Nicole S. Culhane and Kelly R. Ragucci
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the pathophysiologic changes associated with menopause.
2. Identify the signs and symptoms associated with menopause.
3. Determine the desired therapeutic outcomes for a patient taking hormone therapy (HT).
4. Explain how to evaluate a patient for the appropriate use of HT.
5. Recommend nonpharmacologic therapy for menopausal symptoms.
6. List the adverse effects of and contraindications to HT.
7. Differentiate between topical and systemic forms of HT.
8. Explain the risks and benefits associated with HT.
9. Educate a patient regarding the proper use and potential adverse effects of HT.
10. Monitor a patient taking HT for efficacy and toxicity.
11. Recognize that alternative, nonhormonal therapies for menopausal symptoms exist and should be considered in some circumstances for women unable to take HT.
KEY CONCEPTS
Common symptoms of menopause include hot flashes, night sweats, vulvovaginal atrophy, and vaginal dryness. Women less commonly may experience mood swings, depression, insomnia, arthralgia, myalgia, and urinary frequency.
Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms and vulvovaginal atrophy and should be considered for women experiencing these symptoms.
Women should receive a thorough history and physical examination, including assessing for coronary heart disease (CHD) and breast cancer risk factors, before HT is considered. They should be informed of the risks and the benefits of HT and should be encouraged to be involved in the decision-making process. If a woman does not have any contraindications to HT, including CHD or significant CHD risk factors, and also does not have a personal history of breast cancer, HT may be an appropriate therapy option.
Oral or transdermal estrogen products should be prescribed at the lowest effective dose and for the shortest duration possible to provide relief of vasomotor symptoms. Topical products in the form of creams, tablets, or rings should be prescribed for women exclusively experiencing vulvovaginal atrophy.
Women who have an intact uterus should be prescribed a progestogen in addition to estrogen in order to decrease the risk of endometrial hyperplasia and endometrial cancer.
HT is also indicated for the prevention of osteoporosis but is not recommended for long-term use. Alternative osteoporosis therapies should be considered as first-line therapy for the prevention of osteoporosis, in addition to appropriate doses of calcium and vitamin D.
Combined estrogen plus progestogen should not be used in the prevention of chronic diseases because it increases the risk of CHD, stroke, breast cancer, and venous thromboembolism (VTE). However, colorectal cancer and rates of fracture were reduced with combined hormonal treatment.
HT improves overall well-being and mood in women with vasomotor symptoms but has not demonstrated an improvement in quality of life (QoL) in women without vasomotor symptoms.
In appropriately selected women, HT should be recommended at the lowest dose for the shortest duration and should be tapered before discontinuation in order to prevent the recurrence of hot flashes.
Since the publication of the Women’s Health Initiative (WHI) study, there has been an increase in the use of alternative and nonhormonal therapies for the management of menopausal symptoms. Particularly for women with CHD and/or breast cancer risk factors, these therapies may offer another option to assist with symptom management. A wide range of therapies, both prescription and herbal, have been studied with varying degrees of success. In choosing a particular therapy, it is important to match patient symptoms with a therapy that is not only effective but also safe.
Menopause is the permanent cessation of menses following the loss of ovarian follicular activity. The diagnosis of menopause is primarily a clinical one and is made after a woman experiences amenorrhea for 12 consecutive months. The loss of ovarian follicular activity leads to an increase in follicle-stimulating hormone (FSH), which, on laboratory examination, may help to confirm the diagnosis.
Many women seek medical treatment for the relief of menopausal symptoms, primarily hot flashes; however, the role of hormone therapy (HT) has changed dramatically over the years. HT has long been prescribed for relief of menopausal symptoms and, until recent years, has been purported to protect women from coronary heart disease (CHD). The original reason behind recommending HT in postmenopausal women revolved around a simple theory: If the hormones lost during menopause were replaced through drug therapy, women would be protected from both menopausal symptoms and chronic diseases that often follow after a woman experiences menopause. Recent studies have disproved this theory.
In 1996, the United States Preventive Services Task Force first published its recommendations that not all postmeno-pausal women should be prescribed HT, but rather, therapy should be individualized based on risk factors. This recommendation was further supported with publication of the Heart and Estrogen/Progestin Replacement Study (HERS) in 1998, which demonstrated that women who had established CHD were at an increased risk of experiencing a myocardial infarction within the first year of HT use compared with a similar group of women without CHD risk factors. As a result, the authors concluded that HT is not recommended for the secondary prevention of CHD.1Then, in 2002, the Women’s Health Initiative (WHI) study was published. This trial demonstrated that HT was not protective against CHD but rather could increase the risk in women with underlying CHD risk factors. The risk of breast cancer was also increased after a woman was on therapy for approximately 3 years. As a result of this study, the FDA issued a statement that HT should not be initiated or continued for the primary prevention of CHD.2
This series of trials, and many more, has led to the dramatic change in how HT is currently prescribed and greater understanding of the associated risks. HT, once thought of as a cure-all for menopausal symptoms, is now a therapy that should be used primarily to reduce the frequency and severity of vasomotor symptoms associated with menopause in women without risk factors for CHD or breast cancer. The changes that have occurred over the years in the use of HT further support the importance of evidence-based practice and judicious medication use.
