Menopause is associated with significant adverse changes in the orofacial complex, and dentists need to be mindful of the systemic and dental diseases prevalent in post-menopausal women.

Approximately every 28 days, the hypothalamus in the brain secretes gonadotropin-releasing factor, or GnRH, which stimulates the anterior pituitary gland to secrete follicle-stimulating hormone, or FSH. FSH promotes the growth of the vesicular follicle, which, when mature, produces estrogen. The estrogen and the FSH promote maturation of the ovum and thickening of the uterine lining. The anterior pituitary gland then secretes luteinizing hormone, or LH, which assists in further maturation of the ovum and the ovum’s release from the follicle into the fallopian tube. The follicle, now devoid of its ovum, greatly enlarges and is transformed into a glandlike structure known as the corpus luteum.

Progesterone then is secreted by the corpus luteum and further promotes a thickened, well-vascularized uterine lining (endometrium) capable of nourishing a fertilized ovum if conception occurs. If conception does not occur, the corpus luteum involutes and stops producing estrogen and progesterone. The lining of the uterus breaks down, and is discharged through the vagina during the process of menstruation.¹

	MENOPAUSE TRANSITION AND MENOPAUSE

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Peak ovarian function occurs before age 30 years and then declines gradually. The menopause transition (climacteric, perimenopause), defined as the months and years surrounding the last menstrual period, is precipitated by fewer functioning follicles and ova, a consequent reduction in the estrogen level and an inability to respond to the pituitary GnRH, FSH and LH. The initial sign of the transition, which may begin in the 40s, is a reduction in menstrual flow. This usually is followed by missed periods. Menopause, which is defined as the complete and permanent cessation of menstrual flow (amenorrhea) for one year, occurs at a mean age of 51 years. Women who smoke and women who are thin tend to experience an earlier menopause, while those who are overweight experience menopause later because of the availability of estrogen in adipose tissue.

Hot flashes. About 75 percent of women develop uncomfortable symptoms during the menopause transition because of very low levels of estrogen and significant fluctuations in the FSH and LH levels. The initial symptoms are related to the central nervous system, or CNS. Estrogen deficiency leads to dysregulation of the hypothalamic temperature control center, resulting in vasomotor symptoms. Hot flashes occur while awake, beginning with a headache and then proceeding to a flushing of the face, with occasional development of red blotches on the neck, chest, back and arms. This occurs as the arterioles in the skin dilate and the skin temperature rises several degrees. Hot flashes are accompanied by sweating, occasional palpitations and dizziness, and may be followed by a chill. These episodes can last a few minutes or more than one-half hour. Hot flashes arise spontaneously or in association with emotional stress or eating certain foods.

Night sweats. Night sweats occur while asleep and are associated with drenching perspiration that causes the woman to awaken several times during the night, which can lead to fatigue and irritability. These vasomotor symptoms usually resolve spontaneously within two to four years of the last menses.² Alterations in estrogen levels during menopause transition also can induce changes in the limbic system (a site that processes emotions) and result in mood swings, depression (dysphoria) and difficulties with concentration.

These wide variations in hormone levels can cause many women to experience unpredictable heavy menstrual bleeding, with the risk of anemia and endometrial hyperplasia. Pain during sexual intercourse also may arise because of a loss of elasticity and lubrication of the vagina, and postcoital bleeding can result from the tearing of poorly estrogenized mucosa. Urinary tract infections, increased urinary frequency and stress-induced incontinence also are frequently reported, as is dry, less pliable and easily damaged skin.

	MEDICAL DISEASES

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Cardiovascular disease. Cardiovascular disease (particularly coronary artery disease and stroke) is the most common cause of death among postmenopausal women.³ Before menopause, the extent of atherosclerosis in a woman is equivalent to that of a man 10 to 15 years her junior. However, after menopause the risk of a fatal myocardial infarction secondary to atherosclerosis of the coronary vessels more than doubles.^4,5 Similarly, the risk of stroke resulting from atherosclerosis of the carotid artery triples in postmenopausal women.^6,7 Epidemiologic studies have noted that 16 percent of women die of a stroke, whereas only 8 percent of men die of a stroke.⁸

These high rates of disease among women have been shown to result from a decrease in the estrogen level, with a consequent increase in atherogenic risk factors.⁹ Specifically, there is an increase in the total cholesterol level, low-density lipoprotein, or LDL, cholesterol level and lipoprotein(a); a decrease in the high-density lipoprotein, or HDL, cholesterol level; increased thrombic tendency; and an occasional development of insulin resistance.¹⁰ This insulin resistance is extremely important given that diabetes mellitus is associated with a doubling of the risk of an ischemic stroke and an eightfold higher risk of coronary artery disease.^11,12

Osteoporosis. Osteoporosis is a metabolic bone disease characterized by low bone mineral density, or BMD, and microarchitectural deterioration that leads to fragility and the susceptibility to bone fracture.¹³ The disease affects almost 18 million American women older than age 50 years, because estrogen receptors on the bone-resorbing osteoclasts recognize the paucity of estrogen and respond by increasing their activity level.¹⁴ Although estrogen receptors on the bone-forming osteoblasts also recognize the paucity of estrogen, they respond by decreasing their activity level.^15–18

Thus, during the skeleton’s continuous remodeling process, the rate of trabecular (cancellous) and cortical bone resorption exceeds that of trabecular and cortical bone formation. During this postmenopausal osteoporotic process, women lose 30 to 50 percent of the trabecular bone and 25 to 35 percent of the cortical bone mass that was present during the peak bone mass years between ages 20 and 30 years.¹⁹ Factors contributing to bone loss include family history, physical inactivity, low body weight, cigarette smoking, inadequate calcium and vitamin D intake, excessive alcohol and caffeine consumption, certain medications (for example, steroids) and fair complexion (whites and Asians).^20,21

Bone loss is most rapid in early menopause, followed by a slowing eight to 10 years after the last menstrual period. The disease results in more than 40 percent of postmenopausal women experiencing a fractured bone sometime during the rest of their lives.²² These women most commonly suffer fractures of the wrist (distal radius [Colles’ fracture]), spine (vertebral compression) and hip (femoral neck or intertrochanteric fractures). The mortality and morbidity associated with hip fractures in this group of people is devastating, with 20 percent dying in the first year, 15 to 25 percent losing their independence and being confined to long-term facilities and 50 percent experiencing long-term loss of mobility.²³

Alzheimer’s disease. Alzheimer’s disease, or AD, is a degenerative brain disorder that develops in middle (65 years and older) to late (80 years and older) adult life. AD is characterized neuropathologically by the presence of senile plaques that form outside the neuron and consist of deteriorating neuronal tissues surrounded by deposits of amyloid beta protein and neurofibrillary tangles (that is, twisted protein fibers) located within nerve cells. These plaques and tangles decrease cholinergic neuronal transmission (in which acetylcholine acts as the neurotransmitter) in the cerebral cortex and hippocampus and lead to progressive loss of memory and intellectual functioning.²⁴

Observational studies have shown that long-term estrogen deficiency arising from spontaneous or surgically induced menopause seems to be related to a higher risk of developing AD. The prevalence of AD among women aged 65 years and older is approximately 6 percent.^25,26 This rate of disease is two to three times greater than that found in men.²⁷ Women with AD also suffer more severe cognitive impairment than do men with AD.²⁸ These findings may be explained in part by the fact that women with AD have lower levels of endogenous estrogen than do those without AD.²⁹ These findings are elucidated further by an animal model study that showed that an ovariectomy impairs memory-related behaviors by causing a decrease in high-affinity choline uptake and choline acetyltransferase activity in the hippocampus and frontal cortex.³⁰

