KEY POINTS

■ The North American Menopause Society estimates that 6,000 women daily and more than 2 million women each year enter menopause. Many of these women will experience symptoms during and after the menopausal transition that might be effectively treated with hormone therapy (HT).

■ HT fell out of favor when two landmark studies appeared to show that its risks outweighed its benefits. However, new studies suggest that for women aged 50 to 59 years—the group most likely to benefit from HT—the risks are not as prevalent as once believed.

■ HT is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar/vaginal atrophy in symptomatic women and the prevention of postmenopausal osteoporosis.

■ HT should be initiated at the lowest available dosage. After 8 to 12 weeks of therapy, symptoms should be reassessed, and the dosage adjusted accordingly. Length of use should be re-evaluated annually. HT can be discontinued after 2 to 3 years but resumed if symptoms recur.

Clinicians are accustomed to treating patients who have medical illnesses; however, managing the symptoms associated with menopause—a natural, biologic process—is quite different. Hormone therapy (HT) using estrogen either with or without progesterone remains the most effective, and most studied, treatment.1 But many patients and clinicians have reservations about using HT because of the controversy surrounding it. All clinicians, regardless of their specialty, may encounter patients who have questions about the use of hormones. In family medicine practices, women may inquire about hot flashes and night sweats; in orthopedics practices, the treatment and prevention of osteoporosis; and, in gynecology practices, dyspareunia and vaginal atrophy. Clinicians should be able to respond with accurate, upto- date information on the recommendations for HT as well as its known risks and benefits.

The North American Menopause Society (NAMS) estimates that 6,000 women daily and more than 2 million women each year enter menopause.2 Menopause occurs in three stages: perimenopause, menopause, and post menopause. Perimenopause is when estrogen levels begin sporadically increasing and decreasing, leading to irregular menstruation and adverse symptoms, such as hot flashes. Perimenopause begins the transition to menopause and can last for 5 years or longer. Menopause is defined as the final cessation of menstrual periods and is confirmed after 12 consecutive months of amenorrhea. A woman is then considered to be postmenopausal. At this time, her ovaries produce very little estrogen and no progesterone, and ovulation has ceased. Typically, a woman experiences natural menopause between the ages of 45 and 54 years.

For clarification, this article uses the NAMS terminology: ET refers to unopposed estrogen therapy; EPT refers to combination estrogen and progestogen therapy; and the term progestogen refers to both progesterone and progestins. NAMS describes progesterone as being identical to the hormone produced by the ovaries, whereas progestins are synthesized compounds that act like progesterone. HT refers collectively to both ET and EPT.3

HISTORY OF HORMONE THERAPY

The first commercial hormone preparations became available in the 1920s.4 HT was initially prescribed for the prevention and/or treatment of chronic conditions. In the 1980s and 1990s, researchers believed that HT provided coronary benefits and potentially decreased the risks of osteoporosis, Alzheimer's disease, and overall morbidity. Its benefits were thought to outweigh the risks for women of all ages and at all stages during climacteric. Therefore, many clinicians and women were taken aback when the results of the Heart and Estrogen/progestin Replacement Study (HERS), published in 1998, showed that HT did not reduce the risks of coronary heart disease (CHD) events.5 In another surprise, the Women's Health Initiative (WHI) was stopped in 2002 because an increased incidence of CHD and breast cancer was seen among some study participants.6 In light of these study results, the risks of HT were then believed to outweigh the benefits for all women.

CONTEXT IS KEY

Researchers have since revisited the HERS and WHI studies and re-evaluated much of their data. Started in 1993, the HERS study was sponsored by the makers of Prempro, who were seeking approval for use of the EPT for secondary prevention of heart disease.5 The study enlisted 2,763 women with existing heart disease. All the participants had a history of prior MI, angioplasty, cardiac surgery, or catheterization. The researchers found that EPT did not prevent further cardiac problems in women with existing coronary disease.5

The WHI was the first randomized, controlled trial (RCT) designed to investigate the potential benefits of HT, which at that time were supported only by observational and retrospective studies.6 The effects on MI and stroke were of par ticular interest. The WHI, a much larger study than HERS study, enrolled a total of more than 161,000 women aged 50 to 79 years for a set of clinical trials. Researchers saw a remarkable increase in breast cancer, heart disease, stroke, and blood clots among the 16,608 participants in the clinical trial on postmenopausal hormone use, which led them to stop the study earlier than expected.6 Many researchers now believe that the increase in adverse effects highlighted by WHI do not apply to all women older than 50 years.