EPIDEMIOLOGY AND ETIOLOGY
Menopause is a period of time marked by the cessation of menses. It occurs in all women either naturally or surgically and usually occurs between the ages of 40 and 58 years. The median age for a woman to experience menopause is 52 years. However, women who have undergone a total abdominal hysterectomy (surgical menopause) generally experience menopause earlier compared with women who experience natural menopause. Some other factors that may be associated with early menopause include low body weight, increased menstrual cycle length, nulliparity, and smoking. Smokers generally experience menopause approximately 2 years earlier than nonsmokers.3
The usual transitional period prior to menopause, known as perimenopause or the climacteric, is a period when hormonal and biologic changes begin to occur. These changes may begin 2 to 8 years prior to menopause and eventually lead to irregular menstrual cycles, an increase in cycle interval, and a decrease in the length of menses. During this time, women also may experience physical symptoms similar to menopausal symptoms, primarily vasomotor symptoms, and they may require treatment depending on symptom severity.3,4
Because the perimenopausal and postmenopausal periods are marked by many biologic and endocrinologic changes, women should inform their health care provider when they experience any signs and symptoms in order to discuss the most appropriate therapeutic approach.
PATHOPHYSIOLOGY
Reproductive physiology is regulated primarily by the hypothalamic-pituitary-ovarian axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to secrete FSH and luteinizing hormone (LH). FSH and LH regulate ovarian function and stimulate the ovary to produce sex steroids. All of these hormones are influenced by a negative-feedback system and will increase or decrease based on the levels of estradiol and progesterone.
The pathophysiologic changes that occur during the perimenopausal and menopausal periods are caused by the decrease and eventual loss of ovarian follicular activity. As women age, the number of ovarian follicles decreases, and the remaining follicles require higher levels of FSH for maturation and ovulation. During perimenopause, FSH concentrations rise during some menstrual cycles but can fall again during subsequent menstrual cycles, leading to irregular and unpredictable menses. During menopause, FSH concentrations increase 10- to 15-fold, LH concentrations increase fivefold, and levels of circulating estradiol decrease by over 90%.5
Vasomotor symptoms (hot flashes, night sweats), as well as other menopausal symptoms such as vulvovaginal atrophy, vaginal dryness, mood swings, and insomnia, occur in over 50% of perimenopausal women and over 80% of menopausal women.4 Menopausal symptoms tend to be more severe in women who undergo surgical menopause compared with natural menopause because of the more rapid decline in estrogen concentrations. Women who seek medical treatment should undergo laboratory evaluation to rule out other conditions that may present with similar symptoms, such as abnormal thyroid function or pituitary adenoma. Once symptoms have been evaluated and other conditions have been excluded, HT should be considered.
TREATMENT
Desired Outcomes
HT remains the most effective treatment for vasomotor symptoms and vulvovaginal atrophy and should be considered for women experiencing these symptoms. The goals of treatment are to alleviate or reduce menopausal symptoms and to improve the patient’s quality of life (QoL) while minimizing adverse effects of therapy. The appropriate route of administration should be chosen based on individual patient symptoms, and therapy should be continued at the lowest dose for the shortest duration consistent with treatment goals for each patient.
General Approach to Treatment
Women suffering from vasomotor symptoms should attempt lifestyle or behavioral modifications before seeking medical treatment. Women who seek medical treatment usually suffer from symptoms that diminish their QoL, such as multiple hot flashes per day or week, sleep disturbances, vaginal dryness, or mood swings. HT should be considered for these women, but is not the most appropriate choice for all women. Women should receive a thorough history and physical examination, including assessing for CHD and breast cancer risk factors, before HT is considered. They should be informed of the risks and the benefits of HT and encouraged to be involved in the decision-making process. If a woman does not have any contraindications to HT, including CHD or significant CHD risk factors, and also does not have a personal history of breast cancer, HT would be an appropriate therapy option (Fig. 50–1). Women who have undergone a hysterectomy need only be prescribed estrogen. A progestogen should be added to the estrogen only for women with an intact uterus. Alternative and nonhormonal treatment options are available for women who are not candidates for HT, but they are less efficacious than hormonal therapies. These treatments should be chosen based on the efficacy and safety profile of the treatment and the patient’s past medical history and current medications.
