Metabolism and skin diseases
Metabolic processes play an essential role in the development and physiological function of human skin [1, 2]. Thus, human skin cells contain hormone-specific receptors and are targets of several hormones exerting various effects . From the viewpoint of modern endocrinology, however, the skin is not only regarded as a recipient of signals from distant glands. It is also an organized cell community, in which cells use molecular signals with endocrinologic/metabolic functions for (a) local intercellular communication (intracrinology) and (b) transmission of information to the other organs of the body. Indeed, hormones are activated in the skin cells and are released into the systemic circulation. Given its dimensions (2 m2, 8–10 kg), the skin represents a quite large gland of the human organism .
1 Metabolic pathways and skin functions
In this issue of Reviews in Endocrine and Metabolic Disorders, several aspects of these complex skin functions are reviewed. Extra-gonadal steroidogenesis is mainly accomplished in the skin, which metabolizes various hormones from their precursors, while it also synthesizes de novo a broad palette of sex steroids and glucocorticoids from cholesterol . Nikolakis et al.  review the major steroidogenic properties of human skin and suggest that steroidogenesis impairment is a cardinal factor for various pathological inflammatory conditions such as acne, rosacea, atopic dermatitis, and androgenic alopecia.
Growth hormone (GH) receptors are found in almost all skin cell types, while the expression of insulin-like growth factor-1 is restricted to melanocytes. Both GH excess states, as in the case of acromegaly in adults or gigantism in growing children, and GH deficiency are associated with various skin manifestations . Kanaka-Gantenbein et al.  review the main dermatologic findings in GH dysregulation, namely skin thickening, coarsening of facial features, acrochordons, puffy hands and feet, oily skin and hyperhidrosis in GH excess, and thin, dry skin, and sweating disorder in GH deficiency. Moreover, special disorders associated with GH excess exhibit specific characteristics, such as café-au-lait spots in patients with neurofibromatosis and large café-au-lait skin regions with irregular margins in patients with McCune-Albright syndrome.
The high glucose serum levels in patients with diabetes mellitus also affect the skin among systemic organs. Makrantonaki et al.  indicate in their review that skin disorders can often predict the onset of diabetes. Cutaneous manifestations of diabetes mellitus can be classified in (a) skin diseases with a direct association with diabetes (necrobiosis lipoidica, diabetic dermopathy, diabetic bullae, yellow skin, eruptive xanthomas, perforating disorders, acanthosis nigricans, oral leucoplakia, lichen planus), (b) infections (bacterial, fungal), (c) cutaneous manifestations of diabetic complications (microangiopathy, macroangiopathy, neuropathy), and (d) skin reactions to diabetic treatments .
Stratakis  reports that characteristic skin lesions are among the most diagnostic manifestations of Cushing’s syndrome. They include violaceous striae, facial acne, hirsutism, acanthosis nigricans, fungal infections, hyperpigmentation, and easy bruisability. Facial plethora (along with acne and other facial skin changes) is a typical sign of Cushing’s syndrome, occurring due to increased perfusion. The severity of the manifestations does not correlate with the biochemical indices of the disease .
The skin is affected by neurohormonal triggers, especially those related to stress. Several skin cells produce stress and sex hormones implicating them in a local “hypothalamic-pituitary-adrenal axis.” Theoharides et al.  review the function of the peptide corticotropin-releasing hormone and neurotensin, which are produced by skin cells and have synergistic action in stimulating and degranulating mast cells. These peptides are also elevated in the serum of patients with inflammatory skin diseases exacerbated by stress.
At last, Alexopoulos and Chrousos  review the bidirectional communication pathways between the brain and the skin, which play significant roles in integrating interactions among skin cells, nerves, and inflammatory cells. They also present the underlying mechanisms that link stress to the common dermatoses according to the latest scientific findings.
2 Association of metabolic and skin disorders
Although metabolic pathways have been progressively identified in influencing skin physiology and pathophysiology, their clinical relevance for common skin diseases, such as psoriasis, acne, and hidradenitis suppurativa, has not allowed the application of this new knowledge in everyday clinical practice.
Apart from the skin alterations, psoriasis was currently shown to be associated with the metabolic syndrome and to increase the risk of type 2 diabetes mellitus and cardiovascular disorders. Wolk and Sabat  review the research data of the last years, which demonstrated a dysregulated adipokine balance as an important link between inflammation, metabolic syndrome, and consequent disorders. Selective adipokines play a potential role in the metabolic comorbidity of psoriasis patients and can, therefore, become a future target of effective anti-psoriatic treatment .
