Periodontium And Sex Hormones – A Review

INTRODUCTION

Periodontitis is a complex disease in which disease expression involves intricate interactions of the Biofilm with the host immune-inflammatory response and subsequent alterations in bone and connective tissue homeostasis.^1,2 However, it has also been shown that without a susceptible host the periodontal pathogens are necessary but not sufficient for disease to occur. Hence, the systemic factors/conditions of the host must be understood since they may affect disease prevalence, progression, and severity.³ Among these, sexual hormones have been suggested as important modifying factors that may influence the pathogenesis of periodontal diseases.⁴ Hormones are specific regulatory molecules that modulate reproduction, growth and development and the maintenance of internal environments as well as energy production, utilization and storage.⁵ Reports of the effects of sex steroid hormones in the Periodontium have been noted for over a century. Currently accepted periodontal disease classification recognizes the influence of endogenously produced sex hormones on the periodontium. Under the broad category of dental plaque induced gingival diseases that are modified by systemic factors, those associated with the endocrine system are classified as puberty, menstrual cycle and pregnancy associated gingivitis.⁶ The goal of this review article is to provide the reader with current information about the relationship between sex steroid hormones and cells of the periodontium.

Because of their complexity and diversity, hormones are difficult to arrange into discrete groups, although they can be divided into four subgroups based upon their chemical structure – steroids, glycoproteins, polypeptides, and amines. Steroid sex hormones are derived from cholesterol and as a common structure they have three rings of six carbon atoms. They are believed to play an important role in the maintenance of the skeletal integrity, including the alveolar bone. The steroid sex hormones such as estrogen and estradiol have been known for their effect on bone mineral metabolism. Other bone turnover-related hormones include progesterone, testosterone and dihydrotestosterone, and rostenedione, dihydroepiandrostenedione, and sex hormone-binding globulin. Among these, estrogens, progesterone, and testosterone have been most linked with periodontal pathogenesis.⁷

Androgens (Testosterone)

All natural androgens are derived from a 19-carbon tetracyclic hydrocarbon nucleus known as androstane. One of the most potent androgenic hormones, testosterone is synthesized by the Leydig's cells of the testes, the thecal cells of the ovary and the adrenal cortex. In men, testosterone is the principal plasma androgen and is reduced to dihydrotestosterone the mediator of most actions of the hormone. There are two types of androgens: gonadal androgen, dihydrotesterone (DHT), and adrenal androgen, dehydroepiandrosterone.

Androgens may play a significant role in the maintenance of bone mass and inhibit osteoclastic function, inhibit prostaglandin synthesis and reduce interleukin-6 (IL-6) production during inflammation⁸, testosterone stimulates bone cell proliferation and differentiation and therefore has a positive effect on bone metabolism.⁹ Specific receptors for these hormones have been isolated in the periodontal tissues.¹⁰ Testosterone has also been associated with bone metabolism, playing a role in the maintenance of bone mass.¹¹ A very effective way to analyze the effect of androgens on bone metabolism is the evaluation of the presence of biochemical markers of bone remodeling on bone tissue under the influence of those hormones. One of the bone remodeling markers that has been used for this objective is osteoprotegerin (OPG), which is a secreted decoy receptor that inhibits osteoclast formation and activation by neutralizing its cognate ligand¹² During periodontal disease progression, OPG action is associated with a reduction in the loss of bone mineral density¹³ and serum concentrations of OPG increase significantly with age, and are positively correlated with free testosterone index and free estradiol index¹⁴. Effects of Androgens on periodontium are given in Table 1.^9,14-17

Estrogen and Progesterone

Estrogen and progesterone are responsible for physiological changes in women at specific phases of their life, starting in puberty. Estrogen induces several of the pubertal developmental changes in females, and progesterone acts synergistically with estrogen to control the menstrual cycle and to inhibit follitroppin secretion by the anterior pituitary gland18 Estrogen and progesterone have significant biological actions that can effect other organ systems including the oral cavity¹⁹ Estrogen receptors found in osteoblast-like cells provide a mechanism for the direct action on bone, These receptors were also located in periosteal fibroblasts, scattered fibroblasts of the lamina propria²⁰ and periodontal ligament (PDL) fibroblasts. Progesterone is another sex hormone that has also been demonstrated to have direct effects on the Periodontium. It is active in bone metabolism and may play an important role in the coupling of bone resorption and bone formation²¹. It may exert its action directly on bone by engaging osteoblast receptors or indirectly by competing for a glucocorticoid receptor²². Effects of Estrogen and Progesterone on periodontium is given in Table 2^23-28 & Table 3^7&29-34.

