W hen talking about hormonal aspects of acne, I think there are two questions we need to ask. How do hormones affect the development of acne? How can we manipulate these hormones to improve acne? What We Already Know To answer the first question, let’s take a look at some of the things we do know about acne. First and foremost, we know that the pathogenesis of acne is multi-factorial. Here’s a look at what else we know: • Follicular hyperkeratosis or abnormal follicular keratosis plays a role. The pathogen Propionibacterium Acnes (P. Acnes), causes inflammation and excess sebum production. • Sebum is largely under hormonal control, and we know that androgen stimulates sebum production and proliferation by binding to the androgen receptor. In addition, 5-alpha reductase type I enzyme activity is present at the sebum site. This activity converts less potent androgens, such as testosterone and also androsterone, into dihydrotestosterone (DHT). This more potent hormone has a greater effect on sebum production. We also know that sebum levels remain relatively constant far into the adult years, so why does acne seem to spontaneously resolve in many people? In addition, why is it that some people who have oily skin don’t develop acne? This reiterates the idea that acne is multi-factorial. • We also know estrogens have an inhibitory influence — they increase the sex hormone binding globulin, which is what “soaks up” testosterone. Estrogens also feed back into the hypothalamus and pituitary glands. This decreases the release of gonadotropin-releasing hormone, and subsequently, gonadotropins. So, less androgen is secreted from the ovaries and adrenal glands. • Total testosterone is not the important value — free testosterone is more important. In general, the higher your sex hormone binding globulin, the lower the amount of free testosterone. The levels of free testosterone in males is 9 to 30 nanograms per deciliter, and in females it’s 0.3 to 1.9 nanograms per deciliter. So, again, if sebum was the only factor contributing to acne development and testosterone was the cause of this excess sebum, then all men, and no women, would have acne. Obviously, this isn’t the case. • The ovaries can produce androgens, as well, so the pituitary releases leutinizing hormone (LH) and this can lead to the enhancement of ovarian androgen release. A gonadotropin, LH causes the gonads to produce and secrete hormone. Also, adrenocorticotrophic hormone (ACTH) from the pituitary gland can influence the adrenal gland, and subsequently produce the androgenic steroid dehydroepiandrosterone (DHEA). Now both DHEA and ovarian androgen at the sebocyte level can be transformed by 5-alpha reductase type I to the more potent androgen dehydroxytestosterone, and both of these then bind to the androgen receptor and stimulate sebocyte proliferation. • Progestogens don’t have a lot of impact, although when discussing oral contraceptives that’s another story. A Look at the Studies How often do women with acne have abnormal circulating androgens? There have been numerous studies and literature looking at hyperandrogenism in women. One 1983 study conducted by Ann Lucky, M.D., reviewed six different androgen hormone levels. The results showed that 52% of the women (about 23 of 44 women) tested had at least one abnormal androgen level. This included acne patients who were non-hirsute and who had normal menstrual periods. In another study, which was reported in 2001, Slayden found that 63% of these non-hirsute acne patients had at least one androgen value that was greater than 95% of controls. Another study by Henze found that 30% of the patients tested had an elevated testosterone and/or DHEA level. Some criticism has been voiced about a few of these studies because many of them took place in large referral centers, where they may have more cases of late-onset acne or acne that’s been resistant to treatment. Also, the studies may have been slightly skewed toward participants who had polycystic ovary disease or other endocrinologic abnormalities. But in general, we do know that acne may be a manifestation of hyperandrogenism in some women; however, most non-hirsute acne patients with normal menstrual periods have normal androgen values. A Look at End Organ Hyper-Responsiveness huge role, if something is going on at the sebocyte level, it causes some people to react differently. There was a study on pre-pubescent boys done in 1998 and published in the British Journal of Dermatology. They were given a 2% testosterone cream that was applied to half of the forehead. Three of the subjects had a 15-fold increase in their sebum excretion rate. I believe it was just after 6 weeks of treatment. Two had a moderate increase and then three had no increase. This was a small number, but it was interesting because the same medicine was applied in these individuals. These different responses didn’t seem to have anything to do with age or pre-pubescent development or family history of acne. Maybe what’s going on here is hyper-responsiveness at the end organ in those people who were already predestined to have acne. We’ve talked about 5-alpha reductase type I, and there have been several studies that have shown that 5-alpha reductase type I is present in greater quantities and amounts in areas of the body where it would be more likely to have acne. Dr. Thiboutot looked at a group of individuals with and without acne, men and women, and she found no significant difference in 5- alpha reductase activity in either group. She did find that all men had more 5-alpha reductase type I activity than women. All of the women with acne had higher levels of circulating steroids than the women without acne, but they were still all within the normal range. In summary, androgenic hormones stimulate sebaceous glands and sebum production. Excess sebum is just one pathogenic factor for the development of acne. Androgen excess may contribute to acne. Most acne patients have normal circulating androgen levels and there may be an end organ hyper-responsiveness in some patients. Altering Hormones to Improve Acne Now that we’ve discussed how hormones factor into the development of acne for our patients, we need to answer our second question and discuss the tools we have to alter the hormones and improve acne. So how do we block androgens? Well, we can block the development of the production of androgens, we can decrease their conversion by inhibiting that 5-alpha reductase type I, or we, can block the androgen receptor itself. Oral Contraceptive Pills Oral contraceptive pills (OCPs) increase sex hormone binding globulin and, therefore, they decrease free testosterone, which can help reduce the occurrence of acne. They also, because of the negative feedback of