Effect of Hypoestrogenism on Oral Cavity

Abstract

Postmenopause is the period or period that occurs after women enter menopause. Menopause is the cessation of menstruation for 12 consecutive months. Menopause occurs due to the cessation of ovulation and hypoestrogenism or a decrease in the hormone estrogen, in this case, estradiol, a potent hormone owned by women. Hypoestrogenism causes various changes, including changes in the oral cavity. Some changes in the oral cavity are reduced salivary flow so that the mouth becomes dry. Dry mouth or xerostomia can increase the prevalence of caries in the oral cavity. In addition to decreased salivary flow, there is also a thinning of the gingival epithelium, which facilitates bacterial invasion and reduces alveolar bone mineral density associated with bone resorption, thereby increasing the risk of tooth mobility and even tooth loss. Prevention and treatment of periodontal destruction need to be done at this time, considering this is one of the factors that can improve the quality of life.

1. Introduction

Postmenopause is the period after menopause in which the ovaries are no longer functioning. The level of the hormone estradiol is usually between 20 and 30 pg/ml [1, 2]. In postmenopausal, low estrogen hormone or hypoestrogenism causes androgens to maintain estrogen by changing androgens in peripheral fat (adipose) tissue so that the more subcutaneous fat a woman has, the higher the estrogen level [3]. After menopause, physiologically, women will enter the postmenopausal period; this period is marked by an increase in follicle-stimulating hormone (FSH) in the blood due to the ovaries being no longer active in producing hormones and the end of menstruation. This period begins with the end of menopause [4, 5].

The end of the menopausal transition is marked by amenorrhea (cessation of menstruation) at 60 days or more. The menstrual cycle at the end of the menopausal transition is characterized by increased cyclical variability, extreme hormone fluctuations, and an increased prevalence of anovulation. At this stage, FSH will increase, and sometimes the amount is the same as in the early reproductive years, which is associated with high estradiol levels. According to international standards and research data, the total FSH level is >25 IU/L at the end of the transition period or according to the standard pituitary gland; the average number is more than 40 IU/L [6, 7]. After menstruation stops for 12 months or enters menopause, women will undergo a postmenopausal period characterized by increased FSH in the blood and decreased estrogen hormone [5].

Factors that can affect menopause are as follows: (a) maternal age at menopause; (b) age at menarche; and (c) gestational age, and in this case, the women have first pregnancy at a later age has been related to the onset of menopause; (d) irregular menstrual cycles in women at forties as a marker of perimenopause or irregular cycles between the age 20 and 30 years had later age at menopause because prolongation of erratic menstrual functioning or delayed depletion of viable oocytes; (e) use of oral contraceptives; (f) number of pregnancies; (g) body mass index (BMI); (h) smoking and drinking alcohol; (i) physical activity; (j) serum lead levels; (k) polyunsaturated fat consumption; (l) socioeconomic status; (m) levels of education; (n) genetics; and (o) area of residence [8, 9, 10].

2. The process of postmenopause

Biological changes in women are broadly divided into two things: before entering the menstrual period and after the cessation of menstruation, which is directly influenced by hormonal changes. Hormones are specific molecules that regulate and potentially affect the development and integrity of tissues in the body. A woman’s life is a complex biological journey from entering puberty to entering menopause. After menopause, women will experience a postmenopausal period [11, 12].

During puberty, sex hormone production will increase significantly during the reproductive period. After entering puberty, which is marked by the menstrual phase where there is an increase in the production of estrogen and progesterone secretions in a cyclic pattern that begins the onset of puberty, this cycle is called the reproductive or menstrual cycle [12]. Females change physically through the production of sex hormones at puberty. It begins with the secretion of increased dilation of blood vessels, thereby increasing permeability and increasing the production of prostaglandins by the anterior pituitary of gonadotropin hormones (follicle-stimulating hormone and luteinizing hormone), which causes the ovaries to initiate cyclical production and secretion of female sex hormones (estrogen and progesterone) [13].

Menopause is a biological condition due to ovarian failure, diagnosed when menstruation has stopped for 12 months. This condition cannot be explained through a pathological process, but it is associated with increased FSH in the blood of more than 40 IU/L; after that, women will experience a postmenopausal period. The physiology of menopause is the reduction of primary oocytes in the ovaries with atresia due to aging coupled with decreased sensitivity of the remaining oocytes to gonadotropins [14, 15]. Millions of women have undergone the menopausal transition; this period often has clinical implications that significantly affect women’s health conditions. Changes during menopause occur due to hypoestrogenism, especially estradiol (E2), the most potent estrogen in the body. Estrogen and progesterone are responsible for the physiological changes of women in every phase of their life [16, 17].

