Das Thema Akne und Hormone ist viel komplexer. Um die Diskussion auf ein höheres Niveau zu heben poste ich mal eine Review zum Thema aus dem Jahre 2004:
Zitat:
Acne: Hormonal concepts and therapy
Diane Thiboutot MD, , a
a Department of Dermatology, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA
Available online 17 November 2004.
Abstract
Acne vulgaris is the most common skin condition observed in the medical community. Although we know that hormones are important in the development of acne, many questions remain unanswered regarding the mechanisms by which hormones exert their effects. Androgens such as dihydrotestosterone (DHT) and testosterone, the adrenal precursor dehydroepiandrosterone sulfate (DHEAS), estrogens such as estradiol, and other hormones, including growth hormone and insulin-like growth factors (IGFs), may be important in acne. It is not known whether these hormones are taken up from the serum by the sebaceous gland, whether they are produced locally within the gland, or whether a combination of these processes is involved. Finally, the cellular and molecular mechanisms by which these hormones exert their influence on the sebaceous gland have not been fully elucidated. Hormonal therapy is an option in women with acne not responding to conventional treatment or with signs of endocrine abnormalities.
This article discusses the role of hormones in acne, the workup for a suspected endocrine abnormality, and the various options for hormonal therapy in treating acne. These treatment options differ on an international level, especially with regard to the available antiandrogens.
Androgens in acne
Both clinical observations and experimental evidence confirm the importance of androgens in the pathophysiology of acne. The majority of circulating androgens are produced by the gonads and the adrenal gland. Androgens can also be produced locally within the sebaceous gland from the adrenal precursor hormone, DHEAS. The major androgens that interact with the androgen receptor are testosterone and DHT. Androgen receptors have been localized to the basal layer of the sebaceous gland and the outer root sheath keratinocytes of the hair follicle.[1 and 2] DHT is approximately 5-10 times more potent than testosterone in its interaction with androgen receptors. The cellular and molecular mechanisms by which androgens exert their influence on the sebaceous gland have not been fully elucidated.
An essential role for androgens in stimulating sebum production is supported by the following clinical evidence:
1. The development of early acne in the prepubertal period has been associated with elevated serum levels of DHEAS, a precursor for testosterone.[3 and 4]
2. Androgen-insensitive subjects who lack functional androgen receptors do not produce sebum and do not develop acne.[5]
3. Androgen-producing tumors of the ovary or the adrenal gland are often associated with the development of acne.
4. Systemic administration of testosterone and DHEAS increases the size and secretion of sebaceous glands.[6]
5. Severe acne is often associated with elevated serum androgen levels.[7 and 8]
Androgen metabolism within the skin
It is unclear whether acne is mediated by serum androgens, locally produced androgens, or a combination of both. Recent insights into the local metabolism of androgens within sebaceous glands[9] may be of benefit in designing new acne therapies. The skin and sebaceous gland are capable of producing and metabolizing androgens. DHEAS, the major adrenal androgen precursor, circulates in the blood stream in relatively high levels compared with other hormones with the exception of cortisol. In fact, in postmenopausal women, all sex steroids produced in the skin derive from adrenal steroid precursors, especially DHEAS. Secretion of this precursor steroid by the adrenals decreases progressively from age 30 years to less than 50% of its maximal value by age 60 years. [10] The enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD) acts on DHEAS to convert it to androstenedione ( Fig 1). This conversion may take place in the adrenal gland and such tissues as the sebaceous gland in which activity of the 3beta-HSD enzyme has been identified by several investigators.[11, 12 and 13] There are two known forms or isozymes of 3beta-HSD. The type I isozyme is active in skin, placenta, and mammary tissue, whereas the type II isozyme is active in the adrenal gland and the gonads. [14] In human skin, type 1 3beta-HSD transforms DHEAS into androstenedione. The reversible conversion of androstenedione into testosterone is then catalyzed in the human skin by 17beta-HSD, a short-chain alcohol dehydrogenase related to retinol-metabolizing enzymes. [15] This reversible enzyme can both oxidize and reduce androgens and estrogens. It is responsible for converting the weak androgen androstenedione into the more potent androgen testosterone. It can also interconvert weak and potent estrogens, such as estrone and estradiol. There are 11 isozymes of 17beta-HSD that differ in their tissue localization and their preference to either reduce or oxidize hormones. [10, 15 and 16] Expression of type 2, type 5, and type 11 17beta-HSD has been reported in sebaceous glands. [17 and 18] The 17beta-HSD enzyme may represent a regulatory point in androgen and estrogen metabolism within the skin.
