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Topical Estrogen
By Topical Estrogen
Mar 13, 2003, 10:00pm

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Any discussion of estrogen must begin with the controversial, highly publicized cessation of the estrogen/progestin arm of the Women's Health Initiative during the summer of 2002. Results from the halted phase of the National Heart, Lung, and Blood Institute–sponsored initiative linked the study medication with an elevated risk of breast cancer, thromboembolic disease, and cardiovascular disease.

Physicians should note that only this hormone replacement therapy (HRT) phase was halted; the estrogen replacement therapy (ERT) phase, showing dissimilar results thus far, continues. (HRT combines estrogen with progestin and is indicated for women who have undergone natural menopause; ERT is an estrogen-only regimen indicated for women whose menopause is surgically induced.)

The basis for topical estrogen study stems from the findings of a correlation between natural estrogen depletion and chronologic aging, especially aging of the skin.

Estrogen is a dynamic hormone that is matched with an equally impressive array of exogenous replacement products. The family of estrogen products includes estrogens in conjugated or esterified forms, ethinyl estradiols, estradiols, estradiol derivatives such as estradiol valerate and estradiol cypionate, estriols, and estrones.

Effect of estrogen on the skin: Histologic evidence of decreased skin thickness in postmenopausal women is well known. The epidermis is thinned, exhibiting a loss of rete ridges. ERT has been shown to reverses these alterations, buttressing the hypothesis that it is the lack of estrogen that causes them in the first place (Maturitas 35[2]:107-17, 2000). In a clinical trial, Dr. A. Callens evaluated 98 postmenopausal women, comparing the skin of patients on HRT with the skin of those not receiving hormone therapy. Patients on HRT exhibited greater skin thickness as assessed by B-mode ultrasound high-resolution echography (Dermatology 193[4]:289-94, 1996).

Current theory suggests that skin thickness alterations associated with aging are due to hormonal effects on collagen (Maturitas 15[2]:113-19, 1992), elastic fibers (Ann. Chir. Gynaecol. Suppl. 202:39-41, 1987), and dermal hyaluronic acid content (J. Invest. Dermatol. 87[5]:668-73, 1986). By elevating acid mucopolysaccharides and hyaluronic acid in the skin—and perhaps regulating the function of the stratum corneum—estrogen has been shown to maintain skin moisture (Am. J. Clin. Dermatol. 2[3]:143-50, 2001).

The decline in skin collagen that coincides with aging is known to occur at a greater rate during the first few years after menopause. One study found that within the first 5 years after the onset of menopause, roughly 30% of skin collagen is lost, with an average decline of 2.1% per postmenopausal year over a period of 20 years (Br. Med. J. [Clin. Res. Ed.] 287[6402]:1337-38, 1983). Patients in this study who were treated with ERT experienced an increase in skin collagen. In fact, women on HRT had a skin collagen content 48% higher than those not on HRT.

Estrogen levels may also be proved to alter glycosaminoglycans content in the skin.

Wrinkles, vascularization, and hair: Type 1 collagen content, glycosaminoglycans content, and skin thickness all play a role in wrinkle formation. It is not surprising then that women on HRT, which has been demonstrated to affect each of these factors, would exhibit reduced wrinkling.

A recent study showed that HRT in postmenopausal women limited the number and depth of wrinkles, measured by optical profilometry and computerized image analysis (J. Am. Geriatr. Soc. 45[2]:220-22, 1997). Research also shows that topical estradiol (17--estradiol and 17--estradiol) can promote the development of new connective repair areas in photodamaged skin as effectively as all-trans-retinoic acid (Arch. Dermatol. Res. 294[5]:231-36, 2002).

Research has identified both estrogen and androgen receptors on dermal fibroblasts and epidermal keratinocytes (J. Reprod. Med. 35[11]:1015-16, 1990). Distribution is inconsistent, with a preponderance of estrogen receptors located on skin overlying the female external genitalia, as well as the face, breast, and thigh. The areas of the epidermis found to be most sensitive to estrogen are concentrated in the granular layer, although estrogen-sensitive structures are also present throughout the epidermis, in hair follicles, and the sebaceous glands (Br. J. Dermatol. 117[2]:217-24, 1987).

Although the presence of estrogen receptors on the skin is well established, the mechanism by which estrogen affects the skin remains unknown. Further, some have speculated that the epidermis is not a target structure for estrogens under clinical conditions, despite the abundance of estrogen receptors found there (Maturitas 11[3]:229-34, 1989).

One potential benefit of estrogen therapy is increased vascularization of the skin or limiting the devascularization that occurs in normal aging. Women on HRT have been reported to exhibit a 20%-30% increase in nail capillary blood flow (Maturitas 22[1]:37-46, 1995), compared with those not on hormone replacement. Long-term estrogen therapy in postmenopausal women has yet to show changes in resting or maximal skin blood flow, however (J. Appl. Physiol. 85[2]:505-10, 1998).

