US Pharm. 2006;31(9):89-96.

Although hormone therapy is the gold standard for the treatment of menopausal symptoms such as vasomotor symptoms and urogenital atrophy, much controversy exists about its use. Most of this controversy arose after publication of the Women's Health Initiative (WHI) study, a large prospective, randomized, double-blind, placebo-controlled study that looked at the effects of estrogen therapy (ET; 0.625 mg/day conjugated equine estrogen [CEE]) alone, as well as combination hormone therapy (HT; 0.625 mg/day CEE and 2.5 mg/day medroxyprogesterone acetate), on the incidence of certain diseases, especially coronary heart disease (CHD), breast and colorectal cancer, and fractures.1,2 Results of the WHI, which were first published in July 2002, indicated that many of the risks of combination therapy outweighed the benefits in terms of CHD, stroke, pulmonary embolism, and breast cancer1; in contrast, women receiving ET had no increased risk for CHD, breast cancer, or pulmonary embolism.2 Both treatment approaches significantly reduced the risk of fractures, and HT significantly reduced the incidence of colorectal cancer. It is important to recognize, however, that these studies did not address the use of HT and ET for the relief of menopausal vasomotor symptoms as a primary outcome--in fact, women who were experiencing severe vasomotor symptoms were excluded from these trials.

In general, many patients are still confused about whether they should use ET/HT. A recent telephone survey that was conducted among members of Kaiser Permanente of Northern California, a large health maintenance organization, included feedback from 670 female members, ages 50 to 69 years, who had regularly used HT from July 1, 2001, through June 30, 2002. Results showed that most women (93%) reported hearing about the WHI study. However, women's knowledge of the findings from the WHI was generally poor: 64% did not know what the findings were, 7% were unsure of their knowledge, and 6% had incorrect knowledge.3 Similarly, the 40,000-member database of the National Association of Female Executives was used to survey members regarding their experience with menopause and thoughts and knowledge about HT. Among the 961 women (?35 years old) who completed the survey, of those familiar with the WHI, 30% stated that the findings confused them.4 However, despite not understanding the findings of the WHI, many women appear to be discontinuing their therapy. In the telephone survey, published in Obstetrics and Gynecology, 56% of women reported discontinuing HT in the six to eight months after the WHI study results were published.3 In a retrospective study of 85 women in a university-based family medicine clinic, discontinuation rates of HT were 8% during the 12 months prior to the WHI information release and 38% during the six months after its release, with 80% of the patients discontinuing within three months.5 In addition, prescriptions for Prempro and Premarin, the two products used in the WHI, declined by 66% and 33%, respectively, from January to June 2002 and from January to June 2003.6 Thus, it appears that many women have stopped taking HT without understanding why.

By 2020, there will be 51 million women older than 51--the current average age of menopause.7 Thus, more and more women--many of them active and working full time and all of them desiring and needing a good quality of life--will begin experiencing menopause and the often disturbing symptoms that accompany the end of the reproductive years. The two general indications for ET/HT are treatment of menopausal symptoms and prevention of osteoporosis. However, better options (e.g., bisphosphonates) exist for osteoporosis management. ET or HT remains a first-line option for menopausal symptoms.

As a health care provider, it is critical to guide patients toward the most appropriate treatment options that will provide relief of menopausal symptoms without unduly increasing the risks for other health concerns. To help practitioners understand and address the current concerns about ET/HT, several medical organizations have published guidelines regarding the use of ET/HT. These organizations include several that specialize in the treatment of women, including the American College of Obstetricians and Gynecologists (ACOG), the North American Menopause Society, and the American Society of Reproductive Medicine, as well as the FDA and the U.S. Preventive Services Task Force. Guidelines were developed to help guide physicians in determining whether ET/HT is an appropriate choice for each of their menopausal patients and to highlight some of the key issues that must be addressed on an individual basis. This article provides an overview of some of the guidelines issued by these agencies regarding the use of ET/HT for menopausal vasomotor symptoms.



