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2002 Selected Articles

Periodontal Disease and the Female Patient

Kenneth Bueltmann, DDS; Naomi Stillman, DDS, MPH

A growing body of evidence suggests that periodontal disease (PD) is associated with a number of oral and systemic conditions of particular relevance to women, including sex-hormone-induced changes in periodontal health, adverse pregnancy outcomes, and osteoporosis. In addition, PD has been linked with diabetes mellitus (DM) and cardiovascular disease (CVD). Although PD may be accompanied by obvious signs and symptoms such as halitosis, painful periodontal abscesses, or the mobility and loss of teeth, it is often an asymptomatic, "silent" infection that goes undetected by both patient and physician. Because the systemic health outcomes associated with PD can be serious and costly, it is essential to understand the possible relationships between periodontal and systemic health, and to recognize the importance of appropriate periodontal diagnosis, referral, and treatment.¹

OVERVIEW

Periodontal disease is a chronic, infectious condition estimated to affect 35% of the adult US population.² Research shows that nearly one in three US adults aged 30 to 54 years, and 50% of adults aged 55 to 90 years have some form of periodontitis. In males, the number increased from 34% to 56% in these age categories and from 23% to 44% in females, suggesting that periodontitis is more prevalent in males than females.² It is characterized by inflammation of the supporting structures of the teeth with destruction of the periodontal ligament and alveolar bone, and is the most common cause of tooth loss in adults. For most of the twentieth century, scientists believed that PD had a nonspecific bacterial etiology that was best treated by mechanical and surgical elimination of accumulations of bacterial plaque and calculus from the crown and root surfaces of teeth. Today, PD is known to be a multifactorial disease; specific pathogenic bacteria, host defense mechanisms, and genetic and acquired risk factors all play a part in PD pathogenesis. Mechanical treatment is still the mainstay of periodontal therapy, but a more comprehensive medical approach is required to address the many contributing etiologic factors of PD.

Periodontal bacteria form a biofilm that is resistant to host defenses and to antibiotics.³ This periodontal biofilm (plaque) can release gram-negative bacteria and bacterial lipopolysaccharides (LPS) into the circulation, and/or induce production of inflammatory mediators. Among the mediators implicated in PD pathogenesis are prostaglandin E2 (PGE2), interleukin-1a (IL-1a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a). In addition, recent studies have shown that C-reactive protein (CRP), an inflammatory marker and risk predictor for CVD, is elevated in the presence of specific periodontal bacteria.⁴ Chronic inflammatory insult stemming from plaque build-up could help explain why patients with PD may be more susceptible to certain systemic conditions.

Host risk factors also influence individual susceptibility to PD. Risk factors include cigarette smoking, DM, and acquired or inborn abnormalities in neutrophil function. Genetic IL-1 polymorphisms have been strongly associated with adult periodontitis.⁵

The existence of an association between PD and sex-hormone-associated tissue changes, adverse pregnancy outcomes, osteoporosis, DM, and CVD supports a growing recognition of the complex pathogenesis of many prevalent disorders.⁶ Common underlying pathogenic processes may account for the connections between these seemingly disparate diseases.

HORMONAL INFLUENCES

Changes in a woman's hormonal milieu are reflected in her periodontal tissues throughout her life. The gingiva has specific high-affinity estrogen receptors, so elevated estrogen levels are associated with gingival edema and increased gingival crevicular fluid flow. Sex hormones may also affect host defense mechanisms against bacterial plaque; elevated androgen levels have been shown to cause a decrease in IL-6 production, thus compromising resistance to bacterial insult.7 Finally, hormonal fluctuations can alter the gingival bacterial microenvironment.⁸

Changes in estrogen and progesterone levels associated with puberty, menses, and the use of oral contraceptives (OCs) can provoke a disproportionate gingival inflammatory response. Complaints of bleeding, swollen, and/or sensitive gums may thus accompany the premenstrual period, the onset of menses, or OC use.^7,9 Pregnancy, too, can induce an exaggerated gingival response to local irritants such as bacterial plaque and calculus. Gingivitis is the most common oral manifestation of pregnancy, occurring in 60% to 75% of pregnant women, with gingival changes being most obvious between the second and eighth months of gestation. The inflamed gingiva may be fiery red in color and may bleed easily on brushing. Up to 10% of pregnant women develop growths known as "pregnancy tumors" on the gingiva, usually in the second trimester. Although these lesions tend to resolve partially postpartum, surgical excision may be required for complete resolution. An increase in generalized tooth mobility during pregnancy has also been reported.¹⁰ From a clinical perspective, patients should be urged to pay special attention to their periodontal health at times of hormonal fluctuation.

Possible drug interactions between OCs and antibiotics are also of concern to the female patient and her physician. While it is well known that the use of oral antibiotics may cause OC failure, pharmacokinetic studies have not shown a systematic correlation between the use of commonly prescribed periodontal antibiotics (eg, tetracycline, penicillin derivatives) and OC failure. However, some women have been shown to experience decreases in plasma concentrations of OC components when taking such oral antibiotics. Because it is impossible to predict which women will have this response, it is best to advise patients to use back-up methods of contraception when they are taking periodontal antibiotics.¹¹

ADVERSE PREGNANCY OUTCOMES

Preterm birth and low birthweight (LBW) are responsible for 70% of all perinatal deaths and 50% of all long-term neurologic morbidity in the United States.¹² Despite the introduction of tocolytic drugs to arrest preterm labor, the incidence of LBW and preterm delivery in this country has not decreased in the past 20 years. For this reason, efforts to elucidate the role of remote infection in LBW, preeclampsia, cerebral palsy, and other serious neonatal sequelae are increasingly important. Periodontal disease may be among the remote infections that increase the risk for LBW and other adverse pregnancy outcomes.¹² Possible mechanisms include the ability of bacterial endotoxin to stimulate prostaglandin production in amniotic tissue, and the production of cytokines that can mediate preterm labor.

FIGURE 1. Cross Section of Tooth Showing Normal Gums/Periodontal Disease
Source: American Academy of Periodontology

A PD-LBW association is supported by clinical studies. A 1996 case-controlled study of 124 pregnant or postpartum women found PD to be a significant risk factor for preterm LBW, with an odds ratio (OR) of 7.5 to 7.9.¹³ Preliminary findings from a prospective study of 1,313 women showed overall adjusted ORs of 2.83 and 4.18 for patients with mild to moderate and severe PD, respectively.¹⁴ Interim findings from the 5-year Oral Conditions and Pregnancy (OCAP) study also indicate that PD is associated with LBW, even after adjustment for age, race, smoking, vaginosis treatment history, previous preterm delivery, and marital status.¹⁵

A causal link between PD and adverse pregnancy outcomes has not yet been proved. The role of PD-related infection in causing LBW can easily be obscured by other risk factors such as smoking, alcohol use, and multiple gestation, and only randomized, controlled intervention trials are needed to prove that treatment of PD could decrease the incidence of preterm birth.¹⁴ The efficacy, risks, and benefits of interventions such as local periodontal therapy, systemic antibiotics, and cytokine blockers remain to be explored.12 Nonetheless, it is prudent for the physician to be alert to the pregnant patient's periodontal status and risk profile. Oral examinations should include inspection for signs of periodontitis (eg, swollen, friable gums). Patients should be asked if they have ever had PD or "gum pockets," and whether they have periodontal symptoms such as bleeding gums or abscesses. All patients with periodontal signs or symptoms who are not already under the care of a periodontist should be referred to one. Pregnant patients and patients contemplating pregnancy should be advised that maintaining good periodontal health may help to promote a good pregnancy outcome.

OSTEOPOROSIS

Increasing evidence suggests an association between osteoporosis and PD.¹⁶ Although osteoporosis is a metabolic bone disease and PD is an infectious-inflammatory process, several shared features could explain a possible link. Both are multifactorial diseases generally associated with advancing age, and both appear to have a hereditary or familial component.¹⁷ Osteopenia is a defining feature of both diseases. Smoking, DM, and chronic corticosteroid treatment are among the risk factors that are often involved in both osteoporosis and PD pathogenesis.^17,18

The bone resorptive process is the nexus of the connection between osteoporosis and periodontal disease. It has been suggested that inflammatory mediators implicated in both periodontal disease and osteoporosis may account for an osteoporosis-PD association.¹⁷ In particular, IL-6, which is strongly implicated in periodontitis pathogenesis, has been shown to stimulate osteoclastic bone resorption in osteoporosis.¹⁹

The possible effectiveness of osteoporosis treatments in the management of periodontitis has been examined in many studies.²⁰ Research suggests that hormone replacement therapy (HRT) decreases tooth loss in postmenopausal women,²¹ and that dietary calcium levels are inversely correlated with the prevalence of periodontitis.10 Bisphosphonates may also hold promise for the management of chronic periodontitis.²² The effects of HRT on periodontal health parameters have been especially well studied. It has been shown that estrogen repletion is correlated with decreased gingival bleeding, less tooth loss, and improved bone density.¹⁹

Existing studies of the osteoporosis-PD connection are suggestive, but not conclusive. Well-designed, large-scale clinical trials are needed to understand the osteoporosis link and to derive clinical implications for prevention and treatment. Participants in the recent periodontal-systemic connection symposium sponsored by the National Institute of Dental Research (NIDR) and the American Academy of Periodontology (AAP) emphasized the importance of including an oral health component in the many osteoporosis studies designed by the National Institutes of Health (NIH) and industry groups.^10,18,20

OTHER SYSTEMIC CONNECTIONS

Although DM and CVD are not of exclusive concern to the female patient, both diseases are important causes of morbidity and mortality among women. For this reason, a summary of the association between each of these diseases and periodontal disease follows.

Diabetes Mellitus

Multiple studies support a link between PD and DM.²³ Classic studies of the Pima Indians, a population with the world's highest reported prevalence of type 2 DM, have demonstrated that the age of onset, severity, and prevalence of PD are all adversely affected by type 2 DM.^24,25 Diabetic individuals are up to 4.2 times as likely to develop PD as their nondiabetic counterparts. The evidence that diabetics have greater severity and prevalence of PD has been sufficiently convincing to earn PD the characterization of "the sixth complication" of DM.²⁶

The association between PD and DM is a bidirectional one. While the presence of DM increases the risk of PD, the presence of severe periodontitis is associated with poor glycemic control.²³ Mechanical periodontal treatment with adjunctive antibiotics has been shown to improve glycemic control in diabetic patients, suggesting that treating a patient's periodontitis could decrease insulin requirements.²⁷
The body's inflammatory and immune responses could account for the association between PD and DM.28 Diabetes has long been known to increase susceptibility to infection. Conversely, infections in general, and PD in particular, induce increased production of such inflammatory cytokines as IL-1b and TNF-a, ultimately causing increased insulin resistance and poor glycemic control in diabetics.²⁷
Another mechanism linking PD and DM is the formation of advanced glycation end-products (AGE) in the gingiva of diabetics in the presence of hyperglycemia. By adversely affecting collagen metabolism, vascular integrity, and the immune response, AGEs foster a chronic inflammatory state in the periodontal tissues.²⁸ Evidence also suggests that DM-associated hyperlipidemia can diminish tissue repair capacity and induce cytokine production, indicating the need to consider serum lipid levels when evaluating PD in the diabetic patient.²⁹

Cardiovascular Disease

The inflammatory process is the most likely link between PD and CVD. Inflammatory mediators and markers such as IL-1, IL-6, TNF-a, and CRP have been associated with both CVD and PD,⁴ and infectious and inflammatory processes have been shown to be important in the pathogenesis of both CVD³⁰ and PD.³¹ The cell-mediated immune (CMI) response to periodontal pathogens may play a part in atheroma formation,⁴ and IL-1 polymorphisms common to CVD and PD could contribute to a PD-CVD association.³²

Despite the theoretical plausibility of these mechanical pathways, clinical evidence has not been definitive.³³ A number of studies have suggested the existence of an association between CVD and PD. A 15-year prospective study of 1,000 healthy men found that PD conferred an increased risk for the development of CVD, stroke, and CVD mortality (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.04; 2.14).³⁴ A recent study of 10,590 men and women found a significant association between PD and elevated cholesterol and low-density lipoprotein (LDL) cholesterol levels.³⁵ In contrast, three recent longitudinal studies have found no convincing evidence of a PD-CVD connection.33 These conflicting results demonstrate the difficulty of proving an association between complex, multifactorial diseases such as CVD and PD and the need for future studies to be carefully designed and sufficiently large to prove or disprove what might be a weak association between PD and CVD.^31,33

CONCLUSION

Periodontal disease is a complex, multifactorial infection. Fluctuations in sex hormone levels appear to induce periodontal tissue changes at puberty, in the premenstrual period, during menses and pregnancy, and at menopause. In addition, studies support, but do not prove, the existence of associations between PD and a number of systemic conditions of concern to women. Interventional studies to verify and elucidate some of these associations are currently underway. If it is established that PD is a risk factor for adverse pregnancy outcomes, osteoporosis, DM, and/or CVD, appropriate periodontal intervention could decrease the incidence and severity of these serious threats to women's health.

Kenneth Bueltmann, DDS, is president of the American Academy of Periodontology and practicing peridontist in Glenview Ill. Naomi Stillman, DDS, MPH, is a medical writer in Brookline, Mass.

References

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6. Kiberstis P, Roberts L. It's not just the genes. Science. 2002; 296(26):685.
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10. Nishida M, Grossi SG, Dunford RG, et al. Calcium and the risk for periodontal disease. J Periodontol. 2000;71: 1057-1066.
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19. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Ann Rev Med. 2000;51:245-270.
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30. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340(2):115-126.
31. Lowe G. The relationship between infection, inflammation, and cardiovascular disease: an overview. Ann Periodontol. 2001;6:1:1-8.
32. Kornman KS, Duff GW. Candidate genes as potential links between periodontal and cardiovascular diseases. Ann Periodontol. 2001;6:1:48-57.
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