Beruflich Dokumente
Kultur Dokumente
PERIODONTOLOGY 2000
ISSN 0906-6713
59
Infections
Endocrinopathies
Type 1 diabetes usually results from cellularmediated autoimmune destruction of the insulin
producing b cells of the pancreas (Table 2) (10). One
or more markers of autoimmune destruction are
generally present, such as autoantibodies to pancreatic islet cells, insulin, glutamic acid decarboxylase, or
tyrosine phosphatases IA-2/IA-2b (5). Pancreatic b
cells are destroyed when genetically predisposed
individuals are exposed to a triggering event such
as a viral infection, which induces an autoimmune
response. There are also idiopathic forms of type 1
diabetes in which there is no evidence of autoimmunity. Onset of type 1 diabetes is usually abrupt, its
management can be difficult, and it predisposes to
diabetic ketoacidosis if not well controlled.
Type 2 diabetes results from insulin resistance and
a relative insulin deficiency, not an absolute lack of
Type 2 diabetes
Age at onset
Racial preference
White
Common
Obese
Abrupt
Slow
Pathophysiology
Autoimmune b-cell
destruction
None
Susceptibility to ketoacidosis
High
Low
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blood glucose levels most of the time, often manifesting hyperglycemia only after challenge with a large
glucose load (5). Those with impaired fasting glucose
have elevated fasting glucose levels, but may be normal in a fed state. Impaired fasting glucose and glucose tolerance are not considered to be clinical
entities in and of themselves. Instead, they are risk
factors for development of diabetes (24). They can be
seen as intermediate stages in all types of diabetes.
Endogenous insulin production is normal, and
remains so in the majority of these patients. However, about 3040% of patients with impaired fasting
glucose or glucose tolerance develop type 2 diabetes
within 10 years after initial diagnosis (116). In these
patients, insulin resistance increases and insulin
secretion is impaired. Eventually, the patient manifests overt clinical and laboratory signs of diabetes.
Glucose intolerance during pregnancy may lead to
gestational diabetes. This condition usually develops
during the third trimester of pregnancy, but can
occur earlier. Like impaired glucose tolerance,
impaired fasting glucose, and type 2 diabetes, gestational diabetes is strongly associated with insulin
resistance (5). An increased prevalence of gestational
diabetes is seen in women who have a family history
of diabetes, are over 25 years old, are obese, and are
members of ethnic groups with higher prevalence
rates for type 2 diabetes (black, Hispanic, American
Indian) (40).
Diabetes may also be associated with various
genetic defects in the function of pancreatic b-cells
or defects in insulin action (Table 1) (5). Injuries to
the pancreas or pancreatic diseases may induce secondary diabetes, as can certain infections. Diabetes
may occur subsequent to other endocrine disorders.
One of the most common forms of secondary diabetes occurs due to use of certain drugs such as
corticosteroids.
Complications of diabetes
Diabetes has been classically associated with a group
of microvascular and macrovascular complications
(Table 3). The microvascular complications of retinopathy, nephropathy and neuropathy are specifically associated with diabetes, and the risk of
macrovascular disease is greatly increased in diabetic
patients (5). Diabetic patients have a dramatically
increased risk for visual impairment or blindness,
kidney failure, limb amputation, stroke, and myocardial infarction (60, 84, 175, 176). Sustained hyperglycemia plays a primary role in both the onset and
progression of these complications.
Blindness
Nephropathy
Renal failure
Neuropathy
Sensory
Macrovascular
disease
Autonomic
Peripheral vascular disease
Cardiovascular disease
(coronary artery disease)
Cerebrovascular disease (stroke)
Macrovascular complications are strongly associated with the increased atherosclerosis common
in diabetes (5, 116). Hyperglycemia results in alterations in lipid metabolism as well as nonenzymatic
glycation of proteins such as collagen. These changes
result in altered function of cell membranes and
changes in cellcell and cellmatrix interactions. This
may then lead to increased vessel wall thickness and
formation of atheromas and microthrombi in large
vessels, and alterations in endothelial cell function
and vascular permeability in the microvasculature.
