As the epithelium thins after menopause, the capillary bed shines through as a diffuse or patchy reddening. Rupture of surface capillaries produces irregularly scattered petechiae, and a brownish discharge may be noted. Further atrophy of the vaginal epithelium renders its capillary bed increasingly sparse, so that the hyperemic appearance gives way to a smooth, shiny, pale epithelial surface. The epithelium lacks glycogen, which leads to a reduction in lactic acid production and an increase in the vaginal pH to 5.0–7.0. This is associated with disappearance of lactobacilli. Early in the process, local bacterial invasion may initiate vaginal pruritus and leukorrhea. Vaginal burning, soreness, dyspareunia, and a thin watery or serosanguineous discharge may also occur. Minimal trauma with examinations or coitus may result in slight vaginal bleeding. Urinary complaints, including urinary frequency, urgency, dysuria, and urge incontinence, have also been described in association with atrophic vaginitis.
There is no specific test that reliably quantifies the degree of atrophy. Clinical decision making is therefore generally based on patient symptomatology and findings on physical examination. However, vaginal cytology has been used to assist in the diagnosis of atrophic vaginitis. The degree of maturation of exfoliated vaginal epithelial cells, as revealed by stained vaginal smears, is an index of estrogenic activity. Among the various methods of assessing the smears, the following are most commonly used: the maturation index consists of a differential count of 3 types of squamous cells—parabasal cells, intermediate cells, and superficial cells, in that order—expressed as percentages (eg, 10/85/5); a greater percentage of parabasal cells reflects a greater degree of atrophy. The cornification count is the percentage of precornified and cornified cells among total squamous cells counted. This is actually a simplified maturation index, because this percentage is essentially the same as that of the superficial cells.
The assessment of exfoliated vaginal epithelial cells is influenced not only by the level of estrogenic activity, but also by other hormones (particularly progesterone and testosterone), local vaginal inflammation, local medication, vaginal bleeding, the presence of genital cancer, the location of the vaginal area sampled, and variations in end-organ (epithelial) responses to estrogenic influence. Thus women with identical levels of circulating estrogens may have quite different cytograms.
The great variation in cytologic findings leads to the following conclusions regarding the use of smears in the clinical management of postmenopausal women: (1) the smear is only a rough measure of estrogenic status, and it may sometimes be grossly misleading. (2) The vaginal cytogram cannot predict whether or not an individual woman is experiencing menopausal signs and symptoms. (3) The smear cannot be used as the sole guide to steroid supplementation therapy; clinical signs and symptoms are more dependable for this purpose.
Symptomatic atrophic vaginitis may be managed with water-soluble lubricants and/or topical vaginal estrogens, which are available in the form of creams, tablets, or estradiol-releasing rings (see Estrogen Therapy). Systemic estrogens are also effective in the treatment of atrophic vaginitis, but vaginal preparations are preferred when estrogen therapy is being used solely for the treatment of vulvovaginal atrophy.
The most common and characteristic symptom of the climacteric is an episodic disturbance consisting of sudden flushing and perspiration, referred to as a hot flash or flush. It is observed in approximately 75% of women who go through the physiologic menopause or have a bilateral ovariectomy. Of those having flushes, 82% experience the disturbance for more than 1 year, and 25–50% complain of the symptom for more than 5 years. Most women indicate that hot flushes begin with a sensation of pressure in the head, much like a headache. This increases in intensity until the physiologic flush occurs. Palpitations may also be experienced. The actual flush is characterized as a feeling of heat or burning in the face, neck, and chest, followed immediately by an outbreak of sweating that affects the entire body but is particularly prominent over the head, neck, upper chest, and back. Less common symptoms include weakness, fatigue, faintness, and vertigo. The duration of the whole episode varies from momentary to as long as 10 minutes; the average length is 4 minutes. The frequency varies from 1–2 per hour to 1–2 per week. In women with severe flushes, the mean frequency is 54 minutes.
Investigators have characterized the physiologic changes associated with hot flushes and have shown that the symptoms result from true alterations in cutaneous vasodilation, perspiration, reductions of core temperature, and elevations of pulse rate. Fluctuations in electrocardiographic data probably reflect changes in skin conductance. Changes in heart rhythm and blood pressure have not been observed.
