OPTIONS FOR THE HORMONAL THERAPY OF ACNE IN WOMEN

Once the decision has been made to initiate hormonal therapy, the various options
to choose from include: (i) androgen receptor blockers, or antiandrogens (this class
of drugs block the effect of androgens on the sebaceous gland); (ii) inhibitors of
androgen production by the ovary or adrenal gland such as oral contraceptives
or glucocorticosteroids, respectively; or (iii) in the future, it may be possible to
inhibit the activity of androgen metabolizing enzymes in the skin or sebaceous
gland itself.
Agents that Block the Androgen Receptor
Within the class of androgen receptor blockers, therapeutic options include spirono-
lactone, cyproterone acetate, and flutamide. In the United States, spironolactone is
the most commonly used drug, although flutamide is also available.
Spironolactone
Oral spironolactone decreases sebum excretion rate by 30% to 50%. Recommended
doses are 50 to 100 mg taken with meals (36,37). However, many women with
sporadic outbreaks of inflammatory lesions or isolated cysts 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 generally well-tolerated. However, if this drug is
used in older women who may have other medical problems, or if higher doses
are used for conditions such as hirsutism or androgenetic alopecia, serum electro-
lytes should be monitored. Side effects of spironolactone include breast tenderness
and menstrual irregularities. Additionally, it is important that pregnancy be
avoided during treatment with spironolactone due to the potential for abnormal-
ities of the male fetal genitalia such as hypospadias.
Cyproterone Acetate
Cyproterone acetate is available in many parts of the world, but not in the United
States. It possesses dual activity in that it serves as a progestogen in oral contracep-
tives in addition to its direct inhibition of the androgen receptor. It can be given in
doses of 2 to 100 mg per day as a single agent, in which case there can be improve-
ment in 75% to 90% of women with acne. Cyproterone acetate, however, is most
commonly used in the form of an oral contraceptive combined with ethinyl estra-
diol in varying doses (38). Numerous clinical studies support the efficacy of these
oral contraceptive preparations in women with acne.
Flutamide
Flutamide is apotent nonsteroidal antagonist of the androgenreceptor.Althoughmost
commonly used to treat prostate cancer, flutamide has been reported to be efficacious
in the treatment of acne, hirsutism, and androgenic alopecia (39). It can be given in
doses of 250 mg twice daily in combinationwith an oral contraceptive. Fatal hepatitis
has been reportedwith this drug. Liver function tests shouldbemonitoredand serious
consideration should be given to the risk/benefit ratio of its use in acne (40).Addition-
ally, because it is an antiandrogen, pregnancy issues are a concern.
Inhibitors of Adrenal Androgen Production
Another option in hormone therapy is to block the production of androgens either
by the adrenal gland or ovary, which can be accomplished through the use of low-
dose glucocorticoids or oral contraceptives, respectively.
Glucocorticoids
Low-dose glucocorticoids are most commonly used to treat patients 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 steroid precursors that are shunted into the
androgen biosynthetic pathway. Low-dose prednisone (2.5 to 5 mg a day, at bedtime)
can be used. Low doses of dexamethasone can also be used, but the risk of adrenal
suppression is higher. To ascertain if therapy with glucocorticoids is having the
desired effect, serum DHEAS can be monitored for a decrease or normalization of
the level of DHEAS. To check for adrenal suppression, an adrenocorticotrophin
hormone (ACTH) simulation test can be performed. This consists of injecting
ACTHand assessing the plasma cortisol 30minutes later. If plasma cortisol has risen
by an appropriate amount, the adrenal gland is not suppressed.
Inhibition of Ovarian Androgen Production
Gonadotropin-Releasing Agonists
Androgen production in the ovary can also be blocked by gonadotropin-releasing
hormone agonists such as buserelin, nafarelin, or leuprolide. These gonadotropin-
releasing agonists block ovulation by interrupting the cyclic release of FSH and LH
fromthe 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 ovarian production of estrogens,
thereby eliminating the function of the ovary. Thus, the patient could develop meno-
pausal 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 generally contain an estrogen (most commonly ethinyl estra-
diol) and a progestin. In their early formulations, oral contraceptives contained
over 100 mg of estrogen. In these and higher doses, estrogens themselves can sup-
press sebum production. Estrogens also act on the liver to increase the synthesis of
sex hormone-binding globulin that binds testosterone and lowers the circulating
levels of free testosterone. In addition, oral contraceptives inhibit the ovarian pro-
duction of androgens by suppressing ovulation. This, in turn, decreases serum
androgen levels and reduces sebum production. The concentrations of estrogen
in oral contraceptives have decreased over the years from 150 to 35 mg, and in
the most recent forms, to 20 mg, in order to reduce the side effects associated
with estrogen (41). Oral contraceptives containing low doses of estrogen are
listed in Table 1.
Progestins
The progestins contained in oral contraceptives include estranges and gonanes,
which are derivatives of 19-nortestosterone, cyprotereone acetate, and a novel pro-
gestin, drosperinone. Members of the estrane and gonane class of progestins
(Table 2) can cross-react with the androgen receptor, which can lead to increased
androgenic effects and could aggravate acne, hirsutism, or androgenic alopecia.
These progestins 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,
the third generation progestins, including norgestimate, desogestrel, and gesto-
dene, are more selective for the progesterone receptor rather than the androgen
receptor. The biological relevance of these differences, however, is uncertain. For
years, it has been known that almost all oral contraceptives are beneficial in the
treatment of acne (42). 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 proges-
tin, will inhibit serum androgen levels. Moreover, although some progestins might
be more androgenic than others, there is an increase in sex hormone-binding globu-
lin with the use of any oral contraceptives and an improvement of the acne in
women who are treated with them.
Drospirenone is a novel progestin that is derived from 17a-spironolactone. It
possesses antiandrogenic and antimineralocorticoid activity, which can be of
benefit in androgenic-related conditions such as acne and hirsutism and in the
estrogen-related fluid retention associated with some oral contraceptives (43).