Managing Menopausal Symptoms in the Geriatric Population: Moving Beyond Menopausal Hormone Therapy

Introduction

Although many women over age 65 have persistent menopausal symptoms, there are limited data to guide therapy among older women. Approximately 9-16% of women over the age of 65 continue to have menopausal symptoms,^1,2 and 13.7% of those women are using some form of menopausal hormone therapy (HT).³ The purpose of this review is to describe the pathophysiologic symptoms related to the menopausal transition (vasomotor, urogenital, and skin aging/breast ptosis), differentiate estrogen deficiency from normative aging, discuss treatment options for women over age 65 years, and address quality-of-life implications and counseling for women who have been on long-term HT.

Physiologic Changes During Menopause

Menopause occurs as a result of a genetically programmed loss of ovarian follicles.⁴ The earliest stage of menopause, typically around 2 years prior to the onset of menstrual irregularity, begins when inhibin B concentrations fall due to a decreased number of follicles, which causes serum follicle-stimulating hormone (FSH) levels to rise. During this transition, estradiol secretion is relatively preserved (normal or high estradiol levels) due to an increase in aromatase activity.^5,6 As menopause progresses, serum concentrations of FSH and estradiol change dramatically; high FSH and low estradiol levels occur as a result of decreased aromatase and inhibin B activity, which may be initiated by the hypothalamus, and result in the clinical manifestations of menopause.⁷

Available Data Sources

Most of the literature on menopause and HT were from studies conducted among women 45-60 years of age. This includes many small, short-term, randomized controlled trials (RCTs), several large observational studies (including the Nurses’ Health Study and the Melbourne Women’s Midlife Health Project), and one large randomized trial—the Women’s Health Initiative (WHI). The WHI is a large, ongoing national health study of 161,808 women (age range 50-79 yr; mean age, 63 yr, at inception). This study includes a RCT of HT and an observational study examining dietary patterns, calcium and vitamin D supplementation, and health outcomes such as cardiovascular disease (CVD) and osteoporosis. The WHI Postmenopausal Hormone Therapy Trials include 27,347 women randomized to either estrogen plus progestin (E+P) or estrogen-alone (E-Alone), depending on whether they had an intact uterus (www.nhlbi.nih.gov/whi). Both trials were stopped early; the E+P arm was stopped in 2002 after an average of 5.6 years of follow-up because of an increased risk of breast cancer and some increased risk of CVD in the active therapy group. The E-Alone arm was stopped in 2004 after an average of 6.8 years because of increased risk of stroke and no benefit for CVD in the active therapy group. The women were invited to continue follow-up (without intervention) for long-term chronic disease outcomes through 2010. The WHI has been criticized for including a large number of asymptomatic older women. However, WHI provides helpful information for the 65-and-older age group, especially in terms of understanding the impact of HT on chronic disease risks.

Menopausal Symptoms

The common complaints of hot flashes, night sweats, and vaginal dryness are the only menopausal symptoms that have been shown to be conclusively associated with estrogen deficiency.² Vasomotor symptoms are the most common complaint of menopause.⁸ Recent studies found the average duration of these symptoms to be 4-5 years.^9,10 An estimated 15% of women age 66 or older and 10% of women over age 70 have persistent bothersome symptoms 10-20 years post-menopause.² Unlike vasomotor symptoms, urogenital symptoms persist and often worsen with age. Urogenital atrophy is associated with vaginal dryness, itching, irritation, and dyspareunia, as well as dysuria and more frequent urinary tract infections. Urogenital symptoms affect 50-66% of all postmenopausal women. The degree and frequency of urogenital symptoms appear to increase with age.^11,12 Although urinary stress incontinence and frequency is more common among postmenopausal women, it appears to be associated with aging and other risk factors (ie, obesity, increased parity) rather than menopause. HT has not been found to improve urinary stress incontinence/frequency and, in fact, was found to worsen it in the WHI trial,¹³ suggesting that incontinence is not a direct result of estrogen deficiency.  Skin aging and breast ptosis (“sagging”) may also be associated with declining estrogen levels.¹⁴ Cognitive disturbances, urinary incontinence, sexual dysfunction, mood changes, and fatigue have not been directly linked to the hormonal changes that occur during menopause. Many of these symptoms are also noted in men of the same age.

