Women’s health issues have come to the forefront of medical research only within the last decade. This came about only after significant pressure was exerted by physicians and activist groups that recognized that the majority of clinical trials involved men primarily and that sex differences were not being addressed.1 These inequities prompted the National Institutes of Health to begin funding research into sex differences as they relate to hypertension and cardiovascular disease, or CVD. This, in turn, triggered other investigations into a variety of women’s health issues, and an increasing body of sex-specific scientific literature has emerged regarding CVD, breast cancer, osteoporosis and obesity.
The literature suggests that more sex-specific research is essential to determine the strategies needed to prevent and treat diseases that have particular impact on women.
At the same time, scientific evidence has emerged in the field of periodontology linking periodontitis to a person’s overall health.2 Periodontitis is one of the most ubiquitous diseases and is, by definition, an inflammatory disease of specific bacterial origin that affects the supporting structures of the teeth.3,4 Researchers and clinicians believe that the destructive process begins with the accumulation of biofilms on the tooth surface that contain bacterial masses in the range of 1 to 2 x 1011 bacteria per gram at or below the gingival margin.5 The destruction continues with the release of toxic products from the pathogenic plaque bacteria and is compounded by the host response elicited against these bacteria and their products. The subsequent inflammatory response may result in ulceration of the gingivae, which might allow the entry of bacterial cells, their products (including lipopolysaccharides, or LPS; peptidoglycan fragments; and hydrolytic enzymes), or both into the systemic circulation.2
Research has demonstrated that the host response to periodontal infection results in the local production of cytokines and biological mediators such as prostaglandins and interleukins, as well as the systemic production of serum antibodies.6–8 Researchers have suggested that an association exists between periodontitis and CVD, adverse pregnancy outcomes, respiratory disease, diabetes mellitus, osteoporosis, human immunodeficiency virus and certain inherited chromosomal disorders.
The emergence of sex-specific relationships and the associations between periodontitis and certain systemic disorders have prompted researchers to investigate the possibility of associations between periodontitis and specific women’s health issues. We review some of the potential associations as they relate to women’s health through the examination of hormonal changes and the development of periodontitis. In addition, we examine the combined effect of these entities with respect to the systemic ramifications observed in adverse pregnancy outcomes, CVD and osteoporosis.
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HORMONE LEVELS
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Changes in hormone levels such as those that occur during puberty, pregnancy, menstruation and menopause, as well as those that occur with the use of hormone supplements (including oral contraceptives) have long been associated with the development of gingivitis and are well-documented in the literature.9–15 Estrogen, progesterone and chorionic gonadotropin (during pregnancy) all affect the microcirculatory system by producing the following changes: swelling of endothelial cells and periocytes of the venules, adherence of granulocytes and platelets to vessel walls, formation of microthrombi, disruption of the perivascular mast cells, increased vascular permeability and vascular proliferation.16–18 The patterns of gingivitis appear to follow the normal cycle of hormonal changes and may be seen with varying degrees of significance.
Of perhaps even greater importance than the above changes, however, is the shift in microbiota, which has been documented during these hormonal changes. Kornman and Loesche19 found that during pregnancy, the ratio of bacterial anaerobes to aerobes and the proportions of Bacteroides melaninogenicus, Prevotella intermedia and Porphyromonas gingivalis increased.
Jensen and colleagues20 studied the effect of hormone levels on the gingival status of 54 pregnant women, 23 nonpregnant women who received oral contraceptive therapy and 27 non-pregnant control subjects. They found that the pregnant women had a level of bacteroides species 55 times higher than that of the nonpregnant control group. In addition, women who received oral contraceptive therapy had a 16-fold higher level of bacteroides species compared with women in the control group. It appears, however, that the bacterial increases are cyclical in nature, because they follow the normal physiological changes and generally are of no consequence.
