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Periodontology 2000, Vol. 64, 2014, 81–94 Printed in Singapore. All rights reserved © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd PERIODONTOLOGY 2000 Influence of sex steroids on inflammation and bone metabolism H A R L A N J. S H I A U , M A R Y E. A I C H E L M A N N -R E I D Y & M A R K A. R E Y N O L D S Sex steroids exert profound biologic effects on sexual phenotype and reproductive capacity as well as on immune function and bone metabolism. The periodontium is also responsive to dynamic levels of sex steroids associated with reproductive events and sexual development. For example, the onset of exuberant inflammation in the gingiva has been described in relation to puberty (80). In addition, changes in sexsteroid levels during the menstrual cycle appear to have an effect on the inflammatory status of the gingiva (8, 12). Well-established clinical changes to the periodontium, in response to the endocrine changes of pregnancy, are also presented in the literature. Pregnant women display gingival inflammation and bleeding to a greater extent than the general population; this difference may be attributable to alterations in the formation and composition of the bacterial biofilm as well as in the circulating sex-steroid levels (2). Changes in sex steroids govern pregnancy and sexual development, with ensuing ‘secondary’ transient clinical manifestations in the periodontium. Sex steroids also modulate a considerable set of target organs, or systems, beyond those associated with reproduction or sexual development. Both the immune system and bone are targeted by sex steroids, which therefore make such alterations important within the context of destructive periodontal disease. In this capacity, sex steroids could plausibly alter the course and/or severity of destructive periodontal disease. Age-associated temporal changes in circulating sex steroids, such as estrogen deficiency during the perimenopause, illustrate this interaction. Specifically, estrogen represents a major risk factor for osteoporosis in women (47, 125); evidence demonstrates that estrogen deficiency is associated not only with the rapid bone loss associated with early menopause but is also linked to the later slow phase of bone loss attributed to aging (61). Furthermore, studies suggest that estrogen deficiency has a similar impact on alveolar bone (71, 105). Here, the implication is that underlying bone (quality) might be a crucial factor for postmenopausal periodontal disease progression, with adverse changes in bone density or quality then linked to greater susceptibility to destructive periodontal disease. Epidemiological studies support this association between low systemic bone-mineral density and worse periodontal disease measures (118), including reduced alveolar crest height in postmenopausal women (142). The purpose of this paper was to review the modulatory role of sex steroids on the immune system as well as on bone homeostasis, remodeling and repair. Finally, evidence will be presented on the potential for drug and protein therapies that may affect the risk for periodontitis and implant failure. Basic biology of sex steroids Sex steroids exert their biologic effects by two possible mechanisms: genomic effects and nongenomic effects. The former comprises hormone-bound nuclear receptors that up- or down-regulate gene expression by binding to the hormone response elements of target genes. In addition, steroid modulation of transcription factors also serves to regulate patterns of gene expression (10, 121). The latter (nongenomic) effects of sex steroids involve interaction with cell-surface binding sites, which rapidly induces a variety of intracellular signals, such as calcium or cAMP, or the activation of mitogen-activated protein kinases (74); the consequence is the up- or down-regulation of the expression of certain genes. 81 Shiau et al. The major sex steroids share common pathways of biosynthesis derived from cholesterol. The cholesterol molecule consists of a hydrocarbon tail, a ring-structure region with four hydrocarbon rings, and a hydroxyl group. Specific enzymes are required for modification of carbons from the hydrocarbon tail region to produce the three main classes or parent compounds of steroids derived from cholesterol: estranes (C18; estrogen precursors), androstanes (C19; androgen precursors) and pregnanes (C21; progestin and corticosteroid precursors). Biosynthesis of steroid hormones requires a series of oxidative enzymes located in both mitochondria and endoplasmic reticulum; trophic hormones and feedback mechanisms control their expression (14). Classically, the role of sex-steroid hormones was confined to normal reproductive development and function. Notably, the hypothalamic–pituitary–gonadal axis provides hormonal regulation and feedback loops that are active during fetal development, neonatal development and from puberty through the reproductive years (66). The gonadotropins luteinizing hormone and follicle-stimulating hormone are produced by the