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ISSN: 2157-7536
Journal of Steroids & Hormonal Science

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Gender Differences in Skin Aging and the Changing Profile of the Sex Hormones with Age

Miranda A. Farage1*, Kenneth W. Miller1, Christos C. Zouboulis2, Gérard E. Piérard3 and Howard I. Maibach4

1Feminine Care Innovation, The Procter & Gamble Company, Cincinnati OH 45224, USA

2Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany

3Department of Dermatopathology, Laboratory of Skin Bioengineering and Imaging, University of Liège, Belgium

4Department of Dermatology University of San Francisco, Medical School, San Francisco, California, USA

*Corresponding Author:
Dr. Miranda Farage
The Procter & Gamble Company, Winton Hill Business Center
6110 Center Hill Rd, Cincinnati, OH 45224, USA
Tel: (513) 634-5594
Fax: 866-622-0465
E-mail: [email protected]

Received date: February 28, 2012; Accepted date: April 07, 2012; Published date: April 10, 2012

Citation: Farage MA, Miller KW, Zouboulis CC, Piérard GE, Maibach HI (2012) Gender Differences in Skin Aging and the Changing Profile of the Sex Hormones with Age. J Steroids Horm Sci 3:109. doi: 10.4172/2157-7536.1000109

Copyright: © 2012 Farage MA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Keywords

Aging; Skin; Gender; Estrogen; Androgens; Testosterone; Menopause; Partial Androgen Deficiency in the Aging Male (PADAM)

Abbreviations

DHEA: dehydroepiandrosterone; ADIONE: androstenedione; ADIOL: androstenediol; DHT: dihydrotestosterone; E2: estradiol; E1: estrone

Introduction

Endocrine functions change with age. Changes in three systems are intricately linked to skin aging: the hypothalamic-pituitary-gonadal axis, which affects gonadal function; the adrenals, which produce the sex hormone precursor, dehydroepiandrosterone (DHEA); and the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis, which affects GH production and IGF-I release by systemic organs such as the liver.

Alterations in the hypothalamo-pituitary-gonadal axis initiate the menopause, a seminal transition in the aging woman. Menopause, the cessation of ovarian function and menstrual cycling, is associated with vasomotor symptoms (“hot flashes”); osteoporosis; cardiovascular and immune system effects; changes in mood and sleep patterns; impairments in sexual and cognitive function; and changes in skin and urogenital epithelia. In the aging man, functional changes in the hypothalomo-pituitary-gonadal axis are subtler and the concept of a male andropause has been debated [1-3]. Although the sudden arrest of gonadal activity-a biological equivalent to the female menopausedoes not occur in aging men, gonadal function slows progressively with a concurrent decline in circulating androgens. Conceptually, this has been described as partial androgen decline in the aging male (PADAM), a term that better describes this condition than the term andropause [4]. Coincident with this phenomenon, men experience clinically significant alterations in several domains, such as changes in lean body mass and muscle strength; declines in bone mineral density; cardiovascular changes; altered cognition, mood and sleep patterns; urogenital effects (e.g. benign prostatic hypertrophy); changes in sexual function (low libido, erectile dysfunction); and changes in skin and hair [4,5].

Besides the diminished gonadal production of estrogens and testosterone, age-related declines in adrenal production of the sex steroid precursors, dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS), occur in both sexes (adrenopause). Hypothalamic secretion of GH-releasing hormone and the response to GH-releasing hormone also are attenuated. GH release by the pituitary slows with concomitant declines in release of insulin-like growth factor-1 (IGF- 1) by the liver and other organs (somatopause). A complex interplay exists between these endocrine changes and other hormonal systems affected by aging, such as production of melatonin, leptin, etc.

Changes in gonadal, adrenal and peripheral production of the sex hormones impacts skin physiology [6]. Estrogens (specifically, estradiol) and androgens (specifically, testosterone and 5α-dihydrotestosterone) mediate their skin effects by activating specific cellular receptors. Much of the research on the role of the sex steroids in skin aging has been compartmentalized. The role of estrogen has been elucidated to a large degree by comparing skin physiology in premenopausal and postmenopausal women; much of the research on the role of androgens in skin aging has been conducted in men or in male animal models. However, the signaling pathways of estrogens and androgens are interrelated and their serum concentration profiles in men and women are affected differently by age. This review examines the changing profiles of the sex steroids with age and their potential relationship to gender differences in skin aging.

Production of the Sex Steroids

Sex steroids are produced by the gonads, the adrenals and by peripheral tissues. The ovaries are a primary source of estradiol in younger women and the testes a primary source of testosterone in younger men. Estrogens and androgens produced by the gonads enter the circulation for transport to distant target sites. The adrenals secrete inactive prohormones, DHEA and androstenedione, that serve as precursors of androgens and estrogens produced in peripheral tissues.

DHEA and its sulfate form, DHEAS (interconvertible by extraadrenal sulfotransferase and sulfatase activity), are the most abundant sex steroids in plasma. Plasma DHEAS levels in adult men and women are 100 to 500 times higher than those of testosterone and 1000 to 10,000 times higher than those of estradiol (table 1). Circulating DHEA and DHEAS form a reservoir of prohormones for peripheral conversion to active androgens (testosterone and dihydrotestosterone, DHT) and estrogens (estradiol, E2 and estrone, E1) (Figure 1). The hydroxysteroid dehydrogenases transform DHEA into androstenediol and androstenedione, precursors of testosterone. Tissue aromatization of androstenedione and testosterone gives rise to estrone and estradiol, respectively. Only testosterone and its highly potent metabolite, dihydrotestosterone, have direct, receptor-mediated androgenic activity [7]. Estradiol, which exerts its effects through interaction with nuclear and membrane bound receptors, is the more potent estrogen.

