The Endocrine Function of the Skin: An Analytical Narrative

Abstract

Background:

Historically regarded as a protective barrier organ, the skin is now recognized as an active endocrine organ capable of synthesizing, and secreting diverse hormones and signaling molecules. This review intends to investigate the endocrine function of the epidermis, focusing on its role in hormone synthesis, metabolism, and signaling pathways.

Objective:

This article aims to provide a comprehensive overview of the endocrine function of the skin, including the identification of key hormones generated in the skin, their regulation, and their physiological significance. In addition, it intends to investigate the relationship between the epidermis and the endocrine system to elucidate the mechanisms underlying hormonal communication within the body.

Methodology:

Using electronic databases, including PubMed, Scopus, and Web of Science, a comprehensive search of the literature was conducted. Included are relevant studies, evaluations, and articles published between 1990 and 2023. The search strategy centered on the epidermis, endocrine function, hormones, and signaling pathways-related keywords. The retrieved literature was evaluated, and significant findings were analyzed.

Results:

The epidermis produces and responds to numerous hormones, including corticosteroids, sex hormones, thyroid hormones, Vitamin D, and growth factors, according to the findings. These hormones influence processes, including hair growth, wound healing, immune response, inflammation, and cell proliferation. In addition, the epidermis functions as a target for circulating hormones, participating in feedback loops, and regulating endocrine homeostasis.

Conclusion:

The skin’s endocrine function extends beyond its barrier function to play a significant role in hormonal regulation and communication. Enlightening the precise mechanisms and clinical implications of the endocrine function of the epidermis is necessary for the development of novel therapeutic approaches and interventions.

INTRODUCTION

The earlier concept of the endocrine system as a collection of various hormone-producing organs has been replaced by the notion that the endocrine system is an organized community of cells that discharge, receive, and coordinate molecular signals to and from distant sources, such as established endocrine organs, their neighbors, and themselves. The skin as an endocrine organ is gradually becoming highlighted in medical science. The skin is known to express and role certain hormone receptors, produce hormones from important groups of chemicals used by the body generally, remove hormones in specialized skin cells, and exert biological activity. The human skin and its appendages are increasingly acknowledged as endocrine organs in and of themselves, in addition to acting as a significant target tissue for hormones in the body. The skin plays a significant role in the endocrine system in addition to its many other functions in the body. Research on several of its endocrine activities is still ongoing, but other well-known aspects include Vitamin D production and the effects of retinoids on skin sebocytes and keratinocytes. A number of peptides, neurotransmitters, and hormones involved in the hair cycle are both targets and sources of the small organs known as hair follicles on the scalp. Sebocytes, adipocytes, and keratinocytes of the skin are now known to be sources of neurotransmitters, peptide hormones, and steroids. Recent years have seen a rapid accumulation of new knowledge in the following areas: the appearance and function of particular hormone receptors; the synthesis of hormones from main classes of compounds used by the body for general purposes; organized metabolism; the inactivation, activation, and elimination of hormones in specialized skin cells; and action of biological activity and release of tissue hormones into the circulation.^[1,2]

HORMONE SYNTHESIS IN HUMAN SKIN

Human skin released hormones that are secreted into circulation and vital to the body’s general health and functionality. The biochemical machinery needed to produce glucocorticoids, androgens, and estrogens from body-derived precursors or alternatively, from the conversion of cholesterol to pregnenolone, which is then converted to biologically active steroids, is already present in skin cells, according to recent research. Significant amounts of estrogens and androgens in both women and men are created from the dormant adrenal precursors dehydroepiandrosterone (DHEA) and androstenedione in peripheral target tissues, with sex steroids being one of the most notable instances. Locally generated cytokines, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone may control their local production. Androgens, estrogens, and glucocorticoids generated locally affect immunological activity, as well as the functions of the epidermis and adnexal tissues. Autoimmune illnesses or inflammatory disorders may develop as a result of any type of dysfunction of these steroidogenic actions. The steroidogenic activity of the skin can also have important systemic consequences, which are emphasized by the fact that it distresses blood levels of androgens and/or estrogens. In addition, the localized CYP11A1 activity may lead to the synthesis of new 7-steroids and secosteroids with biological activity. Hence, local steroidogenic activity may be modulated as a possible therapeutic method for the usage of inflammatory diseases, autoimmune disorders, or other skin problems.^[3,4]

Several articles claim that the skin serves as an extrapineal site for melatonin production. Many articles and manuscripts that have been previously evaluated begin with the false claim that “melatonin is largely generated in the pineal gland.” Meanwhile, according to some experts, melatonin is also produced in extrapineal regions. However, this production of melatonin is often greatly overestimated.^[5]

