Q U I N T E S S E N C E I N T E R N AT I O N A L
PERIODONTOLOGY
Association of periodontal inflammation, systemic
inflammation, and duration of menopausal years in
postmenopausal women
Neha Sharma, MDS1/Rajinder Kumar Sharma, MDS2/Shikha Tewari, MDS2/Meenakshi Chauhan, MD3/
Anu Bhatia, MDS 4
Objective: The influence of menopause on vascular inflam-
mation and systemic bone loss has been documented. The
purpose of this cross-sectional study was to assess the peri-
odontal status, high-sensitivity C-reactive protein (HsCRP)
level, and estrogen level in women with early menopause and
women with normal menopause. Method and Materials: A
total of 103 participants comprising normal menopausal
women (n = 53) and early menopausal women (n = 50) were
examined. Periodontal parameters, anthropometric param-
eters, and metabolic parameters including serum levels of
HsCRP and estrogen were recorded. Results: Women with
early menopause (age 49.02 ± 2.70 years, postmenopausal
period 5.86 ± 2.48 years) had higher clinical attachment loss
(CAL) and HsCRP along with increased sites with bleeding on
Key words: chronic periodontitis, C-reactive protein, estrogen, menopause
1 Postgraduate Student, Department of Periodontics and Oral Implantology,
Postgraduate Institute of Dental Sciences, Rohtak, Haryana, India.
2
Professor, Department of Periodontics and Oral Implantology, Postgraduate
Institute of Dental Sciences, Rohtak, Haryana, India.
3 Professor, Department of Obstetrics and Gynecology, Postgraduate Institute of
Medical Sciences, Rohtak, Haryana, India.
4
Senior Resident, Department of Periodontics and Oral Implantology, Postgradu-
ate Institute of Dental Sciences, Rohtak, Haryana, India.
Correspondence: Professor Rajinder K. Sharma, Department of Periodon-
tics and Oral Implantology, Postgraduate Institute of Dental Sciences,
Rohtak, Haryana 124001, India. Email: rksharmamds@yahoo.in
VOLUME 49 • NUMBER 2 • FEBRUARY 2018
Neha Sharma
probing (BOP) as compared with normal menopausal women
(age 50.56 ± 1.94 years; postmenopausal period 2.03 ± 1.15).
On partial correlation analysis after controlling for age, Plaque
Index (PI), and body mass index (BMI), CAL correlated positive-
ly and significantly with HsCRP and duration of menopause
(P = .000), and negatively with estradiol in pooled data.
Multivariate linear regression analysis revealed that CAL
(dependent variable) has significant association with HsCRP
(P = .000, r2 = .343) and duration of menopause (P = .001,
r2 = .343). Estrogen status also correlated with HsCRP.
Conclusion: CAL and HsCRP were higher in women with
early menopause. CAL was significantly correlated with post-
menopausal period and HsCRP in the population studied.
(Quintessence Int 2018;49:123–131; doi: 10.3290/j.qi.a39512)
Periodontitis is a chronic inflammatory process charac-
terized by destruction of tooth-supporting tissues by
virtue of the immunologic response to bacterial chal-
lenge originating from dental plaque.1,2 Onset and
progression of periodontitis is modified by behavioral
and systemic risk factors.3 Among these, sex hormones
have been suggested as important modifying factors
that may influence the pathogenesis of periodontal
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Sharma et al
diseases.4-6 Estrogen receptors are also found in osteo-
blast-like cells,7 fibroblasts of the lamina propria,8 and
periodontal ligament (PDL) fibroblasts9 proving the
direct action of sex hormones on different periodontal
tissues.
As women approach menopause, concentration of
circulating estradiol decreases.10 Estrogen deficiency is
associated with an increased production of tumor
necrosis factor (TNF) and interleukin-6 (IL-6) by acti-
vated T cells. TNF increases osteoclast formation and
bone resorption both directly and by augmenting the