Hormone or binding protein Younger adults Older adults
Men Reference Women
(Premenopause)
Reference Men Reference Women
(Postmenopause)
Reference
DHEAS ≈ 12 µmol/L
Age 20 yrs
[159] ≈ 6 µmol/L
Age 20 yrs
[159] ≈ 3 µmol/L
Age 60 yrs
[159] ≈ 1.5 µmol/L
Age 60 yrs
[159]
   8.5 µmol/L
(3110 ng/mL )
Age < 40 yrs
[160] 7.7 µmol/L
(2824 ng/mL)
Age < 40 yrs
[160] 1.5 µmol/L
(551 ng/mL)
Age 90-99
[160] 1.0 µmol/L
(364 ng/mL)
Age 90-99
[160]
Age 90-99
  7.0 ± 4.0 µmol/L
(2600 ± 1500 ng/mL)
Ages 40-70
[13] 3.64 µmol/L
(95% CI 1.6–1.72)
[161] 4.3 ± 2.7 µmol/L
(1600 ± 1000 ng/mL)
Ages 46-80
[13] 1.9 nmol/L
(95% CI 0.8 – 4.4)
Median age, 54
[14]
DHEA 20 – 25 nmol/L
Age 20 - 30
[162] 20-27 nmol/L
Age 20 - 30
[162] 4 – 6 nmol/L
Ages 50 - 80
[9] 6 – 7 nmol/L [9]
Total testosterone 13 – 40 nmol/L
Age 30
[163] 0.6 – 2.5 nmol/L
(0.2 - 0.7 ng/mL)
Age unspecified
[162] 6 – 26 nmol/L
Age 80
[163] 0.56 ± 0.26 nmol/L
Ages 50-89
[22]
  18.0 ± 6.1 nmol/L
(5.2 ± 1.8 ng/mL)
Ages 40-70
[13] 1.66 nmol/L
(95% CI 1.6–1.72)
Ages < 50
[161] 15.7 ± 5.6 nmol/L
(4.5 ± 1.6 ng/mL)
Ages 46-80
[13] 1.4 nmol/L
(95% CI 0.6 – 2.4)
Median age, 54
[14]
  22 ± 7 nmol/L [164] 1.2 ± 0.7 nmol/L [165] 15.8 ± 0.17 nmol/L
(4.57 ± 0.05 ng/mL)
Ages 69-80
[10] 0.5 ± 0.01 nmol/L
(0.14 ± 0.004 ng/mL)
Ages 55-65
[10]
Free testosterone 0.097 ± 0.039 ng/mL
(0.34 ± 0.14 nmol/L)
Ages 40-70
[13] 12.8 ± 5.5 pmol/L [165] 0.075 ± 0.032 ng/mL
(0.26 ± 0.11 nmol/L)
Ages 46-80
[13] 0.14 ± 0.07 nmol/L
Ages 50-89
[22]
DHT  0.91 ± 0.58 nmol/L
(0.26 ± 0.17 ng/mL)
Ages 40-70
[13] 0.43 nmol/L
(0.12 ng/mL)
Ages 30-49
[166] 1.19 ± 0.70 nmol/L
(0.35 ± 0.20 ng/mL)
Ages 46-80
[13] 0.22 ± 0.11 nmol/L
(62.4 ± 32 pg/mL)
Age ≤ 69
[167]
SHBG 32 ± 16 nmol/L
Ages 40-70
[13] 53.1 nmol/L
(95% CI 50.7–50.5)
Ages < 50
[161] 32 ± 16 nmol/L
Ages 46-80
[13] 50.5 nmol/L
(95% CI 21.0–99.8)
Median age, 54
[14]
Estradiol 84.0 ± 22.4 pmol/L
Ages 24-31
[39] 381 pmol/L
(95% CI
356 –407.6)
[161] 88.1 ± 24.6 pmol/L
Ages 70-79
[39] 18 ± 9 pmol/L
Ages 50-89
[22]
  81.5 ± 23.1 pmol/L
Ages 37-46
[39] 79.0 ± 1.1 pmol/L
(21.5 ± 0.3 pg/mL)
Ages 69-80
[10] 15.4 ± 0.7 pmol/L
(4.2 ± 0.2 pg/mL)
Ages 55-65
[10]
Estrone  156 ± 75 pmol/L
Age 40-70
[13] 409.9 pmol/L
(95% CI
383.4 –436.4)
[161] 124 ± 78 pmol/L
Age 46-80
[13] 70 ± 34 pmol/L
Ages 50-89
[22]
  139 ± 2 pmol/L
Ages 69-80
[10] 65.9 ± 1.8 pmol/L
Ages 55-65
[10]

Table 1: Serum concentrations of the sex hormones by age and gender.

steroids-hormonal-science-steroids-adrenal-precursors

Figure 1: Production of sex steroids from the adrenal precursors, dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS). DHEA, an inactive prohormone, is produced by the adrenal glands from cholesterol. DHEA and DHEAS are interconvertible by the actions of sulfatases and sulfotransferases. In peripheral tissues, the hydroxysteroid dehydrogenases (HSD) convert DHEA to androstenedione and androstenediol, precursors of testosterone. The action of 5a-reductases converts testosterone to its potent metabolite, dihydrotestosterone (DHT). Aromatases produce estrogens by converting testosterone to estradiol and androstenedione to estrone.

The action of sex steroids on target tissue depends both on circulating levels and on local formation within the tissue itself (Figure 2). Androgens and estrogens produced within tissues can act on neighboring cells (paracrine activity) or within the same cells (intracrine activity). Sex steroids produced in peripheral tissues (such as adipose tissue) also enter the circulation. This source becomes especially significant as gonadal production declines with age. For example, in postmenopausal women, peripherally synthesized estrone is the primary source of estrogen. In men aged 60-75, adrenal DHEA contributes about 40% to the total pool of androgens [8]. Indeed, comparable amounts of sex steroids are synthesized outside the gonads in older men and women [8,9]: using circulating DHT metabolites as a measure, it is estimated that that postmenopausal women synthesize almost half as much androgen as men of similar age, the excess in men being attributable to testicular origin [10].

steroids-hormonal-science-steroids-young-men

Figure 2: Sources of the sex steroids in young men and women. Sex hormones are produced by the gonads, the adrenals, and by peripheral tissues. The ovary, adrenal gland, and testis are shown at the top of the chart. The white box in the central field denotes the circulatory compartment. The left side of the circulatory compartment below the ovary shows circulating levels of the sex hormones in young women; the right side of the circulatory compartment, below the testis, shows circulating levels of sex hormones in young men. The gray box with a bold border below the adrenal gland denotes the peripheral tissue compartment and illustrates peripheral conversion of the adrenal prohormone, DHEA, to sex hormones. Bold arrows denote primary sources of the sex hormones. The ovaries and testes are primary sources of circulating estradiol and testosterone in young women and men, respectively. The peripheral tissues (mainly adipose tissue) are a primary source of circulating estradiol in men and of estrone in both sexes.

DHEA: dehydroepiandrosterone; ADIONE: androstenedione; ADIOL: androstenediol; DHT: dihydrotestosterone; E2: estradiol; E1: estrone

Age-related Changes in the Sex Steroids

Changes in prohormones and androgens

Production of DHEA and DHEAS begins during adrenarche. Serum concentrations of DHEAS reach their peak (in the order of 10-8 M and 10-6 M, respectively) between the ages of 20 and 30 years [9], then decline markedly to about 20% of peak levels by age 70 and 5% of peak levels by age 90 [11-15]. Because of their importance as sex steroids precursors, this decline in DHEAS and DHEA is thought to contribute to some of the degenerative changes seen with aging.

