Downgrading skin climacteric aging by hormone replacement therapy

For years, hormone replacement therapy (HRT) for menopausal women appeared straightforward for the believers. It markedly improved climacteric changes in many organs, including the skin. However, emerging information suggested that combined HRT increased the risks of cardiovascular diseases and invasive breast cancer [1,2]. Many healthcare providers and women were soon impressed by the alarmist lay press regarding the use of these hormones. These pessimistic views were more recently challenged. Indeed, it was demonstrated that the administration of estrogens alone in hysterectomized women did not significantly increase the incidence of coronaropathies and breast cancer [3]. The bulk of recent studies also confirmed that estrogens or estroprogestins effectively suppress the climacteric syndrome and genital atrophy, while significantly decreasing the risk of osteoporotic fractures. The cardiovascular risk appears more prominent in late menopausal HRT users than in early menopause, and the risk of venous thromboembolism can be reduced strongly by using transdermal instead of oral estrogens [4]. Regarding the risk of breast cancer, the additional absolute risk of postmenopausal women using estroprogestins is only 0.08 per 100 women per year, whereas estrogens alone do not increase the risk [3,5].

Skin climacteric aging

In westernized societies, a woman’s appearance is largely appreciated through her skin presentation reflecting, in part, her general health. Skin is a complex organ, corresponding to the birthday suit. The more it is cared for, the longer it remains attractive. Menopause appears as a turning point in life spotting a decline in skin qualities. Any part of the skin can be altered, including the epidermis, dermis and hair. As such, a prominent role in the psychosexual dimension of the climacteric is ascribed to the skin.

Some skin changes of climacteric aging can be detected as early as in the early postmenopausal years, when HRT might be of benefit to control them. Cutaneous changes observed in the decade following menopause are both age and hormone related [6,7]. Postmenopausal women usually complain of generalized dry, easily bruised and wrinkled skin. Dermal thickness decreases with time after the menopause. However, it is difficult to differentiate the consequences of menopause from age-associated changes related to a decline in growth hormone.

Estrogens and other sex steroids exert profound influences on both skin biology and composition, thus, it is believed that adequate hormone levels are required to control its structural integrity and functional capacity. Skin contains receptors to estrogens and androgens. Aromatase activity has also been identified in fibroblasts, adipocytes and sebaceous cells in postmenopausal women. Thus, androgens can be converted in situ into estrogens. The relative estrogen reduction that accompanies the menopause contributes to, and exacerbates the negative effects of age. As a consequence, the role of HRT on skin is, not surprisingly, an important one that has deservedly attracted much interest [6–8].

HRT & the dermis

The extracellular matrix of the dermis tends to become thinner during menopausal transition and in the following years. Its collagen content is, in part, influenced by the sex hormone status and it appears to decline in relation to the time elapsed since menopause. The decline supervening immediately after the menopause apparently occurs at a much more rapid rate than in the later years.

Most of the studies on the effects of HRT on the dermis looked for changes in thickness, collagen content and mechanical properties. HRT modalities were clearly different among studies. Various estrogens were used, and progestins were given cyclically in some instances to prevent endometrial hyperplasia. The information has been discussed collectively without trying to distinguish the effects of estrogens from those of estrogens and progestin in combination [7].

Globally, skin collagen content and the dermal thickness appear to increase in those receiving HRT compared with age-matched untreated women [9]. In women with a low skin collagen content, estrogens are believed to be initially of therapeutic, and later of prophylactic value, while in those with a mild reduction of collagen content in the early menopausal years estrogens are of prophylactic value only [8]. Thus, a decrease in skin collagen can be, in part, corrected but not overcorrected. The replenishment in skin collagen content may show regional variability with a more pronounced effect on the abdomen than the thigh [8]. However, it should be stressed that there is no consensus regarding the effect of estrogen replacement therapy on the dermis. Some reports even deny any benefit on this aspect of aging [10].

The normal water content in the dermis is bound to the hydrophilic glycosaminoglycans. This characteristic may protect the skin against excessive tissue compression while maintaining its suppleness. Estrogens increase dermal hydroscopic properties, probably through enhanced synthesis of dermal hyaluronic acid [8].