Factors influencing the effect of sex hormones on periodontium

Gender

Studies have reported that 80% of the osteoporotic patients are female, correlating with the higher frequency of hip fractures in females, who are also more likely to experience hormonal imbalance throughout their lives than males³⁵. it was found that the residual ridge in women is lower than that in men³⁶ this might be associated with the decreased amount of circulating estrogen found in women during menopause, since this condition is associated with a higher frequency of alveolar bone height loss, as well as decreased crestal and subcrestal bone density.³⁷

Age

The biological changes on the periodontal tissues during different time points such as puberty, the menstrual cycle, pregnancy, menopause, and oral contraceptive use have heightened interest in the relationship between steroid sex hormones and the health of the periodontium.

Puberty

Along with the dramatic rise in female sex steroid levels during the circumpubertal period, several cross-sectional and longitudinal studies have demonstrated an increase in gingival inflammation without an accompanying increase in plaque levels³⁸ Several studies have noted a concomitant increase in subgingival black-pigmented anaerobic bacteria that parallels the onset of puberty and the increase in gingival inflammation observed during this time³⁹ It has been suggested that these gram-negative bacteria are able to substitute estradiol and progesterone for menadione, an essential vitamin K growth factor for this bacterium⁴⁰ A study evaluating increased serum estradiol and progesterone levels during puberty noted a positive correlation with significant increases in proportion, number, and serum IgG antibody levels to Prevotella intermedia⁴¹ Changes in Periodontium in puberty is summarised in Table 4.^5,41

Menstrual Cycle

The onset of increased production, and secretion of estrogen and progesterone in a cyclic pattern accompanies the onset of puberty and is referred to as the reproductive or menstrual cycle. Significant and observable gingival inflammatory changes have been documented in association with the menstrual cycle⁴² Progesterone has been associated with increased permeability of the microvasculature, altering the rate and the pattern of collagen production in the gingiva⁴³ increases folate metabolism 34 stimulates the production of prostaglandins and enhances the chemotaxis of polymorphonuclear leukocytes (PMNL)⁴⁴ during the menstrual cycles, women without clinical gingivitis showed no increase in gingival fluid, whereas those with gingivitis showed increases in gingival fluid. In addition to gingival inflammation, intraoral recurrent aphthous lesions⁴⁵ Changes in Periodontium during menstrual cycle is summarised in Table 5.^33,42

Pregnancy

The hormonal changes that occur during pregnancy include an elevation of both progesterone and estrogen. By the end of the third trimester, progesterone and estrogen reach peak plasma levels of 100 ng/ml and 6 ng/ml respectively, which represents 10 and 30 times the levels observed during the menstrual cycle⁴⁶ Susceptibility to infections increases during early gestation due to alterations in the immune system and can be explained by the hormonal changes observed during pregnancy, suppression on T-cell activity⁴⁷ decreased neurophil chemotaxis and phagocytosis, altered lymphocyte response and depressed antibody production⁴⁸ chronic maternal stress, and even nutritional deficiency associated with increased nutritional demand by both the mother and the fetus. These immunologic changes might also be responsible for periodontal pathologic conditions observed during pregnancy such as pregnancy gingivitis⁴⁹, pregnancy granuloma, periodontitis, and dental caries. The increased synthesis of PGE2 observed when estradiol and progesterone are present in higher concentrations, such as occurs during pregnancy, may also contribute to these pathologic changes. periodontal pathogens such as Prevotella Intermedia (Pi) and Porphyromonas gingivalis (Pg) can also use female sex hormones such as progesterone or estradiol as a source of nutrients. These bacteria are generally increased in the gingival crevicular fluid of pregnant women, a situation that is positively correlated with the severity of pregnancy gingivitis.⁷

Apart from a transient increase in bleeding, gingivitis and a subgingival microbial shift, pregnant women in good health are unlikely to experience any significant gingival response that would have serious clinical implications. Although pregnant women with Periodontitis may not experience exacerbation of their periodontal condition, it would be prudent to seek treatment to avoid periodontal abscess formation that may cause bacteremia. In general, pregnant women should note that preventive measures consisting of dental prophylaxis and meticulous plaque control help to prevent development of any periodontal condition. Clinical and microbial changes is summarised in Table 6.^50-55

