Acne Vulgaris Treatment guidelines in adult women
The role of androgens is central in the pathogenesis of acne vulgaris. Androgen production leads to an increase in sebum production by sebaceous glands. Before the onset of puberty, the adrenal glands produce increasing amounts of dehy-droepiandrosterone sulfate (DHEAS), which becomes metabolized in the skin to more potent hormones [e.g., testosterone and dihydrotestosterone (DHT)] by the enzymes sulfotransferase, 30-hydroxysteroid dehydrogenase (30-HSD), 170-HSD, and 5oc-reductase (5oc-R) (1). Onset of acne lesions tends to coincide with the onset of puberty during which there is an increase in the production of androgens that results in excessive sebum production (2 6).
Accumulation of sebum and keratinous material within pilosebaceous follicles blocks and dilates the follicular infundibulum resulting in the formation of microcomedones. Microcomedones provide an anaerobic, lipid-rich medium for the proliferation of Propionibacterium acnes. Consequently, P. acnes induces an inflammatory reaction by releasing chemotactic factors that attract lymphocytes and neutrophils, activating Toll-like receptors and inducing follicular keratinocyte secretion of interleukin-1 leading to keratinocyte proliferation (7,8). Interestingly, the serum levels of DHEAS correlate with the severity of comedonal acne in prepubertal females (9,10).
Additionally, although still within normal limits, the serum level of circulating androgens is significantly increased in women with acne compared with women without acne (11,12). The severity of acne may also be related to the sexual maturity of males and females, which may be associated to an increase in sensi-tivity of the sebaceous gland to androgens (13,14). Thus, androgens play a prominent role in the pathogenesis of acne vulgaris and treatment modalities aimed at minimizing their effects may be required.
Choosing the most appropriate patient population for hormonal therapy is essential. Hormonal therapy may be the most effective option, especially in women who desire oral contraception. Additionally, women with severe sebor-rhea, clinically apparent androgenic alopecia, seborrhea/acne/hirsutism/alopecia (SAHA) syndrome, late-onset acne (acne tarda), and proven ovarian or adrenal hyperandrogenism may benefit from hormonal therapy (15). Although most women with acne will have androgen levels within normal limits, it is important to screen for an underlying endocrinopathy in women with (i) acne that is resistant to conventional therapy; (ii) a sudden onset of severe acne; (iii) acne associated with clinical signs of virilization, irregular menses, or signs of hyperandrogenism (SAHA syndrome); and (iv) relapsing acne lesions shortly after isotretinoin therapy (15). The most common endocrinopathies associated with acne include polycystic ovary syndrome (PCOS), late-onset adrenal hyperplasia (LOAH), or a virilizing tumor.
The clinical presentation of women who may benefit from hormonal therapy include those with varying acneiform lesions along the mandible and chin who often have flares that correlate with their menstrual cycles (16). These women usually do not have increased androgen levels above normal. However, women who present with this particular pattern of acne and other signs of virilization (e.g., hirsutism) should be screened for an underlying endocrinop-athy. Signs and symptoms of androgen excess include menstrual irregularity, infertility, hirsutism, truncal obesity, polycystic ovaries detected on sonogram, recalcitrant acne, infrequent menses, female-pattern or male-pattern alopecia, deepening voice, and cliteromegaly. Women with any of these signs and women with severe acne or acne associated with hirsutism or irregular menstrual periods should be screened for an underlying endocrinopathy. Additionally, acanthosis nigricans in addition to other signs of androgen excess (e.g., HAIR-AN syn-drome, hyperandrogenicity, insulin resistance, and acanthosis nigricans) should also warrant hormonal screening.