Skin aging, defined by the loss of collagen, elastin, and hyaluronic acid, manifested by the appearance of wrinkles, accelerates rapidly after menopause. Thought to be secondary to declining estrogen levels,^15-17 it is also influenced by cumulative sun exposure. Systemic HT with estrogens in postmenopausal women improves the skin’s appearance, resulting in decreased slackness, wrinkling, and roughness. At microscopic levels, HT seems to affect dermal collagen, increasing its content and augmenting dermal thickness.^16,17 Estrogens also have been found to enhance vascularization and decrease diffuse hair loss that often accompanies aging in postmenopausal women.¹⁸ However, given the known risk profile of HT, it is not indicated for treatment of skin aging.

Breast ptosis is another common complaint of postmenopausal women and occasionally a motivation for taking HT. Ptosis of the breasts is partially related to estrogen deficiency. Degeneration of elastic fibers and tissues within the breast begins during ages 30-40, and the degree of breast ptosis is directly related to increasing parity. Ptosis increases after menopause as milk ducts and lobes begin to shrink; however, this shrinking process begins several years prior to the onset of menopause. Though we are not aware of studies specifically addressing the effects of HT on breast augmentation, it is speculated that HT slows, but does not reverse, progression of breast ptosis.¹⁹

Managing Postmenopausal Low Bone Mineral Density

Effective nonhormonal therapies for osteoporosis, including bisphosphonates, are available and have fewer long-term risks than HT. A recent systematic review outlines the risks and benefits of available treatment options.²⁰ A woman’s risk of osteopenic fracture can be made using the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX®; www.shef.ac.uk/FRAX), which combines the T-score with age and other risk factors to predict 10-year fracture risk. Women with osteopenia (T-score between -1 and -2.5) without prior fragility fracture or other significant risk factors do not warrant pharmacologic therapy but should be followed closely, encouraged to participate in weight-bearing exercise, and supplemented with calcium and vitamin D. Women with osteoporosis or prior fragility fracture warrant pharmacologic therapy, exercise, and calcium/vitamin D supplementation. First-choice treatment for osteoporosis should be bisphosphonates, raloxifene, parathyroid hormone, or calcitonin rather than HT because of their more desirable risk-to-benefit profiles. Women with new or progressive osteoporosis already being treated with HT should be changed to more effective therapy directed at bone health.²⁰

Reducing Postmenopausal Cardiovascular Risk

Similar to osteoporosis, the use of HT for prevention of CVD is not recommended.²¹ The WHI demonstrated more risk than benefit with the use of HT for prevention.^22,23 Medications such as statins and antihypertensives have a greater risk reduction for CVD than HT and have fewer side effects.^24-27

Addressing Women’s Symptoms and Quality of Life

The menopausal transition is often anticipated as a negative experience by premenopausal women with fear of loss of sexuality, femininity, and fertility, as well as the anticipation of hot flashes.²⁸ However, more postmenopausal women rate menopause as a positive experience than those who are anticipating menopause. Women who have a healthy relationship with a partner have a more positive menopausal experience.²⁹ In the large Study of Women’s Health Across the Nation cohort, health-related quality of life (HRQOL) was more related to specific symptoms, stressors, and unrelated medical conditions than to the menopausal transition itself.³⁰ Whether HT improves HRQOL is still controversial, and studies have mixed results. The WHI concluded that combination HT did not improve HRQOL based on five categories (depression, sleep disturbance, sexual function, cognition, and menopausal symptoms). However, women with moderate-to-severe menopausal symptoms were discouraged from participating in the study.²³

In discussing menopause with an individual patient, it is important to assess the symptoms being experienced, the impact of symptoms on HRQOL, and what the patient considers an acceptable improvement. One study of symptomatic women found that an average decrease in hot flashes by 50% would be considered an adequate response from non-HT.³¹ However, there was significant variability, with some women expecting a minimal decrease in hot flashes, and others desiring complete cessation.