The glycation of proteins, lipids and nucleic acids
in diabetic patients results in accumulation of these
glycated proteins in the small blood vessels of endorgans such as the retina, glomerulus and endoneurial region, and in the walls of large blood vessels (21,
201). These glycated proteins, known as advanced
glycation end-products (AGEs), form in diabetic and
non-diabetic individuals; however, their accumulation is greatly increased in diabetic patients with
sustained hyperglycemia. The result of their accumulation is increased basement membrane thickness in
the retina and around the nerves, thickening of the
mesangial matrix in the glomerulus, and accumulation of collagen in larger vessels. The cumulative
effect is a progressive narrowing of the vessel lumen
and decreased perfusion of affected organs.
AGEs form on collagen, causing increased collagen
cross-linking, and resulting in formation of highly
stable collagen macromolecules that are resistant
to normal enzymatic degradation and tissue turnover
(21, 125, 201). In the blood vessel wall, AGE-modified
collagen accumulates, thickening the vessel wall and
narrowing the lumen. AGE formation occurs in both
central and peripheral arteries, and is thought to
contribute significantly to the macrovascular complications of diabetes. AGE-modified collagen in vessel
walls covalently cross-links with circulating low
density lipoprotein, contributing to atherosclerosis.
AGE modification of collagen also occurs in the
basement membrane of small blood vessels. Again,
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Diabetes has been associated with several oral conditions, including alterations in salivary flow and
constituents of saliva, increased incidence of oral
infection, burning mouth, changes in wound healing,
and increased prevalence and severity of periodontal
disease. Xerostomia and parotid gland enlargement
may occur in people with diabetes, and may be
related to the degree of glycemic control (31, 66,
173, 191). Xerostomia may be associated with the
sensation of burning mouth syndrome. Fungal infections such as candidiasis may increase on dry mucosal surfaces, although studies on the incidence of
candidiasis in diabetic subjects are not consistent
(49, 145). Guggenheimer et al. (62) found that
15.1% of 405 type 1 diabetes mellitus subjects had
candidiasis, compared to only 3.0% of 268 non-diabetes mellitus control subjects. The prevalence of
Candida hyphae on cytologic smears was 23.0% in
diabetes mellitus and 5.7% in non-diabetes mellitus
subjects. Multivariate regression analysis found the
presence of Candida hyphae to be significantly
related to poor glycemic control.
The influence of diabetes on dental caries is controversial. Some studies have shown an increased
caries rates in diabetes mellitus (74); however, others
have demonstrated similar or lower caries incidence
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by the same factors as studies of gingivitis. In a thorough meta-analysis examining this relationship,
Papapanou (142) concluded that the majority of
studies demonstrate a more severe periodontal condition in diabetic adults than in adults without diabetes. These studies, including over 3,500 type 2
diabetes mellitus adults, clearly demonstrated a
significant association between periodontitis and
diabetes.
In younger individuals, diabetes mellitus has been
associated with an increased risk of periodontitis. In
a group of 263 type 1 diabetes mellitus patients compared to 59 non-diabetic siblings and to 149 nondiabetic, unrelated controls, Cianciola et al. (26)
found no periodontitis among the diabetes mellitus
subjects under the age of 12. Between ages 13 and 18,
however, 13.6% of the individuals had periodontitis.
Individuals from 19 to 32 years old had a prevalence
of 39%. Periodontitis was not found in the non-diabetes mellitus siblings of the diabetes mellitus
patients, while a prevalence of 2.5% was noted in
the non-diabetic, unrelated control subjects. Diabetes mellitus subjects with periodontitis had a
longer duration of diabetes than did those without
periodontitis. Not all studies of diabetes mellitus
children find an increase in risk for periodontitis.
In both cross-sectional and longitudinal studies,
Sbordone et al. (162, 163) found no differences in
probing depth or clinical attachment level between
type 1 diabetes mellitus children and their non-diabetes mellitus siblings.
Epidemiologic studies in adults have often shown
an increase in extent and severity of periodontitis in
individuals with diabetes mellitus (12, 39, 169, 186).
