Periodontology 2000, Vol. 64, 2014, 81–94 © 2013 John Wiley & Sons A/S.

y & Sons A/S. Published by John Wiley & Sons Ltd

Printed in Singapore. All rights reserved 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 menopause but is also linked to the later slow phase
phenotype and reproductive capacity as well as on of bone loss attributed to aging (61). Furthermore,
immune function and bone metabolism. The peri- studies suggest that estrogen deficiency has a similar
odontium is also responsive to dynamic levels of sex impact on alveolar bone (71, 105). Here, the implica-
steroids associated with reproductive events and sex- tion is that underlying bone (quality) might be a cru-
ual development. For example, the onset of exuberant cial factor for postmenopausal periodontal disease
inflammation in the gingiva has been described in progression, with adverse changes in bone density or
relation to puberty (80). In addition, changes in sex- quality then linked to greater susceptibility to
steroid levels during the menstrual cycle appear to destructive periodontal disease. Epidemiological
have an effect on the inflammatory status of the gin- studies support this association between low systemic
giva (8, 12). Well-established clinical changes to the bone-mineral density and worse periodontal disease
periodontium, in response to the endocrine changes measures (118), including reduced alveolar crest
of pregnancy, are also presented in the literature. height in postmenopausal women (142).
Pregnant women display gingival inflammation and The purpose of this paper was to review the modu-
bleeding to a greater extent than the general popula- latory role of sex steroids on the immune system as
tion; this difference may be attributable to alterations well as on bone homeostasis, remodeling and repair.
in the formation and composition of the bacterial Finally, evidence will be presented on the potential
biofilm as well as in the circulating sex-steroid levels for drug and protein therapies that may affect the risk
(2). for periodontitis and implant failure.
Changes in sex steroids govern pregnancy and
sexual development, with ensuing ‘secondary’
transient clinical manifestations in the periodontium. Basic biology of sex steroids
Sex steroids also modulate a considerable set of target
organs, or systems, beyond those associated with Sex steroids exert their biologic effects by two possi-
reproduction or sexual development. Both the ble mechanisms: genomic effects and nongenomic
immune system and bone are targeted by sex ste- effects. The former comprises hormone-bound
roids, which therefore make such alterations impor- nuclear receptors that up- or down-regulate gene
tant within the context of destructive periodontal expression by binding to the hormone response ele-
disease. In this capacity, sex steroids could plausibly ments of target genes. In addition, steroid modulation
alter the course and/or severity of destructive peri- of transcription factors also serves to regulate
odontal disease. Age-associated temporal changes in patterns of gene expression (10, 121). The latter (non-
circulating sex steroids, such as estrogen deficiency genomic) effects of sex steroids involve interaction
during the perimenopause, illustrate this interaction. with cell-surface binding sites, which rapidly induces
Specifically, estrogen represents a major risk factor a variety of intracellular signals, such as calcium or
for osteoporosis in women (47, 125); evidence dem- cAMP, or the activation of mitogen-activated protein
onstrates that estrogen deficiency is associated not kinases (74); the consequence is the up- or down-reg-
only with the rapid bone loss associated with early ulation of the expression of certain genes.