In a study of women who stopped HT after the WHI findings were released, 82% of women experienced some menopausal symptoms. However, only 49% of these women sought advice from their physician, and an equal number sought a trial of complementary and alternative medicine (CAM) therapy.³² There is general dissatisfaction surrounding the role of their primary physician in the management of menopause. In a small study of women who sought out CAM,³³ a primary goal for these women was controlling their menopausal experience. They perceived that a physician would offer HT but not work to create an individualized care plan to address the symptoms of menopause. In this study, women were more likely to obtain information from other resources such as friends, magazines, and the Internet. These women were also more likely to not disclose use of CAM due to fear of negative response from their physicians. The lack of attention and treatment of menopause-related symptoms has resulted in frustration and distrust among many menopausal women.³⁴

Treatment of Menopausal Symptoms

Because most menopausal therapies treat the individual symptoms of menopause, multiple modalities are often needed. HT is the only available treatment that addresses many symptoms of menopause, but it also has the most associated risks. Currently, there are several methods and dosages of HT, all of which carry general and specific risks. The WHI, as well as the Women’s International Study of Long-Duration Oestrogen after Menopause (WISDOM), found that starting HT several years after menopause increased the risk of cardiovascular events. In WHI, seven more coronary heart disease events and eight more strokes were observed per 10,000 person-years of observation in the E+P group.^22,35 Therefore, non-HT would be preferred over commencing HT in women over 65 years of age, particularly in women with other risk factors for CVD. Determining the correct therapy is an individualized process that needs to occur between a provider and an informed patient.

Nonmedical and Complementary Treatment
Practical advice, such as dressing in layers, keeping a fan nearby, maintaining cool ambient temperatures (especially in the bedroom), avoiding hot drinks, caffeine, and hot or spicy foods, and keeping an ice pack under a bed pillow, are helpful for many women. These measures are simple, inexpensive, and risk-free. However, they may be inadequate for women with moderate vasomotor symptoms. General health improvement steps, such as quitting smoking or decreasing alcohol consumption, have consistently been shown to decrease the severity of vasomotor symptoms. Smoking cessation may also improve vaginal vascularity and decrease atrophy.^36-38

Previously, exercise was thought to help reduce hot flashes, but several studies have now shown no significant benefit.^39-41 However, women who exercise regularly may have a shorter duration of menopausal symptoms.^10,42 The many other health benefits of regular exercise make it worthwhile for postmenopausal women. Weight training may decrease the appearance of breast ptosis by increasing pectoralis muscle tone, but this is speculative. Relaxation and stress management techniques (specifically deep breathing and stretching) have been shown to decrease vasomotor symptoms by 30-50%.^43,44 Other modalities such as yoga, acupuncture, and massage do not appear to improve vasomotor symptoms beyond placebo effect, though there are few large, rigorous studies of these techniques.⁴⁵

Vaginal moisturizers have been shown to improve vaginal dryness and decrease dyspareunia. Two RCTs comparing a nonhormonal vaginal moisturizer to vaginal estrogen cream found the vaginal moisturizer to be as effective as vaginal estrogen at reducing symptoms of vaginal irritation and dyspareunia.^46,47 In additional to regular use of a vaginal moisturizer, personal lubricants available over the counter applied just before sexual activity may also be helpful. Regular sexual activity also may be helpful in improving symptoms, apparently due to increases in vaginal blood flow during intercourse.⁴⁸