Gender differences exist in serum concentrations of these hormones (table 1). Circulating levels of DHEAS in adult women are consistently lower than those in men at all ages [12,16,17]. In both men and women, most of the decline in circulating DHEAS occurs before age 60 [9]. In men, the age-related decrease in plasma levels is curvilinear, with the rate of decline slowing in the elderly; in women, the change is stepwise: concentrations fall 40% between ages 50 and 60, remain constant to about age 80 [9], then decline about 18% more in the succeeding decade [16].

The decline in these prohormones is clinically important in both sexes, but especially so in women. In men, gonadal androgen production declines slowly, such that peripheral production of contributes some 40% to the total androgen pool in men by age 65 [8]. However, in postmenopausal women, DHEA is the exclusive source of sex steroids for all tissues except the uterus [8]. However, large variability exists in the circulating levels of DHEA in women: an almost 8-fold difference between high and low levels has been found [18], with the low end being barely detectable. This wide range could help explain why some older women experience few signs of hormone deficiency while others experience significant signs and symptoms [18].

About 30% to 50% of total androgens in adult men [19] and about 50% to 100% in adult women, depending on age, are derived from DHEA and DHEAS [20]. In women androstenedione levels decline with age up to the menopause, remain fairly stable in the early years after menopause [21,22] then decline by about 20% by 30 years after menopause [22]. Early studies suggested that the postmenopausal ovary was a source of androgens [20], but this is controversial. Recent studies indicate that expression of steroidogenic enzymes by the postmenopausal ovary is limited [23,24] and that absent the adrenals, postmenopausal women have no detectable circulating androgens [25].

Testosterone and its highly potent metabolite, dihydrotestosterone (DHT), exert receptor-mediated activity. About 1-2% of circulating testosterone is free, 32% loosely bound to albumin and 66% bound to sex hormone binding globulin (SHBG). Free and albumin-bound testosterone are bioavailable to tissues.

In younger men, the testicular Leydig cells produce 95% of testosterone and a smaller amount of DHT (Figure 2). In premenopausal women, 25% of circulating testosterone comes from the adrenals, 25% from the ovaries [26] and the rest from peripheral conversion of androstenedione in adipose tissue [27].

In healthy men, total testosterone and free testosterone decline slowly with age [13,28,29]. The decline in total testosterone is modest, but comparatively greater for free testosterone due to the concurrent age-related rise in SHBG [30]. Data from a large, population-based cohort of men aged 40 to 70 at baseline who were followed for 7 to 10 years (the Massachusetts Male Aging Study) showed that total testosterone declined by age cross-sectionally (between subjects) at 0.8% per year and free and albumin-bound testosterone declined at about 2% per year, while SHBG concentrations rose about 1.6% per year. Longitudinally (within subjects), total testosterone declined 1.6% per year, bioavailable testosterone by 2-3% per year and SHBG levels rose at 1.3% per year [13].

The age-related decline in testosterone in men is due to reductions in the number of productive Leydig cells as well as to changes in the response to Leutinizing Hormone (LH) and Human Chorionic Gonadotropin (hCG) in older men. Besides age, obesity is associated with lower total and free testosterone and SHBG; a change in BMI from nonobese (<25 kg/m2) to obese (≥ 30 kg/ m2) is equivalent to a 15-year fall in testosterone levels [30]. It has been postulated that age primarily affects testicular function, whereas obesity impairs hypothalamic and pituitary function. In addition, the circadian rhythm, with higher testosterone levels in the morning than in the evening, is lost in older men [31].

In women, testosterone levels decline with age in the reproductive period between the ages of 20 and 50 [32]. However, the menopausal transition itself does not appear to affect testosterone levels significantly. A prospective study in 172 women failed to show a change in total testosterone in the time span from 5 years before to 7 years after the final menstrual period [14]. Other studies found a slight decrease in levels of bioavailable testosterone in the early years after menopause [21,22], followed by a rise to premenopausal levels in the second decade following the menopausal transition [22]. Hence, declines during the decades preceding the menopause, rather than the menopausal transition itself, have the most significant impact on testosterone levels in older women. These observations may reflect the relative importance of adrenal and peripheral sources of androgens in women. Overall trends in circulating levels of sex hormones in aging men and women are summarized in table 2.

  Prohormone or hormone Change with advancing age
Men Women
DHEAS Substantial decrease Substantial decrease
DHEA Decrease Decrease
Testosterone Decrease Decrease
DHT No significant change No significant change
Estradiol No significant change Substantial decrease
Estrone No significant change Decrease

Table 2: Trends in circulating levels of sex steroids in aging men and women.

Changes in estrogens

Menopause occurs when senescence of the ovarian follicles reduces the gonadal production of estradiol to miniscule levels (table 1). During the menopausal transition, circulating levels of estradiol decline from over 300 pmol/L to about 20 pmol/L, whereas levels of luteinizing hormone and follicle-stimulating hormone rise considerably above premenopausal levels [21,33].

Estrone, a weaker estrogen produced from androstenedione in peripheral tissues, is the predominant form of estrogen in postmenopausal women (Figure 2). Estrone is also the principal source of postmenopausal estradiol, but only 5% of estrone is converted [34]. Adipose tissue is a major site of peripheral estrone synthesis; hence estrogen levels are higher in postmenopausal women with a high body mass index.

In men, 80% of plasma estradiol is produced by peripheral aromatization of testosterone, which occurs principally in fat tissue [35]; the testes produce only 20% of plasma estradiol [36,37]. The mean plasma estradiol concentration in men is 2-3 ng/dL (about 80 pmol/L) and the mean concentration of estrone is 3-6 ng/dL (about 100-200 pmol/L) [38] (table 1). In younger men, 5-10 μg/day of estradiol is produced by the Leydig cells, 20 μg/day derives from peripheral conversion of plasma testosterone and 5 μg/day from androstenedione [39]. As in women, plasma estrone derives principally from tissue aromatization of androstenedione, with 20% secreted directly by the adrenals.

In men, plasma estradiol levels do not decrease significantly with age [11,28,40] (Tables 1 and 2), although some investigators have reported declines [41,42]. Despite the age-associated decline in testosterone, it has been postulated that plasma estradiol levels remain relatively unchanged because of a rise in aromatase activity coincident with the age-associated increase in body mass fat [43]. As a result, plasma estradiol levels in older men are significantly higher than in postmenopausal women (table 1).

Intracrine Production of the Sex Steroids and Sex Steroid Receptor Localization in the Skin

The skin is affected not only by the action of circulating sex steroids but also by locally synthesized androgens and estrogens. Local production of the sex steroids depends on the expression of androgenand estrogen-synthesizing enzymes in individual skin structures and cell types (table 3). The expression of sex steroid receptors in skin varies by cell type and by sex. Androgen target cells, such as sebocytes, express little cytochrome p450c17, which is necessary for synthesis of DHEA and androstenedione from cholesterol; however, sebocytes, sweat glands and dermal papilla hair cells express enzymes that convert these adrenal prohormones into testosterone and DHT [44,45]. Indeed, under normal circumstances, human sebocytes selectively use DHEA than other prohormones to produce active androgens [46]. Interestingly, a newly identified pathway leads to DHT synthesis from DHEA in human sebocytes without requiring testosterone as an intermediate. The sebaceous glands, the outer and inner root sheath cells of anagen terminal hair follicles and dermal papilla cells express aromatases that convert testosterone and androstenedione into estrogens (table 3) [47,48].