sensitivity of maturing osteoclasts to the essential
osteoclastogenic factor, ie receptor activator of nuclear
factor-κB (NF-κB) ligand (RANKL).11,12 IL-6 is an import-
ant cytokine involved in many immunologic processes
including metabolic regulation of C-reactive protein
(CRP).13 IL-6 and CRP can have undesirable effects on
periodontium during inflammatory response to infec-
tion or trauma. Clinically, estrogen-sufficient post-
menopausal women have been reported to have less
gingival inflammation in spite of increased amounts of
plaque when compared to a similar population with
deficient levels of estrogens.14 Some studies observed
that postmenopausal women using hormone replace-
ment therapy (HRT) have increased tooth retention15
and decreased periodontal destruction.16,17
Menopause occurring between the ages of 40 and
45 years is considered as early menopause,18 and
menopause above the age of 45 is considered as nor-
mal menopause.
Epidemiologic studies have revealed that early
menopausal onset may increase heart failure risk and
depression and that women who undergo natural
menopause before 45 years of age are at increased risk
of cardiovascular diseases.19 Investigations related to
periodontitis during menopause are either linked to
bone mineral density or HRT to date. No study has been
undertaken to assess periodontal status of menopausal
women taking account of postmenopausal duration,
systemic inflammation, and estrogen level. Thus, the
present study was undertaken in an attempt to investi-
gate the relationship between periodontal status,
estrogen level, and systemic inflammation in terms of
124
serum high-sensitivity CRP (HsCRP) in women with
early menopause and those with normal menopause.
METHOD AND MATERIALS
Study population
This cross-sectional study was conducted in the Depart-
ment of Periodontics and Oral Implantology, Post Grad-
uate Institute of Dental Sciences (PGIDS), Rohtak, in
collaboration with the Department of Obstetrics and
Gynaecology, Post Graduate Institute of Medical Sci-
ences (PGIMS), Rohtak. The study protocol was carried
out in accordance with the ethical standards outlined in
the 1975 Declaration of Helsinki, as revised in 2013. The
protocol was approved by the postgraduate board of
studies, Pt. B. D. Sharma University of Health Sciences,
Rohtak, and ethical approval was given by the institu-
tional ethical committee (Ethical approval no: PGIDS/
IEC/ 2015/ 61). The study period was from April 2015 to
October 2016. The study population comprised two
groups: Group 1, 53 normal postmenopausal women
(NPMW); and Group 2, 50 early postmenopausal
women (EPMW). Systemically healthy postmenopausal
women aged 45 to 54 years, with chronic periodontitis
and at least 20 natural teeth were included in the study.
Periodontitis criteria were at least two interproximal
sites with clinical attachment loss (CAL) ≥ 3 mm, at least
two interproximal sites with probing depth (PD)
≥ 4 mm (not on the same tooth), or one site with
PD ≥ 5.20 Exclusion criteria included history of systemic
disease or condition that may affect the course of peri-
odontal disease (like diabetes mellitus and hematologic
disorders); women on HRT; history of the following
drugs in the previous 3 months: nonsteroidal anti-in-
flammatory drugs, steroids, immune-suppressants,
statins, bisphosphonates, or any other host modulatory
drug; a recent history or presence of any other acute or
chronic infection; systemic antibiotic treatment within
the previous 3 months; periodontal treatment within
the past 2 years prior to inclusion into the study; cur-
rent or past smokers or use of smokeless tobacco in any
form; history of autoimmune disease like hypothyroid-
ism, Crohn’s disease, systemic lupus erythematous,
VOLUME 49 • NUMBER 2 • FEBRUARY 2018

Fig 1 Clinical photograph of patient with early menopause.
rheumatoid arthritis; history of treatment for ovarian
cancer/radiation therapy; history of hysterectomy.
Information regarding age and personal and family
history was obtained through oral interview. Informa-
tion regarding the duration of menopausal years was
collected from the patient’s history based on their
memory recall (self-report). Medical history as well as
consultation with a gynecologist was relied upon to
rule out the presence of any of the above-mentioned
diseases. Informed written consent was taken from
each patient after explaining the risks and benefits in
their own language.
Anthropometric measurement
Standardized measurements of weight in kilogram and
height in centimeters were taken in light clothing with
shoes removed. Body mass index (BMI)21 was calculated
as weight in kilograms divided by height in meters
squared.
Biochemical parameters
All the blood samples were collected in the morning
after overnight fasting; 4 mL of venous blood was
drawn from anticubital veins after applying a tourni-
quet in a plain vacutainer without additive. Serum
HsCRP levels were assessed using a kit (C-Reactive Pro-
tein [Latex] High-Sensitivity Assay, Roche Diagnostics)
with high-sensitivity methodology in an autoanalyzer
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Sharma et al
Fig 2 Clinical photograph of patient with normal menopause.
(Konelab Clinical Chemistry Analyzer, Thermo Fisher
Scientific) according to the manufacturers’ instructions.
Serum estrogen was assessed by estradiol assay
using Elecsys reagent kit (Roche Elecsys). It employs a
two-step competitive test principle using two monoclo-
nal antibodies specifically directed against 17β-estradiol.
Periodontal parameters
The clinical protocol included measurement of the fol-
lowing periodontal parameters: Plaque Index (PI), Gin-
gival Index (GI), bleeding on probing (BOP), PD, and
CAL. These parameters were recorded on each tooth
(except third molars) with a UNC-15 periodontal probe
(Hu-Friedy)(Figs 1 and 2).
BOP, PD, and CAL were recorded at six sites per
tooth. PI22 and GI23 were recorded at four sites per
tooth. The dichotomous assessment of the number of
sites with BOP was recorded as a percentage.
To preclude inter-examiner variability, periodontal
examination was performed by a single trained and
calibrated examiner (NS) who was masked to the group
affiliation of the participants. Reproducibility of clinical
measurements was verified by carrying out double clin-
ical periodontal data recording for PD and CAL on 10%
of the sample. Intra-examiner reproducibility was deter-
mined by calculating the percentage of the site exam-
ined where the scores were matching. Assessment of
mean difference in the scores (kappa value 0.82 for PD
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Sharma et al
and 0.78 for CAL) indicated that there was no system-
atic bias in the measurements.
Statistical analysis
The sample size was calculated by power calculations
using statistical software (G-power 3.0.10, Hein-
rich-Heine University Düsseldorf). Assuming fixed effect
size to be 0.6 with alpha error 0.5 and power 0.80 with
allocation ratio 1, the sample size calculated was 47 in
each group. The normality of distribution of data was
determined using the Shapiro-Wilk test. Data of both
the groups were found to be non-normally distributed
except PI, BOP, and BMI. Nonparametric tests were
applied for all the variables except PI, BOP, and BMI, for
which parametric analysis was performed. Intergroup
comparison of anthropometric, metabolic, and peri-
odontal parameters was done by either independent
sample t test (parametric) or Mann-Whitney U test
(nonparametric), whichever was applicable. Spearmen
correlation analysis was performed to assess the rela-
tionship among all the variables. Partial correlation
among variables was assessed after controlling for
potential confounders (age, BMI, and PI). Multiple linear
stepwise regression analysis was used to develop mod-
els of predictor variables associated with the depen-
dent variable. All statistical analyses were two-tailed
with significance level at .05, as calculated using soft-
ware (SPSS v.19, IBM).
RESULTS
A total of 180 individuals were examined, and of them
103 women meeting the study criteria were recruited.
All the parameters of recruited participants were
recorded and taken into consideration for statistical
analysis. All participants completed the study protocol.
Table 1 depicts intergroup comparison of anthropo-
metric, metabolic, and periodontal parameters. Statisti-
cally significant difference was noted between the two
groups in the following parameters: age, HsCRP, BOP,
CAL, duration of menopause, and BMI. HsCRP and BOP
of EPMW were found to be higher than NPMW (P = .010
and .041, respectively). There was a significant differ-
126
ence between the mean postmenopausal duration and
BMI of the two groups (P = .000 and .000, respectively).
The mean CAL of EPMW was found to be higher than
NPMW (P = .033). Table 2 depicts the distribution of
periodontal variables (mean percentage sites) of the
study population. The mean percentages of sites with
PD of 4 to 5 mm and those with CAL ≥ 3 mm were sig-
nificantly higher in EPMW compared to NPMW. Table 3
depicts correlation of all the variables by Spearman’s
correlation analysis and Table 4 displays the results of
partial correlation after controlling for confounders
(age, BMI, and PI) simultaneously in pooled data of
both groups. HsCRP was found to be positively cor-
related to GI (r = .244, P = .014) and CAL (r =.484,
P = .000). Serum estrogen levels were negatively cor-
related with hsCRP (r = −.279, P = .005). CAL was
strongly and positively correlated to HsCRP (r = .484,
P = .000) and duration of menopause (r = .423, P = .000),
and negatively correlated to serum estradiol levels
(r = −.231, P = .021). Postmenopausal period was posi-
tively correlated to HsCRP, estradiol, and CAL. Multiple
linear regression (Table 5) revealed that mean CAL was
significantly associated with HsCRP (P = .000, r2 = .343)
and duration since menopause (P = .001). Also, mean
HsCRP was found to be significantly associated with
duration since menopause (P = .025, r2 = .358), CAL
(P = .000, r2 = .358), and age (P = .046, r2 = .358).
DISCUSSION
Estrogen is known to have anti-inflammatory actions,
including inhibition of proinflammatory cytokines
(mainly IL-6),24 reduction of T-cell-mediated inflamma-
tion,25 inhibition of polymorphonuclear leukocytes
(PMNs), and chemotaxis.26 Acceleration of osteoclastic
bone resorption that accompanies the state of estrogen
depletion during menopause appears to be mediated
through inflammatory cytokines.27-29 Loss of ovarian
function and subsequent deficiency of endogenous
estrogens after menopause has been shown to signifi-
cantly affect periodontal health.30 If endogenous estro-
gens protect against periodontal disease, an early onset
of menopause might incur a higher risk, because of
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Table 1 Intergroup comparison of anthropometric, metabolic, and periodontal parameters between two
groups

Parameters NPMW (mean ± SD) EPMW (mean ± SD) P

Age (y) 50.56 ± 1.94 49.02 ± 2.70 .002*
HsCRP (mg/dL) 0.26 ± 0.17 0.39 ± 0.30 .010*
Estradiol (pg/mL) 20.65 ± 12.05 17.56 ± 9.15 .269
PI 1.28 ± 0.54 1.36 ± 0.63 .446
GI 1.13 ± 0.48 1.26 ± 0.57 .415
BOP (%) 37.00 ± 18.4 44.00 ± 19.88 .041*
PD (mm) 2.10 ± 0.75 2.19 ± 0.77 .514
CAL (mm) 2.29 ± 0.78 2.60 ± 0.95 .033*
Postmenopausal period (y) 2.03 ± 1.15 5.86 ± 2.48 .000*
BMI (kg/m2) 24.67 ± 2.71 26.86 ± 2.90 .000*
*Significant at P ≤ .05.

Table 2 Distribution of the periodontal condition variables (mean ± SD) of the study population

Parameter NPMW EPMW P

Mean (%) sites with PD 1–3 mm 55.97 ± 10.73 52.19 ± 9.42 .071
Mean (%) sites with PD 4–5 mm 38.48 ± 10.23 42.87 ± 10.95 .048*
Mean (%) sites with PD ≥ 6 mm 5.26 ± 3.27 4.74 ± 2.96 .369
Mean (%) sites with CAL 0–2 mm 55.07 ± 12.76 42.36 ± 11.51 .000*
Mean (%) sites with CAL ≥ 3 mm 44.92 ± 12.76 57.63 ± 11.35 .000*
*Significant at P ≤ .05.

lower exposure to estrogen. Evidence for this hypothe-
sis, however, has been inconclusive. Comparing the
periodontal status of early versus normal postmeno-
pausal women may add to the data available for analyz-
ing the impact of menopause on periodontal status. No
study has previously attempted to examine the associ-
ation of clinical periodontal parameters with the quan-
titative estimation of serum estrogen concentration and
systemic inflammatory marker (HsCRP) simultaneously.
Postmenopausal period (mean time elapsed since
menopause) in EPMW (5.86 ± 2.48 years) was greater
than in NPMW (2.03 ± 1.15 years). CAL was found to be
higher in EPMW (2.60 ± 0.95 mm) as compared to NPMW
(2.29 ± 0.78 mm), despite the slightly higher mean age in
NPMW. Moreover, percentage sites with CAL ≥ 3 mm
and those with PD of 4 to 5 mm were found to be higher
in EPMW. These findings indicate that early menopause
and subsequently greater years spent in the postmeno-
pausal phase might be an influencing factor in affecting
the periodontal parameters. Kritz-Silverstein and Bar-
rett-Connor31 showed that elderly women reporting
early menopause or fewer reproductive years have a
higher incidence of osteoporosis and significantly
lower bone density. Sudden decrease in estrogen levels
occurs in menopause, and this is considered to be the
main cause of primary osteoporosis. It has been sug-
gested that this reduction in bone mineral density
could contribute to periodontal disease progression.32
Reinhardt et al33 have shown that estrogen-deficient
women with periodontitis had a higher frequency of
gingival crevicular fluid IL-1β positive sites than estro-
gen-sufficient women. During supportive periodontal

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Table 3 Spearman’s correlation analysis

Estra- Dura-
Correlation Age HsCRP diol PI GI BOP PD CAL tion BMI
Correlation coefficient 1.000 .312 −.084 −.092 −.116 −.081 −.131 .120 .123 −.058
Age
Sig. (2-tailed) NA .001* .400 .356 .245 .414 .188 .228 .216 .560
Correlation coefficient .312 1.000 −.182 −.036 .211* .186 .088 .310 .354 .170
HsCRP
Sig. (2-tailed) .001* NA .066 .716 .032* .060 .374 .001* .000* .086

Estra- Correlation coefficient −.084 −.182 1.000 .031 −.038 −.007 −.025 −.240* −.185 .078
diol Sig. (2-tailed) .400 .066 NA .756 .701 .941 .802 .015* .061 .436
Correlation coefficient −.092 −.036 .031 1.000 .350 .368 .264 −.111 .090 .016
PI
Sig. (2-tailed) .356 .716 .756 NA .000* .000* .007* .265 .364 .876
Correlation coefficient −.116 .211* −.038 .350 1.000 .539 .317 .104 .140 .185
GI
Sig. (2-tailed) .245 .032* .701 .000* NA .000* .001* .296 .158 .061
Correlation coefficient −.081 .186 −.007 .368 .539 1.000 .359 .004 .160 .138
BOP
Sig. (2-tailed) .414 .060 .941 .000* .000* NA .000* .967 .105 .164
Correlation coefficient −.131 .088 −.025 .264 .317 .359 1.000 .104 .152 .153
PD
Sig. (2-tailed) .188 .374 .802 .007* .001* .000* NA .295 .126 .122
Correlation coefficient .120 .310 −.240 −.111 .104 .004 .104 1.000 .391 .076
CAL
Sig. (2-tailed) .228 .001* .015* .265 .296 .967 .295 NA .000* .447

Dura- Correlation coefficient .123 .354 −.185 .090 .140 .160 .152 .391 1.000 .264
tion Sig. (2-tailed) .216 .000* .061 .364 .158 .105 .126 .000* NA .007*
Correlation coefficient −.058 .170 .078 .016 .185 .138 .153 .076 .264 1.000
BMI
Sig. (2-tailed) .560 .086 .436 .876 .061 .164 .122 .447 .007* NA
*Significant at P ≤ .05.

treatment, estrogen-sufficient women are reported to
display a mean net gain in alveolar bone density,
whereas the estrogen-deficient women displayed a
mean net loss in alveolar bone density.34 Findings of
the present study along with previous literature war-
rant ongoing evaluation of the potential perio-protec-
tive mechanisms of sex hormone (estrogen) exposure
in women.
A rise in CRP after menopause might occur due to
several concurring events. Aging, sex hormone fluctua-
tions, periodontal inflammation, longer duration of
menopause, and BMI are some of the factors in the
present study that may affect CRP levels.
The mean value of HsCRP in the EPMW (0.39 ± 0.30)
was found to be more than that in NPMW (0.26 ± 0.17).
This finding likely indicates that lower estrogen level in
EPMW may contribute to higher systemic inflammatory
status, in comparison to women with NPMW. However,
higher periodontal inflammation contributing to raised
HsCRP levels in EPMW cannot be ruled out.
Results of partial correlation analysis reveal that
HsCRP is negatively and significantly correlated with
estrogen levels (controlling for confounders). However,
this association seems to be a weaker one. A single
measure of estrogen level may be less predictive of
HscCRP levels. Also, in the present study, CAL and dura-
tion of menopausal years were strongly positively asso-
ciated with age-adjusted CRP levels. CRP stimulates
release of inflammatory cytokines such as IL-1β, IL-6,
and TNF-α,35 and further may contribute to directly to a
pro-inflammatory state by stimulating phagocyte
cells.36 The present findings lend credence to the
notion that higher systemic inflammation owing to low
estrogen status may act as a modifying factor in the