Screening tests for hyperandrogenism should be obtained in the luteal phase of the menstrual cycle and include serum DHEAS, total testosterone, free testosterone, luteinizing hormone/follicle-stimulating hormone (LH/FSH) ration, prolactin, and 17-hydroxyprogesterone (17 19). Normal total testosterone and DHEAS levels in addition to normal imaging may exclude an androgen-secreting tumor of the adrenals or ovaries. To determine whether the adrenal gland is the source of excess androgen, serum DHEAS can be measured. Serum DHEAS > 8000 ng/mL is highly suggestive of an adrenal tumor, and patients should be referred to an endocrinologist for further evaluation. Serum DHEAS levels in the range of 4000 to 8000 ng/mL may indicate congenital adrenal hyperplasia.
Elevated serum total testosterone levels may indicate an ovarian source of excess androgen. Patients with polycystic ovary disease will have irregular menstrual periods, reduced fertility, obesity, insulin resistance, hirsutism, and serum total testosterone in the range of 150 to 200 ng/dL or an increased LH/ FSH (>2 3). Higher levels of serum testosterone may indicate an ovarian tumor.
Androgens are thought to be central to the pathogenesis of acne vulgaris because of their effects on sebum production and follicular keratosis (1,4). The effec-tiveness of hormonal therapy may be due to its effect on lowering circulating and local androgen levels and opposing the effect of androgens on the sebaceous gland and, possibly, on follicular keratinocytes (19,20). Specific hormonal treatments used in the treatment of acne vulgaris include antiandrogens (androgen receptor blockers) and agents used to decrease endogenous production of androgens by the ovary or adrenal gland [e.g., estrogens, combined oral contraceptives, oral glucocorticoids, and gonadotropin-releasing hormone (GnRH) agonists].
Antiandrogens, or androgen receptor blockers, competitively inhibit the binding of dihydrotestosterone to its receptor (21) and include cyproterone acetate (CPA), drospirenone, spironolactone, and flutamide. Use of antiandrogens is contraindicated in men because they result in feminization and in women during pregnancy as they can feminize a male fetus (15).
CPA (10 mg, 50 mg) is a progestational antiandrogen that inhibits binding of dihydrotestosterone to its receptor. It reduces the activity of 5oc-reductase, preventing the transformation of testosterone to dihydrotestosterone. It also blocks ovarian function and decreases serum androgen levels by inhibiting production of FSH and LH (15,22). Treatment with CPA should begin on the first day of the menstrual cycle. CPA is usually prescribed at doses between 2 and 100 mg daily and is often combined with ethinyl estradiol (EE) in the form of oral contraceptive (OC) Dianette/Diane-35 that is used in Europe for the treatment of acne (15). However, CPA/estrogen-containing OCs are not approved for use in the United States. CPA at a dose of 50 to 100 mg daily (with or without EE 50 µg) has been shown to result in improvement in 75% to 90% of patients treated (15,23). Reported side effects include menstrual abnormalities, breast tenderness and enlargement, nausea/vomiting, fluid retention, leg edema, headache, and melasma. Other side effects include fatigue, changes in body weight, liver dysfunction, and, rarely, blood-clotting disorders (24).
Spironolactone is an androgen receptor blocker, 5oc-reductase inhibitor, and aldosterone antagonist that has been used for the treatment of hirsutism and hypertension. At doses of 50 to 100 mg twice daily, it exerts its effects by blocking androgen receptors (25) and has been shown to reduce sebum pro-duction by 30% to 50% leading to decreased acne production (15,17,22,25,26). Low doses of 25 mg twice daily or 25 mg daily may be sufficient for women with sporadic outbreaks of inflammatory lesions or isolated cysts (27). Main-tenance doses range from 25 to 50 mg daily (15). Additionally, use of spi-ronolactone in combination with an OC pill containing 30-µg EE/3-mg drospirenone has been shown to be effective and well tolerated (28).
The US Food and Drug Administration has not formally approved use of spironolactone for the treatment of acne; however, it may be used for females who have failed other therapeutic interventions. Spironolactone in low doses is generally well tolerated. However, use of spironolactone at higher doses or in females with cardiac or renal dysfunction may result in hyperkalemia. Other side effects include menstrual irregularity, breast tenderness, gynecomastia, head-ache, and fatigue. Spironolactone is contraindicated in women who are pregnant or at increased risk of breast cancer (29).
