Periodontology 2000, Vol.

61, 2013, 69–88  2013 John Wiley & Sons A/S

Printed in Singapore. All rights reserved PERIODONTOLOGY 2000

Endocrinology of sex steroid

hormones and cell dynamics in
the periodontium
ANGELO MARIOTTI & MICHAEL MAWHINNEY

It is intriguing that the steroid sex hormones are so stane. One of the most potent androgenic hormones,
similar in chemical composition yet produce such testosterone (17-hydroxy-androst-4-en-3-one), is syn-
dramatically different effects. Consider that testoster- thesized by the testicular Leydig cells, the thecal cells
one, with its powerful virilizing effects, differs from the of the ovary and the adrenal cortex (see Fig. 1). In
feminizing influences of estradiol by only one carbon men, testosterone is the principal plasma androgen
atom and four hydrogen atoms. These apparently and is enzymatically reduced within target tissue
superficial differences in the molecular structure of cells to dihydrotestosterone (17-hydroxy-5-andro-
steroid hormones alter the moleculeÕs shape and stan-3-one) (see Fig. 1). Relative to testosterone,
qualitatively change its biological activity. dihydrotestosterone exhibits a preferential affinity for
The intimate relationship of sex steroid hormones the intacellular androgen receptor and appears to be
with the morphogenesis and maintenance of the the active intracellular androgen (120). The irrevers-
reproductive system has been the object of an enor- ible metabolic conversion of testosterone to dihyd-
mous breadth of investigation for the past 100 years. rotestosterone occurs only in tissues that contain the
Surprising, however, has been the accrual of a myriad of enzyme 5a-reductase (210). Testosterone (but not
observations suggesting a connection between andro- dihydrotestosterone) can also be aromatized to
gens, estrogens and progestins and the functional estradiol by a number of extragonadal tissues (e.g.
milieu of the oral cavity. More specifically, research primarily adipose tissue and skeletal muscle), which
into the relationship between gonadal hormones and is a common route of estrogen production in men. In
periodontal tissues has established a significant link to women, the major plasma androgen is androstene-
both normal function and pathophysiology of disease. dione (androst-4-ene-3,17-dione), which can be se-
To appreciate the actions and interactions of sex creted into the bloodstream or converted into either
steroid hormones in the oral cavity from both con- testosterone or estradiol by the ovary. Once secreted
temporary and teleological perspectives, an overview into the bloodstream, the majority of androgens are
of steroid hormone physiology with a particular focus transported to their sites of action by a hepatic-se-
on the periodontium will be provided. In addition, creted high-affinity carrier protein designated as sex
a critical evaluation of evidence-based theories hormone-binding globulin (44% bound) as well as
regarding the roles of sex steroid hormones in peri- low-affinity serum albumins and other proteins (54%
odontal pathogenesis will follow. bound) (21). Secreted plasma androgens are also
metabolized to physiologically weak or inactive
Sex steroid hormone fate and molecules consisting of either 17-ketosteroids or
polar compounds (diols, triols and conjugates) for
effects in target tissues excretion by the kidney or liver (73).
The biological activities of androgens can be
Androgens
divided into irreversible morphogenic and reversible
All natural androgens are derived from a 19-carbon excitatory ⁄ maintenance effects. Morphogenic func-
tetracyclic hydrocarbon nucleus, known as andro- tions of androgens include in utero induction of

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Mariotti & Mawhinney

Estrone

Estriol

Testosterone

Estradiol

5 α - reductase
Fig. 2. Chemical formulae: estrone, estradiol and estriol.

rived from the peripheral conversion from adrenal

androstenedione (206, 212). Like other lipid-soluble
Dihydrotestosterone hormones, estrogens are transported in the blood
principally bound to carrier proteins; for example,
estradiol in the plasma is bound by either albumin
(60% bound) or sex hormone-binding globulin (38%
bound), leaving only 2% of the hormone free (211).
Fig. 1. Chemical formulae: testosterone and dihydrotes-
Both estradiol and estrone are metabolized princi-
tosterone. pally to estriol, which is the major estrogen detected
in the urine.
The biologic activities of estrogens in women in-
differentiation of the male reproductive tract,
clude: development, growth and maintenance of
pubertal changes in voice tone, growth cessation
secondary sex characteristics; uterine growth; feed-
postpuberty and male-pattern baldness. Mainte-
back control of pituitary gonadotropins; thickening of
nance ⁄ excitatory effects involve pubertal develop-
the vaginal mucosa; and ductal development in the
ment of the adult male phenotype, including the
breast. In men, the physiologic significance of estro-
growth and maintenance of male sex accessory or-
gens is in the regulation of pituitary gonadotropin
gans as well as anabolic actions on skeletal muscle
release, sexual behavior and the reabsorption of fluid
and bone, facilitation of libido and regulation of
in the efferent ducts of the testes. Specifically, the
specific metabolic processes in the liver, kidney and
administration of anti-estrogens to men results in
salivary glands (120).
increased levels of luteinizing hormone and plasma
testosterone, reflecting the tonic inhibitory activity of
endogenous estrogens on gonadotropin release (43).
Estrogens
Although not established in humans, male libido in
The naturally occurring estrogens, estrone (3-hy- laboratory animals, such as the rat, is dependent on
droxyestra-1,3,5[10]-triene-17-one), estradiol (estra-1, the combined actions of estradiol and dihydrotes-
3,5[10]-triene-3,17-diol) and estriol (estra-1,3,5[10]- tosterone in the central nervous system (112). Based
triene-3,16,17-triol), are characterized by an aromatic on research in estrogen receptor knockout mice,
A ring, a hydroxyl group at C-3 and either hydroxyl estrogens play a critical role in stimulating reab-
groups (C-16 and C-17) or a ketone group (C-17) on sorption of fluid from the efferent ductules of the
the D ring (see Fig. 2). Estradiol is the most potent testes. Estrogen receptor knockout animals displayed
estrogen and is secreted by the ovary, testis and pressure atrophy of the testes with loss of sper-
placenta, as well as by peripheral tissues. Estrone is matogenesis (52).
also secreted by the ovary; however, the principal
source in both women and men is through extrago-
Progestins
nadal conversion of androstenedione in peripheral
tissues (166). In premenopausal women, the most The natural progestins, or steroids that have proges-
significant physiologic estrogen is estradiol, and in tational activity, are derived from a 21-carbon
both men and postmenopausal women, the most saturated steroid hydrocarbon known as pregnane.
significant plasma estrogen is estrone, which is de- Corticosteroids are also derived from pregnane but