  Skin structure Enzyme acitvity Sex steroid receptors
17 β-HSD 3β-HSD 5α-reductase Aromatase AR ERβ          ERα
Epidermal keratinocytes +
(4- isotypes)
  +
(1- isotype)
  + +  
Melanocytes         + + +
Hair follicles     +
(1- isotype)
(2- isotype in beard)
       
Follicular keratinocytes         + +  
Root sheath +
(2- isotype)
    +   +  
Matrix epithelium         + +  
Dermal papilla cells       + + +  
Sebaceous glands +
(3- and 5- isotypes)
+
(1- isotype)
+
(1- isotype)
+ + + +
Sweat glands     +
(1- isotype)
  +    
Eccrine           +  
Apocrine     +   + +  
Dermal fibroblasts         + + +
Endothelial cells         + +  

Table 3: Localization of sex steroidogenic enzymes and androgen and estrogen receptor activity in the skin.

As in other steroidogenic organs, six enzyme systems are involved in the activation and deactivation of androgens in the skin: steroid sulfatase, 3-hydroxysteroid dehydrogenase Δ5-4 isomerase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), steroid 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD) and aromatase [49]. The pilosebaceous unit and the sweat glands contribute to local synthesis of androgens and estrogens. Steroid sulfatase hydrolyses DHEAS to DHEA [50], possibly in the sebocytes or in the dermal papillae of terminal hair follicles, which show enzymatic activity. Sebocytes are key to maintaining androgen homeostasis [46,47]. In sebocytes, the 1- isotype of 3β-HSD converts DHEA to androstenedione and the 3- and 5- isotypes of 17β-HSD convert androstenedione to testosterone. Conversely, the 2- isotype (present in the root sheath cells of hair follicles) and the 4- isotype (in epidermal keratinocytes) deactivate testosterone in the reverse direction and play a protective role against androgen excess [49]. Hence, within the pilosebaceous unit, testosterone is produced from adrenal precursors and also inactivated in order to maintain androgen homeostasis. Keratinocytes also are responsible for androgen degradation [47].

Sebocytes are likely the major site of 5α-reductase activity in the skin. The type 1 isotype of 5α-reductase, expressed in sebaceous glands and sweat glands (with lesser activity in epidermal cells and hair follicles) [51], converts testosterone to the highly potent androgen, DHT. The type 2 isotype is active in beard hair follicles. A newly detected type 3 isotype, sensitive to finasteride, a 5α-reductase inhibitor, is strongly expressed in sebaceous gland cells [52].

Testosterone and DHT act through a single nuclear androgen receptor (AR) and their activity on the skin depends on receptor distribution. AR is present in epidermal and follicular keratinocytes, sebocytes, sweat glands, dermal papilla cells, dermal fibroblasts, endothelial cells and genital melanocytes [53,54]. Two isozymes of 3α-HSD deactivate DHT by conversion to 3α-androstanediol.

Aromatases in the sebaceous glands, the outer and inner root hair cells of anagen hair follicles and dermal papillae cells [47,48], convert androstenedione and testosterone to estrogens. Aromatase expression is much higher in scalp hair follicles of women than of men and the enzyme is rarely expressed in telogen hair follicles [55].

Two distinct intracellular estrogen receptors, ERα and ERβ, belong to a superfamily of nuclear hormone receptors. Cell membrane-bound estrogen receptors also exist that activate signaling cascades via second messengers. ERβ is the predominant receptor in adult human scalp skin, strongly expressed in the stratum basale and stratum spinosum of the epidermis [53,56]. ERα and ERβ are expressed in the sebaceous gland [53]. In addition, in women, both ERα and ERβ are expressed in primary cultures of dermal fibroblasts: ERα was detected in both the cytosolic and nuclear compartments, whereas ERβ was weakly detectable and was found predominantly in the nuclear compartment [57,58].

Studies suggest that ERβ is the mediator of estrogen effects on skin and hair. Estradiol upregulates the expression of ERβ in dermal fibroblasts from postmenopausal women [57]. ERβ is strongly expressed in anagen hair follicles of the human scalp, where it is localized to nuclei of the outer root sheath, epithelial matrix and dermal papilla cells [52]. ERβ is also highly expressed in epidermis, sebaceous glands, blood vessels and dermal fibroblasts (table 3).

The apocrine gland develops from the hair follicle. ERβ but not ERα is expressed in the secretory epithelium of the apocrine gland [53] as well as in the ecrrine gland. Estrogen receptor also is expressed in normal melanocytes [59] and in nevi of pregnant and non-pregnant women [60].

Effects of Sex Hormones on the Structure, Characteristics and Function of Aging Skin

Chronologic or intrinsic skin aging refers to those age-related changes that occur in areas unexposed to the sun, such as the upper inner arm and, in most cases, genitalia and buttocks. Photoaging refers to cumulative changes mediated by UV exposure that occur on sunexposed skin and which are superimposed on intrinsic aging.

Clinically obvious signs of skin aging are wrinkling, pigmentary changes, loss of skin elasticity and sagging. Exposed, photoaged skin has coarser and deeper wrinkles, a roughened, leathery surface, mottled pigmentation and, a more pronounced loss of elasticity. Intrinsically aged skin has a dry, smoother texture, with fine wrinkles and an unblemished surface; loss of elasticity is less severe. Aging skin is also thinner and more vulnerable to damage. In addition to these changes, the growth rate of the hair and nails slows, the nail plate thins and its surface becomes ridged and lusterless. The hair loses pigment and the density of hair follicles on the scalp decreases, independent of androgenetic alopecia (genetically driven patterns of balding). Vellus hairs in the ears, nose and eyebrows of men and hair on the upper lip and chin of women convert to more obvious terminal hairs. The influence of the sex steroids on these changes and the resulting gender differences in aging skin aging are summarized in table 4 reviewed in detail below.