CAM therapies, including herbs, are popular topics in the lay press with regard to menopausal symptoms. Studies of these therapies tend to be small, of short duration, not rigorously conducted, and performed in selected populations. CAM treatments are not covered by the same Food and Drug Administration regulations that govern medications. Lack of product standardization and questions about safety, correct dosage, and interactions with other medications indicate that they should be used with caution, especially in women over age 65, for whom polypharmacy may be an issue. Use of ginseng, evening primrose, Dong quai (Angelica sinensis), kava, red clover, St. John’s wort, or vitamin E appears not to be efficacious for the relief of vasomotor symptoms.^49-52 There are few high-quality trials of phytoestrogens, black cohosh, and newer agents using Angelica sinensis and Matricaria chamomilla, and these trials have yielded mixed results.⁵³ Phytoestrogen extracts and soy products appear to have little effect on menopausal symptoms but are postulated to have positive health effects on plasma lipid concentrations.⁵⁴ Because it is not known whether phytoestrogens act in a similar fashion as estrogens, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian) should not use soy or other phytoestrogen-based therapies. We recommend that individuals using CAM therapies be referred to www.medlineplus.gov to review the available information on efficacy, as well as drug-herb interactions and side effects, along with their provider.

Nonhormonal Medications for Vasomotor Symptoms  
Nonhormonal prescription medications for vasomotor symptoms, including clonidine, gabapentin, and some antidepressants, are an alternative to HT. In two RCTs, one with breast cancer survivors and one with women with no history of breast cancer, paroxetine reduced hot flashes by 30% and 25%, respectively, over placebo.^55,56 The other selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, and sertraline have not shown benefit.^57-59 Venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), showed some benefit over placebo for vasomotor symptoms in breast cancer survivors, but that benefit was not reproducible among women without breast cancer.^60,61 Clonidine may be modestly helpful in reducing hot flashes versus placebo.⁶² However, its use is limited by side effects, and its risks outweigh its benefits, particularly in geriatric patients. Gabapentin at higher doses decreased hot flashes 23-30% over placebo in women with and without breast cancer.^63,64 Paroxetine, gabapentin, and clonidine only treat vasomotor symptoms, not the other symptoms such as vaginal atrophy, skin aging, or breast ptosis.

Hormonal Therapy for Vasomotor Symptoms
HT is the treatment proven to be most effective for treating all symptoms of estrogen deficiency.⁶⁵ HT substantially reduces the frequency (74.3% reduction) and severity of vasomotor symptoms,66 usually within 1 month. However, because initiating HT several years after menopause increased the risk of cardiovascular events, it is not recommended to commence HT in women who are already beyond menopause or are at increased risk for CVD.^35,67 Combined E+P increases risk of coronary heart disease (especially when started several years after menopause), stroke, invasive breast cancer, venous thrombosis, cholecystitis, and dementia.^35,45 Unopposed estrogen increases the risk of stroke and venous thrombosis.^22,68 HT should only be considered in nonsmokers who are experiencing bothersome vasomotor symptoms and/or who have failed other treatment approaches.

Several varieties of HT are currently available, summarized in the Table along with nonhormonal treatment options. Dosage, formulation (conjugated vs unopposed estrogen), and route of administration (implants, patches, cream, pills, vaginal rings) can be used to target treatment of specific menopausal symptoms. Risks of breast cancer, venous thrombosis, and stroke are minimized with topical/local estrogen relative to systemic estrogens, but patients should be aware that even local HT can have systemic effects.⁶⁹ Systemic HT (oral or transdermal preparations) is the most effective treatment for vasomotor symptoms,⁷⁰ while intravaginal forms (ring, tablet, or cream) are more effective for urogenital atrophy. Transdermal preparations decrease vasomotor symptoms similar to oral preparations.⁷¹ Because head-to-head comparisons of different types of HT have not been conducted,⁶⁵ little is known about their relative comparative effectiveness.