The patient's awareness of symptoms does not correspond exactly with physiologic changes. Women become conscious of symptoms approximately 1 minute after the onset of measurable cutaneous vasodilation, and discomfort persists for an average of 4 minutes, whereas physical changes persist for several minutes longer.
The exact mechanism responsible for hot flushes is unknown, but physiologic and behavioral data indicate that symptoms result from a defect in central thermoregulatory function. Several observations support this conclusion: (1) the 2 major physiologic changes associated with hot flushes—perspiration and cutaneous vasodilation—are the result of different peripheral sympathetic functions. Excitation of sweat glands results from sympathetic cholinergic fibers, and cutaneous vasodilation is under the control of tonic α-adrenergic fibers. It seems unlikely that any peripheral event could cause both cholinergic excitation of sweat glands and α-adrenergic blockade of cutaneous vessels, and it is well recognized that these are the 2 basic functions triggered by central thermoregulatory mechanisms that lower the central temperature. (2) During a hot flush, the central temperature decreases because of cutaneous vasodilation and perspiration. If hot flushes were the result of some peripheral event, the body's regulatory mechanisms would be expected to prevent such a decrease. (3) There is also a change in behavior associated with hot flushes. Women feel warm and have a conscious desire to cool themselves by throwing off the bedcovers, standing by open windows or doors, fanning themselves, or by other means. This behavior is observed even in the presence of a steady or decreasing central temperature.
Most investigators believe the core temperature of the body is maintained near a central set point that is controlled by central thermoregulatory centers, particularly those in the rostral hypothalamus. This central set point temperature is analogous to a thermostat setting. Hot flushes appear to result from a narrowing of the thermoregulatory set point such that smaller than normal increases in core body temperature activate heat loss responses. As a consequence, heat loss mechanisms, both physiologic and behavioral, are activated so that the core temperature will be brought in line with the new set point; this results in a fall of central temperature.
Because hot flushes occur after the spontaneous cessation of ovarian function or following oophorectomy, it is presumed that the underlying mechanism is initiated through endocrinologic changes related primarily to ovarian estrogen withdrawal. Low estrogen levels alone do not appear to trigger hot flushes; prepubertal children and patients with gonadal dysgenesis have low estrogen levels but not flushing. Patients with gonadal dysgenesis do experience symptoms if they are given estrogens that are later withdrawn. Thus it appears that estrogen must be present and then withdrawn for hot flushes to be experienced.
Changes in central nervous system (CNS) concentrations of norepinephrine (NE) and serotonin likely play an important role in the development of hot flushes. Animal and human studies indicate that NE plays an important role in the etiology of hot flushes. Increased levels of NE have been correlated with a narrowing of the thermoneutral zone, and it has been demonstrated that plasma levels of metabolites of NE increase after a hot flush. In addition, use of pharmacologic agents that alter central noradrenergic activity (ie, clonidine, serotonin and norepinephrine reuptake inhibitors [SNRIs]) have been shown to lessen the severity and/or frequency of vasomotor symptoms.
Studies also suggest a role for serotonin in the development of vasomotor symptoms. Serotonin is thought to be important in thermoregulation, as studies have shown an increase in stimulation of serotonin receptors after a thermostimulus, which then results in sensation of a hot flush. In addition, an association between serotonin levels and severity of vasomotor symptoms in menopausal women has been demonstrated. Finally, the selective serotonin reuptake inhibitors (SSRI) class of drugs has been shown to be effective in the management of vasomotor symptoms in postmenopausal women.
A close temporal association between the occurrence of flushes and the pulsatile release of LH has been demonstrated. However, the observation that flushes occur after hypophysectomy suggests that they are not directly caused by LH release. The appearance of hot flushes in women with defects in GnRH release or synthesis (Kallmann's syndrome) also suggests GnRH itself is not involved in the flushing mechanism. The absence of hot flushes in women with hypothalamic amenorrhea and hypoestrogenemia is intriguing. These women have defects in neurotransmitter or neurochemical input to their GnRH neurons. In particular, excessive endogenous opioid and dopamine input to GnRH neurons may account for chronic suppression of GnRH release, leading to hypothalamic amenorrhea. The absence of hot flushes in these women suggests that altered afferent input of neurotransmitters or neurochemicals to the GnRH neuron that is secondary to hypogonadism leads to hot flushes.
