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ORIGINAL ARTICLE
Year : 2017  |  Volume : 21  |  Issue : 4  |  Page : 276-284  

Correlative analysis of plasma and urine neopterin levels in the pre- and post-menopausal women with periodontitis, following nonsurgical periodontal therapy


1 Department of Periodontics, Panineeya Institute of Dental Sciences and Research Centre, Hyderabad, Telangana, India
2 Department of Conservative and Endodontics, Panineeya Institute of Dental Sciences and Research Centre, Hyderabad, Telangana, India

Date of Submission27-Oct-2017
Date of Acceptance28-Dec-2017
Date of Web Publication29-Jan-2018

Correspondence Address:
Dr. Jammula Surya Prasanna
Department of Periodontics, Panineeya Institute of Dental Sciences and Research Centre, Road No-5, Kamala Nagar, Dilsucknagar, Hyderabad - 500 060, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisp.jisp_278_17

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   Abstract 

Context: Periodontitis is an inflammatory condition which is distinguished by the devastation of the supported tooth structures. In such inflammatory conditions, some biomarkers such as neopterin will be secreted and elevated in the body fluids, which can be used as a diagnostic marker for the present and future disease activity. Aims: Assessment of the neopterin as a biomarker in inflammatory conditions such as menopause and periodontitis. Settings and Design: A cross-sectional interventional study. Materials and Methods: Sixty female individuals with a mean age of 40–60 years with chronic periodontitis were included in this study. All were categorized into two groups of thirty each, depending on their menstrual history: Group I – thirty premenopausal women and Group II – thirty postmenopausal women. Urine and plasma were collected from both groups to estimate neopterin levels. ELISA kit was used to assess the neopterin levels at baseline and after 3 months of nonsurgical periodontal therapy (NSPT). Statistical Analysis Used: IBM SPSS version 21 software. Results: A significant depreciation in the mean values of all the parameters from baseline to 3 months (P < 0.001), in the intragroup analysis, was observed. Plasma (0.006) and urine (0.004) reduction was seen. Conclusions: In both the groups, in 3 months after NSPT, decreased neopterin levels were found, suggesting that the NSPT is the definitive therapy. Further, suggesting that, neopterin levels in the plasma and urine can be used as an index to identify the periodontal inflammation and destruction.

Keywords: Menopause, neopterin, nonsurgical periodontal therapy, periodontitis, scaling and root planing


How to cite this article:
Prasanna JS, Sumadhura C, Karunakar P, Rekharani K, Himabindu G, Manasa A. Correlative analysis of plasma and urine neopterin levels in the pre- and post-menopausal women with periodontitis, following nonsurgical periodontal therapy. J Indian Soc Periodontol 2017;21:276-84

How to cite this URL:
Prasanna JS, Sumadhura C, Karunakar P, Rekharani K, Himabindu G, Manasa A. Correlative analysis of plasma and urine neopterin levels in the pre- and post-menopausal women with periodontitis, following nonsurgical periodontal therapy. J Indian Soc Periodontol [serial online] 2017 [cited 2019 Dec 13];21:276-84. Available from: http://www.jisponline.com/text.asp?2017/21/4/276/223967


   Introduction Top


Spreading of inflammation surrounding the soft and hard tissues of the tooth is called periodontitis. Amelioration of the diagnostic research in measuring the biomarkers may help identify early periodontitis. Specific circulating inflammatory marker levels can be compared with the austerity of the periodontal disease activity.[1]

The investigators and clinicians both face a challenge to diagnose the progressive phases of periodontal diseases, and assessing the patients is at major risk. The liability of such circumstances can be subtended using the biomarkers for diagnosis which are expressed in the body fluids such as gingival crevicular fluid (GCF), saliva, serum, plasma, and urine.[2]

A biomarker is a biologic measure that can be used as an index. It may be particularized and guesstimated as a pointer of normal, pathogenic, biological processes or pharmacological responses to a curative intercession.[3] Till today, the available predictor biomarker for periodontal disease is bleeding on probing (BOP). According to researcher's reports,[3] there are false-positive assumptions associated with it. Despite such conclusions, the absence of BOP is considered as a very precise negative predictor of disease activity.[3]

