Production of DHEA and DHEAS begins during adrenarche. Serum concentrations of DHEAS reach their peak (in the order of 10⁻⁸ and 10⁻⁶ M, respectively) between the ages of 20 and 30 years [8]. Then DHEAS concentrations decline with age, being reduced to 20 % of peak levels by age 70 and 5 % of peak levels by age 90 [4, 6, 19–21]. Because DHEAS and DHEA serve as sex steroid precursors in peripheral tissue, this decline in circulating levels is thought to contribute to some of the degenerative changes seen with aging.

Gender differences exist in serum concentrations of these hormones (see Table 11.1). Circulating levels of DHEAS in adult women are consistently lower than those in men at all ages [20, 22, 23]. 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 [18]. By contrast, in postmenopausal women, DHEA is the exclusive source of sex steroids for all tissues except the uterus [18]. Nevertheless, large variability exists in the circulating levels of DHEA among women: an almost eightfold difference between high and low levels has been found [24], with the low end being barely detectable. This wide range could help explain why some older women experience fewer signs of hormone deficiency after menopause, while others experience significant signs and symptoms [24].

About 30–50 % of total androgens in adult men [25] and about 50–100 % in adult women, depending on age, are derived from DHEA and DHEAS [26]. In women, androstenedione levels decline with age up to menopause, remain fairly stable in the early years after menopause [10, 27], and then decline by about 20 % by 30 years after menopause [10]. Early studies suggested that the postmenopausal ovary was a source of androgens [26], but this is controversial. Recent studies indicate that expression of steroidogenic enzymes by the postmenopausal ovary is limited [28, 29], and that, absent the adrenal production, postmenopausal women have no detectable circulating androgens [30].

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 testosterones are bioavailable to tissues.

In younger men, the testicular Leydig cells produce 95 % of testosterone and a smaller amount of DHT (see Fig. 11.2). In premenopausal women, 25 % of circulating testosterone comes from the adrenals, 25 % from the ovaries [31], and the rest from peripheral conversion of androstenedione in adipose tissue [32].

In healthy men, total testosterone and free testosterone decline slowly with age [4, 33, 34]. The decline in total testosterone is modest, but comparatively greater for free testosterone due to the concurrent age-related rise in SHBG [35]. Data from a large, population-based cohort of men aged 40–70 at baseline who were followed for 7–10 years (the Massachusetts Male Aging Study) showed that total testosterone declined by age cross-sectionally (between subjects) at 0.8 %/year, free and albumin-bound testosterone declined at about 2 %/year, and SHBG concentrations rose about 1.6 %/year. Longitudinally (within subjects), total testosterone declined 1.6 %/year, bioavailable testosterone declined by 2–3 %/year, and SHBG levels rose at 1.3 %/year [4].

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). Moreover, 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 [35]. 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 [36].

In women, testosterone levels decline between the ages of 20 and 50 [37]. 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 [6]. Other studies found a slight decrease in levels of bioavailable testosterone in the early years after menopause [10, 27], followed by a rise to premenopausal levels in the second decade following the menopausal transition [10]. Hence, declines during the decades preceding menopause 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.

In women of reproductive age, the ovaries are the principal source of estradiol. Menopause occurs when senescence of the ovarian follicles reduces the gonadal production of estradiol to miniscule levels (see Table 11.1). During this transition, circulating levels of estradiol decline from over 300 pmol/L to about 20 pmol/L [27, 38].

Estrone, a weaker estrogen produced from androstenedione in peripheral tissues, is the predominant form of estrogen in postmenopausal women (see Fig. 11.2). Estrone is also the principal source of postmenopausal estradiol, although only 5 % of estrone is thus converted [39]. 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 [40]; the testes produce only 20 % of plasma estradiol [41, 42]. In younger men, 20 μg/day of estradiol derives from peripheral conversion of plasma testosterone, 5 μg/day from androstenedione, and 5–10 μg/day from the testicular Leydig cells [16]. As in women, plasma estrone derives principally from tissue aromatization of androstenedione, with 20 % secreted directly by the adrenals. 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) (see Table 11.1) [43].

In men, plasma estradiol levels do not decrease significantly with age [19, 33, 44] (see Tables 11.1 and 11.2), although some investigators have reported declines [45, 46]. It has been postulated that plasma estradiol levels remain relatively unchanged despite declines in testosterone because of a rise in aromatase activity coincident with the age-associated increase in body fat mass [47, 48]. Consequently, plasma estradiol levels in older men are significantly higher than in postmenopausal women (see Table 11.1).

