The hormone factory skin never sleeps or Methusalem drugs and other ancient friends, revisited!

The wide spectrum of content of the articles published in this issue of Dermato-Endocrinology reflects the close and fascinating, but vulnerable vice versa relationship of the “hormone factory skin” with other hormone-producing organs, including thyroid, pancreas, liver, and kidneys. The discovery of cutaneous correlatives for many of the classical endocrine pathways, including parathyroid hormone related peptide-, thyroid hormone-, and vitamin D pathways, has greatly improved our understanding of the pathophysiology of many diseases and has opened many promising new avenues for the pharmacologic treatment of these disorders. Some examples of important interactions between the skin and other hormone-producing organs are presented by the papers published in this issue.

In the first paper, Blazej Zbytek et al. discuss the putative role of HIF transcriptional activity in melanocytes and melanoma biology. They explain that Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. They state that expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. The authors now have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). They discuss that, while some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. The authors explain that, although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.

In the second paper, Hartmut Glossmann and Norbert Reider discuss a marriage of two “Methusalem” drugs for the treatment of psoriasis and present arguments for a pilot trial with metformin as add-on for methotrexate. They explain that the “antidiabetic” drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.g., important for cellular growth or function in many tissues including T-lymphocytes. The authors explain that clinical observations as well as experimental results argue for anti-inflammatory, antineoplastic and antiproliferative activities of metformin and a case-control study suggests that the drug reduces the risk for psoriasis. They discuss that patients with psoriasis have higher risk of metabolic syndrome, type 2 diabetes and cardiovascular mortality. Metformin has proven efficacy in the treatment of prediabetes and leads to a pronounced and sustained weight loss in overweight individuals. The authors expect that addition of metformin to methotrexate can lead to positive effects with respect to the PASI score, reduction of the weekly methotrexate dose and of elevated cardiovascular risk factors in patients with metabolic syndrome and psoriasis. For several reasons they suggest that only male, overweight patients are to be included in a pilot trial. They state that on the other side of the coin are concerns that the gastrointestinal side effects of metformin are intolerable for patients under low dose, intermittent methotrexate therapy. Metformin has another side effect, namely interference with vitamin B12 and folate metabolism, leading to elevated homocysteine serum levels. The authors explain that, as patients must receive folate supplementation and will be controlled with respect to their B12 status increased hematological toxicity is unlikely to result.

In the third paper, M. Julie Thornton summarizes our present understanding of the relevance of estrogens for aging skin. She explains that estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. The author states that estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. Its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer. The author discusses that skin aging can be significantly delayed by the administration of estrogen. In her paper, she reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SERMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. She concludes that understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies.

In the following communication, Roberto d’Ovidio et al. report their clinical observation of reduced 25-hydroxyvitamin D levels in chronic/relapsing Alopecia Areata. They discuss that current observations link vitamin D deficiency to many autoimmune diseases, but that there are limited data on the impact of vitamin D for Alopecia Areata, an autoimmune disease which in the experience of the authors shows seasonality in most of its remitting-relapsing forms. In this paper, they demonstrate 25-hydroxyvitamin D (25OH-D) insufficiency in many patients with various clinical forms, that correlated with an expected increase of the values of Parathyroid Hormone (PTH). In conclusion, the authors discuss the possible clinical use of vitamin D in the management of this frustrating disease.

In the next report, Darina Bassil et al. analyze the relevance of hypovitaminosis D in the Middle East and North Africa, focusing on prevalence, risk factors and impact on outcomes. They state that the Middle East and North Africa (MENA) region registers some of the highest rates of hypovitaminosis D worldwide. In their work, the authors systematically review the prevalence of hypovitaminosis D, rickets and osteomalacia, their predictors and impact on major outcomes, in the region. Medline, Pubmed and Embase search engines, entering keywords and concepts, combined with individual countries of interest, were used. Search was limited to years 2000–2012; however review articles were used for the period preceeding year 2000. The authors convincingly demonstrate that rickets and osteomalacia still occur in this sunny region. Hypovitaminosis D prevails, with rates varying 30–90%, considering a desirable serum 25 hydroxyvitamin D [25(OH)D] of 20 ng/ml. Advancing age, female gender, multi-parity, clothing style, season, socio-economic status and urban living are recognized predictors of hypovitaminosis D in adults. The authors explain that prolonged breastfeeding without vitamin D supplementation and low dietary calcium intake are the recognized risk factors for rickets and hypovitaminosis D in children. Associations with pain score and disease activity in rheumatologic disorders, viral load and interleukins in hepatitis C, BMI, lipids and insulin sensitivity, blood pressure, heart failure and mortality are described. Sun exposure in adults decreased prevalence of metabolic syndrome in one study. Few randomized vitamin D trials revealed that the majority of mothers or children failed to achieve a desirable 25(OH)D level, even with doses by far exceeding current recommendations. A trial in adolescent girls reveals substantial bone and lean mass increments. The authors conclude that hypovitaminosis D is prevalent in MENA. However, the lack of populations based studies, gaps in studies in infants, pre-pubertal children and pregnant women, hinder the development of region specific guidelines and constitute a major obstacle to impact this chronic and most often subclinical disease.