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ADVERSE PREGNANCY OUTCOMES
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What has come to the forefront of recent periodontal investigations, however, is the relationship between periodontitis and adverse pregnancy outcomes. In 1996, Offenbacher and colleagues21 suggested a correlation between periodontitis and the birth of preterm (< 37 weeks’ gestation) low-birth-weight, or PLBW, infants. They proposed that periodontal infections that serve as reservoirs for gram-negative anaerobic organisms, LPS and inflammatory mediators (including prostaglandin E2, or PGE2, and tumor necrosis factor alpha, or TNF-
) might pose a threat to the fetal-placental unit through hematogenous transmission.
In their case-control study involving 124 pregnant or postpartum women, the authors found that women who had PLBW infants had significantly worse periodontitis than did subjects whose infants were of normal birth weight. After controlling for other risk factors and covariants, Offenbacher and colleagues21 found that the subjects with clinical evidence of periodontitis were 7.5 times more likely to have PLBW infants than were the control subjects.
More recently, Offenbacher and colleagues22 examined 44 women in another case-control study. They found that mothers of PLBW infants had significantly elevated levels of biochemical and microbiological markers of current periodontal disease activity, as measured by gingival crevicular fluid levels of PGE2 and interleukin-1 beta, or IL-1ß, along with higher plaque levels of P. gingivalis, Bacteroides forsythus, Actinobacillus actinomycetemcomitans and Treponema denticola. All of the aforementioned pathogens are invasive and possess specific virulence factors that enable them to colonize and evade host defenses.
In a recent report, Jeffcoat and colleagues23 indicated that the risk of preterm birth was directly related to the severity of periodontitis in the mother. Patients with more severe periodontitis had an odds ratio of 4.45 for preterm delivery before 37 weeks’ gestation. The adjusted odds ratio increased to 5.28 for preterm delivery before 35 weeks’ gestation and to 7.07 for preterm delivery before 32 weeks’ gestation.
Although the exact mechanism has yet to be determined, exposure to systemic bacterial products such as LPS from periodontal pathogens has been well-documented. Researchers have proposed that biologically active molecules such as PGE2 and TNF-, which are elevated normally during parturition, can become elevated to abnormally high levels by the infection process and can be fed by a constant source of bacteria, bacterial components (such as LPS) and immune modulators from periodontitis.2 If, for example, the levels of PGE2 necessary to initiate labor are reached before the completion of the gestational period, preterm labor could ensue, with the result being a preterm birth. The rapidity with which these critical levels are reached would determine the degree of prematurity and the weight of the infant.
Clearly, additional work is needed to clarify and confirm the relationship between periodontitis and PLBW, particularly if intervention opportunities exist that have the potential to decrease the incidence of preterm births. Large prospective studies are under way that will provide us with some important additional information.
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CARDIOVASCULAR DISEASE
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Hormone replacement therapy and CVD risk.
At the other end of the reproductive cycle lies the menopausal stage, which harbors its own set of health care concerns, including systemic risks of CVD and osteoporosis, as well as local effects such as xerostomia, burning mouth, aphthous ulcers and lichen planus. Menopause literally means "without estrogen" and is, by definition, the time at which cyclic ovarian function, as manifested by menstruation, ceases.
Women deciding whether to receive hormone replacement therapy, or HRT, must weigh the treatment effects carefully. Because estrogen has a direct effect on smooth muscle, platelet aggregation, atherogenesis and lipid profiles, it appears to attenuate the effect of menopause on CVD risk. Grodstein and colleagues24 examined the relationship between postmenopausal hormone therapy and mortality among a selected group of women in the Nurses Health Study. After adjusting for confounding variables, they found that hormone users had a lower mortality rate from CVD than did subjects who had never received hormone therapy. However, the longer the duration of hormone use, the more the benefit of any CVD protection was overshadowed by an increased incidence of breast cancer in their study population.24
In a 1998 review of seven studies of estrogen therapy in women with established CVD, Grodstein and Stampfer25 reported that all studies found fewer recurrent cardiovascular events with an improved survival rate in women in the estrogen group compared with women who did not receive estrogen. More recently, however, Herrington and colleagues26 reported that in a short-term study of women with established CVD, neither the administration of estrogen alone nor the administration of estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis, even though both hormonal therapies resulted in significant reductions in low-density lipoproteins and significant increases in high-density lipoproteins. This conflicting evidence regarding the protective effect of hormone administration in established CVD suggests the need for further investigation.
Modification of risk factors.
Because CVD is the leading cause of death in women in the United States and in most developed countries, this disease is the greatest health care–related issue for most women.27,28 Epidemiologic research with randomized clinical trials has provided compelling evidence that CVD can be prevented largely through the modification of certain identified risk factors, including poor diet, obesity, sedentary lifestyle and smoking.
Hu and colleagues29 examined trends in heart disease in 85,941 women enrolled in the Nurses Health Study. A separate investigation from the Nurses Health Study involving 84,129 of the same women examined the combined effect of lifestyle-related risk factors on the development of CVD.30 The findings of these studies overwhelmingly supported the modification of risk factors and improvement in lifestyle as a means of preventing the onset of CVD in women.
Unfortunately, however, the classical risk factors—both modifiable and nonmodifiable—account for only one-half to two-thirds of the variation in the incidence of CVD cases. Therefore, it is likely that other risk factors—perhaps unrecognized to date—also contribute to CVD development. Indeed, researchers have suggested for many years that infection is a possible risk factor because of the nature of the development of atheromatous plaques.
Syrjanen and colleagues31 and Marcus and Haijar32 demonstrated that gram-negative microorganisms, their associated LPS, or both can induce inflammatory cell infiltration, vascular smooth-muscle proliferation, vascular fatty degeneration and intravascular coagulation. The microorganisms and their associated LPS also have been found to invade the connective tissue and vascular endothelium of the periodontium,33,34 have been found within vascular pathological plaques35,36 and can elicit a circulating antibody response.37,38
What is needed are all-female studies that can clarify the relationship between periodontitis and cardiovascular disease in the female population.
Important role of LPS.
Increasing evidence suggests that LPS in particular plays a critical role in triggering a number of events promoting atherogenesis, because it has the ability to activate intercellular adhesion molecules, trigger the release of TNF- and IL-1ß, initiate platelet aggregation and adhesion, and promote the formation of lipid-laden foam cells with the subsequent enhancement of atheroma formation.32 The cytokine cascade of TNF- and IL-1ß alone leads to increased levels of serum proinflammatory cytokines that alter tissue dynamics such that enhanced lipogenesis, increased lipolysis and reduced lipid clearance result. These collective metabolic changes result in an elevation of serum free fatty acid levels, low-density lipoprotein levels and triglyceride levels.8 The potential magnitude of LPS as an initial trigger has led investigators to search for an infection site that would provide a source of LPS and initiate the aforementioned events.
We know that the periodontium can serve as a reservoir for microorganisms and their associated LPS. Indeed, the evidence supporting an association between periodontitis and heart disease was published initially by Syrjanen and colleagues,31 Mattila and colleagues39 and Kweider and colleagues,40 who used case-controlled studies. Their research, although involving mostly male subjects, demonstrated a significant association between periodontal disease severity and coronary atherosclerosis, myocardial infarction and stroke.
In 1989, Mattila and colleagues39 found an association between poor dental health and CVD, even after adjusting for CVD risk variables including age; total cholesterol levels; high-density lipoprotein, or HDL, levels; triglyceride levels; C peptide levels; hypertension; diabetes mellitus; and smoking. More recently, Mattila and colleagues41 concluded that dental infections were the only factor outside the scope of classic coronary risk factors that exhibited an independent association with adult coronary atherosclerosis in a multivariate assessment.
The most compelling evidence, however, was reported by DeStefano and colleagues42 from the Centers for Disease Control and Prevention. They used data from the National Health and Nutrition Examination Study, or NHANES I. In a population of more than 20,000 people who were followed up for a median of 14 years, these authors demonstrated that subjects with periodontitis had a greater risk of developing CVD even when the traditional cardiovascular risk factors were controlled for. This landmark study identified periodontitis as a statistically significant risk factor for the development of CVD.42
These and subsequent studies have continued to expand the body of knowledge linking periodontitis to CVD through the chronic infection paradigm. However, most of the subjects selected for these studies have been male. What is needed now are all-female studies that can clarify the relationship between periodontitis and CVD in the female population, as well as identify sex differences. It may be, for example, that periodontitis is less of a risk factor in the development of CVD in women than in men, or it may be that periodontitis becomes a greater risk factor after the onset of menopause as a result of changes in hormone levels.
The research to date raises interesting questions. For example, how much of a difference exists between postmenopausal women who receive HRT and those who do not? Does HRT provide a protective effect against the development of CVD in all women or only in certain subsets of the female population? Does this, in turn, mean that periodontitis is not as great a risk factor for CVD development in women who receive HRT? These and other questions need to be examined prospectively and retrospectively in female-based research to effectively identify the sex-specific associations between periodontitis and CVD.
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OSTEOPOROSIS
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HRT and osteoporosis.
HRT also must be viewed with regard to its effect on osteoporosis in postmenopausal women. It has been well-established that a reduction of estrogen results in accelerated bone loss. This loss is particularly evident during the first decade after the onset of menopause,43 suggesting that early intervention would be best. Because women live longer than ever before, they will be menopausal for a longer time than previous generations of women, and need to seriously consider the long- and short-term benefits as well as the disadvantages of HRT.
Hormone replacement therapy also must be viewed with regard to its effect on osteoporosis in postmenopausal women.
Osteoporosis is the most common metabolic bone disease and the most common skeletal disorder in the world; as such, it constitutes a major public health problem.43 It is one of the major causes of morbidity, mortality and medical expense. It affects an estimated 75 million people in the United States, Europe and Japan combined, including one in three postmenopausal women and a majority of elderly people.44 Data indicate that one in two women and one in six men are likely to sustain an osteoporosis-related fracture by the time they reach age 90 years, and approximately 10 to 20 percent of these people will die of fracture-related complications.45,46
Age-related fractures.
An estimated 1.3 million osteoporotic-related fractures occur annually in the United States alone,43 the most common of which are hip, radius and vertebral compression fractures. The incidence of osteoporotic fractures is increasing and can be expected to escalate as life expectancy continues to lengthen. These figures are staggering when one considers that more than 325 million people in the world are aged 65 years or older, and this figure is expected to increase to more than 1.5 billion by 2050.47 Based on current trends, this means that the number of age-related fractures is expected to more than triple by 2050.
Risk factors for osteoporosis.
Osteoporosis is a generalized, progressive, systemic loss of bone mineral and bone matrix that results in bone of normal composition but decreased mass. From a functional standpoint, osteoporotic bone is characterized by an increased propensity to fracture.48 While the primary risk factors related to the development of osteoporosis include female sex and increasing age, other risk factors have been identified: early menopause (younger than 45 years), cigarette smoking, high alcohol consumption, lack of physical activity, thin body frame, race (Asian or white), low calcium intake, excessive caffeine intake, certain medications (such as glucocorticoids and cytotoxic drugs) and certain diseases.49 Because osteoporosis is a systemic skeletal disease, many have questioned its significance to the maxilla and mandible with regard to decreased bone mass and its possible effect on the progression of periodontitis.
Periodontitis and osteoporosis.
A number of studies50,51 have investigated a possible relationship between periodontitis and osteoporosis, and although the literature supports a relationship, the extent remains unclear, because of small sample sizes, noncomparable study populations, varying study methods used to assess periodontitis and osteoporosis, and inadequate control of confounding factors. In spite of these limitations, a relationship does exist and the more recent investigations have been designed to provide more specific information.
von Wowern and colleagues52 examined 26 dentulous white women (consisting of a 12-member osteoporotic group and a 14-member control group) for plaque, gingival bleeding and loss of attachment on the six Ramfjord Index teeth. They determined bone mineral content using dual-photon absorptiometry for the mandible and forearm. The results revealed significantly less bone mineral content in the mandible and forearm bones in the osteoporotic subjects than in the control subjects. In addition, they noted significantly greater loss of periodontal attachment in subjects in the osteoporotic group.
Preliminary data from the oral ancillary study of the Women’s Health Initiative, which was designed to determine a possible association between systemic osteoporosis and oral bone loss, suggested a significant correlation between the mandibular basal bone mineral density (as measured by standardized, digitized and referenced intraoral radiographs) and hip bone mineral density (as measured by dual-energy X-ray absorption).50
Tezal and colleagues51 examined 70 post-menopausal white women aged 51 to 78 years. They assessed skeletal bone mineral density using dual-energy X-ray absorptiometry at the lumbar spine and femur. Periodontal status was evaluated clinically by measuring pocket depths; clinical attachment loss, or CAL; bleeding on probing; plaque; and calculus. The authors evaluated periodontal status radiographically via inter-proximal alveolar bone loss.
After adjusting for age, age at onset of menopause, estrogen supplementation, cigarette smoking, supragingival plaque and body mass index, the authors demonstrated that loss of skeletal bone mineral density was related substantially to interproximal alveolar bone loss. To a lesser extent, skeletal bone mass also was related to CAL. These data implicate post-menopausal osteoporosis as a risk indicator for periodontal disease in postmenopausal white women.
CAL.
Ronderos and colleagues53 reported that data gleaned from the NHANES III study suggested that osteoporosis is a risk factor for periodontitis, as indicated by association analysis and the protective effect of estrogen. The primary measure of periodontitis in NHANES III was CAL, but other clinical periodontal parameters were used, including probing depths, bleeding on probing and calculus deposits. Bone mineral density data were used to classify subjects according to criteria published by the World Health Organization. After adjusting for complicating factors, Ronderos and colleagues53 observed more CAL in patients with osteoporosis than in patients with osteopenia, as well as more CAL in post-menopausal women who did not receive estrogen therapy than in those who did.
The relationship between skeletal loss of mineral density and increased periodontal bone loss may be due to several factors. It may be that more periodontal bone loss occurs simply because the bone surrounding the teeth is less dense and therefore less resistant to resorption. Genetic predisposition to systemic and periodontal bone loss also may be a factor, as well as environmental or lifestyle factors that predispose some people to both diseases. What is needed now are large, well-designed studies that will examine the role of osteoporosis as it relates to the prevalence, incidence, severity and progression of periodontitis. Intervention studies also may be considered to determine if enhancement of bone mineral density can deter the advancement of periodontal disease.
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CONCLUSION
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Sex-specific medicine is medicine tailored to meet the specific needs of men and women, based on the results of scientific research. Clearly, more research is needed, particularly as it relates to women. Studies are under way and more are being designed to answer specific questions and determine specific strategies to prevent and treat diseases that have particular impact on women.
We have examined the relationships between hormonal changes and periodontitis and the impact of these entities on pregnancy outcomes, CVD and osteoporosis. As additional studies are conducted, more information will be forthcoming, and it behooves us as clinical practitioners to be aware of these relationships and the possible contributions of oral bacteria to systemic disease. The emergence of periodontal medicine demands that dentists assume a larger responsibility for the overall health of their patients, and acquire a knowledge of relevant systemic conditions to interact more meaningfully with medical colleagues to achieve the ultimate goal of providing better patient care.
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ABSTRACT
HORMONE LEVELS
