Human TNF-α is a non-glycosylated protein that triggers inflammatory responses [11]. In the skin, TNF-α is synthesized by monocytes, macrophages, keratinocytes [1], and fibroblasts [12]. These cells produce membrane-bound TNF-α which is then converted to a soluble protein by TNF-α-converting enzyme. Both soluble and insoluble TNF-α are capable of forming non-covalently linked homotrimers that are biologically active [13].

Epidermal keratinocytes and dermal fibroblasts produce an increased amount of TNF-α on exposure to ultraviolet B (UVB) radiation which leads to increased inflammation [14]. Macrophages in old skin secrete only low levels of TNF-α compared to younger skin. In old skin less antigen-specific CD4+ T cells are recruited from the blood to skin areas where antigens enter because of defective activation of dermal blood vessels as a result of less TNF-α secretion [15]. As a consequence, old age brings with it decreased immunity [16] and increased skin infections [17]. This is reflected in decreased skin delayed-type hypersensitivity (DTH) responses when exposed to previously sensitized antigens [15].

Cutaneous macrophages have been studied in order to determine the reason for decreased TNF-α levels in old skin biopsies. Old cutaneous macrophages are inactivated, but not defective. This is because there is an increase in TNF-α secretion when Toll-like receptor (TLR) ligands are added [15]. CD4+Foxp3+ regulatory T cells inhibit TNF-α secretion from macrophages besides inhibiting macrophage activation [18]. These regulatory T cells occur in a high level in old people’s skin [15, 19].

When intradermal injections of different recall antigens and organisms (Candida albicans, bacterium tuberculin purified protein derivative, and varicella zoster virus) are introduced into skin, there is a low DTH response in old skin [15]. Younger people are less susceptible to skin malignancy and infections, but the reaction of skin to antigens decreases with age [17]. This occurs because TNF-α aids leukocyte diapedesis from blood vessels into the skin dermis by increasing the expression of VCAM-1, ICAM-1, and E-selectin adhesion molecules on endothelial cells [15].

A defect with TLR4 expression and function of cutaneous macrophages has been detected in old skin [10, 20, 21], but this finding is not always present [22]. Secretion of TNF-α by macrophages may be low because of defective TLR1 and TLR2 function after ligands bind to the receptors [23]. This was noted when C. albicans was used as a recall antigen to infect skin [15]. The defect in these three different receptors seems to be reversible as skin monocytes and macrophages secrete a higher quantity of TNF-α when these receptors are stimulated in vitro [15]. However, the skin samples used by Agius et al. lacked the cytokine Interferon-gamma (IFN-γ) which is necessary for macrophages to become activated and reach their maximum functional capacity. This reason could contribute to the low number of T cells that moved to the antigen challenge site. Several cytokines are needed for macrophages to become activated besides signals from TLRs [15].

Various genes of macrophages including the major histocompatibility complex (MHC) class II genes need IFN-γ for their expression. Macrophage MHC class II present antigens to T cells [24]. This immune response does not take place in old people because antigen presentation does not occur, thus producing a block in the cascade [15]. Chronic nonspecific inflammatory responses are common in old age because there is decreased memory T cell immunosurveillance as a result of decreased macrophage activation. This can also predispose to malignancy and infection of aged skin, as well as to crystal arthritis, because debris is allowed to accumulate in blood vessels and skin tissue [15, 25].

The level of TNF-α in the circulation is higher after menopause [3, 26, 27], and this inhibits collagen synthesis while increasing collagenase synthesis [28].

TNF-α is involved in skin inflammatory responses. It modulates matrix metalloproteinase (MMP) gene expression and induces MMP-9 production. MMP-9 damages skin and inhibits its repair, thus causing the skin to age [29]. Persistent exposure of epidermal cells to TNF-α disturbs MMP-9 production and can damage the epidermis irreversibly [29]. MMP gene transcription is controlled by nuclear factor kappa B (NF-κB) [29] and activator protein-1(AP-1) [30], both of which are transcription factors. TNF-α increases MMP-9 production by increasing the binding activity of AP-1 and NF-κB to the MMP-9 DNA sequence [29].

The 3-deoxysappanchalcone decreases MMP-9 expression and inflammation [29]. 3-deoxysappanchalcone is a flavonoid that has antioxidant, anti-inflammatory, and antiallergic properties [31, 32]. It inhibits the expression and DNA binding activity of AP-1 proportionally to its concentration, hence decreasing MMP-9 protein expression [29]. Besides acting on AP-1, 3-deoxysappanchalcone directly inhibits NF-κB without affecting inhibitory kB (IκB) [29]. 3-deoxysappanchalcone inhibits MMP-9 expression at the mRNA and protein level in human keratinocytes. This is achieved by inhibiting the activation of AP-1 and NF-κB transcription factors. This is used by some pharmacological products that help skin renewal [29].