Flutamide is a nonsteroidal antiandrogen used for the management of prostatic hypertrophy, prostate cancer, and hirsutism. For the treatment of acne or hirsutism in females, it has been used at doses of 250 mg twice a day in combination with OCs (15,18,22). In a study comparing spironolactone and flutamide therapy in the treatment of acne, flutamide therapy was shown to have a greater effect at reducing total acne and seborrhea after three months (30). Although effective in the treatment of acne, the use of flutamide should be done with careful monitoring of liver function enzymes as cases of fatal hepatitis have been reported (31). Finasteride and other compounds with possible anti-androgenic effects (e.g., cimetidine and ketaconazole) have not been shown to be effective in the treatment of acne (32).
BLOCKING OVARIAN ANDROGEN PRODUCTION
In women who desire oral contraception and those who are concurrently being treated with isotretinoin, OCs may be an ideal choice for treatment of acne. Indications of OC treatment in acne include women with acne flare-ups before menstruation, during treatment with isotretinoin, or when oral contraception is desired; women whose acne does not respond to other therapeutic interventions; women with polycystic ovary syndrome; women with clinical signs of hyper-androgenism; women with late-onset acne; and women with proven ovarian hyperandrogenism or proven adrenal hyperandrogenism.
Estrogen in combination with a progestin (used to avoid the risk of endometrial cancer associated with unopposed estrogens) suppresses ovarian production of androgens by direct gonadotropin suppression and prevention of ovulation (9,15). Earlier generations of progestins used in OCs (e.g., estrane and gonane classes) have been reported to cross-react with androgen receptors resulting in androgenic effects and increased acne, specifically at higher doses than that which is present in newer OCs (18). Second-generation progestins such as ethynodiol diacetate, norethindrone, and levonorgestrel have the lowest androgenic activity. The third-generation progestins, including norgestimate, desogestrel, and gestodene, are more selective for the progesterone receptor and have the lowest androgenic activity since these agents are metabolized to lev-onorgestrel (15). Drospirenone, a progestin derived from spironolactone, has antiandrogenic and antimineralocorticoid activity and improves acne, hirsutism, and estrogen-related fluid retention associated with some OCs (33).
OCs effectively decrease acne lesions via their ability to suppress ovarian production of androgens, which reduces serum androgen levels and sebum production. The dose of estrogen required to suppress sebum production is at least 100 µg, which is greater than the dose required to suppress ovulation (32). The effect of OCs is unlikely to be local at the level of the sebaceous gland. Rather, OCs exert their effects by suppressing the secretion of pituitary gona-dotropins, thereby reducing ovarian androgen production, or by increasing liver synthesis of sex hormone binding globulin, resulting in the decrease of free serum testosterone (15,22).
The use of OCs (20 µg of EE/100 µg of levonorgestrel, 35 µg EE/nor-gestimate) has been shown to be effective and safe for the treatment of acne in women (10,34 36). Reduction in inflammatory lesions by 30% to 60%, improvement of acne in 50% to 90% of patients, and noninflammatory facial acne lesions have been shown following six to nine months of use (37,38). Additionally, OCs containing drospirenone have been shown to be superior to a triphasic OC containing EE/norgestimate in the treatment of acne and had comparable efficacy to Diane-35 (39).
The World Health Organization has developed a list of absolute and rel-ative contraindications to the use of OCs (40). Absolute contraindications include pregnancy, history of thromboembolic or heart disease, liver disease, and active smoking in patients older than 35. Relative contraindications include hypertension, migraine, breast-feeding, and malignancies (29,41,42). OCs can worsen insulin resistance and are contraindicated in patients with a history of diabetes, clotting disorders, thrombophlebitis, cerebrovascular disease, and impaired liver function and in patients with increased risk of break cancer (29). A modest increase in the relative risk of developing breast cancer has also been reported in women; however, OCs may also simultaneously provide a protective effect against ovarian and endometrial cancer (43). Although the most serious side effect reported is thromboembolism, the advent of modern formulations containing reduced doses of estrogen has decreased the incidence of this particular side effect.