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The major sex steroids share common pathways of stream gene expression (69, 147). One of the most
biosynthesis derived from cholesterol. The cholesterol important and classically appreciated roles of estro-
molecule consists of a hydrocarbon tail, a ring-struc- gen is its mitogenic action upon hormone-sensitive
ture region with four hydrocarbon rings, and a hydro- tissues – the uterus and the breast (27, 107). Animal
xyl group. Specific enzymes are required for and human studies have demonstrated the ability of
modification of carbons from the hydrocarbon tail natural and synthetic estrogens to act, by exerting
region to produce the three main classes or parent prolonged mitogenic stimulation, as etiologic factors
compounds of steroids derived from cholesterol: estr- in the induction of estrogen-associated cancers (83,
anes (C18; estrogen precursors), androstanes (C19; 90, 150).
androgen precursors) and pregnanes (C21; progestin
and corticosteroid precursors). Biosynthesis of steroid
hormones requires a series of oxidative enzymes Progesterone
located in both mitochondria and endoplasmic retic-
ulum; trophic hormones and feedback mechanisms Progesterone is produced in the ovaries, adrenal
control their expression (14). glands and placenta during pregnancy. As with the
Classically, the role of sex-steroid hormones was other four-hydrocarbon-ring sex steroids, progester-
confined to normal reproductive development and one is synthesized from pregnenolone, which is
function. Notably, the hypothalamic–pituitary–gona- derived from cholesterol. Pregnenolone undergoes an
dal axis provides hormonal regulation and feedback oxidation and keto-enol tautomerization, resulting in
loops that are active during fetal development, progesterone (94).
neonatal development and from puberty through the Progesterone is a sex hormone that governs ovarian
reproductive years (66). The gonadotropins luteiniz- physiology and, as such, is essential for the establish-
ing hormone and follicle-stimulating hormone are ment and maintenance of pregnancy (9, 26). The pro-
produced by the anterior pituitary control steroido- gesterone-receptor-deficient mouse model has
genesis (94). Consequently, estrogens, progesterone confirmed the crucial role of progesterone in the
and testosterone are the major sex-steroid hormones development and function of various aspects of the
produced (Fig. 1). female reproductive events, including fertilization,
pregnancy and lactation (75). An additional physio-
logic role of progesterone is mediation of signals
Estrogens needed for sexually responsive behavior. Animal
studies have established progesterone-mediated
The major naturally occurring estrogens (estriol, effects, specifically in the hypothalamus and pre-optic
estrone and estradiol) are formed from the androgen areas, that are related to reproductive behavior (32,
derivatives testosterone or androstenedione via the 103). Recent research indicates that progesterone has
action of aromatase (CYP19a1) (Fig. 1). Estriol is the effects on bone by regulating the expression and
principal estrogen structure produced during preg- function of matrix proteins and metalloproteinases
nancy, specifically at placental sites. Between menar- involved in bone remodeling and resorption, serving
che and menopause, estradiol is the form produced a protective role against bone loss (98, 146). This pro-
within the ovarian follicle, whereas estrone is the pri- tective mechanism may be mediated by expression of
mary estrogen structure in postmenopausal women the progesterone receptor on osteoblastic cells as well
(7). Estrogen is also produced, via aromatase, in the as by the interaction of progesterone with the gluco-
male gonad and has a critical paracrine role in sper- corticoid receptor (109).
matogenesis (1). In men and women, the synthesis of
estrogens also occurs at several extragonadal sites,
namely adipose tissue, brain, breast and bone (92, 122, Testosterone
134, 135). Unlike ovarian-based estrogen biosynthesis,
the extragonadal sites depend on the presence of cir- As with estrogens, the derivative of testosterone is syn-
culating precursor C19 steroids (127). For women, thesized from pregnenolone through the intermediate
after menopause, the mesenchymal cells of adipose progesterone. The androgen product androstenedione
tissue are the site of greatest estrogen synthesis (129). is created following the hydroxylation (C17) and side-
Estrogens produce varied biologic effects that result chain cleavage (involving C20 and C21) of the proges-
from a direct interaction of the sex steroid with an terone intermediate. The reduction of the 17-keto
intracellular receptor that is responsible for down- group of androstenedione yields testosterone (14).

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 Influence of sex steroids on inflammation and bone metabolism

C D
B

Fig. 1. (A) Neuroendocrine control of sex steroidogenesis. serum concentration = 9–25 nM). In women, the ovaries,
Sex hormone production is partly regulated by elements of adrenal organs and peripheral conversion accounts for tes-
the hypothalamic–pituitary–adrenal axis. Gonadotropin- tosterone production (mean serum concentration = 0.5–
releasing hormone is synthesized and released from neurons 2.5 nM). (C) Ovaries/theca and follicular cells. The conver-
within the hypothalamus. This trophic peptide hormone sion of cholesterol to progesterone and testosterone occurs
stimulates the production of luteinizing hormone and folli- in the theca cells, analogous to steroid metabolism in Leydig
cle-stimulating hormone from the anterior pituitary. Testos- cells. Androgens can be subsequently converted via aroma-
terone production is under the control of luteinizing tase activity in the granulosa cell. Follicle-stimulating hor-
hormone. (B) Testes/Leydig cells. Luteinizing hormone (and mone is essential to induce maturation of ovarian follicles to
follicle-stimulating hormone) bind to the corresponding a mature, pre-ovulatory phenotype, resulting in the genera-
receptors located in the sex organs. A cascade of events is tion of mature eggs (data not shown) and the production of
triggered (dotted line/tan arrows) that includes the expres- estrogen via transcription of steroidogenic enzymes, such as
sion of transport proteins, allowing cholesterol to be moved p450 aromatase. Estrogens are also produced in smaller
into the mitochondria and be metabolized by the mitochon- amounts by other tissues such as the liver, adrenal glands,
drial enzyme p450 side-chain cleavage system (p450scc), breasts and adipose tissue. These secondary sources of estro-
converted to pregnenolone. Pregnenolone undergoes fur- gens are especially important in postmenopausal women.
ther steroid metabolism and can be converted to testoster- AE, androstenedione; DHEA, dehydroepiandrosterone; ER,
one via progesterone or dehydroepiandrosterone as endoplasmic reticulum; FSH, follicle-stimulating hormone;
intermediary compounds. Ninety-five per cent of testoster- GnRH, gonadotropin-releasing hormone; LH, luteinizing
one production in men takes place in Leydig cells (mean hormone; Mito, mitochondria; PROG, progesterone.