70
 Sex steroid hormones in the periodontium

differ from progestins because they contain an of very-low-density lipoprotein and high-density
a-ketol group at C-17 and a ketone or hydroxy group lipoprotein, diminishes insulin action, stimulates the
at C-11. The principal progestational hormone se- hypothalamic respiratory center, elevates basal core
creted into the bloodstream is progesterone (pregn- body temperature at ovulation and enhances sodium
4-ene-3,20-dione), which is synthesized and secreted excretion by the kidneys.
by the corpus luteum and placenta (see Fig. 3).
Similarly to androgens, the vast majority of circulat-
ing progesterone is bound to globulin and albumin Evidence for the periodontium as a
proteins (97). The fate of plasma progesterone is target tissue for sex steroid
dependent on hepatic, extrahepatic and extra-adre- hormones
nal metabolism. Both 5a-dihydroprogesterone and
deoxycorticosterone (21-hydroxy-4-ene-3,20-dione) Although research suggests that all four tissues of the
are the most probable active progesterone metabo- periodontium are modulated by androgens, estro-
lites; nonetheless, metabolic inactivation of proges- gens and progestins, the gingiva has been extensively
terone to pregnanediol (5-pregnane-3,20-diol) is studied and is indeed responsive to steroid sex hor-
accomplished by the liver (97). mones.
The biological activities of progestins are manifest
during the luteal phase of the menstrual cycle and
Clinical phenomena
pregnancy. Following ovulation and in prepara-
tion for potential nidation, corpus luteum-derived Evidence implicating the gingiva as a target tissue for
progesterone arrests estrogen-induced endometrial sex steroid hormones was based on clinical mani-
proliferation and stimulated glandular differentiation festations of morphological and inflammatory re-
in both the endometrium and mammary glands. sponses during periods of hormone fluctuation. Such
Progesterone plays a critical role in the maintenance observations have confirmed an increased prevalence
of pregnancy by stimulating endometrial glandular of gingival diseases with fluctuating sex steroid
structure and function, decreasing the contractility hormone levels, even when oral hygiene remained
of the myometrium and suppressing the immune unchanged. In large part, the periodontal changes
system to prevent rejection of the developing have been characterized in premenopausal women
fetus. Progesterone also decreases hepatic secretion because they have definitive cycles of sex steroid
hormone secretion. Nonetheless, there is a growing
body of evidence that men also have changes in the
periodontium when androgen levels fluctuate.

Progesterone Puberty

Epidemiological data have shown that gingivitis in

children is a ubiquitous condition (17, 50, 185). It has
been hypothesized that the incidence and severity of
gingivitis in childhood is influenced by plaque levels,
dental caries, mouth breathing, crowding of the
teeth, tooth eruption and puberty. In fact, the dra-
matic rise in steroid hormone levels during puberty
17 α - hydroxylase
in both sexes was believed to have a transient effect
on the inflammatory status of the gingiva (109).
Several early studies demonstrated an increase in
17α-hydroxy
progesterone
gingival inflammation in circumpubertal age indi-
viduals of both sexes, but data in these studies were
not available on the pubertal status of the individual
(50, 142, 185). In a cross-sectional study examining
7,380 children, gingival inflammation increased at
11 years of age in both sexes (50), while plaque levels
remained constant in all age groups (personal com-
Fig. 3. Chemical formulae: progesterone and 17a- munication from Dr Hefti). Sutcliffe (185) examined
hydroxyprogesterone. 127 school-age children in a 6-year longitudinal study

71
Mariotti & Mawhinney

and found an abrupt and transitory increase in the depths (96) and gingival crevicular fluid levels of a
incidence of gingivitis without a change in plaque cytokine (e.g. interleukin-6), a serine protease
levels. The mean age at which girls and boys reached (e.g. tissue plasminogen activator), a prostaglandin
their maximum gingivitis experience was 12 years (e.g. prostaglandin E2) and a coagulation factor (e.g.
and 10 months and 13 years and 7 months, respec- plasminogen activator inhibitor-2) (10) were not dif-
tively. In a 4-year longitudinal study of 22 boys and 20 ferent at any time of the menstrual cycle. Unlike the
girls, a clinically and statistically significant increase small changes noted in gingival inflammation during
in gingival inflammation was correlated with testic- ovulation, other investigators have not been able to
ular growth in boys and with breast development in detect any alterations in the gingival tissues during
girls (119). Finally, a longitudinal study following the human menstrual cycle. Holm-Pedersen & Löe
male and female children to puberty has demon- (56) examined exudates from gingival crevices but
strated that elevated testosterone in boys and found no change in gingival exudates during the
elevated estradiol and progesterone in girls were menstrual cycle. This study was unable to verify
positively correlated with increases in gingival changes in crevicular fluid flow, probably because of
inflammation (127). differences in methodology and subject selection
In most longitudinal or cross-sectional studies, the (107). Finally, in a small histologic study evaluating
data strongly indicate that there is a short period of gingival tissues during different stages of the men-
time when children experience an exaggerated gin- strual cycle in young women, the investigators were
gival inflammatory response to plaque. However, unable to distinguish histological signs of inflam-
even though the increase of gingival inflammation in mation during any stage of the menstrual cycle (31).
children has been associated with puberty, the The other significant observation that has been
prevalence, severity and time to onset of the gingival described during the menstrual cycle is the appear-
inflammation has varied depending on the study (16, ance of aphthous ulcers. In early studies, several
111, 119, 124, 185). investigators described specific populations of wo-
men who developed aphthous ulcers during the lu-
Menstrual cycle
teal phase of the menstrual cycle (29, 184), whereas
In general, the periodontium does not exhibit clini- other studies were unable to demonstrate any influ-
cally obvious changes during the menstrual cycle. ence of the menstrual cycle on aphthous ulcer for-
Nonetheless, two different clinical findings have been mation (158, 161). The different outcomes of these
reported to occur in the oral cavity. One observation studies result from the variation in study design, lack
deals with the inflammatory changes that develop in of statistical analysis, small study populations and
gingival tissues of periovulatory women (10, 69, 83, use of retrospective data (107). Despite the conflict-
98, 123). In a very small percentage of women, ing findings of these early studies, there are no per-
ulcerations of the oral mucosa, vesicular lesions and suasive data to support that aphthae development is
bleeding have been described during ovulation or related to hormonal changes during the menstrual
several days before menstruation. Muhlemann (123), cycle (113).
clinically and histologically, described a case of Ôgin- In summary, during the menstrual cycle, there is a
givitis intermenstrualisÕ where bright-red, hemor- small increase in gingival inflammation that has been
rhagic lesions of the interdental papilla developed noticed in clinical research studies. This subclinical
prior to the menses. The more common inflamma- inflammation is, to all intents and purposes, asymp-
tory changes that develop in the gingiva seem to in- tomatic. In regard to aphthous ulcers, there are no
volve less dramatic clinical alterations in this tissue. consistent data to suggest that their occurrence
For example, during the menstrual cycle, the amount is influenced by hormonal changes during the
of gingival exudate (an indicator of gingival inflam- menstrual cycle. Nonetheless, anecdotal reports of
mation) has been shown to increase during ovula- individuals with aphthous ulcer formation or exces-
tion. Lindhe & Attstrom (83) described an increase in sive gingival inflammation during the menstrual cy-
the production of gingival exudate during ovulation, cle suggests that there is a very small and unique
which returned to baseline during menses. In 88% of population of women whose oral mucosa exhibits
the subjects evaluated, there was an increase of at sensitivity to cyclic hormonal changes.
least 20% in the amount of gingival crevicular fluid
Oral contraceptives
present during ovulation. Recent studies have con-
firmed a modest increase in gingival inflammation Oral contraceptive agents are one of the most widely
during ovulation (10, 98), but changes in probing utilized classes of drugs. It has been estimated that