Hot flushes are a greater annoyance than most physicians recognize. Patients frequently complain of night sweats and insomnia. There is a close temporal relationship between the occurrence of hot flushes and nighttime awakening. Women with frequent flushes may experience flushes and awakening episodes hourly, which may cause a profound sleep disturbance that may, in turn, cause cognitive (memory) and affective (anxiety) disorders in some women.
are the principal medications used to relieve hot flushes. Estrogens block both the perceived symptoms and the physiologic changes. Their use also relieves some aspects of the sleeping disorder. Estrogen administration has been shown to enhance hypothalamic opioid activity in postmenopausal women. This increase of hypothalamic opiates may be involved in the relief of hot flushes with estrogen administration.
Progestins also block hot flushes and represent a reasonable form of substitutional therapy in women who cannot take estrogens. However, because addition of progestins to hormone therapy has been associated with an increased risk of breast cancer, a progestogen would not be the ideal alternative to estrogen for women who are seeking to avoid effects on breast disease. Clonidine, a centrally acting alpha agonist, is more effective than a placebo but is associated with side effects. More recently, certain SSRIsand SNRIs have been shown to be effective in the treatment of hot flashes. Their side effects may limit their overall benefit, but they are one of the first alternative choices in women who are not taking estrogen. Certain SSRIs may also affect the metabolism of tamoxifen to its active metabolite through the enzyme, CYP2D6, a member of the cytochrome P450 oxidase enzyme system. SSRIs such as paroxetine and fluoxetine have been associated with increased breast cancer recurrence and/or death amongst women using tamoxifen. Therefore, until further studies are available, caution must be used when using SSRIs, particularly paroxetine and fluoxetine, in women receiving tamoxifen. Black cohosh may have modest effects in decreasing hot flashes, but concerns remain regarding its potential to stimulate breast and uterine tissue. Gabapentin also decreases hot flashes by 50–80% and is therefore comparable to estrogen according to certain studies. However, sedation is a major side effect that limits its acceptability for many women. Small doses at night may be useful for women suffering from night-time awakening due to vasomotor symptoms. Tibolone is a synthetic steroid with estrogenic, progestogenic, and androgenic properties that alleviates menopausal symptoms and has been used in other countries for this purpose, as well as to preserve bone mineral density. However, its long-term safety profile with regard to breast and endometrial cancer remains controversial. Its mechanism of action would suggest that it is unlikely to increase the risk of breast cancer. However, the Million Women Study reported an increased risk of breast cancer among participants using tibolone as compared with controls. In addition, tibolone was associated with an increased risk of breast cancer recurrence in a randomized trial of breast cancer patient using tibolone for relief of vasomotor symptoms. Tibolone's action on the endometrium also suggests that it is unlikely to cause endometrial proliferation. This is supported by findings from studies demonstrating a low incidence of vaginal bleeding and an absence of endometrial hyperplasia on histology. However, rates of endometrial cancer were also increased in the Million Women Study. Further study is required to ascertain whether tibolone can be used long term without increased risks for breast and endometrial cancer. Tibolone's potential to modify risk for cardiovascular disease is also unknown. However, a study evaluating the effect of tibolone on myocardial blood flow demonstrated that tibolone improved myocardial blood flow in women with ischemic heart disease. Vitamins E and K, mineral supplements, and phytoestrogens have all been tried to alleviate menopausal symptoms, but have not been proven beneficial. Many women express a preference for bioidentical hormones (BHT), with the expectation that they are safer, with comparable efficacy. The term may be used to describe varying formulations and therefore is not used consistently amongst patients or practitioners. For some, the term refers to hormones that are chemically identical to those produced by humans and includes formulations that are well-tested, US Food and Drug Administration (FDA)–approved brand names. For the majority of others, the term refers to custom-made hormone formulations that provide different doses and routes of administration of estrogens and progestogens. These compounded formulations are not subject to the same regulatory approval process as brand name formulations, and therefore safety, efficacy, and consistency are in no way assured. Cost to the patient can also be greater for these compounded formulations because they are often not covered by third-party payers. The FDA has declared that claims of compounding pharmacies stating that BHT drugs avoid the risks of FDA-approved treatments and these drugs reduce the risk of serious illness such as heart disease, stroke, or breast cancer are not supported by credible scientific evidence. They further state that safety and efficacy of estriol in these formulations has not been proven. Therefore, incorporation of estriol into these formulations may not occur without an investigational new drug authorization. According to the 2010 North American Menopause Society position statement: "Filled prescriptions for BHT should include a patient package insert identical to that required for products that have regulatory-agency approval. In the absence of efficacy and safety data for any specific prescription, the generalized benefit-risk ratio data of commercially available HT products should apply equally to BHT."