In the next report, Elżbieta Karczmarewicz et al. analyze the effect of vitamin D status on pharmacological treatment efficiency and the impact on cost-effective management in medicine. They explain that at least 80% of the whole Polish population, including prepubertal children and adolescents, adults and seniors, are vitamin D deficient, defined as 25(OH)D < 50 nmol/L. The authors state that 83% of Polish newborns start their lives at the state of vitamin D deficiency because 78% of their mothers are also deficient. It was observed that treating patient vitamin D deficiency to vitamin D status serum 25(OH)D) 75–100 nmol/L increased effectiveness of therapies in infectious diseases (chronic hepatitis C, tuberculosis), osteoporosis, multiple sclerosis, epilepsy, Chronic Kidney Diseases and atopic dermatitis. The authors conclude that for these reasons doctors should take special attention to vitamin D status in patients suffering for these diseases properly implementing recent vitamin D recommendation.

In the following communication, Nidhi Choudhary et al. report a case of acquired perforating dermatosis and Addison’s disease due to disseminated histoplasmosis. They explain that acquired perforating dermatosis (APD) is a rare disorder characterized by transepidermal elimination of contents from dermis with minimal disruption of surrounding structures, believed to be due to altered expression of dermal proteins. The suthors state that its occurrence in patients with systemic mycosis has never been reported. They report a 60-y gentleman who presented with features of adrenal insufficiency (nausea vomiting, hypotension and increased pigmentation) for 4 mo, multiple hyperpigmented pruritic nodules with central keratinous plug over extensor surface of both lower limbs along with hepatosplenomegaly of one month duration. Investigations revealed low cortisol (2.3 μg/dl; normal: 5–34 μg/dl), elevated ACTH (68 pg/ml; normal: 5–15 pg/ml), enlarged bilateral adrenals with hepatosplenomegaly on CT. Methanamine silver staining of fine needle aspiration from the adrenals and bone marrow aspiration showed numerous oval yeast cells suggestive of histoplasma. Histopathology of biopsy of one of the skin nodules revealed transepidermal elimination process characterized by invagination of epidermis with extrusion of collagen bundles suggestive of APD. Patient improved with hydrocortisone replacement and there was clinical improvement with resolution of skin lesions following amphotericin-B and itraconazole therapy. This is probably the first reported case of APD in a patient with disseminated histoplasmosis who had presented with Addison’s disease.

In the following communication, Susanna við Streym et al. report no effect of season of birth on risk of type 1 diabetes, cancer, schizophrenia and ischemic heart disease, while some variations may be seen for pneumonia and multiple sclerosis. They explain that the risk of type 1 diabetes (T1DM), infections, cancer, schizophrenia and multiple sclerosis (MS) has been associated with environmental factors including vitamin D status. In their study, data were obtained from all children born in Denmark in 1940 (n = 72,839), 1977 (n = 89,570), and 1996 (n = 74,015). Information on contacts to hospitals (1977–2009) was obtained from the National Hospital Discharge Register. The main exposure variable was season of birth as a proxy variable for vitamin D status (summer: April–September and winter: October–March). The authors explain that no associations between season of birth and risk of MS were seen in the 1940 cohort or the 1996 cohort. In the 1977 cohort, there was a borderline statistically significant decreased risk of MS in those born during wintertime compared with those born during summertime (HR = 0.70, 95% CI: 0.47–1.04, p = 0.07). There were no significant differences within the groups regarding season and risk of T1DM at any age, T1DM before 10 y, infection, any type of cancer, schizophrenia and myocardial infarction. In the 1977 cohort the risk of pneumonia was significantly lower among those born in the summer compared with the winter at any age (HR 0.91, 95% CI 0.85–0.97, p < 0.01) and at age < 10 y (HR 0.90, 95% CI 0.84–0.97, p < 0.01). The authors concluded that MS and pneumonia in young subjects may be related to season of birth and thus maternal vitamin D exposure. Low sunlight exposure in the winter time leading to low vitamin D levels during pregnancy may be a potential explanation.