The skin is affected not only by the action of circulating sex steroids but also by locally synthesized androgens and estrogens. Local production depends on the expression of androgen- and estrogen-synthesizing enzymes in individual skin structures and cell types (Table 11.3). Moreover, the expression of sex steroid receptors in the skin varies by cell type and by sex. Cytochrome p450c17, an enzyme necessary for the synthesis of DHEA and androstenedione from cholesterol, is not expressed to a great extent in androgen target cells, such as sebocytes; however, sebocytes, sweat glands, and dermal papilla hair cells do express enzymes that convert these adrenal prohormones into biologically active testosterone and DHT [49, 50]. Indeed, human sebocytes selectively use DHEA to produce active androgens [51]. A newly identified pathway in human sebocytes synthesizes DHT from DHEA 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 (see Table 11.3) [52, 53].

As in other steroidogenic organs, six enzyme systems are involved in the activation and deactivation of androgens in the skin: steroid sulfatase, 3β-hydroxysteroid dehydrogenase Δ⁵⁻⁴ isomerase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), steroid 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD), and aromatase [54]. The pilosebaceous unit and the sweat glands contribute to local synthesis of androgens and estrogens. Steroid sulfatase hydrolyses DHEAS to DHEA [55] (possibly in the sebocytes or in the dermal papillae of terminal hair follicles, which show enzymatic activity).

Within the pilosebaceous unit, testosterone is both produced from adrenal precursors as well as inactivated; this maintains androgen homeostasis [51, 52]. 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 [54]. Keratinocytes also are responsible for androgen degradation [52].

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) [56], 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 [57]. 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 [52, 53] 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 [58].

Androgens (specifically testosterone and 5α-dihydrotestosterone (DHT)) and estrogens (specifically estradiol) mediate their skin effects by activating specific cellular receptors. 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 [59, 60].

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 [59, 61]. ERα and ERβ are expressed in the sebaceous gland [59] and in primary cultures of dermal fibroblasts [62, 63].

Studies suggest that ERβ is the mediator of estrogen effects on skin and hair. 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 [59]. ERβ is also highly expressed in the epidermis, sebaceous glands, blood vessels, and dermal fibroblasts (see Table 11.3).

The apocrine gland develops from the hair follicle. ERβ but not ERα is expressed in the secretory epithelium of the apocrine gland [59] as well as in the eccrine gland. Estrogen receptor also is expressed in normal melanocytes [64] and in nevi of pregnant and nonpregnant women [65].

Human male skin is thicker and drier than female skin throughout the life span (from ages 5 to 90 years) [66, 111]. In part, this is because androgens stimulate epidermal hyperplasia in adult human skin [83]. Although the skin thins with age in both sexes, in men, skin thickness decreases linearly beginning at age 20, whereas in women, it remains relatively constant until about age 50 and then decreases [112]. Epidermal thickness decreases about 6.4 % per decade on average, but faster in postmenopausal women than in men [67]. Dermal thickness decreases by up to 20 % in both genders [68], although in sun-protected sites, significant dermal thinning occurs only after the eighth decade [113].

The 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 disorganized, especially in photoaged skin, as the matrix metalloproteinases, which degrade collagen, are upregulated by UV exposure [69]. When the balance between collagen synthesis and degradation is disturbed, the collagen fibers fragment, disrupting the tension on dermal fibroblasts that exists in a healthy collagen matrix and causing fibroblasts to collapse [74, 75].

Elastin calcifies and degrades with age and its turnover declines [114]. 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 [68].

DHEA plays a role in maintaining skin structure. It regulates the synthesis and degradation of extracellular matrix protein; it promotes procollagen synthesis; and it limits collagen degradation by decreasing the synthesis of collagenase and matrix metalloproteases and increasing the production of tissue inhibitors of matrix metalloproteinase [72, 73]. Consequently, the substantial decline in DHEA with age reduces procollagen synthesis and elevates collagen degradation.

Oral DHEA treatment in men and women aged 60–79 for 1 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 [99]. 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 to a relatively greater degree from DHEA supplementation.

Most studies on the effects of estrogen on aging skin have examined the uses of systemic or topical estrogens in postmenopausal women. Estrogen slows or reverses these manifestations of skin aging, maintaining skin thickness, collagen content, and hydration.

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 [115]. Other studies found that postmenopausal women receiving HRT achieved skin thickness levels comparable to those of premenopausal women [116].

Collagen reduction is a major factor responsible for skin atrophy. The declines in the quality of collagen and elastin with age are more pronounced in aging women, probably due to estrogen deficiency. After a slight delay following the onset of menopause [76], total collagen content declines an average of 2.1 %/year in the first 15 postmenopausal years [76, 117]. Clinical studies have demonstrated beneficial effects of oral, topical, and subcutaneous estrogen treatment on collagen content (reviewed in [118–120]). The benefits of HRT or estrogen supplementation on collagen content are proportional to baseline levels at the time of treatment [76, 117].

Estrogen also benefits skin elasticity. In the first 5 years following menopause, facial skin distensibility increases 1.1 %/year and elasticity decreases by 1.5 %/year [78, 79, 121]. 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 [79, 102, 122, 123], although topical estrogen treatment seems to be effective only in sun-protected skin [124]. The extent to which the effect is due to improvements in elastin fiber quality is unclear.