Osteoporosis is defined as a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in fragility of bone and susceptibility to risk of fracture. Although gradual bone loss occurs in all humans with aging, this loss is accelerated in women after cessation of ovarian function. After attainment of peak bone mass by age 25–30 years, bone loss begins, accelerates in women at menopause, and then slows again but continues into advanced years at a rate of 1–2% per year (Fig. 59–3). Women can lose up to 20% of their bone mass in the 5–7 years after menopause.
Changes in metacarpal cortical width, as determined by sequential measurements in pre- and postmenopausal women, age range 30–50 years. Note bone loss in postmenopausal women.
(Reproduced, with permission, from Nordin BEC, et al. Postmenopausal osteopenia and osteoporosis. Front Horm Res
Osteoporosis affects an estimated 10 million Americans 50 years of age or older, 80% of whom are women. Of Americans 50 years of age or older, 34 million are estimated to have low bone mass at the hip, placing them at increased risk for osteoporosis. Osteoporosis is most severe in women who have had early oophorectomy or premature ovarian failure, and in those with gonadal dysgenesis. Osteoporosis occurs most often in whites, followed by Asians, Hispanics, and African Americans.
Bone loss produces minimal symptoms, but leads to reduced skeletal strength. Thus osteoporotic bones are more susceptible to fractures. The most common sites of fracture are in the vertebral body, proximal femur, and distal forearm/wrist. Recent figures from the National Osteoporosis Foundation show that osteoporosis is responsible for more than 1.5 million fractures per year. Due to the aging population, the prevalence of osteoporosis is expected to increase such that by 2020, 1 in 2 Americans is expected to have or be at risk for osteoporosis of the hip. Approximately 1 in 2 women older than the age of 50 years will have an osteoporosis-related fracture in her remaining lifetime. The incidence of hip fractures in women is 2–3 times that in men. The mortality rate associated with hip fractures is between 10 and 20% within 12 months after the injury. Of survivors, 15–25% are permanently disabled. The estimated cost for osteoporosis-related fractures in the United States totals more than $17 billion per year. According to the Surgeon General, these costs could double or triple by the year 2040.
Risk factors include certain lifestyle choices (ie, increased caffeine intake, smoking, excessive alcohol intake, lack of exercise, lifetime of low calcium intake), hormonal factors (ie, estrogen deficiency from menopause, eating disorders), genetic factors (ie, family history, cystic fibrosis, Ehlers Danlos), endocrinologic disorders (hyperparathyroidism, adrenal insufficiency, hyperthyroidism), medical disorders (ie, lupus, malabsorption syndromes, lymphoma), medication use (ie, corticosteroids, chemotherapy, excess thyroid supplementation), vitamin D deficiency, slender body size, and advanced age.
Bone loss occurs because bone resorption is excessive, bone formation is decreased, peak bone mass is low, or a combination of all 3 factors. Bone remodeling is regulated by many factors, including systemic hormones, local cytokines, prostaglandins, and local growth factors. Of the systemic hormones, sex steroids, parathyroid hormones, glucocorticoids, thyroid hormones, and growth hormone/insulinlike growth factors likely play a role.