72
 Sex steroid hormones in the periodontium

over 100 million women worldwide are currently investigations also demonstrated that the severity
using these agents (191). Current oral contraceptives of gingival inflammation was independent of the
consist of low doses of estrogens (£ 50 lg ⁄ day) and ⁄ amount of plaque and did not result in attachment
or progestins (£ 1.5 mg ⁄ day); however, it should be loss (44, 58, 134, 167, 188). Furthermore, gingival
noted that early formulations of oral contraceptives probing depths were larger (44, 58, 92, 116), bleeding
contained higher concentrations of sex steroid on probing or during toothbrushing increased (4, 44,
hormones and that early clinical studies examined 116, 188) and the amount of gingival crevicular fluid
gingival conditions in women using these higher was elevated (13, 58). Women who were pregnant
doses of estrogens and ⁄ or progestins. Moreover, also exhibited a low prevalence (0.5–0.8%) of local-
numerous early clinical studies of women who used ized gingival enlargements (92, 101). These preg-
oral contraceptives reported gingival enlargement nancy-induced gingival overgrowths were reversed
(66, 96, 177), excessive inflammation (23, 86, 141) following parturition (218).
and, controversially, attachment loss (71, 141). With the various inflammatory changes that occur
The presence of inflammatory changes in gingival in the periodontium during pregnancy, there has
tissues noted in early studies that evaluated the been concern regarding appropriate periodontal
effects of oral contraceptives are in contrast to management of these special needs patients. Studies
current findings of a lack of gingival inflammation in have shown that periodontal treatment during preg-
women using present-day oral contraceptive formula- nancy is a safe and effective method for reducing
tions (107). The reasons for the decline in gingival periodontal inflammation while improving peri-
inflammation from the use of oral contraceptives are odontal health (5, 99, 134).
multifactorial and have been exhaustively reviewed
Adult men
by Preshaw (148). In short, oral contraceptives
should not be viewed as a risk factor for gingival or The effects of androgens on periodontal tissues in
periodontal disease. adult men have not been thoroughly cataloged. In an
attempt to understand the actions of these anabolic
Pregnancy
steroids, the effects of androgens on the periodontium
The increases in sex steroid levels that begin before have been investigated in men who: (i) had higher-
fertilization, (i.e., during the luteal phase of the than-normal plasma androgen levels as a result of
menstrual cycle), continue once implantation of the exogenous hormone administration; or (ii) exhibited
embryo occurs and are maintained until parturition. lower-than-normal plasma androgen levels as a result
For example, pregnant women near or at term produce of endocrine disease. Studies examining men with low
large quantities of sex steroid hormones (20 mg of plasma androgen levels have generally not demon-
estradiol, 80 mg of estriol and 300 mg of progesterone) strated a greater loss of periodontal attachment over
on a daily basis. This prominent increase in plasma controls (18, 192), whereas high plasma androgen
hormone levels over several months has a dramatic levels, as a result of exogenous hormone administra-
effect on the periodontium throughout pregnancy. tion, in healthy adult men, has been shown to
During pregnancy the prevalence and severity of stimulate the growth of gingival tissues (139). The
gingivitis has been noted (4, 30, 44, 58, 91, 92, 99, 134, periodontal changes in men associated with andro-
188). In one of the early studies, Löe & Silness (92) gens (e.g., studies showing a sexual dimorphism for
used a cross-sectional study to examine 121 pregnant periodontal diseases and a possible biologic basis for
and 61 postpartum women for changes in gingival androgen-induced periodontal changes) has been
inflammation. During pregnancy, 100% of women exhaustively reviewed by Haytac and colleagues (48).
exhibited gingival inflammation when compared
Menopause, andropause and afterwards
with postpartum controls. The prevalence and
severity of gingival inflammation were significantly During menopause, ovarian function declines and
higher in the pregnant vs. the postpartum patients, there is a significant reduction in the production and
even though plaque scores remained the same be- secretion of sex steroid hormones. In the next two
tween the two groups (167). Similar results have been decades, approximately 40 million women in the USA
observed in numerous longitudinal studies of women will pass through the menopause. In men, an age-
during and following pregnancy (30, 44, 58, 134, 188). related decline in circulating plasma testosterone
In addition to confirming that the severity of gingival levels, which may lead to physiologic changes, has
inflammation was exacerbated throughout preg- been termed andropause. Unlike menopause, there is
nancy and reduced following parturition, these a gradual reduction of free testosterone in men dur-