CUTANEOUS PRODUCTION OF VITAMIN D3

Uncommonly, Vitamin D is essential for bone health and maintenance throughout our lifetimes as well as for the growth and mineralization of a child’s skeleton. Surprisingly, the majority of our Vitamin D originates from incidental sun contact of human skin, even in nations (like the US) where some foods, like milk, are fortified with Vitamin D. 7-dehydrocholesterol (provitamin D), which is found in the cytoplasm of cells, is attacked by solar radiation with wavelengths ranging from 290 to 315 nm when exposed to sunlight. Previtamin D1 is created when provitamin D undergoes isomerization, which breaks the bond between carbons 9 and 10. This process involves the absorption of energy. A thermally dependent process called internal isomerization is used to convert the thermally unstable molecule previtamin D into Vitamin D. The dermis stores the remaining 50% of the total cutaneous Vitamin D storage, with the epidermis storing around 50% of it. However, the viable layers of the epidermis contain more than 80% of the previtamin D that is created in both children’s and adults’ skin. This is because only a limited number of high-energy photons are transmitted to the dermis to promote the conversion of provitamin D3 to previtamin D, whereas the majority of photons that photolyze provitamin D are absorbed in the epidermis. Vitamin D is produced in epidermal cells and then exits these cells by an unidentified pathway and enters the dermal capillaries. A particular serum-binding protein may facilitate this migration (Vitamin D-binding protein). In addition, levels of circulating insulin-like growth factor (IGF)-binding protein-3 are evidently increased by both growth hormone (GH) and IGF-1. IGF-binding protein-3 also originates in greater abundance in the skin than in the liver. Protein that binds to IGF Skin RNA levels is affected by both GH and IGF-I, proposing that dermal fibroblasts may govern IGF-binding protein-3 production more proficiently than the liver.^[6,7]

ACTIVATION AND INACTIVATION OF HORMONES IN HUMAN SKIN

Even though it is generally accepted that hormones are essential for the development of human skin tissues and their ability to produce and release more hormones. Similar to how it catalyzes the inactivation of T4 and T3 through inner-ring deiodination to rT3 and 3,3′-diiodothyronine (3,3′-T2, respectively), skin likewise metabolizes hormones to activate or deactivate them.

5-reductase type 1 is extensively stated in nearly all skin cells, but especially in sebocytes, where it catalyzes the further activation and conversion of testosterone into 5-DHT. While androgen inactivation to androsterone or 3-androstanediol occurs in epidermal keratinocytes that strongly express the necessary enzyme 3-hydroxysteroid dehydrogenase, androgen conversion to estrogens occurs in dermal fibroblasts that express the necessary enzyme cytochrome P450 19 (aromatase) in the skin.^[4]

HORMONE RECEPTORS IN HUMAN SKIN

Immune cells found in circulation and the skin also express neurotransmitter and neuropeptide receptors that are equal to those found in the central nervous system. The skin is objective for neurotransmitters hormones, and neurohormones, according to clinical observations in a variety of endocrine illnesses with cutaneous symptoms. Table 1 enlists selected hormone and neurotransmitter receptors expressed in keratinocytes and melanocytes.^[8]

Table 1

Selected hormone and neurotransmitter receptors expressed in keratinocytes and melanocytes

Sex steroid hormone receptors

Sex steroid hormones play a role in various pathological skin occurrences as well as the regulation of skin development and functioning. According to various researches, the majority of the keratinocytes in the epidermis express androgen receptors (AR). AR was found in roughly 10% of fibroblasts in the dermis. Both basal cells and sebocytes were shown to express AR in sebaceous glands. AR expression in hair follicles was restricted to dermal papillar cells. Only a small number of secretory cells were found to express AR in eccrine sweat glands. Sebocytes were the only cells that had low levels of estrogen receptor alpha expression.^[9,10]

Calcitonin gene-related peptide receptors and proteinase

Activated receptors–are present on sebocytes and Langerhans cells.^[11]

Substance P

Substance P (SP) in particular and neuropeptides, in general, may play a contribution in the genesis of cutaneous allergic inflammation. SP, IFN-gamma, and Spantide I can affect the expression of NK-1R in HaCaT cells and fibroblasts at the protein and transcriptional levels. This shows that NK-1R may be important in the development of cutaneous allergic inflammation (CAI) and that fibroblasts and keratinocytes are involved in regulating skin immunity.^[12]

Dopamine receptors

Particularly in the dermis layer of human plantar skin, dopamine receptors D1 are found. With the exception of the corneal layer, they are abundant in the lower epidermal layers and scarce in the subcutaneous tissue. On the other hand, the subcutaneous tissue close to the veins has a high density of D2 dopamine receptors.^[13]

