Mrs Jones, who is 60 years old, says that HRT keeps her looking youthful and wants to stay on it. What does the evidence suggest?

 

The menopause represents a natural process that occurs once a woman has experienced 12 months of amenorrhoea and, on average, occurs at 51 years of age. It is associated with many symptoms, including vasomotor problems (i.e., hot flushes and night sweats which affect around 75% of women),1 vaginal dryness, as well as an impairment of sexual function. While predominately used to provide relief from menopausal symptoms, the evidence suggests that hormone replacement therapy (HRT) can also preserve bone density (preventing osteoporosis) and may offer benefits for colorectal cancer, depression and cognitive decline.2

The loss of oestrogens during the menopause leads to accelerated aged-related changes in the skin. The thickness of both the epidermis and dermis is reduced, collagen and elastin levels decrease, and the cumulative impact of these changes lead to dryness and pruritus, wrinkles and fragility, which increases the risk of skin trauma. Given that these changes are due to the menopause, how effective is HRT at reversing these structural changes and thus improving skin health?

Oestrogens and the skin

The skin consists of two layers, an upper epidermis and lower dermis, which is mainly composed of two fibrous proteins, elastin and collagen. The latter accounts for approximately 80% of the dry weight of skin3 and provides tensile strength to the dermis (i.e., resistance to being torn by stretching). There are at least 20 different types of collagen and the three most common are types I,II and III.  Although the skin contains as many as 14 different collagens, the most common are type I (80%) and type III (15%).3 In contrast, although elastin makes up only 2 to 4% of the dermis volume, it has a central role in providing resilience and suppleness,4 restoring the skin to its initial shape after stretching. The skin also contains various glycosaminoglycans (GAG), such as hyaluronic acid, which is a humectant, i.e. a compound able to bind water, which helps to maintain hydration.

The fact that oestrogens have an influence on the skin is recognised through its effect on various cutaneous diseases. For instance, the increased levels encountered during pregnancy are associated with a reduction in the severity of psoriasis,5 but can worsen atopic eczema.6 Furthermore, oestrogens in the combined oral contraceptive pill, suppresses androgen production, leading to improvements in acne7 and the hyperpigmentation disorder melasma can be induced during pregnancy and through the use of oestrogen containing contraceptives.

The importance of oestrogens in the maintenance of healthy skin during the menopause was first suspected in 1941, when it was observed that elderly women who had experienced an osteoporotic fracture had thin skin.8 Later work in 1985 revealed how up to 30% of dermal collagen was lost in the first 5 years after the menopause9 and that levels subsequently reduce at a rate of 2% per menopausal year.10 Although levels of collagen naturally reduce with age, there is a suggestion that in women, this decrease is related to the lack of oestrogen rather than chronological aging.11 Moreover, skin elasticity has been estimated to decrease in postmenopausal women at a rate of approximately 0.55% per year.12

During the 1990s, the discovery of oestrogenic receptors on dermal fibroblasts (which are responsible for the production of collagen) and keratinocytes provided a mechanism through which the hormone could exert an effect on the skin. Oestrogen stimulates keratinocyte proliferation, which leads to a thickening of the epidermis and therefore reduced water loss.

The influence of HRT on skin changes in postmenopausal women

The importance of oestrogens in maintenance of skin health offers the possibility that HRT could reduce the menopausal signs of atrophy (thinning), dry skin and wrinkles. Moreover, one observational study in more than 3,000 women found that compared to non-users, HRT use was associated with a statistically significant reduction in dry skin and wrinkling but not atrophy.13  

HRT appears to boast dermal collagen levels and thereby improves skin health. This has been the subject of several trials,14 in which all but one demonstrated an improvement in collagen levels. It has been suggested that HRT was ineffective in one trial because the women had been amenorrhoeic for a short period of time (between 4 months and 2 years) and that any hypoestrogenic effects would have been small during this initial period of time.15 The longest study of topical HRT continued for 4.8 years and used 0.06% estradiol gel or transdermal patches to maintain a daily estradiol dose of 1.5mg. The trial observed increases of skin thickness of between 7% and 15% in several areas of the body.16 In contrast, a randomised, double-blind trial with oral conjugated oestrogen therapy, detected a 30% increase in dermal thickness after only 12 months.17

