Tissue Structure and Physiology of the Vulva

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Miranda A. Farage

Feminine Care Clinical Sciences, The Procter & Gamble Company, Cincinnati, Ohio, U.S.A.

Howard I. Maibach

Department of Dermatology, University of California School of Medicine, San Francisco, California, U.S.A.


The vulva is composed of specialized tissue with regional differences in embryonic derivation, structure, and morphology. The vulva comprises the mons pubis, the labia majora and minora, the clitoris, the vulvar vestibule surrounding the urethral orifice and vaginal introitus, and the hymen, a membrane at the juncture of the vulvar vestibule and the vagina. This chapter describes variations in epithelial structure, blood flow, hormonal and immune responsiveness, barrier function, permeability, irritant susceptibility, and microbial colonization of the vulva in women of reproductive age (Table 1).

Portions of this chapter appeared in Farage MA, Maibach HI. The vulvar epithelium differs from the skin: implications for cutaneous testing to address topical vulvar exposures. Contact Dermatitis 2004; 51:201. Reprinted with permission from Blackwell Publishing.

Table 1 Qualitative Differences Between Exposed Skin and Vulvovaginal Epithelia

Characteristic Exposed skin Vulvar skin

Embryonic derivation Ectodermal

Tissue structure Keratinized, stratified squamous epithelium

Blood flow Hydration Occlusion Friction

Hormonal influences

Depends on anatomical site Depends on anatomical site Depends on anatomical site Depends on anatomical site

Menstrual cycle variability in water barrier function and susceptibility to irritants (53,54)

Higher blood flow than exposed forearm skin More hydrated than forearm skin (28,29) Greater occlusion than forearm skin Higher coefficient of friction than forearm skin (31) Thickness unchanged over the course of menstrual cycle (1) Menstrual cycle variability in barrier function and irritant susceptibility unknown

Vulvar vestibule Vaginal epithelium

Endodermal Mesodermal

(estrogen dependent) Nonkeratinized epithelium with less distinct stratification No data

Hydrated by cervicovaginal secretions Greater occlusion than exposed skin Not determined

Not determined Menstrual cycle variability in epithelial thickness, glycogen content, and nuclear pyknosis (13,15)


Immune cell densities


Varies by site; influenced by skin thickness (33)

Diverse population of immune cells

Diverse population includes Staphylococcus aureus, coagulase-negative staphylococci, streptococci, diphtheroids, yeasts, etc.

Permeability affected by increased hydration and occlusion (34,35)

Langerhans cells most common No difference in Langerhans cell density between keratinized and nonkeratinized regions (16)

Significantly more permeable than keratinized skin (45)

Microflora affected by hydration, occlusion, and vaginal and perineal cross-colonization. Higher densities of S. aureus, streptococci, lactobacilli, Candida, than exposed skin (55)

Microflora influenced by cervicovaginal secretions, perineal and urethral cross-colonization

Langerhans cell densities lowest at fornix, highest at introitus (17) Highly diverse, mixed aerobic and anaerobic microflora. Acid-producing microbes are dominant in healthy women (83)


The lower urogenital tract is the only portion of the female anatomy derived from all three embryologic layers (ectoderm, endoderm, and mesoderm) (Table 2). In the vulva, cutaneous epithelium derived from the embryonic ectoderm is juxtaposed closely with nonkeratinized epithelium derived from the embryonic endoderm (1,2).

The embryonic ectoderm gives rise to the keratinized cutaneous epithelium of the mons pubis, labia majora, clitoris, labia minora, and perineum. Like skin at other anatomical sites, the epidermis of the mons pubis, labia majora, and perineum has a keratinized, stratified squamous structure with sweat glands, sebaceous glands, and hair follicles (Fig. 1). Cutaneous thickness and degree of keratinization are relatively high on the mons pubis and labia majora, but decrease over the anterior portions of the clitoris and decline progressively from the outer surface to the inner surface of the labia minora (3).