In the following paper, Sadeem Alsubaie and Mussa H. Almalki present a case of metformin induced acute pancreatitis. The authors explain that acute pancreatitis frequently presents with abdomen pain but may presents with various skin manifestations as rash and rarely, pancreatic panniculitis. Metformin, one of the most effective and valuable oral hypoglycemic agents in the biguanide class was linked to acute pancreatitis in few cases. Here, the authors report a case of metformin-induced acute pancreatitis in a young healthy man with normal renal function.

In the next communication, Apostolos Pappas, Jared Fantasia and Theresa Chen discuss age and ethnic variations in sebaceous lipids. Their study was conducted to compare lipid components of sebum from persons from three ethnic backgrounds—Caucasian, African American and Northern Asian. Men and women with no acne in two age groups (18‒25 y and 35‒45 y) were recruited. Skin surface hydration (SkiCon 200EX and NovaMeter), barrier function (Delfin VapoMeter), high-resolution clinical imaging, self-assessments and two pairs of sebutapes on the forehead that extracted the lipids on the surface of their skin were used. Significant differences (p < 0.05) in skin hydration between African Americans and Caucasians in both age groups were noted, with the order from highest to lowest absolute values: African American > Northern Asian > Caucasian. Transepidermal water loss (TEWL) measurements demonstrated that African Americans and Caucasians were significantly different (p < 0.05), with the trend being the inverse of the hydration trend—Caucasian > Northern Asian > African American, which would indicate better barrier function for African Americans with a lower TEWL. African American women had more total lipid production than Northern Asian or Caucasian women. When analyzing the three lipid classes (free fatty acids, triglycerides and wax esters), the trend became significant (p < 0.05) in the wax ester fraction when directly comparing African Americans with Caucasians. Additionally, six lipids were identified in the wax ester fractions that were significantly different in quantity (p < 0.05) between African Americans and Caucasians. These results identified significant differences in sebaceous lipid profiles across ethnic groups and determined that the differences correlated with skin barrier function.

Last but not least, Marjonneke Mook-Kanamori et al. demonstrate ethnic and gender differences in advanced glycation end products measured by skin auto-fluorescence. They explain that advanced glycation end products (AGEs) have been shown to be a predictor of cardiovascular risk in Caucasian subjects. In this study the authors examine whether the existing reference values are useable for non-Caucasian ethnicities. Furthermore, they assessed whether gender and smoking affect AGEs. In their study, AGEs were determined by a non-invasive method of skin auto-fluorescence (AF). AF was measured in 200 Arabs, 99 South Asians, 35 Filipinos and 14 subjects of other/mixed ethnicity in the Qatar Metabolomics Study on Diabetes (QMDiab). Using multivariate linear regression analysis and adjusting for age and type 2 diabetes, they assessed whether ethnicity, gender and smoking were associated with AF. Results: The mean AF was 2.27 arbitrary units (AU) (SD: 0.63). Arabs and Filipinos had a significant higher AF than the South Asian population (0.25 arbitrary units (AU) (95% CI: 0.11–0.39), p = 0.001 and 0.34 (95% CI: 0.13–0.55), p = 0.001 respectively). Also, AF was significantly higher in females (0.41 AU (95% CI: 0.29–0.53), p < 0.001). AF associated with smoking (0.21 AU (95% CI: 0.01–0.41), p = 0.04) and increased with the number of pack-years smoked (p = 0.02). The authors concluded that their study suggests that the existing reference values should take ethnicity, gender and smoking into account. They discuss that larger studies in specific ethnicities are necessary to create ethnic- and gender-specific reference values.

In summary, the articles published in this issue demonstrate, besides the marriage of “Methusalem Drugs,” the close relationship of the “hormone factory” skin, pharmacotherapy and internal medicine. They underline the fact, that the interaction of skin with “ancient friends,” including other organs and hormones is perfect in a healthy person but may exert in many diseases deleterious effects. Some examples of challenges and promises mediated by these important interactions are presented by the papers published in this issue. In summary, the articles published in this issue demonstrate, again, the importance of Dermato-Endocrinology, not only for skin physiology and for a broad variety of common or rare skin diseases, but also for internal medicine and other medical disciplines.