WHI study participants had very diverse backgrounds, and many were quite different from the population that HT is prescribed for today. Many WHI participants were asymptomatic. In addition, the women had higher risks for cardiovascular disease: 34% had a body mass index higher than 30 kg/m2, 36% had hypertension, and 49% were current or former smokers.1 Some had a history of MI and stroke, and others had previously used HT.

Age is an important factor to consider. The average age of participants was 63.3 years, an average of 10 years older than the age of most of the women who begin HT today.1 Only 10% of WHI participants were aged 50 to 54 years, and only 16% had experienced onset of menopause less than 5 years before initiating HT.1 Finally, the indications for use were also different. WHI and HERS assessed the benefits of long-term HT as treatment for or prevention of CHD.

The adverse events experienced by the older women discouraged many younger women from considering HT. The negative outcomes of the two studies were initially thought to apply to women of all ages; therefore, many women discontinued HT and faced the symptoms of menopause without medical assistance. However, new studies have focused specifically on women aged 50 to 59 years. The good news for this younger population is that although the known benefits are the same or have improved, the risks are not as prevalent as once believed. The scales of risk versus benefit have again started to tip, this time in favor of HT for menopausal symptoms in younger, symptomatic women.

CURRENT RECOMMENDATIONS

Today, HT is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar/vaginal atrophy in symptomatic women and the prevention of postmenopausal osteoporosis.7 NAMS and the American Association of Clinical Endocrinologists (AACE) recommend prescribing the smallest dosage for the shortest amount of time necessary to effectively relieve the patient's symptoms.1,3 As with any other treatment, HT should be considered based on the risks and potential benefits for each patient.

A thorough knowledge of the patient's specific symptoms, age, years since menopause, and health status is essential when determining if HT is an appropriate treatment choice. Contraindications should also be reviewed (Table 1). In general, risks are low and benefits prevail for peri- and postmenopausal women younger than 60 years and within 10 years of menopause. The risks for adverse events increase with age, but the benefits do not change, which makes timing of treatment an important variable.

The severity, frequency, intensity, and duration of symptoms vary greatly for each patient. To determine risk versus benefits of HT, the patient should consider the severity of her symptoms and their impact on her quality of life. In addition to vasomotor symptoms and the effects of vaginal atrophy, other symptoms may include urinary incontinence, trouble sleeping, sexual dysfunction, depression, anxiety, labile mood, and memory loss.8 If the patient feels her symptoms are mild, lifestyle modifications or alternative therapies may be sufficient. However, the relief provided by HT may outweigh the risks of treatment for patients with moderate to severe symptoms.

A comprehensive history and physical examination and mammography within the past 12 months are vital before initiating HT. Some patients may need to undergo other tests, such as bone densitometry.3 Unopposed estrogen should be prescribed for women who have had a hysterectomy. Women with a uterus should receive some form of progestogen to protect the endometrial lining and decrease the risk of endometrial cancer.3 Table 2 summarizes study findings on HT for patients with various comorbid conditions. NAMS provided the following guidelines for HT in its 2008 position statement:

• Vasomotor symptoms HT is considered the gold standard of treatment for hot flashes and night sweats. Longterm HT for vasomotor symptoms is usually not needed, as these symptoms are transient. In one study, 30% to 50% of women had improvement in vasomotor symptoms after a few months of HT, and 85% to 90% of women experienced resolution of symptoms within 4 to 5 years.9

• Vaginal atrophy Ten percent to 40% of postmenopausal women are affected by vaginal atrophy. Unlike vasomotor symptoms, vaginal atrophy is progressive and often requires treatment.10 It is caused by an absence of estrogen in the vagina; therefore, estrogen replacement is the most effective treatment. A low dose of local estrogen is recommended for patients who are seeking relief solely from vaginal symptoms.1,3

• Sexual function Local estrogen can improve dyspareunia associated with atrophy but does not correct disorders of libido or low sexual desire.