Recommendations by the North American Menopause Society (NAMS) are to use the lowest effective dose for the shortest amount of time.⁶⁷ Lower doses of HT may not be as effective as higher doses, but differences may be small. Standard-dose HT (oral conjugated equine estrogen at 0.625 mg daily) reduces the frequency of hot flashes by approximately 94% as compared to a 44% reduction among women taking placebo, whereas lower doses (0.45 mg or 0.30 mg daily) reduce symptoms by 78%.⁷¹ Absolute contraindications to HT include pregnancy, unexplained vaginal bleeding, active or chronic liver disease, acute CVD or immobilization, history of breast or endometrial cancer, hormone-sensitive cancers, and history of CVD (coronary heart disease or stroke). Given the increased risk of venous thrombosis with estrogen alone⁶⁸ and estrogen plus progesterone,⁷² prior history of any thromboembolism should be reviewed with the patient and viewed as a contraindication to HT. Relative contraindications include increased risk for breast cancer, CVD, gallbladder disease, hypertriglyceridemia, and migraine headache.^65,70,73

Stopping Hormonal Therapy: Evidence and Approaches

Long-term use of HT for disease prevention is no longer recommended.⁷⁴ Even though HT has small protective effects on osteoporotic fracture and colorectal cancer,²² the net risks of long-term treatment outweigh the benefits. HT use beyond 5 years is associated with increased risk of breast cancer.^75,76 The benefit-risk ratio for menopausal HT is favorable close to menopause among symptomatic women but decreases with age and time since menopause.⁷³ For women over age 65 who have been on HT longer than 5 years, consideration should be given to the initial symptoms for which treatment was started. Additional considerations include effects on HRQOL, and any new or changed risks for that particular patient (eg, venous thrombosis, stroke, breast cancer).

Despite knowledge of the risks of long-term HT, many women are still reluctant to discontinue treatment. Based on a survey of 100 women who had been on HT for an average of 17 years, 100% stated that they were aware of the risks of estrogen based on the WHI, and 76% were aware of the risks of breast cancer. However, only 3% of these women were willing to discontinue therapy, and only 26% were willing to lower the dose. Most women reported reluctance to stop because of symptoms they experienced before starting HT. Only 20% of women believed that the risk of breast cancer was duration-dependent.⁷⁷ Thus, counseling women who have been on long-term HT may be a difficult, yet necessary, task. Counseling should present all forms of treatment offered to menopausal women, outlining benefits, risks, and side effects. The risk of breast cancer associated with HT varies according to dosage, duration, and preparation, and needs explanation.^69,75,76 Reassurance and practical advice may be sufficient to reduce or remove some of the fears of discontinuing HT. Starting an alternative nonhormonal form of treatment may help decrease rates of resuming HT.

The best approach to discontinuing HT has not been established. The NAMS panelists recommend either abrupt cessation of HT or slow tapering by either decreasing the dose or the number of days between doses.⁶⁷ Very few studies have looked at the preferred method for discontinuation. One study with only 91 women (mean age, 57 yr) randomized women into two HT discontinuation methods: abrupt discontinuation versus slow taper over 6 months. This study showed that the slow taper method postponed the return of menopausal symptoms, but at 9 months approximately 30% of women had recurrence of vasomotor and/or urogenital symptoms.⁷⁸ Between 15-30% of these women elected to restart HT after discontinuation secondary to return of menopausal symptoms.⁷⁸ We recommend a trial of nonestrogenic therapy directed toward the most bothersome symptom as an alternative to restarting HT.

Summary

Approximately 10% of women over the age of 70 continue to have persistent menopausal symptoms decades after menopause. Some of these women have been on long-term HT for symptom management. Because the long-term chronic disease risks associated with HT increase as a woman ages, these risks are important considerations among women over age 65. Several safer nonhormonal treatment options are available to treat lingering menopausal symptoms or to treat low bone mineral density and hyperlipidemia. An informed discussion and an individualized approach should include consideration of the risks of a therapy, as well as the impact of particular symptoms on HRQOL. Considering a change to a nonhormonal treatment and counseling women about the risks and benefits of long-term HT is necessary to ensure quality healthcare.

The authors report no relevant financial relationships.

Dr. Davis is from the Department of Medicine and Dr. Wierman is from the Division of Geriatrics, Maine Medical Center, Portland; Dr. Fairfield is from the Department of Medicine and the Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Maine Medical Center; and Dr. Col is from the Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute.