing what are now considered high doses of estrogens, had a beneficial effect on acne but were heavily laden with side effects. For the past 30 years, a gradual reduction in estrogen content has occurred, and concurrently a number of new progestins have appeared. The difficulty has been trying to find a product that has the least stimulus to induction of new acne. Until recently, all of the progestins available have been androgenic to various degrees, and because androgenicity correlates roughly with acnegenicity, these products have been problematic with regard to the continued stimulation of acne. 4 The net effect of androgenicity (positive from the androgenic progestins) and anti-androgenicity (negative from the estrogenic component) has led to the selection of certain brands of OCs for acne management. Paradoxically, that net effect has led to some androgenic progestins being included in OCs that are FDA approved for acne therapy. The new exception is drospirenone, whose acnegenicity rating is zero. Indeed, it is not only non-androgenic; it is an active anti-androgen by virtue of its ability to compete for space at the nuclear androgen receptor, similar to the action of its relative spironolactone. Whether used with a low level of 20µg ethinyl estradiol compound (marketed as Yaz,Berlex) and FDA approved for the indication of acne) or as the original 30µg ethinyl estradiol version (marketed as Yasmin, Berlex), hormone control is normally achieved quite successfully in most cases over a six-month course with marked improvement in most cases of acne. It is, of course, an important part of maintenance as well. To improve the degree of acne suppression in younger women, it is now possible to advocate extended courses of these oral contraceptives. This entails (for the 21 day cycled Yasmin) use of multiples of 21 pills taken without a break, for instance 42, 63, 84, 105 or other multiples of 21, delaying the onset of menses and concurrently increasing the percentage time of androgen suppression by 33 percent. 5 This has the additional advantage of avoiding the monthly drop in estrogen support, which, for women with estrogen-deficiencyrelated headache and other estrogen-mediated problems, is a major advantage. Most clinical dermatologists are aware of the numerous cases of acne (both vulgaris and rosacea types) occurring in women of middle age. Estimates range as high as 40 percent for this age group. While many of these cases are diet-associated, hormonal imbalances associated with polycystic ovarian syndrome, endometriosis, stress-associated menstrual irregularity, persistent corpus luteum cysts, and the obesity/insulin resistance/syndrome X complex must be considered and ruled out. In addition to its usefulness in these cases, the ethinyl estradiol/drospirenone compound is now FDA-approved for what was once called PMS and is now premenstrual dysphoric disorder (PMDD). Additionally, drospirenone is now available in a 0.5mg dose 34 Practical Dermatology June 2007

4 combined with 1mg estradiol (real estradiol, not ethinyl estradiol), marketed as Angeliq (Bayer Healthcare) for postmenopausal hormone replacement therapy. This is likely to prove valuable in managing the ever-increasing numbers of women with acne climacterica that we now see in the post-whi era, among women who are no longer using estrogen support as they have in the past. Looking to the future, we can look forward to drospirenone being available as a standalone fairly soon. Influencing adrenal androgens is another story. Over the years, attempts have been made with nocturnal doses of dexamethasone or prednisone to suppress the acnegenic effects of adrenal androgens. While theoretically this should work, it is difficult to justify from a practical point of view, except in the occasional and unusual cases of late onset congenital adrenal hyperplasia. The Dairy Androgens/Acnegens It has taken years to nail down the impact of androgenic hormones in milk. Although the association of milk and acne has now been well-documented, the question remains What in milk actually causes the trouble? Milk is a complex compound with at least 60 growth factors present. 6 Milk is, after all, designed to make small mammals grow. Because we know that the final common pathway for acne is through dihydrotestosterone, it would seem natural to look for precursors of this compound in milk. That has been done in the past, but the work needs to be updated. We do know that in addition to many other steroidal hormones progesterone, testosterone, 5α-androstanedione and 5α-pregnanedione are present. All four are precursors of dihydrotestosterone and therefore must be suspect. To complicate matters, there is published work that links the ingestion of milk to increases in insulin-like growth factor I (IGF-I) and insulin, and, as a result of this combined influence, increases in testosterone and decreases in sex hormone binding globulin occur. 