73
Mariotti & Mawhinney

ing andropause. It has been shown that in men, a In men, the changes that occur in the periodon-
steady reduction of androgen levels starts at 50 years tium as a result of an age-related decline in free
of age and continues throughout life, despite no plasma androgen levels have not been adequately
change in the total concentrations of the steroid until documented. It is known that androgen deprivation
after 70 years of age (155, 179). The gradual reduction is associated with appendicular bone loss (181) and
of secretion of luteinizing hormone, the protracted that elderly men have increased amounts of
decrease in responsiveness of Leydig cells to chemi- destructive periodontal disease and tooth loss as
cal signals and the slow increase in the amount of they age; however, the causal relationship between
sex-hormone-binding globulin in the plasma (95) declining plasma androgen levels and periodontal
contributes to the decline in the free plasma andro- diseases has not been demonstrated (48).
gen concentration. This decrease in plasma androgen
levels does not mean that infertility is inevitable be-
Tissue specificity of localization
cause men can father children into the ninth decade
of life (156). Sex steroid hormone receptors are not ubiquitous but
The changes observed in the gingiva during and are found at high concentrations in hormone-sensi-
after menopause are quite different from other times tive tissues, termed target tissues. Cytoplasmic and
in a womanÕs life. There are no endogenous hormone- nuclear receptors that bind specific hormones lead to
induced increases in gingival inflammation or size; the preferential accumulation and retention of hor-
instead, there is a process where the gingival mones in target tissues. Almost all work on the tissue
epithelium becomes thin, atropic and prone to localization of sex steroid hormones in the peri-
inflammatory changes (32, 35, 90, 152). Clinically, odontium was accomplished in the late 20th century
postmenopausal women may exhibit oral discomfort and has been reviewed in detail (107). In summary,
that is characterized by a burning sensation or des- these studies have revealed that estrogens (7, 33, 198),
quamations of gingival epithelium. The question has androgens (197) and progestins (117, 205) were
arisen as to whether gingival vesiculobullous lesions, preferentially localized and retained in periodontal
which develop in women after the climacteric, are a tissues (28), which was determined by the expression
manifestation of one of several different vesiculobul- of specific steroid hormone receptors.
lous diseases, a variant of a single vesicular dermato-
logic disorder or a distinct disease under hormone
Sex steroid hormone receptors
control. Desquamative gingival diseases affected by
menopause were first described in the late 19th Specificity of the hormone response depends on the
century (189). The clinical data available to support a presence of intracellular proteins, called receptors,
role of sex steroid hormones in desquamative gingival which specifically recognize and selectively bind the
lesions sensitive to reductions in plasma estrogen hormone and act in concert with the hormone ligand
levels (76, 131, 152, 153, 163, 168, 169, 194, 219) have to regulate gene expression (107). Generally, steroid
been extensively reviewed (104, 107). To sum up, hormone receptors consist of asymmetric protein
limited evidence has suggested that some desquama- subunits with long (10:1) axial ratios. These subunits,
tive gingival lesions in a small and unique population which form either dimers or tetramers at low ionic
of women may be estrogen-sensitive. strengths, range in weight from 80 to 100 kDa. As a
In postmenopausal women, positive correlations class of regulatory proteins, the different steroid
between estrogens and bone density have been dem- hormone receptors have a high degree of homology.
onstrated (61, 180) and the bone mass from edentu- Each protein can be divided into six sections, desig-
lous mandibles has shown age- and sex-related dif- nated as regions A–F (107). Unlike the androgen and
ferences (55, 62, 77, 122, 164, 174, 187, 201, 202). progesterone receptors, the estrogen receptor has
Manifestations of systemic bone loss may be a two genetically distinct forms, referred to as a and b,
reflection of reductions found in orofacial bone min- that have different functions and vary in presence
eral density and could result in loss of attachment and and concentration from tissue to tissue (130, 214).
tooth loss (8, 19, 42, 102, 118, 144, 151, 154, 187); Initial observations of how sex steroid hormones
however, other studies have failed to find an associa- bind to intracellular proteins (40, 60), have led to the
tion (53, 77, 145, 146, 203, 204, 207). To ascertain if a current hypothesis of sex steroid action (37, 47, 110,
causal relationship exists between osteopenia and 133, 157, 159, 209) (see Fig. 4). Sex steroid hormone
destructive periodontal diseases, additional, thor- action begins with secretion of the hormones into the
ough, longitudinal investigations are required. bloodstream, where they circulate, principally bound

74
 Sex steroid hormones in the periodontium

manner, sex steroid hormones can affect neural

transmission (68, 79), modify the transport of calcium
ions into cells (12) and stimulate the intracellular
concentration of polyamines (74).
In the periodontium, the majority of our under-
standing of hormone action has accumulated from
preliminary observations during the late 20th century.
For periodontal tissues, intracellular binding proteins
have been partially characterized for estrogens (81,
126, 178, 198), androgens (175, 197) and progesterone
(196). The human gingival cytosol receptor for estro-
gen is a high-affinity (Kd  340 ƒM), low-capacity
( 4.5 ƒmol ⁄ mg of protein), heat and proteolytic
enzyme-sensitive protein that exhibits steroid speci-
ficity of binding to estradiol but not to cortisol, pro-
gesterone or testosterone (198). During periods of
gingival inflammation, the number of gingival estro-
philes is elevated approximately 10-fold (178). Further
Fig. 4. Mechanism of action of sex steroid hormones. S, classification has shown estrogen receptor-b to be the
sex steroid hormone. Reprinted with permission from the predominant estrogen receptor found in the gingiva
textbook, ‘‘Medical Physiology, 2nd Edition’’ edited by RA (193). In the periodontal ligament, fibroblasts have
Rhoades and GA Tanner. been shown to express both estrogen receptor-a (140)
and estrogen receptor-b (63, 82, 140, 186) subtypes.
(approximately 98%) to plasma proteins. In the cir- Human gingiva also contains an androgen cytosol
culation, the unbound or free hormone can enter the receptor that binds with high affinity (Kd  2.2 gM)
cell by diffusion and bind to macromolecules called and low capacity ( 190 ƒmol ⁄ mg of protein) to a
receptors. These large intracellular protein receptors heat-sensitive protein that exhibits preferential
are located in both the cytoplasm and the nucleus of affinity for dihydrotestosterone (i.e. the principal
the cell. Depending on the type of steroid hormone, mediator of androgen action in adult tissues) but not
the intracellular localization of the receptor will vary. to progesterone, dexamethasone, cortisol, andro-
Gonadal hormones are considered to reside princi- stenedione or estradiol (175). Additional techniques
pally in the nuclear component of target cells. When using immunohistochemical detection have identi-
the steroid hormone is bound to the receptor, it fied androgen receptors in the nuclei of basal gingival
transforms the receptor to an active configuration epithelial cells and gingival fibroblasts (57, 136).
and the activated receptor–steroid hormone complex Little is known about the progesterone receptor in
binds with high affinity to specific nuclear sites (e.g. human gingiva, except that progesterone recognizes
discrete DNA sequences, the nuclear matrix, a cytosolic protein (199); the specificity and affinity of
nonhistone proteins and the nuclear membrane). the protein remain to be described. In contrast to
The activation step of this process may occur in the humans, progesterone receptors have been charac-
cytoplasm or the nucleus. Once the receptor– terized in rabbit gingiva and exhibit high-affinity (Kd
hormone complex is bound to nuclear regulatory  2.7 gM), low-capacity ( 10 ƒmol ⁄ mg of protein)
elements, gene activation and transcription of binding to a heat- and proteolytic enzyme-sensitive
mRNA occurs. Following the nuclear interaction, the protein that demonstrates a pattern of steroid spec-
receptor–hormone complex disassociates, leaving an ificity similar to progesterone receptors obtained
unoccupied receptor and the steroid hormone. from other target tissues (196). In an immunohisto-
Although the regulation of gene transcription by chemical study, low levels of nuclear progesterone
hormone–receptor complexes in the nucleus appears receptors were detected in six different human
to be the major biological action of sex steroid hor- fibroblast strains (67).
mones, these molecules also have other behaviors
that are independent of the genome. Studies have
Sex steroid hormone metabolism
shown that androgens, estrogens and progestins have
membrane effects and can thus influence the pro- The metabolism of sex steroid hormones in target
duction of second messenger systems (138). In this tissues will either degrade and inactivate the