anterior pituitary control steroidogenesis (94). Consequently, estrogens, progesterone and testosterone are the major sex-steroid hormones produced (Fig. 1). Estrogens The major naturally occurring estrogens (estriol, estrone and estradiol) are formed from the androgen derivatives testosterone or androstenedione via the action of aromatase (CYP19a1) (Fig. 1). Estriol is the principal estrogen structure produced during pregnancy, specifically at placental sites. Between menarche and menopause, estradiol is the form produced within the ovarian follicle, whereas estrone is the primary estrogen structure in postmenopausal women (7). Estrogen is also produced, via aromatase, in the male gonad and has a critical paracrine role in spermatogenesis (1). In men and women, the synthesis of estrogens also occurs at several extragonadal sites, namely adipose tissue, brain, breast and bone (92, 122, 134, 135). Unlike ovarian-based estrogen biosynthesis, the extragonadal sites depend on the presence of circulating precursor C19 steroids (127). For women, after menopause, the mesenchymal cells of adipose tissue are the site of greatest estrogen synthesis (129). Estrogens produce varied biologic effects that result from a direct interaction of the sex steroid with an intracellular receptor that is responsible for down- 82 stream gene expression (69, 147). One of the most important and classically appreciated roles of estrogen is its mitogenic action upon hormone-sensitive tissues – the uterus and the breast (27, 107). Animal and human studies have demonstrated the ability of natural and synthetic estrogens to act, by exerting prolonged mitogenic stimulation, as etiologic factors in the induction of estrogen-associated cancers (83, 90, 150). Progesterone Progesterone is produced in the ovaries, adrenal glands and placenta during pregnancy. As with the other four-hydrocarbon-ring sex steroids, progesterone is synthesized from pregnenolone, which is derived from cholesterol. Pregnenolone undergoes an oxidation and keto-enol tautomerization, resulting in progesterone (94). Progesterone is a sex hormone that governs ovarian physiology and, as such, is essential for the establishment and maintenance of pregnancy (9, 26). The progesterone-receptor-deficient mouse model has confirmed the crucial role of progesterone in the development and function of various aspects of the female reproductive events, including fertilization, pregnancy and lactation (75). An additional physiologic role of progesterone is mediation of signals needed for sexually responsive behavior. Animal studies have established progesterone-mediated effects, specifically in the hypothalamus and pre-optic areas, that are related to reproductive behavior (32, 103). Recent research indicates that progesterone has effects on bone by regulating the expression and function of matrix proteins and metalloproteinases involved in bone remodeling and resorption, serving a protective role against bone loss (98, 146). This protective mechanism may be mediated by expression of the progesterone receptor on osteoblastic cells as well as by the interaction of progesterone with the glucocorticoid receptor (109). Testosterone As with estrogens, the derivative of testosterone is synthesized from pregnenolone through the intermediate progesterone. The androgen product androstenedione is created following the hydroxylation (C17) and sidechain cleavage (involving C20 and C21) of the progesterone intermediate. The reduction of the 17-keto group of androstenedione yields testosterone (14). Influence of sex steroids on inflammation and bone metabolism A B C D Fig. 1. (A) Neuroendocrine control of sex steroidogenesis. Sex hormone production is partly regulated by elements of the hypothalamic–pituitary–adrenal axis. Gonadotropinreleasing hormone is synthesized and released from neurons within the hypothalamus. This trophic peptide hormone stimulates the production of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary. Testosterone production is under the control of luteinizing hormone. (B) Testes/Leydig cells. Luteinizing hormone (and follicle-stimulating hormone) bind to the corresponding receptors located in the sex organs. A cascade of events is triggered (dotted line/tan arrows) that includes the expression of transport proteins, allowing cholesterol to be moved into the mitochondria and be metabolized by the mitochondrial enzyme p450 side-chain cleavage system (p450scc), converted to pregnenolone. Pregnenolone undergoes further steroid metabolism and can be converted to testosterone via progesterone or dehydroepiandrosterone as intermediary compounds. Ninety-five per cent of testosterone production in men takes place in Leydig cells (mean serum concentration = 9–25 nM). In women, the ovaries, adrenal organs and peripheral conversion accounts for testosterone production (mean serum concentration = 0.5– 2.5 nM). (C) Ovaries/theca and follicular cells. The conversion of cholesterol to progesterone and testosterone occurs in the theca cells, analogous to steroid metabolism in Leydig