7 The net effect is to produce more androgen, more acnegenicity, and more acne. Further clinical experimental work is in progress. In patients, the milk/acne link has been suspected for decades, with references to milk restriction as part of acne management going back into the 1930s. The practical management of acne patients particularly active teenagers remains a challenge, particularly if one attempts to restrict or eliminate all dairy products. Nevertheless, over the years, I have found this a valuable and clinically rewarding part of therapy. Certainly, not all patients who stop all dairy consumption improve 100 percent. The problem is that the acnegens in patients lives are multisourced. It is essential that patients understand that the three major sources are the gonads, the adrenal glands, and dairy products. These three sources stack up on one another. If the stack of hormone sources is high enough, it gets beyond one s personal acne threshold, and acne results. If one can reduce the level of acnegens by eliminating dairy, controlling gonadal sources when possible, and minimizing stress, then one can usually get the hormone level down below the acne threshold, and significant improvement occurs with time. The time required of the dermatologist during an initial acne visit to explain all this to the impatient teen and parents is significant. While I cannot provide detailed direction regarding this process here in this article, I would recommend visiting the website, particularly the No Milk Acne Diet and the Physicians Guidelines pages. Applying the Principles So how does one integrate hormonal management into daily practice? The twin keys to success in hormonal acne treatment are education (your responsibility) and comprehension (the patient s responsibility). Two sets of three simple items are presented, three on cause and three on therapy: Regarding the cause of acne, patients are told that the hormones that cause acne come from three sources: 1. the ovaries or testicles, 2. the adrenals ( stress glands), and 3. dairy products and that they June 2007 Practical Dermatology 37

5 Hormones and Acne need to reduce or eliminate as many of the acne-causing hormones as possible. The individual patient s case is then considered under each heading, a customized approach combining further history-taking, teaching, and investigation of therapeutic options, usually with parental input solicited along the way. When it comes to therapy, patients are offered three different approaches to therapy: 1. The Natural approach. Stop all dairy products no exceptions for six to 12 months and see what happens. Other dietary considerations can be undertaken, but that s another story. 2. The Standard approach. As above, all dairy is stopped, but the patient is then treated with all the comedolytics, antibiotics, anti-inflammatories, hormones and hormone blockers, and other physical and chemical modalities directed at eliminating the epiphenomena of inflammation and infection. 3. The Pedal to the Metal approach. Isotretinoin is the only therapy that consistently shuts down sebum production, shrinks the sebaceous glands to normal size, and both lyses and ejects the retained follicular plug. Hormone control and standard therapy are emphasized and continued while the ipledge requirements are being debated and, one hopes, met by patient and family. It is not uncommon that patients who are isotretinoin candidates at presentation will choose a conservative approach initially and find, after a few months of hormone management, that they can set aside the consideration of isotretinoin because of the improvement that ensues. The opposite is also the case. Those in whom the inflammatory activity and foreign body reaction is so entrenched and self-perpetuating that aggressive standard therapy simply may not work are offered a trial of the dairy-free Standard approach with the promise that isotretinoin will be made available on request. Other Hormonal Blockers Spironolactone has been a valued tool for years. The mother of drospireneone, spironolactone still has a place in acne therapy on occasion when extra androgen suppression is needed. It can It is essential that patients understand that the three major sources are the gonads, the adrenal glands, and dairy products. These three sources stack up on one another. be added to the drospirenone-containing OCs for additional effect. My personal approach is to start with one 25mg tablet daily for the first month, two tabs daily the second month, and so on, usually peaking out at 100mg (when the patient is switched to the 100mg tablet). Higher doses may be needed on occasion. Spironolactone should be avoided if pregnancy is a possibility because of anti-androgenic fetal effects. It can also cause break-through bleeding (in the non-pregnant patient), requiring a reduction in dose. Flutamide is theoretically a perfect anti-androgen, acting at the nuclear androgen receptor level, where it is presumed capable of blocking even the 5αandrostanedione and 5α-pregnanedione present in milk. In doses used to date, occasional liver toxicity has been a worry. Lower dose studies are anticipated. Finasteride was initially hoped to be of value, but it blocks only isoenzyme II of 5α-reductase. This is not significant in pilosebaceous control. Dutasteride blocks both isoenzymes and it (or relatives to be developed) may prove valuable. No Hormones, No Acne Acne management is incomplete without active consideration of the hormones that drive the disease, paired with an aggressive therapeutic policy designed to identify and quantitate the sources and then a concerted effort to eliminate, reduce, substitute or block the responsible hormones. Remember the rule we started with: No hormones, no acne. 1. Darling JA, Laing AH, Harkness RA. A survey of the steroids in cows' milk. J Endocrinol 1974 Aug;62(2): Adebamowo CA, Spiegelman D, Danby FW, Frazier AL, Willett WC, Holmes MD. High school dietary dairy intake and teenage acne. J Am Acad Dermatol 2005 Feb;52(2): Thiboutot D. Acne: hormonal concepts and therapy. Clin Dermatol 2004 Sep;22(5): Dickey RP. Managing Contraceptive Pill Patients. 12 ed. EMIS Inc., Foidart JM, Sulak PJ, Schellschmidt I, Zimmermann D. The use of an oral contraceptive containing ethinylestradiol and drospirenone in an extended regimen over 126 days. Contraception 2006 Jan;73(1): Koldovsky O. Hormones in milk. Vitam Horm 1995;50: Hoyt G, Hickey MS, Cordain L. Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk. Br J Nutr 2005 Feb;93(2): Practical Dermatology June 2007