Due to the central role of the sebaceous gland in acne pathogenesis, early research had focused on its lipogenic activity. Zouboulis et al.  review the less studied aspects of the sebaceous gland role in the skin, such as the regulation of cellular differentiation by transcription factors, the significance of specific lipid fractions, the endocrine, and, especially, the neuroendocrine role of the sebaceous gland, its contribution to the innate immunity and the detoxification of the skin, sebaceous stem cell biology, and its role in skin aging, which have only recently attracted the attention of researchers from different disciplines. These new findings on sebaceous gland physiology and metabolic activity may stimulate the development of novel therapeutic strategies targeting specific molecular pathways involved in the pathogenesis of inflammatory skin diseases .
The typical onset of the disease after puberty, the female predominance, the pre-menstrual flare-ups, and the improvement of hidradenitis suppurativa/acne inversa (HS) during pregnancy, suggest a contribution of metabolic/endocrinologic factors to this chronic inflammatory, debilitating skin disorder . Furthermore, the reported efficacy of anti-androgen treatment on HS indicates a possible involvement of androgens. Karagiannidis et al.  report that the metabolic syndrome, which increases the HS prevalence more than fourfold, points to possible interactions between metabolic alterations and HS development and describe the current views on hormonal dysregulation and its role in HS.
Gulliver et al.  present a holistic evidence-based approach which implements Level of Evidence and Strength of Recommendation for the treatment of HS. The diagnosis of HS should be made by a dermatologist or other healthcare professionals with expert knowledge in HS. All patients should be offered adjuvant therapy as needed (pain management, weight loss, tobacco use cessation, treatment of superinfections, and application of appropriate dressings). The treating physician should be familiar with disease severity scores, especially Hurley staging, physician global assessment, and others. The routine use of patient-reported outcomes, including Dermatology Life Quality Index, itch, and pain assessment (Visual Analogue Scale) is strongly recommended. The need for surgical intervention should be assessed in all patients depending upon type and extent of scarring, and an evidence-based surgical approach should be implemented. Evidence-based medical treatment of mild disease consists of topical clindamycin 1% solution/gel 2×/day for 12 weeks or tetracycline 500 p.o. 2×/day for 4 months for more widespread disease. If the patient fails to exhibit a response to treatment or for patients with moderate-to-severe disease, clindamycin 300 p.o. 2×/day with rifampicin 600 p.o. 1×/day for 10 weeks should be considered. If the patient is not improved, adalimumab 160 mg at week 0, 80 mg at week 2, then from week 4 40 mg s.c. weekly should be administered. If improvement occurs, then therapy should be maintained as long as HS lesions are present. If the patient fails to exhibit a response, then a consideration of second or third line therapy is required .
Abdel Naser and Zouboulis  review the association of male fertility and skin diseases. Several genodermatoses affect the skin and the male reproductive system, commonly in the form of cryptorchidism and hypogonadism. The most relevant syndromes are associated with dyschromias, such as de Sanctis-Cacchione, congenital poikiloderma, LEOPARD, and H syndrome, others with ichthyosis, such as Rud, and trichothiodystrophy or a group of unrelated genodermatoses, such as ablepharon macrostomia, Coffin-Siris, Gorlin-Goltz, and Werner. Acquired skin diseases may also affect male fertility, usually in the form of orchitis or epididymal obstruction or androgen antagonists. These include infections (leprosy and HIV), autoimmune (erythema nodosum leprosum), granulomatous (sarcoidosis, Langerhans cell histiocytosis), nutritional deficiency (zinc), and malignancy. In addition, several skin disease treatments affect male fertility, such as methotrexate, irradiation, and anti-androgens .
Stratakis  reviews the Carney complex, a familial lentiginosis syndrome, which covers a wide phenotypic spectrum ranging from a benign-inherited predisposition to develop cutaneous spots not associated with systemic disease to associations with several syndromes. Carney complex is caused by PRKAR1A mutations and perturbations of the cyclic AMP-dependent protein kinase (PKA) signaling pathway. In addition to the cutaneous findings, primary-pigmented nodular adrenocortical disease, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly, thyroid and gonadal tumors, including a predisposition to thyroid cancer, myxomas of the heart, breast and other sites, psamommatous melanotic schwannomas, and a predisposition to a variety of cancers have been described .
Hannah-Shmouni et al.  review cutaneous flushing as a common complaint in endocrine disorders. Episodic flushing is mediated by the release of endogenous vasoactive mediators or medications, while persistent flushing results in a fixed facial erythema with telangiectasia and a cyanotic tinge owing to the large cutaneous blood vessels that contain slow-flowing deoxygenated blood. The differential diagnosis of cutaneous flushing in neuroendocrine disorders encompasses a broad spectrum of benign and malignant entities, including carcinoid syndrome, pheochromocytoma, Cushing’s syndrome, medullary thyroid cancer, and pancreatic neuroendocrine tumors .