the hypothalamus and pituitary glands, decrease androgen formation. All available OCPs in the United States are a combination of an estrogen component and a progesterone component. In this country, the estrogen component is ethinylestradiol, and doses can range from 20 micrograms to 50 micrograms. The progestogen can be one of a number of different progestogens, such as levonorgestrel. The brand Yasmin is another oral contraceptive that has drospirenone as the progestogen, a true anti-androgen progestin. Several studies have looked at the effectiveness of treating acne with OCPs. There were studies done with Ortho Tri-Cyclen. Dr. Lucky participated in this. She was lead author on one paper and Dr. Redmond on the other. For these two studies, 462 patients were included overall and 228 received the drug. There was a 49.6% decline in total lesion count in people receiving the drug. There was a 30% decrease in sebum, and that may just be due to increased skin care and also regular office visits with a physician. The free testosterone dropped by 43% in the treatment group, and there wasn’t a significant change in the placebo group. Another study by Thorneycroft evaluated 58 patients who received a lower dose of the estrogen components — 20 micrograms. The study revealed that when this smaller amount of estrogen was combined with progesterone, the OCP still had a positive effect on diminishing acne. Participants were treated with three cycles of treatment and in both groups, despite which progestogen was used, they did have an improvement in their acne. It doesn’t matter what the combination pill is; all of them increase sex hormone binding globulin. Of course, there are risks involved with using oral contraceptive pills (OCPs), and I think this is probably what precludes some of us from prescribing these (See OCP Side Effects on the left). One is venous thromboembolism, and patients who take OCPs have nearly a three-time increased risk of developing venous thromboembolism. The mortality rate doubles in women as they reach ages 35 to 44. Interestingly, there’s no evidence that smoking or varicose veins in any way increase this risk in users of OCPs. Keep in mind the following advantages when you think about prescribing an oral contraceptive: • They all have an anti-androgen effect. • Also, lower dose estrogen pills are associated with fewer side effects, and they’re also associated with less risk of ischemic events — venous thrombi embolism and ischemic stroke. • Oral contraceptives are safest when used in women under 35 years of age who don’t smoke cigarettes, those who don’t have a history of migraine headaches, and for those who are normotensive. Other Anti-Androgen Products Spironolactone, a diuretic, is another known anti-androgen many dermatologists use off-label to treat acne, which works really well. It binds to the androgen receptor and therefore it inhibits the binding of DHT and testosterone. It also inhibits androgen biosynthesis, probably by its action of the cytochrome P450 system. It also inhibits 5-alpha reductase. Side effects you might expect when prescribing spironolactone (Aldactone, Aldactazide), include: • polyurea • menstrual disturbances • gynecomastia (breast tenderness and swelling) • dizziness • headache • weight gain. Dr. Shaio, in Chicago, evaluated 85 female patients who had failed prior treatment with more traditional acne treatments or had what he called signs of hormonal influence. That could be anything from worsening menstrual periods to lower face and jaw distribution of acne. It’s hard to analyze this study because the patients could also be on antibiotics or taking oral contraceptives. So spironolactone might have been added to what many of those patients were already taking. But, an interesting point is that the dosage was lower than many of us may use. It was 50 grams to 100 grams a day versus 200 mg a day. And 66% of patients had greater than 50% improvement. There were menstrual irregularities noted in 17% of patients, and mild hyperkalemia in 14%. There was another small study with 38 patients receiving 50 mg twice a day on days 5 through 21 of the menstrual cycle. Ninety-seven percent had at least some improvement in their acne; 29%, though, had menstrual irregularities. No electrolyte abnormalities were noted in this particular study. Spironolactone is an anti-androgen. I think we should keep in mind that we can use lower doses. With 50 mg to 100 mg a day, you can keep dosages lower so patients experience fewer potential side effects. Periodically monitor potassium, blood pressure and weight in these patients. That’s a good idea even though the incidence of abnormality is low. Also, I believe this drug should be co-administered with oral contraceptives. This normalizes some of those potential menstrual irregularities, and it also prevents pregnancy and thus the risk of feminization of the male fetus. More to Choose From There are a few other anti-androgens. Though flutamide (Eulexin) is a 5-alpha reductase type I inhibitor, it doesn’t work that well in acne. People who have been treated with flutamide, didn’t see much drop in their sebum excretion rates. That’s because this is a 5-alpha reductase Type II receptor versus the Type I receptor, so it doesn’t work as well in sebocytes. There are some 5-alpha reductase Type I inhibitors that may play a role in the treatment of acne. One is NK386. It’s Type I selective. There are also some polyunsaturated fatty acids like gammalitalaic acid that may be 5-alpha reductase Type I inhibitors. In addition, some cations like zinc may inhibit 5-alpha reductase Type I. Even some of the major constituents of green tea may work. There’s also isotretinoin (Accutane), which may have some anti-androgen effect. In fact, some studies have shown there is a decrease in formation of 5-alpha reduced androgens in urine samples because there was a reduction in metabolites. There’s also been shown to be a decrease in liver 5-alpha reductase in patients on isotretinoin, and there has been a 2.6-fold reduced androgen binding capacity, not affinity — the affinity doesn’t change but a lessened capacity of androgen binding in people on isotretinoin. And some have hypothesized this is just because there’s less sebocyte available after or during treatment with isotretinoin. Other studies have shown there is no appreciable change in the sebum hormone levels in people on isotretinoin and who are effectively treated with isotretinoin. A Proposal So I have a challenge for you today, and that is to think about the potential role that androgens and hormones may be playing in your patients who have acne. Also, I urge you to consider adding these potentially anti-androgenic medications to your acne treatment armamentarium.