Patient Encounter, Part 1
BW, a 50-year-old woman with a history of osteoarthritis and hypothyroidism, presents to the clinic complaining of hot flashes, vaginal dryness, and insomnia. She states that she experiences approximately two hot flashes per day and is awakened from sleep at least three to four times a week in a “pool of sweat” requiring her to change her clothes and bed linens. Her symptoms began about 3 months ago, and over that time, they have worsened to the point where they have become very bothersome. On questioning, she states her last menstrual period was 1 year ago.
Which of the patient’s symptoms and past medical history are consistent with menopause?
What additional information do you need to know in order to make an appropriate therapeutic plan for this patient?
Clinical Presentation and Diagnosis of HT in Menopause
Menopausal Symptoms
• Vasomotor symptoms (hot flashes, night sweats)
• Irregular menses
• Episodic amenorrhea
• Sleep disturbances
• Mood swings
• Vaginal dryness
• Depression
Less Common Symptoms
• Fatigue
• Irritability
• Migraine
• Arthralgia
• Myalgia
Diagnosis
• Amenorrhea for 1 year
• FSH greater than 40 mIU/mL (40 IU/L)
• Fivefold increase in LH
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
BW’s work-up reveals the following additional information:
PMH: Osteoarthritis of the lower back for 5 years controlled on acetaminophen 500 mg two tablets by mouth 3 to 4 times daily; hypothyroidism since age 25, currently controlled
FH: Father: Alive with HTN and CHD (MI at age 60). Mother: Alive with hypothyroidism and GERD. Siblings: Two sisters alive and well
SH: Occupation: nurse; nonsmoker; drinks one to two glasses of red wine with dinner on the weekends; denies illicit drug use
Meds: Acetaminophen 500 mg two tablets by mouth 3 to 4 times daily; synthroid 0.075 mg by mouth once daily; multivitamin by mouth once daily
ROS: (+) hot flashes, night sweats, vaginal dryness and itching; (+) insomnia, myalgias, bowel changes, weight gain, constipation
PE:
VS: BP 128/82, P 78, RR 16, T 37.0°C (98.6°F), wt 74.5 kg (164 lb)
HEENT: WNL
Neck: Supple; no bruits, no adenopathy, no thyromegaly
Breasts: Supple; no masses
CV: RRR, normal S1 and S2; no murmurs, rubs, or gallops
Abd: Soft, nontender, nondistended; (+) BS, no masses
Genitourinary: Pelvic examination normal except (+) mucosal atrophy
Labs:
FSH: 76 mIU/mL (76 IU/L)
TSH: 2.5 μU/mL (2.5 mIU/L)
Chem-7: Na 135 mEq/L (135 mmol/L), K 4.5 mEq/L (4.5 mmol/L), Cl 109 mEq/L (109 mmol/L), CO2 25 mEq/L (25 mmol/L), BUN 9 mg/dL (3.21 mmol/L), SCr 0.9 mg/dL (80 μmol/L), Glucose 98 mg/dL (5.44 mmol/L)
CBC: Hgb 13 g/dL (130 g/L or 8.06 mmol/L), Hct 39% (0.39 volume fraction), WBC 5.5 × 103/mm3 (5.5 × 109/L), platelets 234 × 103/mm3 (234 × 109/L)
Fasting lipid levels: TC 232 mg/dL (6 mmol/L), low-density lipoprotein (LDL) 145 mg/dL (3.76 mmol/L), high-density lipoprotein (HDL) 45 mg/dL (1.17 mmol/L), Triglycerides (TG) 200 mg/dL (2.26 mmol/L)
Assess the patient’s condition based on this additional information.
What are the goals of treatment for this patient?
Assess the patient’s risk factors for heart disease and breast cancer.
Recommend nonpharmacologic and pharmacologic treatment for this patient. Justify your recommendations.
Nonpharmacologic Therapy
Nonpharmacologic therapies for menopause-related symptoms have not been studied in large randomized trials, and evidence of benefit is not well documented. Owing to minimal adverse effects with these types of interventions, it is prudent for patients to try lifestyle or behavioral modifications before and in addition to pharmacologic therapy. The most common nonpharmacologic interventions for vasomotor symptoms include the following:3,8,9
• Smoking cessation
• Limit alcohol and caffeine
• Limit hot beverages (e.g., coffee/tea, soups)
• Limit spicy foods
• Keep cool, and dress in layers
• Stress reduction (e.g., meditation, relaxation exercises)
• Increase exercise
• Paced respiration
Exercise demonstrated an improvement in QoL but did not improve vasomotor symptoms. Paced respiration, a form of deep, slow breathing, improved vasomotor symptoms in a small group of patients.
Dyspareunia may result from vaginal dryness. Water-based lubricants may provide relief for several hours after application. Moisturizers may provide relief for a longer period of time and potentially can prevent infections by maintaining the acidic environment in the vagina. Both these treatments require frequent application.