Testosterone is essential for the development of 5a-reductase reduces testosterone to yield dihyd-
male sexual behavior, muscle mass and the mainte- rotestosterone, a potent embryonic androgen that
nance and development of testes (144). The enzyme initiates the development and differentiation of the

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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 skele-
tal 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 con-
centration of testosterone is 0.5–2.5 nM in premeno-
pausal adult women (94).
Fig. 2. Immune and bone system inter-relationships. Sex-
steroid hormones are essential in skeletal development
A broader perspective on the role of and for the maintenance of bone health throughout adult
life. Estrogen modulates elements related to immune func-
sex steroids tion and osteoimmunology, which, in turn, regulate osteo-
clastic activity with final implications on bone mass. There
The source, target and function of sex hormones are is increased production of proinflammatory cytokines with
not confined to the reproductive organs or sexual age; a close link between age-related systemic inflamma-
tion and osteoporosis is well documented. Estrogen
development. What is increasingly apparent is that
deficiency (E ). Proinflammatory cytokines (blue arrow)
these hormones are not temporally limited in their may mediate pathways related to increased bone resorp-
actions to the activities of early development and are tion; estrogen deficiency increases pre-osteoclastogenic
not limited to gender expression (i.e. testosterone is cells via promotion of differentiation and activation. In
not simply a ‘male’ hormone, and estrogen is not sim- RANKL signaling (green arrows) the differentiation and
activity of osteoclastogenic cells increase, and the apopto-
ply a ‘female’ hormone) (99, 114). At extragonadal
sis of osteoclastogenic cells decreases. Osteoblast precur-
sites (such as the immune system, adipose tissue, sor cells secrete osteoprotegerin, a soluble decoy receptor
bone and brain), sex steroids exert intracellular as that neutralizes RANKL. The presence of estrogen
well as local effects (104, 128). These interactions will increases osteoprotegerin. (E+) Estrogen presence up-reg-
be considered, focusing on the impact and direct ulates transforming growth factor-beta, an inhibitor of
bone resorption that acts directly on osteoclastogenic cells
relevance of sex steroids to destructive periodontal
to decrease activity and increase apoptosis. IL, interleukin;
diseases, namely the host immune response and OC, osteoclastogenic cells; OPG, osteoprotegerin; TGF-b,
bone homeostasis, remodeling and repair (Fig. 2). transforming growth factor-beta; TNF, tumor necrosis
factor.

higher rate of nosocomial infection and multiple

Sex steroids modulate the immune organ failure following injury and infection (132).
system Women, in contrast, respond to infection and trauma
with increased antibody production compared with
Sex-steroid hormones modulate the function of cells men (36), consistent with a greater predominance of
involved in the immune response. Notably, cells of autoimmune diseases such as systemic lupus erythe-
both the lymphoid and myeloid lineages express matosus and rheumatoid arthritis (5). While sex
receptors for both estrogen and androgens (11, 64). steroids appear to explain a substantial number of
Indeed, clinical observations of sexual dimorphism in sex-related dimorphisms in immune function (124), it
disease and conditions that critically involve immune should be noted that dimorphism in the sex-specific
function have logically been explained by sex-steroid genetic architecture, and male–female variation
differences. For example, men are at a greater risk of within the autosomal genome may also offer a plausi-
morbidity compared with women in outcomes of ble account (30, 95, 111).
shock, trauma and sepsis (31, 123). Experimental and Generally, experimental and clinical evidence
clinical investigations have shown that men have a suggests that men present a heightened innate

