Periodontology 2000, Vol.

32, 2003, 5981

Printed in Denmark. All rights reserved

Copyright # Blackwell Munksgaard 2003

PERIODONTOLOGY 2000
ISSN 0906-6713

Hormonal influences: effects of

diabetes mellitus and
endogenous female sex steroid
hormones on the periodontium
Brian L. Mealey & Alan J. Moritz

Hormonal influences on the periodontium are many,

with widely varying clinical presentations and
degrees of effect. The primary hormonal factors discussed in this chapter are those associated with diabetes mellitus and female sex steroid hormones.

Effects of diabetes mellitus on the

periodontium
Diabetes mellitus is the term used to describe a group
of metabolic disorders distinguished by altered glucose tolerance and impaired carbohydrate metabolism (5). Diabetes is characterized by hyperglycemia
(elevated blood glucose) that results from defects in
secretion of the hormone insulin, or from impaired
insulin action, or both. Alterations in lipid and protein
metabolism are also seen. Chronic hyperglycemia is
associated with long-term dysfunction and damage to
numerous end-organs, with marked effects on the
eyes, kidneys, heart, nerves, and blood vessels.
It is important that the dentist and other oral health
care providers have a thorough knowledge of diabetes,
if for no other reason than its widespread prevalence.
More than 16 million Americans have the disease
(122). The prevalence has risen from 4.9% in 1990 to
almost 7% in 1999 (123). Thus, for every 1000 patients
in an average dental practice, 70 have diabetes. Unfortunately, 40 to 50% of individuals with diabetes are
unaware of their disease and remain undiagnosed.
The prevalence of diabetes varies with ethnicity.
About 6.2% of whites have the disease, compared to
8.0% of Hispanics and almost 10% of blacks. Approxi-

mately 800,000 new cases of diabetes are diagnosed

every year, and the incidence continues to rise (122).
The increased incidence of diabetes correlates strikingly with the rapid increase in obesity in the United
States, the prevalence of which has risen from 12.0%
in 1991 to 18.9% in 1999 (121, 123). Obesity is clearly
linked to an increased risk for developing diabetes
(50, 153). As the prevalence and incidence of diabetes
increase, so do the costs, both financially and in
terms of morbidity and mortality. In 1997, the direct
and indirect costs associated with diabetes were estimated at $98 billion (4). Diabetes is the seventh leading cause of death in the U.S., and is a major
contributor to hypertension, stroke, heart disease,
blindness, kidney failure, and amputations. With an
expected prevalence of over 9% by 2025, the effect of
diabetes on oral health and on the practice of dentistry will only increase in the future (6).
The most current classification of diabetes was provided by the American Diabetes Association in 2001
(5). The terms insulin-dependent and non-insulin
dependent are no longer used, nor are the terms
adult-onset, maturity-onset, and juvenile-onset diabetes. Currently accepted diagnostic categories
include: type 1 diabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting glucose, gestational
diabetes, and other specific types of diabetes such as
those secondary to diseases of the pancreas, drug therapy, endocrinopathies, infections, and genetic disorders (Table 1). Impaired glucose tolerance and
impaired fasting glucose are terms used to describe
an intermediate metabolic stage that lies between normal glucose metabolism and frank diabetes.

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Mealey & Moritz

Table 1. Classification of diabetes mellitus

Type 1 diabetes (formerly insulin-dependent diabetes)
Type 2 diabetes (formerly non-insulin-dependent diabetes)
Gestational diabetes
Other types of diabetes
Genetic defects in b-cell function
Genetic defects in insulin action
Diseases of or injuries to the pancreas

Pancreatitis, neoplasia, cystic fibrosis, trauma,

pancreatectomy, others

Infections

Congenital rubella, cytomegalovirus, others

Drug-induced or chemical-induced diabetes

Glucocorticoids, thyroid hormone, dilantin,

thiazides, others

Endocrinopathies

Acromegaly, Cushings syndrome, glucagonoma,

pheochromocytoma, hyperthyroidism

Other genetic syndromes with associated diabetes

Downs syndrome, Huntingtons chorea,

myotonic dystrophy, others

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

insulin production, as occurs in type 1 (Table 2).

Autoimmune destruction of the pancreatic b cells
does not occur. The pancreas still produces insulin,
yet tissue resistance to insulin decreases its activity
and ability to facilitate glucose metabolism at the
cellular level (116). Most type 2 patients are overweight, and obesity itself often leads to insulin resistance (19). The onset of type 2 diabetes is gradual; in
fact, type 2 usually goes undiagnosed for an
extended period of time, often years. Ketoacidosis
is uncommon in type 2 diabetes and usually occurs
in association with the stress of other illnesses such
as infection (196).
The terms impaired glucose tolerance and
impaired fasting glucose describe a metabolic state
lying between normal glycemia and diabetes. Many
people with impaired glucose tolerance have normal

Table 2. Characteristics of type 1 and type 2 diabetes

Type 1 diabetes

Type 2 diabetes

Age at onset

Generally < 30 years

Generally in adulthood (prevalence in

young is increasing)

Racial preference

White

Black, Hispanic, American Indian, Pacific Islanders

Presence of family history

Common

More common than type 1

Most common morphotype

Thin or normal stature

Obese

Onset of Clinical Disease

Abrupt

Slow

Pathophysiology

Autoimmune b-cell
destruction

Insulin resistance, impaired insulin secretion, increased

liver glucose production

Level of endogenous insulin

production

None

Decreased, normal, or elevated (depends on

stage of disease)

Susceptibility to ketoacidosis

High

Low

Common treatment regimens

Insulin, diet, exercise

Diet (weight loss), exercise, oral agents, insulin

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Hormonal influences on periodontium

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.