DHT is produced from testosterone within peripheral tissues, such as the skin, by the action of the 5alpha-reductase enzyme. Two isozymes of 5alpha-reductase have been identified.[19] The type 1 isozyme is active within the sebaceous gland. [20 and 21] The type 2 isozyme is most active in the prostate gland, where it can be inhibited by such drugs as finasteride.
Activity of 5alpha-reductase and 17beta-HSD exhibits regional differences depending on the source of the sebaceous glands.[9] The activity of type 1 5alpha-reductase in sebaceous glands in skin prone to acne, such as facial skin, is greater than that in sebaceous glands in non-acne-prone skin. [20] This implies that more DHT is being produced in sebaceous glands from facial skin compared with other areas of the body that are not prone to develop acne. The net effect of the activity of these two enzymes is the greater production of potent androgens, such as testosterone and DHT, within sebaceous glands of facial areas, which may partially account for the development of acne in these areas.
Sebaceous glands as steroidogenic tissue
The skin and sebaceous glands are capable of synthesizing cholesterol de novo from acetate.[22, 23 and 24] Although this cholesterol is utilized in cell membranes, in the formation of the epidermal barrier, and is secreted in sebum, its use as a substrate for steroid hormone synthesis had not been established until recently. For steroid synthesis to occur, cholesterol needs to be translocated from the outer to the inner mitochondrial membrane. This process is regulated by the steroidogenic acute regulatory protein (StAR) and a functional homolog, MLN 64. [25 and 26] The cytochrome P450 side chain cleavage enzyme catalyzes the conversion of cholesterol into a steroid, pregnenolone. This enzyme is located on the inner mitochondrial membrane in proximity to its cofactors adrenodoxin reductase and adrenodoxin. [27] The P450c17 enzyme catalyzes both 17beta-hydroxylase and 17,20-lyase activities. The 17beta-hydroxylase reaction leads to conversion of pregnenolone to 17-hydroxypregnenolone, which is converted to the androgen precursor DHEAS by the 17,20-lyase ( Fig 1). P450c17 is active in the production of androgens in the adrenal gland and ovary and is linked to the development of polycystic ovary syndrome, [28] a condition often associated with acne, androgenetic alopecia, and hirsutism. Steroidogenic factor (SF)-1 is an orphan nuclear receptor that regulates steroidogenic genes, including P450scc, P450c17, StAR, adrenocorticotrophic hormone receptor, 3%u03B2-HSD, 17%u03B2-HSD, and aromatase. [29] SF-1 is partially responsible for the tissue-specific expression of these genes. It plays a pivotal role in the maintenance of differentiated function and steroidogenic capacity in steroidogenic cells of the adrenal cortex and gonads. SF-1 expression has recently been described in human skin, where it is speculated to play a role in cutaneous steroidogenesis. [30]
The presence of P450 cholesterol side-chain cleavage, adrenodoxin reductase, cytochrome P450c17, and SF-1 has been documented in human facial skin, human sebocytes, and a recently developed SV40-immortalized human sebocyte cell line (SEB-1).[31] Using immunohistochemistry, antibodies to the aforementioned proteins were found localized to the epidermis, hair follicles, sebaceous ducts, and sebaceous glands in sections of facial skin. Biochemical activity of P450sc and P450c17 was demonstrated in these sebocytes in vitro. These data demonstrate that the skin is in fact a steroidogenic tissue. The clinical significance of this finding in mediating androgenic skin disorders, such as acne, hirsutism, and androgenetic alopecia, remains to be established.
Androgen targets in sebum production
The exact mechanisms by which androgens increase the size and secretion of sebaceous glands is unknown. Testosterone and DHT form complexes with nuclear androgen receptors. The androgen-receptor complex then interacts with DNA in the nuclei of sebaceous cells to regulate genes involved in cell growth and lipid production. The particular target genes have not been identified, but likely candidates include genes encoding various growth factors or enzymes involved in lipid production (lipogenic enzymes). Androgens may act directly, indirectly, or both on epithelial cells within the pilosebaceous unit by regulating the production of growth factors by dermal fibroblasts. The stromal-epithelial interaction of sex steroid hormones and growth factors is an important phenomenon in the local regulation of other endocrine-responsive tissues, including the prostate, breast, endometrium, and ovary.[32 and 33] Evidence exists for the importance of these autocrine and paracrine effects of androgens and growth factors in the regulation of sebaceous glands.
Estrogens in acne
Very little is known about the role of estrogens in modulating sebum production. Any estrogen given systemically in sufficient amounts will decrease sebum production; however, the dose of estrogen required to suppress sebum production exceeds the dose required to suppress ovulation.[34] The major active estrogen, estradiol, 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 17beta-HSD enzyme. Both aromatase and 17beta-HSD are present in the skin. [17 and 35] As in the case of androgens, whether circulating estrogens or locally produced estrogens are important in modulating sebum secretion is not known. Estrogens may act by several mechanisms, including (1) directly opposing the effects of androgens locally within the sebaceous gland, (2) inhibiting the production of androgens by gonadal tissue via a negative feedback loop on pituitary gonadotrophin release, and (3) regulating genes that negatively influence sebaceous gland growth or lipid production.
Growth hormone and growth factors in acne
Secreted by the pituitary gland, growth hormone acts on the liver and peripheral tissues to stimulate the production of IGFs, formerly known as somatomedians. IGF is found in two forms, IGF-1 (the most prevalent) and IGF-2. It has been hypothesized that growth hormone may be involved in the development of acne.[36] Acne is most prevalent in adolescence, a time of maximal growth hormone secretion and the highest serum levels of IGF-1. 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 seborrhea 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.
Rat preputial cells serve as a model for human sebocytes.[37] In cultures of rat preputial cells, growth hormone increased lipid droplets in the presence of insulin. Growth hormone was more potent than IGF-1 and -2 in increasing lipid droplets. IGF-1 was the most potent mitogen. DHT plus insulin induced lipid-forming colonies. These data suggest that growth hormone stimulates sebocyte differentiation beyond that found with IGF or insulin, yet has no effect on growth. Increases in growth hormone and IGF-1 production may contribute in complementary ways to the increase in sebum production during puberty and in patients with acromegaly. [38]
Evidence exists for the role of epidermal growth factor (EGF), IGF-1, and keratinocyte growth factor (KGF) in modulating sebaceous gland growth. Sebocytes express receptors for growth factors, including EGF and IGF-1.[39] Growth of sebocytes in vitro is enhanced by supplementation of cell culture medium with EGF and insulin. Treatment of experimental animals with KGF stimulates growth of hair and sebaceous glands. [40 and 41] In cultures of hamster sebocytes, EGF, transforming growth factor-alpha, and basic fibroblast growth factor each augmented the growth of hamster auricular sebocytes, whereas each of these agents suppressed the intracellular accumulation of triglycerides. [42]
Other hormones in acne
Melanocortins
Mice that lack the melanocortin-5 receptor exhibit reduced sebum production.[43 and 44] Melanocortins, including include melanocyte-stimulating hormone (MSH) and adrenocorticotrophic hormone (ACTH), play a role in regulating feeding behaviors, body weight, pigmentation, and immune functions. In rodents, melanocortins have been found to increase sebum production. Although the melanocortin-5 receptor has also been identified in human sebaceous glands, epidermis, and hair follicles, the mechanism by which this receptor mediates sebaceous gland function is unknown. [45]
Allelic variation in the melanocortin-5 receptor locus was studied in diverse human populations and candidate disease groups.[46] The melanocortin-5 receptor was detected in normal skin and in cultured keratinocytes, but not in melanocytes or fibroblasts. There was a global distribution of melanocortin-5 receptor variants. Variations were also studied in 21 patients with acne, in 4 patients with hidadrenitis suppuritiva, and in various samples of sebaceous gland neoplasms; no additional mutations were found. There was no difference in the increase in cyclic AMP in response to stimulation with alpha-MSH between the wild type and the receptor variants. No evidence for a causative role of the melanocortin-5 receptor in sebaceous gland dysfunction, and no association between genetic variations of the melanocortin-5 receptor and the various disease groups, was found.