The cutaneous epithelium consists of four layers:

1. A basal germinative layer (stratum basale), which rests on the basal lamina between the epidermis and the dermis.

2. A spinous or prickle cell layer, forming the bulk of the epidermal thickness (stratum spinosum).

3. A granular layer (stratum granulosum).

4. A surface layer of flattened, keratinized cells embedded in hydrophobic intercellular lipid (stratum corneum).

Three specialized cells—melanocytes, Langerhans cells, and Merkel cells—also reside in the epidermis. Melanocytes represent one-tenth to one-fifth of the cells in the cutaneous basal layer (4). They convert tyrosine to melanin pigment, which protects the basal cells from ultraviolet (UV) damage. Melanocytes respond regionally to hormones: at puberty, pigmentation of the mons pubis and labia majora increases; during pregnancy, steroid hormones stimulate

Table 2 Embryologie Derivation of the Female Lower Urogenital Tract




Skin of the labia majora and

part of the labia minora


Vulvar vestibule

Bladder (except trigone)

Anterior urethral wall


Hymenal membrane

Posterior urethral wall

Bladder trigone

Estructura Vulva
Figure 1 Epithelial structure of vulvar skin. Source: Adapted from Ref. 84. (See color insert p. 2.)

melanogenesis in the areola, nipples, and perineum and on the midline of the anterior abdominal wall.

Langerhans cells are dendritic cells found in the epidermis, in thymic and mucosal tissues, and in lymph nodes. Their chief function is to sample antigen at the epithelial surface, process it, and present it to circulating T lymphocytes, the activation of which initiates the cell-mediated immune response.

Merkel cells are found in the basal epidermal layer. Their cell bodies form synapse-like contacts with the terminal endings of myelinated nerve fibers. They release neurotransmitters in response to sensory excitation (5). Merkel cells serve as skin mechanoreceptors that shape sensitivity to soft touch.

The nonkeratinized epithelium of the vulvar vestibule is the only portion of the female genital tract of endodermal origin (2,6). The epithelial structure of the vulvar vestibule resembles that of the vagina and buccal mucosa (Fig. 2) (2,7). Its superficial stratum bears large, moderately flattened cells lacking keratin but containing glycogen granules and, frequently, pyknotic nuclei. Differentiation of the inner epithelial layers is indistinct: loosely packed, polyhedral cells alter in size and organelle density as they migrate upward from the generative basal layer, but do not form clearly demarcated strata as desmosomc basement membrane pyknotic nu desmosomc basement membrane pyknotic nu

stratum superficiale stratum spinosum sub-epithelial tissue stratum basale/ parabasale

Figure 2 Epithelial structure of the vulvar vestibule. Source: Adapted from Ref. 84. (See color insert p. 2.)

observed in the skin. Langerhans cells are present in the epithelium of the vulvar vestibule.


The vulva is a highly vascularized and well-innervated structure (8). Arterial blood supplies the vulva bilaterally and derives from branches of the internal iliac and femoral arteries; venous drainage eventually reaches the femoral and internal iliac veins.

Blood flow in labia majora skin is more than twice that in forearm skin (Table 3) (9). Studies of vulvar skin have demonstrated increased blood flow in response to histamine at doses to which forearm skin is unresponsive (10).

Innervation of vulvar tissue reflects its role in the sexual response. The vulva has both somatic and autonomic innervation. Motor components mediate pelvic muscle contraction and vascular engorgement of clitoral and vaginal tissue. Sensory components convey touch, pain, itch, temperature, wetness, dis-tention of the anal canal and vagina, and sensations related to sexual arousal. In the clitoris, nerve fibers from the small and large trunks of the dorsal nerve form extensive plexuses in the deeper regions of the dermis and subcutaneous layers (8). In the upper regions of the dermis, the nerve fibers display terminal fibrils with endings that penetrate the epidermis. These epidermal nerve endings vary from simple axon terminals to highly branched and encapsulated structures. Although such structures are found in other regions of the vulva, they decrease in number in a lateral direction from the clitoris.

Innervation of the labia majora differs from that of the rest of the vulva: although both superficial and deep neural nets are present, superficial nerves are reduced markedly. Most nerve endings in the labia majora are parafollicular and do not extend into the epidermis (8).

Table 3 Quantitative Comparison of Biophysical Variables, Permeability and Irritant Susceptibilities in Forearm and Vulvar Skin (Labia Majora)

Parameter assessed (units)



Statistical significance (n — number of subjects)


Transepidermal water loss (g/m2hr)

3.5 + 0.3

14.5 + 1.3

p < 0.001s


(« = 44)

Friction coefficient (p., unitless)

0.48 + 0.01

0.66 + 0.03

p < 0.001s


(« = 44)

Blood flow (Absorbance units)

22.0 + 3.0

59.5 + 7.4

p < 0.001s


(« = 9)

Hydrocortisone penetration

2.8 + 2.4

8.1 + 4.1

p < 0.01b


(% of applied dose absorbed in 24 hr)

(« = 9)

Testosterone penetration

20.2 + 8.1

25.2 + 6.8



(% of applied dose absorbed in 24 hr)

(« = 9)

Frequency of irritant reactions to 20%



Not determined


maleic acid solution (%)

(n = 21)

Mean intensity of irritant reactions to 20%

0.86 + 0.36

1.29 + 0.83

p = 0.036s


maleic acid at 24 hr postapplication

(n = 21)

(0-3 visual scale)

Frequency of irritant reactions to 17%



Not determined


benzalkonium chloride solution (%)

(n = 21)

Mean intensity of irritant reactions to 17%

0.19 + 0.33

1.00 + 0.88

p = 0.0003s


benzalkonium chloride solution at 24 hr

(n = 21)

postapplication (0-3 visual scale)

Irritant reactions to 1 % sodium lauryl sulfate at



p < 0.05d


day 2 postapplication

(« = 10)

(proportion of scores > 1 on 0-4 scale)

Sf c

(proportion of scores > 1 on 0-4 scale)

"Student t test.

bOne-way analysis of variance followed by Neuman-Keuls multiple range test. cNot significant.

dWald-Wolfowitz two sample test.


Vulvar skin has a higher concentration of epidermal androgen receptors than skin at nongenital sites (11). At puberty, androgens direct the maturation of vulvar sebaceous glands and hair follicles (12).

The vaginal epithelium has a high level of estrogen receptors and is responsive to ovarian hormone cycling. At midcycle, vaginal epithelial cell proliferation, glycogen content, and nuclear pyknosis increase in response to estrogen. A small but statistically significant increase in vaginal epithelial cell layers as been found at midcyle (13), but no significant difference in epithelial thickness has been observed between follicular and luteal phases (13,14). The concentration of estrogen receptors decreases progressively from the vagina to the vulva, with the lowest levels on keratinized vulvar skin (11). The thickness of the vulvar epithelium remains constant over the course of the menstrual cycle, but its surface cells are predominantly orthokeratotic (lacking nuclei) at the beginning and end of the cycle, and increasingly parakeratotic (bearing a degenerated nucleus) at midcycle (1,15).

Progesterone receptors are not found on vulvar skin; they are restricted to the transitional epithelium of the inner aspect of the labia minora and to the nonkeratinized epithelia of the vagina and vulvar vestibule (11).


Immune cell infiltration of the vulva is most evident during the reproductive years (12). Langerhans cells are the most common immune cell type in the vulva; intraepithelial and perivascular lymphocytes are found infrequently (16). A gradient in Langerhans cell density exists along the lower female genital tract. In Rhesus macaques, for example, cell densities are lowest at the vaginal fornix and highest at the introitus (17). Human studies demonstrate a higher density of Langerhans cells in the vulva than in the vagina, with no difference between keratinized and nonkeratinized regions (16). Langerhans cell densities were estimated at 19 per 100 basal cells in the vulvar epithelium, 13 per 100 basal cells in the cervix, and 6 per 100 basal cells in the vagina.

By contrast, lymphocytes predominate in the vagina: the CD8+ subtype, which dominates in human mucosal epithelia, is the most common vaginal immune cell (14). The CD4+ subtype constitutes the second largest population of vaginal immune cells and tissue macrophages represent the third.

Growing evidence suggests that immune responsiveness is modulated differentially along the reproductive tract. Transplantation studies suggest that the cervix is immunologically privileged in order to protect the fetus from maternal alloresponses to antigens in ejaculate (18). Cervical mucus, which protects the entry to the uterus, contains secretory antibodies, particularly IgA. These secretory antibodies inactivate antigens by forming nonabsorbable complexes with them. They are bacteriocidal in the presence of lysozyme and complement, and can agglutinate bacteria and opsonize them for phagocytosis by macrophages.

Langerhans cells, the concentration of which varies in different regions of the genital tract, are part of the dendritic cell system. They serve as sentinels, sampling antigen at the epithelial surface, then transporting and presenting it in immunogenic form to responsive T lymphocytes in regional lymph nodes. The deficit in vaginal Langerhans cells relative to their vulvar concentrations may be one of several adaptations to the antigenic challenges posed by resident vaginal microflora and foreign proteins encountered during intercourse. Seminal fluid also contains a variety of inhibitors that suppress immune function in the vagina and cervix.

Different regions of the genital tract exhibit distinct responses to antigen. Antigen application to vulvar skin can result in sensitization; indeed, allergic contact dermatitis to topical agents is a prime contributor to persistent vulvar discomfort (19-21). By contrast, antigen application to nonkeratinized mucosa may induce tolerance. This phenomenon, best characterized in the oral mucosa, is not due to the phenotype of resident Langerhans cells, but results from altered responses at the level of the draining lymph nodes (22,23). Studies in animal models demonstrate that tolerance induction also occurs in the vagina, where the phenomenon is hormonally regulated (24). In mice, vaginally induced tolerance occurred only during the estrogen-dominant phase of the estrus cycle when sperm exposure would occur.

Conflicting data exist on the hormonal modulation of immune cell densities in the human vaginal epithelium. Langerhans cell densities are of particular interest, since these cells are involved in the mechanisms of sensitization and tolerance and have been suggested to be the major target of vaginally transmitted HIV infection in women (25,26). Several investigators reported the number and distribution of vaginal immune cells to be stable throughout the menstrual cycle (13,14). One study demonstrated an increase in the density of vaginal Langerhans cells in response to vaginally administered progesterone (27). However, no such effect was found in women using the synthetic, long-acting progestin contraceptives depot medroxyprogesterone acetate (DMPA) or levo-norgestrel. DMPA caused a selective increase in CD8+ T lymphocytes, levonor-gestrel increased the CD4+:CD8+ ratio, and the combined oral contraceptive caused no cell population changes (14). Further research is needed to elucidate the mechanisms by which hormonal cycling may modulate the immune response of the lower genital tract.


Vulvar tissue is more hydrated and has a lower barrier function than exposed skin, as assessed by transepidermal water loss (TEWL). Water diffuses across the stratum corneum of the labia majora at a higher rate than across the stratum corneum of forearm skin (Table 3) (28,29). To a degree, this reflects elevated skin hydration due to occlusion. However, vulvar skin also presents an intrinsically lower barrier to water loss: steady-state TEWL values remain higher on the vulva than on the forearm after equilibration with the environment or after the prolonged drying of both sites with a desiccant (29,30). The comparatively greater hydration of occluded vulvar skin raises its friction coefficient (Table 3), which may make vulvar skin more susceptible to mechanical damage (31).


Predicting tissue permeability is complex. The phenomenon depends on the extent to which the penetrant partitions into the tissue, the rate at which the penetrant diffuses through the tissue, and the distance to be traversed (32). Consequently, vulvar penetration of exogenous agents is influenced by regional differences in epithelial structure and lipid composition, the physicochemical characteristics of the penetrants, and the nature of the applied vehicle.

Permeability of Labia Majora Skin

Table 4 illustrates skin permeability to hydrocortisone by anatomic site (33). Vulvar skin is substantially more permeable than forearm skin to this agent (34,35). Probable contributing factors include elevated vulvar skin hydration, the higher concentration of hair follicles and sweat glands on vulvar skin, and increased cutaneous blood flow. Tissue penetration rates also depend on the

Table 4 Relative Permeability to Hydrocortisone (% of Dose Absorbed) by Anatomical Site

Permeability relative


to forearm skin

Forearm (ventral)


Forearm (dorsal)


Foot arch (plantar)


Ankle (lateral)

0.42 x


0.83 x


1.7 x







Vulva (labia majora)


Jaw angle



42 x

Source: Adapted from Refs. 33, 34, 35.

Source: Adapted from Refs. 33, 34, 35.

properties of the penetrant. For example, there is no difference in the rate of testosterone penetration through vulvar and forearm skin (Table 3) (35). However, the skin at both sites is far more permeable to testosterone than to hydrocortisone. This is probably due to the greater hydrophobicity of testosterone and because of the presence of androgen receptors in the skin.

Permeability of the Vulvar Vestibule and Vaginal Epithelium

Nonkeratinized epithelia are more generally permeable to external penetrants. This has been described best in oral tissue which, like the vulva, displays regional differences in structure and keratinization (36,37). The nonkeratinized buccal mucosa, which resembles the vaginal epithelium morphologically, is tenfold more permeable to water than is keratinized skin (38). Buccal mucosa is more permeable than the skin to horseradish peroxidase, although absolute penetration rates of this large molecule are lower than those of water (36).

The heightened permeability of nonkeratinized tissue results from several factors. First, the absence of a stratum corneum removes a principal barrier to entry of external agents. Second, the more loosely packed cell layers create a structure with less resistance to paracellular movement, the principal route by which most penetrants traverse tissues (39,40). Third, such tissues have a less-structured lipid barrier with lower resistance to molecular diffusion (41,42). Finally, thinner epithelia (such as the buccal mucosa and vulvar vestibule) present a shorter path length to be traversed.

Nonkeratinized tissue is also more vulnerable to breaches in tissue integrity, which can augment tissue penetration. For example, buccal tissue was 40-fold more permeable than keratinized skin to the organic base nicotine, an irritant that increases the penetration of coadministered compounds (43,44).

The heightened permeability of the vulvar vestibule can be inferred from studies on vaginal and buccal epithelia, which serve as surrogate tissues. Vaginal and buccal epithelia have similar ultrastructural features and lipid composition. Moreover, comparable tissue penetration rates at coadministered sites have been observed for a range of model penetrants, including water, estra-diol, vasopressin, and low molecular weight dextrans (45-48). Like these epi-thelia, the thin, non-keratinized vulvar vestibule may be more permeable than keratinized skin and more vulnerable to the effects of externally applied agents.


Vulvar skin differs from exposed skin in its susceptibility to applied irritants. However, irritant effects are difficult to predict. The available evidence suggests that elevated skin hydration plays a role in vulvar susceptibility to polar irritants. For example, vulvar skin was more reactive than forearm skin to high aqueous concentrations of maleic acid (20% concentration) and benzalkonium chloride (17% concentration) (Table 3) (49). Because polar or charged materials do not penetrate the hydrophobic lipid barrier of the stratum corneum readily, the comparatively greater hydration of vulvar skin may have facilitated skin penetration of the polar irritants at this site.

The surfactant sodium lauryl sulfate (SLS) caused a different response. Vulvar skin was less reactive than forearm skin to low concentrations of this agent (Table 3) (50-52). This result may relate to the structure of the penetrant: the surfactant molecule bears both a charged head and a hydrophobic tail. Notably, hydrophobic molecules partition far more readily into the lipid barrier of the stratum corneum than do charged materials, and lipid partitioning is more favored when the applied medium is relatively polar. In the case of aqueous SLS, skin penetration of the charged head would be highly disfavored; therefore, lipid partitioning of the hydrophobic surfactant tail may have been a driving force for heightened effects on less hydrated forearm skin.

An effect of the menstrual cycle on vulvar skin reactions has not been documented. However, evidence from other anatomical sites suggests that skin barrier function and reactivity to irritants may exhibit cyclical variability. Water barrier function on the back and forearm (as measured by baseline TEWL values) was significantly lower on days just prior to menstruation compared to days just prior to ovulation (53). In women, forearm skin exhibited stronger reactions to SLS on day 1 than during days 9-11 of the menstrual cycle, while no difference was detected in a male control group evaluated over the same period (54).


