The steroid hormone oestrogen plays a pivotal role in the normal development, physiology and reproductive processes in vertebrates (Harris, 2006). Oestrogen deprivation is a major factor accountable for many age-related events, including poor wound healing in postmenopausal women (Hall and Philips, 2005). Many of these processes are modulated by the activity of two intracellular oestrogen receptors (ER); ERα and ERβ (Pearce and Jordan, Petterson et al., 2000). They both bind to 17β-oestradiol (17β-(E2) to regulate gene transcription factors with similar affinity (Thornton, 2005). This primarily leads to the activation of transcriptional genes via recruitment of co-activators and co-repressor proteins resulting in changes in ER conformation (Gruber et al., 2004). However recent evidence has suggested that oestrogen can also elicit non-transcriptional activity via membrane coupled ERs (Revelli, A., 1998). Specifically this type of signaling via ERs through the non-genomic pathways can occur in both reproductive and non-reproductive tissues (Morley, P., et al., 1992).
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Cutaneous wound healing is an event that employs various sequential, over lapping stages (Schmidt, et al., 1994). The classical model of wound healing occurs in multisteps; tissues undergo complex and important events that are required for the prompt closure of the wound prior to re-establishment of the skin barrier (Hackam, et al., 2002). The initial healing stage of this process involves blood clot formation (haemostasis) and inflammation. The inflammatory response mediates the proliferatory and migratory responses of dermal and epidermal cells to re-establish the skin barrier (re-epithelialisation) and close the wound (Hackam, et al., 2002). The final step involves skin tissue recovery and restoration of skin aesthetics through tissue remodeling and differentiation (Hackam, et al., 2002).
Aging and Hormone Replacement Therapy (HRT)
Aging is associated with impaired acute and chronic wound healing, although administration of oestradoil and dehydroepiandrosterone (DHEA) can reverse this age-related chronic wound healing impairment (Ashcroft. et al., 2002). Additionally with aging the permanent cessation of menstruation occur due to loss of ovarian function, defined as menopause (World Health Organization (WHO), 1981).
The effects of oestrogen on skin are further understood from comparative studies between administration of HRT in post-menopausal women and those without HRT.
After menopause most women experience common symptoms of dry, flaky skin and easy bruising. Within six months of administration of oestrogen through short-term HRT has shown to reverse and improve these symptoms (Brincat and Studd, 1988).
Numerous in vitro studies were attempted for topical administration of oestrogen on the skin. A recent study has confirmed an increase in epidermal thickness post-topical treatment (Son et al 2005; Patriarca, et al, 2007). Other oestrogenic effects include improved skin hydration from systemically (Pierard-Franchimont., et al 1995) or topically administered oestrogen (Sator, et al 2001). Furthermore mid-term usually 12-months oral HRT has shown increased dermal thickness in post-menopausal women (Maheux et.; 1994). Additional skin wrinkling in relation with aging is affected from the contributing influences by environmental and/or hormonal factors. Decreased oestrogen production in post-menopausal women plays a role in wrinkle formation, however following topical short-term oestrogen replacement therapy (ERT); reduced wrinkles in these women have been seen (Dunn et al., 1997). Furthermore in vivo studies in wound healing has shown worsened healing in overiectomized rats, but improved healing rate following oestrogen treatment (Ashcroft et al. 1997, 1999).
In post-menopausal women, HRT is without risk-free and the significant beneficial effects according to recent studies of mid-term HRT have proved delayed skin aging (Brincat 2000; Sator et al, 2004), protection from the development of osteoporosis, heart disease and other age related illnesses (Bushnell and Chlebowski et al., 2005). As a result the potential risks and benefits associated with long-term HRT were studied by the Women's Health Initiative (WHI) in 1993. This study was conclusive and provided evidence of insufficient protective benefits against increasing risk for breast and ovarian cancers among those administered ERT (Brownley and Cauley et al., 2003). Other studies in post-menopausal women have shown that chronic wounds can be prevented via HRT (Margolis and Berard, et al., 2001). HRT is prescribed to supplement the decreased levels of hormones to post-menopausal women.