Ovarian estrogen and estrogen administered postmenopausally are protective against osteoporosis. The exact mechanisms by which estrogen regulates bone remodeling are incompletely understood. Estrogens likely modulate osteoclast and osteoblast function possibly via effects on cytokines and growth factors such as transforming growth factor-β and tumor necrosis factor-α (TNF-α). Estrogens may decrease the depth of erosion of osteoclasts.
Interleukin-1 (IL-1) and TNF-α derived from bone marrow macrophages stimulate bone resorption and may inhibit bone formation. There is evidence to suggest they may be regulated by estrogen, as IL-1 activity in bone increases immediately after the menopause or oophorectomy. Furthermore, it has been shown in animal models that inhibition of IL-1 and TNF-α after ovariectomy attenuates bone loss. IL-6 and prostaglandins, especially prostaglandin E2, are also involved in bone remodeling and are regulated by sex steroids. Other factors, such as insulin-like growth factor and fibroblast growth factor, also likely play a role in the pathogenesis of osteoporosis and may be regulated by sex steroids.
Androgens play a role in bone remodeling as androgen deficiency is associated with increased bone loss. The precise mechanism by which androgens alter bone remodeling is unknown but may involve conversion to estrogen. For example, men with aromatase deficiency have an elevated risk of developing osteoporosis, possibly due to decreased conversion of androgen to estrogen.
Progestogens may affect bone remodeling in a similar way to estrogens and androgens, but the mechanisms underlying these effects are not well understood. It is possible that they work through glucocorticoid receptors.
Parathyroid hormone (PTH) also plays a role in bone remodeling. PTH stimulates bone resorption, and absence of this hormone inhibits development of osteoporosis in animal and human studies. Thus far, it does not appear that PTH is elevated in most women with osteoporosis or that the sensitivity of bone to PTH is enhanced. It is interesting that the amino-terminus of PTH (1-34) inhibits bone resorption.
Thyroid hormones increase bone resorption. The exact mechanism is not fully understood, but possibly involves accelerated osteoclast function and altered calcium metabolism.
Growth hormone stimulates bone remodeling; however, studies evaluating the effect of exogenous growth hormone administration on established osteoporosis are inconclusive. Recently, new factors were discovered that are involved with the regulation of bone remodeling: osteoprotegerin, a naturally occurring protein, and RANKL (receptor activator of nuclear factor kappa beta ligand) both regulate osteoclastogenesis and bone resorption.
Genetic factors may also affect risk for osteoporosis. Variants in the estrogen receptors α and β expressed in bone are associated with altered risk for osteoporosis and fracture. Variants in the vitamin D receptor gene and bone morphogenetic protein 2 may also play a role in the pathogenesis of osteoporosis.
Although much has been done to study urinary and serum factors as predictors of osteoporosis, the most predictive test remains bone densitometry with dual-energy x-ray absorptiometry (DXA). Results are given in grams or g/cm2. In 1994, the World Health Organization created a clinically useful definition of osteoporosis. Bone mineral density (BMD) results are reported using T and Z scores. The T score is the number of standard deviations (SD) above or below the mean bone mineral density for sex-matched young normal controls. The Z score compares the patient with an age- and sex-matched population. Normal bone density is defined as a T score > –1.0 SD at the spine, hip or forearm. Osteopenic patients have T scores between –1.0 and –2.5, whereas osteoporotic patients have T scores below –2.5. In most studies, a decrease by 1 SD in mass increases the risk of fracture 2–3-fold. In postmenopausal women, the WHO T-score criteria should be applied. In premenopausal women, WHO BMD criteria should not be applied and other criteria should be used (ie, ethnic or race adjusted Z-scores, with –2.0 indicating low bone density for chronologic age).
Assessment of risk factors has not been nearly as predictive of fracture risk as density measurement. Similarly, assessment of biochemical markers of bone turnover have not been shown to be useful for diagnosing osteoporosis but may give some indication of future risk for fracture and/or be useful for monitoring response to antiresorptive therapy. Markers of bone formation include serum bone-specific alkaline phosphatase and osteocalcin. Markers of bone resorption include serum C-telopeptide (CTX) and urinary N-telopeptide (NTX).