75
Mariotti & Mawhinney

hormone or alter the hormone and increase the po- nificance of hormone action in the periodontium
tency. Similarly to the studies that determined tissue have dealt with the effect of hormones on microbial
localization of steroid hormones, most of the seminal organisms, the vasculature, the immune system and
work that evaluated the metabolism of steroid hor- specific cells in the periodontium (Table 1). The
mones by periodontal tissues was accomplished response of the periodontium in disease is probably
during the late 20th century. The periodontium of not a single mechanism but, rather, is multifactorial
humans and animals has been shown to contain the in nature (see Fig. 5). Nevertheless each theory of
necessary enzymatic machinery to metabolize all sex how sex steroid hormones induce disease in the
steroid hormones by common metabolic pathways periodontium will be examined.
and has been extensively reviewed (107). To sum up,
the metabolism of estrogens (27, 28), androgens (25,
Sex steroid hormones and microbial
137, 195, 200) and progestins (24, 26, 135, 136) has
organisms
been noted in gingival tissues, and metabolism has
been reported to increase in inflamed periodontal Gingivitis is considered to be primarily a microbial
tissues (24, 25, 27, 28, 135, 136, 200). disease that can be modulated by different systemic
and environmental factors (103). It was therefore
natural to assume that exacerbations in gingival
Putative etiologies of periodontal inflammation observed during increases in plasma
endocrinopathies sex steroid hormones were caused by hormone-in-
duced alterations in the microbial flora of the gingival
Although evidence has accumulated to implicate the sulcus. The presumed changes induced by the puta-
periodontium as a target tissue for steroid hormones, tive periodontal pathogens has come into question
the specific relationship of sex steroid hormones with (107), and the effects of gonadal hormones on oral
periodontal endocrinopathies remains an enigma. To microbial organisms has been exhaustively reviewed
date, the most prominent explanations for the sig- by Kumar (78). In summary, data to support a tran-

Table 1. Summary of potential etiologies for periodontal endocrinopathies

Proposed mechanism for Comments Literature reviews

steroid-induced periodontal disease

Sex steroid-induced increase in Changes in putative periodontal Kumar (78)

specific periodontal microbiota microbial pathogens and hormone
status are not correlated

Sex steroid hormones alter vascular Primary evidence supports Arnal et al. (6)
characteristics estrogen-induced effects on vascular Losordo & Isner (94)
permeability and proliferation. Magness & Rosenfeld (100)
Progesterone has a modest effect,
at best, on endothelial cells. Androgen
effects on blood vessels are poorly
documented
Immune-endocrine interactions Numerous autoimmune diseases Shiau & Reynolds (160)
exacerbate periodontal responses related to the sex of the individual Straub (183)
are exacerbated by fluctuations in
hormone levels. Changes to periodontal
tissues during periods of increased
hormone secretion (e.g. pregnancy)
have been linked to elevated levels
of immune cells

Specific populations of fibroblasts Gingival inflammation, enlargement, Mariotti (104, 107)

and epithelial cells are modulated desquamative lesions and periodontal
by sex steroid hormones attachment loss are the result of
specific resident cell populations
that secrete soluble and insoluble
signals

76
 Sex steroid hormones in the periodontium

Sex steroid hormones

the rise in plasma estrogen levels in the follicular
phase; inversely, endometrial blood flow decreases
during the luteal phase of the menstrual cycle when
Microbiota Immune cells
estrogen levels are decreasing and progesterone lev-
els are elevated (149).
The mechanisms for the estrogen-induced blood
Cells of the periodontium vessel responses are currently being investigated. It is
known that endothelial cells synthesize estrogens and
Altered gene expression
that blood vessel function is modulated by both
estrogen receptor-a and estrogen receptor-b (6).
Several putative mechanisms by which estrogens
Change in clinical phenotype may control blood vessel tone include inhibiting the
movement of calcium ions through the voltage-
Fig. 5. Actions of sex steroid hormones on periodontal sensitive calcium channels of uterine arteries after
cells. metabolic conversion to catechol estrogens (182),
influencing the release (11) or disposition (46) of
sympathetic transmitter, or affecting alpha-adreno-
sient increase in a specific microorganism during ceptor number or affinity (15, 54). Estrogens may
puberty or pregnancy have been equivocal, and often increase capillary permeability by stimulating the
the speculative interpretation of specific results has release of various mediators (e.g. adenosine, brady-
been overzealous. kinin, vasoactive intestinal polypeptide, neurotensin,
Substance P, various prostaglandins, AMP, ADP, ATP,
cAMP, guanosine, thymidine, histamine, cytidine,
Sex steroid hormones and the
uridine, acetylcholine, isoproterenol and glycosami-
periodontal vasculature
noglycans); however, none of these mediators alone
As with all inflammatory reactions, the increase in has been able to mimic the qualitative and quanti-
blood vessel permeability that occurs in gingivitis is a tative changes in blood flow induced by estrogen
classic outcome of the disease (106). Early studies (100). Recent studies have shown that activation of
evaluating putative etiologies responsible for the in- the estrogen receptor-a was responsible for nitric
creased, hormone-induced gingival inflammation oxide-induced vasodilation (6), re-endothelialization
pointed to the effects of sex steroid hormones, (6) and angiogenesis (94).
especially progestins, in changing the quality and In contrast to the principal effects induced by
quantity of gingival blood vessels. The concept that estrogen on blood vessels, progesterone may have
progesterone is responsible for the changes in vas- little or no direct effect on the vasculature (100).
cular number and permeability has been a flawed Progesterone has been reported to antagonize the
cornerstone for explaining the inflammatory changes actions of estrogen, presumably by reducing estrogen
observed during puberty, pregnancy and ⁄ or with the receptor numbers (100). Furthermore, progestins
use of oral contraceptives in women. Specifically, it is have been shown to have an inhibitory effect on
very likely that estrogens, and not progestins, are angiogenesis (94). In men, testosterone, which can be
responsible for the changes that occur to periodontal metabolized to estradiol, will cause a sharp, transient
blood vessels (107). dilation of arterioles and venules in sex accessory
In women, estrogen is the principal sex steroid organs (72).
hormone responsible for alterations in blood vessels. Similarly to uterine blood vessels, the gingival
In both intact and hormone-treated castrated ani- vasculature also appears to be sensitive to sex steroid
mals, one of the early responses of gonadal hormones hormones. Several clinical studies have correlated
in accessory reproductive tissues involves increased elevated levels of gingival crevicular fluid (which is a
blood volume, flow rate, hyperemia and enlarged surrogate indicator of blood vessel function) with the
microvascular surface (176). For example, in the presence of sex steroid hormones. In pregnant
uterus, estrogen stimulates blood flow (41, 65) and women, the amount of gingival crevicular fluid is
increases the movement of fluid and plasma proteins elevated by as much as 54% when compared with
across blood vessel walls within minutes of admin- gingival crevicular fluid levels from postpartum
istration (34, 49). During the human menstrual cycle, controls (58). Furthermore, exogenous estrogen and ⁄ or
endometrial blood flow increases concomitantly with progesterone administration will significantly in-