In contempt of chronic periodontitis (CP) is considering as a site-specific disease, its perspicacity to a patient and site-specific is still ambiguous. As a result of that since 1990, wide research activities have been commenced to figure out the importance of individual biomarker activities related to periodontal diseases in different body fluids.[4]

Among all biomarkers, nonperiodontitis (NP) is a precise biomarker of cellular immunity. The role of NP in cell-mediated immune reactions is distinguishable. Hence, dogmatism of NP concentrations in different body fluids is of a diagnostic interest in diseases originated from T-lymphocytes and macrophages. NP production also elevated in infections caused due to intracellular living bacteria and parasites.[5],[6]

Reactive oxygen species levels and NP concentration are directly proportional to each other and inversely related to the serum concentration of antioxidants such as α-tocopherol. Hence, NP can be used as a marker of reactive oxygen species formed by an activated cellular immune system.[7]

Literature is proving that there is much dissimilarity in various health aspects of postmenopausal women when compared with premenopausal women. In this study, computation of plasma and urine neopterin levels in patients with periodontitis in pre- and post-menopausal women was done to perceive what extent the variations will be seen. We also aimed to evaluate the teeter-totter levels of neopterin to nonsurgical periodontal therapy (NSPT).


   Materials and Methods Top


Patient selection criteria

The Institutional Review Board Committee has approved this research decorum. This study was registered under https://clinicaltrials.gov (NCT02357745). This study was performed in between January 2016 and August 2016. A total of 60 female patients aged ranging 40–60 years were included in this study. On an average, the age criteria was 50 years, who met the selection criteria, were subsequently included in this study [Flow chart 1]. The sample size was estimated by setting α value at 0.05 and power to 80% (1 − β =0.8). After the detailed explanation of the study design, written informed consent was procured from all the individuals. Depending upon the menstrual history, all the individuals were categorized into two groups; each group consists of thirty patients. Group I and Group II encompass thirty premenopausal and thirty postmenopausal women with CP, respectively. CP was diagnosed hinged on the American Academy of Periodontology classification.[8] To choose periodontitis patients, Russell's periodontal index [9] was kept as a frame of reference to categorize from gingivitis cases. Inclusion criteria of this study were individuals having periodontal pocket depth ≥4 mm. After ruling out all other possible systemic problems by a physician, only systemically healthy individuals with at least 15 natural teeth present, no smoking habits, and neither undergone any dental treatment nor taken any medications for any other sickness from the past 6 months only were included in this study. If anyone was on hormonal therapy and/or taking any medications were not included in this study. Other than periodontitis, if anybody has other pathology in the oral cavity, were strictly eliminated from this study. NP levels were analyzed at baseline and 3 months after NSPT in all the individuals by screening plasma and urine samples.



Grouping of menopause patients

Group 1

Premenopausal-only age-matched participants who have menstrual irregularities caused due to age-induced hormonal imbalance only were included; other menstrual disturbances caused by any other means were excluded. A gynecologist was confirmed this after thorough clinical and diagnostic evaluation.

Group 2

Postmenopausal participants who were fulfilling the criteria had amenorrhea for the past 12 months or more were included. Gynecologist examined all participants if any obvious pathology was found those individuals were excluded from this study.

Plasma collection

Five milliliters of peripheral venous blood was drawn from brachial plexus through vein puncture method. Whole blood was collected in EDTA tubes (4 ml, CML Biotech [P] Ltd, Kerala, India). Plasma was obtained by centrifuging at 3000 × g for 10 min in a centrifuge (R-4C, REMI Laboratory Instruments, Mumbai, India), immediately liquid component, plasma was transferred into a clean polypropylene tube (0–15 mi, Thermo Scientific-Laboratory Plastic ware, Glassw) using a Pasteur pipette (Ajosha Bio Teknik Pvt. Ltd., Kanjurmarg West, Mumbai, India).