In the Pima Indian population of Arizona, a population with the highest prevalence of type 2 diabetes in
the world, the prevalence of attachment loss and
bone loss was greater among diabetes mellitus subjects than among non-diabetes mellitus control subjects in all age groups (39, 169). These differences
were most pronounced in younger individuals. In
addition, the severity of periodontitis was greater in
diabetes mellitus patients, with greater mean bone
loss and attachment loss. Again, the differences in
disease severity were greatest in the younger age
groups. Diabetes mellitus subjects aged 1534 years
had mean attachment loss and bone loss scores
approximately twice as high as similarly aged nondiabetes mellitus subjects. In a multivariate risk analysis, diabetic subjects had a 2.83.4-fold increased
risk of periodontitis compared to non-diabetes
mellitus subjects, after adjusting for the effects of
confounding variables such as age, sex, and oral
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Mechanisms of interaction
Over the years, many potential mechanisms have
been studied by which diabetes could affect the periodontium (Table 4). These mechanisms may explain
the alterations in periodontal disease expression,
initiation, and progression that have been found by
numerous authors in individuals with diabetes.
Alterations in subgingival microbiota and gingival
crevicular fluid
Altered microbiota
Change in gingival crevicular fluid composition
rods and filaments was seen. In young type 1 diabetes mellitus subjects, Mashimo et al. (111) reported
an increase in proportions of Capnocytophaga species, while Fusobacterium and Bacteroides species
remained at low levels. Sastrowijoto et al. (160) found
a high prevalence of Capnocytophaga in type 1 diabetes mellitus subjects, but the proportion of organisms was low in both diseased and healthy sites. High
proportions of Prevotella intermedia were also found
in diseased sites, but this organism was frequently
detected in healthy sites as well. Other studies have
failed to show an increase in Capnocytophaga in
diabetes mellitus patients (105, 214).
In fact, most studies show very few differences in
the subgingival microbiota of periodontitis sites in
diabetes mellitus subjects compared to similar sites
with periodontitis in non-diabetes mellitus subjects
(63, 162, 163, 192, 214). When comparing type 1 diabetes mellitus children to their non-diabetes mellitus
siblings, Sbordone et al. (162, 163) found no significant differences in subgingival pathogens. One study
showed an increased prevalence of Porphyromonas
gingivalis in type 1 diabetes mellitus subjects compared to non-diabetes mellitus controls (192). Type 2
diabetes mellitus subjects with periodontitis have a
fairly similar microbiota to non-diabetes mellitus
periodontitis patients, although Zambon et al. (214)
demonstrated a different serotype of P. gingivalis in
diabetes mellitus subjects. In diabetes mellitus
patients, the level of glycemic control does not
appear to alter the subgingival flora either. In type 1
diabetes mellitus subjects, similar species were
detected from poorly controlled and well controlled
subjects, with no change following improvement in
glycemic control through intensive insulin therapy
(160, 161). Similar findings occurred in type 2 diabetes mellitus subjects (187). Overall, one can conclude that the differences in periodontal disease
expression often seen in individuals with diabetes
Changes in collagen synthesis, maturation, and turnover are common in diabetes mellitus. Since the
periodontium is composed primarily of collagen,
these changes in collagen metabolism may contribute to alterations in wound healing and to periodontal disease initiation and progression. Skin and
gingival fibroblasts from diabetic animals produce
decreased amounts of collagen and glycosaminoglycans (205, 209). The rate of collagen production can
be restored by administration of insulin to normalize
blood glucose levels (151). In addition to decreased
synthesis, newly formed collagen is susceptible to
degradation by collagenase, a matrix metalloproteinase which is elevated in diabetic tissues, including
the periodontium (56, 58, 152, 156, 172). The primary source of collagenase in the gingival crevicular
fluid of diabetes mellitus patients appears to be the
neutrophil (172). A greater percentage of this collagenase is in active form in patients with diabetes
mellitus compared to non-diabetes mellitus patients (172).
Use of tetracycline antibiotics results in a reduction in collagenase production (58, 113). This is
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accomplished through mechanisms that are independent of the antimicrobial properties of these agents.
Low dose tetracyclines and chemically modified tetracyclines, which have no antimicrobial effect, have
been shown to significantly decrease collagenase production and collagen degradation as well (13, 59, 61).
Although chemically modified tetracyclines are not
yet available for routine use, tetracyclines such as
doxycycline, minocycline and tetracycline HCl have
been used for many years. Low dose doxycycline is
now available as well, although its use in diabetic
patients has not yet been reported (23). Due to their
anticollagenolytic effect, tetracyclines and chemically
modified tetracyclines have potential benefits in inhibiting the onset and progression of periodontitis,
arthritis, and osteoporosis, among other conditions
(61). Since collagenase production is increased in
diabetes mellitus, these drugs may have beneficial
effects by normalizing collagen metabolism and
wound healing events.
In addition to decreased collagen production and
increased collagenase activity, collagen metabolism
is altered by accumulation of AGEs in the periodontium. Changes affecting the blood vessels of the
glomerulus and retina also occur in the periodontium, and these changes are related to AGE formation. Increased thickness of gingival capillary
endothelial cell basement membranes and the walls
of small blood vessels may be seen in diabetic individuals (51, 98, 168). This thickening may impair
exchange of oxygen and metabolic waste products
across the basement membrane. Schmidt et al. (166)
demonstrated a two-fold increase in accumulation of
AGEs in the periodontium of diabetes mellitus
patients, compared to non-diabetes mellitus individuals. Increased oxidant stress was also noted in
diabetic tissues. Elevated oxidant stress has been
suggested as the probable mechanism responsible
for the widespread vascular injury associated with
diabetes. AGE formation also stimulates proliferation
of arterial smooth muscle cells, increasing thickness
of vessel walls and decreasing the vessel lumen.
AGE accumulation results in increased cross-linking of collagen, reducing collagen solubility and
decreasing turnover rate (21, 125, 201). Increased
collagenase activity in diabetes mellitus results in
greater degradation of newly formed, more soluble
collagen. Conversely, the accumulation of AGEs
causes greater cross-linking of mature collagen. The
net effect is a predominance of older, highly crosslinked AGE-modified collagen. In the capillaries, this
accumulation of highly cross-linked collagen in the
basement membrane increases membrane thickness
66
With few major differences in the subgingival microbiota in diabetes mellitus patients, attention has
turned to differences in the host immunoinflammatory response to this bacterial challenge as a possible
explanation for the increased prevalence and severity
of periodontitis often seen in the diabetes mellitus
population. The polymorphonuclear leukocyte plays
a major role in maintaining a healthy periodontium
in the face of periodontopathic microorganisms. In
diabetes mellitus, numerous studies have shown a
reduction in polymorphonuclear leukocyte function,
including chemotaxis, adherence and phagocytosis
(68, 91, 106, 107, 114). Diabetes mellitus patients with
severe periodontitis have been shown to have
depressed polymorphonuclear leukocyte chemotaxis
compared to diabetes mellitus patients with mild to
moderate periodontitis (18, 106, 107). Depressed
polymorphonuclear leukocyte chemotaxis has been
found in non-diabetes mellitus siblings of diabetes
mellitus children, suggesting a defect with a genetic
component (91). Chemotaxis may be improved in
those with better glycemic control (57, 91). Defects
affecting polymorphonuclear leukocytes, the first
line of defense against subgingival microbial agents,
may result in significantly increased tissue destruction. Polymorphonuclear leukocyte function has
been demonstrated to be normal in many individuals
with diabetes mellitus. Oliver et al. (136) have even
suggested hyper-responsiveness or increased numbers
of polymorphonuclear leukocytes within the gingival
crevice of poorly controlled diabetic patients, as indicated by elevated levels of the polymorphonuclear
leukocyte-derived enzyme b-glucuronidase.
In addition to the polymorphonuclear leukocyte,
another critical cell line in the periodontal immunoinflammatory response to pathogens is the monocyte/macrophage line. Studies suggest that many
diabetic patients possess a hyper-responsive monocyte/macrophage phenotype in which stimulation by
bacterial antigens such as lipopolysaccharide results
in dramatically increased pro-inflammatory cytokine
production (135). Salvi et al. (158) have demonstrated
significantly increased production of pro-inflammatory cytokines such as tumor necrosis factor-a by
monocytes derived from patients with diabetes
mellitus. When challenged with lipopolysaccharide
from P. gingivalis, diabetic monocytes showed a
diabetes mellitus subjects with moderate to advanced periodontal disease, scaling and root planing
resulted in similar clinical changes when compared
to non-diabetes mellitus subjects with similar levels
of periodontal disease (25). Conversely, poorly controlled diabetes mellitus patients often have a less
favorable response to treatment than those with well
controlled diabetes. Tervonen et al. (188) found that
the initial response to scaling and root planing was
good in diabetes mellitus subjects, but the incidence
of disease recurrence over the subsequent 12 months
was greater in poorly controlled diabetes mellitus
individuals compared to well or moderately controlled
subjects. Westfelt et al. (206) performed a longitudinal
assessment of periodontal therapy, including scaling
and root planing, modified Widman flap surgery, and
regular maintenance, in diabetes mellitus subjects
and non-diabetes mellitus controls with moderate to
advanced periodontitis. At the 5-year re-evaluation,
diabetes mellitus patients had a similar percentage of
sites gaining or losing attachment, and a similar percentage of sites with stable attachment levels, compared to non-diabetes mellitus subjects. Most of the
diabetic patients in this study had well or moderately
controlled glycemia. These data suggest that individuals with well controlled diabetes mellitus respond
to periodontal therapy in a fashion similar to non-diabetes mellitus patients, but that poorly controlled
patients may have a less favorable response.