National Osteoporosis Foundation has created a set of guidelines for the use and interpretation of measurement of bone mineral density. Measurements of bone mineral density are recommended for the following groups: (1) all postmenopausal patients younger than age 65 years who have ≥1 additional risk factors for osteoporosis (other than being white, postmenopausal, and female); (2) all women age 65 years and older regardless of additional risk factors; (3) postmenopausal women who present with fractures; (4) women considering therapy for osteoporosis if testing would facilitate the decision; (5) women who have been on hormone replacement therapy for prolonged periods; (6) women who have been on treatment to monitor the treatment effect; and (7) women considering discontinuation of treatment.
Another tool to assess risk and guide treatment is the Fracture Risk Algorithm (FRAX). This tool incorporates BMD, as well as other factors, to assess 10-year probability of hip fracture and 10-year probability of major osteoporotic fracture. It is most useful in patients with low hip BMD as opposed to low spine BMD. Special consideration needs to be taken into account for patients with normal hip BMD but low spine BMD, as FRAX incorporates hip BMD measurements. It is also intended for postmenopausal women, not for younger women. Therapy can be considered in patients with a 10-year probability of hip fracture of ≥3% and 10-year probability of major osteoporosis-related fracture of ≥20%. The FRAX calculator can be accessed at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9.
All individuals at risk for or who have been diagnosed with osteoporosis should be advised to consume adequate calcium (minimum of 1200 mg elemental calcium per day). The National Osteoporosis Foundation recommends vitamin D (800–1000 IU/d). Smoking cessation, avoidance of excessive alcohol intake, and participation in regular weight-bearing and muscle strengthening exercise should be encouraged. Pharmacologic therapy should be strongly considered in women with a hip or vertebral fracture, in women with BMD scores below –2.5 with no risk factors, and in women with BMD T-scores below –1.0 with a 10-year probability of hip fracture of ≥3% or a 10-year probability of major osteoporotic fracture of ≥20%. Current pharmacologic therapy for osteopenia/osteoporosis, listed in alphabetical order, includes (1) bisphosphonates, (2) calcitonin, (3) estrogens (with or without progestogens), (4) parathyroid hormone, (5) raloxifene, and (6) denosumab.
Bisphosphonates are excellent choices for prevention and treatment of osteoporosis. They are potent antiresorptive agents that bind to hydroxyapatite crystals on the surface of bones, enter osteoclasts, and decrease resorptive actions by reducing the production of hydrogen ions and lysosomal enzymes. In addition, they have indirect effects, causing osteoblasts to produce substances that inhibit osteoclasts. They increase bone mineral density at the spine, wrist, and hip in a dose-dependent manner and decrease the risk of vertebral fractures by 30–50%. In addition, they reduce the risk of subsequent nonvertebral fractures in women with osteoporosis. There are 4 bisphosphonates currently available for oral administration. Alendronate is approved by the FDA for the prevention of osteoporosis (5 mg daily and 35 mg weekly) and for the treatment of established osteoporosis (10 mg daily or 70 mg weekly). Risedronate is approved by the FDA for prevention and treatment of postmenopausal osteoporosis. The recommended daily dose is 5 mg daily or 35 mg weekly. Ibandronate is approved for both prevention and treatment of postmenopausal osteoporosis. It has the advantage of being available in an oral daily (2.5 mg) and oral monthly (150 mg) dosing regimen, as well as an intravenous regimen of 3 mg given every 3 months. The 2.5-mg daily and 150-mg monthly oral doses are approved for prevention and treatment of osteoporosis. The 3-mg intravenous dose is approved for treatment of osteoporosis. Zoledronic acid is approved for prevention and treatment of osteoporosis in postmenopausal women. It is given as 5-mg intravenous infusion over 15 minutes once yearly for treatment or once every 2 years for prevention. Intestinal absorption of bisphosphonates is poor, and therefore these medications should be taken in the morning with 8 ounces of water, before consumption of any food or beverage. Nothing else should be taken by mouth for at least 30–60 minutes after oral dosing. The patient should also remain upright for 30 minutes after administration. The most common side effects of bisphosphonates are gastrointestinal. Pain in the joints, bone, and muscle may also occur. Risks include gastric and esophageal ulceration and, rarely, osteonecrosis of the jaw. Most cases of osteonecrosis of the jaw have been described in cancer patients being treated with intravenous bisphosphonates, but some cases have occurred in patients being managed for postmenopausal osteoporosis. Some studies suggest an increased risk of esophageal cancer following bisphosphonate use, but others do not. Further study is needed to assess whether there is a direct link between use of bisphophonates and esophageal cancer. More recently, an increase in the risk of atypical fracture of the femur has been reported in women using bisphosphonates for >5 years. The risk is probably small, but should be discussed with patients who are considering use of this class of drug, or who have been using these drugs for prolonged periods of time. The FDA has required a labeling change of bisphosphonates to reflect this risk and will continue to monitor these outcomes closely. Clinicians and patients should be aware that diagnosis of these atypical fractures has been preceded by new onset thigh or groin pain.