Table 3. Classic complications of diabetes mellitus

Retinopathy

Blindness

Nephropathy

Renal failure

Neuropathy

Sensory

Macrovascular
disease

Autonomic
Peripheral vascular disease
Cardiovascular disease
(coronary artery disease)
Cerebrovascular disease (stroke)

Altered wound healing

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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Mealey & Moritz

AGE-modified collagen accumulates and increases

basement membrane thickness, altering normal
homeostatic transport across the membrane.
AGEs have major effects at the cellular level. A
receptor for AGEs known as RAGE (receptor for
AGE) has been identified on the surface of endothelial cells, neurons, smooth muscle cells, and monocytes/macrophages (164, 165, 202). Hyperglycemia
results in increased expression of the receptor and
increased AGERAGE interaction. The effect on
endothelial cells is an increase in vascular permeability and thrombus formation (42). AGEs are chemotactic for monocytes. Interaction between AGEs
and the receptor, RAGE, on monocyte/macrophage
membranes induces increased cellular oxidant stress
and activates the transcription factor NF-kB. This
signals a change in the monocyte/macrophage phenotype and results in increased production of proinflammatory cytokines such as interleukin-1 (IL-1)
and tumor necrosis factor, and growth factors such
as platelet-derived growth factor and insulin-like
growth factor (82, 166, 200). These cytokines and
growth factors contribute to the chronic inflammatory process in atheroma formation.

(182, 184). Some authors have speculated that

decreased salivation or increased glucose concentrations in saliva and gingival crevicular fluid account
for an increased caries risk. However, most diabetic
patients limit their fermentable carbohydrate intake,
and this less cariogenic diet may decrease caries risk.
Autonomic neuropathy, a complication of diabetes
mellitus, may result in alteration of salivary secretion
(117). Many diabetic patients have conditions other
than diabetes for which they are medicated, and
many of these medications produce xerostomia as
a side effect. Xerostomia may therefore result not
from the diabetic condition itself, but from medications taken by the patient.
In studies of type 2 diabetes mellitus subjects and
non-diabetes mellitus controls, no significant differences in salivary flow rates or organic constituents of
saliva were seen (117). Likewise, there were no differences in the prevalence of coronal caries or root caries
(29). The salivary counts of yeasts and of acidogenic
streptococci and lactobacilli were also similar
between the groups. However, the effect of xerostomic
medications on salivary flow rates was greater in diabetic individuals than in control patients.

Diabetes and oral diseases

Diabetes and periodontal diseases

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

Understanding the relationships between diabetes

and periodontal diseases is complicated by the variability in diagnostic parameters used to describe the
metabolic state in study populations. In addition,
study designs lack commonality in populations studied, use or non-use of control populations, and
periodontal parameters assessed to describe the clinical conditions present. Many studies find no specific
relationship between periodontal parameters and
duration of diabetes mellitus, presence of various
diabetic complications, or degree of glycemic control. Conversely, other studies do find such relationships. Due to the absence of homogeneity in study
design, firm conclusions are difficult to make.
Diabetes has been associated with increased prevalence and severity of gingivitis. Gusberti et al. (63).
studied children with type 1 diabetes mellitus. Before
puberty, poorly controlled diabetes mellitus children
had a higher incidence and severity of gingival
inflammation than did well controlled children. During puberty, there was a general increase in gingivitis,
independent of glycemia. Cianciola et al. (26). confirmed an increase in gingivitis in type 1 diabetes
mellitus children after the age of 11 when compared
to non-diabetes mellitus controls. In other studies,
poorly controlled diabetes mellitus children had

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Hormonal influences on periodontium

higher levels of gingival inflammation than did well

controlled patients, regardless of plaque levels (48,
78). Improvement in glycemic control was associated
with decreased signs of gingival inflammation (78,
161). DePommereau et al. (36) found a significantly
greater percentage of sites with gingivitis in diabetes
mellitus children (48%) compared to non-diabetes
mellitus control children (26%) with similar plaque
levels, although gingivitis was not associated with the
level of glycemic control in the diabetic subjects.
Attachment loss was generally not seen in either
group.
Conversely, Firalti et al. (47) found no increase in
gingival inflammation in diabetic children, but did
find increased probing depth and clinical attachment
loss, when compared to age- and sex-matched nondiabetes mellitus control subjects. There was a positive correlation between clinical attachment loss and
the duration of diabetes, with a greater prevalence
and severity of disease in children with long-standing
diabetes mellitus. Other authors have also found no
increase in gingivitis in children with diabetes mellitus (162, 163).
In adult type 1 diabetes mellitus patients considered as a single group, Ervasti et al. (41) found no
significant difference in gingival inflammation compared to non-diabetes mellitus control subjects.
However, when diabetes mellitus patients were stratified according to their level of glycemic control,
significantly greater gingival bleeding was seen in
poorly controlled patients. Conversely, well controlled patients had less gingival bleeding than did
non-diabetes mellitus control subjects. In general,
the number of bleeding sites decreased as glycemic
control improved. Guthmiller et al. (65) found greater
gingival inflammation in pregnant women with
type 1 diabetes mellitus than in pregnant women
without diabetes mellitus. Cutler et al. (33) demonstrated greater gingival inflammation in type 2 diabetes mellitus adults than in non-diabetes mellitus
controls, with the highest level of inflammation in
subjects with poor glycemic control. While gingival
inflammation was greater in diabetes mellitus adults
than in non-diabetes mellitus controls, Bridges et al.
(20) found no relationship between gingivitis and the
level of glycemic control. These studies show that the
presence of diabetes mellitus is often, but not always,
associated with increased gingival inflammation;
furthermore, the level of glycemic control may play
a role in the gingival response to bacterial plaque in
many individuals.
The relationship between diabetes and periodontitis has been extensively studied, and is complicated

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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Mealey & Moritz

hygiene measures. The most significant risk factors

for periodontitis were age, presence of calculus, and
presence of type 2 diabetes mellitus. Smaller crosssectional studies have generally confirmed greater
risk for attachment loss and bone loss in diabetes
mellitus adults (20, 30, 33, 65, 126, 189).
In addition to cross-sectional studies, longitudinal
research has shown an increased risk for progressive
periodontal destruction in people with diabetes mellitus. In a 2-year longitudinal study (183), type 2 diabetes mellitus Pima Indians had a significantly
increased risk of progressive alveolar bone loss compared to non-diabetes mellitus subjects, with an
odds ratio of 4.2. When compared to similarly aged
non-diabetes mellitus individuals, the greatest risk of
progressive bone loss occurred in those diabetes
mellitus subjects under the age of 34.
The relationship between metabolic control of diabetes and periodontal disease is unclear, although
many studies find poorer glycemia associated with
increased periodontal destruction (137). Some diabetic
patients with poor glycemic control develop extensive
periodontal destruction, while others do not. Conversely, many well controlled diabetic patients have
excellent periodontal health, but others develop periodontitis. In this way, periodontal disease is similar
to the classic complications of diabetes, with significant heterogeneity of both onset and progression of
complications within the affected population.
Over 23 years, Seppala et al. (167) demonstrated
that poorly controlled diabetes mellitus subjects had
significantly greater bone loss and attachment loss
than did well controlled diabetes mellitus subjects.
Tervonen & Oliver (186) showed that type 1 diabetes
mellitus subjects with poor metabolic control over
the preceding 25 years had a significantly greater
prevalence of deep probing depths and advanced
attachment loss than did subjects with good glycemic control. This trend has been confirmed by
others. In a study of 71 type 1 diabetes mellitus
patients with a 16.5-year mean duration of diabetes,
subjects with poor glycemic control had more interproximal attachment loss and bone loss than well
controlled subjects (157). In the same patient population in which Ervasti et al. (41) showed increased
gingivitis in poorly controlled versus well controlled
diabetes mellitus subjects, Tervonen & Knuuttila
(185) also showed increasing prevalence of deeper
pockets as metabolic control worsened.
In the longitudinal Pima Indian studies, poor glycemic control of type 2 diabetes mellitus was associated with significantly increased risk of progressive
bone loss compared to better metabolic control

64

(183). Diabetes mellitus subjects with poor glycemic

control had a significantly increased risk of progressive bone loss, with an odds ratio of 11.4, compared
to non-diabetes mellitus controls. Conversely, well
controlled diabetes mellitus subjects had no significant increase in risk. Thus, metabolic control of diabetes may be an important variable in both the onset
and progression of periodontal disease, with well
controlled patients having a similar risk as non-diabetes mellitus individuals.
Some studies have given only marginal support to
the relationship between glycemic control and extent
or severity of periodontitis, while others have shown
no relationship. Tervonen et al. (189) found a trend
toward increasing prevalence of alveolar bone loss as
glycemic control worsened. The mean percentage of
sites with > 15% bone loss went from 28% in well
controlled type 1 diabetes mellitus subjects to 44% in
poorly controlled subjects. However, the difference
did not reach statistical significance, perhaps due to
the small size of the study population. While Bridges
et al. (20) found deeper probing depths and greater
gingival inflammation, bleeding on probing, and
attachment loss in 118 diabetes mellitus subjects
compared to 115 age-matched controls, the level of
glycemic control among the diabetes mellitus subjects did not correlate to the periodontal parameters
measured. Some studies have found no evidence of a
relationship between glycemic control and periodontal status (14, 160). It is important to note that
periodontal disease prevalence and severity varies
greatly within the non-diabetic population, just as
it does in the population with diabetes mellitus. Presence of periodontal disease in some diabetic individuals may be related more to other risk factors for
periodontitis such as poor oral hygiene and smoking
than to the mere presence of diabetes.

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

Early studies demonstrated a shift in the subgingival

microbiota of animals in which diabetes was induced
chemically (115). Deepening of periodontal pockets
and a shift to a flora predominated by gram-negative

Hormonal influences on periodontium

Table 4. Mechanisms of interaction between diabetes mellitus and periodontium

Changes in subgingival environment

Altered microbiota
Change in gingival crevicular fluid composition

Altered tissue homeostasis and wound healing

Decreased collagen production

Increased matrix metalloproteinase activity
Accumulation of advanced glycation endproducts
Decreased tissue turnover

Changes in host immunoinflammatory response

Decreased polymorphonuclear leukocyte chemotaxis,

adherence, phagocytosis
Elevated pro-inflammatory cytokine response from
monocytes/macrophages
Increased tissue oxidant stress

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

are not explained simply by differences in periodontopathic microorganisms.

Increased glucose levels in gingival crevicular fluid
often accompany elevated blood glucose levels in
diabetes (46, 83). Nishimura et al. (134) showed
decreased chemotaxis of periodontal ligament fibroblasts in response to platelet-derived growth factor
when cultured in a hyperglycemic environment,
compared to normoglycemic conditions. Elevated
glucose levels in the gingival crevicular fluid of individuals with diabetes may, thus, adversely affect periodontal wound healing and the local host response
to microbial challenge.
Collagen metabolism, advanced glycation
endproducts, and wound healing

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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Mealey & Moritz

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

(51, 98, 168). These events may play a role in altering

the tissue response to periodontal pathogens, resulting in increased severity and progression of periodontitis.
Changes in host immunoinflammatory response

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

Hormonal influences on periodontium

2432-fold increased production of tumor necrosis

factor-a compared to non-diabetic monocytes. Production of prostaglandin E2 and interleukin-1b was
also significantly higher in diabetes mellitus subjects
than in non-diabetes mellitus subjects (159). In diabetes mellitus patients with periodontitis, the gingival
crevicular fluid levels of prostaglandin E2 and interleukin-1b were significantly higher than in non-diabetes
mellitus subjects with a similar degree of periodontal
destruction.
Not all people with diabetes mellitus have a hyperresponsive monocyte/macrophage phenotype, and it
is likely that there is a genetic component to this
phenomenon (135). AGE formation plays an important role in upregulation of the monocyte/macrophage cell line. Accumulation of AGEs in the
periodontium stimulates migration of monocytes to
the site. Once in the tissue, AGEs interact with receptors for AGEs (RAGE) on the cell surfaces of monocytes (164, 165). This AGERAGE interaction results
in immobilization of monocytes at the local site.
AGE-RAGE interaction then induces a change in
monocyte phenotype, upregulating the cell and significantly increasing pro-inflammatory cytokine production. This provides another explanation for
increased gingival crevicular fluid production of tumor
necrosis factor-a, prostaglandin E2 and interleukin-1b
noted in diabetic patients with periodontitis (159). This
interaction also increases oxidant stress within the tissue, resulting in tissue destruction (166). Interestingly,
in diabetes mellitus animal models, blocking the
receptor RAGE decreases levels of the pro-inflammatory cytokines tumor necrosis factor-a and IL-6 in gingival tissues, decreases levels of tissue-destructive
matrix metalloproteinases, lowers AGE accumulation
in periodontal tissues and decreases alveolar bone loss
in response to P. gingivalis (89).
These alterations in the host immunoinflammatory response suggest that diminished polymorphonuclear leukocyte function in some diabetes mellitus
individuals may prevent effective elimination of bacteria and bacterial products. The subsequent persistence in bacterial challenge may then be met with an
elevated monocyte/macrophage response, which
results in increased tissue destruction.

Response to periodontal treatment in

patients with diabetes
Clinicians are often faced with managing periodontal
diseases in patients with diabetes mellitus. The question arises, Do diabetic patients respond well to
periodontal therapy? In a study of well controlled

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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Mealey & Moritz

Table 5. 1999 International Workshop Classification

for Periodontal Diseases: Section specific to endogenous female sex steroid hormones (Armitage (9))
1. Gingival diseases
A. Dental plaque-induced gingival diseases
2. Gingival diseases modified by systemic factors
a. Associated with the endocrine system
1) Puberty-associated gingivitis
2) Menstrual cycle-associated gingivitis
3) Pregnancy-associated
a) Gingivitis
b) Pyogenic granuloma

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.

Effects of endogenous female sex

steroid hormones on the
periodontium
Currently accepted periodontal disease classification
acknowledges the influence of endogenously produced female sex steroid hormones on the periodontium. These effects are primarily seen as gingival
manifestations (Table 5) (9). Under the broad category of dental plaque-induced gingival diseases that
are modified by systemic factors, those associated
with the endocrine system are classified as puberty,
menstrual cycle, or pregnancy-associated gingivitis.
The pyogenic granuloma, or pregnancy tumor, is
a reactive lesion also classified under pregnancyassociated gingival disease. Given that distinct

68

hormonally-related events such as menstruation

and pregnancy may result in endocrinotropic manifestations visible in the gingival tissues, it is understandable that such gender-specific observations
have come to light.
Exaggerated gingival responses during pregnancy
were first described in the 1800s (37, 146) and further
evidence has since established that multifactorial
mechanisms involving the endocrine system are
involved in the homeostasis of the periodontium.
Female sex steroid hormones are neither necessary nor sufficient to produce gingival changes by
themselves. However, they may alter periodontal tissue responses to microbial plaque, and thus indirectly contribute to periodontal disease (55). This
section reviews and discusses the various factors
and influences involving endogenous sex steroid hormones on the periodontium of women from puberty
through postmenopause. Hormone replacement therapy and osteoporosis will not be addressed here and
are covered in other chapters in the current volume.

Physiology and production of female

sex steroid hormones
Although androgens may also play a role in modulating periodontal tissue responses in women, the main
sex steroid hormones with evidence for such an
effect are the estrogens and progestins. Produced
by the female gonad, the ovary, the principal premenopausal estrogen in plasma is estradiol, whereas the
main postmenopausal estrogen is estrone (204, 212).
Less potent than estradiol, estrone does not demonstrate cyclic changes (213). Estradiol is additionally
secreted by the placenta and certain peripheral tissues. Estrogens perform many vital activities in
women including the development and maintenance
of secondary sex characteristics, uterine growth, pulsatile release of luteinizing hormone from the anterior pituitary gland, thickening and sustainment of
the vaginal mucosa, and ductal development of the
breast. (22, 109).
The principal female progestin is progesterone,
secreted by the corpus luteum, placenta, and the
adrenal cortex. Progesterone is important for many
vital activities in the female including endometrial
development and sustainment, mammary gland
development, maintenance of the pregnant state,
as well as decreasing very low density lipoprotein
and high density lipoprotein secretion, decreasing
insulin action, and enhancing sodium excretion by
the kidneys (22, 109). Estrogens may regulate progesterone activities by inducing the production of

Hormonal influences on periodontium

progesterone receptors, thus promoting increased

responsiveness of tissues to progesterone (72).
Estrogen formation in the ovary begins between 8
and 10 weeks of gestation, and oogonia in the ovaries
begin developing into primary oocytes by 1011
weeks. A finite number of these germ cells are contained in the ovary with a peak of about 7 million
oogonia present by the 5th to 6th month of gestation.
Thereafter, through the process of atresia, the germ
cells decrease in number until only 1 million primordial follicles containing a single ovum each remain at
birth. The majority of these follicles fail to develop
and after further atresia, approximately 400,000
remain at puberty, and only a few are left at menopause (22). It is during puberty that the final maturation of the ovarian follicle commences.
The onset of increased production and secretion of
estrogen and progesterone in a cyclic pattern accompanies the onset of puberty and is referred to as the
reproductive or menstrual cycle (Fig. 1). The mean
age of the onset of menses (menarche) in the United
States has decreased about 34 months per decade
over the last 100 years and is now about 12 years (22).
The duration of a normal reproductive cycle is 28
days, with the first half of the cycle referred to as
the follicular or proliferative phase. This phase is
initiated with the release by the hypothalamus of
gonadotropin releasing factor (GnRH). Subsequently,
two major gonadotropic hormones regulating follicular development are produced in the anterior
pituitary follicle stimulating hormone and luteinizing hormone. Follicle stimulating hormone promotes
the growth of a Graafian follicle that typically contains a single, maturing ovum. The mature follicle

then produces a fluid rich in estrogens. Together with

follicle stimulating hormone, estrogen promotes
further maturation of the ovum and thickening of
the uterine lining tissues. The rise in circulating
estrogens initiates a burst of luteinizing hormone
secretion which results in release of the mature ovum
into the fallopian tube. After ovulation at approximately day 14 of the cycle, the secretory or luteal
phase begins, and is characterized by the synthesis
and release of both estrogen and progesterone by the
follicular cells, which have now become the corpus
luteum. If fertilization does not occur, the corpus
luteum will degenerate, plasma levels of estradiol
and progesterone will decline, and a large portion
of the endometrium will be released as menstrual
flow.
If fertilization and pregnancy do occur, the corpus
luteum will continue to synthesize estrogen and progesterone in ever increasing amounts. The placenta
develops as an endocrine organ which contributes
additionally to estrogen and progesterone production. Plasma progesterone levels during pregnancy
may reach 100 ng/mL, approximately 10 times that
seen during the luteal phase of the reproductive
cycle. Estradiol levels in plasma may similarly be
increased up to 30 times (140).
In stark contrast to pregnancy, menopause is characterized by the irregular and declining production
and secretion of estrogen and progesterone. This
correlates significantly with the reduced number of
ovarian follicles having the potential for maturation,
along with the progressive loss of ovarian function.
During the reproductive cycle, estradiol, which constitutes 60% of circulating estrogens, is formed primarily by the ovaries, and the remainder is estrone,
formed mainly in extraglandular tissues. After menopause, extraglandular formation becomes the major
route of estrogen formation, with the predominant
plasma estrogen being estrone (22). The permanent
cessation of menstrual flow (amenorrhea) during
menopause occurs in women at an average age of
51 years (22). Considering current life expectancy, it
is apparent that approximately one third of a
womans life will be lived after reproductive function
ceases.

Periodontal manifestations related to

female sex steroid hormones
Puberty
Fig. 1. Hormonal variations accompanying the female
reproductive cycle. FSH follicle stimulating hormone;
LH luteinizing hormone.

Along with the dramatic rise in female sex steroid

levels during the circumpubertal period, several

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Mealey & Moritz

cross-sectional and longitudinal studies have

demonstrated an increase in gingival inflammation
without an accompanying increase in plaque levels
(32, 67, 85, 109, 112, 130, 143, 178). This gingivitis
manifests as marginal and interdental gingival enlargement found primarily on the facial surfaces, with
the lingual surfaces remaining relatively unaltered
(55). An increased gingival bleeding tendency has
also been reported (64). Although other factors such
as caries, mouth breathing, tooth eruption status,
and crowding of teeth may influence the increase
in gingival inflammation seen, current disease classification distinguishes this type of gingivitis as having the propensity toward developing clinical signs of
inflammation with relatively small amounts of plaque present during this period (110). Nevertheless,
evidence for this phenomenon is not absolute and for
the most part may be considered circumstantial at
the present time (80). The reason for this is that most
studies cited as evidence for this phenomenon have
relied mainly on the chronological age of the cohorts
examined, although age in and of itself is not the best
predictor of the onset of puberty (109). Additionally,
few of the studies have evaluated the hormonal levels
of the subjects, which would lend itself to a more
exacting analysis of any association. Nakagawa et al.
(130) did evaluate serum female sex hormone levels
during puberty and found a slight but statistically
significant increase in gingival index (99) over prepubertal conditions, which was positively correlated
with an increase in serum estradiol and progesterone
levels. In this study as in others, the increased gingival inflammation was not accompanied by a significant change in mean plaque index (171). Studies also
exist that have not found any correlation between
pubertal onset and the gingival condition in females
(193, 211). Further examination to determine a definitive correlation between increased sex steroid
levels is required; however, the data available to date
give some indication that a transient period of
enhanced gingival inflammatory response to dental
plaque does indeed exist during this period of female
development.
Several studies have noted a concomitant increase
in subgingival black-pigmented anaerobic bacteria
that parallels the onset of puberty and the increase
in gingival inflammation observed during this time
(34, 64, 124, 129, 130, 210). The microbial changes
noted have been postulated to result from a selective
enhancement of the growth of black-pigmented
anaerobic rods, primarily Prevotella intermedia, by
female sex hormones. It has been suggested that
these gram-negative bacteria are able to substitute

70

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

Significant and observable gingival inflammatory

changes have been documented in association with
hlemann
the menstrual cycle (69, 93, 110, 178). Mu
(128) over 50 years ago described a case of gingivitis
intermenstrualis, which he observed as consisting
of bright red hemorrhagic lesions of the interproximal papillae identified prior to menstruation. Gingival manifestations of bleeding and swollen gingiva
(45, 69, 93, 178), an increase in gingival exudate most
pronounced in the presence of preexisting gingivitis
(69, 70, 93), and a minor increase in tooth mobility
(93) have been reported in the literature. In a longitudinal evaluation, Hugoson (71) reported gingival
exudate increases of at least 20% during ovulation in
more than 75% of the females participating in his
study. The level of exudate appears to peak just
before ovulation, coinciding with the highest levels
of estradiol and progesterone in the circulation (70,
93). Nevertheless, most women with a clinically
healthy periodontium experience few significant periodontal changes as a result of menstruation (3).
Lindhe & Attstro m (93) noted that during their menstrual cycles, women without clinical gingivitis
showed no increase in gingival fluid, whereas those
with gingivitis showed increases in gingival fluid. In
addition to gingival inflammation, intraoral recurrent aphthous lesions (44), herpes labialis lesions,
and infections with Candida albicans (140) have
been documented in some women and seem to be
associated with increased progesterone levels during
the reproductive cycle.

Hormonal influences on periodontium

Fig. 2. Clinical appearance of pregnancy gingivitis. Significant generalized gingival enlargement and inflammation
are evident.

Pregnancy

The significant increases in plasma hormone levels

accompanying pregnancy manifest as some of the
most remarkable endocrine-related oral alterations
seen in women. Pregnancy gingivitis is extremely
common and affects 30100% of all pregnant women
(35, 73, 92, 100, 102) (Figs 2 and 3). Its occurrence has
been acknowledged for a substantial period of time,
as pregnancy gingivitis was first described in 1877
(146), although descriptions had been given even
earlier (37). Gingival inflammatory changes in pregnancy usually begin during the 2nd month and
increase in severity through the 8th month, after
which there is an abrupt decrease related to a concomitant reduction in sex steroid hormone secretion
(100). The greatest involvement appears to be in
anterior areas of the oral cavity, with interproximal
sites most commonly affected (99). Longitudinal and
cross-sectional studies have confirmed that the prevalence and severity of gingival inflammation is

Fig. 3. Clinical view of pregnancy gingivitis in the right

posterior.

significantly higher in pregnant women compared

to postpartum, and appears unrelated to the amount
of plaque present (7, 71, 99). Hugoson (71) additionally confirmed that the severity of gingival inflammation correlated to elevations of sex steroid hormones
during pregnancy, and was reduced following parturition and the concomitant drop-off in hormone
production. Other clinical periodontal changes that
have been described during pregnancy include
increased gingival probing depths (71, 99, 119, 150),
increased bleeding upon probing or mechanical stimulation (7, 119), increased gingival crevicular fluid
flow (71), and increased tooth mobility (27, 99, 150).
Preexisting gingivitis or periodontitis in pregnant
women has been noted to worsen dramatically (73,
100). However, Tilakaratne et al. (194) studied pregnant women and found that pregnancy increased the
clinical measures of gingival inflammation, but
attachment levels were not affected. Although significant adverse gingival conditions may develop during
pregnancy, there are no studies presently available
indicating that periodontitis development is a natural sequela of steroid sex hormone-induced gingivitis (76, 79). There is, however, current evidence that
periodontal inflammation and destruction may be
increased in pregnant diabetic patients compared
to non-diabetic pregnant patients (65). Nevertheless,
in otherwise systemically healthy females, this has
not been demonstrated.
In addition to the gingival changes seen due to an
enhanced inflammatory response during pregnancy,
0.59.6% of women who are pregnant also experience
localized gingival enlargement consistent with pyogenic granulomas (8, 88, 104, 217) (Figs 4 and 5). First
described in 1874 (28), the pregnancy-associated
pyogenic granuloma, or pregnancy tumor, is not
a neoplasm at all, and clinically and histologically
cannot be distinguished from pyogenic granulomas
occurring in women who are not pregnant. These
lesions have been described as a painless, exophytic
mass that has either a sessile or pedunculated base
extending from the gingival margin or, in most
instances, from the interproximal tissues in the maxillary anterior (170). The pregnancy tumor develops
as the result of an exaggerated inflammatory
response to an irritation (often calculus), enlarges
rapidly, bleeds easily, and may range in color from
purplish red to deep blue, although most commonly
is red in color with small fibrin spots (3). It rarely
reaches more than 2 cm in size and has a tendency
to recur if not completely removed. The gingiva is
involved in 70% of cases, followed by the tongue,
lips, and buccal mucosa (17). Following parturition,

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Mealey & Moritz

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.

Hormonal influences on the microbiota

Fig. 4. Clinical presentation of a pregnancy-associated

pyogenic granuloma (pregnancy tumor) with typical
presentation on the gingiva.

the lesion may regress or completely disappear

(217).
The etiologic means by which female sex steroid
hormones may influence the periodontium of
women, especially during pregnancy, are varied
and differ from those ordinarily associated with plaque-induced gingivitis. Human gingiva contains
receptors for estrogen and progesterone, and
increased plasma levels result in an increase in accumulation of these hormones in gingival tissues (11,
144, 198, 199). In addition to the observed effects of
increased sex steroid hormone levels on subgingival
microbial parameters described earlier for circumpubertal gingival changes, estrogens, and progestins
may influence the periodontal tissues by affecting
gingival vasculature, the local immune system, and
the specific cells of the periodontium. Which etiologic factor plays the greatest role in fostering the exaggerated inflammatory response to bacterial plaque,
regardless of plaque quantity, has not been determined, and appears to most likely be a multifactorial

Fig. 5. Pregnancy-associated pyogenic granuloma with

exuberant tissue response.

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

Hormonal influences on periodontium

made observations in this regard. First, P. intermedia

is seen to increase during the second trimester of
pregnancy followed by a decline to postpartum
values during the third trimester, despite highly elevated hormone levels still present during the third
trimester. Additionally, there was no analysis of competitive inhibition with other steroid-like molecules
performed in the heretofore cited studies; therefore,
it is open to question whether the accumulation of
estradiol or progesterone in second trimester plaque
samples or pure cultures of P. intermedia was sex
steroid hormone specific or merely dependent on
the lipophilic nature of the plaque sample.
As discussed for circumpubertal gingival responses, it has still not been absolutely established
that increases in plasma estrogen or progesterone
during pregnancy stimulate specific bacterial species. At the present time, data indicate that absolute
numbers of P. intermedia may be elevated during
pregnancy. However, the relationship of this bacterial species to the development of exaggerated gingival inflammatory responses during pregnancy or
whether its growth is enhanced as a direct result of
increasing sex steroid hormone concentrations has
still to be definitively established.

Hormonal influences on the gingival

vasculature
The effects of estrogens and progestins on the gingival vasculature could potentially explain the
increased edema, erythema, gingival crevicular exudate, and hemorrhagic gingival tissues noted during
pregnancy as well as other stages of the reproductive
cycle. An increase in gingival crevicular fluid flow has
been correlated to elevated sex steroid levels (71),
which indicates that these hormones may affect vascular permeability in the gingival sulcus. Estrogen is
the main sex steroid hormone responsible for alterations in blood vessels in target tissues in females (52,
77), stimulating endometrial blood flow during the
rise in plasma estrogen seen during the follicular
phase. Subsequently, endometrial blood flow
decreases during the luteal phase of the cycle with
waning estrogen levels (147). Progesterone, in contrast, has been shown to have little effect on the
vasculature of systemic target tissues (103). The
effects of these hormones on the local vasculature
of the gingiva may be similar; however, the roles of
estrogen and progesterone may be reversed.
In gingiva and other non-periodontal intraoral tissues, more evidence has accumulated for progesterone affecting the local vasculature than for estrogen.

In addition, progesterone has been shown to reduce

corpuscular flow rate, allowing for accumulation of
inflammatory cells (94), increased vascular permeability (70, 95, 120), and increased vascular proliferation (96, 97). Lindhe et al. (97) administered
progesterone systemically in beagle dogs and
observed that the hormone may induce increased
leakage of leukocytes and plasma proteins from
post-capillary venules by affecting the endothelial
lining. Estrogens in these studies were found to have
minimal effect on the vasculature. Many of these
studies used significantly higher than pharmacologic
doses of sex hormones in animal models and should
be interpreted with caution. Nevertheless, each of the
effects elaborated have the propensity to contribute
to enhanced inflammation in the gingival tissues. It is
evident that further research is needed to fully understand the contribution of sex hormone induced
alterations of the gingival vasculature to the expression of enhanced gingival inflammation.