Additionally, the reduced estrogen dose formulations have also reduced the incidence of other serious side effects, such as hypertension, in young healthy women (15). The most frequently reported side effects include metrorrhagia, nausea, vomiting, breast tenderness, headache, lower extremity edema, and weight gain. A transient flare of inflammatory acne may also occur in the beginning of OC therapy. The effectiveness of oral contraception is not reduced when used in combination with oral antibiotics, with the exception of rifampin (44,45). Specifically, studies comparing the contraceptive failure rate of patients taking OCs with antibiotics compared with patients who were not taking antibiotics found no significant difference (45 47).
BLOCKING ADRENAL ANDROGEN PRODUCTION
Low-dose glucocorticoids effectively suppresses the adrenal production of androgens and are indicated for use in patients (male or female) who have an elevated serum DHEAS, often associated with 11- or 21-hydroxylase deficiency (15). In acute flares of acne or in severe acne, glucocorticoids may be used in low doses (prednisone 2.5 5 mg or dexamethasone 0.25 0.75 mg) daily or every other day to suppress adrenal androgen production. It should be noted that patients treated with dexamethasone are at particularly higher risk for adrenal suppression (15). During treatment, patients should be followed closely for signs of adrenal suppression with ACTH (cosyntropin) stimulation tests performed two to three months after initiation of therapy. Plasma cortisol level should rise to >16 µg/dL 30 minutes after administration of cosyntropin, indicating that adrenal suppression is absent. The effectiveness of glucocorticoid therapy can be monitored by measurement of serum DHEAS, which should be decreased or normalized (18). Treatment with glucocorticoids should not exceed six months because of the risk of osteoporosis (48).
GONADOTROPIN-RELEASING HORMONE AGONISTS
GnRH agonists inhibit ovarian androgen production by blocking the cyclic release of LH and FSH from the pituitary, leading to the suppression of ovarian steroidogenesis. GnRH agonists include agents such as nafarelin, leuprolide, and buserelin, which are only available as nasal sprays or injectables (15). Thus far, only one study has demonstrated efficacy of GnRH agonists in the treatment of acne (49). In six women with acne and six women with hirsutism, treatment with Buserelin nasal spray for six months led to a decrease in ovarian steroids, LH and FSH, and acne and hirsutism. The use of GnRH agonists is limited by their expense and side effects, including ovarian estrogen suppression and the development of menopausal symptoms, headaches, and bone loss (50).
INHIBITION OF 5a-REDUCTASE
There are currently no therapies available that inhibit local androgen production within the sebaceous gland. Future research lies in designing specific inhibitors of androgen metabolizing enzymes in the skin such as 5oc-reductase type 1 inhibitors. 5oc-reductase inhibitors would block the local conversion of testos-terone to dihydrotestosterone and are currently being developed (51 53).
EFFECTIVE HORMONAL THERAPY
Appropriate patient selection is essential when considering hormonal therapy in the treatment of acne and its success. In general, hormonal therapy in acne may be used as first-line therapy in women who desire oral contraception, have signs of hyperandrogenism, or have proven ovarian or adrenal hyperandrogenism (54,55). Hormonal therapy may also be indicated for patients with acne tarda or severe seborrhea, or when repeated courses of isotretinoin are needed to control acne. Of note, hormonal therapy works best in adult women and sexually active teens with premenstrual acne flares (18). Combined OC therapy can also be used as first-line therapy for hirsutism and acne in women with PCOS (15). Addi-tionally, hormonal therapy can be effective in women with normal androgen levels (32).
Hormonal therapies in combination with oral antibiotics, topical retinoids, or benzoyl peroxide should be considered in patients who have recalcitrant acne. Combination therapy is the most effective treatment modality for targeting as many pathophysiologic factors as possible (27).
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