Oestrogen receptors α and β functional domains in the non-genomic pathway
Two distinct intracellular oestrogen receptors, ER-β, discovered in 1996 (Kuiper, et al., 1996) and ERα have been identified. Both are members of the steroid hormone nuclear super family (Evans, 1988). ERβ is expressed in a series of tissues including normal and malignant tissues, of which some are seen to also express ERα (Koehler, et al. 2005). ERβ is an essential hormone receptor with many functions; including anti-proliferative action, regulation of apoptosis and the modulation of immune responses (Evans, 1988). Moreover the ERα functions as a transcription factor which binds to oestrogen response element (ERE) to regulate and enhance gene expression (Hayashi et a., 1997). The over-expression of ERα is seen in the progression of breast cancer. Both these nuclear receptors are encoded by two different genes (Nilsson et al., 2001) within the nucleus and/or cytoplasm and expressed in various cells of the human skin. ERα is encoded by the human oestrogen receptor (ESR1); and ERβ in the ESR2 (Greene, et al., 1986). The compounds selectively specific to these agonists vary, propyl-pyrazole-triol (PPT specific ERα) and diarylpropionitrile (DPN, selective ERβ modulator). Although different tissues have ERs, the subtypes of ERs varies; with some tissues having predominantly ERα generally restricted to fibroblasts while ERβ is expressed in fibroblasts and keratinocytes entirely across the epidermis (Haczynski and Pelletier. et al., 2004). The skin fibroblast cells have both (Kawasaki, T., et al, 2008).
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Two 17β-(E2) mechanism exists; the classical (genomic) and the non-classical (non-genomic) signaling pathways (figure 1). In the genomic signaling pathway, the actions of oestrogens are mediated through the interaction and activation of specific ERs. In the absence of oestrogen, the ERs reside in the cytoplasm. The ER migrates from the cytoplasm and into the nucleus and precedes the dimerization of the receptor. Consequently the receptor-ligand complex binds to specific DNA sequences known as the hormone response element (HRE) located in the regulatory region of the target genes. The DNA-receptor-ligand complex recruits other cellular components responsible for transcription to either activate or suppress transcription of the target gene in a promoter and cell-specific manner (Speroff, et al., 2000)65. ER has the ability to associate with the cell surface membrane and is rapidly activated following oestrogen exposure to cells (Zivadinovic, et al., 2005)66. This signal transduction is mediated through the non-genomic oestrogen signaling pathway. The ER associate with the cell membrane and form complexes with the receptor tyrosine kinases (RTKs). Through the RTKs the signals are sent into the cell nucleus. 17β-(E2) responses include rapid activation of a series of major signaling pathways; such as phospholipase C/ protein kinase C, p38, MAPK and, JAK STAT (Acconcia and Kumar, 2005).
Oestrogen and Skin
The human skin is the largest mammalian organ and plays an important role in anatomical immunity. The skin consist of three major layers consisting of epidermis, dermis and subcutis (in order from external to internal) which acts as the physical barrier between the body and the environment against factors that may affect the physiological status (Haake, A., Holbrook, K. 1999).
A wide range of cutaneous cell types are involved in normal skin fibroblasts (Grohé C, Kahlert, Löbbert K, et al, 1997) and wound fibroblasts such as endothelial cells (Linder V, Kim SK, Karas RH, et al, 1998), keratinocytes (Thornton MJ, 2002) and inflammatory cells, (Lambert, et al; 2005) express ER in young and aged of both sexes indicating potential oestrogen responsiveness and propose oestrogen signaling process play a vital role in wound healing. Conversely the expression of both ER-α and ER-β differ among cells and tissue types; although the mesenchymal cell, dermal fibroblast associated with wound healing can express both oestrogen agonists, ERα and ERβ (Stevenson S., et al.2008). Mesenchymal cells are responsible for tissue and organ development, wound healing and inflammation (Chang et al. 2002).
Oestrogen acts on multiple cell types in the skin to modulate all stages of the wound healing process. Studies have shown oestrogen to have several beneficial and protective roles in the skin (Thornton. MJ, 2002, 2005).
The aim of this study was to establish the direct effects of selective agonists of ERα and ERβ to mediate the migration of cultured adult human epidermal; keratinocytes, following mechanical wounding in vitro.
The re-epithelialisation by keratinocytes is the main objective of this study; during this phase in the wound healing by keratinocytes is achieved by the recruitment of cell migration and mitosis in the epidermal proximal to the central of the wound gap (Santoro and Gaudino., 2005).
Figure 1. Schematic illustration of the molecular mechanisms of oestrogen in the genomic and non-genomic pathways in hormone target cells adapted from Lorenzo J. Clin Invest. The classical genomic pathways (1 and 2) depend on direct binding of oestrogen-receptor complex in the nucleus which activates ERE. Activated ERE mediates gene transcription (1) or interact with other transcription factors (2) to influence cellular activity. The more rapid non-classical pathways (3 and 4) rely on the ability of oestrogen binding with cell surface either non-steroid hormone receptors (3) or steroid hormone receptors in the cell membrane (4). This leads to activation of kinases that eventually regulate transcription of specific genes.