3 Metabolic diseases and skin tumors
Not only mutations but also metabolic dysregulations and chronic inflammation can lead to the development of skin and other tumors. In a further review, Stratakis  reports on Peutz-Jeghers syndrome, Carney complex, Cowden disease, neurofibromatosis type-1 and tuberous sclerosis as multiple endocrine neoplasias (MEN), since they predispose to a variety of endocrine tumors and characteristic skin manifestations .
Karimi et al.  report on the dramatic increase in incidence of both obesity and many cancers, including skin cancer, and review the literature linking obesity to melanoma and non-melanoma skin cancer. The molecular mechanisms underlying the association between obesity and skin cancer are not clearly understood but emerging evidence points to changes in the tumor microenvironment including aberrant cell signaling and genomic instability in the chronic inflammatory state many obese individuals experience .
Reichrath et al.  report on the importance of skin for vitamin D synthesis and the consequences of vitamin D deficiency. Approximately 90% of all needed vitamin D has to be photosynthesized in the skin through the action of ultraviolet-B irradiation. The skin represents a key organ of the human body’s vitamin D endocrine system, being both the site of vitamin D synthesis and a target tissue for biologically active vitamin D metabolites. Numerous studies, including cDNA microarray analyses of mRNAs, indicate that as many as 500–1000 genes may be regulated by vitamin D receptor ligands that control various cellular functions including growth, differentiation, and apoptosis. The induction of terminal differentiation and inhibition of the proliferation of human keratinocytes has resulted in the use of vitamin D analogs for the treatment of psoriasis. Moreover, the regulation of the vitamin D endocrine system is relevant to the management of inflammatory and malignant skin diseases .
Wissner Greene et al.  review systemic mastocytosis, which is characterized by accumulation of clonal, neoplastic proliferations of abnormal mast cells in one or more organ systems including the skin. The presence of D816V (KIT) mutation and elevated serum tryptase levels are minor criteria for diagnosis. The manifestations of systemic mastocytosis depend on the degree of mast cell proliferation, activation, and degranulation with variable prognosis and presentation, from indolent to “smoldering” to life-threatening disease. Particularly, bone manifestations can include osteopenia with or without lytic lesions, osteoporosis with or without atraumatic fracture, osteosclerosis with increased bone density, and isolated lytic lesions leading to increased risk of bone fracture. Treatment of systemic mastocytosis is generally palliative .
4 Skin health and aging: nutritional and environmental metabolic factors
Aging is a complex process, characterized by a progressive loss of function in multiple tissues, which leads to an increased probability of death. Kanaki et al.  review the environmental aging promoters and their individual roles in aging and point out the need of biomarker development for the elucidation of pathogenesis and the introduction of individual preventive measures. Because of the complexity of skin aging, the discovery of biomarkers is still a major research challenge; however, several biomarkers already have been identified and studied .
Pappas et al.  summarize the long association between nutrition and skin health, including all possible aspects from beauty to the aging process. Multiple pathways within skin biology are associated with the onset and clinical course of various common skin diseases, such as acne, atopic dermatitis, aging, but also with photo-protection. These conditions are critically affected by nutritional patterns and dietary interventions; well documented studies have demonstrated beneficial effects of essential nutrients on impaired skin structural and functional integrity, while they have restored skin appearance and health .
Last, Ju and Zouboulis  review the endocrine-disrupting chemicals and their ability to disrupt the production and actions of hormones through direct or indirect interaction with hormone receptors and their effects on the skin as a result of individual occupational, dietary, or environmental exposure. Endocrine-disrupting chemicals perturb the endocrine system by activating the aryl hydrocarbon receptor signal pathway and can be immunotoxic and/or carcinogenic to human skin, inducing inflammatory and allergic skin diseases, chloracne, disorders of skin pigmentation, skin cancer, and skin aging.
We had a great time putting the different parts on Metabolism and skin diseases together, we hope that you will find this thematic issue interesting and wish you a pleasant and informative reading.
The contribution of Dr. C.A. Stratakis to this work was supported by the Intramural Research Program, NICHD, NIH, USA.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 6.Stratakis CA. Skin manifestations of Cushing’s syndrome. Rev Endocr Metab Disord. 2016. doi: 10.1007/s11154-016-9399-3.
- 8.Alexopoulos A, Chrousos GP. Stress-related skin disorders. Rev Endocr Metab Disord. 2016. doi: 10.1007/s11154-016-9367-y.
- 14.Stratakis CA. Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 2016. doi: 10.1007/s11154-016-9400-1.
- 16.Stratakis CA. Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. Rev Endocr Metab Disord. 2016. doi: 10.1007/s11154-016-9401-0.