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 Influence of sex steroids on inflammation and bone metabolism

inflammatory responsiveness to injury compared type in the early inflammatory periodontal lesion,
with women. By contrast, women appear to have a mediating the initial host response to microbial chal-
more responsive and protective cell-mediated and lenge (140), sex steroids thereby alter immune
humoral immune response to antigenic challenge defense.
compared with men (82). The innate immune response to microbial patho-
Sex steroids are known to exert effects within the gens appears to be relatively heightened in men com-
innate immune system – the nonspecific rapid pared with women with respect to inflammatory
defense that follows injury or infection. Continual cytokine production. A congruent explanation is that
activation of innate immunity is known to contribute the regulation of innate immunity is more controlled
to establishment of chronic disease, as is the case of in women. For example, in vitro and experimental
chronic periodontitis (57). Temporal and sex-related animal models have demonstrated elevated produc-
changes in circulating sex-steroid hormones are con- tion of immunosuppressive factors (e.g. prostaglan-
sistent with a role of sex steroids in modulating cer- dins and interleukin-10) that function to
tain components of the innate immune system. counterbalance the progression of inflammation in
Menopausal women, as well as men, have an women compared with men (33, 73).
increased number of circulating monocytes com- Sex steroids also appear to exert influence on the
pared with women in the follicular phase of the men- adaptive immunity – a crucial means of establishing a
strual cycle (18). Estrogen, and possibly progesterone, focus on infection escaping the innate host response.
decreases the number of monocytes circulating in Sex steroids affect primary cell types involved in
serum. Estrogen replacement therapy has been adaptive immunity, such as B-lymphocytes and
shown to suppress monocyte counts when adminis- T-lymphocytes, as reflected by the stronger antibody
tered to menopausal women (13). Several consistent response of women compared with men in infection
findings emerge with respect to the effects of sex ste- and vaccination (44, 85). Estrogen may, in part,
roids on monocyte function. Estrogen appears to explain this observed sexual dimorphism – estrogen
decrease plasma levels of the inflammatory cytokine, inhibits CD8+ T-cell suppression of B-cells (100).
interleukin-6 (56, 112). Furthermore, monocytes from Stimulated peripheral blood mononuclear cells have
men respond with increased tumor necrosis factor- been found to increase the production of IgG and
alpha and interleukin-1beta production following IgM in the presence of 17b-estradiol (55). Animal
stimulation compared with cells from women. Tes- models support similar conclusions; in a murine
tosterone exposure increases monocyte production of arthritis model, the administration of 17b-estradiol
interleukin-12 in response to stimulation with lipo- found in pregnancy resulted in an increase in anti-
polysaccharide. Interleukin-12 is a crucial chemokine collagen IgG1 (72). Conversely, testosterone has been
bridging nonspecific and specific immunity – induc- shown to inhibit the production of IgG and IgM by
ing type 1 helper T-cell differentiation and stimulat- peripheral blood mononuclear cells (55). Jointly,
ing functional activity of natural killer cells and these findings offer a mechanistic explanation for the
activated macrophages (137), thereby affecting differentially higher incidence of B-cell-dependent
immune response. autoimmune diseases, such as myasthenia gravis and
Neutrophils, another critical component of innate systemic lupus erythematosus, in adult women dur-
immunity, also appear to be responsive to sex ste- ing their reproductive years, compared with later in
roids. Neutrophil chemotaxis, for example, is aug- life.
mented in the presence of progesterone but Estrogen levels in reproductive periods, periovula-
diminished in the presence of estrogen (86, 87). Estro- tory to pregnancy, produce disparate effects on
gen and progesterone have also been shown to mod- T-lymphocyte function. Frequently, the influence of
ulate neutrophil degranulation activity, although the estrogen on the T-cell response is dichotomous or
reported effect of these sex steroids has been incon- biphasic. Multiple sclerosis studies examining the role
sistent (29). Nitric oxide production, which exerts of estrogens on T-cell function have demonstrated
anti-inflammatory effects by preventing neutrophil that 17b-estradiol stimulates interleukin-4, interleu-
adhesion to the endothelium, has been observed to kin-10 and interferon-gamma production (43). Yet,
change with respect to reproductive status – nitric estrogen exerts both inhibitory and stimulatory
oxide production is highest in the presence of estro- effects on production of the cytokine, interleukin-1
gen (40). Estrogen has been shown to up-regulate (108). Furthermore, estrogen displays a biphasic
nitric oxide synthase expression in neutrophils ex vivo effect on antigen-stimulated secretion of tumor
(133). As neutrophils are a predominant immune-cell necrosis factor alpha, a T-helper 1-associated

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Shiau et al.