Estrogen also has been shown to regulate the anagen-telogen cycle (Proc. Natl. Acad. Sci. USA 93[22]:12,525-30, 1996). The higher levels of estrogen during pregnancy cause the hair to grow by increasing the amount of hair in the anagen phase. The hair loss often seen in postmenopausal women is likely the result, at least partially, of the increased amount of hair in the telogen phase.

More research with topical estrogen: Research shows that topical estrogen acts like oral HRT in preserving skin thickness and increasing collagen and glycosaminoglycans content of the skin. Dr. J.B. Schmidt and colleagues examined the effects of topical 0.01% estradiol and 0.3% estriol, and after 6 months of treatment, the investigators found improvements in skin elasticity, firmness, and wrinkle depth similar to that seen in studies using oral or transdermal HRT (Int. J. Dermatol. 35[9]:669-74, 1996).

In light of the observed effects of topical estrogen on skin thickness and connective tissue, interest emerged on the potential results for facial skin of topical estrogen administration.

Side effects: Adverse local side effects, such as allergic contact dermatitis, are seen in about 20% of patients who use transdermal estradiol (J. Reprod. Med. 47[6]:507-09, 2002). Patch testing can be used to identify susceptibility. Women who use topical estrogen and typically have close contact with children should be aware that gynecomastia, rapid growth, and advanced bone age can result when prepubescent children are indirectly exposed to excessive amounts of topical estrogen (Pediatrics 105[4]:E55, 2000). It should be noted that the Food and Drug Administration does not regulate custom-compounded topical estrogen formulations, which can contain high levels of estrogen.

Products: Although Premarin is better known as an oral ERT, this product is available as a vaginal cream and has been tested for facial use. In a randomized, double-blind, parallel group study, Premarin was found to be significantly more effective than placebo at enhancing the appearance of fine wrinkles after 12 and 24 weeks. The Premarin group also exhibited significantly greater skin thickness at week 24 (Maturitas 19[3]:211-23, 1994). A 1-month supply of Premarin cream is available for $50.

Estrace is the most commonly prescribed oral estradiol. One milligram of Estrace is comparable to 0.625 mg of Premarin. Because Estrace can be easily excreted from the system, patients are often advised to take a half dose by mouth in the morning and a half dose at night. A 1-month supply of Estrace cream sells for $42.

Climara is an estradiol patch available at 3.8 mg ($15 per package of four patches) and 7.6 mg ($22 per package of four patches). Estraderm is another estradiol patch available in packets of eight: 0.025 mg ($20), 0.05 mg ($22), and 0.1 mg ($36).

Vivelle-Dot is the smallest transdermal estradiol patch delivery system. This product is available in dose strengths of 0.025, 0.0375, 0.05, 0.075, and 0.1 mg per day. The smallest dose strength is indicated only for the prevention of postmenopausal osteoporosis.

Estrogel became available 4 years ago as the first estrogen gel to treat natural or surgically induced estrogen deficiency or menopausal symptoms such as hot flashes, vaginal atrophy, mood swings, and sleep disturbances. This ERT is a transdermal preparation combining a hydroalcoholic gel and 0.06% 17--estradiol derived from yam. Estrogel has a low side effect profile and is associated with a lower incidence of skin irritation, compared with transdermal estrogen patches, and has a 20-year track record of safe, effective use in Europe.

Estrasorb, an estradiol topical emulsion, might be the first FDA-approved ERT in a topical lotion. Estrasorb (3 g contains 7.5 mg estradiol) incorporates 17--estradiol in a soy-based oil formulation designed to deliver systemic levels of estrogen through the skin. A new drug application was withdrawn in April 2002 to address chemistry, manufacturing, and controls questions, but Estrasorb manufacturer Novavax Inc. resubmitted the new drug application at the end of October 2002. Estrasorb is intended for short-term therapy.

There are also several generic forms of estradiol available. In all cases, they're made from plant sources (phytoestrogens) and micronized.

With an increasing number of women from the baby boom generation entering menopause, it is safe to assume that pharmaceutical manufacturers with an already significant stake in hormone and estrogen replacement therapies are expanding research efforts to find safer, more effective estrogen therapies. It is likely that the positive effects that topical estrogens may confer on facial skin will achieve greater prominence in the coming years.

I prescribe topical Estrace for all postmenopausal women not on HRT who do not have a contraindication. These women usually report decreased dryness, increased tone, and plumpness of the skin within 2 weeks. Although this evidence is anecdotal, I plan to pursue future clinical trials using these topical estrogens.

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