cells. Androgens can be subsequently converted via aromatase activity in the granulosa cell. Follicle-stimulating hormone is essential to induce maturation of ovarian follicles to a mature, pre-ovulatory phenotype, resulting in the generation of mature eggs (data not shown) and the production of estrogen via transcription of steroidogenic enzymes, such as p450 aromatase. Estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, breasts and adipose tissue. These secondary sources of estrogens are especially important in postmenopausal women. AE, androstenedione; DHEA, dehydroepiandrosterone; ER, endoplasmic reticulum; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; Mito, mitochondria; PROG, progesterone. Testosterone is essential for the development of male sexual behavior, muscle mass and the maintenance and development of testes (144). The enzyme 5a-reductase reduces testosterone to yield dihydrotestosterone, a potent embryonic androgen that initiates the development and differentiation of the 83 Shiau et al. male phenotype (126). As shown in Fig. 1, estrogens are derived from androgens via minor carbon-chain modifications (14). Commonly in men, testosterone can also be aromatized to estradiol by a number of extragonadal tissues such as adipose tissue and skeletal muscle (25). In women, the major circulating serum androgen, androstenedione, is converted into either testosterone or estradiol in the ovary (6). Ninety-five per cent of testosterone production in men occurs in Leydig cells. The average total serum concentration of testosterone is 9–25 nM in adult men. In women, the ovaries, adrenal organs and peripheral conversion account for testosterone production. The average total circulating serum concentration of testosterone is 0.5–2.5 nM in premenopausal adult women (94). A broader perspective on the role of sex steroids The source, target and function of sex hormones are not confined to the reproductive organs or sexual development. What is increasingly apparent is that these hormones are not temporally limited in their actions to the activities of early development and are not limited to gender expression (i.e. testosterone is not simply a ‘male’ hormone, and estrogen is not simply a ‘female’ hormone) (99, 114). At extragonadal sites (such as the immune system, adipose tissue, bone and brain), sex steroids exert intracellular as well as local effects (104, 128). These interactions will be considered, focusing on the impact and direct relevance of sex steroids to destructive periodontal diseases, namely the host immune response and bone homeostasis, remodeling and repair (Fig. 2). Sex steroids modulate the immune system Sex-steroid hormones modulate the function of cells involved in the immune response. Notably, cells of both the lymphoid and myeloid lineages express receptors for both estrogen and androgens (11, 64). Indeed, clinical observations of sexual dimorphism in disease and conditions that critically involve immune function have logically been explained by sex-steroid differences. For example, men are at a greater risk of morbidity compared with women in outcomes of shock, trauma and sepsis (31, 123). Experimental and clinical investigations have shown that men have a 84 Fig. 2. Immune and bone system inter-relationships. Sexsteroid hormones are essential in skeletal development and for the maintenance of bone health throughout adult life. Estrogen modulates elements related to immune function and osteoimmunology, which, in turn, regulate osteoclastic activity with final implications on bone mass. There is increased production of proinflammatory cytokines with age; a close link between age-related systemic inflammation and osteoporosis is well documented. Estrogen deficiency (E ). Proinflammatory cytokines (blue arrow) may mediate pathways related to increased bone resorption; estrogen deficiency increases pre-osteoclastogenic cells via promotion of differentiation and activation. In RANKL signaling (green arrows) the differentiation and activity of osteoclastogenic cells increase, and the apoptosis of osteoclastogenic cells decreases. Osteoblast precursor cells secrete osteoprotegerin, a soluble decoy receptor that neutralizes RANKL. The presence of estrogen increases osteoprotegerin. (E+) Estrogen presence up-regulates transforming growth factor-beta, an inhibitor of bone resorption that acts directly on osteoclastogenic cells to decrease activity and increase apoptosis. IL, interleukin; OC, osteoclastogenic cells; OPG, osteoprotegerin; TGF-b, transforming growth factor-beta; TNF, tumor necrosis factor. higher rate of nosocomial infection and multiple organ failure following injury and infection (132). Women, in contrast, respond to infection and trauma with increased antibody production compared with men (36), consistent with a greater predominance of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (5). While sex steroids appear to explain a substantial number of sex-related dimorphisms in immune function (124), it should be noted that dimorphism in the sex-specific genetic architecture, and