Table 1. Sex-steroid effects on select components of the host immune response

Immunity Component Sex steroid Comments

type (effect)

Innate Monocytes circulating Estrogen ( ) Inferred from observations of sexual dimorphism, and in
immunity postmenopausal women (18)
Inferred from estrous cycle data: follicular phase (13)
Monocyte function Estrogen ( ) Estrogen depresses some pro-inflammatory functions/responses,
Androgen (+) 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 – Progesterone (+) Example: estrogen interferes with the expression of potent
chemotaxis Estrogen ( ) chemoattractant cytokine-induced neutrophil chemoattractant-
2beta for neutrophils in vitro and in vivo (86)
Neutrophil function – Inconclusive There are inconsistent reports of progesterone and estrogen on
degranulation neutrophil degranulation (29)
Adaptive T-lymphocyte function – Estrogen (+/ ) Estrogen at peri-ovulatory and pregnancy levels stimulate (+)
immunity cytokine production 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-lymphocyte-
dependent immunity (28, 43)
B-lymphocyte function – Estrogen (+) Estrogen attenuates CD8+ lymphocyte suppression of B-lymphocytes
antibody production Sexual dimorphism with greater antibody titers in response to
infection/vaccination (female) (100)

cytokine, with inhibition at high concentrations and response to infections; estrogen replenishment to
enhancement at low doses (28). ovariectomized female mice protects them from
Estrogen has been shown to affect cytokine herpes simplex virus-2 infection and, similarly,
production of both the type 1 and type 2 helper T-cell hormone pretreatment of female rhesus macaques
subsets; however, the T-cell response has been found increases protection from simian immunodeficiency
to be highly dependent on steroid concentration and virus transmission (42, 130).
the model system (17, 44). In animal and human Furthermore, sex steroids serve as a surrogate
pregnancy studies, there is a shift from the T-helper 1 effector of the mammalian stress/hypothalamic–pitu-
to the T-helper 2 immune response, presumably itary–adrenal axis to act upon the immune response.
driven, in part, by sex hormones (120, 145). The hypothalamic–pituitary–adrenal axis is crucial in
As described above, sex steroids appear to exert enabling organisms to maintain homeostasis when
effects on both innate and adaptive elements of exposed to environmental stress. Notably, glucocor-
immunity, indicated by experimental studies, as well ticoids regulate the stress response at a molecular
as study investigations in the context of temporal and level by modulating gene expression and primarily
age-related changes in sex-steroid levels (see generate anti-inflammatory effects through inhibition
Table 1). Multiple reports have consistently docu- of cytokines (66). Glucocorticoids may also indirectly
mented sexual dimorphism in components of the achieve immune suppression by leveraging effects on
innate immunity, in particular, which are probably the reproductive system; the production of gonado-
mediated by sex steroids or their receptors. Animal tropin-releasing hormone can be restricted as well as
studies have demonstrated that the sex hormones secretion of progesterone and estradiol (23). Estrogen
estradiol and progesterone have the ability to modu- has mostly an enhancing effect on inflammatory
late the immune response to infections (76). For reactions through actions upon immune targets/cells,
example, the T-cell response to vaccination is dimin- as described previously. In addition, estrogens
ished in ovariectomized rhesus macaques and is par- enhance inflammatory effects through an up-regula-
tially improved upon administering hormone therapy tion of local corticotrophin-releasing hormone
(35). Female sex hormones modulate immune production (52, 119). These inter-relationships of the