Calcitonin is a peptide hormone that inhibits osteoclast activity and therefore inhibits bone resorption. It demonstrates positive effects on bone mineral density at the lumbar spine, although less effectively than estrogen or bisphosphonates. Salmon calcitonin is the most potent form and is available for intranasal administration or as a subcutaneous injection. Calcitonin 100 IU is given subcutaneously daily or every other day; the intranasal calcitonin dose is 200 IU daily. The most frequent side effect with the intranasal route is rhinitis. Other antiresorptive therapies, such as bisphosphonates, are preferred over calcitonin, as they produce greater increases in bone mineral density. However, because of calcitonin's analgesic properties, calcitonin is the preferred therapy in patients with pain from vertebral fracture.
Until recently, estrogen was the mainstay of therapy for prevention and treatment of postmenopausal osteoporosis. However, with the findings from the Women's Health Initiative (WHI) trial demonstrating overall greater health risks than benefits from hormone therapy, it is no longer first-line therapy for prevention of osteoporosis. Osteoporosis prevention does remain an FDA-approved indication for estrogen therapy, however. It is best used in women who would otherwise use estrogen/hormone therapy for management of menopausal symptoms, or in women who cannot tolerate alternate antiresorptive therapies.
In observational studies, estrogen decreases the risk of hip fractures by 25–50%, of vertebral fractures by approximately 50%, and reduces the risk of other fractures. Daily dosages of 0.3–0.625 mg of conjugated estrogens, 0.5–1 mg of micronized estradiol, 1.25 mg of piperazine estrone sulfate, 0.025–0.05 mg of transdermal estradiol, and a new low dose (0.014 mg) of transdermal estradiol all are appropriate for the prevention of osteoporosis. The lower doses (ie, 0.3 mg of conjugated equine estrogens) are not as effective as higher doses but do prevent bone loss. For best results, therapy should begin soon after the menopause.
Parathyroid hormone, teriparatide (PTH [1-34]) has been approved by the FDA for use in women and men who are at high risk for fracture, including those with previous fracture, multiple risk factors for fracture, and previous failed treatment. Despite its potential deleterious effect on bone, intermittent administration of recombinant PTH stimulates bone formation, and clinical trials support its use in the treatment of osteoporosis. It should only be used in high-risk patients because of its high cost, the need for daily injection, and a possible risk for osteosarcoma.
Selective estrogen receptor modulators (SERMs) are nonhormonal agents that bind to estrogen receptors and may exhibit either estrogen agonist or antagonist activity. Currently, there are 3 SERMs approved for use in humans (tamoxifen, toremifene, and raloxifene); however, raloxifene is the only SERM approved for the prevention and treatment of osteoporosis. It exhibits estrogen agonist properties in the bone (inhibits osteoclast function) and the liver (decreases low-density lipoprotein cholesterol) and acts as an antagonist in the breast and uterus. Raloxifene 60 mg daily for 24 months is associated with a 1–2% increase in lumbar spine and hip bone density.