Contraceptives

Hormonal contraceptives are based on the use of gestational hormones inducing a hormonal condition that simulates a state of pregnancy to prevent ovulation. However, the use of oral contraceptives carries a number of significant implications for the health of women. A number of studies have shown various effects of contraceptive influence on gingival tissue. It was found that there was an increase in clinically assessed inflammation for women using oral contraceptives⁵⁶, and an increased amount of gingival exudate following 12 months of regular use of oral contraceptives⁵⁷. As well as these signs, there are no significant differences in plaque index and gingival index scores and attachment level between the oral contraceptive group and the controls⁵⁸. However, a 16-fold-increase in Bacteroides species has been noted in the oral contraceptive user group versus a non-pregnant group despite the lack of statistically significant clinical differences in gingival index or crevicular fluid⁵⁹ Effect on peridontium by the use of contraceptives is summarised in Table 7.^43,60,61

Menopause and Post menopause

Menopause usually begins between 45 and 55 years of age unless accelerated by hysterectomy and/or ovariectomyIn the premenopausal women, the principal circulating estrogen is 17b-estradiol. As women approach menopause, the levels of estrogen begin to drop mainly during the late follicular and luteal phase of the menstrual cycle⁶². Progesterone is another sex hormone that may play an important role in bone metabolism during pre- and post menopause. It is believed that ovarian deficiency and associated alterations, but not aging, are the predominant causes of bone loss during the first two decades after menopause⁶³. Researches have shown that progesterone may compete with glucocorticoids for an osteoblast receptor and inhibit the glucocorticoid-induced osteoporosis. Therefore, postmenopausal bone density reduction may be the result of a combination of the inhibition of osteoclast downregulation by reduced estrogen and the increased cortisol inhibition of osteoblasts via the reduction of competition with progesterone⁷. Osteoporosis is also responsible for less crestal alveolar bone per unit volume, a condition that may promote quicker bone loss when encountered with infections such as periodontal infections⁶⁴. Eighty-five osteoporotic women demonstrated a significant correlation between skeletal bone mass and the number of teeth remaining in the Mandible. The results demonstrated that the height of the edentulous ridge correlated with total body calcium and mandibular mass⁶⁵ All of these studies speculated osteopenia is a risk factor for periodontal disease in postmenopausal women. Changes in periodontium during menopause and post menopause is summarised in Table 8.^66-68

Hormone replacement Therapy

Peri or postmenopausal women take hormone replacement therapy (HRT) for relieving climacteric symptoms and increasing the quality of lif e . Symptoms of the c lima c t e ri c and postmenopausal period have been shown to disappear with administration of exogenous estrogens, either alone or in combination with progestogens,although hormonal replacement in an adequate dosage can slow or prevent bone loss. Only a small percentage of postmenopausal women receive such therapy, and many who do fail to comply with the prescribed regimen because of the fear of cancer, irregular bleeding, and other minor side effects⁶⁹. Progesterone alone is not effective in preventing postmenopausal bone and tooth loss, but when combined with estrogen it is believed to uncouple formation and resorption to diminish bone resorption induced by estrogen⁷. The available data indicate that hormone replacement therapy should be suggested for women during menopause since several pathologic conditions common during this period of time can be avoided or at least reduced in severity.Effect of HRTon peridontium is summarised in Table 9.^70-72

Influence of Sex Hormones on Periodontal /Implant Wound Healing

At a molecular level, research has also shown that sex hormones have a regulatory effect on growth factors involved in the wound healing such as the keratinocyte growth factor⁷³ which has been known to have wound healing regulatory effect including stimulation of proliferation, migration, and morphogenesis of pluripotential cells. However, the influence of sex hormones on periodontal wound healing is still largely unknown.

CONCLUSION

It is evident from this review that multifactorial mechanisms involving the endocrine system are involved to a significant degree in the homeostasis of the periodontium during each of the life stages of the human female. The notable periodontal changes related specifically to female sex steroid levels, primarily those manifested as pathologic alterations in the gingiva, attest to the dramatic potential these hormones possess to impact the oral tissues beyond normal homeostatic functions. Nevertheless, it is also apparent that female sex steroid hormones are neither necessary, nor sufficient to produce pathologic gingival alterations by themselves, and attests to the need for further elucidation of the biomolecular mechanisms at work to fully understand how these hormones may exert their significant effects.