male–female variation within the autosomal genome may also offer a plausible account (30, 95, 111). Generally, experimental and clinical evidence suggests that men present a heightened innate Influence of sex steroids on inflammation and bone metabolism inflammatory responsiveness to injury compared with women. By contrast, women appear to have a more responsive and protective cell-mediated and humoral immune response to antigenic challenge compared with men (82). Sex steroids are known to exert effects within the innate immune system – the nonspecific rapid defense that follows injury or infection. Continual activation of innate immunity is known to contribute to establishment of chronic disease, as is the case of chronic periodontitis (57). Temporal and sex-related changes in circulating sex-steroid hormones are consistent with a role of sex steroids in modulating certain components of the innate immune system. Menopausal women, as well as men, have an increased number of circulating monocytes compared with women in the follicular phase of the menstrual cycle (18). Estrogen, and possibly progesterone, decreases the number of monocytes circulating in serum. Estrogen replacement therapy has been shown to suppress monocyte counts when administered to menopausal women (13). Several consistent findings emerge with respect to the effects of sex steroids on monocyte function. Estrogen appears to decrease plasma levels of the inflammatory cytokine, interleukin-6 (56, 112). Furthermore, monocytes from men respond with increased tumor necrosis factoralpha and interleukin-1beta production following stimulation compared with cells from women. Testosterone exposure increases monocyte production of interleukin-12 in response to stimulation with lipopolysaccharide. Interleukin-12 is a crucial chemokine bridging nonspecific and specific immunity – inducing type 1 helper T-cell differentiation and stimulating functional activity of natural killer cells and activated macrophages (137), thereby affecting immune response. Neutrophils, another critical component of innate immunity, also appear to be responsive to sex steroids. Neutrophil chemotaxis, for example, is augmented in the presence of progesterone but diminished in the presence of estrogen (86, 87). Estrogen and progesterone have also been shown to modulate neutrophil degranulation activity, although the reported effect of these sex steroids has been inconsistent (29). Nitric oxide production, which exerts anti-inflammatory effects by preventing neutrophil adhesion to the endothelium, has been observed to change with respect to reproductive status – nitric oxide production is highest in the presence of estrogen (40). Estrogen has been shown to up-regulate nitric oxide synthase expression in neutrophils ex vivo (133). As neutrophils are a predominant immune-cell type in the early inflammatory periodontal lesion, mediating the initial host response to microbial challenge (140), sex steroids thereby alter immune defense. The innate immune response to microbial pathogens appears to be relatively heightened in men compared with women with respect to inflammatory cytokine production. A congruent explanation is that the regulation of innate immunity is more controlled in women. For example, in vitro and experimental animal models have demonstrated elevated production of immunosuppressive factors (e.g. prostaglandins and interleukin-10) that function to counterbalance the progression of inflammation in women compared with men (33, 73). Sex steroids also appear to exert influence on the adaptive immunity – a crucial means of establishing a focus on infection escaping the innate host response. Sex steroids affect primary cell types involved in adaptive immunity, such as B-lymphocytes and T-lymphocytes, as reflected by the stronger antibody response of women compared with men in infection and vaccination (44, 85). Estrogen may, in part, explain this observed sexual dimorphism – estrogen inhibits CD8+ T-cell suppression of B-cells (100). Stimulated peripheral blood mononuclear cells have been found to increase the production of IgG and IgM in the presence of 17b-estradiol (55). Animal models support similar conclusions; in a murine arthritis model, the administration of 17b-estradiol found in pregnancy resulted in an increase in anticollagen IgG1 (72). Conversely, testosterone has been shown to inhibit the production of IgG and IgM by peripheral blood mononuclear cells (55). Jointly, these findings offer a mechanistic explanation for the differentially higher incidence of B-cell-dependent autoimmune diseases, such as myasthenia gravis and systemic lupus erythematosus, in adult women during their reproductive years, compared with later in life. Estrogen levels in reproductive periods, periovulatory to pregnancy, produce disparate effects on T-lymphocyte function. Frequently, the influence of estrogen on the T-cell response is dichotomous or biphasic. Multiple sclerosis studies examining the role of estrogens on T-cell function have demonstrated that 17b-estradiol stimulates interleukin-4, interleukin-10 and interferon-gamma production (43). Yet, estrogen exerts both inhibitory and stimulatory effects on production of the cytokine, interleukin-1 (108). Furthermore, estrogen displays a biphasic effect on antigen-stimulated secretion of tumor necrosis factor alpha, a T-helper 1-associated 85 Shiau et al. Table 1. Sex-steroid effects on select components of the host immune response Immunity Component type Sex steroid (effect) Comments Innate Monocytes circulating immunity Estrogen ( ) Inferred from observations of sexual dimorphism, and in postmenopausal women (18) Inferred from estrous cycle data: follicular phase (13) Monocyte function Estrogen ( ) Androgen (+) Estrogen depresses some pro-inflammatory functions/responses, such as interleukin-6, and is also evident in postmenopausal individuals (56) Testosterone aids in monocyte function (e.g. interleukin-12). There is a sexual dimorphism, with tumor necrosis factor-alpha and interleukin-1 beta production being higher in men compared with women (137) Neutrophil function – chemotaxis Progesterone (+) Example: estrogen interferes with the expression of potent Estrogen ( ) chemoattractant cytokine-induced neutrophil chemoattractant2beta for neutrophils in vitro and in vivo (86) Neutrophil function – degranulation Inconclusive Adaptive T-lymphocyte function – Estrogen (+/ ) immunity cytokine production B-lymphocyte function – Estrogen (+) antibody production There are inconsistent reports of progesterone and estrogen on neutrophil degranulation (29) Estrogen at peri-ovulatory and pregnancy levels stimulate (+) interleukin-4, interleukin-10 and interferon-gamma, and inhibits ( ) tumor necrosis factor from CD4+ lymphocytes. It is proposed, overall, that this would contribute to a down-regulation of T-lymphocytedependent immunity (28, 43) Estrogen attenuates CD8+ lymphocyte suppression of B-lymphocytes Sexual dimorphism with greater antibody titers in response to infection/vaccination (female) (100) cytokine, with inhibition at high concentrations and enhancement at low doses (28). Estrogen has been shown to affect cytokine production of both the type 1 and type 2 helper T-cell subsets; however, the T-cell response has been found to be highly dependent on steroid concentration and the model system (17, 44). In animal and human pregnancy studies, there is a shift from the T-helper 1 to the T-helper 2 immune response, presumably driven, in part, by sex hormones (120, 145). As described above, sex steroids appear to exert effects on both innate and adaptive elements of immunity, indicated by experimental studies, as well as study investigations in the context of temporal and age-related changes in sex-steroid levels (see Table 1). Multiple reports have consistently documented sexual dimorphism in components of the innate immunity, in particular, which are probably mediated by sex steroids or their receptors. Animal studies have demonstrated that the sex hormones estradiol and progesterone have the ability to modulate the immune response to infections (76). For example, the T-cell response to vaccination is diminished in ovariectomized rhesus macaques and is partially improved upon administering hormone therapy (35). Female sex hormones modulate immune 86 response to infections; estrogen replenishment to ovariectomized female mice protects them from herpes simplex virus-2 infection and, similarly, hormone pretreatment of female rhesus macaques increases protection from simian immunodeficiency virus transmission (42, 130). Furthermore, sex steroids serve as a surrogate effector of the mammalian stress/hypothalamic–pituitary–adrenal axis to act upon the immune response. The hypothalamic–pituitary–adrenal axis is crucial in enabling organisms to maintain homeostasis when exposed to environmental stress. Notably, glucocorticoids regulate the stress response at a molecular level by modulating gene expression and primarily generate anti-inflammatory effects through inhibition of cytokines (66). Glucocorticoids may also indirectly achieve immune suppression by leveraging effects on the reproductive system; the production of gonadotropin-releasing hormone can be restricted as well as secretion of progesterone and estradiol (23). Estrogen has mostly an enhancing effect on inflammatory reactions through actions upon immune targets/cells, as described previously. In addition, estrogens enhance inflammatory effects through an up-regulation of local corticotrophin-releasing hormone production (52, 119). These inter-relationships of the Influence of sex steroids on inflammation and bone metabolism hypothalamic–pituitary–adrenal axis, sex steroids and immune system offer additional insight in understanding why women develop a more effective immune response to infectious challenge than do men (18). Sex steroids influence bone metabolism Sex steroids are critical for skeletal development and for the maintenance of bone health throughout adult life. Estrogen modulates elements related to immune function and bone metabolism, as reflected in the T-cell activation of osteoclasts. Ovariectomy experimental models underscore the latter observation. In T-cell-deficient nude mice, ovariectomy fails to induce significant bone loss (21, 39, 117). Similarly, mice treated with agents that block T-cell activation (abatacept is a fusion protein that prevents antigenpresenting cells from delivering costimulatory signals to T-cells) and induce T-cell apoptosis also fail to exhibit trabecular and cortical bone loss upon ovariectomy (45). The provocation of bone resorption in response to estrogen deficiency appears mainly to be the result of a cytokine-driven increase in osteoclast formation (50). Estrogen induces the formation of osteoclastogenic factors by activated T-cells. The osteoclast, arising from monocyte precursors in the hematopoetic compartment, is a vital component of the skeletal system, contributing to activities ranging from bone resorption to normal physiologic bone remodeling, as well as calcium homeostasis (138). RANKL and macrophage colony-stimulating factor are two major chemokines needed for osteoclast formation (59) (see Fig. 2). Bone marrow stromal cells and osteoblastic cells produce these factors (149). RANKL is part of the tumor necrosis factor superfamily and binds to the transmembrane receptor RANK, which is expressed on the surface of osteoclasts and its precursors. RANKL also binds to osteoprotegerin, a soluble decoy receptor and crucial anti-osteoclastogenic molecule that is produced by the hematopoietic cell lineage (65). Tumor necrosis factor is a cytokine produced or regulated by activated T-lymphocytes that regulates stromal cell production of RANKL and macrophage colony-stimulating factor (101). Tumor necrosis factor has also been demonstrated to inhibit osteoblastogenesis; the resulting net effect is that tumor necrosis factor acts in a bone-resorptive capacity (48). Estrogen is able to modulate or spare boneresorptive activity in this manner via tumor necrosis factor, as demonstrated in experimental and clinical models (3, 62, 113). Roggia and et al. (117) demonstrated the connection of estrogen deficiency with in vivo bone-loss patterns. In this work, ovariectomy was shown to up-regulate tumor necrosis factor production by increasing the number of tumor necrosis factor-producing T-cells. Specifically, increased T-cell production of tumor necrosis factor may be mediated by estrogen deficiency via a mechanism involving antigen-presenting cells and regulatory cytokines, interferon gamma, interleukin-7 and transforming growth factor-beta. For example, in-vivo bone destruction has been shown to involve interleukin-7 (88), probably through its influence on T-cell development and homeostasis (38). Treatment of mice with interleukin-7 causes in-vivo bone loss in a mechanism involving increased T-cell secretion of RANKL and tumor necrosis factor (136). In this manner, estrogen deficiency, associated with an elevated interleukin-7 level, may leverage an effect on bone resorption. Indeed, the up-regulated levels of interleukin-7 in ovariectomized mice and associated bone loss can be overcome and protected when treated with an anti-IL-7 antibody (148). Sex steroids and collagen regulation Sex hormones regulate, via genomic or nongenomic effects, various aspects of cutaneous or connective tissue biology. The importance of this regulatory role is highlighted by the transient effects of progesterone and estrogen on the normal menstruation of women of reproductive age (89). The proliferative and secretory phases of menstruation involve steroid-driven biologic processes that include cell proliferation, apoptosis, vascular remodeling and activation of matrix metalloproteinases (51, 70, 79). Another example of sex-steroid regulation of connective tissue is taken from the vascular biology of arteries. Sex steroids directly control expression of crucial structural proteins that determine vessel biomechanical properties (91). Female sex steroids appear to favor an elastic matrix profile that may be responsible for differences in large-artery rigidity observed between men and women (15) and correlate with hormonal fluctuations experienced during the lifespan of women (143). Natoli and et al. (91) demonstrated, in a relevant human experimental model, that sex steroids influence expression of important matrix proteins, including collagen, elastin and fibrillin-1, and their regulators (i.e. matrix metalloproteinases). 87 Shiau et al. The periodontal literature describes the role of sexsteroid hormones on the physiology of the periodontal soft tissues, focusing primarily on keratinocytes and fibroblasts; sex steroids increase proliferation or modulate keratinization of gingival epithelium, as shown in histological findings (81). The periodontal ligament connective tissue and cells, which are responsible for the production and maintenance of collagen, are critical for maintaining the periodontium in health and disease. Although estrogen receptors (estrogen receptor beta) are present in periodontal ligament cells, estrogen does not appear, in ex-vivo investigations, to mediate major changes in collagen synthesis by periodontal ligament cells (54). Estrogen has been shown to regulate periodontal ligament cell proliferation and promote osteoblastic cell differentiation (77). The cellular effects of estrogen on parameters such as collagen synthesis may largely be organ- or site-specific (19). Whether sex steroids exert a relevant role in connective tissue metabolism that would manifest in altered clinical disease susceptibility or impaired repair/regeneration requires further investigation. One study focusing on oral mucosal wound healing suggests that testosterone levels play a role in re-epithelialization and angiogenesis events; the measured serum levels of other sex hormones did not correlate with oral wound closure time (34). Sex steroids and bone homeostasis Nonetheless, studies are strongly suggestive that sex steroids impactfully modulate the host immune response and bone homoeostasis – herein arises the potential for alterations in the course of destructive periodontal disease. A first appraisal of this interaction can be made when considering age-associated temporal patterns of sex steroids. Notably, estrogen deficiency, in light of menopause, has distinctly been recognized as a major risk factor for osteoporosis in women (47, 125); the effects of estrogen on the skeleton have been the focus of intense investigation (116). Evidence demonstrates that estrogen deficiency is associated with not just the rapid bone loss associated with early menopause but also with the later slow phase of bone loss attributed to aging (61). There are studies which lend support to the concept that the sex steroid-depleted state of postmenopause has an equivalent impact on alveolar bone (71, 105). Specifically, these studies suggest that the underlying bone might be a crucial factor for postmenopausal periodontal disease progression, with adverse changes in bone density or quality then linked to 88 greater susceptibility to destructive periodontal disease. A cross-sectional evaluation of adults from National Health and Nutrition Examination Survey III suggests that low systemic bone mineral density is associated with worse periodontal disease measures (118). Wactawski-Wende and et al. (142) similarly confirmed an association between osteoporosis and reduced alveolar crest height in postmenopausal women. While men do not exhibit a period of rapid bone loss akin to menopause of women, their bone health status declines progressively with age (116). Male osteoporosis is largely ignored and overshadowed, despite a worldwide incidence of osteoporoticrelated fractures of nearly 40% in men (53). There are two explanations for the normal age-related decline in testosterone bioavailable levels: (i) decreased production by Leydig cells; and (ii) an increased level of sex hormone-binding globulin in blood, preventing the interaction of testosterone with target cells (22). However, contemporary experimental and clinical studies point to the importance of both estrogen and testosterone in the health of men’s bone. Some of the challenges in providing a clear model include inconsistent age trends of estrogen levels in aging men (16, 139). Estrogen appears to forestall the deterioration of bone-health status in elderly men but not in young men (102). Testosterone is observed to function in maintenance and skeletal growth via androgen receptors, which are present in nearly all bone cells (141). Androgen deficiency or castration produces similar bone changes resembling bone of postmenopausal women – an enhanced osteoclastogenesis, which overshadows a minor increase in osteoblast progenitors in this scenario. This imbalance in resorption and formation leads to a decrease in bone trabecular volume and thickness (78). Epidemiological data indicate that elderly men with higher testosterone levels are less disposed to fracture, and bone mineral density is more conserved (102, 139). Drugs and sex steroids Modulating sex-steroid action remains a fairly common treatment to conserve bone mass and prevent osteoporosis-related fractures in postmenopausal women (60). Herein exists the potential for treatments—medications that replace or modulate sex steroids—to reduce the risk for initiation or exacerbation of destructive periodontal disease. Clinical investigations indicate an association of hormone replacement therapy and decreased gingival bleeding indices (93, 115). Notably, women using hormone Influence of sex steroids on inflammation and bone metabolism replacement therapy presented with a significantly lower percentage of bleeding sites, independent of plaque levels (115). In this same investigation, which followed a cohort of 59 osteoporotic postmenopausal women for 1 year, hormone replacement therapy was found to be associated with less clinical attachment loss. Haas and et al. (46) found that postmenopausal women not on hormone replacement therapy were twice as likely to have periodontitis compared with premenopausal women. Moreover, the periodontal status of postmenopausal women on hormone replacement therapy was similar to that