 

Whether or not the use of HRT can improve the appearance of wrinkles on sun-exposed areas of the body is equivocal

 

An increase in skin hydration has been demonstrated after 6 months use of topical 0.01% estradiol and 0.3% estriol for six months.18 Although the mechanism through which oestrogens increase skin hydration is unclear, studies in mice indicate that estradiol increases the level of hyaluronic acid and thereby the water content of the skin.19

Reducing wrinkles

Collagen is broken down in the skin by a group of enzymes termed metalloproteinases, which have an important role in tissue repair and remodelling. A reduction in the amount and integrity of collagen within the dermis leads to progressive slackness of the skin, a loss of elasticity and subsequent wrinkle formation. This process is exacerbated on sun-exposed areas of skin such as the face, which is subject to photo-aging.

Whether or not the use of HRT can improve the appearance of wrinkles on sun-exposed areas of the body is equivocal. One study found that HRT was able to reduce skin slackness20 (and potentially wrinkle appearance, but this was not assessed). Another study using Premarin cream (0.625mg conjugated oestrogens) in women aged between 52 and 70 for 24 weeks did produce a significant improvement in fine wrinkles.21 A third study in women using HRT for at least 5 years also produced improvements in skin elasticity with less pronounced wrinkling.22 In contrast, however, other trials have failed to demonstrate any benefits. In the largest of these studies, Phillips et al23 enrolled 485 patients using oral HRT for 48 weeks and found no difference in facial wrinkling. Similarly, Yoon et al,24 using topical oestrone 1% or placebo on sun-exposed skin for 24 weeks, found no difference compared to placebo. In a third study, application of topical estradiol 0.05% cream to photo-exposed skin (face) for 30 days did not observe changes in the expression of metalloproteinase-1 enzyme (which degrades collagen).25

More recent studies have demonstrated that alternatives to HRT, such as selective oestrogen receptor modulators (SERMS) (for example raloxifene), are able to increase collagen synthesis26 in dermal fibroblasts and increase skin elasticity.27

In summary, there is no doubt that oestrogens exert several beneficial effects on the skin. The reduction in oestrogen levels during the menopause has a detrimental impact on the skin, which can be corrected to some degree through the use of HRT. Whether HRT can improve the appearance of wrinkles, especially on sun-exposed areas such as the face, appears to be less likely.

HRT is not licensed for the management of cutaneous symptoms and women should therefore not make the decision to use HRT solely for the improvement of skin problems induced by the menopause.

 

References  

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  2. Minelli C et al. BMJ 2004; 328: 371
  3. Phuoung, C et al in Farage MA et al (eds). Textbook of Aging Skin. Berlin Heidelberg: Springer-Verlag (2017): 764-772
  4. Waller JM et al. Skin Res Technol 2006; 12(3): 145-54
  5. Danesh M et al. Int J Women’s Dermatol 2015; 1(2): 104-107
  6. Danesh M et al. Obstet Gynecol Int J 2015; 2(3): 2-4
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  15. Archer DF. Gynecol Endocrinol 2012; 28(Suppl 2): 2- 6
  16. Callens A et al. Dermatology 1996; 193(4): 289-94
  17. Maheux R et al. Am J Obstet Gynecol 1994; 170(2): 642-49
  18. Schmidt JB et al. In J Dermatol 1996; 35(9): 669-74
  19. Sobel H et al. Steroids 1970; 30: 458-64
  20. Pierard GE et al. J Am Geriatr Soc 1995; 43(6): 662-65
  21. Creidi P et al. Maturitas 1994; 19(3): 211-23
  22. Wolf EF et al. Fertil Steril 2005; 84: 285-288
  23. Phillips TJ et al. J Am Acad Dermatol 2008; 59: 397-404
  24. Yoon et al. Acta Derm Venereol 2014; 94: 4-8
  25. Neder L. An Bras Dermatol 2012; 87(1): 70-75
  26. Surazynski A et al. Int J Mol Mol 2003; 12(5): 803-39
  27. Sumino H et al. Maturitas 2009; 62(1): 53-57.

Rod Tucker

Pharmacist with a special interest in dermatology