*3.1.2.2.2 Vasculature*

Similar to reproductive system vasculature, the blood vessels of gingiva is also responsive to sex steroid hormones. Many scientific investigations have correlated the increased flow of GCF, coinciding with the periods of fluctuation of sex steroid hormones. A comparison of the amount of gingival crevicular fluid in pregnant women versus postpartum controls has revealed approx. 54% elevation in pregnant females [115]. In a few animal studies, exogenous estrogen and/or progesterone administration has shown a significant increase in the amount of crevicular fluid irrespective of the inflammatory status of the status [116–118]. Both estrogen receptors a and b have effects on blood vascular functions [119].

Several mechanisms have been put forth to explain how the hormone may control the tonicity of the blood vessels by:


Resident Cells Estrogen is known to regulate periodontal ligament cell proliferation including fibroblasts, keratinocytes, and promote osteoblastic cell differentiation [127, 128].

## *3.1.2.2.3 Epithelial cells*

Several investigators perceived that estrogens increased epithelial keratinization and stimulated proliferation [129, 130]. Trott noticed a reduction in keratinization of the marginal gingival epithelium in postmenopausal women when plasma estrogens levels were declining [131]. Androgens were perceived to stimulate an increase in epithelial cell number [132, 133].

### *3.1.2.2.4 Connective tissue cells*

The cellular effects of estrogen on collagen synthesis may largely be organ or site-specific [134]. In contrast to testosterone and progesterone, estrogens appear to be stimulatory in gingival fibroblasts derived from either feline or human drug enlarged gingiva [135]. Mariotti reported increased cell proliferation in fibroblasts derived from clinically healthy human gingiva of premenopausal women, with physiological concentrations of estradiol in vitro. They reported a characteristic estrogen-sensitive cellular subpopulation within the whole parent cell population of fibroblasts from premenopausal women [136]. Estradiol also induces a dosedependent increase in interleukin-6, interleukin-8, and vascular endothelial growth factor in gingival fibroblasts [137]. In periodontal ligament cells, estrogens caused downregulation of lipopolysaccharide-induced cytokines while enhancing the production of osteoprotegerin [138, 139]. Natoli et al. demonstrated the expression of matrix proteins including collagen, elastin, and fibrillin-1, and their regulators as impacted by estrogen [140].

#### *3.1.2.2.5 Bone cells*

Sex steroids play a critical for skeletal development and for the maintenance of bone health throughout adult life [141]. The deficiency of estrogen increases osteoclast precursor cells. Estrogen increases osteoprotegerin, upregulates transforming growth factor-beta, an inhibitor of bone resorption that acts directly on osteoclastogenetic cells to decrease activity and increase apoptosis [142–144].

Specifically, increased T-cell production of tumor necrosis may be mediated by estrogen deficiency via a mechanism dependent upon regulatory cytokines, for example, in vivo bone destruction has been shown to involve interleukin-7, probably through its influence on T-cell development and homeostasis [141, 145].

#### *3.1.2.2.6 Immune cells*

Straub proposed that sex steroid hormones modulate the immune system via multiple ways: the immune stimulus and antigen-specific immune response; the target cells involved; the microenvironment of the tissue; hormone concentration; the variability of receptor isoforms; and the intracellular metabolism of hormones to either biologically active or inactive forms [146–148].

#### *3.1.2.2.7 Intracellular signaling*

Infectious challenge studies have revealed that males produce a significantly higher level of the inflammatory cytokine IL-6 and the acute phase protein LPSbinding protein (LBP) than females, after in vivo endotoxin exposure male-derived macrophages produce higher levels of IL 1b and lower levels of prostaglandin E2 than similarly treated female derived cells on exposure to LPS [147]. Estrogen and progesterone have antagonizing effects on neutrophil chemotaxis [149, 150]. Estrogen has

*Gender-Associated Oral and Periodontal Health Based on Retrospective Panoramic… DOI: http://dx.doi.org/10.5772/intechopen.93695*

been shown to upregulate nitric oxide synthase expression in neutrophils ex-vivo, with nitric oxide production being the highest [151, 152].

### *3.1.2.2.8 Adaptive immunity*

**B cells:** documented evidence suggests that estrogen acts as a polyclonal B cell activator and has been shown to alter B lymphocyte function. Estrogen inhibits CD8+ T- cell-mediated suppression of B cells, the accelerated maturation of B cells into plasma cells; or increased amounts of the antibody produced per cell [152]. Similar findings have been demonstrated in animal models [153]. Testosterone has been shown to inhibit immunoglobulin IgG and IgM production of peripheral blood mononuclear cells [154].

**T cells**: Estrogen displays a biphasic effect on the antigen-stimulated secretion of TNF-α, with inhibition at high concentrations and enhancement at low doses [155]. Pregnancy and periovulatory levels of estrogen enhance IL-10 and IFN-γ response in CD4+ cells in humans and mice [156]. Estrogen inhibits IL-6 cytokine production in T cells. In healthy men and women, the polarization of immune response into Th1 or Th2 cytokines or cellular types is not absolute but the ratio of these components varies according to physiological demand and clinical conditions [157, 158]. Estrogen is known to be a potential physiological regulatory factor for the peripheral development of CD4 + CD25+ Treg cells [159]. Additionally, it was discovered that hormones peripherally activated prohormones and regulated the Th1/Th2 balance [160–163].

#### *3.1.2.2.9 Antigen-presenting cells*

(APCs) regulate Th cell differentiation and Th cell functioning under resting and activated conditions of the immune system in both the gender.IL6pathways regulates the homeostasis of the Th cell network in women, while this homeostasis is regulated by IFNγ pathways in men. Physiological homeostasis between Treg, Th17, and Th9 cells in the resting state in the transition to the activation phase and in the return to the resting state [157].

#### *3.1.2.2.10 Immunosenescence-Gender-specific effects*

Contemporary studies about the immune system functions have documented that there exists a differential effect on the activities and regulation of T helper (Th) cytokine pathways, which is affected by aging, but not to the same extent in both genders. Different cytokines regulate the development of immune response in humans at different phases, based on gender, for example, early evolution by the positive inter regulation of IFNγ-IL10 and IL6-IL4 in males, and the negative interrelation of IL6-IL10 in females whereas, the late evolution by the positive inter regulation of IFNγ-IL4 in males and by IL6-IFNγ in females. Alterations in these gender-specific cytokines regulatory pathways during aging could adversely affect the success of the immune response [158].