Until recently, most studies of vulvar and vaginal microbial colonization have employed traditional culture techniques. Using these techniques, higher cell densities of Staphylococcus aureus, coagulase-negative staphylococci, streptococci, diphtheroids, lactobacilli, and yeasts have been measured on the labia majora than on exposed skin (Table 5) (55).

Table 5 Microbial Cell Densities (cfu/cm2) on Vulvar and Forearm Skin




Table 5 Microbial Cell Densities (cfu/cm2) on Vulvar and Forearm Skin




Staphylococcus aureus







Coagulase negative staphylococci














Lipophilic diphtheroids







Non-lipophilic diphtheroids







Gram negative rods







Lactobacillus species














Source: From Ref. 55.

Source: From Ref. 55.

Traditional culture methods suggest that the vulva is the primary site of genital carriage of S. aureus; isolation frequencies as high as 60% to 70% have been found at this site (55). However, despite an epidemiological association between vulvar and vaginal carriage of S. aureus (56,57), lower vaginal isolation frequencies, in the range of 3-12%, have been found by these methods (58-61).

Modern detection techniques suggest that vaginal carriage of S. aureus may be more common than previously thought. For example, the technique of fluorescence in situ hybridization revealed the presence of S. aureus in 100% of 44 vaginal specimens obtained from 15 women, while standard microbial culture methods produced positive results in only 34% of the specimens (62).

Microbes derived from the intestinal tract are also part of the endogenous vulvovaginal flora. Nonpathogenic levels of such organisms can reside on the perineum, on the external labia majora, and in the vagina. Pathogenic strains of Escherichia coli cause urinary tract infections, but the mere presence of E. coli microbes on the vulva does not lead to urethral and bladder colonization; host factors and sexual activity play a more important role in determining individual susceptibility to infection (63-65). The most important risk factor for recurrent urinary tract infection in women of reproductive age is sexual intercourse (66,67), which promotes colonization of the introitus and urethra in susceptible women (68-70).

Candida species are found in the endogenous vulvovaginal microflora. These fungi exist as blastopheric spores or as germinative mycelia. The spore form can be associated with symptom-free vulvovaginal colonization, but adhesion, germination, and epithelial invasion are necessary for pathogenesis. Host predisposing factors play a role in the development of frank vulvovaginal candidiasis (VVC). Healthy women appear to possess an innate and noninflammatory form of local immunity that prevents symptomatic infection (71); suppression of this innate immunity is suspected of playing a role in recurrent VVC (72,73). Genetic polymorphisms in mannose binding lectins—surface recognition molecules involved in the immune defense against microorganisms— also play a role in individual susceptibility to Candida infection (74,75).

Elevated estrogen is another risk factor for symptomatic VVC. Use of highestrogen oral contraceptives, for example, is linked epidemiologically to an elevated VVC risk (76). Acute episodes of VVC are more common during pregnancy and during the luteal phase of the menstrual cycle, when both estrogen and progesterone levels are elevated; experimental studies indicate that this link relates solely to the elevation of estrogen (77). The mechanism by which estrogen promotes symptomatic infection has not been elucidated fully. Estrogen raises the vaginal concentration of glycogen, which may serve as a nutritional source, and the hormone may act as a growth-promoting signal for some Candida strains (78).

People with diabetes mellitus and pregnant women are at elevated risk of developing symptomatic VVC. In these higher risk groups, the degree of glycemic control plays a role in the prevalence of Candida colonization at various body sites (79). In addition, Candida adherence to vaginal epithelial cells is enhanced in people with diabetes and during pregnancy (80).

Some studies link antibiotic therapy, which suppresses protective acid-producing microbes in the vagina, to an increased risk of subsequent VVC episodes (81); however, not all studies are consistent and the association of antibiotic use with clinical candidiasis remains controversial (82).


The vulva is a highly specialized tissue with regional distinctions in embryologic derivation and tissue structure. Unique physiological characteristics have been documented in blood flow, innervation, hormonal and immune responsiveness, skin friction, tissue hydration, permeability, and microbial populations. Most of these distinctions appear to represent adaptations to reproductive function. However, the characteristics of elevated skin friction and skin hydration, coupled with differences in tissue permeability, may also mediate genital susceptibility to various exogenous irritants and infectious agents.


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