86
 Influence of sex steroids on inflammation and bone metabolism

hypothalamic–pituitary–adrenal axis, sex steroids and factor, as demonstrated in experimental and clinical
immune system offer additional insight in under- models (3, 62, 113). Roggia and et al. (117) demon-
standing why women develop a more effective strated the connection of estrogen deficiency with in
immune response to infectious challenge than do vivo bone-loss patterns. In this work, ovariectomy
men (18). was shown to up-regulate tumor necrosis factor pro-
duction by increasing the number of tumor necrosis
factor-producing T-cells.
Sex steroids influence bone Specifically, increased T-cell production of tumor
metabolism necrosis factor may be mediated by estrogen defi-
ciency via a mechanism involving antigen-presenting
Sex steroids are critical for skeletal development and cells and regulatory cytokines, interferon gamma,
for the maintenance of bone health throughout adult interleukin-7 and transforming growth factor-beta.
life. Estrogen modulates elements related to immune For example, in-vivo bone destruction has been
function and bone metabolism, as reflected in the shown to involve interleukin-7 (88), probably through
T-cell activation of osteoclasts. Ovariectomy experi- its influence on T-cell development and homeostasis
mental models underscore the latter observation. In (38). Treatment of mice with interleukin-7 causes
T-cell-deficient nude mice, ovariectomy fails to in-vivo bone loss in a mechanism involving increased
induce significant bone loss (21, 39, 117). Similarly, T-cell secretion of RANKL and tumor necrosis factor
mice treated with agents that block T-cell activation (136). In this manner, estrogen deficiency, associated
(abatacept is a fusion protein that prevents antigen- with an elevated interleukin-7 level, may leverage an
presenting cells from delivering costimulatory signals effect on bone resorption. Indeed, the up-regulated
to T-cells) and induce T-cell apoptosis also fail to levels of interleukin-7 in ovariectomized mice and
exhibit trabecular and cortical bone loss upon ovari- associated bone loss can be overcome and protected
ectomy (45). The provocation of bone resorption in when treated with an anti-IL-7 antibody (148).
response to estrogen deficiency appears mainly to be
the result of a cytokine-driven increase in osteoclast
formation (50). Sex steroids and collagen
Estrogen induces the formation of osteoclastogenic regulation
factors by activated T-cells. The osteoclast, arising
from monocyte precursors in the hematopoetic com- Sex hormones regulate, via genomic or nongenomic
partment, is a vital component of the skeletal system, effects, various aspects of cutaneous or connective
contributing to activities ranging from bone resorp- tissue biology. The importance of this regulatory role
tion to normal physiologic bone remodeling, as well is highlighted by the transient effects of progesterone
as calcium homeostasis (138). and estrogen on the normal menstruation of women
RANKL and macrophage colony-stimulating factor of reproductive age (89). The proliferative and secre-
are two major chemokines needed for osteoclast for- tory phases of menstruation involve steroid-driven
mation (59) (see Fig. 2). Bone marrow stromal cells biologic processes that include cell proliferation,
and osteoblastic cells produce these factors (149). apoptosis, vascular remodeling and activation of
RANKL is part of the tumor necrosis factor superfam- matrix metalloproteinases (51, 70, 79). Another exam-
ily and binds to the transmembrane receptor RANK, ple of sex-steroid regulation of connective tissue is
which is expressed on the surface of osteoclasts and taken from the vascular biology of arteries. Sex ste-
its precursors. RANKL also binds to osteoprotegerin, a roids directly control expression of crucial structural
soluble decoy receptor and crucial anti-osteoclasto- proteins that determine vessel biomechanical proper-
genic molecule that is produced by the hematopoietic ties (91). Female sex steroids appear to favor an elastic
cell lineage (65). Tumor necrosis factor is a cytokine matrix profile that may be responsible for differences
produced or regulated by activated T-lymphocytes in large-artery rigidity observed between men and
that regulates stromal cell production of RANKL and women (15) and correlate with hormonal fluctuations
macrophage colony-stimulating factor (101). Tumor experienced during the lifespan of women (143).
necrosis factor has also been demonstrated to inhibit Natoli and et al. (91) demonstrated, in a relevant
osteoblastogenesis; the resulting net effect is that human experimental model, that sex steroids influ-
tumor necrosis factor acts in a bone-resorptive capac- ence expression of important matrix proteins, includ-
ity (48). Estrogen is able to modulate or spare bone- ing collagen, elastin and fibrillin-1, and their
resorptive activity in this manner via tumor necrosis regulators (i.e. matrix metalloproteinases).

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Shiau et al.