Epidermal TNF-α secretion increases after premalignant keratinocytes are irradiated with UVB. This leads to elimination of the G2/M checkpoint of the keratinocyte cell cycle and increases apoptosis while inhibiting DNA repair [13]. Since cells escape the checkpoint, they accumulate mutations and tumors develop. TNF-α regulates the atypical protein kinase C (aPKC) and activates protein kinase B (Akt). The aPKC-Akt axis reduces DNA repair. Treatment of keratinocytes with infliximab inhibits DNA repair despite enhancing the G2/M cell cycle checkpoint and apoptosis [13].

TNF-α increases cutaneous infections in old skin because of decreased skin immunity [16, 17]. It also inhibits collagen synthesis and increases collagen degradation hence producing skin aging [28, 29].

IL-1 together with eight other cytokines belongs to the IL-1 structural family, also known as IL-F [33]. The outermost layer of the epidermis known as the stratum corneum contains active IL-1 [34]. IL-1α has both cytokine and transcription factor properties and it is located intracellularly. IL-1β is initially produced inactive until it is cleaved by cysteine protease caspase-1 [33]. IL-1β levels are raised in the inflammatory mechanisms of aging and atherosclerosis. They bring about elevated levels of amyloid A and C-reactive protein [33].

Keratinocytes produce both IL-1α and interleukin-1 receptor antagonist (IL-1ra). IL-1ra acts on several target cells by binding to common receptors by competitive inhibition [34]. This is however debatable as other investigators reported that IL-1ra binds to the IL-1 receptor type I only [33]. IL-1α release from keratinocytes is triggered by various stimuli including UVB radiation. It causes skin inflammation by activating different cytokines and adhesion molecules. IL-1α is inhibited by IL-1ra; the balance between these two cytokines maintains skin homeostasis [34].

The level of IL-1 in the stratum corneum in facial skin (exposed to UVB) does not change significantly with age, while IL-1α level is higher in aged skin samples taken from the inside of the upper arm (not exposed to UVB) compared with samples taken from younger skin. Conversely, the level of IL-1ra measured from skin biopsies taken from the inside of the upper arm was found to decrease with age [34]. However, an increase in the level of IL-1ra with aging has been observed in cultured human keratinocytes, while a decrease in level noted in photoaged cells [35]. No difference in the level of IL-1 cytokines present in the stratum corneum between males and females was observed [34].

IL-1 release form keratinocytes in the epidermis induces cortisol synthesis which controls wound healing [36]. Conversely, insulin-like growth factor-1 decreases the production of cortisol. The epidermis produces various enzymes necessary for de novo cortisol synthesis like steroid 11β-hydroxylase (CYP11B1) and 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) that converts active cortisol into inactive cortisone and controls negative feedback responses. Glucocorticoids (GCs) inhibit the healing process of wounds and limit the degree of inflammation in acute wounds. CYP11B1 enzyme inhibitor (metyrapone) inhibits cortisol synthesis in skin keratinocytes while ACTH promotes synthesis [36].

Upon tissue injury, keratinocytes release preformed IL-1 [37]. IL-1 is the initial signal of tissue injury that has both autocrine and paracrine functions. It activates keratinocytes to migrate and proliferate while they secrete more proinflammatory molecules [38]. Cessation of inflammation and tissue healing is brought about by activated keratinocytes that transition into a differentiating phenotype [36]. This is facilitated by IL-10, IL-receptor antagonist, GCs, and transforming growth factor-β1 (TGF-β1) that reverse the activation of keratinocytes and bring about resolution [36]. Treatment of keratinocytes with GC inhibits the synthesis or signalling of several inflammatory cytokines including IL-1β, IL-4, IL-8, INF-γ, and TNF-α and growth factors like TGF-β, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) that take part in the inflammatory part of wound healing [39]. IL-1, IL-6, and TNF-α act on the hypothalamic-pituitary-adrenal axis to increase cortisol synthesis [40].

IL-1β is a proinflammatory cytokine that increases the expression of CYP11B1 and hence the production of cortisol and activates the GR pathway involved in wound healing both in vivo and ex vivo. Epidermal cortisol synthesis may serve locally as a negative feedback to proinflammatory cytokines because when cortisol synthesis is inhibited, the production of IL-1β is increased. This regulatory mechanism prevents excessive inflammation form occurring during wound healing that may otherwise damage the tissue even more. When GC synthesis is inhibited, the wound closure process is faster in vivo [36].

The epidermis is unique in its properties and characteristics. Although it lacks its own vascular supply, it is the “first line of defense” that comes in contact with foreign antigens, pathogens, and commensals and is exposed to various forms of injury. Keratinocyte activation and timely regulated release of IL-1β together with other proinflammatory cytokines and growth factors are the main features that enable skin to function as an effective barrier [38].

In vitro studies showed that the production of both IL-1α and IL-1β increased in cocultured keratinocytes more than in monocultures. Keratinocytes by producing IL-1 actively stimulate fibroblasts to produce keratinocyte growth factor that stimulates the proliferation of keratinocytes. IL-1 does not have a direct effect on keratinocyte proliferation as was observed in monocultures. IL-1 thus regulates skin homeostasis through a double paracrine mechanism. This was also observed in blocking experiments; when IL-1α and IL-1β neutralizing antibodies together with IL-1 receptor antagonist were applied to cocultures, the proliferation of keratinocytes was reduced. This inhibition was reversible because when the antibodies were removed, keratinocyte proliferation rate was the same as in controls [41]. Various other cytokines and growth factors have been detected in keratinocytes and fibroblasts including IL-6, IL-8, TGF-α, TGF-β, granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), and nerve growth factor (NGF) [42].

Dermal fibroblasts in aged human skin produce a higher level of CCN1 than in younger skin. CCN1 upregulates the level of IL-1β, decreasing the skin collagen content in two ways: by increasing the amount of MMPs that degrade collagen and by downregulating the rate of collagen synthesis [43, 44]. IL-1β also downregulates TGF-β type II receptors impairing TGF-β signalling. This increases the risk of developing inflammatory and degenerative disease in osteoarthritis [43, 44].

The postmenopausal drop in estrogen is accompanied by a rise in IL-6 level [3]. During infection or tissue injury, the level of IL-6 rises much more than the postmenopausal level [45].

IL-6 is both a pro- and anti-inflammatory cytokine. It achieves these opposite functions by working through different signalling mechanisms [46]. Human keratinocytes produces IL-6 upon induction by TGF-α [47]. The IL-6 produced stimulates keratinocyte proliferation [48]. However, other researchers did not observe a rise in keratinocyte proliferation upon IL-6 expression in transgenic mice [49]. The stratum corneum of transgenic mice became thicker after IL-6 expression, but epidermal proliferation was not increased, and there was no leukocyte infiltration. This suggested that although IL-6 is elevated in inflammatory conditions, it is does not have a direct proinflammatory activity on the skin [49]. IL-6 is also produced by dermal fibroblasts [44].

Besides TGF-α, IL-1, IL-4, TNF-α, and IFN-γ also induce the production of IL-6 in keratinocytes [50, 51]. CCN1 induces dermal fibroblasts to produce IL-6 through reactive oxygen species (ROS) and integrin pathways [44]. Ultraviolet radiation increases IL-6 production. IL-6 plays a role in skin aging, wrinkle formation [51], and tissue damage [44]. It is considered a health status marker in the elderly [52].

Chronic elevated levels of IL-6 together with IL-1β in aged skin contribute to sustained high levels of MMPs that degrade collagen, and thus these cytokines are negative regulators of collagen homeostasis. Furthermore, IL-6 decreases the rate of collagen synthesis [52].

In women aged between 25 and 82 years, there is no significant difference between 25-hydroxyvitamin D status (through UVB exposure) and IL-6 in women with regular versus not regular UVB exposure, unlike for serum TNF-α which had an inverse relationship with vitamin D level [53]. While most in vivo studies did not show that IL-6 serum levels are affected by vitamin D status [54], in vitro studies showed that 1,25-dihydoroxyvitamin D inhibits IL-6 production in different cells [55]. However, one study involving hemodialysis patients showed that a 6-month course treatment of both iv and oral 1,25-dihydroxyvitamin D significantly suppressed IL-6 concentrations [56]. Parathyroid hormone (PTH) induces IL-6 production by osteoblasts [57] although there is no significant relationship between circulating IL-6 and intact PTH (p = 0.8) [53]. Vitamin D supplementation decreases the level of PTH and hence its indirect effect on IL-6 concentrations [53].

In a study involving 47 healthy postmenopausal women taking daily 1 g of calcium and 800 U cholecalciferol for 12 weeks, there was no change observed in serum IL-6 level. A significantly inverse correlation was found between IL-6 and osteoprotegerin (p = 0.004). Furthermore, a significant correlation was obtained between insulin and IL-6 levels (p = 0.0005) [58].

IL-6 plays a key role in bone resorption by activating osteoclasts. It is also involved in other diseases that occur more frequently in menopausal women like atherosclerosis, diabetes, and cardiovascular disease [3, 59].

A significant positive association was found between menopausal status and IL-6 (R ²  = 0.0764, p = 0.0246) and between age and IL-6 (R ²  = 0.09413, p = 0.0116) with analysis of potential covariates [53].

IL-8, formerly known as neutrophil-activating peptide-I (NAP-I), serves to activate neutrophils and also as a chemoattractant. It is produced by fibroblasts, keratinocytes, melanocytes, endothelial cells, monocytes, and Langerhans cells [60]. Serum IL-8 level is significantly higher in menopausal women (p = 0.001) compared to women in their reproductive age [61].

The expression of IL-8 is increased by IL-1 and TNF [62]. Besides being a neutrophil chemoattractant, IL-8 is also a T-cell chemoattractant. However it has no effect on monocytes and eosinophils. The action on neutrophils is brought about by increasing the expression of Mac-1 (a cell adhesion molecule) on neutrophils [1].

When IL-8 is injected into the dermis, it causes neutrophils to accumulate in the dermis surrounding the blood vessels [63]. Excess IL-8 is found in psoriatic skin and causes neutrophils to accumulate in the epidermis [64]. Excess IL-8 also plays a role in cutaneous T-cell lymphoma [65].

IL-10, a potent anti-inflammatory cytokine [66], is known as cytokine synthesis inhibitory factor (CSIF) because it inhibits the production of several cytokines including IL-2, IL-3, TNF, and GM-CSF and also inhibits the proliferation of T lymphocytes [67–69]. It has an immunosuppressive role [67]. IL-10 is produced by keratinocytes, macrophages, and B lymphocytes [67]. UV light increases the production of IL-10 in human keratinocytes [1, 70].

The difference in circulating IL-10 levels is not significant between postmenopausal and fertile women [71]. Levels of 25-hydroxyvitamin D in healthy women showed no statistically significant relationship with circulating IL-10 measured using highly sensitive ELISA kits, suggesting that the body status of vitamin D does not affect the secretion of IL-10 into the systemic circulation in healthy individuals [53]. Furthermore, a positive relationship between 25-hydroxyvitamin D and IL-10 in the circulation was found in diseased individuals [72].

IL-18 belongs to the IL-1 structural family and is similar in structure to IL-1β [33]. Previously, it was known as interferon-gamma-inducing factor (IGIF). IL-18 is produced by dendritic cells, macrophages, and epithelial cells [33]. IL-12 increases the expression of IL-18 receptors on natural killer cells, T lymphocytes, and thymocytes [73]. It functions as an immunoregulatory and proinflammatory cytokine and is involved in the aging process, atherosclerosis, and autoimmune diseases. The aging process might be slowed down by therapeutic strategies that reduce IL-18 [33]. IL-18 binding protein (IL-18BP) is an inhibitor of IL-18. When this inhibitor is overexpressed, mice deficient in apolipoprotein E do not develop atherosclerosis [33].

The circulating level of IL-18 is higher in postmenopausal women compared to fertile women [71]. IL-18 inactive precursor becomes active upon cleavage by cysteine protease caspase-1 [33]. This immunoregulatory cytokine has the ability to induce IFN-γ [74]. Research has shifted towards blocking IL-18 activity in autoimmune diseases as it inhibits the production of IFN-γ [33].

This proinflammatory cytokine enhances the production of cell adhesion molecules, nitric oxide, and chemokines [33]. It is also involved in type 2 T-helper cell (Th2) polarization. Both allergic and nonallergic skin inflammation are worsened with overexpression of IL-18 [75]. When combined with IL-12, IL-18 stops the production of immunoglobulin (Ig) E [33]. On the other hand, IL-18 prevents UV-induced immunosuppression and protects the skin from damage after exposure to UVB radiation by promoting DNA repair [76]. Unlike other proinflammatory cytokines, IL-18 does not produce fever [77] and prostaglandin E₂ [78].