Parameter Change Gender differences Impact of Sex hormones
Wrinkles Develop and become more pronounced with age No established gender differences. Wrinkling may be related to reduced stimulation of collagen and glycosaminoglycan synthesis by estrogen.
Skin thickness Becomes thinner with age in both sexes (atrophy).
Epidermal thickness decreases 6.4% per decade [67].
Dermal thickness decreases 20% by old age [68].
Skin of adult men is thicker then that of women [62].
Skin thickness decreases faster in older women than in older men [67].
Much of the decrease in skin thickness is thought to result from collagen changes in the dermis (see below)
Collagen (dermis) Fibers more disorganized; balance between synthesis and degradation shifts toward greater degradation [70].
Collagen matrix degrades and fibroblasts collapse [71,72]
See above. Androgens promote thicker skin and higher collagen production in murine models [91,92]
DHEA declines result in lower procollagen synthesis and more collagen degradation [73,74].
DHEA is the principal source of estrogen synthesis in postmenopausal women. Estrogen supplementation in postmenopausal women increases skin collagen content [78,168]
Elastin (dermis) Fibers degrade; skin less elastic Alterations more pronounced in older women [68].
In the first 5 years following menopause, facial skin elasticity declines 1.5% per year [83,84].
Women who received HRT in the first 5 years following menopause exhibited no significant change in skin elasticity [83,84].
Skin barrier function Baseline barrier function (as measured by TEWL) unchanged [100,101].
Once compromised, barrier integrity takes longer to be restored [101-103]
No established gender differences [104] Androgens reduce skin barrier function and estrogens increase it [64,105,106]
Skin moisture and water holding capacity Reduced water content of stratum corneum [108].
Reduced water-holding capacity of the dermis due to declines in glycosaminoglycans and hyaluronic acid [109].
No established gender differences. Estrogens increase skin moisture and water-holding capacity [110] by increasing levels of hyaluronic acids [112,169] and glycosaminoglycans [113]
Sweating and thermoregulation Impaired with advancing age [117-119]. Men sweat to a greater degree than women in similar situations [114,115].
Elevated temperature thresholds for sweating and reduced sweat response more pronounced in older women than in men [119].
Sweat glands express 5α-reductase (which converts androgens to DHT) and the androgen receptor through which DHT exerts its action.
Sebum production Gradual decrease in women. In men, sebum levels change minimally from puberty until about age 80.
In women, sebum secretion decreases gradually from menopause through age 80, after which no appreciable change occurs [124].
Sebocytes regulate the effect of androgens in the skin.
DHEA enhances sebum production in both sexes [75], but not through direct action on sebocytes [128]
Testosterone promotes DHT synthesis in sebocytes and stimulates sebum production [126].
In older women, estrogen supplementation suppresses sebum production; progesterone overcomes this effect [87].
Sebum production is affected by the interplay of growth factors (IGF-1), estrogen, progesterone and androgens (DHEA) [127,128].
Hair growth Androgenetic alopecia usually begins around age 30 in genetically susceptible men and women. Male-pattern baldness is more common and severe can start as early as late adolescence.
Female-pattern baldness is less common and usually milder.
Both androgens and estrogens affect hair growth. DHT acts on hair follicles to release growth factors in androgen dependent areas (beard, axilla, pubis) [131].
In male androgenetic alopecia, DHT causes susceptible scalp follicles miniaturize; the number of follicles in anagen phase decreases.
In women, scalp hair follicles have lower 5α-reductase levels, lower AR levels, and higher aromatase activity, limiting the impact of DHT.
Estrogens act on hair follicles through ERβ, which is present at sites of hair renewal in follicles of women but not of men.
Wound healing Skin is more susceptible to mechanical damage [141] and wound healing declines [142] Men display lower rates of wound healing at all ages. Androgens depress wound healing by increasing inflammation, proteolysis, and matrix degradation [148].
Estrogens promote wound healing by inhibiting inflammation and promoting keratinocyte mitogenesis, deposition of matrix components, and angiogenesis [170]
Subcutaneous DHEA restores wound healing rates in ovarectomized mice and promoted wound healing in aged mice, likely through local conversion to estrogen [158]

Table 4: Age-related changes in skin structure and physiology affected by the sex steroids in men and women.

Skin structure and thickness

Human male skin is thicker and drier than female skin from ages 5 through 90 years [61,62]. In part, this is because androgens stimulate epidermal hyperplasia and suppress epidermal barrier function in adult human skin [63]. The skin thins with age in both sexes. In men, skin thickness decreases linearly beginning at age 20, whereas in women it remains constant until about age 50 and then decreases [64]. The unexposed epidermis thins up to 50% between the ages of 30 and 80 and reductions are more pronounced on exposed areas [65]. Overall, epidermal thickness decreases about 6.4% per decade on average, but faster in postmenopausal women than in men [66]. Dermal thickness decreases by up to 20% in both genders [67], although in sun protected sites significant dermal thinning occurs only after the eighth decade [68].

A decline in dermal thickness accounts for most of the measurable thinning of aging skin. The major extracellular components of the dermis (collagen, elastin and hyaluronic acid) are affected by age. Collagen fibers become thicker and more disorganized. In photoaged skin, collagen bundles and fibers decrease markedly, primarily because matrix metalloproteinases, which degrade collagen, are up-regulated [69]. Consequently, the balance between collagen synthesis and degradation is deranged and collagen fibers fragment, which in turn disrupts the tension on dermal fibroblasts that exists in a healthy collagen matrix, causing fibroblasts to collapse [70,71].

In addition, elastin calcifies and degrades; elastin turnover also declines [65]. These changes make the skin less elastic, less extensible under force and more vulnerable to injury by shear forces. These properties erode more dramatically in women than in men [67].

The sex steroids affect skin structure, thickness and elasticity. DHEA plays a role in maintaining skin structure. It regulates the synthesis and degradation of extracellular matrix protein. It promotes procollagen synthesis and limits collagen degradation by decreasing the synthesis of collagenase and matrix metalloproteases and increasing the production of tissue inhibitor of matrix metalloproteinase [72,73]. Consequently, the substantial decline in DHEA with age results in lower procollagen synthesis and higher collagen degradation. Oral DHEA treatment in men and women aged 60-79 for one year improved epidermal thickness and skin hydration, increased sebum production and reduced facial pigmentation, with effects being more dramatic in women over 70 than in men [74]. DHEA is the primary source of sex steroid production in skin: because older women have lower circulating levels of DHEA than older men, they may have benefited more from DHEA supplementation.

As noted earlier, adult skin is thinner in women and declines in the quality of collagen and elastin are more pronounced in aging women. Estrogen slows or reverses these manifestations of skin aging, maintaining skin thickness, collagen content and hydration. Most studies on the effects of estrogen on aging skin have examined the uses of systemic or topical estrogens in postmenopausal women.

Estrogens affect skin thickness and elasticity primarily through their impact on constituents of the dermis. Hormone replacement therapy maintains or improves skin thickness following menopause, largely by affecting dermal thickness. For example, nuns treated with oral conjugated estrogens for 1 year experienced a significant increase in dermal and overall skin thickness compared to placebo-treated controls [75]. In another study, women receiving HRT achieved skin thickness levels comparable to those of premenopausal women [76].