	ORAL DISEASES

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Menopause also is associated with significant adverse changes in the orofacial complex. Post-menopausal women have decreased unstimulated and stimulated submandibular and sublingual salivary gland flow compared with pre-menopausal women, a finding unrelated to any medication effect.³¹ The paucity of saliva has been implicated as a cause of increased dental caries, and may be responsible for the increased prevalence of oral dysesthesia and taste alterations.^32–34 Some women develop concurrent senile atrophic gingivitis, in which an abnormal paleness of the gingival tissues develops. Other people develop a condition known as menopausal gingivostomatitis, which is characterized by gingivae that are dry and shiny, bleed easily and range in color from abnormally pale to quite erythematous.

Postmenopausal women with osteoporosis and concurrent periodontitis also are likely to exhibit an exaggerated response to dental plaque, as evidenced by increased bleeding on probing, a loss of dentoalveolar bone height and decreased BMD of the alveolar crestal and subcrestal bone.³⁵ Furthermore, these women are at high risk of experiencing early loss of posterior teeth as a result of BMD loss.^36–39 The results of animal model studies also imply that postmenopausal women may suffer greater resorption of the residual ridges during the healing process after dental extractions than do premenopausal women.⁴⁰ Loss of BMD, if unchecked, may lead to edentulism and markedly resorbed residual alveolar ridges that are unsuitable for construction of conventional dentures and are inadequate sites for dental implants.⁴¹

Dental implants placed before menopause. Using animal models, Pan and colleagues⁴² recently studied the effects of menopause on continued osseointegration of implants placed before menopause. Their study showed that the trabecular bone surrounding previously placed dental implants (free of occlusal stress) undergoes rapid modeling after an animal’s ovaries are surgically removed. The subsequent estrogen deficiency caused a decrease in trabecular bone volume around the implants and a decrease in contact between the implant and the trabecular bone. However, the lack of estrogen induced only a slight decrease in contact between the cortical bone and the implant.

Dental implants placed after menopause. Similarly, large numbers of postmenopausal women will seek placement of dental implants. Recent studies using animal models have examined the effects of the paucity of estrogen on the initial osseointegration of these dental implants.^43,44 These studies showed that when new implants (without functional occlusion) are placed in previously ovariectomized animals, the trabecular bone volume around the implant and contact between the implant and new trabecular bone are markedly decreased in comparison with the results for nonovariectomized animals. The lack of estrogen, however, did not produce any change in cortical bone volume around the implant or affect the cortical bone contact with the implant.

The clinical importance of these animal model studies is bolstered by a recent report by August and colleagues,⁴⁵ which demonstrated that implants placed in the maxilla (but not in the mandible) of postmenopausal women not receiving hormone replacement therapy, or HRT, failed to integrate with bone considerably more often (13.8 percent) than implants placed in pre-menopausal women (6.3 percent) and post-menopausal women receiving HRT (8.1 percent). These results suggest that estrogen deficiency and the resultant bony changes associated with menopause may be risk factors for implant failure in the maxilla.

Diagnosing systemic osteoporosis. Oral and maxillofacial radiologists recently developed methods of diagnosing systemic osteoporosis in postmenopausal women via dental radiographs obtained in clinical practice. One group of researchers using digitized periapical radiographs noted that women with osteoporosis of the spine and hip have altered patterns of bone trabeculation in the anterior maxilla and posterior mandible.⁴⁶ Thus, digitized periapical radiographs may be used in the future to diagnose osteoporosis of the spine and hip.

Another group of scientists has noted that abnormalities in the width and morphologic structure of the mandibular inferior cortex, as imaged on a conventional panoramic radiograph, may be indicative of postmenopausal systemic osteoporosis.⁴⁷ Panoramic dental radiographs also are being used to identify postmenopausal women at risk of developing a stroke. Friedlander and Altman⁴⁸ recently reported that 30 percent of neurologically asymptomatic women with a mean age of 70 years had carotid artery atheromas in the soft tissues of the neck.