Messenger RNA for the melanocortin-1 receptor and immunoreactivity with antibodies to the receptor protein have also been demonstrated in normal skin, sebaceous glands, hair follicles, and SZ95-immortalized human sebocytes, also suggesting a functional role for pro-opiomelanocortins in the skin.[47]
Corticotrophin-releasing hormone
Numerous studies have documented the presence and activity of pro-opiomelanocortin, corticotrophin- releasing hormone, and corticotrophin-releasing hormone receptor genes in human skin and sebaceous glands.[48 and 49] Corticotrophin-releasing hormone has been shown to regulate lipogenesis in immortalized human sebocytes. [49]
When to suspect an endocrine disorder in acne patients
Although hormones influence acne, it is clear that most acne patients do not have an endocrine disorder. Hyperandrogenism should be considered in female patients whose acne is severe, sudden in onset, or associated with hirsutism or irregular menstrual periods. Additional clinical signs of hyperandrogenism include cushingoid features, increased libido, clitoromegaly, deepening of the voice, acanthosis nigricans, and androgenetic alopecia. Women with hyperandrogenism also may have insulin resistance. They are at greater risk for diabetes and cardiovascular disease. It is therefore important for these patients' long-term health to identify hyperandrogenism so that they can receive appropriate therapy from an endocrinologist or gynecologist.
Screening for endocrine disorders
Medical history and physical examination should be focused on eliciting signs and symptoms of hyperandrogenism. Screening laboratory tests for hyperandrogenism include serum DHEAS, total testosterone, free testosterone, and luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio. These tests should be obtained apart from the time of ovulation, to avoid the hormone surge associated with ovulation. From a practical standpoint, it may be easiest to suggest that the patient undergo these tests either just before or during the menstrual period. Taking oral contraceptives at the time of hormonal testing may mask an underlying hyperandrogenemia. (This does not occur with antiandrogens, such as cyproterone or spironolactone.) Therefore, it is best that the patient discontinue oral contraceptives 4-6 weeks before 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 level >8000 ng/mL may have an adrenal tumor and should be referred to an endocrinologist for further evaluation. Some adrenal tumors may also produce testosterone. DHEAS values in the range of 4000-8000 ng/mL may be associated with congenital adrenal hyperplasia, which most commonly results from 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 biosynthetic pathway into the androgen biosynthetic pathway.
An ovarian source of excess androgens may be suspected in cases of elevated serum total testosterone. Serum total testosterone in the range of 150-200 ng/dL or an increased LH/FSH ratio (>2-3) occur in polycystic ovary disease. This condition 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 merit an appropriate referral. In some cases, modest elevations in both DHEAS and testosterone may be detected. A serum level of 17-hydroxypregneneolone can be obtained to discern between an ovarian or adrenal source of androgens. An elevated 17-hydroxypregneneolone level indicates an adrenal source of hyperandrogenemia, most often secondary to late-onset congenital adrenal hyperplasia. Keep in mind that there is a significant degree of normal variation in 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 workup.
The importance of a pelvic ultrasound in the diagnosis of polycystic ovarian syndrome is a matter of debate. This test can be nonspecific, in that women with normal androgens may have ovarian cysts, and, conversely, women with hyperandrogenism 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 based more heavily on the serum hormone profile and associated clinical findings.
Most women with acne have normal serum androgen levels, yet will respond if treated with hormonal therapy. Studies that have shown that as a group, women with acne may have higher levels of serum DHEAS, testosterone, and DHT than those without acne.[7 and 50] However, although higher, these laboratory values may still be within the normal range. 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. [50]
Options for hormonal therapy for acne in women
Once the decision has been made to initiate hormonal therapy, the various options from which to choose include androgen receptor blockers, or antiandrogens, which block the effect of androgens on the sebaceous gland, and inhibitors of androgen production by the ovary or adrenal gland, such as oral contraceptives or glucocorticosteroids. 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
The class of androgen receptor blockers includes spironolactone, cyproterone acetate, and flutamide. In the United States, spironolactone is the most commonly used, although flutamide is also available.
Spironolactone
Oral spironolactone decreases sebum excretion rate by 30-50%. Recommended doses are 50-100mg, taken with meals.[51 and 52] 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/day. These low doses in healthy young women are generally well tolerated. However, serum electrolyte levels should be monitored was spironolactone is administered to older women who may have other medical problems, or if higher doses are used to treat such conditions as hirsutism or androgenetic alopecia. Side effects of spironolactone therapy include breast tenderness and menstrual irregularities. Additionally, it is important that pregnancy be avoided during treatment with spironolactone, due to the potential for abnormalities 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 exerts dual activity, in that it serves as a progestogen in oral contraceptives and also directly inhibits the androgen receptor. It can be given in doses of 2-100 mg per day as a single agent (producing improvement in 75-90% of women with acne); however, it is most commonly used in the form of an oral contraceptive combined with ethinyl estradiol in varying doses.[53] Numerous clinical studies support the efficacy of these oral contraceptive preparations in treating women with acne.