• Urinary health HT is useful for urge incontinence and urinary symptoms that are secondary to vaginal atrophy. Stress incontinence, however, is not an indication for HT. A urinary tract infection should always be ruled out first.

• Osteoporosis Treating bone loss with HT is a true riskversus- benefit issue. HT greatly reduces bone loss and number of fractures. Unfortunately, these benefits disappear quickly when treatment is discontinued. Replacing initial HT with a bisphosphonate or a selective estrogen receptor modulator (SERM) for long-term management of osteoporosis can be considered.11

ROUTE AND DOSAGE

HT preparations are available with various administration routes and dosages.12 Therapy should be initiated at the lowest available dose. Symptoms should be reassessed after 8 to 12 weeks of therapy, and the dosage adjusted accordingly. Approximately 10% of patients may need to have their dosage increased.11

The most common forms of HT are oral medications, transdermal patches, topical gels and creams, vaginal creams, tablets, or rings. To date, no RCTs indicate any advantages of one route over another. Oral preparations are subject to first-pass effect; however, because of the effects of higher estrogen levels on the liver when taken orally, the transdermal forms are preferred for women with hypertension, hypertriglyceridemia, or a high risk for cholelithiasis.1 In addition, some observational data indicate that the risk for deep vein thrombosis is lower with transdermal estrogen than with oral estrogen.3

Progestogen doses in EPT should be high enough to protect the endometrium but low enough to avoid the associated adverse events. Side effects range from headaches, nausea, abdominal pain, water retention, and weight gain to more serious events such as blood clots leading to MI, stroke, pulmonary embolism, or eye problems. Protective properties depend on the corresponding dose and frequency of estrogen and the progestogen preparation used.8 Progestogen can be administered continuously or cyclically. It is taken for 10 to 14 days every month when administered cyclically and produces a monthly menstrual cycle. Women who take progestogen continuously or daily experience amenorrhea, which typically results in better adherence.1

Unopposed estrogen should be administered as a vaginal preparation. Local estrogen is highly effective and is preferred over systemic estrogen for women with only vaginal symptoms. Systemic absorption is limited with vaginal preparations; therefore, concomitant progestogen is not indicated.10 Local estrogen, however, has no effect on vasomotor symptoms or osteoporosis prevention, and this should be explained to patients.

DURATION OF THERAPY

The length of HT use is based on the reason for therapy. Ideally, the patient's symptoms and the dosage and form used should be reevaluated as part of her annual examination.11 The need for further treatment is determined by discontinuing HT after 2 to 3 years. If symptoms recur, treatment can be resumed.

Some women may need long-term therapy. The NAMS guidelines recommend that as long as a woman is aware of her personal risks, she should be allowed to continue HT if she feels that the benefits outweigh her risks.3 This is especially true if her symptoms recur after an attempt to discontinue HT.3 A patient who opts for long-term therapy should be taking the lowest effective dosage. Patients may also choose to extend treatment when alternative therapies are not appropriate, cause unacceptable side effects, or the benefit-risk ratio of long-term use of an alternative therapy is unknown.3

DISCONTINUATION OF THERAPY

Most women are able to discontinue HT in less than 1 year.1 Researchers are divided, however, on how to discontinue HT. Many researchers recommend tapering the dose, but this has not been shown to result in any fewer side effects than stopping HT abruptly. Nonetheless, some clinicians recommend gradually decreasing the daily dosage, the number of days taken per week, or both.13 In one study, 25% of women were unable to discontinue HT because they developed withdrawal symptoms.14 Of the women who successfully stopped, 71% were stopped abruptly and 29% had their doses tapered.14