Hormones fluctuate rapidly when women enter menopause. Changes in the mean values of FSH and estradiol indicate that FSH will continue to increase while estradiol will continue to decline for about 2 years. This is a critical factor in responding to symptoms related to the oral cavity. Raviraj et al. showed that oral symptoms were more common in postmenopausal women than in andropause men [18]. Female sex hormones and neuropathic factors are related to each other, so it is thought that neuropathic sensory fibers from the oral mucosa use discomfort in the oral cavity. Women experienced more dental caries, abrasion, erosion, burning mouth sensation, and dentin hypersensitivity [2, 19].

3. Changing the oral cavity in postmenopausal

The mouth is a mirror of overall health, strengthening that oral health is an integral part of general health. In the elderly population, poor oral health has been considered a risk factor for public health problems. On the other hand, parents are more susceptible to disorders [20]. The oral cavity is a complex of many anatomical structures with different functions. It is made of soft and hard tissue, and the scope of its activity is vast. The oral cavity is susceptible to mechanical and chemical stimuli. Therefore, diseases in this area are often very unpleasant and burdensome to the patient. Awareness of oral health during the menopausal period is critical to minimize the inevitable discomfort due to hormonal changes [18, 21].

3.1 Burning mouth syndrome

Menopause initiates several physiological changes in women. One of them is a change in oral health. Discomfort in the oral cavity is found in menopausal women. Symptoms that often arise are dry mouth, pain in the mouth due to various causes, and burning mouth syndrome. Burning mouth syndrome is one of the main complications in menopause and postmenopause. It is a chronic condition characterized by a burning sensation of the oral mucosa, with or without dysgeusia (distortion of the sense of taste) and xerostomia in the absence of clinical lesions, laboratory abnormalities, or systemic causes [22]. The postmenopausal period affects the maturation of oral epithelial cells; this causes the epithelium to atrophy so that it is ultimately susceptible to inflammation complaints of the burning mouth that are often complained of in postmenopause. Some salivary functions are mediated by the level of expression of estrogen and estrogen receptors in the blood. Women also frequently complain of xerostomia associated with reduced estrogen [23].

Hormones fluctuate rapidly when women enter menopause. This is a key factor in responding to symptoms related to the oral cavity. Cell growth and function regulated by estrogen receptors, namely ERa and ER, are mediated by estrogen receptors. The soft tissues of the mouth and salivary glands will express ERβ receptors. This suggests that estrogen can play an important role in maintaining homeostasis in the oral cavity and salivary glands [18]. Inhibition of estrogen occurs after women complain of dry mouth due to decreased salivary secretion and sensation of burning of the mouth and tongue. Some women develop a condition known as menopausal gingivostomatitis, characterized by dry and shiny gingiva, bleeding easily, and varying in color from pale to erythematous [24, 25].

3.2 Xerostomia

Diseases of the oral mucosa often have a significant impact on the emotional state of the patients who experience them. Further aggravation of the unpleasant oral condition that accompanies menopause is associated with activation of the autonomic nervous system caused by chronic emotional anxiety. Oral health awareness during the menopausal period is critical to minimize the inevitable discomfort due to hormonal changes. Dry mouth or xerostomia is one of the most common symptoms women report in menopause. Xerostomia is a dry mouth condition most often caused by a decrease in saliva or when salivary factors are standard but with fewer components [21]. Besides hormonal factors, drugs such as antidepressants, antihistamines, antihypertensives, and diuretics, which are taken continuously in postmenopausal women, also cause reduced salivary flow [25]. Reduced salivary flow (intrinsic cleaning mechanism) and poor oral hygiene (extrinsic cleaning mechanism) can accumulate heavy plaque on the teeth and denture surfaces. It is a condition that predisposes to and increases periodontal disease and dental caries [20, 26].

3.3 Dental caries

Saliva plays an important role in defense of tissues in the oral cavity and avoiding foreign objects entering the body. When saliva flow is reduced, the tendency to experience disturbances in the oral cavity will increase [27]. Decreased secretion of saliva, a compelling defense of the oral cavity, can cause many problems, such as increased dental caries, oral infections, dysphagia, impaired taste, and increased mucosal sensitivity against mechanical injury. The normal flow of unstimulated and stimulated saliva is essential to ensure adequate and continuous lubrication of the oral tissues. The salivary fluid’s characteristics are critical for forming a food bolus, dissolving taste substances, and transporting them to taste receptors. It also facilitates chewing, swallowing food, and talking. Insufficient saliva can disrupt the balance of microbes that benefit pathogens, such as Candida albicans and Streptococcus mutans, because a moist environment is also essential for the colonization and growth of microorganisms on the oral surface [21, 28, 29].

