The role of androgen and androgen receptor in skin-related disorders

Androgen and androgen receptor (AR) may play important roles in several skin-related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for these androgen/AR-involved diseases, which target the synthesis of androgens or prevent its binding to AR, can cause significant adverse side effects. Based on the recent studies using AR knockout mice, it has been suggested that AR and androgens play distinct roles in the skin pathogenesis, and AR seems to be a better target than androgens for the treatment of these skin diseases. Here, we review recent studies of androgen/AR roles in several skin-related disorders, including acne vulgaris, androgenetic alopecia and hirsutism, as well as cutaneous wound healing.     

SAHA综合征研究进展

SAHA综合征是女性患者雄激素功能过强而引起的一组皮肤症候群,主要临床特征为皮脂溢、痤疮、多毛及雄激素脱发。该综合征可在一系列疾病导致的外周雄激素水平增高基础上发生,也可由毛囊皮脂腺组织对正常循环雄激素水平过于敏感的应答导致。临床分为特发型,卵巢型,肾上腺型,高催乳素型和高雄激素一胰岛素抵抗一黑棘皮型。应在明确病因和临床类型的基础上个体化治疗。     

Dermatology of androgen-related disorders

Hyperandrogenism in women can be caused by various conditions, the most prevalent of which is polycystic ovary syndrome. Common dermatologic manifestations of hyperandrogenism include hirsutism, acne, acanthosis nigricans, and androgenic alopecia. Hirsute women often have increased activity of 5 alpha-reductase, the enzyme that converts the androgen testosterone to its active metabolite, in hair follicles. Likewise, androgens affect the formation of acne by increasing sebum production from sebaceous glands in the skin. The diagnosis of polycystic ovary syndrome includes a complete history, physical examination with emphasis on evidence of androgen excess, and appropriate laboratory investigation to exclude other causes of hyperandrogenism. Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, antiandrogens, and insulin-sensitizing medications.     

Hormonal therapy in dermatology

Hormonal therapy in dermatology is used primarily to reverse or diminish the effect of androgens, which are responsible for causing acne, hirsutism, and androgenetic alopecia. Although hormonal therapy is one of many treatments for acne, it is the only medical therapy available for hirsutism, and likely the only hope for the successful medical treatment of androgenetic alopecia. This article addresses the pathophysiologic rationale for the use of hormonal therapies in dermatology, the patients, the diseases for which they are used, the drugs most used, and what pretreatment evaluation should be considered.     

Contraceptive use in acne

Acne vulgaris is an inflammatory disorder of the pilosebaceous follicle. It is well established that androgen hormones play a major role in sebum production and excretion, and are vital in the pathogenesis of acne. Isotretinoin notwithstanding, hormonal therapies such as combined oral contraceptives (COCs) and spironolactone are the only treatments that can affect sebum production and the androgen component of acne. Contraceptives are also used during isotretinoin therapy for pregnancy prevention. It is important for a dermatologist to be familiar with all the available methods of contraception to provide essential counseling to patients. The aim of this paper is to review the role of hormones in acne pathogenesis, discuss the use of hormonal therapies for acne, and detail various alternative contraceptive methods in relation to isotretinoin treatment and pregnancy prevention.     

Dermatologic indications for anti-androgenic treatment]

In spite of remarkable therapeutic results obtained by gestagens with antiandrogenic activity, usually combined with estrogen, in oily seborrhea, acne, Fox-Fordyce disease, androgenetic alopecia and hirsutism many dermatologist still hesitate to treat the named disorders by hormones. The reason for their hesitation appears to be the erroneous belief, that the named disturbances represent hormonal disorders the treatment of which does not belong to dermatology. After a survey on the mechanism of action of antiandrogens the basic difference between androgen dependent skin disorders and endocrinopathies with manifestation on the skin and its appendages is explained. Androgen dependent skin disorders, like oily seborrhea and most cases of acne are not the result of endocrine disturbances in the sense of an pathologically increased or decreased production of sexual hormons. Administering sexual hormons the physician takes advantage of the sebosuppressive effect of female sexual hormons as he does of the antiallergic activity of the hormon cortisol (and related compounds) in the treatment of eczemas. The antiandrogenic treatment of androgenetic alopecia, hirsutism and androgenetic acne--with their underlying hormonal disturbance, consisting in an increased production of androgens, represents an quasi etiological therapy. As in these cases the hormonal disturbances finds its expression mainly or exclusively in disorders of the skin or hair growth, the dermatologist, preferentially in cooperation with endocrinogists and/or gynacologists remains entitled to take over the treatment. The available drugs are discussed and suggestions are made for their appropriate use.     

Androgen action on human skin – from basic research to clinical significance

Abstract:  Androgens affect several functions of the human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to nuclear androgen receptors. Androgen activation and deactivation are mainly intracellular events. They differ from cell type to cell type and between cells at different locations. The major circulating androgens, dehydroepiandrosterone sulfate and androstenedione, are predominantly produced in the adrenal glands, and testosterone and 5α-dihydrotestosterone are mainly synthesized in the gonads. Testosterone in women and 5α-dihydrotestosterone in both genders are also synthesized in the skin. Skin cells express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens and the development of hyperandrogenism-associated conditions and diseases, such as seborrhea, acne, hirsutism and androgenetic alopecia. The major thrust of drug design for the treatment of androgen-associated disorders has been directed against several levels of androgen function and metabolism. Partial effectiveness has only been achieved either by androgen depletion, inhibition of androgen metabolism or blockade of the androgen receptor.     

Antiandrogen therapy for skin and hair disease

Androgen hormones play an important role in common skin and hair conditions including acne vulgaris, hirsutism, and androgenetic alopecia. Blocking this androgen effect may lead to significant improvements in these conditions. Several medications that work through a variety of different mechanisms may be prescribed safely and effectively as antiandrogen therapies in the dermatology arena.     

Dermatologic Manifestations of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women and is one of the most common endocrine disorders in women. The disorder is commonly characterized by elevated levels of androgen and insulin. Women with PCOS may present with a range of signs and symptoms, and face increased risks of reproductive, metabolic, cardiovascular, psychologic, and neoplastic sequelae, particularly if the condition is left unrecognized or untreated. The clinical definition of PCOS has changed in recent years and includes as one of its cardinal criteria the dermatologic manifestations of hyperandrogenism, chiefly hirsutism, acne vulgaris, and androgenetic alopecia. Acanthosis nigricans, a cutaneous sign of hyperinsulinemia, may also be present. These dermatologic features may provide early clinical clues to recognition of PCOS, and treatment of these cutaneous conditions may improve the patient's quality of life and psychologic well-being. The effects of androgen on pilosebaceous units in the skin can vary by anatomic location, producing pathophysiologic effects on hair growth and differentiation, sebaceous gland size and activity, and follicular keratinization. Treatment modalities may include hormonal therapy intended to modulate androgen production and action as well as non-hormonal therapies directed toward specific dermatologic conditions.     

Hirsutism and the variable response of the pilosebaceous unit to androgen

The pilosebaceous unit (PSU) response to androgen is variable. Certain population of PSU respond to androgen in a distinctive pattern that results in sexual hair development in some, sebaceous gland development in others. Furthermore, androgen excess is variably manifest in women as hirsutism, acne vulgaris, seborrhea, or pattern alopecia. Although sebaceous cells act as intracrine cells, activating pro-hormones to potent androgens that act within the sebocyte, hair follicle metabolism predominantly inactivates testosterone. Androgen action in the sexual hair follicle appears to be mediated by the dermal papilla and possibly, by inducing expression of a specific keratin, hHa7, in the hair medulla. The data do not clearly support a relationship between idiopathic hirsutism, the hirsutism that occurs in the absence of androgen excess, and variations in androgen mechanism of action. Androgens are prominent among the hormones that modulate the biological mechanism regulating the hair cycle. However, the basis for the variable pattern of PSU response to androgen is unclear, as is the basis for the variable development of hirsutism in response to androgen excess and the incomplete reversal of hirsutism by anti-androgen treatment. Improved treatment of hirsutism awaits improved understanding of the nature of the interaction between androgens and other determinants of hair follicle biology.     

Hormonal therapy for acne

Acne affects more than 40 million people, of which more than half are women older than 25 years of age. These women frequently fail traditional therapy and have high relapse rates even after isotretinoin. Recent advances in research have helped to delineate the important role hormones play in the pathogenesis of acne. Androgens such as dihydrotestosterone and testosterone, the adrenal precursor dehydroepiandrosterone sulfate, estrogens, growth hormone, and insulin-like growth factors may all contribute to the development of acne. Hormonal therapy remains an important part of the arsenal of acne treatments available to the clinician. Women dealing with acne, even those without increased serum androgens, may benefit from hormonal treatments. The mainstays of hormonal therapy include oral contraceptives and antiandrogens such as spironolactone, cyproterone acetate, or flutamide. In this article, we discuss the effects of hormones on the pathogenesis of acne, evaluation of women with suspected endocrine abnormalities, and the myriad of treatment options available.     

Hormonal therapy for acne: why not as first line therapy? facts and controversies

Standard systemic therapeutic agents used in acne include oral antimicrobials, isotretinoin, and hormonal agents. Appropriate patient selection is the key to decide when to use hormonal agents as first-line therapy as well as to achieve optimal results. Indications of hormonal therapy in acne in girls and women include proven ovarian or adrenal hyperandrogenism, recalcitrant acne, acne not responding to repeated courses of oral isotretinoin, acne tarda, polycystic ovary syndrome, or the presence of clinical signs of hyperandrogenism such as androgenic alopecia or the presence of the seborrhea, acne, hirsutism, alopecia syndrome. We describe the hormonal agents currently available for acne treatment, discuss their indications and contraindications, and address the question of whether they may be used as a first-line therapy in acne.     