77
Mariotti & Mawhinney

crease the amount of crevicular fluid in either in- (9:1), GraveÕs disease (7:1) and rheumatoid arthritis
flamed or noninflamed canine dentitions (59, 84, 85). (2.5:1) (1), whereas there is a male predilection for
Curiously, several studies have implied that pro- ankylosing spondylitis (3:1) (147). Second, autoim-
gesterone was primarily responsible for a reduction mune diseases can improve or flare with hormonal
in corpuscular flow rate (87), increased vascular fluctuations (2, 3, 45, 51, 93, 125) indicating that sex
permeability (88) and vascular proliferation (89). The hormones probably play a role in many autoimmune
predominance of progesterone-induced vascular diseases. Third, sex steroid hormones have been
changes of these studies must be placed in perspec- shown to modulate the production of cytokines (183).
tive with respect to hormone dose and the tissues As immunological reactions play an important role
used to evaluate the hormone effects. More specifi- in the pathogenesis of periodontal diseases (38), our
cally, pharmacologic (not physiologic) doses of ultimate understanding of the effects of sex steroid
estrogens (e.g. up to 400 million times the plasma hormones on the immune system in the periodon-
concentration found in nonpregnant women) and tium is paramount. Low concentrations of estradiol
progesterone (e.g. up to one million times the plasma (1.5 gM) have been shown to reduce polymorpho-
concentration found in nonpregnant women) were nuclear leukocyte chemotaxis by as much as 26.8%
used to examine the effects of ovarian hormones in (115). In addition, the concentrations of a number of
nonperiodontal tissues (e.g. the hamster cheek pouch immune-sensitive cells, including CD1 cells (i.e. pri-
and the ears of rabbits). marily LangerhansÕ cells) and CD3 cells (i.e. the
Although estrogens are primarily responsible for majority of mature T lymphocytes) in the oral gingi-
vascular changes reported in reproductive target tis- val epithelium, as well as CD4 cells (i.e. helper T cells)
sues, such as the uterus, several periodontal studies in the oral and sulcular gingival epithelium, were
have suggested that increased vascular permeability elevated during pregnancy (150). For androgens,
in the gingiva was essentially the result of proges- immunologic functions related to adaptive immunity
terone. As noted, these studies were principally and innate inflammatory responsiveness have been
descriptive in nature and ⁄ or used concentrations of hypothesized to affect the progression of periodontal
hormones far higher than those normally found in disease in men (160).
women. It would be naı̈ve to believe that blood ves-
sels in the gingiva behave differently from those
Sex steroid hormones and cells of the
found in reproductive tissues. As such, it is reason-
periodontium
able to regard the changes observed in the gingival
vascular to be primarily the result of actions by In the oral cavity, androgens, estrogens and proges-
estrogens. tins are known to affect several cell types, and in the
periodontium reports dealing with the actions of sex
steroid hormones have focused primarily on two cell
Sex steroid hormones and the immune
types: the keratinocyte (see Table 2) and the fibro-
system
blast (see Table 3).
There is a large and growing body of literature Many of the histologic studies that examined the
describing the interactions of the immune and effects of gonadal hormones on gingival epithelial
endocrine systems. Straub (183) proposed that the cells were purely descriptive in manner and the
effects of sex steroid hormones on the immune sys- investigators were usually not blinded to the
tem are dependent on: the immune stimulus and treatment modalities. Bearing this in mind, several
antigen-specific immune response; the target cells investigators perceived that estrogens increased
involved; the microenvironment of the tissue; hor- epithelial keratinization and stimulated prolifera-
mone concentration; the variability of receptor iso- tion (153, 217). Trott (190) noticed a reduction
forms; and the intracellular metabolism of hormones in keratinization of marginal gingival epithelium
to either biologically active or inactive forms. in postmenopausal women when plasma estrogen
Detailed descriptions of changes in immune function levels were declining. In senile mice, estrogens were
that are dependent on sex steroid hormones reported to increase the down-growth of epithelial
have been reported. First, there are a number of attachment (132). Beagrie (9) found an increase in
autoimmune diseases that exhibit a gender-related thymidine uptake in murine oral epithelium and
susceptibility. For example, there is a female sex epithelial attachment; however, no analysis was
predilection for HashimotoÕs thyroiditis (13:1), sys- attempted to determine if these differences were
temic lupus erythematosus (9:1), SjogrenÕs syndrome significant. In one of the few studies to quantify