There is ample evidence that a decline in the mechanical properties of the skin occurs with progressive aging [11]. Some wrinkles are the result of these functional changes [7]. The climacteric period appears to be among the most affected period in life affected by evolving wrinkles, particularly on the forearms and the face. Several controlled trials have shown the benefit of HRT for mitigating these changes [12,13].

The quantitative changes and the decrease in the size and compactness of the collagen bundles in the dermal extracellular matrix leads to skin slackness. The resulting aging aspect is characterized by a progressive increase in extensibility associated with a loss of elasticity [11]. Fine wrinkling, atrophy and a progressive deepening of facial creases ensue. These skin alterations have been reported to be reversed partially in postmenopausal women with estrogen or combined HRT [13]. A marked increase in skin extensibility occurs in untreated perimenopausal women, but is limited by HRT which, therefore, helps prevent skin slackness [13]. Smokers are prone to develop more severe wrinkling, which may respond to estrogen replacement therapy [12]. However, HRT may exert a beneficial effect on the facial skin by reducing the age-related rheological changes without limiting the number and depth of wrinkles [7]. The maximal effect at preventing skin aging appears to occur when HRT is initiated early.

Estrogens appear to promote vasodilation in the skin [8,14]. The beneficial effect of HRT on the skin’s blood flow has, however, been challenged. HRT users may have fewer chronic leg ulcers and pressure-induced ulcers and estrogen might increase the wound healing rate in the elderly [15]. These studies warrant confirmation before recommending HRT to improve wound healing.

The one area that has fulfilled the hope of the HRT research has been the changes that occur in the skin and bone. The changes occurring in the dermis and bone, both in the climacteric period and with HRT, apparently parallel each other [16,17]. There is also a correlation between some skin biomechanical properties and bone density [18,19]. It is probably the combination of skin thickness, dermal biomechanical properties and bone mineral density that presents the greater sensitivity and specificity in identifying women vulnerable to osteoporotic fractures following the menopause.

HRT & skin epithelia

Xerosis is an alteration of the stratum corneum known as dry skin to the laity. This condition results from an altered desquamation process that is often associated with decreased hydration of the upper layers of the stratum corneum and with weakening of the barrier function of the skin. Both the skin water-holding capacity and the barrier function of the stratum corneum appear to increase following HRT [20,21].

Hair loss, particularly frontal fibrosing alopecia has been associated with menopause, and it appears to persist despite HRT. Tibolone, which is an alternative to HRT, may increase the severity of diffuse alopecia and induce facial hypertrichosis [22]. Sebum excretion on facial skin shows large inter-individual differences. In untreated menopausal women sebum excretion may increase in the perimenopause and later declines with chronologic aging [23]. HRT-treated women show less prominent variations. However, the benefit differs among women and is very difficult to predict. Globally, HRT might increase the casual sebum level [23–25], but there is a lack of consensus regarding this aspect.

Conclusion

In summary, the administration of HRT appears both safe and effective, provided adequate patient selection is made, and contraindications and appropriate use of hormones (nature, dosages, regimens and routes of administration) are respected [8]. It remains that at the present time, the pros and cons of HRT make it a complex issue for the physicians taking care of skin changes [7,26].

It is acknowledged that skin suffers from some decline in its aspect and physical properties after the menopause. HRT appears to protect the skin, in part, from some of the negative changes. HRT acts on the skin at several different sites and thus exhibits a multifactorial effect. The effects can be mediated by a direct hormonal effect when the cells contain the adequate receptors. These stimulated cells can further produce some paracrine signals to other cells, which are thus indirectly influenced by HRT. It is the interplay between the various skin cell types and their signaling pathways that probably control the skin aspect and healthy appearance.

Findings, to date, indicate that chronological aging, the menopause, estrogen deficiency and HRT exert profound effects on various parts of the skin. In many cases the deleterious effects of low estrogenemia on the skin are reflected in the internal organs. HRT has been shown in many studies to either partially or completely reverse some of the skin changes. The skin represents the one target organ where HRT benefits are immediately visible to the woman and her relatives.

Financial disclosure

The authors have no relevant financial interests, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties related to this manuscript.