Normalized androgen ratio: its application to clinical dermatology

It is generally accepted that the biological activity of androgens is a function of their free (non-protein bound) concentration. The free androgen concentration is determined by the relative concentrations of total androgens and the proteins to which they bind. It can be expressed as a normalized androgen ratio (NAR). Total serum androgen concentration (TSA) and NAR have been estimated in a series of 114 patients with acne vulgaris, hirsutism or androgenetic alopecia. Hormone therapy has been instituted in a proportion of the cases using the TSA and NAR values as the determinant of the treatment regime. Gilliland, Smeaton & Rowland (1978) have described a simple, rapid and inexpensive method of determining an index of free (unbound) serum androgen (17β-OH steroid) concentration. It is expressed as a normalized androgen ratio (NAR). They demonstrated a raised NAR in 42% of a series of ninety-nine hirsute females. Of these, 50% showed raised total serum 17β-OH steroid concentration with normal testosterone-estradiol-binding-globulin (TEBG) activity, while 43% had normal total 17β-OH steroid concentration with decreased TEBG activity. As the biological activity of androgens depends on free (unbound) 17β-OH steroid concentration, it would seem likely that the estimation of NAR could be useful in cases of acne vulgaris, hirsutism and androgenetic alopecia where excess androgen activity can be reasonably expected. Over a period of 18 months, total serum androgen (TSA) and NAR estimations have been determined in a series of 114 female patients suffering from acne vulgaris (sixty-four), hirsutism (thirty-two) and androgenetic alopecia (eighteen). Raised NAR values were found in 16%, 31% and 42% of the patients respectively. The patients in this series were referred for biochemical analysis where clinical assessment suggested that a knowledge of androgen activity could be helpful in the management of their case.     

Update and future of hormonal therapy in acne

Hormonal therapy is an important component in the treatment of women with acne who may or may not have elevated serum androgens. The mainstays of hormonal therapy include oral contraceptives and antiandrogens such as cyproterone acetate, flutamide or spironolactone. Recent research over the past several years has unraveled some of the details regarding the way that the skin and sebaceous glands synthesize and metabolize hormones. The knowledge gained from this work may provide an impetus for future drug discovery in the hormonal treatment of acne and lead to improvements in the care of our patients with acne.     

Therapie der Akne mit Antiandrogenen – Eine evidenzbasierte Übersicht

Background: Increased sebaceous gland activity with seborrhea is one of the major pathogenetic factors in acne. Antiandrogen treatment targets the androgen‐metabolizing follicular keratinocytes and the sebaceous gland leading to sebostasis, with a reduction of the sebum secretion rate of 12.5 – 65 %. Antiandrogens can be classified based on their mechanism of action as androgen receptor blockers, inhibitors of circulating androgens by affecting ovarian function (oral contraceptives), inhibitors of circulating androgens by affecting the pituitary (gonadotropin‐releasing hormone agonists and dopamine agonists in hyperprolactinemia), inhibitors of adrenal function, and inhibitors of peripheral androgen metabolism (5α‐reductase inhibitors, inhibitors of other enzymes). Methods: All original and review publications on antiandrogen treatment of acne as monotherapy or in combination included in the MedLine system were extracted by using the terms “acne”, “seborrhea”, “polycystic ovary syndrome”, “hyperandrog*”, and “treatment” and classified according to their level of evidence. Results: The combinations of cyproterone acetate (2 mg)/ethinyl estradiol (35 µg), drospirenone (3 mg)/ethinyl estradiol (30 µg), and desogestrel (25 µg)/ethinyl estradiol (40 µg) for 1 week followed by desogestrel (125 µg)/ethinyl estradiol (30 µg) for 2 weeks showed the strongest anti‐acne activity. Gestagens or estrogens as monotherapy, spironolactone, flutamide, gonadotropin‐releasing hormone agonists, and inhibitors of peripheral androgen metabolism cannot be endorsed based on current knowledge. Low dose prednisolone is only effective in late‐onset congenital adrenal hyperplasia and dopamine agonists only in hyperprolactinemia. Treatment with antiandrogens should only be considered if none of the contraindications exist. Conclusion: Antiandrogen treatment should be limited to female patients with additional signs of peripheral hyperandrogenism or hyperandrogenemia. In addition, women with late‐onset or recalcitrant acne who also desire contraception can be treated with antiandrogens as can those being treated with systemic isotretinoin. Antiandrogen treatment is not appropriate primary monotherapy for noninflammatory and mild inflammatory acne.     

