Periodontology 2000, Vol.

64, 2014, 8194

Printed in Singapore. All rights reserved

2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PERIODONTOLOGY 2000

Inuence of sex steroids on

inammation 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
inammation 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 inammatory 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 inammation 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
biolm 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 deciency
during the perimenopause, illustrate this interaction.
Specically, estrogen represents a major risk factor
for osteoporosis in women (47, 125); evidence demonstrates that estrogen deciency 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 deciency 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.

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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. Specic enzymes are required for
modication 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
conned to normal reproductive development and
function. Notably, the hypothalamicpituitarygonadal 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, specically 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-

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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-decient mouse model has
conrmed 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, specically 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).

Inuence of sex steroids on inammation and bone metabolism

Fig. 1. (A) Neuroendocrine control of sex steroidogenesis.

Sex hormone production is partly regulated by elements of
the hypothalamicpituitaryadrenal 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-ve per cent of testosterone production in men takes place in Leydig cells (mean

serum concentration = 925 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

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Shiau et al.

male phenotype (126). As shown in Fig. 1, estrogens

are derived from androgens via minor carbon-chain
modications (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-ve per cent of testosterone production in
men occurs in Leydig cells. The average total serum
concentration of testosterone is 925 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 0.52.5 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 conned 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

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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 nal implications on bone mass. There
is increased production of proinammatory cytokines with
age; a close link between age-related systemic inammation and osteoporosis is well documented. Estrogen
deciency (E ). Proinammatory cytokines (blue arrow)
may mediate pathways related to increased bone resorption; estrogen deciency 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-specic
genetic architecture, and malefemale 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

Inuence of sex steroids on inammation and bone metabolism

inammatory 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 nonspecic 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
ndings emerge with respect to the effects of sex steroids on monocyte function. Estrogen appears to
decrease plasma levels of the inammatory 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 nonspecic and specic 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-inammatory 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 inammatory 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 inammatory
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 inammation in
women compared with men (33, 73).
Sex steroids also appear to exert inuence 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 reected 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 ndings 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 inuence 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

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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-inammatory 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 immunodeciency
virus transmission (42, 130).
Furthermore, sex steroids serve as a surrogate
effector of the mammalian stress/hypothalamicpituitaryadrenal axis to act upon the immune response.
The hypothalamicpituitaryadrenal 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-inammatory 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 inammatory
reactions through actions upon immune targets/cells,
as described previously. In addition, estrogens
enhance inammatory effects through an up-regulation of local corticotrophin-releasing hormone
production (52, 119). These inter-relationships of the

Inuence of sex steroids on inammation and bone metabolism

hypothalamicpituitaryadrenal 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 inuence 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 reected in the
T-cell activation of osteoclasts. Ovariectomy experimental models underscore the latter observation. In
T-cell-decient nude mice, ovariectomy fails to
induce signicant 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 deciency 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 deciency 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.
Specically, increased T-cell production of tumor
necrosis factor may be mediated by estrogen deciency 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 inuence 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 deciency, 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 prole that may be responsible for differences
in large-artery rigidity observed between men and
women (15) and correlate with hormonal uctuations
experienced during the lifespan of women (143).
Natoli and et al. (91) demonstrated, in a relevant
human experimental model, that sex steroids inuence expression of important matrix proteins, including collagen, elastin and brillin-1, and their
regulators (i.e. matrix metalloproteinases).

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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 broblasts; sex steroids increase proliferation or
modulate keratinization of gingival epithelium, as
shown in histological ndings (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-specic (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 rst appraisal of this interaction can be made when considering age-associated
temporal patterns of sex steroids. Notably, estrogen
deciency, 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 deciency 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). Specically, 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
conrmed 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 mens 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 deciency 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 treatmentsmedications that replace or modulate sex
steroidsto 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

Inuence of sex steroids on inammation and bone metabolism

replacement therapy presented with a signicantly

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 ndings of this study bolster the
concept that an estrogen-decient 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 conrmed 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
deciency on alveolar bone resorption, evaluating
estrogen-sufcient compared with estrogen-decient
postmenopausal women, and following them for
1 year (106). This study concluded that estrogen deciency 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 bodys 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 (Nolvadex), are used clinically to manage osteoporosis and hormone
responsive cancer (breast cancer); the challenges of
these medications, as a result of tissue-specic 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 benets 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 modication 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 nasteride, 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
deciency in men is associated with a signicant
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 nasteride 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-specic 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. Chronic infection and
inammatory conditions, such as periodontal disease, provide a unique platform for exploring the
interface of sex steroids, immunity and bone metabolism.

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