Flutamide
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 treating acne, hirsutism, and androgenic alopecia.[54] It can be given in doses of 250 mg twice daily, in combination with an oral contraceptive. Fatal hepatitis has been reported with flutamide. Liver function tests should be monitored and serious consideration given to the risk/benefit ratio of its use in acne. [55] Additionally, because flutamide 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 by either the adrenal gland, using low-dose corticosteroids, or the ovary, using oral contraceptives.
Glucocorticoids
Low-dose glucocorticoids are most commonly used to treat patients with late-onset congenital adrenal hyperplasia, an inherent defect in the 21-hydroxylase or the 11-hydroxylase enzyme. This defect causes a block in the cortisol biosynthetic pathway, resulting in a buildup of steroid precursors that are shunted into the androgen biosynthetic pathway. Low-dose prednisone (2.5%u20135 mg/day, at bedtime) may be used. Low doses of dexamethasone also may be used, but the risk of adrenal suppression is higher. To ascertain whether therapy with glucocorticoids is having the desired effect, the serum DHEAS level can be monitored for a decrease or normalization. To check for adrenal suppression, an ACTH simulation test can be performed. This involves injecting ACTH, then assessing the plasma cortisol level 30 minutes later. A rise in plasma cortisol by appropriate amount indicates that 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 from the pituitary. These drugs, available in injectable and nasal spray forms, are efficacious in treating acne and hirsutism. However, besides 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 potentially develop menopausal symptoms and suffer from hypoestrogenism. Headaches also may develop, as may bone loss, due to the reduction in estrogen.
Oral contraceptives
Oral contraceptives generally contain an estrogen (most commonly ethinyl estradiol) and a progestin. In their early formulations, oral contraceptives contained 100 ug of estrogen. In these and higher doses, estrogens themselves can suppress sebum production. Estrogens also act on the liver to increase the synthesis of sex hormone-binding globulin, which binds testosterone and lowers the circulating levels of free testosterone. In addition, oral contraceptives inhibit the ovarian production of androgens by suppressing ovulation. This in turn decreases serum androgen levels and reduces sebum production. The concentration of estrogen in oral contraceptives has decreased over the years from 150 ug to 35 ug, and in the most recent formulations to 20 %ug, to decrease the adverse effects associated with estrogen.[56] 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 progestin, drosperinone. Members of the estrane and gonane class of progestins (Table 2) can cross-react with androgen receptors, producing increased androgenic effects and thus aggravating acne, hirsutism, and androgenic alopecia. These progestins can also cause changes in lipid metabolism and can increase serum glucose, leading to glucose intolerance and also possibly interfering with the beneficial effect of estrogen on the sex hormone-binding globulin. However, the third-generation progestins (eg, norgestimate, desogestrel, and gestodene) are more selective for the progesterone receptor than for the androgen receptor. The biological relevance of these differences remains unclear, however. For years it has been known that most all oral contraceptives are beneficial in treating acne.[57] 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, will inhibit serum androgen levels. Moreover, although some progestins might be more androgenic than others, all oral contraceptives produce an increase in sex hormone-binding globulin and an improvement of acne.
Drospirenone, a novel progestin derived from 17beta-spironolactone, has antiandrogenic and antimineralocorticoid activity. This can be of benefit in treating androgenic-related conditions, such as acne and hirsutism, as well as the estrogen-related fluid retention associated with some oral contraceptives.[58]
Oral contraceptives studied in acne treatment
The use of oral contraceptives to treat acne has received much study (Table 3). These contraceptive agents include those containing ethinyl estradiol in combination with cyproterone acetate (Diane, Dianette), levonorgestrel (TriPhasil, Alesse), norgestimate (Ortho Tri-Cyclen), desogesterel (Desogen), drosperinone (Yasmin), and ethynodiol diacetate (Demulen). Numerous studies point to the efficacy of the ethinyl estradiol/ cyproterone acetate oral contraceptives (Diane and Dianette) in treating acne. Reductions in inflammatory lesion count on the order of 50-75% have been reported.[59 and 60] Acne treatment with an oral contraceptive containing ethinyl estradiol and levonorgestrel (Triphasil) was studied and found to produce a 75% decrease in comedones, as well as an approximate 50% decrease in inflammatory lesions. [61] Two large studies involving a total of approximately 500 women with moderate acne treated with ethinyl estradiol 35 ug/norgestimate (Ortho Tri-Cyclen) demonstrated improvement in inflammatory lesions, total lesions, and global assessment after 6 months of treatment. [62 and 63] A 50-60% improvement in inflammatory lesions was also seen. A decrease in serum free testosterone and an increase in sex hormone-binding globulin were noted in the active group. Two large (350 and 371 women), 6-month, placebo-controlled trials evaluated the use of ethinyl estradiol 20 %ug/levonorgestrel) (Alesse) in treating acne. [64 and 65] In each study, the oral contraceptive demonstrated significantly greater reduction in acne lesion counts and improvement in global assessment scores compared with placebo. The reduction in inflammatory lesion count was on the order of 47%. A recent study of 128 women with mild to moderate acne compared the efficacy of ethinyl estradiol 30 ug/drospirenone (Yasmin) and ethinyl estradiol 35 ug/cyproterone acetate (Diane-35) in the treatment of acne for nine cycles. [59] Both treatments produced comparable reductions in acne lesion counts and an approximate 60% reduction in inflammatory lesion count. Both treatments also reduced sebum production and yielded comparable increases in sex hormone-binding globulin. Two large placebo-controlled studies, involving a total of approximately 593 women with moderate acne, found improvement in inflammatory lesions, total lesions, global assessment, and quality of life in women treated for 6 months with a triphasic oral contraceptive containing 20-35 ug of ethinyl estradiol in combination with 1.0 mg norethindrone acetate (Estrostep). [66] In these studies, inflammatory lesion counts were reduced by approximately 47%. [66]
Oral contraceptives that have been approved for the treatment of acne in the United States include ethinyl estradiol 35 ug/norgestimate (Ortho Tri-Cyclen) and ethinyl estradiol 20-35 ug/norethindrone acetate (Estrostep).
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 flora bacteria in the gut and thus may interfere with estrogen absorption. This could lead to a possible reduction in the efficacy of oral contraceptives, although pharmakokinetic studies suggest that serum levels of estrogen are unaffected by antibiotics such as tetracycline, doxycycline, and others.[67 and 68] Nevertheless, there have been very few reports in the literature of pregnancies associated with the use of antibiotics in conjunction with oral contraceptives. [69 and 70] Existing reports have focused on tetracycline, and the incidence was 1.2-1.4 pregnancies/100 woman-years of the oral contraceptive use. The failure rate demonstrated by these data is no greater than the background failure rate of oral contraceptives. [69 and 70]
Newer forms of contraceptives
Recently, newer forms of contraceptives have been developed, including contraceptive patches, vaginal rings, and injectable combination hormones. All of these forms are designed to suppress ovulation, and in this regard will decrease the ovarian production of androgens. As of yet, these formulations have not been studied in the treatment of acne. The contraceptive patch (Ortho Evra) contains 20 ug of ethinyl estradiol and 150 ug of the progestin norelgestromin. The patch is worn for 3 weeks and removed for 1 week, during which time menstrual bleeding will occur. The advantages of this formulation are better patient compliance, dosing that remains unaffected by gastrointestinal disturbances, and more consistent serum levels of estrogen serum levels compared with oral dosing.[71] The vaginal ring (NuvaRing) is a contraceptive vaginal ring that releases 15 %u03BCg of ethinyl estradiol and 120 ug of the progestin, etonogestrel. It is placed within the vagina for 3 weeks and removed for 1 week. In one study, the incidence of irregular bleeding was lower than for an oral combination contraceptive. [72] An injectable combination of estradiol cypionate and medroxyprogesterone acetate (Lunelle) has been developed. This is given as a monthly contraceptive injection. Contraceptive efficacy was shown to be comparable to a triphasic oral contraceptive containing ethinyl estradiol and norethindrone (Ortho 7/7/7). [73]
Conclusion
Hormonal therapy is an excellent option for treating women whose acne is not responding to conventional therapy. If there are signs of hyperandrogenism, an endocrine evaluation, comprising such tests as DHEAS, total and free testosterone, and LH/FSH ratio, is indicated. Although hyperandrogenism is an indication for hormonal therapy, women with normal serum androgen levels also respond well to treatment. The mainstays of hormonal therapy include oral contraceptives and spironolactone. Other agents to choose from include cyproterone acetate, flutamide, and glucocorticoids. As more is learned about the hormones involved in acne, including their source and the mechanisms by which they influence sebaceous gland growth and sebum production, new opportunities will arise for the development of novel therapies aimed at addressing the hormonal aspects of acne.
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21.08.2006, 19:45
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