78
 Sex steroid hormones in the periodontium

Table 2. Summary of histological effects of sex steroid the reduction in gingival proliferation was not caused
hormones on gingival epithelium by the direct effects of the progestin but rather by a
reduction of plasma estradiol induced by daily
Hormone Epithelial response
administration of progesterone.
Androgen › proliferation The extracellular matrix of the periodontium is an
Progesterone fl keratinization intricate mosaic of cells (e.g. fibroblasts, mesenchy-
mal cells, mast cells and endothelial cells) inter-
› proliferation
Estrogen spersed among a diverse number of macromolecules
› keratinization (105). The actions of sex steroid hormones on the
extracellular matrix are a prime example of the
changes induced by estrogens in epithelial cells, Lit- dynamic response of cells in gingival connective
wack et al. (90) found the length of rete pegs, the tissue during hormone fluctuations. Early studies
number of basal epithelial cells per area of basement examining the effects of sex steroid hormones on the
membrane and thymidine labeling of epithelial cells gingival extracellular matrix were primarily descrip-
in oral mucosa to be significantly increased after tive in nature and ascribed histologic changes in
administration of estrogen to castrated adult female the composition of the entire tissue. For example,
squirrel monkeys. Moreover, estrogen also stimulated initial histologic studies in humans described the
an increase in the number of basal epithelial cells per maintenance of gingival connective tissue in women
area of basement membrane in the gingiva of squirrel receiving exogenous estrogen (219), whereas andro-
monkeys. gen treatment was effective in stimulating prolif-
In humans, simians and rodents, androgens were eration of connective tissue elements in humans,
perceived to stimulate an increase in epithelial cell castrated rhesus monkeys (216) and rats (162). Later
number (162, 216). In a study using progestins, daily studies began to biochemically analyze the changes
administration of norethisterone acetate to nine that developed in the presence of androgen or
healthy women, between days 3 and 27 of the men- estrogen. A sexual dimorphism was reported in the
strual cycle, resulted in a significant reduction in the amount of gingival sialic acid (129). Moreover, in
keratinization index and the karyopyknotic index young Wistar rats, gingiva from normal female rats
from gingival smears (70). The authors suggested that was found to contain up to 42% more N-acetylneu-

Table 3. Summary of sex-steroid induced effects of gingival fibroblasts in cell culture

79
Mariotti & Mawhinney

raminic acid in comparison to gingiva from age- from either phenytoin-enlarged human or newborn
matched male rats. Testosterone was also found to feline gingiva in media supplemented with 10% fetal
have an effect on extracellular matrix components. bovine serum (36). Unlike testosterone, Coletta et al.
Kofoed (75) demonstrated that gingival hyaluronic (14) found that dihydrotestosterone stimulated the
acid, but not heparan sulfate, chondroitin-4-sulfate, proliferation of fibroblasts derived from either nor-
chondroitin-6-sulfate or dermatan sulfate, was mal human gingiva or hereditary gingival enlarge-
androgen sensitive. More specifically, castration of ments. Several studies have shown that androgens
adult rats induced a 54% reduction in hyaluronic (e.g. testosterone or dihydrotestosterone) inhibit the
acid that could be prevented with subcutaneous production of interleukin-6 (14, 39, 143); however,
injections of testosterone propionate. this androgen-induced reduction could not be
Investigations examining the effect of estrogen on completely blocked by androgen receptor antagonists
collagen synthesis have been limited in the gingiva. (14, 39, 143). Human gingival fibroblasts also
Dyer et al. (22) found no significant effect of a single metabolize testosterone to 5a-dihydrotestosterone,
dose of estrogen on hydroxyproline-specific radio- 4-androstenedione and 5a-androstanediols in cell
activity in gingival or palatal tissues of ovariecto- culture (171), a characteristic shared by classic
mized, nulliparous rats. Although the amount of androgen-dependent tissues. Studies using fibroblast
newly synthesized gingival collagen was not statisti- monolayers or fibroblast cytosols reported a signifi-
cally different between estrogen-treated castrated cant increase above controls in the metabolism of
animals and castrated control animals, differences testosterone to 5a-dihydrotestosterone and 4-andro-
between these two groups may be masked either by stenedione by fibroblasts derived from either
the amount of error around the means or because phenytoin-, nifedipine-, or cyclosporine-enlarged
these experiments allowed for a castration-induced gingival tissues (170, 172). Currently, it is unclear
regression prior to estrogen treatment. Examining whether the increase in androgen metabolism by fi-
estrogen-induced effects on extracelluar matrix pro- broblasts derived from these drug-influenced gingival
teins at a cellular level has shown that both hormone enlargements is caused by the inflamed nature of the
and extracellular matrix affect protein production. donor tissue or the drug involved in increasing tissue
Specifically, stimulation of human gingival fibro- size. A variety of other studies in cell culture have also
blasts derived from noninflamed explants signifi- shown that androgen metabolism can be manipu-
cantly depressed collagen production on plastic and lated by a variety of therapeutic agents (173).
collagen IV matrices, whereas noncollagen protein Similarly to the actions of testosterone on gingival
production on plastic and collagen I matrices fibroblast cultures, the effects of progesterone on
was reduced (108). These results demonstrate the human and feline gingival fibroblast cell cultures
important influence of specific types of extracellular revealed an inhibition of fibroblast proliferation (36,
matricies on protein production by gingival fibroblast 208). Progesterone significantly reduced the prolif-
cells stimulated with estrogens. Unlike the estrogen- erative rate of fibroblasts derived from either phe-
induced depression of protein production by gingival nytoin-enlarged human or newborn feline gingiva in
fibroblasts, estrogen stimulated alkaline phosphatase medium supplemented with 10% fetal bovine serum
activity and mineralized nodule formation by peri- (36). A later study confirmed these results in humans,
odontal ligament fibroblasts in cell culture (121). The demonstrating that 20 lg ⁄ ml of progesterone
difference between the estrogen-induced secretory inhibited DNA synthesis and that 40 lg ⁄ ml of
activity of gingival and periodontal ligament fibro- progesterone reduced protein synthesis by as much
blasts is a result of the unique biology of the cell type as 50% (208). Progesterone also caused a dose-
as well as the concentration of estrogen used to dependent decrease in the production of interleukin-
stimulate these activities in periodontal ligament 6 by gingival fibroblasts in culture (80). In a later
fibroblasts (e.g. 20 ng of estradiol ⁄ ml of culture study, a dose-dependent increase in interleukin-6 by
media) vs. gingival fibroblasts (e.g. 0.30 ng of estra- progesterone was observed in cell culture (213). The
diol ⁄ ml of culture media) in cell culture. discrepancy between these two studies was depen-
The fibroblast is the principal cell type found in the dent on methodological differences and on the
extracellular matrix of the gingiva (128), and con- observation that the progesterone-induced increase
temporary research is demonstrating that gingival of interleukin-6 relied on only one gingival fibroblast
fibroblasts are affected by all three sex steroid hor- strain for this outcome.
mones. Testosterone has been shown to significantly In contrast to testosterone and progesterone,
reduce the proliferative rate of fibroblasts derived estrogens appear to be stimulatory in gingival fibro-