As noted earlier, collagen reduction is a major factor responsible for skin atrophy. In women, after a slight delay following the onset of menopause [77], total collagen content declines an average of 2.1% per year in the first 15 postmenopausal years [77,78]. Clinical studies have demonstrated beneficial effects of oral, topical and subcutaneous estrogen treatment on collagen content [79-81]. The benefits of HRT or estrogen supplementation on collagen content are proportional to baseline levels at the time of treatment [79,80].

Estrogen also benefits skin elasticity. In the first 5 years following menopause, facial skin distensibility increases 1.1% per year and elasticity decreases by 1.5% per year [82-84]. Women who received HRT during this time period experienced no significant changes in skin elasticity. Studies of oral, transdermal and topical estrogen treatment also showed benefits [83,85-87], although topical estrogen treatment seems to be effective only in sun-protected skin [88]. The extent to which the effect is due to improvements in elastin fiber quality is unclear.

Androgens affect skin thickness, but the interplay between estrogens and androgens is incompletely defined. Androgens affect epidermal hyperplasia in humans, which may partly contribute to in part greater skin thickness in men [63]. Moreover, women with androgen excess who are hirsute display greatly increased skin thickness and skin collagen content [89].

Animal studies implicate androgens as important modulators of skin collagen content. In wild type mice, skin collagen content is greater in maturing males than females, depending on the stage of development [90]. The skin of male and female mice with an X-linked mutation that eliminates a functional androgen receptor exhibited significantly decreased levels of collagen, implicating a role for the androgen receptor in modulating the collagen content. In other studies, treatment of murine skin with DHT and DHEA increased dermal thickness by 22% and 19%, respectively [91]. DHT administration to cultures of vulvar skin fibroblasts from healthy women resulted in significant increases in collagen production, whereas DHT treatment produced no change in cultures of perineal fibroblasts from a male patient with androgen insensitivity syndrome [92].

Hydroxyl-proline content is a marker for collagen, but paradoxically, its concentration in skin was reported to decrease linearly in both men and women, in contrast to skin thickness [64]. Nevertheless, the hydroxyl-proline levels of skin biopsies from postmenopausal women treated for 2-10 years with implants containing both estradiol and testosterone was nearly 50% higher than in age-matched postmenopausal women who received no treatment [93].

Although studies on the impact of these sex hormones have focused principally on the role of estrogens in aging female skin and the role androgens in male skin, the changing profiles of both androgens and estrogens must contribute to differential skin thinning and changes in skin tone in aging men and women. Because women have thinner skin and lower skin collagen content to begin with, age-related thinning may be apparent earlier in this sex. Furthermore, skin thickness decreases linearly with age in men but accelerates in women after age 50 [64]. For perspective androgens levels decline slowly with age in men but estradiol levels remain constant and comparable to those of premenopausal women. Conversely, in women, both androgen and estrogen concentrations decrease with age and the postmenopausal drop in estrogen is precipitous. This could explain why skin thinning is more gradual and less pronounced in men and more dramatic following the menopause.

Wrinkles

Wrinkling is related to loss of connective tissue and elasticity. Studies on wrinkling have focused on the potential benefits of estrogen supplementation in women. A large epidemiologic study in 3875 postmenopausal women (NHANES I) found the odds of wrinkling to be substantially lower in estrogen users after adjusting for age, body mass index and sunlight exposure [94]. Clinical trials of estrogen supplementation have given divergent results, some showing improvements in fine wrinkling and wrinkle depth with topical estrogen treatment [95,96] and others showing effects on thickness but not on hydration or wrinkling [97]. The effects of estrogen on collagen and glycosaminoglycan content of the skin may account for the impact of estrogen on wrinkles.

Skin barrier function

The stratum corneum barrier depends on the composition and arrangement of intercellular lipids. Total lipid content declines by as much as 65% with age, depleting levels of some ceramides, triglycerides and sterol esters [98]. However, measurements of trans-epidermal water loss (TEWL) revealed no age-related differences in baseline skin barrier function, although lipid content declined [99,100]. Nevertheless, when barrier integrity is compromised, recovery is slower in aged skin [100- 102].

No gender differences in epidermal barrier function have been established [103]. However, the research suggests that androgens have a negative impact on skin barrier function whereas estrogens help restore it. For example, measurements of skin barrier function in a hypogonadal man who received intermittent testosterone supplementation showed that barrier recovery rates were highest when serum testosterone levels were at a nadir and lowest when serum testosterone was at its peak [63]. Studies of the recovery of skin barrier function after tape stripping in castrated mice showed that recovery was delayed by systemic testosterone replacement [63]. Topical application of testosterone and androsterone delayed barrier recovery after tape stripping in hairless mice, a delay that was overcome by co-application of estradiol [104]. Moreover, male fetal mice develop barrier function more slowly than female littermates. Estrogen administration to pregnant mothers accelerated fetal barrier development; conversely, DHT administration delayed fetal skin barrier development, an effect that was reversed by treating with a testosterone receptor antagonist [105].

In aging men, testosterone levels decline while estradiol levels remain fairly constant, whereas in women androgens decline slowly and estrogens decline dramatically following menopause. Gender differences in the balance of androgens and estrogens with age might be expected to affect barrier function; however, to our knowledge, systematic comparisons of this parameter in age-matched men and women have not been published.

Skin moisture and water holding capacity

No gender-related differences in skin water holding capacity have been found [106]. The water holding capacity of both the epidermis and the dermis is affected by age. The water content of the stratum corneum is lower in aged skin [107]. Water content of the stratum corneum is related to skin barrier function and to the composition and organization of stratum corneum lipids. The water holding capacity of the dermis also declines because aging fibroblasts produce lower levels of glycosaminoglycans and hyaluronic acid [108].

Estrogens affect skin dryness and water holding capacity. Dry skin is very common among older women. A large epidemiologic study in 3875 postmenopausal women found that women not on HRT were significantly more likely to experience dry skin compared to women taking estrogen [94]. In a pilot study of transdermal estrogen, waterholding capacity of the stratum corneum increased at the treatment site [109]. In mice, estrogen treatment increased hyaluronic acid levels of aged skin [110,111] and induced dermal glycosaminoglycans markedly within 2 weeks of therapy [112]. No data were found on gender-related differences in skin moisture and water-holding capacity with age.

Sweating and thermoregulation

Eccrine and apocrine glands located in the dermis produce sweat. Eccrine glands are distributed over the body, whereas apocrine glands are located in the axillar, areola, perineal and perianal areas. Sweat glands express 5α-reductase, which converts testosterone to the potent androgen, DHT. Sweat glands also express the AR through which DHT acts.

Men sweat more than women do in similar situations (approximately 800 mL/h for men vs. 450 mL/h for women during exercise). When corrected for body surface area, the sweat rate in men is still 30% to 40% higher [113,114]. Androgens initiate the differentiation of sweat glands during puberty, but may not be required to maintain function, because androgen treatment does not increase sweat rate in women and androgen antagonists do not diminish sweat rates in men. However, possibly the apocrine rather than eccrine sweat glands remain an androgen target, as type 1 5α-reductase predominates in apocrine glands of patients with excessive sweat odor, irrespective of sex [115].

