Options for Hormonal Therapy

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Once the decision has been made to initiate hormonal therapy, there are various options to choose from:

(1) androgen receptor blockers, or antiandrogens (this class of drugs block the effect of androgens on the sebaceous gland and on the infundibulum of the follicle);

(2) inhibition of androgen production by the ovary or adrenal gland, or (3) in the future, inhibition of androgen metabolizing enzymes in the skin may be possible (see 'Enzyme inhibitors' section below). It is important to note that hormonal therapy is absolutely contraindicated in women who want to become pregnant due to the risk for sexual organ malformation in a developing fetus.

Androgen Receptor Blockers

Spironolactone

Within the class of androgen receptor blockers, the drug options are spironolactone, cyproterone acetate, and flutamide. In the United States, spironolactone is the drug most commonly used. Oral spironolactone decreases sebum excretion rate and inhibits the type 2 17P-HSD [48, 49]. Recommended doses for the treatment of acne are 50-100 mg, taken with meals [50]. However, many women respond well to 25 mg twice daily, and some even respond to just 25 mg a day. These low doses in healthy young women are well tolerated. However, if this drug is used in older women with other possible medical problems, or if higher doses are used for conditions such as hirsutism or androgenic alopecia, serum electrolytes should be monitored. Side effects to be aware of include breast tenderness and menstrual irregularities.

Cyproterone Acetate

Through dual activity, cyproterone acetate inhibits ovulation and blocks the androgen receptor. There are two ways to use cyproterone acetate: low dosage at 2 mg per day in combination with ethinyl estradiol in an oral contraceptive (Diane, Dianette) or high dosage at 50-100 mg from days 5 to 14 of the menstrual cycle [51]. There can be improvement in 75-90% of patients who are treated with the high-dose regimen.

Flutamide

Flutamide, a very potent antiandrogen that is also used to treat prostate cancer, can be used in the treatment of acne, hirsutism, and androgenic alopecia [52]. It can be given in doses of 250 mg twice daily, in combination with an OC. Fatal hepatitis is a concern with this drug, and liver function tests should be followed [53]. The hepato-toxicity associated with flutamide seems to be dose- and age-dependent [54]. Low dose (62.5-125 mg) has been reported to be safe and effective [55].

Adrenal Androgen Production Blockers

Glucocorticoids

Another option in hormone therapy is to block the production of androgens, which can be accomplished through the use of oral contraceptives and low-dose glucocorti-coids. This is most commonly used to treat the patient with late-onset congenital adrenal hyperplasia, which is an inherent defect in the 21-hydroxylase or the 11-hydroxylase enzyme. This defect causes a block in the cortisol biosynthetic pathway, which results in a buildup of precursors for potent androgens. Low-dose prednisone (2.5-5 mg a day, at bedtime) is one option. Dexametha-sone can also be used, but the risk of adrenal suppression is higher. To ascertain if the therapy is having the desired effect, the serum DHEAS can be monitored. A decrease or normalization of the blood levels indicates that treatment is successful. To check for adrenal suppression, an ACTH-simulation test can be performed. This consists of injecting ACTH and assessing the plasma cortisol 30 min later. If plasma cortisol has risen by an appropriate amount, the adrenal gland is not suppressed.

Ovarian Androgen Blockers

Gonadotropin-Releasing Agonists

In addition to blocking the adrenal production of androgens, production in the ovary can also be blocked through the use of gonadotropin-releasing hormone agonists, such as buserelin, nafarelin or leuprolide. These gonadotropin-releasing agonists block ovulation by inter rupting the cyclic release of FSH and LH from the pituitary. These drugs are efficacious in acne and hirsutism, and are available as injectable drugs or nasal spray. However, in addition to suppressing the production of ovarian androgens, these drugs also suppress the production of estrogens, thereby eliminating the function of the ovary. Thus, the patient could develop menopausal symptoms and suffer from hypoestrogenism. Headaches can also develop, as well as the occurrence of bone loss, due to the reduction in estrogen.

Oral Contraceptives

Oral contraceptives contain two agents, an estrogen (generally ethinyl estradiol) and a progestin. In their early formulations, oral contraceptives had high concentrations of over 100 ^g of estrogen. In doses higher than 100 ^g, estrogens can suppress sebum production. Estrogens also act hepatically to increase the synthesis of sex-hormone-binding globulin. Circulating testosterone levels are reduced by the increased sex-hormone-binding globulin production, leading to a decrease in sebum production. Oral contraceptives inhibit the ovarian production of androgens by suppressing ovulation. This, in turn, decreases serum androgen levels and reduces sebum production.

Oral contraceptives containing cyproterone acetate such as Diane® and Dianettte® are highly effective for the treatment of acne and have often served as the 'gold standard' for efficacy evaluation in clinical trials. It is available in Europe, Canada and Asia, but not in the United States. It is of use in patients with acne resistant to other therapies and reduces sebum production. In addition, it may have a direct effect on comedogenesis, which is known to be androgen mediated. Dianette® may represent a treatment of choice in patients who need oral therapy and who are sexually active and need a contraceptive pill or in those patients who need hormonal therapy to regulate irregular periods.