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Table 4 Correlation of different parameters applying partial correlation analysis after controlling for
confounders (age, PI, and BMI) in the pooled data

Parameters HsCRP Estradiol GI BOP PD CAL Duration

Correlation NA −.279 .244 .172 .094 .484 .388
HsCRP
Significance NA .005* .014* .088 .351 .000* .000*
Correlation −.279 NA −.078 −.068 −.028 −.231 −.267
Estradiol
Significance .005* NA .442 .503 .781 .021* .007*
Correlation .244 −.078 NA .449 .285 .148 .140
GI
Significance .014* .442 NA .000* .004* .142 .166
Correlation .172 −.068 .449 NA .389 .061 .176
BOP
Significance .088 .503 .000* NA .000* .546 .080
Correlation .094 −.028 .285 .389 NA .108 .121
PD
Significance .354 .781 .004* .000* NA .287 .229
Correlation .484 −.231 .148 .061 .108 NA .450
CAL
Significance .000* .021* .142 .546 .287 NA .000*
Correlation .388 −.267 .140 .176 .123 .450 NA
Duration
Significance .001* .007* .166 .080 .229 .000* NA
*Significant at P ≤ .05.

Table 5 Multiple linear regression analysis

Dependent
variable Model predictors β Unstandardized Standard error β Standardized P r2
Constant .958 1.485 NA .520
HsCRP 1.279 .318 .373 .000*
CAL
Duration .098 .030 .302 .001* .343
Age .014 .030 .039 .647
Constant −. 990 .439 NA .260
CAL .107 .027 .368 .000*
HsCRP Duration .020 .009 .213 .025*
.358
Age .018 .009 .171 .046*
GI .072 .040 .151 .072
*Significant at P ≤ .05.

progression of chronic periodontitis during the post-
menopausal period.
BOP is accepted as a sign that enables the detec-
tion of hidden periodontal inflammation.37 There is a
strong correlation between BOP and gingival inflam-
mation. Moreover, absence of BOP has high predict-
ability values for disease progression.38 Hence, it is a
vital parameter in the assessment of the degree, as
well as the extent of inflammatory periodontal dis-
ease.39 The mean percentage of BOP-positive sites is
greater (44.00 ± 19.88) in EPMW than that in NPMW
(37.00 ± 18.40).
Postmenopausal duration was positively associated
with CAL in the present study. Also, estradiol levels are
negatively and significantly correlated to duration since
menopause. This observation likely indicates that early

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start of menopause and greater number of years spent
in the postmenopausal phase may impact attachment
loss.
Postmenopausal women of narrow age range but
with different postmenopausal periods along with
stringent inclusion and exclusion criteria are some of
the strengths of the present study.
One of the limitations of this study is that estrogen
levels were assessed at a single time point. Moreover,
results of the present study should be interpreted with
a caution as the sample size is not sufficient to draw
definite conclusions. Multicenter, large sample sized
prospective studies with serial measures of serum
estrogen concentrations in postmenopausal women
could elucidate the impact of this hormone on the peri-
odontium. In the present study, the time spent in the
postmenopausal phase is a short period (5.86 vs 2.03
years), especially in NPMW. The impact of longer dura-
tion of postmenopausal phase on the periodontium
should be investigated. Lastly, the scope of the present
study is confined to finding association.
Longitudinal cohort studies, involving large sample
sizes, evaluating periodontal status in the premeno-
pausal phase to postmenopausal period with estima-
tion of estradiol and inflammatory markers at local and
systemic levels at different points of time are recom-
mended to fully elucidate the menopausal effect on the
periodontium.
CONCLUSION
Serum HsCRP, CAL, percentage of BOP sites, as well as
sites with higher CAL are found to be greater in post-
menopausal women with early menopause. Clinical
attachment loss is correlated with postmenopausal
period and systemic inflammation in chronic periodon-
titis. Higher systemic inflammatory status as revealed
by raised serum HsCRP during menopause is found to
be associated with gingival inflammation as well as
clinical attachment loss. However, longitudinal studies
with assay of local and systemic inflammatory cytokines
are required to fully elucidate the effect of menopause
on the periodontium.
130
ACKNOWLEDGMENT
The present study was supported by the authors’ institution without
any external funding.
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