Sweating and thermoregulation are impaired with age [116]. The number of eccrine glands diminishes and the output of both the eccrine and apocrine glands is reduced. Men over 60 or 70 display lower sweat rates and higher core temperatures in response to exercise than young men or boys [117,118] and the temperature threshold to induce sweating is 0.5°C higher in aged men [118]. The elevated temperature threshold for sweating and reduced sweat response was even more pronounced in aged women [118]. However, a small study comparing 8 women aged 50-62 with 8 young women aged 20-30 found that in a hot-dry environment, the older women’s whole body and local sweat rates were significantly lower than those of younger women, but in a warm-humid environment, there was no age-related difference [119].

Sebum production

Most sebaceous glands are connected to hair follicles. Their concentration is greatest on the scalp, forehead, cheeks and chin. Beginning at puberty androgens act in conjunction with ligands of the peroxisome-proliferator activated receptor (PPAR) to stimulate the proliferation and differentiation of the sebaceous gland and the production of sebum. The degree of proliferation depends on the anatomical location; the effect is greatest on facial sebocytes [120]. A Korean study of 30 men and women found a strong positive correlation between the male sex, pore size and sebum excretion [121]. DHT is thought to stimulate sebaceous gland activity, especially in acne [122].

In men, sebum levels change minimally after puberty until about age 80, whereas in women a gradual decrease in sebum secretion occurs from menopause through the seventh decade, after which no appreciable change occurs [123].

As noted earlier, sebocytes play a critical role in modulating androgen levels in the skin [47]. Due to the decline of their activity in aged individuals, sebaceous glands become hypertrophic to compensate this dysfunction (sebaceous gland hypertrophy) [124]. In human sebocytes, testosterone is converted to DHT, which stimulates sebum production; moreover, cofactors such linoleic acid, a ligand of the PPAR, exert synergistic effects [125]. By contrast, estrogen replacement in older women suppresses sebum production, although addition of progesterone overcomes this effect [86].

In vitro, treatment of sebocytes with a mixture of growth factors (IGF-1), estrogen, progesterone and androgens (DHEA), at quantities that approximate the circulating levels at different ages, mimics the reduction of sebum production seen with age in vivo [126,127]. However, although oral supplementation for one year with the sex steroid precursor, DHEA, enhanced sebum production in both sexes [74], direct DHEA treatment of human sebocytes in vitro at agespecific levels has no effect on their activity [127]. Taken together, these observations indicate that changes in sebum production with age require conversion of DHEA to sex hormones and are modulated by the interplay of both the sex hormone and the growth hormone signaling pathways.

Hair growth

A hair follicle consists of epithelial components (inner and outer root sheath and hair shaft) and mesenchymal components (the dermal papillae and connective tissue sheath). The hair growth cycle involves anagen (growing), catagen (transitional) and telogen (resting) phases. The bulge region of the outer root sheath contains stems cells for hair follicle keratinocytes that regenerate the follicle during each anagen phase of the hair cycle; the dermal papilla cells provide the signal that initiates anagen and instructs the follicular stem cells to divide [128]. The hair growth cycle is not synchronized: each hair strand is in its own phase of development.

Both androgens and estrogens affect hair growth and the interplay of their signaling pathways is relevant to gender differences in hair follicle stimulation. DHT, produced by the action of 5α-reductase on testosterone, mediates androgenic effects on hair follicles. DHT interacts with the AR on dermal papilla cells [51,129], causing the release of growth factors that then act on other cells in the hair follicle [130]. The response to androgens at different body areas is genetically determined; single polymorphisms in AR are associated with hirsutism in women and androgenetic alopecia in men. In androgen-dependent areas (male beard, axillary and pubic hair) androgens promote enlargement of hair follicles; however, in scalp follicles of susceptible men they cause the follicles to miniaturize and reduce the amount of hair in the anagen phase, leading to male pattern baldness [131].

Men with a deficiency in type 2 5α-reductase display little or no beard growth and do not develop androgenetic alopecia; moreover, finasteride inhibition of the enzyme slows or reverses the progression of alopecia [132]. In male pattern balding, the expression of type 2 5α-reductase is higher in dermal papilla cells from sites of androgenetic alopecia and beard than those from other sites; AR expression also 30% higher in sites of alopecia; and the AR coactivator Hic-5/ARA55 is more highly expressed in dermal papilla cells of hair follicles from sites of androgenetic alopecia and beard [55,133]. The consequence is heightened sensitivity to DHT.

DHT stimulates synthesis of transforming growth factor-β2 (TGF-β2) in dermal papilla cells. TGF-β2 in turn suppresses proliferation of epithelial cells and stimulates synthesis of certain capsases, which triggers the elimination of epithelial cells through apoptosis. These sequential events contribute to the shortening of the anagen phase of the hair cycle and premature entry into the catagen phase [134].

Female pattern hair loss is more diffuse and usually involves the frontal and parietal scalp areas. It is independent of androgen levels, often begins after age 30 and is more prevalent after menopause. Women may be protected from developing androgenetic alopecia because their frontal and occipital hair follicles have more than 3-times lower 5α-reductase activity and 40% lower AR levels [55,135,136]. This reduces the potential impact of DHT on the hair cycle in women. Moreover, scalp hair follicles in the frontal and occipital area express up to 6-times more aromatase activity in women than in men [55,137]. This suggests that estrogen formation from testosterone also acts as a protective factor.

Estrogens also are potent modulators of hair growth: for example, during pregnancy, high systemic estrogen levels prolong the anagen phase, whereas plummeting postpartum levels cause excess numbers of anagen follicles to enter the telogen phase simultaneously, leading to hair loss [138]. In Europe, estrogens are used to treat androgenetic alopecia in women. The estrogen signaling pathways for hair growth in the two genders are the subject of active research. Human hair follicles in culture express ERβ, but the distribution pattern is gender specific [139]. In men, ER resides predominantly in nuclei of matrix keratinocytes, whereas in women, the receptor resides in the fibroblasts of the dermal papilla of anagen hair follicles and in the bulge region of the outer root sheath, the site of stem cells involved in hair renewal. Hence, in women, estrogen receptor activation occurs at the target sites for hair growth. In addition, estradiol treatment diminishes the amount of DHT formed form testosterone in the epithelial part of the

Wound healing

Aged skin is more fragile. One of the most striking structural changes in aging skin is the flattening of the dermoepidermal junction, which reduces the connecting surface area between the two layers and makes the skin more vulnerable to shear forces [140]. Repair of injury is also affected by age. Epidermal turnover slows by 30% to 50% between the third and eight decades and the capacity for re-epithelialization (wound healing) declines [141]. In the aged, wound healing is slower to start and slower to proceed. Moreover, the tensile strength of healing wounds decreases after age 70; for example, the risk of postoperative wound reopening increases dramatically in people over 80 compared to those in their 30s [102].

