Estrogen and Its Role in Skin Care

Researchers conducted an overview on estrogen levels after menopause in female patients and noted the changes in skin they may experience such as atrophy, wrinkles, hydration, poor wound healing/barrier function, decline in perceived facial attractiveness, and even psychological health. ¹

There was 20 years’ worth of data gathered from August 2000 to August 2020 using the Web of Science (currently maintained by Clarivate Analytics covering over 12,000 journals and 160,000 conference proceedings) and PubMed maintained by the US National Library of Medicine at the National Institutes of Health (USA).

Though local hormone treatment is effective in anti-aging the skin, according to the authors, the long-term effects are uncertain, so there are new treatments that can trigger selective estrogen receptor modulators (SERMs). Two high profile cosmeceuticals that are closely examined in the article are an analog of resveratrol [4′-acetoxy resveratrol (4AR)] and the isoflavonoid compound equol.

Ovarian follicles start to produce estrogen at puberty and peak in the late 20s, while skin collagen and elastin peak around 30 years old. 

“In this regard, several reports suggest positive correlations between circulating estrogen levels and: (a) perceived age, (b) attractiveness, (c) enhanced skin health, and (d) facial coloration in women,” the study authors wrote.

After 30, the signs of aging starts to show along with estrogen decline resulting in skin thinning, dryness, wrinkles, uneven pigment, and slow wound healing.

Once menopause begins between the ages of 45-55 years because of the failure of ovarian follicles to produce sufficient estrogen to stimulate the growth of the endometrium, skin atrophy starts and it is most noticeable in the face, neck and forearms/hands. The skin is also fragile to abrasion.

The classical estrogen receptors (ER), ERα, and ERβ, are members of the superfamily of nuclear hormone receptors according to the authors. ERα activation is a major factor in reproductive cancers. In contrast, ERβ activation appears to be chemoprotective and ERβ activation has been shown to promote wound healing, independent of estrogen’s anti-inflammatory properties. This may be why the SERM’s aimed at ERs have proven to provide skin benefits. Many studies have shown the presence of mitochondrial ERs, which may mean that estrogen plays a role in regulating cellular bioenergetics. 

Menopausal hormone treatment (MHT) for women began in the 1940s and the major estrogen preparation used in the US remains an equine urinary extract of mixed human and equine hormonal compounds termed conjugated equine estrogen (CEE).

The literature on MHT and skin cancer found that race (likely expressed as pigmentation), exposure, smoking, and aging have more influence on the skin rather than MHT.1 There is only 1 prospective, randomized, controlled trial (NCT00144180) that compared the effects of oral or transdermal MHT compared to placebo and in this 5-year, multicenter, double-blind, randomized placebo-controlled trial researchers investigated the effect of CEE + progesterone, or 17B estradiol + progesterone vs control in female patients who were within 3 years of beginning menopause. 

It was found that the strongest predictor of advancement of skin age was race with Black patients having the lowest wrinkle scores vs White patients. MHT did not appear to affect skin wrinkles or rigidity in most areas of the face. These studies contrast earlier trials, but the authors state that may be because of the lack of placebo control in those studies.

Estrogen treatment that is started in female patients who are healthy and 6 to 10 years past menopause does not have excessive cardiovascular complications, according to authors.

“In 2002, the NIH stopped the estrogen-containing arms of a large, randomized trial of menopausal treatments,” wrote the authors. “The misapprehension was due to the inclusion in the Women’s Health Initiative (WHI) of [less than] 10-year postmenopausal women with age-related risk factors for cardiovascular complications. This resulted in an excess of venous thromboembolism among subjects older than 59 years at the time of commencement of the trial with MHT.”

Currently, it is safe to consider estrogen alone treatment (ET) to be comparable to MHT as regards dermal health.¹

The main adverse event (AE) to keep in mind while using a CEE cream is intravascular thrombosis and its related issues for patients 10 or years after menopause. The authors state that those patients should not be exposed to estrogen without physician supervision. There is also the chance of overdose, but this issue has yet to be studied. 

Bioidentical hormone therapy has recently been examined and found to be effective and safe in postmenopausal female patients for dermal care, particularly anti-aging.² 

Cosmeceuticals, which are considered as cosmetics by the FDA, use plants in many of their formulas as they are rich in antioxidants and meet the FDA’s criteria of substances that can be put into topical and over-the-counter formulations. It is important the match the patient and their skin needs with the right active ingredients. 

This is notable as the phytochemicals from these plants have been investigated for there ERβ-agonist properties. While gels, creams, and lotions studying phytoestrogens and isoflavones or genistein alone for skin improvements and in these studies no AEs were found in the formulations using the phytochemical active ingredients. The Nrf2 activation from grapes which leads to the NF-kB signaling have been found to be a key factor in skin aging. 

Resveratrol analogs were studied to determine the human skin benefits and the most potent was 4′-acetoxy resveratrol (4AR). The analysis results showed that 4AR showed greater efficacy compared with all-trans resveratrol. Another study, that was single center, examined 36 female patients for 12 weeks, looking at 8 categories: firmness, smoothness, tone, frown lines/wrinkles, brightness, pore sizes, spots, and hydration. The patients reported improvements by week 12. 

Equol, an isoflavonoid compound, has been found to have efficacy was greater than astaxanthin for antioxidants, extracellular matrix integrity and breakdown, growth factors and inflammatory biomarkers, including the significant stimulation of the anti-aging factor. It has also been suggested to have been effective in treating estrogen-deficient skin.

Overall, when comparing the clinical trials of 4AR and equol it was found that:

• The percent improvement in the eight skin areas for both treatments were similar.¹
• The slightly higher percentages for some of the skin parameters for the 4AR vs the equol technology may be due to the difference in the number of postmenopausal women, where the equol study had 20% more female subjects that were amenorrheic for at least 3 years compared with the 4AR subjects.¹
• The concentration of the 4AR treatment was more than 3 times that of the equol treatment at 1.0% versus 0.3%, respectively.¹

The authors concluded with the development of these 4AR and equol compounds may result in a new direction for the skin care field. 

Disclosures

Edwin D. Lephart has no funding or sponsor conflicts of interest in the decision of the data/research presented in this report and regarding the publication of this manuscript. Edwin D. Lephart is an inventor on equol patents (US and worldwide) on various human health applications. Frederick Naftolin has nothing to disclose.

Reference:

1. Lephart ED, Naftolin F. Menopause and the skin: old favorites and new innovations in cosmeceuticals for estrogen-deficient skin. Dermatol Ther (Heidelb). 2020;11(1):53-69. doi:10.1007/s13555-020-00468-7

2. Rosenthal A, Jacoby T, Israilevich R, Moy R. The role of bioidentical hormone replacement therapy in anti-aging medicine: a review of the literature. International Journal of Dermatology. 2020;59(1):23-29. doi:10.1111/ijd.14684