Invited ReviewOestrogens and wound healing
Introduction
With the declining trends in birth rate and increases in longevity in the Western world, postmenopausal women are representing a greater percentage of the population. The life expectancy of women has steadily increased so that today most spend more than one-third of their life-time postmenopausally in a state of profound oestrogen deprivation [1], [2] and there are increasing medical concerns for their health. The menopause has come to signify much more than just the loss of reproductive capacity; the declining ovarian function and consequent oestrogen deficiency, rapid for some experiencing surgical removal of the ovaries, slower for others experiencing the natural menopause, is reflected physiologically in oestrogen-dependent tissues, provoking a variety of symptomatic consequences in 80% of women [3], [4].
During the past few decades several studies have documented the deleterious impact of the menopause on bone mass [5], [6] and cardiovascular disease, and the reduction of risk in these areas by hormone replacement therapy (HRT) [7]. This may be attributed to the fact that these degenerative disorders are responsible for many fatalities in people over 50 years of age [8]. However, the possible effects of the postmenopausal deficiency in ovarian hormones on skin are less well documented, despite skin being the largest organ of the body and the primary barrier against microbial invasion, dehydration, and mechanical, chemical, osmotic, thermal and photic damage.
After the menopause women start to complain of dry, flaky skin and easy bruising. These symptoms are often reversible with HRT, usually within the first 6 months of administration [9]. It is evident therefore that the sex hormones and in particular oestrogens play an important part in the maintenance of skin quality in women, and thus may also play a pivotal role in the healing of skin post-injury. This is of paramount clinical importance both in terms of financial cost and human suffering, since many of the chronic wounds such as venous ulcers, pressure sores [10] and burns [11] afflict the elderly population, of whom postmenopausal women comprise the majority.
Oestrogen receptors have been demonstrated in the nucleus and/or cytoplasm of various cells in human skin [12], [13], [14] and in cells such as macrophages [15], fibroblasts [16], and endothelial cells [17] all of which play vital roles in the healing process, suggesting a direct effect of oestrogens on both intact and wounded skin. However, there is a paucity of information regarding the effects of oestrogens on these targets. There have been a number of studies on epidermal [18] and dermal thickness [19], skin mitotic figures [20], elastic properties [21] and collagen content of skin [22]; however, collectively the results have been inconclusive. Furthermore, few and contradictory observations have been reported on the influence of oestrogens on wound healing in extragenital tissues.
The aim of this review is to provide a survey of the literature that is available regarding the physiological effect of oestrogens on the various phases of cutaneous repair described by Clark [23]: (1) inflammation; (2) new tissue formation (proliferation); and (3) matrix formation and remodelling, although many of the studies were performed in the 1960s and 1970s before much of our current knowledge on wound repair was acquired. Research carried out on the effects of oestrogens, both in terms of their deficiency and replacement, on the process of tissue repair in various animal models is described and discussed, together with the very limited work undertaken in humans.
Some of the earliest work was investigated in gingival tissue in the field of periodontology, prompted by the clinical symptoms of chronic gingival inflammation in pregnant women [24], [25]. The studies that followed examined, in laboratory animals, the influence of female sex hormones on healing using subcutaneous implantation of cellulose sponges, stainless steel and Teflon® cylinders, the production of sterile abscesses etc in addition to cutaneous wounds.
In recent years there has been negligible work on the effects of oestrogens on the repair of wounded cutaneous tissue, emphasising the need for further experimentation in this area. However, some of the more up-to-date research on the influence of oestrogens on the individual cell types e.g. neutrophils, macrophages, fibroblasts, and components of the extracellular matrix e.g. collagen, elastin, glycosaminoglycans that play a fundamental role in the healing wound is included.
Section snippets
The effects of oestrogens on the inflammatory phase of wound repair
The inflammatory phase of repair is marked by platelet accumulation, coagulation, an increased permeability of the vessels adjacent to the wound and leucocyte migration into the wound bed [26]. Studies investigating the effects of oestrogens on these processes are addressed.
One of the earliest experiments [27] examined the influence of excessive amounts of oestradiol dipropionate on the tissue in the walls of sterile turpentine abscesses produced subcutaneously in both male and female rats. A
The effects of oestrogens on the proliferative phase of wound repair
The proliferative phase of repair is characterised by (1) re-epithelialisation restoring the cutaneous barrier; (2) angiogenesis, the neovasculature supplying much of the nutrition required for healing; (3) fibroplasia, during which the matrix of the granulation tissue and scar tissue is formed; and (4) wound contraction, reducing wound size and thus the need for scar tissue [26]. Studies investigating the effects of oestrogens on these processes are addressed.
Taylor et al. [61] investigated
The effects of oestrogens on matrix formation and remodelling
The remodelling phase of tissue repair takes place over a period of months during which the skin responds to injury with a dynamic continuation of collagen synthesis and degradation, and the once highly vascular granulation tissue undergoes a process of devascularisation, as it matures into less vascular scar tissue [26]. Studies investigating the effects of oestrogens on this process, particularly on tensile strength of scar tissue, are addressed.
Taylor et al. [61] testing the tensile strength
Conclusions
In this review the literature that is available regarding the involvement and influence of oestrogens on the various phases of cutaneous repair, has been presented and discussed. The investigations described demonstrate contradictory findings as to the effects of ovarian hormone deficiency, replacement, or excess on the process of wound healing, making it difficult to draw valid conclusions from the studies. The discrepancies in the observed results may be explained by the usage of: (1)
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