Three cases of androgen-dependent disease associated with myotonic dystrophy

Three cases of androgen-dependent disease in females with myotonic dystrophy are described. Serum androgens in individuals affected by myotonic dystrophy are known to be lower on average than in normal controls. Despite this these three females developed diseases that are androgen dependent, including acne, hidradenitis suppurativa, androgenetic alopecia and keratosis pilaris. These cases support the hypothesis that the peripheral response to androgens rather than absolute circulating levels of androgens is important in androgen-dependent conditions.     

Androgen metabolism in sebaceous glands from subjects with and without acne.

OBJECTIVE: To determine if there are differences in the activity of 17beta-hydroxysteroid dehydrogenase and 5alpha-reductase (responsible for the production of testosterone and dihydrotestosterone, respectively) in sebaceous glands obtained from men and women with and without acne. DESIGN: Single-center examination of androgen levels and sebaceous gland enzyme activity in a cohort of volunteers. SETTING: Academic referral center. PATIENTS: Thirty-four subjects, consisting of 8 women with acne, 10 women without acne, 8 men with acne, and 8 men without acne. INTERVENTIONS: Single visit for blood sampling and 2 biopsies of forehead skin. MAIN OUTCOME MEASURES: Serum levels of androgens were determined and compared with the activity of 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase in sebaceous glands microdissected from skin samples. RESULTS: No significant differences in the activity of 5alpha-reductase or 17beta-hydroxysteroid dehydrogenase in sebaceous glands according to the presence of acne were noted in either men or women. The activity of 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase was significantly greater in sebaceous glands from men (n = 16) than women (n = 17). The oxidative activity of 17beta-hydroxysteroid dehydrogenase was 2-fold higher in men than women. Serum levels of dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were significantly higher in women with acne than in women without acne. No differences in serum androgen levels were noted in men on the basis of the presence of acne. CONCLUSIONS: Higher serum androgen levels are associated with the presence of acne in women. A role for locally produced androgens in this process, however, cannot be excluded.     

Practical Approach to the Hormonal Treatment of Acne

Acne is a disease of the pilosebaceous units and these are mainly under hormonal control. In female patients, hormonal therapy is a unique opportunity for the treatment of acne. Several combined oral contraceptives (COCs), cyproterone acetate, spironolactone, flutamide, and others, have been tried for the control of acne. An overview on the use of the most useful drugs in clinical practice was conducted. COCs are thoroughly discussed, also taking into consideration their potential side effects. A practical approach with guidelines on the use of COC in acne is proposed.     

Practical approach to the hormonal treatment of acne

Acne is a disease of the pilosebaceous units and these are mainly under hormonal control. In female patients, hormonal therapy is a unique opportunity for the treatment of acne. Several combined oral contraceptives (COCs), cyproterone acetate, spironolactone, flutamide, and others, have been tried for the control of acne. An overview on the use of the most useful drugs in clinical practice was conducted. COCs are thoroughly discussed, also taking into consideration their potential side effects. A practical approach with guidelines on the use of COC in acne is proposed.     

Ethinylestradiol/Chlormadinone acetate: dermatological benefits

Acne vulgaris, hirsutism, seborrhea and female pattern hair loss (FPHL) are common disorders of the pilosebaceous unit (PSU). In some women with hyperandrogenemia, an excess of androgens at the PSU can lead to the development of these dermatological manifestations. These manifestations can cause many psychiatric and psychological implications, such as social fears and anxiety, and can adversely affect quality of life. High androgen levels at the PSU as a possible underlying cause of acne vulgaris, hirsutism, seborrhea and FPHL supports the rationale for using combined oral contraceptives for the management of these conditions in women. The purpose of this review is to describe these dermatological manifestations of the PSU and the management of these conditions through the use of the oral contraceptive ethinylestradiol/chlormadinone acetate (EE/CMA). EE/CMA 0.03/2 mg is a combined monophasic contraceptive pill with anti-androgenic properties. It is approved in Europe for contraception and has been investigated in phase III trials for the treatment of acne. EE/CMA was better than placebo and similar to another low-dose oral contraceptive (ethinylestradiol/levonorgestrel) in improving symptoms of acne in two phase III randomized controlled trials in patients with mild to moderate papulopustular acne. In addition, in trials investigating the contraceptive efficacy of EE/CMA, limited data suggest that there were also improvements in hirsutism, FPHL and seborrhea in small subgroups of patients. EE/CMA has a good safety profile. The most commonly reported adverse events are breast tenderness/pain, headache/migraine and nausea. Evidence in the literature indicates that the use of EE/CMA for the treatment of dermatological disorders under the control of androgens may be a valid treatment option. Further investigation is warranted.