A decline in estrogen concentrations also may be associated with urinary stress incontinence. Kegel exercises are recommended as a first-line intervention for stress incontinence, although pharmacologic therapy also may be necessary. Kegel exercises strengthen the pelvic floor muscles and help to keep the urethra from opening at inappropriate times, such as when lifting heavy objects, coughing, or sneezing. These exercises have no adverse effects, take little time, may be done inconspicuously, and when done correctly, may help to restore normal urine flow.
FIGURE 50–1. Treatment algorithm for postmenopausal women. (From Refs. 2, 6, 7.)
Pharmacologic Therapy
Estrogens
Estrogen currently is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy associated with menopause. In addition, it is indicated for the prevention of postmenopausal osteoporosis in women with significant risk; however, it is recommended that nonestrogen medications receive consideration for long-term use. Oral or transdermal estrogen products should be prescribed at the lowest effective dose and for the shortest duration possible to provide relief of vasomotor symptoms. Topical products in the form of creams, tablets, or rings should be prescribed for women exclusively experiencing vulvovaginal atrophy.
Many systemically administered estrogen products are available in the United States, but conjugated equine estrogens (CEEs), prepared from the urine of pregnant mares, is the most widely prescribed. Transdermal estrogen preparations are also available and usually are prescribed for patients who experience adverse effects, elevated triglycerides (TG), or liver function abnormalities while taking an oral product. Transdermal preparations also have a lower incidence of venous thromboembolism (VTE) than oral preparations.10
Progestogens
Women who have an intact uterus should be prescribed a progestogen in addition to estrogen in order to decrease the risk of endometrial hyperplasia and endometrial cancer.11 Progestogens should be prescribed for at least 12 to 14 days of the month and often are prescribed continuously. Low doses of oral estrogen therapy, as well as some vaginal preparations, require daily or intermittent administration of a progestogen in order to provide endometrial protection. Table 50–1 lists estrogen and progestogen preparations and dosages.
Adverse Effects
Therapy with estrogen with or without a progestogen should be initiated at the lowest dose in order to minimize adverse effects. Because the adverse effects of these preparations can be similar, it may be difficult to assess whether the estrogen or the progestogen is the cause. Changing preparations, particularly the progestogen, or changing the method of administration may help to alleviate adverse effects. Table 50–2 lists the adverse effects that may be associated with estrogen and progestogen preparations.
Contraindications
HT should not be prescribed to women with a history of or active thromboembolic disease, breast cancer or estrogen-dependent neoplasm, pregnancy, liver disease, or undiagnosed vaginal bleeding. It also should not be used for the prevention or treatment of cardiovascular disease, cerebrovascular disease, or dementia.4
Methods of Administration
Cyclic Estrogen and Progestogen
Estrogen is administered daily, and progestogen is administered for 12 to 14 days of the month. The disadvantage of this method of administration is the return of monthly menses in approximately 90% of women 1 to 2 days following the last progestogen dose. However, the withdrawal bleeding does not last as long or is not as heavy as a typical menstrual period. Women may view this scheduled bleeding as an advantage to this method of administration as it limits spotting or soiling of undergarments.
Continuous Combined Estrogen and Progestogen
Estrogen and progestogen are administered daily and result in endometrial atrophy. Therefore, women do not experience a withdrawal bleed but may experience unanticipated break-through bleeding or spotting during the month. Although this may sound more appealing than a withdrawal bleed, women may view the unpredictable bleeding or spotting as a disadvantage to this type of administration. Women should be educated that the bleeding or spotting usually resolves within 6 to 12 months. If bleeding persists beyond this time period, women should seek medical attention to rule out more serious conditions such as endometrial hypertrophy or carcinoma.
Low-Dose HT
Lower doses of HT have become more popular following publication of the WHI study results. There is an increasing body of evidence proving the effectiveness of these regimens in the management of menopausal symptoms. The Women’s Health, Osteoporosis, Progestin/Estrogen (HOPE) trial demonstrated that lower doses of CEE ± medroxyprogesterone acetate (MPA) (CEE 0.45 mg or 0.3 mg ± MPA 2.5 mg or 1.5 mg) decreased hot flashes comparable with standard HT, improved vulvovaginal atrophy, increased bone mineral density (BMD) at the spine and hip, and provided sufficient endometrial protection.14–18 Currently, no data are available on the effects of lower-dose HT on the incidence of VTE, breast cancer, or CHD. Lower-dose HT provides women with an alternative to standard-dose HT for menopausal symptoms but also should be recommended for a short duration. Although many women have switched to lower-dose HT, only time will tell if lower doses translate into lower risks.
Bioidentical HT
Bioidentical hormones are exogenous hormones that are identical to those produced in a woman’s body (e.g., estradiol, estrone, estriol, and progesterone). They are either commercially manufactured or chemically compounded in pharmacies into formulations such as topical creams, gels, and suppositories. The commercially manufactured prescription products are subject to regulation by the FDA and have been tested for potency, purity, efficacy and safety (Table 50–1). Conversely, pharmacist-compounded formulations are not subject to the same regulations and therefore, the efficacy and safety is questionable. Some patients view bioidentical hormones, particularly the pharmacist-compounded formulations, as “natural” and assume these formulations are safer than currently marketed prescription hormone products. However, due to a lack of regulation, these products could potentially cause more harm than benefit. There is little evidence comparing the safety and efficacy of conventional HT to prescription bioidentical HT and thus, the same risks and benefits should be assumed.19,20
Table 50–1 Estrogen and Progestogen Formulations and Dosages
Table 50–2 Adverse Effects of Estrogens and Progestogens
Estrogens
Common adverse effects
Nausea
Headache
Bloating
Breast tenderness
Bleeding
Serious adverse effects
Coronary heart disease
Stroke
Venous thromboembolism
Breast cancer
Gallbladder disease
Progestogens
Common adverse effects
Nausea
Headache
Weight gain
Bleeding
Irritability
Depression
Serious adverse effects
Venous thromboembolism
Decreased bone mineral density
From Refs. 5, 6, 13, 14.
Benefits of HT
Vasomotor Symptoms
HT is indicated primarily for the relief of moderate to severe vasomotor symptoms. It remains the most effective treatment for vasomotor symptoms and should be considered only in women experiencing those symptoms. Women with mild vasomotor symptoms may benefit from nonpharmacologic therapy alone; however, many women will seek medical treatment for these symptoms. The benefits of HT outweigh the risks in women who do not have CHD or CHD and breast cancer risk factors; however, careful consideration should be given to alternative and nonhormonal therapies for the relief of menopausal symptoms in women with these risks. Women should be involved in the decision and may choose to use HT due to the severity of their symptoms despite having some risk factors. Regardless of the situation, HT should be prescribed at the lowest dose that relieves or reduces menopausal symptoms and should be recommended only for short-term use. Women should be reassessed every 6 to 12 months, and discontinuation of therapy should be considered.
Vulvovaginal Atrophy
HT is indicated for the treatment of vulvovaginal atrophy. Approximately 50% of postmeno-pausal women experience vulvovaginal atrophy and seek medical attention for relief. Vulvovaginal atrophy is associated with vaginal dryness and dyspareunia and also may be associated with recurrent urinary tract infections, urethritis, and urinary urgency and frequency. Topical preparations generally should be prescribed as first-line therapy unless the patient is also experiencing vasomotor symptoms. Topical estrogen has demonstrated increased efficacy over systemic estrogen and generally does not require supplementation with a progestogen in women with an intact uterus using low doses of micronized 17β-estradiol.21 Women using regular or high doses of topical estrogen products do require intermittent treatment with a progestogen. Although few data are available on the appropriate progestogen dose, some data indicate that 10 days every 12 weeks may be sufficient to prevent endometrial hyperplasia.22Estradiol in the form of a tablet or a ring is not significantly absorbed systemically and may be used safely in a woman with contraindications to estrogen therapy and symptoms of vulvovaginal atrophy.23
Osteoporosis Prevention
Postmenopausal osteoporosis is a condition that affects millions of women and is characterized by low bone mass with microarchitectural deterioration of bone tissue that can lead to fractures.24 Fractures, particularly hip fractures, are associated with a high incidence of morbidity and mortality and a decrease in QoL. Before the WHI study, only observational data were available regarding the association of HT and the reduction of fractures. The WHI was the first randomized controlled trial (RCT) that demonstrated a reduction in total fractures, including the hip, spine, and wrist.2,25
Because HT should be maintained only for the shortterm, alternative therapies such as bisphosphonates or raloxifene should be considered as first-line therapy for the prevention of postmenopausal osteoporosis, in addition to appropriate doses of calcium and vitamin D. Because of the associated risks, HT should not be prescribed solely for the prevention of osteoporosis.
Colon Cancer
Retrospective observational studies suggested that HT was associated with lower rates of colorectal cancer. The WHI was the first and largest RCT to confirm that HT decreases the risk of colorectal cancer.2However, in the WHI estrogen alone arm, the cases of colorectal cancer were not lower in the estrogen group compared with the placebo group.26 Unfortunately, these data are inconsistent and are not compelling enough to justify long-term use of estrogen therapy to prevent colon cancer.
Risks of HT
Cardiovascular Disease
CHD is the leading cause of death among women in the United States. Retrospective data indicated that HT was associated with a decrease in risk of CHD by 30% to 50%.26 However, the results of recent RCTs demonstrate that HT does not prevent or treat CHD in women and that it actually may cause an increase in CHD events. The HERS, published in 1998, was the first RCT conducted in women with established CHD. This trial demonstrated an increased incidence of CHD events within the first year of treatment with HT and an increased risk of VTE and gallbladder disease. There was a trend of decreasing incidence of CHD death in years 3 to 5 that prompted a continuation of the study.1 The HERS II was an open-label continuation of the HERS for an additional 2.7 years. No difference was found in CHD events between the HT and placebo groups; however, there was an increased risk of VTE and biliary tract surgery in the HT group.27
The WHI was the first RCT conducted in women without established CHD. Women aged 50 to 79 years with an intact uterus were assigned to receive HT (CEE 0.625 mg + MPA 2.5 mg) daily for 8.5 years. The trial was stopped after only 5.2 years owing to an increased incidence of breast cancer in women taking HT compared with placebo. The WHI demonstrated an increased risk of CHD within the first year of treatment of 0.37% in the HT group compared with 0.3% in the placebo group (hazard ratio [HR] 1.29, 95% confidence interval [CI]) 1.02-1.63). This translates into a number needed to treat to harm (NNTH) of 1,428. There also was an increased risk of stroke in the HT group (0.29%) compared with placebo (0.21%) (HR 1.41, 95% CI 1.07-1.85), with an NNTH of 1,250. Therefore, for every 10,000 women treated per year with HT, there would be seven more CHD deaths and eight more strokes.3
The estrogen alone arm of the WHI, which included women aged 50 to 79 years with a history of hysterectomy, continued for another 1.6 years (average follow-up 6.8 years). This arm of the study did not demonstrate an increased risk of CHD compared with placebo. However, there was an increased risk of stroke in the estrogen alone group (0.44%) compared with placebo (0.32%) (HR 1.39, 95% CI 1.10-1.77). This translates into an NNTH of 833 and 12 more strokes for every 10,000 women treated per year with estrogen therapy.26
The results of these trials demonstrate that HT should not be prescribed for the prevention of CHD or in patients with pre-existing CHD. For women suffering from vasomotor symptoms with a history of CHD, including CHD risk factors, alternative nonhormonal therapies should be considered. Additionally, lifestyle modifications should be implemented, and therapies to treat risk factors such as hypertension and hyperlipidemia should be prescribed. It is important to note that the average age of women included in the HERS and the WHI trials was 67 and 63 years, respectively, and they started HT a mean of 10 years after menopause. Therefore, these trials were unable to assess the true risk in younger, potentially healthier women with fewer cardiovascular risk factors.21
Breast Cancer
Breast cancer is the most common cancer in women in the United States. Observational data indicated an association between HT and breast cancer risk. The WHI was the first RCT to demonstrate an increased risk of invasive breast cancer among women taking HT. In fact, the trial was stopped early owing to an increased incidence of breast cancer in women taking HT (0.38%) compared with placebo (0.3%) (HR 1.26, 95% CI 1–1.59). This translates into an NNTH of 1,250 and 8 more cases of invasive breast cancer for every 10,000 women treated per year with HT. The risk of breast cancer was evident after only 3 years of treatment and continued throughout the study duration.2
Breast cancer was not increased in the estrogen-alone arm of the WHI, and in fact, the risk was nonsignificantly lower in this group than in the placebo group.26 These conflicting data point to a possible link of progestogen with breast cancer risk; however, this theory needs to be studied further.
Because the WHI is the best evidence to date linking HT with breast cancer, women with a personal history of breast cancer and possibly even a strong family history of breast cancer should avoid the use of HT and consider some alternative and nonhormonal therapies for the treatment of vasomotor symptoms.
Venous Thromboembolism
The WHI demonstrated an increased risk for venous thromboembolic disease in the HT group (0.34%) compared with placebo (0.16%) (HR 2.11, 95% CI 1.58–2.82). This translates into an NNTH of approximately 555 and 18 more cases of venous thromboembolic events for every 10,000 women treated per year with HT.2 The risk for deep vein thrombosis was also increased in the estrogen alone arm of the WHI, but pulmonary embolism was not increased significantly.26
In summary, combined estrogen plus progestogen should not be used for the prevention of chronic diseases because it increases the risk of CHD, stroke, breast cancer, and VTE. However, colorectal cancer and rates of fracture were reduced with combined hormonal treatment.
Other Effects of HT
QoL and Cognition
Although women generally consider QoL measures when deciding whether to use HT, the effects of HT on overall QoL have been inconsistent. HT did not demonstrate a clinically meaningful effect on QoL; however, women taking HT did have a small improvement in sleep disturbances, physical functioning, and bodily pain after 1 year of therapy.28 Results from the HERS demonstrated that HT did improve emotional measures such as depressive symptoms, but only if women suffered from flushing at trial entry. QoL improvement scores declined significantly in women without flushing symptoms.29
The prevalence of age-associated memory impairment is approximately 17% to 34% in the general population.30 Observational studies have suggested a potential benefit of HT on cognitive functioning and dementia. However, the WHI Memory Study (WHIMS), conducted in postmenopausal women aged 65 years or older, failed to demonstrate an improvement in cognitive function and demonstrated a dementia rate, including Alzheimer’s disease, two times greater than with placebo.30,31 The estrogen alone arm of the WHIMS also demonstrated similar results.32,33
HT improves overall well-being and mood in women with vasomotor symptoms, but it has not demonstrated an improvement in QoL in women without vasomotor symptoms.
Discontinuation of HT
In appropriately selected women, HT should be recommended at the lowest dose for the shortest duration and should be tapered before discontinuation in order to prevent the recurrence of hot flashes. Although vasomotor symptoms in most women will subside within 4 years, approximately 10% of women continue to experience symptoms that interfere with their QoL. Therefore, it is important to continually reassess a woman’s vasomotor symptoms while taking HT and to try to taper the therapy after 1 year. Literature suggests that one of every four women needs to be reinitiated on HT due to persistent and bothersome symptoms.34–36
Limited evidence is available to guide health care providers regarding the most effective, safe, and least disruptive way to taper HT. Slowly discontinuing HT over time may be associated with less risk of symptom return. The time frame for tapering HT is unknown but can take up to 3 to 6 months or longer in some cases. Tapering HT may be done in one of two ways: dose taper or day taper. The dose taper involves decreasing the dose of estrogen over several weeks to months and monitoring closely for a return of symptoms. If symptoms recur, the next reduction in dose should not occur until symptoms resolve or at least stabilize on the current dose. The day taper involves decreasing the number of days of the week that a woman takes the HT dose, for example, decreasing a daily dose of 0.3 mg estrogen to 0.3 mg estrogen 5 days a week. Again, if symptoms recur, continue on the current dose until symptoms resolve or stabilize before trying a subsequent decrease. These tapering regimens have not been studied in clinical trials and may not prove to be beneficial in individual women.36
Nonhormonal and Alternative Treatments
Since publication of the WHI study, there has been an increase in the use of alternative and nonhormonal therapies for the management of menopausal symptoms. Particularly for women with CHD and/or breast cancer risk factors, these therapies may offer another option to assist with symptom management. A wide range of therapies, both prescription and herbal, have been studied with varying degrees of success. In choosing a particular therapy, it is important to match patient symptoms with a therapy that is not only effective but also safe.
A variety of nonhormonal and alternative therapies (Table 50–3) have been studied for symptomatic management of vasomotor symptoms, including antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs] and venlafaxine), herbal products (e.g., soy/isoflavones, black cohosh, evening primrose oil and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine).37,38 The limited and often conflicting evidence demonstrates that these agents are only modestly effective. It is also widely assumed that these agents are safer than HT, when in reality, few have been evaluated in randomized trials.
SSRIs and venlafaxine are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, fluoxetine, citalopram, paroxetine, and sertraline have been studied and demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.37 It is important to note that many of these trials were conducted in women with breast cancer who were also on antiestrogen therapy. Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety.
Alternative therapies used for the relief of menopausal symptoms are purported to act by a number of different mechanisms. Phytoestrogens are plant sterols that are structurally similar to human and animal estrogen. Soy protein is a common source of phytoestrogens.37–39 There has been conflicting results as to the efficacy of phytoestrogens in treating hot flashes and if used, at least 45 to 60 g/day of isoflavone content is necessary for any possible benefit. Because the effect of isoflavones on breast cancer and other female-related cancers, bone mass, and vaginal dryness is unknown, phytoestrogens should not be considered in women with a history of estrogen-dependent cancers.41
Black cohosh has been one of the most studied alternative therapies for vasomotor symptoms, but it has not demonstrated a substantial benefit over placebo. The mechanism of action, safety profile, drug-drug interactions, and adverse effects of black cohosh remain unknown. In non–placebo-controlled trials conducted for 6 months or less, black cohosh (40–80 mg/day) demonstrated a small, nonstatistically significant reduction in vasomotor symptoms.37,38,40 In addition, there have been case reports of hepatotoxicity with the use of black cohosh.42 Caution should be exercised when considering the use of this product, especially in patients with liver dysfunction. There is insufficient evidence to determine the effectiveness of black cohosh and due to safety concerns, it should not be recommended at this time.41,43
Dong quai, evening primrose oil and several other alternative therapies, including passion flower, sage, valerian root, flaxseed, and wild yam, have not demonstrated efficacy with regard to the relief of vasomotor symptoms, and the safety of these products is also questionable.37,38,40 Therefore, these products should not be recommended for the relief of vasomotor symptoms in postmenopausal women.
There are a number of other prescription products that have been studied for the management of menopausal symptoms. Gabapentin is thought to exert its effect by affecting the thermoregulatory process of the pituitary-hypothalamic region through modulation of calcium currents that, in turn, affect adrenergic and serotonergic pathways. In RCTs, gabapentin at doses of 900 mg/day demonstrated significant reductions in severity and frequency of hot flashes compared to placebo. Clonidine is thought to work by reducing small-vessel response, both centrally and peripherally, to various stimuli. It has been studied in several small RCTs at doses of 0.1 to 0.4 mg/day and has demonstrated statistically significant reductions in hot flashes.40 This agent may be considered in women with a history of hypertension, but the adverse effects may outweigh the benefits.
Table 50–3 Nonhormonal Therapies for Menopause
Overall, alternative and nonhormonal therapies are less effective in treating vasomotor symptoms than HT but do offer another option for women experiencing menopausal symptoms who cannot or are unwilling to take HT. SSRIs and clonidine have the best evidence for efficacy, however, health care providers should weigh the benefits and risks of all therapies, and women should be advised to discuss their options with physicians and pharmacists.
OUTCOME EVALUATION
Evaluating the outcomes of any therapy for menopausal symptoms focuses primarily on the woman’s report of symptom resolution. Ask women to report the resolution or reduction of hot flashes, night sweats, and vaginal dryness, and any improvement or change in sleep patterns. Also ask women taking hormonal therapies to report any breakthrough bleeding or spotting. If abnormal or heavy bleeding occurs, refer the woman to her primary care provider. Monitor subjective parameters such as adverse effects and adherence to the therapy regimen, as well as monthly breast self-examinations. In addition, monitor objective parameters, including blood pressure, at every outpatient visit; encourage yearly clinical breast examinations, mammograms, and thyroid-stimulating hormone (TSH) determination, particularly for women with hypothyroidism on thyroid therapy, and conduct a BMD test every 5 years. Also perform endometrial studies, as necessary, in women with undiagnosed vaginal bleeding. Lastly, evaluate the patient’s overall QOL. Because the management of menopause is largely symptomatic, it is important to document symptoms at the beginning of therapy and monitor symptom improvement and potential adverse effects at each visit. Frequent follow-up, proper monitoring, and education will help to ensure that the woman achieves optimal results from any therapy chosen to treat menopausal symptoms.
Patient Care and Monitoring
1. Assess the patient for use of HT by evaluating for the presence of vasomotor symptoms. If the patient is experiencing bothersome vasomotor symptoms, consider the use of HT only after assessing for risk factors for heart disease and breast cancer. If vasomotor symptoms are tolerable and/or the patient has risk factors for heart disease and/or breast cancer, consider alternative, nonhormonal treatments for vasomotor symptoms.
2. Obtain a thorough medication history, including the use of over-the-counter and herbal products.
3. Educate the patient on lifestyle or behavioral interventions that may help to alleviate vasomotor symptoms.
4. Discuss methods of HT administration, and have the patient decide in conjunction with the health care provider which one she feels will work best for her.
5. Recommend the appropriate dose of HT, and use the lowest effective dose for the shortest duration possible.
6. Educate the patient regarding the proper administration, potential adverse effects, and expectations of HT.
7. Monitor the patient for a reduction in vasomotor symptoms, vaginal dryness, and improvement in sleep.
Also monitor for breakthrough bleeding and spotting, adverse effects of HT, and improvement in QOL.
8. Monitor the following objective parameters:
• Blood pressure at every outpatient visit
• Yearly lipoprotein panels
• Yearly fasting plasma glucose determinations
• Yearly breast examinations and mammograms
• Yearly TSH determinations, particularly for women with hypothyroidism on thyroid therapy
• Endometrial studies in women with undiagnosed vaginal bleeding
9. Educate the patient regarding the importance of adhering to the medication regimen.
10. Educate the patient regarding the importance of obtaining a yearly mammogram and Papanicolaou (Pap) smear (if applicable), as well as performing a monthly breast self-examination.
11. Assess patient symptoms every 6 to 12 months, and consider tapering the HT dose and discontinuing treatment after 1 year. If vasomotor symptoms return, determine if a longer tapering schedule is warranted or if long-term treatment is necessary.
Patient Encounter, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for BW’s hot flashes and vaginal dryness. The plan should include:
(a) a statement identifying the patient problem and its severity,
(b) goals of therapy,
(c) a therapeutic plan based on individual patient-specific factors,
(d) subjective and objective monitoring parameters, and
(e) a follow-up evaluation to assess for adverse effects and adherence and to determine if the goals of therapy have been achieved.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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