Cutaneous scarring with tissue fibrosis is the result of a postnatal wound healing process. The longer the duration and the excessive the inflammatory response in the healing course, the more likely is the development of aberrant scarring and severe tissue fibrosis. However, scar formation varies depending on the body site, the skin architecture and anchorage to underlying structures.
Little is known about the pathophysiological processes of genital cutaneous wound repair except for the general clinical statement that genital wounds heal fast, with enormous swelling and almost invisible scarring. In the following, I will describe features that are different between the genitalia and the skin of other areas of the body and that influence acute wound healing or chronic scarring (◘ Fig. 47.10). It is beyond the scope of this chapter to include urethral, vaginal, or anal epithelial repair; tissues that derive from different developmental origins and with differential healing behavior (e.g., ulcerations, adhesion or fistula formation) compared to genital skin.
Skin Architecture and Biomechanics
The genital skin has to master many challenges, for example, fast volume changes during sexual activity, sex steroid sensitivity with permanent hormonal changes, the presence of several body openings with constant commensal microbial presence, and infectious threats deriving from sexual contacts. In that context, it is breathtaking to understand the extraordinary adaption of the genital skin to its multiple tasks. To encounter aforementioned challenges, it is excellently equipped anatomically and physiologically to address specific features of the genital microenvironment.
Notably the male genital skin has to manage fast volume changes that occur during sexual activity and for thermal regulation of the testes. These physiological tasks are addressed by several means: (i) abundance of skin tissue on both the penile shaft and the scrotal sac, (ii) the Dartos fascia on the penile shaft and the Tunica Dartos with the Dartos muscle in the scrotum, and (iii) a high amount of elastic fibers in the dermis. In all three items, the genitalia differ from skin of other body areas that is firmly attached to the underlying structures by a rather immobile fat layer. High skin elasticity and abundance of tissue are the prerequisite for tension-free acute wound healing with unapparent scars—optimal repair conditions present in the genitalia. A drawback is the tendency of the outer genitals to enormous swelling and edema after surgery or trauma. The good side is that due to its elasticity and intricate lymphatics, the swelling of the genital tissue resolves as fast as it occurs in healthy subjects.
Moist Environment and Bacterial Colonialization
Urethral, vaginal, and anal orifices are transition zones between mucous membranes and keratinizing skin. As depicted previously, parts of the genitalia are covered by little or nonkeratinizing squamous epithelia. The secreted fluids of multiple glands prevent the exsiccation of mucous membranes and provide a moist micro-environment. It is an established fact that moist wound healing contributes to faster wound closure and reduced scarring.
The proximity of the genital skin to different orifices is Janus sided. Aside from the beneficial moist milieu, bacterial load and stringent body fluids such as urine bear constant threats to the fragile mucosal skin lacking the protective epidermal cornified layer. And again, the genital mucosal skin is well prepared to address both biological and chemical challenges. In contrast to other parts of the body, keratinocytes and fibroblasts of the genital skin are equipped with a fast immune response to bacterial presence. By secreting antimicrobial peptides (AMPs) and defensins and with glandular mucous fluids, bacteria are held at a distance. The immune response is fast and so is the resolution with quick conversion of M1 to M2 macrophages and reduced expression of proinflammatory cytokines . Upon injury, skin cells increase the interleukin (IL)-1α production 15-fold in comparison to vaginal epithelial cells with only threefold increase. IL-1β and tumor necrosis factor (TNF)-α were only secreted by cutaneous epithelia in contrast to mucous epithelial cells . With regard to profibrotic mediators, TGF-β is significantly elevated in normal skin keratinocytes but not in mucosal epithelia and without induction of fibrotic processes in the underlying connective tissue. In summary, the reduced inflammatory response of mucosal epithelia to injury is sufficient to ensure wound closure without inducing serious scarring.
Increased Aromatase Activity and Intracrine Estrogen Production
Hormone responsivity of tissues has profound impact on wound healing.