Two families, the estranes and the gonanes, comprise the progestin components of other oral contraceptives, with a variety of drugs in each class. Progestins can cross-react with the androgen receptor, which can lead to increased androgenic effects and thus aggravate acne, hir-sutism, or androgenic alopecia [56]. They can also cause changes in lipid metabolism and can increase serum glucose, leading to glucose intolerance, as well as possibly interfering with the beneficial effect of estrogen on the sex-hormone-binding globulin.

However, as with the estrogens, many progestins have been developed over the years and the third-generation progestins, including norgestimate, desogestrel, and ges-todene, are more selective for the progesterone receptor rather than the androgen receptor. In the United States, the only two oral contraceptives approved for use in acne treatment are Ortho Tri-Cyclen® (Ortho-McNeil Pharmaceutical, Raritan, N.J., USA), which is composed of ethi-nyl estradiol and norgestimate and Estrostep (Parke Davis, Detroit, Mich., USA) which contains doses of 20-35 ^g of ethinyl estradiol in combination with 1,000 mg nor-ethindrone acetate. Four large placebo-controlled studies, involving a total of approximately 1,093 women with moderate acne, found improvement in inflammatory lesions, total lesions and global assessment with the estro-gen-norgestimate combination (500 patients) [57, 58] and with the estrogen-norethindrone acetate combination (593 patients) [59].

The biological relevance of the different progestins is also of interest. For years it has been known that oral contraceptives are beneficial in the treatment of acne [60], and it is possible that some women are more sensitive to the androgenic effects of a progestin, but it is more likely that the effect of progestin may be offset by estrogen. All oral contraceptives, regardless of the type of progestin each contains, will inhibit serum androgen levels. Moreover, although some progestins might be more androgenic than others, there is an increase in sex-hormone-binding globulin with the use of any OC and an improvement of the acne in women who are treated with them. One OC, Triphasil™ (Wyeth-Ayerst Pharmaceuticals, Philadelphia, Pa., USA), which contains ethinyl estradiol and levonorgestrel (one of the older progestins), was studied in acne and found to produce a 75% decrease in comedones, as well as a greater than 50% decrease in papules and pustules [61].

Oral Contraceptives with Low-Dose Estrogen

The concentrations of estrogen in oral contraceptives have decreased over the years from 150 to 35 ^g, and in the most recent forms, to 20 ^g, in order to reduce the side effects of estrogen. Three preparations of low-dose (20 ^g) estrogens are available: AlesseTM (Wyeth-Ayerst Pharmaceuticals), which contains ethinyl estradiol and 100 ^g levonorgestrel; Mircette™ (Organon, Inc., West Orange, N.J., USA), which contains ethinyl estradiol and desoges-trel, and Estrostep (Parke Davis) which contains ethinyl estradiol and norethindrone acetate. These formulations offer the advantage of fewer estrogenic side effects, and their role in the treatment of acne is currently being evaluated [59, 62-64].

Oral Contraceptives and Antibiotics

The concern regarding oral contraceptives and antibiotics is essentially theoretical, owing to the action of broad-spectrum antibiotics, which reduce the gut flora bacteria and thus may result in decreased absorption of estrogen. This could lead to a possible reduction in the efficacy of oral contraceptives. Nevertheless, there have been very few reports in the literature of pregnancies associated with the use of antibiotics in conjunction with oral contraceptives [65, 66]. Existing reports have focused on tetracycline, and the incidence was 1.2-1.4 pregnancies/ 100 woman-years of use of the OC. Unfortunately, these data cannot be compared to the background failure rate of oral contraceptives [65].

Enzyme Inhibitors

As previously mentioned, certain enzymes in the skin can produce androgens locally. It is possible that these local enzymes may be mediating sebum production in individuals with acne whose serum levels are at the high end of the normal range. If so, therapies that block the activity of this enzyme may be useful in the treatment of acne [47]. Since dihydrotestosterone (DHT) is the most potent androgen that directly influences acne, in theory, either the enzymes that synthesize DHT from DHEAS (steroid sulfatase, 3a-HSD, 17P-HSD or 5a-reductase) or that 'detoxify' DHT (aromatase or 3P-HSD) can be targeted or modified as a potential means of treating acne. However, since the proximal portion of the pathway of androgen metabolism (steroid sulfatase, 3a-HSD) is also a key to the synthesis of other steroid hormones, it would be safer to target the downstream enzymes such as 5a-reduc-tase. Of note is that testosterone binds to the type 1 5 a-reductase at micromolar concentrations whereas the affinity of testosterone for the type 2 isozyme is in the nano molar range. This implies that much higher doses of a type 1 inhibitor may be required to inhibit this isozyme, as is the case with dutasteride, a dual inhibitor of the types 1 and 2 5a-reductase [67]. Studies also suggest that the type 1 5a-reductase may also be inhibited by green tea extract catechins, phytoestrogens/isoflavonoids and lig-nans, suramin, zinc and azelaic acid [31, 68, 69]. It remains possible that specific, locally acting enzyme inhibitors may be of future use in males with acne in addition to females.

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