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Hormonal acne: Leading to a paradigm shift in the management of acne
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The presence of seborrhoea, acne, hirsutism and alopecia in women has first been summarized as SAHA syndrome in 1982 and can be associated with polycystic ovary syndrome, cystic mastitis, obesity and infertility. In 1994, the association of these androgen-dependent cutaneous signs, was classified according to their etiology into four types: (1) idiopathic, (2) ovarian, (3) adrenal, and (4) hyperprolactinemic SAHA. The HAIRAN syndrome has been currently described as a fifth variant with polyendocrinopathy. The SAHA syndrome generally occurs in young to middle-aged women and involves either the presence of elevated blood levels of androgens or increased androgen-driven peripheral response with normal circulating androgen levels. Peripheral metabolism of androgens takes place in various areas within the pilosebaceous unit, as indicated by local differences in the activities of aromatase, 5alpha-reductase as well as of the presence of the androgen receptors. In cases of SAHA syndrome, careful diagnostic and clinical evaluation has to be performed in order to identify the cause for peripheral hyperandrogenism and to exclude androgen-producing tumors. Treatment will target the etiology, whereas the management in idiopathic cases will aim to improve the clinical features of SAHA.
To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients.
Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls.
We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment.
This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.
Acne vulgaris is the most common disorder seen in ambulatory dermatology practice. Acne causes significant morbidity and the direct costs associated with it exceed $2.2 billion per year in the United States (U.S.). The pathogenesis is multifactorial, and our understanding of the mechanisms involved in the development of acne lesions has improved with time. Follicular hyperkeratinization, sebum production, presence of Propionibacterium acnes (P. acnes), inflammatory mediators, and androgens have been identified as key components of acne pathophysiology. Recent advances have been made in this area with the discovery of P. acnes interaction with Toll-like receptors (TLRs), vaccines targeting P. acnes or its components, antimicrobial peptides and the role of hormones.
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.
The aims of this study were to determine the frequency of late-onset adrenal hyperplasia due specifically to 21-hydroxylase deficiency in a group of Irish women who presented at a Dublin Clinic with symptoms of hyperandrogenism, including hirsutism, menstrual irregularities and/or cystic acne, and to determine if those with 21-hydroxylase deficiency showed particular HLA associations. 119 women had blood samples taken basally and 1 h after an injection of 0.25 mg synacthen with the following hormones profiled: 17-hydroxyprogesterone, 11-deoxycortisol, androstenedione, testosterone, DHEAS and cortisol. Blood sampling was carried out between 0900 and 1000 h during the early follicular phase of the menstrual cycle (when applicable). Ninety-six subjects were new referrals to the Clinic for investigation of hyperandrogenism and 23 were acting as controls. In this study, 6% of patients showed evidence of partial 21-hydroxylase deficiency. In addition, 3 of the 6 with partial 21-hydroxylase deficiency had normal baseline levels of 17-hydroxyprogesterone, with the biochemical abnormality becoming manifest only on synacthen stimulation. Late-onset adrenal hyperplasia due to partial deficiency of this enzyme should always be considered as a possible diagnosis in women who present with symptoms of hyperandrogenism. Synacthen stimulation is an important diagnostic tool in elucidating partial enzyme deficiency as baseline 17-hydroxyprogesterone may be normal in such patients.
Forty-six women affected by late-onset or persistent acne were studied in order to investigate the frequency of hormonal abnormalities and polycystic ovaries. Hirsutism, perioral distribution of acne lesions and irregular menses were recorded. Hormonal measurements and ovarian echographies were performed. Twenty-four patients were affected with polycystic ovaries, detected by ultrasound scanning. Among the acne patients, the women with ovarian abnormalities had higher values of androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate and luteinizing hormone (LH), and a higher LHT/follicle-stimulating hormone ratio than those with acne and without ovarian abnormalities. This study indicates the prevalence of polycystic ovaries in women with late-onset or persistent acne. Moreover, hormonal abnormalities indicate a subgroup of acne patients defined by the presence of ovarian disorders.
Out of 98 female referrals with acne vulgaris it was possible to define ovarian morphology by high resolution ultrasound imaging of the pelvis in 82 (84%). Sixty-eight (83%) were shown to have polycystic ovaries, compared with 19% in a control group without acne. The presence of polycystic ovaries in the acne patients did not correlate with acne severity, infertility, menstrual disturbance, hirsutes, or biochemical endocrinological abnormalities.
We have studied a group of young adult women of mean age 23.8 +/- 6.5 (SD) years with only acne (A, n = 46), only hirsutism (H, n = 10), and acne plus hirsutism (A + H, n = 19) who sought dermatologic care. We measured the androgens, total and free testosterone (T), free 17 beta-hydroxysteroids (17-beta), dehydroepiandrosterone sulfate (DS), and the androgen precursors 17 alpha-hydroxypregnenolone (17-Preg) and 17 alpha-hydroxyprogesterone (17-Prog), as well as testosterone-estrogen binding globulin in all patients. Plasma hormone levels of the patients were compared to those of 23 controls of mean age 25.6 +/- 6.6 years who had neither acne nor hirsutism. Mean levels of all hormones measured, except 17-Preg, were elevated in the women with acne. Fifty-two percent of Group A, 60% of Group H, and 63% of Group A + H patients had at least one abnormal hormone level. The most frequently elevated plasma androgens in all the women with acne were: free T 25%, free 17-beta 23%, and DS 19%. Total T was high in only 12%. Elevations of plasma androgens were present in some women who did not have hirsutism or irregular menses. Identification of endocrine abnormalities in women with acne may potentially offer an opportunity for hormonal therapy.