Estrogens accelerate wound closure whereas testosterone delays healing . Skin is a major source of extraglandular sex steroid hormones that are produced from circulating dehydroepiandrosterone (DHEA, [24, 28]) (◘ Fig. 47.11). The intracellular enzyme aromatase converts DHEA downstream into the weaker estrogen Estrone or via testosterone into the more potent 17β-estradiol. Both estrogens act via the estrogen receptors (ERs) α and β, and stimulate keratinocyte and fibroblast migration . In genital fibroblasts, aromatase expression is androgen dependent. Interestingly, estrogens stimulate fibroblast contractility without increasing alpha-smooth muscle actin expression or myofibroblast differentiation . Upon mechanical wounding, aromatase activity increases 400-fold in
keratinocytes with increased intracellular bioavailability of estrogens. Testosterone reduces aromatase activity, albeit this effect is not present in case of low oxygen levels in tissues. Estrogens reduce the cellular inflammatory response via downregulation of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) , by reduced TLR-4 mediated MAPK activation, by the reduction of macrophage infiltration into wounds and by dampening the proinflammatory signaling of IL-6 and TNF-α . Of note, estrogens are also important antioxidants that reduce cellular oxidative stress and apoptosis and increase keratinocyte migration and collagen synthesis by dermal fibroblasts . In menopausal women,
cutaneous estrogen insufficiency manifests by atrophic skin changes and a diminished defense against reactive oxygen species.
Androgen and Estrogen Receptor Expression in Genital Skin
Estrogens act via estrogen receptors and testosterone via androgen receptors (ARs) that are expressed by many cell types. For instance, AR expression differs between
genital and nongenital skin with upregulation in genital fibroblasts. In general, it appears that sex steroid hormone expression is higher in stromal cells than in epithelial cells, implying higher responsiveness of fibroblasts to hormonal influences. Aside from receptor expression, the binding capacity and metabolism of sex steroid hormones differs between different skin regions. Testosterone binding capacity of the AR is higher in genital compared to nongenital skin cells  from both sexes—independently of age—and testosterone degradation is up to 30 times faster in genital skin compared with nongenital skin .
Sex hormone receptor expression in
genital skin differs between prenatal and adult genital skin due to the terminal differentiation of the external genitalia that is dependent on hormonal influences. In fetal skin, ARs are very similarly expressed in both sexes with the absence of ARs on the preputial skin, penile shaft/labia minora, and scrotal skin/labia majora. ARs are expressed in the tissue of the glans and inner prepuce of both sexes and in the stromal tissue of the labia.
ER was present in fetal female genital skin except for labia minora and majora  and prominent ER staining was found in the entire developing fetal penis including skin, glans, inner prepuce,
and stromal cells . Interestingly, ARs and ERs were colocalized in penile tissues.
Less detailed information is available with regard to adult genital skin. In women, ARs are found in keratinocytes and fibroblasts of the labia majora and minora and in the adjacent extragenital skin. ER immunopositivity was found in the labia minora and nongenital skin. There are no differences in sex hormone receptor expression between pre- and postmenopausal women. Progesterone receptors are not present in
genital skin. In men, ARs were located to basal keratinocytes and stromal fibroblasts of the penile foreskin. No AR expression was found in nongenital cutaneous keratinocytes or fibroblasts but in fibroblasts of hair follicle papillae or in cells of pilosebaceous ducts and glands, skin structures that are influenced by androgens in their function and structure. The highest intensity of AR staining was noted in genital skin. ERs were similarly expressed in postnatal penile skin with localization to basal epithelia and stromal cells adjacent to the urethra and the urethra itself with age-dependent reduction . Aromatase is not colocalized with estrogen receptors, and levels of aromatase,
ERα, and ERβ decrease with age .
In summary, ARs and ERs are highly expressed in genital skin in contrast to skin of other body areas with fast binding and degradation of testosterone or conversion into estrogen by increased aromatase activity. A summary of hormonal differences between genital skin and nongenital skin is given
in ◘ Table 47.2.