Few data have been collected examining the response to dental implant therapy in diabetes mellitus
subjects. Animal studies have suggested decreased
bone-to-implant contact in diabetes mellitus (132,
180, 181). The animals in these studies had extremely
high blood glucose levels. In a human prospective
case series of 89 male type 2 diabetes mellitus subjects, 178 implants were followed for 5 years after
loading (138). The survival rate of implants was
90%, leading the authors to conclude that implant
therapy is a viable option in type 2 diabetes mellitus
individuals. In a large multi-center study of 255
implants in type 2 diabetes mellitus patients compared to 2632 implants in non-diabetes mellitus
patients, the failure rate was 7.8% in diabetes mellitus subjects compared to 6.8% in non-diabetes mellitus patients (127). Implants were followed for at
least 36 months following prosthetic loading. The
difference in failure rate was statistically significant,
but the P value of 0.0498 led the authors to conclude
that the influence of type 2 diabetes mellitus on
implant failure rates was only marginally significant.
No data are presented on the level of glycemic control in diabetes mellitus patients in this study.
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Conclusion
Diabetes mellitus is a risk factor for periodontal
diseases. As with other complications of diabetes,
periodontal status demonstrates significant heterogeneity within the diabetic population. Just as many
diabetic individuals have minimal complications
such as retinopathy, nephropathy and neuropathy,
many have a healthy peridontium. However, others
demonstrate an increased propensity for gingival
inflammation and an increased risk for destructive
periodontitis, just as they do the classic complications of diabetes. This may be particularly true in
patients with poor glycemic control. In addition,
there are clear biologically plausible mechanisms
by which diabetes influences the periodontium,
including changes in the host immunoinflammatory
response and tissue homeostasis. Many of the periodontal changes seen in diabetes reflect similar
changes seen in other end-organ systems such as
the retina and glomerulus. Scientific evidence supports the concept that diabetes truly is the sixth
complication of diabetes.
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estradiol and progesterone for menadione, an essential vitamin K growth factor for this bacterium (85). A
study evaluating increased serum estradiol and progesterone levels during puberty noted a positive correlation with significant increases in proportion,
number, and serum IgG antibody levels to Prevotella
intermedia (130). Capnocytophaga species have also
been noted to increase in number as well as proportion in the subgingival milieu during puberty, and
have been shown to correlate with an increased gingival bleeding tendency (64). However, other studies
have not shown these relationships (63, 211). In a
longitudinal study, Yanover & Ellen (211) were
unable to detect any changes in the oral microbiota
during puberty, and found no correlation between
plasma estradiol levels and levels of black-pigmented
anaerobic bacteria. Thus, more definitive research
may be needed to shed light on the exact mechanisms of gingival involvement seen accompanying the
circumpubertal period.
Menstruation
Fig. 2. Clinical appearance of pregnancy gingivitis. Significant generalized gingival enlargement and inflammation
are evident.
Pregnancy
71
phenomenon (109). Although estrogens play a significant role in collagen maintenance and metabolism, a review of the impact of hormones on bone
maintenance and osteoporosis is not given here and
is specifically addressed elsewhere in this volume.
72
The effects of sex steroid hormones on the subgingival microbiota during pregnancy have been well
documented. Kornman & Loesche (86) reported that
during the second trimester, plaque levels remained
constant, yet gingivitis and gingival bleeding were
shown to increase in severity. At the same time, the
ratio of subgingival bacterial anaerobes-to-aerobes
increased, as well as proportions of Bacteroides melaninogenicus and P. intermedia (2.210.1%). Subgingival plaque samples from these patients during the
second trimester demonstrated a significantly higher
accumulation of estradiol and progesterone than plaque samples at other time periods. Subsequently,
both estradiol and progesterone were shown to be
selectively accumulated by P. intermedia as a substitute for vitamin K (87), and thus postulated to be
acting as a growth factor for this microorganism.