Elevated serum androgen levels have been reported in patients with acne resistant to conventional dermatologic therapy. This study was designed to investigate the relationship between serum androgen levels and the presence of acne in an unselected population of women seen consecutively by a dermatologist for various dermatologic complaints. Elevated serum testosterone levels were associated with acne regardless of whether this was the presenting complaint or an incidental finding. Women with both acne and hirsutism had higher serum testosterone levels than those with acne alone. Higher incidence of irregular menstrual cycles was noted in women complaining of acne. Normal serum testosterone levels were found only in those patients with regular menstrual cycles and the absence of acne or hirsutism. In conclusion, this study suggests that elevated serum testosterone levels are related to the presence of acne. Attention is called to the possibility that acne may be a clinical manifestation of a disorder with systemic and reproductive consequences.
Because severe hirsutism is difficult to reverse, the evaluation of the adolescent girl with progressive hirsutism should aim at the pathophysiology of androgen excess in order to select appropriate therapies. A prospective study was undertaken to determine the occurrence of late-onset 21-hydroxylase deficiency among adolescents with androgen excess. Twenty-two young women (mean age 17.3 +/- 2.6 years) with androgen excess had serum 17-hydroxyprogesterone measured before and after bolus intravenous infusion of synthetic ACTH (Cortrosyn), 0.25 mg. Two patients, aged 13 and 19 years old, had elevated base line 17-hydroxyprogesterone and 30- and 60-minute responses to Cortrosyn consistent with 21-hydroxylase deficiency. Chromosome 6p haplotypes provided supportive evidence of 21-hydroxylase deficiency. The base line androgen levels, clinical presentation, and a four-day dexamethasone test did not distinguish patients with 21-hydroxylase deficiency from other hirsute adolescents. The Cortrosyn test identifies a population of adolescents who need long-term corticosteroid therapy. The use of major histocompatibility complex haplotypes could be of help in identifying affected siblings prior to the development of significant hirsutism.
HAIR-AN syndrome is an acronym for an unusual multisystem disorder in women that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The precipitating abnormality is thought to be insulin resistance, with a secondary increase in insulin levels and subsequent overproduction of androgens in the ovaries. Long periods of hyperinsulinism and, some suspect, hyperandrogenism can result in the cutaneous manifestation of acanthosis nigricans. Patients are often concerned about the physical manifestations of this disorder, including virilization and acanthosis nigricans, and may be less aware of systemic problems. Physicians should assess women with these problems for an underlying endocrine abnormality. Although a treatment regimen for the HAIR-AN syndrome has not been established, antiandrogen therapy and weight loss are useful.
Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1/CRH-R2 = 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10(-7) M and up-regulated mRNA levels of 3 beta- hydroxysteroid dehydrogenase/Delta(5-4) isomerase, although it did not affect cell viability, cell proliferation, or IL-1 beta-induced IL-8 release. CRH, dehydroepiandrosterone, and 17 beta-estradiol did not modulate CRH-R expression, whereas testosterone at 10(-7) M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin.
Acne is traditionally regarded as a skin disorder of the teenage years. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. One recent community-based UK study estimated the prevalence of facial acne in adult women aged between 26 and 44 years to be 14%. It is not clear whether there is a true increase in acne in this age group or whether these patients are less tolerant of their acne and/or better informed of available therapies and so seek advice. The reasons for persistent acne are not fully understood. External factors such as use of certain cosmetics, ingestion of drugs, and endocrine abnormalities should all be considered when managing these patients. Post-adolescent acne in females can be divided into ‘persistent acne’, which represents a continuation of acne from adolescence into adult life, and ‘late-onset’ acne, which describes significant acne occurring sometimes for the first time after the age of 25 years. The clinical picture of each of these forms of acne in adult females can differ slightly from conventional adolescent disease. The course of each form is more indolent. Because of these variations, the approach to investigation and management of these cases may have subtle differences when compared with that for teenage disease. Acne treatment should aim to reduce sebum, comedogenesis, propionibacteria population, and inflammation. Treatment selection will depend on the acne grade and site as well as the patient‘s preference and ability to comply with therapy. Maintenance therapy plays an important role in managing this group of patients. As the response to treatment is inevitably slow, patients must be encouraged to adhere to the chosen treatment regimen.
This article reviews the literature on persistent acne in women in terms of clinical presentation and possible etiologic factors, and outlines principles of therapy related to managing these cases.
Several isolated observations have suggested that acne can develop in groups when a high glycemic index diet is adopted.
This study was designed to examine associations among daily diet glycemic index, glycemic loads, serum insulin levels, and acne.
A total of 49 patients with acne and 42 healthy control subjects were included in the study. At the initial visit, fasting glucose, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein 3, and leptin levels were measured. A voluntary self-completed questionnaire was administered and participants were asked how frequently they consumed the specified amount of food. Overall glycemic index and dietary glycemic load were calculated.
No significant differences were observed between patients with acne and control subjects in serum glucose, insulin, leptin levels, overall glycemic index, or dietary glycemic load.
The information and data obtained from this questionnaire were limited to patients' own recollections.
Results of this study indicate that dietary glycemic index, glycemic load, and insulin levels do not have a role in pathogenesis of acne in younger patients.