The signalling cascade of IL-18 starts with IL-18 binding to IL-18 receptor α (IL-18Rα), which then recruits IL-18Rβ to bring the intracellular Toll domains in close proximity [33]. This complex recruits MyD88 protein that phosphorylates IL-1 receptor activating kinases (IRAKs). TNF factor is then phosphorylated followed by inhibitory κB kinases (IKK) α and β activation. IκB is then phosphorylated and NF-κB moves to the nucleus. Mitogen-activating protein (MAP) kinase p38 is also phosphorylated. IL-18BP located extracellularly can neutralize IL-18 and prevent it from binding to IL-18Rα. IL-18 bound to IL-18BP can form an inactive complex with IL-18Rβ, consuming IL-18Rβ chain to further decrease the chance of cell activation [33].

IFNs are known for their antiproliferative activities, antiviral activities, and regulation of cell differentiation and proliferation [79]. Three major types of IFNs are recognized based on the type of receptors used in signalling: Type I includes IFN-α, IFN-β, and IFN-ω that bind to IFN-α receptor; type II is IFN-γ in humans and binds to interferon-gamma receptor (IFNGR) [80]. The class interferon type III which signals via IL10R2 and IFNLR1 is not universally accepted [81].

CRY61 forms part of the connective tissue growth factor, cysteine-rich protein, and nephroblastoma overexpressed gene (CCN) protein family that together with the other five matricellular protein members of this family, it interrelates with the extracellular matrix [44, 91]. CRY61 is also known as CCN1. Its function is to induce M1 macrophages to become activated and express a proinflammatory genetic profile. It also plays a role in Th 1 cell responses. CCN1 decreases the production of TGF-β, while it enhances the production of the cytokines TNF-α, IL-1α, IL-1β, IL-6, and IL-12b. Furthermore, it alters the mechanism of some cytokines, for example, it induces TNF-α to exhibit cytotoxic properties without inhibiting the activity of NF-κB [92]. This alteration in the genetic profile is brought about via either of two pathways: a delayed response achieved via CCN1-indcued TNF-α or through an immediate-early response that involves direct activation of CCN1 [92].

A high level of CCN1 in aged skin causes dermal fibroblasts to have an “age-associated secretory phenotype” [44]. Fibroblasts produce collagen that is the main component of the skin connective tissue. Fibroblasts also degrade collagen. The fibroblast phenotype in aged skin brings about abnormal homeostasis of type I collagen in the skin, where collagen production is low while degradation increased [93].

CCN1 interacts with integrins to increase the level of ROS [94] which in turn activates MAPK and NF-κB signalling pathways to increase the production of IL-1β and IL-6 [52]. IL-1β and IL-6 increase the production of MMPs in old dermal fibroblasts. These two cytokines further imbalance collagen homeostasis by lowering the rate of collagen production [43, 52]. TGF-β signalling is impaired in dermal fibroblasts of aged skin because IL-1β decreases the TGF-β type II receptors to have a negative effect on collagen homeostasis [93]. All these cause the skin connective tissue to age, and the skin loses its function and integrity [44].

TGF-β is a cytokine family that has many functions, for example, it suppresses inflammatory processes; regulates cell growth, differentiation, and proliferation; controls extracellular connective tissue synthesis; and plays a role in tissue repair and tissue recycling after injury [3, 95, 96]. It acts as an antagonist to proinflammatory cytokines [3]. Three isoforms of this cytokine family are found in mammals: TGF-β1, TGF-β2, and TGF-β3 [95]. They bind to either of the two cell-surface receptors – TGF-β type I receptor (TβRI) and TβRII – and the signal continues via the Sma and Mad (Smad) pathway to bring about their actions [97].

In the skin, TGF-β stimulates dermal fibroblasts to proliferate and increase the production and secretion of most ECM proteins including type I, III, and VII collagens [97] and fibronectin [98]. It also decreases the production of proteolytic enzymes including MMPs, collagenase, and stromelysin that break down the ECM proteins [99].

Estrogen increases the production of TGF-β in various tissue cells including fibroblasts, vascular smooth muscle, osteoclasts, and osteoblasts to inhibit bone resorption [3, 100]. Cutaneous wound biopsies taken from healthy postmenopausal women showed that they had a lower level of TGF-β in their wounds in comparison to younger women and this is associated with a slower rate of wound healing [95]. Application of topical estrogen after cutaneous injury in ovariectomized female rodents induces dermal fibroblasts to increase TGF-β1 secretion by stimulating the TGF-β/Smad pathway and this accelerates cutaneous wound healing [101].

Topical 17β-estradiol improves the symptoms of skin aging like loss of skin elasticity, thin dermal skin, and wrinkling [95]. This is achieved by increasing type I procollagen production which occurs to a bigger extent in the skin of aged females than in aged males [95]. Conversely, the effect of topical 17β-estradiol on MMPs and fibrillin-1 was not found to be significantly different between male and female skin although the investigators suggest that this could be due to the small number of volunteers that took part in the experiments [95]. When anti-TGFβ1 antibody was added together with 17β-estradiol to cultured fibroblasts, there was no increase in procollagen type I [95].

Studies suggest that 17β-estradiol application to aged skin stimulate the TGF-β/Smad pathway to increase fibrillin-1 and elastin production, two main fibers that give skin its elastic properties [95]. Aged skin has less elastin and increased elastic fiber breakdown than younger skin [102].

Although TGF-β inhibits epidermal keratinocyte growth [103], when 17β-estradiol is applied to old skin, there is increased proliferation of epidermal keratinocytes contributing to a thicker epidermis [95]. This might occur through activation of ERK or modulation of the level of estrogen receptors in the nucleus [104] instead of through the TGF-β/Smad pathway [95].

Skin aging is characterized by wrinkle formation that results from rapid loss of collagen which leads to decreased skin elasticity [105]. Climacteric skin aging is a separate entity from chronological aging and photoaging that contributes to cutaneous wrinkling [106]. The loss of collagen as a result of hypestrogenemia in the initial postmenopausal period occurs at a faster rate than that in later menopausal years, with about 30 % loss in the initial 5 years [107]. A study on 186 Korean females of ages varying between 20 and 89 showed that women with more than 10 years since the onset of menopause had significantly greater facial wrinkling than women with less than 5 years in their postmenopausal period, after controlling for sun exposure and age [106]. Korean women had 3.7 times greater risk to develop severe wrinkles than Korean men [108]. Conversely, men under the age of 50 had a significantly greater risk of wrinkling (p < 0.05) than women of similar age [106]. Studies on white Caucasian individuals found out that females in their 60s had a 28-fold increased risk of developing wrinkles compared to women in their 40s, whereas men had only an 11.4-fold increased risk [109]. After the age of 50 years, facial wrinkles increase more rapidly with age in women than in men. This suggests that hypoestrogenism in postmenopausal women contributes more than chronological aging to the decline in skin collagen and wrinkling [106]. Collagen content decreases by 2.1 % every postmenopausal year [110].

HRT prevents wrinkle formation in postmenopausal women. HRT helps the skin to form more mature collagen fibers [111]. Estrogen enhances the production of hyaluronic acid and glycosaminoglycans which increase the water content of dermal collagen [112]. These two mechanisms serve as a protection against facial wrinkling [106].

Wrinkle formation starts with activation of receptors like interleukin-1 receptor, tumor necrosis factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and platelet-activating factor receptor, which lead to signal transduction which eventually activates AP-1 to stimulate the production of MMPs, which degrade collagen. C-jun transcription factor subunit is the limiting factor of AP-1 activity [105]. This subunit is found at a higher level in aged skin (80 years old) compared to younger skin (18–28 years old) [113]. C-jun is the common intermediate protein that takes part in all the five different signal transduction pathways involving all the mentioned receptors. Thus c-jun is the target for new drugs to prevent the wrinkle formation [105].

Hair changes that may occur with menopause include a decrease in body hair and pubic hair and an increase in facial hair [114]. Scalp hair changes include fine-textured hair that inadequately covers the scalp and increased spaces between the hairs on the vertex in comparison to the occiput that is typical of female pattern hair loss (FPHL) [115]. Frontal fibrosing alopecia can also occur (see Chap. 9) [116]. Although hair density decreases with age, this is not related to menopausal status [115]. Estrogen regulates the growth of hair follicles and hair cycles [115]. Human hair follicles contain more estrogen receptor (ER)-β than ER-α [117]. Estradiol increases aromatase activity in scalp follicles of humans [116] to increase the production of estrogen from adrenal androgen [115]. Male and female frontotemporal hair follicles respond to 17β-estradiol differently. In the lower outer root sheath of male hair follicles, TGF-β2 immunoreactivity decreased, whereas it increased in follicles taken from females after 48 h from treatment with 17β-estradiol [118].

Estrogen modulates the production and activity of several cytokines, growth factors, and transcription factors that influence hair growth, but further research of the pathways involved is required [115]. On the other hand, the role of androgens on hair growth has been extensively studied as it has previously dominated the field of hair biology [115].