Jensen et al. (73) studied the effects of hormone
levels on gingival status in pregnant patients and
those using oral contraceptives versus non-pregnant,
non-contraceptive controls. There was a 55-fold
increase over the control group in the population
of Bacteroides species in the pregnant women and
a 16-fold increase in those taking contraceptives. The
concomitant increases in P. intermedia were most
pronounced in the second trimester and were correlated with increased gingivitis scores.
Using an experimental gingivitis model in patients
during pregnancy and again 6 months postpartum,
Raber-Durlacher (150) demonstrated increased
levels of P. intermedia during pregnancy coinciding
with increased gingival inflammation at this time.
This was significantly different from postpartum
clinical parameters which showed less P. intermedia
and gingival swelling, and reduced probing depths
compared to pregnancy. Plaque scores were similar
at all time points. Not all studies have corroborated
these findings, and Jonsson et al. (75) found no difference in levels of P. intermedia at any time during
pregnancy or between pregnant and nonpregnant
controls in a cross-sectional assessment. This has
led to speculation that the increase in P. intermedia
seen during the second trimester of pregnancy may
actually be independent of estrogens or progesterone
and may occur for other reasons. Mariotti (109) has
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in the keratinization of gingival epithelium of postmenopausal women has been shown to accompany
declining plasma estrogen levels (195).
These hormones also act in a dynamic fashion on
the extracellular matrix in the gingiva, and these
effects may be exaggerated during times of significant hormonal fluctuations. Fibroblast proliferation
and collagen maturation in gingival connective tissues may be affected by both estrogen and progesterone. By altering collagen turnover, estrogens may
stimulate the proliferation of gingival fibroblasts, and
the synthesis and maturation of gingival connective
tissues (16, 54, 108). In contrast, Lundgren et al. (102)
demonstrated that progesterone may alter the rate
and pattern of collagen production in the gingiva,
resulting in reduced repair and maintenance potential. This inhibition of human gingival fibroblast proliferation by progesterone has been demonstrated by
others (54, 207). Sex steroid hormones have also been
shown to increase the rate of folate metabolism in
oral mucosa (141, 190). Since folate is required for
tissue maintenance, increased metabolism could
deplete folate stores and inhibit tissue repair. Additionally, progesterone in concentrations corresponding to the third trimester of pregnancy has been
shown to lower the synthesis of glycosaminoglycans,
a major constituent of the connective tissue matrix of
gingiva (208). Although little information exists at the
present time, estrogen and progesterone have been
shown to exert influence on the metabolism of periodontal ligament-derived fibroblasts in vitro (131).
In particular, estradiol and progesterone inhibited
collagen synthesis by these cells. Taken together,
the evidence suggests that female sex steroid hormones may contribute to gingival tissue maintenance and repair and that these interactions have
the potential to significantly contribute to enhanced
gingival inflammation. As in other areas previously
discussed, further research is needed to fully elucidate the exact mechanisms underlying these processes.
Menopause
Unlike the rhythmic patterns of the reproductive
cycle, the onset of menopause is accompanied by
irregular hormonal fluctuations, as estradiol ceases
to be the major circulating estrogen and estrone,
which lacks cyclic influence, predominates. With
the overall reduction in estrogen output after menopause, a significantly different presentation of the
gingiva predominates. Essentially, the sex steroidinduced gingival inflammatory changes witnessed
Conclusion
It is evident from this review that multifactorial
mechanisms involving the endocrine system are
involved to a significant degree in the homeostasis
of the periodontium during each of the life stages of
the human female. The notable periodontal changes
related specifically to female sex steroid levels,
primarily those manifested as pathologic alterations
in the gingiva, attest to the dramatic potential these
hormones possess to impact the oral tissues beyond
normal homeostatic functions. Nevertheless, it is
also apparent that female sex steroid hormones
are neither necessary, nor sufficient to produce
pathologic gingival alterations by themselves, and
attests to the need for further elucidation of the biomolecular mechanisms at work to fully understand
how these hormones may exert their significant
effects.
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