As when initiating HT, discontinuing therapy requires individualized attention. Some women will be able to discontinue HT more quickly—experiencing either no or fewer side effects—than other women. If the risks of continuing therapy are great but symptoms remain, an alternative treatment may be initiated to facilitate the transition. For instance, if hot flashes recur, a selective serotonin-receptor inhibitor (SSRI) or selective norepinephrine receptor inhibitor (SNRI) may be helpful.15

ALTERNATIVE TREATMENT OPTIONS

Women who cannot use HT may find relief with alternative therapies. Simple lifestyle modifications, such as dressing in layers, keeping the home temperature cooler, and practicing deep breathing and relaxation techniques may reduce or relieve hot flashes. Alternative pharmacologic therapies are also available. Low-dose antidepressants, such as venlafaxine 75 mg, an SNRI, were shown to effectively decrease hot flashes.16 Many SSRIs, such as paroxetine, can effectively treat vasomotor symptoms.17 A meta-analysis of RCTs supports using these agents as well as gabapentin and clonidine; however, the latter two agents may carry more side effects.15 Bisphosphonates, such as alendronate, risedronate, and ibandronate, are indicated to prevent and treat osteoporosis. SERMs have the same beneficial effects of estrogen (ie, increasing bone density) but without some of the adverse effects of estrogen in other tissues.15

The most popular OTC remedies are soy products, black cohosh, and vitamin E. Soy products contain isoflavones, a type of phytoestrogen. When metabolized, isoflavones are similar to human estrogen in structure and have a similar effect on estrogen receptors. Results of RCTs on the effectiveness of isoflavones in reducing hot flashes are inconclusive, and women with a history of hormone-dependent cancers, thromboembolic disease, or cardiovascular disease are cautioned about using soy because of its weak estrogenic effects.1 The amount of isoflavones used in studies on treatment of menopausal symptoms was 40 to 80 mg daily for up to 6 months.1 AACE recommends that women who wish to take isoflavones for their menopausal symptoms use whole food sources, not supplements.1

Black cohosh has been used in Germany to treat hot flashes for many years. However, randomized, placebo-controlled trials have yielded inconsistent results regarding efficacy.1 Black cohosh is thought to be relatively safe, but package labeling states it should not be used for more than 6 months. Vitamin E is also considered safe; however, it has not been proven to be any more effective than placebo.1

The efficacy of bioidentical hormones has been debated. The chemical composition of bioidentical hormones is identical to the hormones produced by the human ovaries,3 namely 17 beta-estradiol and progesterone, and some preparations have FDA approval. However, the term bioidentical often refers to non-FDA-approved, custom compounded formulations that are available by prescription from special compounding pharmacies. Ingredients and routes of administration are different with custom compounded preparations compared with those used with standard, commercial hormone preparations. The dosage is usually determined via a saliva test, which is a controversial test that is not proven to be accurate or consistent. These compounded hormones have not been tested for safety or efficacy and are not approved or standardized by any regulatory agencies.3 Patients should assume that compounded hormones have similar or increased risks compared with standard preparations until more evidence is gathered.3

CONCLUSION

Clinicians should adapt their patients' treatment plans and expectations as more information becomes available. The key concepts are individualized care and thorough patient education. Defining an accurate profile of risks and benefits of HT for each patient and involving the patient in the decision-making process will keep expectations realistic and produce more desirable outcomes. Treatment of menopausal symptoms is a complex area of medicine, but HT has promising benefits for symptomatic women. JAAPA

Janie Knotts is a recent graduate of the PA program at Marietta College, Marietta, Ohio, and now works in family medicine in West Virginia. Bill Childers is a professor in the program and was Ms Knotts' advisor. They have indicated no relationships to disclose relating to the content of this article.

DRUGS MENTIONED

Alendronate (Fosamax, generics)
Clonidine (Catapres, generics)
Gabapentin (Gabarone, Neurontin, generics)
Ibandronate (Boniva)
Paroxetine (Paxil, Pexeva, generics)
Conjugated estrogen/medroxyprogesterone acetate (Prempro)
Risedronate (Actonel)
Venlafaxine (Effexor, generics)

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