80
 Sex steroid hormones in the periodontium

blast cell cultures. Estradiol induced proliferation of The central focus of reproductive endocrinology
fibroblasts derived from either feline or human drug- revolves around specific regulatory molecules (i.e.
enlarged gingiva (36). In a study examining fibroblasts hormones) that govern reproduction as well as the
derived from clinically healthy human gingiva of pre- growth and development, maintenance of the inter-
menopausal women, physiologic concentrations of nal environment, energy production and energy uti-
estradiol increased cell proliferation in vitro (108). lization of sex accessory tissues; yet, the effects of
More specifically, the proliferation of gingival fibro- these hormones are not patently obvious in tissues,
blasts derived from the noninflamed papilla of healthy such as the periodontium, that have no function re-
premenopausal women was increased by up to 310% lated to reproduction. Although sex hormones have
by 1 gM estradiol. Further characterization of fibro- been linked to periodontal pathology, it would be
blasts from premenopausal women demonstrated counterintuitive to believe that these potent hor-
a distinctive estrogen-sensitive cell subpopulation mones are purely detrimental to the periodontium. In
within the parent cell population (108). Besides cell consideration of the idea that sex steroid hormones
proliferation, estradiol can also induce, in gingival fi- help to sustain the normal viability of the periodon-
broblasts, a dose-dependent increase in interleukin-6, tium, a teleological argument has been constructed,
interleukin-8 and vascular endothelial growth factor focusing on the importance of inflammatory pro-
(213). In periodontal ligament cells, estrogens caused a cesses for the preservation of the periodontium.
down-regulation of lipopolysaccharide-induced cyto- Inflammation associated with sex steroid hor-
kines (165) while enhancing the production of osteo- mones plays a valuable role in the periodontium. In
protegrin (165, 215); however, estrogen did not affect general, the inflammatory process begins in the
the cell number in culture (64). periodontal vasculature and is a biochemical and
In conclusion, evidence has suggested that gonadal cellular process that takes place approximately in the
hormones mediate the actions of gingival fibroblasts same manner, regardless of the stimulus (106). On
and epithelial cells as well as periodontal ligament injury, blood vessels dilate and become more per-
fibroblasts, and therefore contribute to the mainte- meable, resulting in increased blood flow and leakage
nance of this tissue. It is known that gingival cells of plasma and cells into the extracellular matrix. The
metabolize sex steroid hormones and contain hor- cells and platelets carry out their functions with the
mone receptors. Furthermore, sex steroid hormones support of the three major plasma protein systems
affect the rate of cellular secretion and cellular pro- (the complement system, the clotting system and the
liferation. In the presence of inflammation, altera- kinin system). Inflammation destroys and removes
tions in the metabolism of sex steroid hormones (24, noxious agents, confines the injurious agents for
25, 27, 135, 136, 200) and in the number of hormone efficacious removal, limits systemic effects of cellular
receptors (175, 178, 198) have been noted in cellular agents, enhances the immune response and pro-
elements. Future studies will need to define whether motes wound healing (106). Therefore, the biologic
the actions of gonadal hormones directly affect significance of inflammation is primarily associated
periodontal cells or whether other hormone-stimu- with the defense of the body from injury and infec-
lated autocrine and paracrine growth factors are tion.
responsible for modulating cell function (20, 114). In the periodontium, the effects of sex steroid
hormones are manifest in the endothelium, gingival
epithelium and connective tissue cells found in the
Periodontal teleology gingiva, periodontal ligament, bone and cementum,
as well as in cells from the immune system. Gener-
Life is dependent on a functioning endocrine system ally, at times of significant hormone fluctuations,
whose role is to maintain the internal milieu of a these periodontal cells become reactive. Hence,
multicellular organism by using specific chemical during puberty or pregnancy, the protective nature of
messengers that recognize specialized macromole- sex steroid hormones is expressed as an acute
cules in sensitive cells to transduce a signal into a inflammatory process. More specifically, during these
distinctive response. From an even broader per- times of possible vulnerability of the individual, the
spective, homeostasis of multicellular organisms is intensified inflammatory response in the periodon-
contingent upon communications between the tium is necessary to protect both the local (i.e. peri-
endocrine, nervous and immune systems. If any odontal attachment) and systemic (i.e. toxic sepsis)
component of this triad falters, the survival of the environments by destroying, diluting or walling off
organism is at stake. the invading organisms. It is only when the inflam-

81
Mariotti & Mawhinney

matory response becomes chronic in nature that have implicated sex steroid hormones in the etiology
elevated levels of sex steroid hormones may be of inflammatory gingival diseases because of the
harmful to the periodontium and the individual fluctuating steroid levels during different times of the
(106). life cycle. Although gonadal hormones have been
The protective nature of sex steroid hormones in shown to affect the immune system and inflamma-
the peridontium does not fit easily into our concepts tory processes in the periodontium, there is a paradox
of modern society with contemporary dental care but associated with the modulating effects of these hor-
must be weighed in context to the factors that af- mones on periodontal tissues. For example, estrogens
fected the human species for millennia, from being are important in the homeostasis of the periodontium
hunter-gatherers to the pastoral and agrarian socie- at periovulatory concentrations, and when the con-
ties of the Middle Ages. The preservation of func- centrations of estrogens increase during pregnancy,
tioning teeth and preservation of general health the pro-inflammatory responses of periodontal tis-
during susceptible periods in life would be an sues may be protective by affecting immune cells (e.g.
important component for maintenance of function in monocytes, macrophages, dendritic cells, T ⁄ B cells
a pain-free environment. and neutrophils), neoangiogenesis and cytokine ⁄
growth factor release by resident cell populations
(e.g. fibroblasts, epithelium and endothelium). The
Summary actions and interactions of androgens, estrogens and
progesterone on immune cells and resident cells of
The evidence for hormone-sensitive periodontal tis- the periodontium remain an enigma in many ways;
sues has developed from several salient observations, nonetheless, future investigations into the actions of
including an increased incidence and severity of sex steroid hormones will provide an extraordinary
periodontal diseases during periods of hormone understanding of periodontal endocrinology.
fluctuations, retention and metabolic conversion of
sex steroid hormones and the presence of steroid
hormone receptors in periodontal tissues. Much of References
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