Salivary glands also depend on reproductive hormones, contributing to salivary secretion and consistency changes. This condition affects the teeth and increases the risk of caries. Postmenopausal women with hormone therapy have an improved quality of life as oral discomfort decreases. This is partly due to the increased secretion of salivary flow. Postmenopausal and premenopausal saliva composition appears to be estrogen-dependent. However, hormone therapy does not affect the total number of bacteria in saliva in premenopausal or postmenopausal [21, 30].

Rukmini et al.’s research showed a significant difference in dental caries between postmenopausal women and women who were not yet menopausal. The average number of caries sufferers in postmenopausal women was higher than those who had not experienced menopause [27]. Slowed secretory activity in postmenopause will facilitate bacterial and fungal colonization, which increases dental caries and increases the risk of pathogen access in the subepithelial mucosa due to the weak ability of saliva to perform self-cleaning The level of sex hormones in the saliva is also related to the number of hormones in the blood [31].

Hypoestogenism in postmenopausal affects the salivary flow rate, which at the same time also affects the condition of microorganisms in the oral cavity. The decreased salivary flow will affect the composition of salivary fluid and gingival crevicular fluid. Saliva is a factor that plays a role in maintaining the pH of the oral cavity by neutralizing acids from food and drink as well as bacterial activity to reduce the risk of periodontal disease [32].

3.4 Periodontal change

After menopause, women become more susceptible to periodontal disease. This is partly due to estrogen deficiency which causes gingival inflammation and bone resorption. Estrogen and androgen hormones are present in the periodontium, so postmenopausal hormone imbalances will affect the periodontium. The decrease in the hormone estrogen causes changes in immune function and the ecology of microorganisms in the body, especially in the oral cavity [33, 34, 35]. Microcirculation in the postmenopausal oral cavity shows that the diameter of the loops, tortuosity of blood vessels in the labial mucosa, and changes in the density of the periodontal mucosa predispose to periodontal inflammation [36].

Chronic disease conditions increase the sulcus depth, so food debris and periodontal pathogens accumulate in the sulcus. This is harmful to the periodontal ligament fibers attached to the gingiva and teeth. If the microbial accumulation persists in the sulcus for a long time, the bacteria will penetrate, and gingival inflammation occurs and ultimately destroys the connective tissue and periodontal ligament fibers. This process will continue, causing the sulcus to deepen and form a periodontal pocket [37, 38].

In postmenopause, changes in the oral cavity that occur due to hormonal changes are a picture of physiological aging in oral tissues, so this has the potential to cause periodontitis [33, 39]. The increase in postmenopausal pro-inflammatory cytokines causes changes in anti-inflammatory cytokines, which are associated with weakened monocyte and macrophage function due to estrogen deficiency. This is the beginning of the influence of menopause on tissue function [40, 41].

3.4.1 Gingival

The role of estrogen in periodontal tissue is that estrogen can stimulate the proliferation of gingival fibroblasts, stimulate the synthesis and maturation of the gingival connective tissue, increase gingival inflammation without increasing plaque, increase cellular proliferation in blood vessels, and reduce keratinization through an increase in epithelial glycogen, causing narrowing/shrinking of the epithelial barrier. It also decreases T cells that mediate inflammation, suppresses the number of leukocytes (leukopoiesis) in the bone marrow, stimulates phagocytosis of polymorphonuclear (PMN)), inhibits PMN chemotaxis, and inhibits pro-inflammatory cytokines released by the bone marrow [11, 42, 43, 44]. There are two theories for the action of steroid hormones on gingival cells: (a) changes in the effectiveness of the epithelial barrier against bacterial attack and (b) effects on collagen maintenance and repair. Estrogen receptors are located in the oral mucosa, so changes in this hormone will directly affect the oral cavity. Postmenopausal oral health affects general health and requires attention and other factors [18, 22, 45].

Steroid sex hormones have been shown to, directly and indirectly, influence cell proliferation, differentiation, and growth of target tissues, including keratinocytes and fibroblasts in the gingiva [46]. Different with the stimulatory effect of estrogen on gingival fibroblast proliferation, collagen and non-collagen protein production was reduced when physiological concentrations of estradiol were introduced to fibroblasts. Collagen reduction and non-collagen protein production occur by strained fibroblasts. Therefore, estrogen does not affect collagen synthesized by gingival fibroblasts [47].

3.4.2 Cementum and periodontal ligaments

The periodontal tissue’s complex histological structure becomes affected during women’s postmenopausal fluctuations in sex hormones. The components involved include the gingival epithelium and the underlying connective tissue as well as the extracellular matrix, the periodontal ligament, the alveolar bone and cementum of the tooth roots, the vascular endothelium, and circulating immune cells that explicitly reflect the various activations whose actions are systemically influenced by female sex hormones [48].

Menopause is a physiological phenomenon that occurs in aging women. Periodontal disease is related to changes that occur when entering menopause, one of which is alkaline phosphatase (ALP) which plays a role in the replacement of bone and periodontal tissue in general. Calcium and alkaline phosphatase (ALP) are bone markers associated with accelerated postmenopausal bone loss. Alkaline phosphatase forms the periodontal tissue’s periodontal ligament, cementum, and homeostasis. During the acellular cementum apposition mechanism, vigorous ALP activity was found in the periodontal ligament, so postmenopausal ALP changes also affect periodontal conditions, including cementum [49, 50]. In menopause, the periodontium is directly affected by a neural mechanism against estrogen deficiency. The integrity of the periodontal tissue is regulated by several factors, including the ability of the periodontal ligament to differentiate into osteoblasts or cementoblasts. Hypoestrogenism substantially impacts the etiology, manifestation, and severity through the expression of osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL) in periodontal ligament cells via ER [36, 51].

The significant role of estrogen in the differentiation of periodontal ligament stem cells (PDLSCs) is to exhibit hypoestrogenism on alveolar bone resorption during menopause. In human periodontal ligament cells, there is a decrease in collagen synthesis in fibroblasts due to the influence of estrogen levels. A gradual reduction in estrogen will induce a dependent intensification of procollagen production. Estrogen modulates the activity of target cells to bind to intracellular estrogen receptors. These hormone receptors will assist in the regulation of cell growth and cell differentiation in response to estrogen. When estrogen levels decrease, it will interfere with osteogenic differentiation of periodontal ligament cells, inhibit osteoblast differentiation of human periodontal ligament cells, and interfere with the formation of mineral nodules in the periodontal ligament [52, 53].

3.4.3 Alveolar bone

Periodontitis is a multifactorial infection characterized by a destructive inflammatory process in the supporting tissues of the teeth, causing the formation of periodontal pockets and alveolar bone resorption, which can lead to tooth loss. Periodontal bacteria are the main cause of periodontitis which initiates periodontitis; the host response also determines the progression and severity of the disease. Alteration of the immune response of the host and surrounding cells by periodontal pathogens and their virulence factors results in a complex network of pro- and anti-inflammatory cytokines that play a role in periodontal disease [54, 55].

In patients suffering from progressive periodontitis, the patient must accept the treatment plan given to them to prevent further periodontal destruction. Methods to detect periodontal disease can be done through a diagnostic process, namely interviews, patient history taking, clinical examination, and radiographic examination. The periodontal examination should be standard practice, since it is needed to identify patients at risk and rule out bacteria early on [37]. Low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, and macrophages-stimulating factor that stimulates mature osteoclasts, modulates bone cell proliferation, and induces skeletal and alveolar bone resorption. Age, smoking, socioeconomic factors, and systemic conditions can play essential roles as confounders of the relationship between menopause and tooth loss. The causes of missing teeth are complex but reflect the cumulative state of oral health over time [53, 56].

Swelling of endothelial cells and pericytes of the venules, attachment of granulocytes and platelets to the vessel wall, and proliferation of blood vessels are associated with variations in estrogen levels. Decreased estrogen activity is the leading cause of decreased alveolar bone remodeling. Disruption of positive feedback on the hypothalamic–pituitary axis to the ovary leads to increased alveolar bone resorption [36, 57]. Osteoporosis is the most common cause of estrogen deficiency in postmenopausal women. The risk of osteoporosis and fracture is a dynamic process involving metabolism and bone remodeling that compromises the health of the periodontium [51].

Postmenopausal estrogen deficiency is a critical factor in the pathogenesis of osteoporosis and is involved in rapid bone resorption rather than bone formation and is associated with increased alveolar bone loss resulting in a high risk of tooth loss [53, 58]. Systemic factors are also responsible for postmenopausal osteoporotic bone loss combined with other factors such as periodontal disease, thereby increasing alveolar bone loss. The decrease in bone mineral density in menopause is related to the trabecular pattern and the speed of bone resorption, which predisposes to periodontal disease. The increased cytokine production and bone turnover make the host more susceptible to periodontal disease, so treatment is carried out to reduce the rate of alveolar bone loss and the progression of postmenopausal periodontal disease [58].

4. Conclusion

Diseases of the oral cavity, especially periodontitis and dental caries, are best diagnosed early, so treatment can be started more quickly and tooth loss can be prevented. Periodontal therapy in postmenopausal will be successful if the clinician understands the disease process to establish the right diagnosis to maintain the patient’s oral health. Estrogen is the potential hormone that participates in maintaining stability of their oral health, especially in postmenopausal people who are prone to experiencing diseases in the oral cavitiy due to changes in reproductive hormones. Adequate oral care is one thing that can improve postmenopausal quality of life.