Hormonal influences on the local

immune system
Several studies have focused on the alteration of local
immune system components to explain the impact
that sex hormones may have on the periodontium
during pregnancy. Given similar levels of bacterial
plaque, local immunologic reactions in the gingiva
enhanced by sex steroid hormones might alter the
pathogenesis of the inflammatory lesion, and allow
for exaggerated gingival tissue responses during
pregnancy. This idea is furthered by the observation
that immune system components have been identified as possessing sex steroid receptors (2). Progesterone in particular has been shown to stimulate the
production of the inflammatory mediator prostaglandin E2 and to enhance the accumulation of polymorphonuclear leukocytes in the gingival sulcus (38,
45). Progesterone has also been found to enhance the
chemotaxis of polymorphonuclear leukocytes, while
low concentrations of estradiol have been shown to
reduce polymorphonuclear leukocyte chemotaxis
(118). In this same study, sex hormones were shown
to have no effect on the chemotaxis of monocytes.
Other studies suggest an increased susceptibility
brought on by immune system alterations. For instance, sex steroid hormones may modulate the production of cytokines (179), and progesterone has
been shown to downregulate IL-6 production by
human gingival fibroblasts to 50% of that of control
values (90). Kinane et al. (80) have suggested that it

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may be through IL-6 that estrogen and progesterone

exert their effects on the gingiva.
Kinnby et al. (81) reported that the balance of the
fibrinolytic system may be disturbed as high progesterone levels during pregnancy resulted in lower
levels of plasminogen activator inhibitor type 2
(PAI-2), an important inhibitor of tissue proteolysis.
In addition, the cellular and humoral immune system may be affected by sex steroid hormones. AboulDahab et al. (1) studied pregnant women and nonpregnant controls and found the percentages of CD3,
CD4, and B lymphocytes decreased in gingival tissues during pregnancy, and greater gingival inflammation was seen compared to controls. Other studies
(148, 174) demonstrate a decreased number of CD4
cells in peripheral blood during pregnancy when
compared to postpartum, and Sridama et al. (174)
showed a tendency for the CD4/CD8 ratio to
decrease at the same time, suggesting an immunodeficient state. Elevated levels of sex hormones, especially progesterone, have also been linked to
depressed cell-mediated immunity and phagocytosis
(149). Additionally, peripheral blood lymphocytes
showed a decreased response to bacterial antigens
in vitro, including extracts from P. intermedia (101,
139). Although much work remains to be done to
elucidate the exact mechanisms by which female
sex steroid hormones may impact the local immune
system in the periodontium, enough information is
available to suggest that hormonally related immunologic changes during pregnancy may increase susceptibility to gingival inflammation.

Hormonal influences on cells of the

periodontium
The effects of sex steroid hormones on individual
cells of the periodontium may also play a significant
role in the exaggerated gingival responses seen during the female reproductive cycle and pregnancy. Sex
steroid hormones have been shown to directly and
indirectly exert influence on cellular proliferation,
differentiation, and growth in target tissues, including keratinocytes and fibroblasts in the gingiva (109).
Two theories for the actions of the hormones on
these cells involve the role hormones may play in
altering the effectiveness of the epithelial barrier to
bacterial insult, and in affecting collagen maintenance and repair. Estrogens stimulate epithelial proliferation and increase keratinization of the vaginal
mucosa (3). Some evidence also exists that sex hormones may have a similar effect on the oral mucosal
and gingival epithelia (154, 155, 215), and a reduction

74

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

Hormonal influences on periodontium

during the reproductive years no longer occur to any

degree. The effect of reduced estrogen levels on
epithelial keratinization (195), along with decreased
salivary gland flow independent of medications
(177), may have other significant effects on the periodontium. Friedlander (53) described an atrophic
gingivitis in some post-menopausal women in which
the gingival tissues develop an abnormal paleness. In
other women, a menopausal gingivostomatitis may
develop, characterized by gingival tissues that are
shiny and dry, bleed readily, and may range from
pale to erythematous in color. More commonly
reported gingival lesions seen in women during this
phase of life tend to be desquamative in nature (109).
However, the role that sex steroid hormones play in
the development and progression of these lesions
remains obscure, and only circumstantial data exist
to tie hormones to these lesions. For example, most
of these lesions occur in females of middle age (133),
and exogenous estrogens have been used to treat
these lesions, (197, 216). Oral discomfort is also commonly reported by post-menopausal females, with
2090% of women reporting a burning sensation,
xerostomia, or bad taste (15, 43), while only 6% of
pre-menopausal women report the same (203). As
with desquamative lesions, estrogens have been successfully used to gain pain relief under these circumstances (15, 155, 203), although direct correlation
with these symptoms has yet to be established. In
addition to gingival changes, reduced estrogen levels
certainly may impact overall collagen metabolism,
including bone maintenance, and result in a tendency toward development of osteoporosis.

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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