Urine collection

First urine samples were collected in the morning from nonfasting individuals and were immediately sheathed in tin foil to protect them from the light. These samples were diluted according to protocol before measurement.

Strictly, all the samples were collected under aseptic conditions, and the complete procedure was carried out by a single examiner. All the samples were stored at −20°C till 6 months for NP evaluation, as per the manufacturer's instructions.

Analysis of neopterin

Protocol of the test

A commercially available ELISA kit (Neopterin kit-Alpha Diagnostic Intl, San Antonio, TX 78244, United States [www. 4adi.com] 410/15072 A) was used to determine NP values. The basic concept of neopterin ELISA kit is a precise competitive obligator of human NP and enzyme-labeled NP with NP-definitive antibodies, immobilized on microtiter plates. After washing, the addition of chromogenic substrate, change in color was observed on micro plates. The enzymatic reaction (blue color) was observed due to the amount of NP present, which was inversely proportional to NP in the sample. After adding stopping solution due to termination of reaction, the change in color from blue to yellow was seen. On an ELISA reader at 450 nm, absorbance was measured. With the help of standard curve, NP concentrations in both the groups were calculated.

Sensitivity

The reduced detection limit was determined from the standard curve by determining the resulting concentration of the mean OD of calibrator A (based on 10 replicate analyses) minus 2 standard deviation (SD) accordingly, the sensitivity of this neopterin ELISA kit was set 0.7 nmol/L.

Specificity (cross-reactivity)

Direct neopterin ELISA kit, with neopterin cross-reacting at 100% was used to test the cross-reactivity of these following compounds. Significant interference was not detected at the subsequent concentrations: triglyceride 125 mg/dL, Bilirubin 2.25 mg/dL, and Hemoglobin 35 mg/dL.

Using ELISA 96-well microplate reader, the optical density was measured at 450 nm. The analytical concentration of the sample and the optical density of the number of complexes bound to the plate are inversely related. According to manufacturer's instructions, all samples were determined in duplicates.

Calculation of the results

According to a pamphlet given by the manufacturer, the neopterin concentration of each sample was determined using the standard curve. The discrepancy in the values either low or high than the standard curve extrapolation was not determined.

Statistical analysis

The observations recorded were subjected to statistical analysis using IBM SPSS version 21 software (SPSS v. 21, IBM, Chicago, IL, USA). Then, an average of plasma and urine NP was calculated for each individual in both the groups, and this mean value was used as the response variable. Results were symbolized as the mean ± SD. The differences in clinical variables and amount of NP were examined using the independent sample t-test. The correlation between the levels of NP and clinical variables of the two groups was analyzed separately using a paired t-test. P < 0.05 was considered statistically significant.


   Results Top


The intragroup comparison showed statistically significant reduction in the mean values of all the parameters from baseline to 3 months within Group I and Group II [Table 1].
Table 1: Intragroup comparison at baseline and 3 months

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In Group I, the mean urine NP level was reduced from 304.91 ± 59.86 at baseline to 265.57 ± 53.62 at 3 months after treatment. The mean plasma NP levels had reduced from 11.72 ± 1.49 at baseline to 6.95 ± 0.93 at 3 months after treatment. In Group II, the mean urine NP levels were found to be reduced from 391.22 ± 60.90 at baseline to 290.45 ± 51.56 at 3 months after treatment, and mean plasma NP levels had reduced from 13.52 ± 2.47 at baseline to 7.23 ± 1.07 at 3 months after treatment. There was a statistically significant discrepancy seen from baseline to 3 months of posttreatment in both the parameters in both the groups (P = 0.002 and < 0.001, respectively) [Table 1] and [Figure 1], [Figure 2].
Figure 1: (a) Comparison of plasma and urine neopterin in premenopausal group. (b) Urine neopterin levels in both the groups at baseline and 3 months

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Figure 2: (a) Comparison of plasma and urine neopterin in postmenopausal group. (b) Comparison of plasma neopterin in both the groups at baseline and 3 months