The periodontal literature describes the role of sex- greater susceptibility to destructive periodontal dis-
steroid hormones on the physiology of the periodon- ease. A cross-sectional evaluation of adults from
tal soft tissues, focusing primarily on keratinocytes National Health and Nutrition Examination Survey III
and fibroblasts; sex steroids increase proliferation or suggests that low systemic bone mineral density is
modulate keratinization of gingival epithelium, as associated with worse periodontal disease measures
shown in histological findings (81). The periodontal (118). Wactawski-Wende and et al. (142) similarly
ligament connective tissue and cells, which are confirmed an association between osteoporosis and
responsible for the production and maintenance of reduced alveolar crest height in postmenopausal
collagen, are critical for maintaining the periodon- women. While men do not exhibit a period of rapid
tium in health and disease. Although estrogen recep- bone loss akin to menopause of women, their bone
tors (estrogen receptor beta) are present in health status declines progressively with age (116).
periodontal ligament cells, estrogen does not appear, Male osteoporosis is largely ignored and overshad-
in ex-vivo investigations, to mediate major changes in owed, despite a worldwide incidence of osteoporotic-
collagen synthesis by periodontal ligament cells (54). related fractures of nearly 40% in men (53). There are
Estrogen has been shown to regulate periodontal liga- two explanations for the normal age-related decline
ment cell proliferation and promote osteoblastic cell in testosterone bioavailable levels: (i) decreased pro-
differentiation (77). The cellular effects of estrogen on duction by Leydig cells; and (ii) an increased level of
parameters such as collagen synthesis may largely be sex hormone-binding globulin in blood, preventing
organ- or site-specific (19). Whether sex steroids exert the interaction of testosterone with target cells (22).
a relevant role in connective tissue metabolism that However, contemporary experimental and clinical
would manifest in altered clinical disease susceptibil- studies point to the importance of both estrogen and
ity or impaired repair/regeneration requires further testosterone in the health of men’s bone. Some of the
investigation. One study focusing on oral mucosal challenges in providing a clear model include incon-
wound healing suggests that testosterone levels play a sistent age trends of estrogen levels in aging men (16,
role in re-epithelialization and angiogenesis events; 139). Estrogen appears to forestall the deterioration of
the measured serum levels of other sex hormones did bone-health status in elderly men but not in young
not correlate with oral wound closure time (34). men (102). Testosterone is observed to function in
maintenance and skeletal growth via androgen recep-
tors, which are present in nearly all bone cells (141).
Sex steroids and bone homeostasis Androgen deficiency or castration produces similar
bone changes resembling bone of postmenopausal
Nonetheless, studies are strongly suggestive that sex women – an enhanced osteoclastogenesis, which
steroids impactfully modulate the host immune overshadows a minor increase in osteoblast progeni-
response and bone homoeostasis – herein arises the tors in this scenario. This imbalance in resorption
potential for alterations in the course of destructive and formation leads to a decrease in bone trabecular
periodontal disease. A first appraisal of this interac- volume and thickness (78). Epidemiological data indi-
tion can be made when considering age-associated cate that elderly men with higher testosterone levels
temporal patterns of sex steroids. Notably, estrogen are less disposed to fracture, and bone mineral den-
deficiency, in light of menopause, has distinctly been sity is more conserved (102, 139).
recognized as a major risk factor for osteoporosis in
women (47, 125); the effects of estrogen on the skele-
ton have been the focus of intense investigation (116). Drugs and sex steroids
Evidence demonstrates that estrogen deficiency is
associated with not just the rapid bone loss associ- Modulating sex-steroid action remains a fairly com-
ated with early menopause but also with the later mon treatment to conserve bone mass and prevent
slow phase of bone loss attributed to aging (61). There osteoporosis-related fractures in postmenopausal
are studies which lend support to the concept that women (60). Herein exists the potential for treat-
the sex steroid-depleted state of postmenopause has ments—medications that replace or modulate sex
an equivalent impact on alveolar bone (71, 105). Spe- steroids—to reduce the risk for initiation or exacer-
cifically, these studies suggest that the underlying bation of destructive periodontal disease. Clinical
bone might be a crucial factor for postmenopausal investigations indicate an association of hormone
periodontal disease progression, with adverse replacement therapy and decreased gingival bleeding
changes in bone density or quality then linked to indices (93, 115). Notably, women using hormone