Vasomotor Symptoms
Hot flashes and night sweats are the most frequent symptoms of menopause. Studies have shown that most menopausal women experience some vasomotor symptoms, and 10% to 20% of these women find these symptoms intolerable.8 Symptoms have been reported to last more than five years in 25% to 75% of affected women and can severely impact patient quality of life.8 They can also lead to an increased rate of mood and sleep disorders.8-11

ET/HT has been clearly shown to help relieve vasomotor symptoms. An evidence-based systematic review of double-blind, randomized, placebo-controlled trials of oral HT for at least three months' duration showed that this therapy led to a significant reduction (75%) in weekly hot flash frequency for HT compared with placebo.12 Symptom severity was also significantly reduced with HT compared to placebo (odds ratio, 0.13; 95% CI, 0.07 to 0.23). The authors concluded that oral HT is highly effective in alleviating hot flashes and night sweats.12

Transdermal administration of ET has also been shown to provide relief of vasomotor symptoms. Several 12-week studies have evaluated transdermal delivery for relief of vasomotor symptoms with patches applied every three to four days or weekly. In all studies, transdermal estradiol significantly reduced moderate to severe symptoms.13-19

Unfortunately, although ET and HT are approved for the relief of vasomotor symptoms--and clearly work for this indication--alleviation of these symptoms is frequently not strongly considered when contemplating ET/HT use. However, many organizations do recognize the value of treating vasomotor symptoms with ET or HT and have published guidelines regarding the use of ET/HT for such treatment (Table 1).8,20-23 NIH, although not formally establishing guidelines, publicly recognized the value of using ET for the treatment of vasomotor symptoms, stating, "For most women who have bothersome or debilitating symptoms, low-dose estrogen (equivalent to 0.3 mg CEE) has been shown to be effective for hot flashes and night sweats, according to the 12 independent experts from biology, aging, obstetrics, biostatistics, psychiatry and other fields."24

In general, all agencies recommend that health care providers discuss both the benefits and risks of therapy with their patients. In addition, therapy must be individualized, based on each patient's risk factors and current symptoms. Finally, the continued use of ET/HT should be reassessed periodically (e.g., annually), with the goal of using the lowest effective dose for the shortest possible time to achieve symptom relief. As "the shortest possible time" has not always been clearly defined, the period of use should be individualized.

Urogenital Atrophy
Many women experience changes in the genitourinary tract along with vasomotor symptoms at menopause. These changes are associated with various symptoms; for example, 17% to 43% of women experience vaginal dryness, which is associated with both painful intercourse and a decrease in sexual desire, and 10% complain of vaginal burning.25 Other vaginal symptoms include pruritus and vaginal bleeding or spotting. Urinary symptoms associated with menopause include urgency, frequency, and stress and urge incontinence, as well as recurrent urinary tract infections. These symptoms can all have a negative impact on a woman's quality of life.

One of the primary indications for ET/HT is for the relief of vaginal atrophy. Almost all ET/HT regimens have shown efficacy in reducing vaginal atrophy, including reduced vaginal dryness, irritation, pruritus, and painful intercourse. In addition, many studies have also shown objective improvements in terms of restoration of normal elasticity to the vaginal mucosa, and an increase in vaginal fluid secretions, blood flow, and sensory response. 26-30 In contrast, no trials have shown an improvement in incontinence, and there are limited data showing the effect of ET/HT on recurrent urinary tract infections.25

ACOG recommends that in women with severe atrophic vaginitis, a low dose of estrogen, such as 0.3 mg CEE orally daily or 0.3 mg conjugated estrogen vaginally three times per week, be used to relieve symptoms.25 The recommendations are consistent with FDA guidelines, which recommend the use of a vaginal preparation for women whose only symptom is vaginal atrophy.23