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In the intergroup comparison, the mean concentration of NP levels in urine at baseline was 304.91 ± 59.86 in Group I and 391.22 ± 60.90 in Group II. The mean value of plasma, at baseline, was 11.72 ± 1.49 in Group I and 13.52 ± 2.47 in Group II. Comparing these values showed that the difference in the levels of NP between groups was statistically significant (P< 0.001, 0.001); after 3 months of posttreatment, both the values were statistically insignificant in the intergroup comparison [Table 2].
Table 2: Intergroup comparison at baseline and 3 months

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When we compare these values in both the groups from baseline to 3 months, a statistically significant difference was observed in urine as well as in plasma NP levels (P = 0.004 and 0.006, respectively) [Table 3] and [Figure 3].
Figure 3: Comparison of plasma and urine neopterin in both menopausal groups

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Table 3: Intergroup comparison of change from baseline to 3 months

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   Discussion Top


NP is a biologically stable cellular immune activation marker, which is easily looked over in human body fluids such as GCF, cerebrospinal fluid (CSF), and urine, and it can be applied without difficulty for routine measurements in laboratory diagnosis.[10] The cubic measure of NP optimizes with the intensity of gingival inflammation. Consequently, this is useful for predicting the prognosis and diagnosis of a severe form of periodontal diseases.[11] NP was first diagnosed in larvae of bees, in worker bees, and in royal jelly in 1963 and subsequently in human urine by Sakurai and Goto in 1967.[12] NP is a metabolite of guanosine triphosphate (GTP), and in vitro interferon gamma (IFN-γ) is the only cytokine that induces the production of large amounts of NP in cell culture supernatants. On the other hand, in human monocytes/macrophages and in some cell lines stimulated with this cytokine, NP is produced and released instead of other pteridine derivatives.[13],[14],[15],[16],[17],[18] Periodontitis is a very common chronic infection or inflammation of the tissue surrounding the teeth. Severe attachment loss and bone loss progress if untreated. However, the nature and source of inflammation is unclear, but many studies have proven that periodontal therapy resolves the periodontal as well as systemic inflammation.[19],[20],[21] Recent studies demonstrated that traditional clinical measures of human periodontal diseases do not designate the ongoing future disease progression.[22] Determination of the presence of inflammatory products as a marker may be of value in evaluating both periodontal disease status and outcome of therapy.[23] Evaluation of NP levels in various human biological fluids in various diseases was done by many authors.[24],[25],[26],[27],[28],[29],[30] NP is annihilated by the kidneys, and the concentrations of NP in serum are reflected by an upsurge in the urine levels.[31] According to the current state of information, NP is discharged in body fluids and so is excreted unchanged via the kidneys. Intensification of serum or plasma NP does not differ. No NP receptor is known and it does not undergo extravagation, which makes it a good indicator of the amount of IFN-γ produced.[32] When viruses, fungi, parasites, and other intracellular microorganisms denounce the tissues, the body's immune system gets triggered. In addition, the immunological process can be provoked by endotoxins originated from Gram-negative bacteria that results in the awakening of T-lymphocytes and formation of IFN-γ, which leads to the upsurge of NP concentrations in the body fluids.[32] Some authors say that urine neopterin levels after the bacterial infections were significantly lower levels when compared with their levels after viral infections.[33],[34] Moreover, there was also no significant difference in NP levels between patients with Gram-negative versus Gram-positive infections.[35] The concentration of NP in human plasma is a conventional indicator of IFN-γ synthesis. NP arises as a metabolite of GTP cyclohydrolase II (GTPCII). Nucleoside triphosphate (NTP) is produced when GTPCII becomes markedly activated in human cells. NTP accumulates due to a relative insufficiency of the subsequent enzyme protein tyrosine phosphatases. The human monocytes/macrophages only have a small essential activity of the biopterin-forming enzyme pyruvoyl-tetrahydropterin synthase, unlike other cells and species. Intracellular NTP is then subjected to the action of a phosphatase that is liberated from cells into the circulation and it is nonenzymatically oxidized from dihydro neopterin to yield plasma neopterin. Before any clear function could be ascribed, plasma neopterin levels had been recognized as a sensitive indicator of immune cell activation for clinical diagnosis. In consequence of this, NP is a sensitive marker of cell-mediated immunity.[7],[12],[36],[37] Nearly all human cells produce tetrahydrobiopterin from GTP, the only exception being monocytes/macrophages, in which due to the shortage of 6-pyruvoyl-tetrahydropterin synthetase, NP is found to be a result of 7,8-dihydro neopterin triphosphate hydrolysis and oxidation.[30],[38] Thereupon, NP becomes a marker related to the activity of monocytes/macrophages which commute it into the body fluids.[39] The release of NP begins 3 days before T-cell proliferation reaches to the maximum, and a rise in NP production will be ascertained about 1 week before the pursuance of specific antibodies. Therefore, NP may be of clinical use as an early inflammation marker.[10],[40] NP levels in liquid body substances can be measured by immunoassays (ELISA or radioimmunoassay). The substances such as plasma, serum, and other analogous protein-containing body fluids such as CSF, pancreatic juice, or ascites can be used it for diagnosis without prejudice.[41],[42]

Throughout the women life, many changes will take place; in that, menopause is also not an exception, which causes discernible changes in the women body along with remarkable changes will also be seen in the oral cavity. As exaggerated levels of ovarian hormones, detected in pregnancy and oral contraceptive usage, can lead to an increase in gingival inflammation. On contrary, menopause shows depreciated levels of ovarian sex steroids, which also causes worsening of gingival health.[43]

The accomplishments of the sex hormones as far as involved with gingiva that they can consequence the cellular proliferation, differentiation, and augmentation of fibroblasts and keratinocytes. Alterations in the blood vessels are mainly actualized by estrogen and progesterone triggers inflammatory mediators. Apart from these, estrogens can influence the cytodifferentiation of stratified squamous epithelium, synthesis, and maintenance of fibrous collagen. Furthermore, estrogen receptors (ERs) in the cells, resembling the osteoblasts, bound to straight mechanism of action on bone while ERs in periosteal fibroblasts and periodontal ligament fibroblasts implement a contrivance for unambiguous alertness on distinctive periodontal tissues in menopausal women.[44],[45] Both conditions have some common risk factors and they begin to show their effects mainly after the age of 35. The extent of the relationship between these two still remains uncertain.[43] Estrogen has a number of effects on the modulation of the inflammatory response and immune cell function. These effects are largely mediated by ERs which are preeminently present on monocytes and macrophages.[46] Reinforcing this affirmation, many authors proved that alternative immune action of macrophages is reduced by estrogen treatment in menopause.[47],[48]

Pre- and post-menopause findings were compared in this article because many ways postmenopause was found to be more aggressive and destructive in nature compared to premenopause. Wardrop et al.[49] assessed that the prevalence of oral discomfort was found to be significantly higher [49] along with low flow rates of the saliva [50],[51] with the presence of periodontal disease more frequently.[52] Scardina and Messina examined oral microcirculation, and they observed that the diameter of loops, tortuosity of vessels in labial mucosa, and density of periodontal mucosa were significantly different.[53] The residual ridge resorption after dental extraction in postmenopausal women was also found to be more than that seen in premenopausal women.[54],[55] There is ample of studies showing that postmenopausal women have elevated serum levels of pro-inflammatory cytokines.[55],[56] Increased levels of pro-inflammatory cytokines and changes in serum levels of anti-inflammatory cytokines after menopause may be associated with monocytes and macrophages function, which is impaired due to estrogen deficiency.[57] The implication of these cytokines in the development and progression after menopause gradually leads to an important disease such as osteoporosis. Menopause can also affect bones throughout the body, reducing the relative anchorage that the jaw has on one's teeth.[44] In addition to the Stages of Reproductive Aging Workshop report, there is variability in the bleeding criteria for menopausal transition. Menopausal transition results in adverse effects on adipokine and inflammation levels. Associated adipokine changes leading to an adverse metabolic profile in postmenopausal women.[58] Although some studies about NP activity in plasma and urine were discussed,[10],[59],[60] possible association with menopause and periodontitis plasma and urine NP was not discussed earlier. To the best of our knowledge, this is the first study which correlated these three inflammatory conditions. In the present study, it was determined that the mean total amount of NP values of plasma as well as urine was higher in both the groups, compared to normal values but significantly higher in the postmenopause group. There was a reduction of mean values after periodontal treatment, but the more significant reduction was seen in the premenopause group. According to Novella et al.,[61] postmenopausal women may have augmented circulating markers such as tumor necrosis factor-α, which increases inflammation and increasing artery responsiveness to stimulate vasoconstriction. Studies demonstrated that NSPT reduces inflammation and improves periodontal status.[62] Therefore, it can be assumed that overall inflammatory markers also reduce after NSPT.[19],[20] Vrecko et al. found that NP concentration was only increased in saliva but not in urine.[30] In contrary to this, NP concentration was also increased in plasma as well as urine in both the groups and also decreased levels were seen in both the groups after NSPT, but significant reduction was seen in the premenopause group. This study result of reduced NP levels after NSPT is consistent with the study by Pradeep et al.[63] The neopterin levels were correlated with the intensity of the disease. The increase in neopterin with periodontal disease severity and decrease after treatment showed that neopterin is involved in the periodontal disease process, as confirmed by the previous study,[29] as well as the inflammatory conditions such as menopause. Higher NP levels in a periodontal patient might lead to the intensified macrophage infiltration to the periodontal lesion because neopterin is a macrophage activation marker.[64] Macrophage collagenase may have a significant role in collagen destruction in diseased periodontal tissue. Therefore, we should consider changes in neopterin levels as an omen of the host mechanism leading to tissue destruction.[29] Neopterin production was delineated by activated macrophages; this might be legitimate since macrophage infiltration and activation are known to be characteristics of chronic inflammation such as periodontitis.[65] Toniolo et al. stated that menopause is associated with macrophage activation profiles skewed toward pro-inflammatory phenotype.[48] The results of the present study could be interpreted that higher plasma and urine NP levels were seen in both the groups. However, these levels significantly higher in the postmenopausal women with periodontitis, reflecting that the enhanced macrophage infiltration in menopause as well as periodontal lesions, denoting that, neopterin is a macrophage activation marker. Determination of treatment should be beneficial in observing the direct relationship between neopterin and periodontal status. The decrease in the NP levels after the treatment seems to indicate the effectiveness of the treatment. Within the limitations of the study, the difference at baseline and at follow-up therapy indicated a significant reduction in the NP levels. With this study, it can be put forward that NSPT is an adjunctive therapy to control inflammation. However, these NP levels did not seem to be a precise marker of clinical status. To confirm our presupposition, longitudinal studies conducted on larger patient populations are mandatory. Nevertheless, more clinical investigations conducted on a larger scale are conspicuously necessitated for ancillary firmness of the NP levels in biological fluids in such conditions. Advancements in the research field at the cellular level are required for the early detection of these complexities, thus enabling us to intervene at a very early stage.

Limitations

  1. Postmenopause being natural or hysterectomy was not categorized
  2. Early menopause and normal menopause stage were not categorized
  3. Detection of follicle-stimulating hormone fluctuations in the blood sample is the benchmark to identify pre- or post-menopause, which was not done.



   Conclusions Top


The current state of cellular immune retort can be estimated of NP from the body fluids such as plasma and urine, which also pinpoints not only present response but also succor in the prediction of disease amelioration. The neopterin levels perseverance before and after periodontal therapy should be advantageous to acquire the proficiency of direct relationship between neopterin and periodontal status. In the future studies, differentiating recent menopause and prolonged menopause stages might give more accurate results because more hazardous effects might be observed in the prolonged menopausal stage. Accurate detection of intracellular action and function of macrophages may give exact results. To conclude, long-term and well-controlled clinical trials in a large population are to be carried out for proper authentication. Thus, specific biological markers significant for diagnosis and monitoring of periodontitis are to be determined at molecular levels.

Acknowledgement

We would like to thank Doshi Dolar.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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