Glucocorticoid receptor

Immunoreactive glucocorticoid receptor (GR) were substantially communicated in basal Langerhans cells, keratinocytes, and various cell lines of normal cultured human keratinocytes, whereas they are less expressed in melanocytes. The basal and Langerhans cells of the epidermis seem to be the primary targets of glucocorticoids. The glucocorticoid (GC) GR plays a significant role in the pathophysiology of the skin by mediating the actions of GC ligands that are physiological and pharmacological. In the epidermis, basal keratinocytes – which are important for both inflammatory and regenerative processes – may be the principal target cells for glucocorticoids. Increased GR expression in these proliferative cells may be related to higher control of transcription of genes involved in cell proliferation, improved regulation of the release of immune mediators such as interleukins, and other as-yet-uncharacterized actions. The strong GR staining in langerhans cells (LC) shows these cells may primary target of glucocorticoids, which might affect how well they function as antigen-presenting cells. Glucocorticoids impede early keratinocyte development while encouraging terminal epidermal variations. It also restricts keratinocyte proliferation and leads to skin atrophy. They inhibit keratinocyte migration, delaying the healing of wounds. They hasten the synthesis of lipids, hasten skin aging, and promote the development of hair follicles. As demonstrated in acne lesions, human sebocytes have GR and are increased by glucocorticoid action. The hypothalamo–pituitary–adrenal axis is a tiny version of the hair follicles, which respond to steroids.^[14,15]

Thyroid hormone receptors (TRa and TRb)

Through binding to nuclear receptors, which are known to be expressed in the skin, thyroid hormones exert their effects. As heterodimers with RXRs, TRs interact with thyroid hormone-responsive elements. As a result of thyroid gland dysfunctions, changes in skin design and homeostasis have been noted. Thyroid hormones are known to influence skin formation and function. Thyroid hormones, in particular, have been shown to affect the formation of the barrier, sebum production, hair growth, healing of wounds, keratinocyte proliferation, epidermal oxygen consumption, and keratin gene expression. These results show that, among other types of skin cells, dermal fibroblasts, keratinocytes, and sebaceous gland cells express thyroid hormone receptors.^[16,17]

Retinoic acid receptors α, γ and retinoid X receptor α, β, γ

Retinoids, physiologically active Vitamin A derivatives, have an impact on important biological developments such as cell division, growth, and death as well as the creation, maintenance, and management of homeostasis. Retinoids play a crucial role in skin homeostasis, are frequently used in cosmetics, and are used to treat various skin problems.

RXR, RXR, RAR, and RAR are all expressed in the epidermis, with RXR and RAR being the two most prevalent receptors (Fisher and Voorhees, 1996). Uncertainty surrounds their precise function in regulating the effects of retinoids on the epidermis. RAR-alpha and RAR-gamma were both expressed by fibroblasts and keratinocytes: RAR-alpha was more common in fibroblasts, whereas RAR-gamma expression was similar in the two cell types. RAR-beta was undetectable in keratinocytes. RAR-beta transcripts were either undetectable or weakly expressed in the majority of fibroblast cell lines.^[18,19]

Vitamin D receptors

After being exposed to the UVB spectrum of sunlight, the 7-dehydrocholesterol that is present in the epidermis is transformed into Vitamin D. This method acts as the body’s primary source of Vitamin D because food goods, with the exception of some fatty fish such as salmon, give little Vitamin D unless and until supplemented. The keratinocyte, which makes up the majority of the epidermis, has both 1α hydroxylase (CYP27B1) and 25 hydroxylase (CYP27A1, CYP2R1) activity, which allows it to further convert Vitamin D into 1, 25 dihydroxyvitamin D (1,25(OH)2D), which is its active form. Because the keratinocytes contain Vitamin D receptor (VDR), they can respond to the 1,25(OH)2D produced. Stem cells are located in the basal layer of the stratified epidermis. The stratum corneum eventually forms the permeability barrier after a series of differentiation phases in which the bottom layer cells grow and leave. 1, 25(OH)2D/VDR assists in this process by regulating keratinocyte proliferation in the base layer (stratum basale) and promoting their gradual differentiation as they climb to generate the upper layers. Any irregularity, such as VDR and CYP27B1 mutations or deletions, as well as issues with permeability barrier formation and the innate immune response, causes basal layer cells to overproliferate.^[20,21]

CONCLUSION

The skin is the largest organ of the body, is multifaceted in its role. It is a site of action and production and modulation of different hormones. Considering the gravity of hormones in the human body homeostasis, it is important to understand the role of the skin as an endocrine gland.