Men have slower rates of wound healing at all ages than women and being an older man is a significant risk factor for impaired healing [142,143]. For example, men exhibit impaired healing of chronic venous leg ulcers relative to women [144]; women have survival advantages in response to trauma and their mortality following sepsis is 26% compared to 70% for men [145].

A shift in the balance of circulating estrogens and androgens and gender differences in the response to the hormones contribute to delayed wound healing in older adults. Wound-edge keratinocytes, infiltrating inflammatory cells and dermal fibroblasts express AR [146]. Androgens depress wound healing by increasing local inflammation and promoting excessive proteolysis [147]. Under the influence of androgens, the inflammatory response does not resolve efficiently and restorative matrix accumulation is delayed. Secondly, circulating androgens stimulate matrix degradation: in animal models, for example, castration reduces the levels of matrix metalloproteinases in wounds, thereby reducing matrix degradation and enabling the deposition of type I collagen and fibronectin to rise [148]. This process may be significant to impaired wound healing in the elderly, as the activity of matrix metalloproteinases in wounds is higher in older people of both sexes than in younger adults [69]. Older adults also display defective induction of tissue inhibitors of metalloproteinases (TIMP -1 and TIMP-2) that promote healing. DHT inhibits wound closure by retarding the migration of epidermal keratinocytes [149

By contrast, estrogens are critical promoters of wound healing. Recent studies using a microarray-based approach revealed that differences in gene expression in wounds of both older men and younger people are almost exclusively estrogen-regulated [150], implicating estrogen as central to the wound healing process. A total of 83% of down-regulated probe sets and 80% of up-regulated probe sets in wounds were estrogen-regulated.

Estrogens both inhibit inflammation and promote deposition of matrix components. Topical estrogen treatment reduces neutrophil infiltration, increases the accumulation of type I collagen and fibronectin, decreases fibronectin degradation and increases wound strength in both sexes [142]. Estrogen has a mitogenic effect on keratinocytes, increasing the rate of re-epithelialization of wounds [151]. In vitro, estradiol promotes angiogenesis of endothelial cell monolayers [152]. In postmenopausal women with impaired wound healing, estrogen treatment accelerates re-epithelialization and increases local collagen deposition [151]. In elderly men, however, the response to estrogen is lower than in women

In animal models, some of the anti-inflammatory action of estrogens is mediated through the regulation of macrophage activation. After ovariectomy, which depletes circulating ovarian hormones, macrophages were activated in classical manner, promoting inflammation; estrogen or progesterone supplementation promoted macrophage activation through an alternative pathway, driving wound repair, angiogenesis and remodeling [153].

The multifunctional cytokine, macrophage inhibitory factor (MIF), is a candidate proinflammatory cytokine involved in hormonal regulation of wound healing. MIF is expressed during wound healing by infiltrating neutrophils, endothelial cells and the proliferating epidermis. Estrogen regulates the expression of MIF. MIF expression is markedly higher in wounds of estrogen-deficient mice, but in mice lacking the MIF gene, the wound inflammation associated with estrogen deficiency is reversed [154]. In postmenopausal women, systemic and wound production of MIF increases, but is normalized by topical estrogen treatment or systemic HRT [155].

Recent evidence from mice with specific genetic deletions indicates that estrogen promotes wound healing in skin through ERβ but not ERα. Estrogen treatment actually delayed wound healing in mice deficient in ERβ in the skin [156]. However, estrogen agonists to both ERβ and ERα were anti-inflammatory during skin repair. This indicates that the anti-inflammatory effects of estrogens are decoupled from effects on overall re-epithelialization.

DHEA also influences wound repair. Systemic DHEA protects against chronic venous ulcers in older adults of both sexes compared to age-matched controls [157]. Exogenous DHEA also improved wound healing in aged mice [157]. In ovarectomized mice, subcutaneous DHEA restored the rate of wound healing, likely through local conversion to estrogens [157].

Conclusions

The sex steroids are intricately involved in supporting skin structure and function. The serum concentrations of the sex steroids differ in men and women and are affected differently by age in each sex. Concentration of the sex hormone precursors, DHEA and DHEAS, decline dramatically with age in both sexes, but concentrations are consistently lower in women. This age-related decline is especially important in women, as DHEA is the predominant, if not sole source of androgen and estrogen synthesis following menopause. In men, serum concentrations of testosterone decline slowly with age, but remain higher in older men than in postmenopausal women. Similarly, levels of the highly potent androgen, DHT, are higher in older men than women. Following menopause, estrone, the weaker estrogen formed from DHEA in peripheral tissue, becomes the sole source of estrogens in women, but aging does not significantly affect estradiol levels in men. These profiles impact gender differences in aging skin. Although both androgens and estrogens promote collagen deposition, the marked estradiol deficiency in postmenopausal women results in thinner, drier skin with a lower collagen content and reduced elasticity. By contrast, wound healing is compromised to a greater degree in older men than in older women, placing older men at greater risk from skin injury. Because androgens depress wound healing, this excess risk could be a consequence of the higher concentration of circulating androgens in older men than in women. Sebum production, which is affected by the interplay of growth factors and the sex steroids, changes minimally with age in men and only gradually in women. The formation and action of the sex steroids within the skin also is important. Local differences in the synthesis and receptor-mediated action of androgens and estrogens influence their effects on sweat glands and hair follicles. Sweat glands are androgen targets: they express 5α-reductase (which converts testosterone to DHT) and AR, through which these hormones act. Hence, although the sweat response declines with age overall, evidence exists that men sweat to a greater degree than women at all ages. Senile sebaceous gland hypertrophy is a compensatory mechanism against the decrease in sebum secretion with age [124]. Hair follicles are targets of action of both androgens and estrogens. DHT causes hair follicles of genetically susceptible men to miniaturize and reduces the number of follicles in the growth phase, leading to male pattern baldness (androgenetic alopecia). In women, the impact of DHT is limited because their scalp hair follicles express lower levels of 5α-reductase and AR and higher levels of aromatase, which converts testosterone to estrogen. Estrogen promotes hair growth through action on the ERβ receptor, which is present at sites of hair renewal in the follicles of women but not men. In short, the skin of both men and women is affected by declines in the sex steroids. Although undoubtedly not the only contributing factors, the altered balance in androgens and estrogens and in the expression of key steroidogenic enzymes and receptors within the skin itself, appear to influence some of the salient gender differences in aging skin.

Acknowledgements

The authors acknowledge the editing writing assistance from Deborah Hutchins, PhD ELS, Hutchins & Associates LLC, Cincinnati OH, USA.

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