88
 Influence of sex steroids on inflammation and bone metabolism

replacement therapy presented with a significantly thromboembolism (63). Current drug development of
lower percentage of bleeding sites, independent of selective estrogen-receptor modulators aims to maxi-
plaque levels (115). In this same investigation, which mize therapeutic benefits whilst minimizing the
followed a cohort of 59 osteoporotic postmenopausal aforementioned adverse impacts (20). Hormone ther-
women for 1 year, hormone replacement therapy was apy is utilized to manage active breast cancer – alone
found to be associated with less clinical attachment or in conjunction with surgery – and as a preventive
loss. Haas and et al. (46) found that postmenopausal therapy (37). The modification of susceptibility to
women not on hormone replacement therapy were destructive periodontal disease in patients undergo-
twice as likely to have periodontitis compared with ing hormone therapy related to breast cancer is not
premenopausal women. Moreover, the periodontal known; available literature on the long-term effects of
status of postmenopausal women on hormone cancer treatment, via chemotherapy, is inconclusive
replacement therapy was similar to that of premeno- at best with respect to periodontal health (49).
pausal women. Although limited by some self-report- Examples of medications that modulate androgens
ing elements, the findings of this study bolster the include the 5a-reductase inhibitors, such as dutaste-
concept that an estrogen-deficient state may be a risk ride and finasteride, which dramatically decrease
indicator for probing attachment loss. Clinical inves- serum levels of dihydrotestosterone (4) and testoster-
tigations report that hormone replacement therapy one supplements, which are used to manage male
may improve alveolar bone density. A 3-year, double- hypogonadism. There are randomized control studies
blind, randomized, placebo-controlled trial con- showing the positive effect of testosterone treatment
firmed that hormone replacement therapy positively on bone mineral density in male hypogonadism (58,
affected alveolar bone mass, as determined by digital 131, 145). Fineasteride is used to manage benign
subtraction radiography, as well as lumbar spine and prostatic hypertrophy and treat male pattern bald-
left proximal femur bone mass, as determined by ness (67). Hormonal manipulation is a common strat-
dual-energy X-ray absorptiometry (24). A second pro- egy for managing prostate cancer in which androgen
spective study investigated the impact of estrogen deprivation is accomplished by bilateral orchiectomy,
deficiency on alveolar bone resorption, evaluating use of estrogenic compounds and, more recently,
estrogen-sufficient compared with estrogen-deficient medical castration in the form of luteinizing hor-
postmenopausal women, and following them for mone-releasing hormone analogues or androgen
1 year (106). This study concluded that estrogen defi- blockade with anti-androgens (68). As testosterone
ciency might be a crucial factor in negative bone-den- deficiency in men is associated with a significant
sity changes. decrease in bone mineral density (96), there might be
Hormone therapy for treatment of breast cancer concern for musculoskeletal effects of hormonal
seeks to inhibit the growth of estrogen-receptor-posi- manipulation. A randomized control, double-blinded
tive tumors by blocking the body’s ability to produce placebo trial concluded that suppression of circulat-
hormones or by interfering with hormone action (97). ing serum dihydrotestosterone induced by 5a-reduc-
The broad strategies employed include interfering tase inhibitors for 1 year does not adversely impact
with ovarian function, blocking estrogen production bone (4). Clinicians will need to be aware of potential
and inhibiting the effects of estrogen. The blocking of interactions between sex hormone-modulating
ovarian function is accomplished through either medications and the periodontium in particular as
ovariectomy or gonadotropin-releasing hormone ag- studies of greater duration become available. Recent
onists, which interfere with pituitary gland to ovary publications underscore this importance. Longer
signaling (110). Estrogen production can be impeded (>24 months) trials of finasteride use in treatment of
by use of an aromatase inhibitor (41). Finally, selec- alopecia now suggest a minor increase in sexual
tive estrogen receptor modulators are compounds dysfunction (84).
that interact with intracellular estrogen receptors in
target organs as either estrogen receptor agonists or
antagonists. The selective estrogen receptor modula- Summary
tors, such as tamoxifen (Nolvadexâ), are used clini-
cally to manage osteoporosis and hormone Sex steroids are central to sexual development and
responsive cancer (breast cancer); the challenges of reproduction, exerting pleiotropic effects on multiple
these medications, as a result of tissue-specific ago- tissues and organs throughout the lifespan of the
nist/antagonist receptor behavior, include undesired individual. Sex steroids are fundamental to skeletal
effects of increased incidence of uterine cancer and development, bone homeostasis and immune func-

89
Shiau et al.

tion. The composite effect of sex-specific genetic 11. Bebo BF Jr, Schuster JC, Vandenbark AA, Offner H. Andro-
architecture and the circulating levels of sex-steroid gens alter the cytokine profile and reduce encephalitoge-
nicity of myelin-reactive T cells. J Immunol 1999: 162:
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35–40.
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