Practical Approach to Guideline Recommendations
Given the global recommendation to use ET/HT for the shortest period of time at the lowest possible dose, questions arise about how pharmacists can make specific recommendations to providers and patients to guide patient care. It is important to know that all types and systemic routes of administration of estrogen approved by the FDA are equally effective for vasomotor symptoms. 21 However, women have individual needs based on medical history and symptoms. A woman with a hysterectomy may require higher amounts of estrogen initially (e.g., 0.9 to 1.25 mg/day oral CEE), while many women with vasomotor symptoms at menopause may do well with a lower dose of estrogen, such as 0.025 to 0.05 mg/day transdermal 17-beta-estradiol or 0.3 to 0.45 mg/day of oral CEE. If a woman remains symptomatic while on a lower estrogen dose, the dose may be gradually increased until symptoms are relieved. However, reevaluation of therapy, with discontinuation in mind, should occur annually.8

Unfortunately, there is little evidence to appropriately guide patients through discontinuation of ET/HT. One study evaluating abrupt versus gradual discontinuation of HT in postmenopausal women showed that gradual discontinuation simply postponed, but neither prevented nor minimized, the reappearance of vasomotor symptoms, mood deterioration, and sexual dysfunction. 31 However, when HT is gradually discontinued on an individual basis (not as "prescribed" in a study), it can be titrated to the lowest dose and taken for as long as necessary to control symptoms. Therefore, when a gradual taper is performed, it is recommended through either a "dose taper" or a "day taper."32 The dose taper is a progressive decrease of estrogen dose, such as 0.625 mg/day of CEE to 0.45 mg/day to 0.3 mg/day, then discontinuation. If symptoms recur with a lower dose, the next reduction should not occur until symptoms improve and are tolerable. This may require three to six months between dose reductions for some women. The day taper is a decrease in the number of days per week ET/HT is used. For example, the same dose of ET/HT may be used daily, then decreased to Monday through Friday; if tolerated, therapy may be discontinued on Thursday and so on until complete discontinuation. It is also possible to combine dose and day tapers by first taking half the original dose, then decreasing days of use.

For women who cannot tolerate even slow ET/HT tapers, the benefit of symptom relief may outweigh the risks of therapy. However, tapering should still be encouraged and alternative agents for treatment of symptoms, such as venlafaxine, paroxetine, or clonidine, may be tried during the taper. Black cohosh should not be recommended in combination with ET/HT therapy, and little benefit has been proven with other agents such as soy protein or herbal medications.33,34 Nonpharmacologic measures, such as smoking cessation, dressing in layers, exercise, drinking plenty of water, and using fans are appropriate recommendations for vasomotor symptom improvement.

As stated above, urogenital atrophy is a common complaint during menopause, and vaginal estrogen is the preferred formulation for treating this problem. Dosing is typically individualized based on symptom severity. As with vasomotor symptoms, the lowest dose that will control symptoms should be chosen, and therapy should be discontinued when possible. The usual initial dose of vaginal CEE is 0.5 to 2 g daily. Once symptoms have been controlled, it is appropriate for women to use vaginal therapy two to three times per week to maintain relief of atrophy.

Conclusion
Current recommendations indicate that ET/HT is appropriate to treat menopause-related vasomotor symptoms and vaginal atrophy--symptoms that can adversely impact a woman's quality of life. Therapy should be used at the lowest effective dose for the shortest time possible for the individual. Periodic evaluation is essential, so that women may achieve maximum relief of menopausal symptoms, while minimizing the risk of other long-term health concerns. Many ET/HT formulations are indicated for the prevention of menopause-related osteoporosis, although alternative therapies may be more appropriate for women at risk for osteoporosis who are not experiencing vasomotor symptoms.

Although the WHI has provided a large, useful body of data, quite a few questions remain. In addition, much of the data are not representative of women younger than 50. Often, women as young as 35 face uncomfortable menopausal symptoms for long periods of time. Small relative risk increases for adverse events in otherwise healthy patients early in menopause (<5 years) exist but may be offset by the significant benefits achieved in highly symptomatic patients who begin therapy.

The decision of whether to use ET/HT in menopausal women must be (1) individualized, (2) based on a complete clinical assessment, and (3) account for the benefits, risks, and alternatives available to each woman. The decision should be based on the severity of symptoms as well as the patient's personal attitudes and feelings. An understanding of the current recommendations regarding the use of ET/HT and staying up to date on large observational and randomized trial data can help clinicians counsel their patients and guide each woman toward the best decision for her.

 

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