A number of other diseases with dental manifestations exist whose prevalence increases at or about the time of menopause, but whose relationship to deficiencies in estrogen remains under study. Sjögren’s syndrome, an autoimmune disease, is characterized by chronic inflammation of the salivary, lacrimal and other secreting glands. The disorder leads to xerostomia, keratoconjunctivitis sicca, vaginal dryness and pain during intercourse (dyspareunia). The xerostomia is thought to be responsible for an increase in caries, periodontal disease and oral candidiasis.⁴⁹

Pemphigus vulgaris, an autoimmune disease, is characterized by mucosal and skin erosions and ulcers.⁵⁰ The mucosal ulcers are found in the oral cavity (for example, buccal mucosa, palate, lips and gingiva), esophagus, vulva and anus. The vesicobullouslike lesions initially weep, and then erode and become painful ulcers. Burning mouth syndrome, an illness of multifactorial etiology, is characterized by a burning sensation in the anterior aspect of the tongue, the anterior hard palate or the lower lip mucosa. On clinical and histologic examination, the oral mucosa appears normal. Patients with the disorder frequently report diminished taste sensation and severe menopausal symptoms, and may have oral candidiasis.^51–53

Trigeminal neuralgia also occurs commonly in postmenopausal women. It frequently is precipitated by the superior cerebellar artery compressing one of the branches of the nerve. The disorder is characterized by a unilateral electric shock–like pain in the middle and lower third of the face.⁵⁴ Patients initially may believe that the pain is of odontogenic origin and mistakenly attempt to achieve relief by seeking dental therapeutic interventions.

	MEDICAL INTERVENTIONS

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HRT. HRT is one of the most widely used prescription regimens in the United States. The most common schedule is daily oral administration of tablets containing both estrogen (conjugated estrogen, 0.625 milligrams) and progestin (medroxyprogesterone acetate, 2.5 mg). This continuous combined therapeutic schedule initially is associated with irregular bleeding (spotting episodes), but after about one year of therapy, the endometrium atrophies and bleeding ceases in more than 90 percent of women.

Significantly fewer women receive two sets of tablets, one containing estrogen and the other containing estrogen and progestin. The estrogen tablets are taken for the first 14 days of the cycle and the combination tablets are taken for the last 14 days of the cycle. Subsequent courses are repeated without interruption. This schedule of cyclical therapy results in 70 to 90 percent of women having a regular monthly cycle with period-type vaginal bleeding.

Clinicians usually prescribe HRT to ameliorate the symptoms associated with the menopause transition or to prevent the chronic diseases (for example, osteoporosis) believed to arise, in part, as a result of long-term estrogen deficiency. Observational studies of postmenopausal women who receive HRT demonstrate that they have a 50 percent lower mortality rate from all causes and gain three years in life expectancy compared with women who do not receive HRT.^55,56 However, these statistics may be influenced by healthy user/healthy survivor bias, which acknowledges that women who receive HRT are of higher socioeconomic status, better educated, younger, thinner and more likely to exercise and seek medical care on a regular basis than women who do not receive HRT.^57,58

Approximately 40 percent of women discontinue HRT because of breast tenderness, thromboembolic disorders, or fear of developing breast or endometrial cancer.⁵⁹ The fear of breast cancer arises from an interpretation of the findings of studies that have shown that long-term use (five years or longer) and current use of estrogen is followed by a slight, although significant, increase in the risk of breast cancer, because the hormone causes proliferation of breast epithelium.⁶⁰ In addition, endometrial cancer may develop in women who have not undergone a hysterectomy because of estrogen’s stimulatory effect on the endometrium.⁶¹ However, when added to estrogen, progestin has been shown to moderate the risk of both breast and endometrial cancer.⁶²

Selective estrogen receptor modulators. In view of these concerns, a new class of medications known as selective estrogen receptor modulators, or SERMs, has been approved for use in the United States and Europe. These drugs mimic (agonist) the effects of estrogen in some tissues and act as antiestrogens (antagonist) in others. The ideal compound, yet to be derived, will function as an estrogen antagonist in the breast and uterus and as an estrogen agonist in the skeleton and cardiovascular and CNS systems.

Tamoxifen. Tamoxifen, the first SERM approved for use in the United States, acts as an estrogen antagonist in breast tissue, making it useful for the prevention and treatment of breast cancer. However, the drug also has estrogenlike activity that stimulates proliferation of endometrial tissues, causing endometrial hyperplasia and carcinoma in some cases, while simultaneously improving the lipid profile and BMD.

Raloxifene. This has led to the development of a newer SERM named raloxifene. This medication, approved for the prevention and treatment of postmenopausal osteoporosis, does not stimulate the growth of breast or endometrial tissues, and has been shown to decrease the risk of breast cancer. Raloxifene increases BMD, decreases the incidence of bone fracture and reduces the blood serum level of atherogenic lipoproteins. However, this medication does not ameliorate the vasomotor symptoms associated with menopause; in fact, it increases them by about 3 percent. Use of raloxifene also is associated with an increased risk of thromboembolic events, but not to any greater extent than the risk associated with standard HRT. In addition, raloxifene, unlike standard HRT, does not improve mood and its effects on people with AD remain unknown. Newer agents with a full spectrum of positive effects and fewer, if any, of the negative effects of these SERMs and HRT are under development.^63–66

	EFFECTS OF HRT

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Menopause transition and menopause. About 20 percent of women require HRT to alleviate their vasomotor symptoms. Estrogen diminishes these symptoms in a dose-dependent fashion, with higher doses required by patients with greater symptom severity. Similarly, physicians frequently prescribe HRT to reverse the effects of estrogen deprivation on the genitourinary tract, and its use leads to resolution of the atrophic process, including vaginal dryness, recurrent urogenital infections and incontinence. HRT also is prescribed for some women with climacteric-associated mood disorders.⁶⁷ The medication works by raising the patient’s serotonin level, a CNS neurotransmitter whose paucity is known to be associated with dysphoria.⁶⁸

Cardiovascular disease. In recent years, researchers have shown that HRT begun at the onset of menopause reduces the risk of death from myocardial infarction and stroke by about 40 percent.^69,70 This occurs because estrogen reduces levels of total cholesterol, LDL cholesterol, lipoprotein(a) and fibrinogen, and increases arterial vasodilation and HDL cholesterol levels.^71–74 In addition, animal models have shown that estrogen inhibits LDL oxidation, cholesterol-laden macrophage infiltration of arterial walls and myointimal hyperplasia.⁷⁵ The addition of progestin enhances the ability of estrogen to reduce or halt the progression of atherosclerosis, because it is highly effective in reducing rates of LDL accumulation and degradation in blood vessels.⁷⁶

I should note that two recent studies demonstrated that short-term (that is, three to four years’) administration of HRT (often not initiated for 10 or more years after menopause begins) does not halt the progression of atheromas in the coronary vessels or forestall a nonfatal or fatal myocardial infarct in postmenopausal women with pre-existing coronary artery disease.^77–80 The National Institutes of Health Women’s Health Initiative Study⁸¹ currently is evaluating the effects of HRT on the health of about 30,000 post-menopausal women, and the results should provide definitive clinical data in regard to all aspects of HRT and heart disease.

Osteoporosis. HRT initiated at the onset of menopause and continued indefinitely preserves and, to a modest extent, augments BMD by increasing osteoblastic activity.^82–84 The addition of progestin further enhances the bone-sparing effects of estrogen.^85,86 Concomitant with HRT, physicians also are likely to prescribe 1,500 mg of calcium per day, load-bearing exercise and avoidance of smoking, alcohol consumption and other deleterious habits. A recent clinical study demonstrated that postmenopausal women older than age 60 years receiving HRT (estrogen and progestin) for 36 months gained 5 percent BMD in the spine and 1.7 percent BMD in the hip.⁸⁷ One prospective study^88,89 has shown prevention of vertebral fractures with long-term use of estrogen, and a variety of epidemiologic studies have indicated that estrogen reduces the risk of hip fracture by 50 percent. The exact mechanism of action of estrogen on the skeleton has not been determined.

Alzheimer’s disease. Recent epidemiologic evidence from case-control and prospective cohort studies suggests that long-term administration of HRT reduces the relative risk of developing AD by almost 55 percent compared with the risk for women who have never used it.⁹⁰ HRT also may delay the onset of AD in women who eventually develop the disease, and it decreases the pace of cognitive decline associated with the disease.

These effects are illustrated by in vivo and in vitro studies that have shown that estrogen inhibits the generation and accumulation of amyloid beta protein and protects neurons from hydrogen peroxide and glutamate, each of which has been implicated as a cause of AD. In addition, estrogen promotes growth of cholinergic neurons, augments synaptic excitability in the hippocampal neurons and increases the morphological complexity (that is, synaptic connectivity) of neurons, all of which are associated with enhanced learning, memory and attention. HRT also has been shown to increase cerebral blood flow to the hippocampus, parahippocampal gyrus and temporal lobe regions that form a memory circuit.^91–94 In addition, several small clinical trials have shown that short-term administration of HRT improves cognitive function (attention and verbal memory) in postmenopausal women with AD.^95,96

Oral diseases. Studies have shown that HRT promotes oral health by inhibiting gingival inflammation, periodontitis and the consequent loss of teeth. This probably occurs because estrogen supplementation inhibits proinflammatory cytokines (interleukin-1, or IL-1, tumor necrosis factor- and IL-6) from mononuclear cells, T-cell–mediated inflammation and bone marrow production of leukocytes.^97–100 Thus, post-menopausal women with osteoporosis or osteopenia of the lumbar spine are less likely to suffer tooth loss or need dentures if they are receiving HRT.^101–104 Payne and colleagues¹⁰⁵ and Jacobs and colleagues¹⁰⁶ demonstrated that HRT reduces the extent of menopause-associated mandibular alveolar bone loss and, in some instances, promotes an increase in BMD that parallels the hormone dosage received. HRT also is effective in ameliorating oral dysesthesias irrespective of whether the tissues appear atrophic, normal or erythematous.¹⁰⁷

There is, however, conflicting evidence as to the role of HRT in the development of dental disease, specifically temporomandibular disorders, or TMDs.^108,109 One major study demonstrated that postmenopausal women receiving HRT at a large health maintenance organization were 30 percent more likely to be referred for evaluation and treatment of TMD symptoms than were women who did not receive the medication. In addition, the researchers found a dose-response relationship, with patients who received larger yearly doses of HRT experiencing TMD to a greater extent than those who received more modest doses.¹¹⁰ However, these findings are contradicted by those of another major study that failed to find an association between the use of HRT by postmenopausal women and the development of TMD when demographic, socioeconomic, cultural and health care variables were controlled for.¹¹¹

	CONCLUSIONS

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More than one-third of American women are postmenopausal and they will live an average of 25 to 30 more years. Therefore, dentists treating this large number of patients need to be mindful of both the systemic and dental diseases that are prevalent among this group, as well as the stresses that may be associated with this phase of life. They should refer women who are not under the care of a gynecologist to one for an evaluation to determine the appropriateness of HRT for both its systemic and oral health benefits.

View larger version (140K): [in this window] [in a new window]   Dr. Friedlander is the associate chief of staff and the director, Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System; director of Quality Assurance, Hospital Dental Service, Medical Center at the University of California Los Angeles; and a professor, Oral and Max-illofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Fried-lander, Veterans Affairs Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".