of premenopausal women. Although limited by some self-reporting elements, the findings of this study bolster the concept that an estrogen-deficient state may be a risk indicator for probing attachment loss. Clinical investigations report that hormone replacement therapy may improve alveolar bone density. A 3-year, doubleblind, randomized, placebo-controlled trial confirmed that hormone replacement therapy positively affected alveolar bone mass, as determined by digital subtraction radiography, as well as lumbar spine and left proximal femur bone mass, as determined by dual-energy X-ray absorptiometry (24). A second prospective study investigated the impact of estrogen deficiency on alveolar bone resorption, evaluating estrogen-sufficient compared with estrogen-deficient postmenopausal women, and following them for 1 year (106). This study concluded that estrogen deficiency might be a crucial factor in negative bone-density changes. Hormone therapy for treatment of breast cancer seeks to inhibit the growth of estrogen-receptor-positive tumors by blocking the body’s ability to produce hormones or by interfering with hormone action (97). The broad strategies employed include interfering with ovarian function, blocking estrogen production and inhibiting the effects of estrogen. The blocking of ovarian function is accomplished through either ovariectomy or gonadotropin-releasing hormone agonists, which interfere with pituitary gland to ovary signaling (110). Estrogen production can be impeded by use of an aromatase inhibitor (41). Finally, selective estrogen receptor modulators are compounds that interact with intracellular estrogen receptors in target organs as either estrogen receptor agonists or antagonists. The selective estrogen receptor modulators, such as tamoxifen (Nolvadexâ), are used clinically to manage osteoporosis and hormone responsive cancer (breast cancer); the challenges of these medications, as a result of tissue-specific agonist/antagonist receptor behavior, include undesired effects of increased incidence of uterine cancer and thromboembolism (63). Current drug development of selective estrogen-receptor modulators aims to maximize therapeutic benefits whilst minimizing the aforementioned adverse impacts (20). Hormone therapy is utilized to manage active breast cancer – alone or in conjunction with surgery – and as a preventive therapy (37). The modification of susceptibility to destructive periodontal disease in patients undergoing hormone therapy related to breast cancer is not known; available literature on the long-term effects of cancer treatment, via chemotherapy, is inconclusive at best with respect to periodontal health (49). Examples of medications that modulate androgens include the 5a-reductase inhibitors, such as dutasteride and finasteride, which dramatically decrease serum levels of dihydrotestosterone (4) and testosterone supplements, which are used to manage male hypogonadism. There are randomized control studies showing the positive effect of testosterone treatment on bone mineral density in male hypogonadism (58, 131, 145). Fineasteride is used to manage benign prostatic hypertrophy and treat male pattern baldness (67). Hormonal manipulation is a common strategy for managing prostate cancer in which androgen deprivation is accomplished by bilateral orchiectomy, use of estrogenic compounds and, more recently, medical castration in the form of luteinizing hormone-releasing hormone analogues or androgen blockade with anti-androgens (68). As testosterone deficiency in men is associated with a significant decrease in bone mineral density (96), there might be concern for musculoskeletal effects of hormonal manipulation. A randomized control, double-blinded placebo trial concluded that suppression of circulating serum dihydrotestosterone induced by 5a-reductase inhibitors for 1 year does not adversely impact bone (4). Clinicians will need to be aware of potential interactions between sex hormone-modulating medications and the periodontium in particular as studies of greater duration become available. Recent publications underscore this importance. Longer (>24 months) trials of finasteride use in treatment of alopecia now suggest a minor increase in sexual dysfunction (84). Summary Sex steroids are central to sexual development and reproduction, exerting pleiotropic effects on multiple tissues and organs throughout the lifespan of the individual. Sex steroids are fundamental to skeletal development, bone homeostasis and immune func- 89 Shiau et al. tion. The composite effect of sex-specific genetic architecture and the circulating levels of sex-steroid hormones closely parallels differences in the immune response and may account for corresponding sexrelated differences in risk for chronic periodontitis, with men exhibiting greater susceptibility than women. Age-associated reductions in sex steroids also provide insight into apparent temporal increases in susceptibility to periodontitis and alveolar bone loss, particularly among women. 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