Very little is known about the role of estrogens in modulating sebum production. Any estrogen given systemically in sufficient amounts will decrease sebum production. The dose of estrogen required to suppress sebum production, however, is greater than the dose required to suppress ovulation (27). The major active estrogen is estra- diol, which is produced from testosterone by the action of the enzyme aromatase. Aromatase is active in the ovary, adipose tissue, and other peripheral tissues. Estradiol can be converted to the less potent estrogen, estrone, by the action of the 17b -HSD enzyme. Both aromatase and 17b -HSD are present in the skin (17,28). Estrogens may act by several mechanisms; they may: (i) directly oppose the effects of androgens locally within the sebaceous gland, (ii) inhibit the production of androgens by gonadal tissue via a negative feedback loop on pituitary gonadotrophin release, and (iii) regulate genes that negatively influence sebaceous gland growth or lipid production.
GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTORS IN ACNE
Growth hormone is secreted by the pituitary gland. It acts on the liver and periph- eral tissues to stimulate the production of IGFs, formerly known as somatomedians. There are two forms of IGF, termed IGF-1 and IGF-2. IGF-1 is the more prevalent growth factor. It has been hypothesized that growth hormone may be involved in the development of acne (29). Acne is most prevalent in adolescents during a time when growth hormone is maximally secreted and serum levels of IGF-1 are highest. In addition, IGF-1 can be produced locally within the skin, where it can interact with receptors on the sebaceous gland to stimulate its growth. Furthermore, conditions of growth hormone excess such as acromegaly are associated with sebor- rhea and the development of acne. In some tissues, the actions of IGF-1 can be mediated by androgens. It is possible that androgens may influence IGF-1 action in the sebaceous gland as well.
CLINICAL PRESENTATION OF ADULT FEMALE ACNE
For reasons that are not understood, the distribution of facial acne in many adult females differs from that seen in adolescents and in males. Many adult women
note that acne localizes to the lateral face, chin, and neck (Fig. 2). Oftentimes, acne in these women is not necessarily widespread or severe, but rather it may be low-grade, persistent, and consist of a few isolated deep-seated tender nodules.
Many women note flares of their acne just prior to their menstrual period with reports ranging from 27 – 60% to 70% of women (30 – 32). One study has been pub- lished that provides quantitative documentation of acne lesion counts over the menstrual period (33). In this study of women, who were followed over two men- strual cycles, 63% showed a 25% increase in inflammatory acne lesions prior to the menstrual period. Some women may feel that intermittent acne therapy prior to their menstrual period may be beneficial. There is no evidence for this approach. Since most acne therapy is designed to prevent the formation of lesions and since this process often takes several weeks, it seems unlikely that intermittent therapy would be beneficial. For this reason, it is important to have patients use their medi- cations consistently and to avoid spot treatment.
WHEN TO SUSPECT AN ENDOCRINE DISORDER IN ACNE PATIENTS
Although hormones influence acne, most acne patients do not have an endocrine disorder. Hyperandrogenism should be considered in female patients whose acne is severe, sudden in its onset, or is associated with hirsutism, or irregular menstrual periods. Additional clinical signs of hyperandrogenism include Cushinoid features, increased libido, clitoromegaly, deepening of the voice, acanthosis nigricans, or androgenetic alopecia. Women with hyperandrogenism may also have insulin resistance. They are at risk for the development of diabetes and cardiovascular disease. It is therefore important for the long-term health of these patients to ident- ify hyperandrogenism so that they can receive appropriate therapy from an endo- crinologist or gynecologist.
SCREENING FOR AN ENDOCRINE DISORDER
A medical history and physical examination should be performed that is directed toward eliciting any symptoms or signs of hyperandrogenism. Screening laboratory tests for hyperandrogenism include a serum DHEAS, total testosterone, free testos- terone, and luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio. These tests should be obtained apart from the time of ovulation in order to avoid the surge of hormones associated with ovulation. From a practical standpoint, it may be easiest to suggest that women have these tests performed either just prior to or during the menstrual period. It is important to note that if a patient is on oral contraceptives at the time of hormonal testing, an underlying hyperandrogen- emia may be masked. This does not occur with antiandrogens such as cyproterone or spironolactone. Therefore, it is best that patients discontinue oral contraceptives four to six weeks prior to the endocrine evaluation.
Excess androgens may be produced by either the adrenal gland or the ovary. Serum levels of DHEAS can be used to screen for an adrenal source of excess androgen production. Patients with a serum DHEAS greater than 8000 ng/mL (units may differ depending upon the laboratory) may have an adrenal tumor and should be referred to an endocrinologist for further evaluation. Some adrenal tumors may also produce tes- tosterone. Values of DHEAS in the range of 4000 ng/mL to 8000 ng/mL may be associ- ated with congenital adrenal hyperplasia, which is most commonly due to a partial deficiency in the 21-hydroxylase or 11-hydroxylase enzyme in the adrenal gland.
Such an enzyme deficiency results in the shunting of steroids from the cortisol biosyn- thetic pathway into the androgen biosynthetic pathway.
An ovarian source of excess androgens can be suspected in cases where the serum total testosterone is elevated. Serum total testosterone in the range of
150 ng/dL to 200 ng/dL or an increased LH/FSH ratio (greater than 2 to 3) can be found in cases of polycystic ovary disease. This condition is a spectrum and is often, but not always, associated with irregular menstrual periods, reduced fertility, obesity, insulin resistance, or hirsutism. Greater elevations in serum testosterone may indicate an ovarian tumor and appropriate referral should be made. In some cases, there can be modest elevations in both DHEAS and testosterone. A serum level of 17-hydroxypregneneolone can be obtained to discern between an ovarian or adrenal source of androgens. If 17-hydroxypregneneolone is elevated, it indicates an adrenal source of excess androgens, most often secondary to late onset congeni- tal adrenal hyperplasia. Of note is that there is a significant amount of variation in an individual’s serum androgen levels. In cases where abnormal results are obtained, it is recommended to repeat the test before proceeding with therapy or a more extensive work-up.
Questions arise as to the importance of a pelvic ultrasound in the diagnosis of polycystic ovarian syndrome. This test can be nonspecific, in that women with normal androgens may have ovarian cysts and conversely, women with hyperan- drogenism and other findings associated with polycystic ovarian syndrome may not have ovarian cysts at the time of pelvic ultrasound. For this reason, the diagnosis of polycystic ovarian syndrome is more heavily based upon the serum hormonal profile and associated clinical findings.
In the majority of women with acne, serum androgens are completely normal, yet these women will in fact respond if treated with hormonal therapy. Studies have shown that, as a group, women with acne may have higher levels of serum DHEAS, testosterone, and DHT than those without acne (7,34). However, although higher, these laboratory values may still be within the normal range. Serum levels of DHEAS, DHT, and IGF-1 are reported to correlate positively with acne lesion counts in women, whereas androstenedione and DHEAS correlate with lesion counts in men (35). Reduction of serum androgens or inhibition of their action, as obtained with oral contraceptives or antiandrogens, respectively, can lead to improvement in acne in women with normal serum androgen levels.
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.
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 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 is a potent nonsteroidal antagonist of the androgen receptor. Although most 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 combination with an oral contraceptive. Fatal hepatitis has been reported with this drug. Liver function tests should be monitored and 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.
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
ACTH and assessing the plasma cortisol 30 minutes later. If plasma cortisol has risen by an appropriate amount, the adrenal gland is not suppressed.
Inhibition of Ovarian Androgen Production
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 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 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 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.
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).