Combination Therapy has been evaluated in the prevention and/or treatment of osteoporosis. This typically takes the form of a bisphosphonate (ie, alendronate) and systemic estrogen. Small increases in BMD have been seen with combination therapy, but the effect on fracture risk is unknown.
Other therapies have been proposed for osteoporosis treatment and prevention, some without proven benefit. Progestins decrease biochemical markers of bone resorption and preserve bone density. When used as monotherapy for osteoporosis, they may be more effective at preserving bone in the wrist than in the spine.
Fluoride has been used in Europe and the United States and is associated with a marked increase in trabecular bone, but did not improve fracture rates, and in some studies fracture rates were increased. This may be a result of a lack of increase in cortical bone. Sodium fluoride is generally not recommended for the treatment of osteoporosis.
Phytoestrogens are plant-derived compounds that have weak estrogen-like effects. Although some animal studies are promising, no effects on the incidence of fractures in humans have been shown.
Tibolone (see Hot Flushes) also increases lumbar spine and femoral neck bone density. Its effects on bone are comparable to those of estrogens. As discussed previously, however, issues regarding long-term safety are currently being evaluated.
The determinants of sexual behavior are complex and interrelated. Sexual function is believed to be regulated by 3 general components: the individual's motivation (also called desire or libido), endocrine competence, and sociocultural beliefs. Decreased libido is reported with increasing age. However, the relative contributions of the primary decrease in desire, anatomic limitations to sexual function, or beliefs that sexual behavior is inappropriate in older women to this decreased libido are unknown.
The hypoestrogenemic state leads to atrophy of the internal genitalia. Although dyspareunia is the most obvious symptom of vaginal atrophy, suboptimal sexual functioning can occur without frank dyspareunia. Diminished genital sensation (and therefore decreased sensory output in the arousal phase), lessened glandular secretions, less vasocongestion, and decreased vaginal expansion may not be perceived as discrete symptoms by the postmenopausal female, but may influence her perception that she is less responsive.
Genital atrophy, one cause of postmenopausal sexual dysfunction, responds to estrogen therapy. The specific impact of estrogen on libido has been difficult to determine. Improved anatomy may also have a positive psychologic impact and may indirectly encourage sexual motivation.
The role of androgen therapy in female sexual dysfunction is an active area of investigation. Despite the fact that the postmenopausal ovary continues to be a major source of androgens for several years after menopause, androgen levels overall are decreased, and this may contribute to the decrease in libido seen during menopause. Furthermore, the addition of testosterone to hormone therapy has been shown to improve sexual function in women in randomized, placebo controlled trials. However, improvements in sexual function have been modest at best. In addition, long-term safety has not been established. Some studies have suggested an increased risk of breast cancer amongst women using androgens. Therefore, its use remains controversial.
Campisi R, Camilletti J, Mele A, Erriest J, Pedroni P, Guiglioni A. Tibolone improves myocardial perfusion in post-menopausal women with ischemic heart disease: an open-label exploratory pilot study. J Am Coll Cardiol
Dimitrakakis C, Keramopoulos D, Vourli G, Gaki V, Bredakis N, Keramopoulos A. Clinical effects of tibolone in postmenopausal women after five years of tamoxifen
therapy for breast cancer. Climacteric
Gambone J, Meldrum DR, Laufer L, Chang RJ, Lu JK, Judd HL. Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes. J Clin Endocrinol Metab
Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: A double blind, randomized, non-inferiority trial. Lancet Oncol
Krapf JM, Simon JA. The role of testosterone
in the management of hypoactive sexual desire disorder in postmenopausal women. Maturitas
National Osteoporosis Foundation. Physician's Guide To Preven-tion and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010.
Ness RB, Albano JD, McTiernan A, Cauley JA. Influence of estrogen plus testosterone
supplementation on breast cancer. Arch Intern Med
North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause
Panay N, Al-Azzawi F, Bouchard C, et al. Testosterone
treatment of HSDD in naturally menopausal women with the ADORE study. Climacteric
Rapkin AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obst Gynecol
World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser