Cochrane for Clinicians

Putting Evidence into Practice

Hormone Therapy in Postmenopausal and Perimenopausal Women

Susanna R. Magee, M.D., M.P.H., and Julie Scott Taylor M.D., M.Sc.
Brown Medical School, Providence, Rhode Island

The Cochrane Abstract on the above is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Susanna R. Magee, M.D., M.P.H., and Julie Scott Taylor, M.D., M.Sc., present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/ en/ab004143.html.

Clinical Scenario

A healthy 66-year-old woman has been taking combined continuous hormone therapy for menopausal symptoms for six months. She asks for how long she can safely continue taking the medication.

Clinical Question

In perimenopausal and postmenopausal women, is long-term, combined continuous hormone therapy safe and effective?

Evidence-Based Answer

Relatively healthy women taking combined continuous hormone therapy have higher risks of myocardial infarction and venous thromboembolism after one year, stroke after three years, and breast cancer after five years. In women who take hormone therapy continuously for five years, there is a lower incidence of fractures and colon cancer. Although it may be relatively safe and effective for short-term symptom control, hormone therapy should not be given routinely for prevention or chronic disease management.1

Practice Pointers

In the past, based on the results of multiple small observational studies, the health benefits of long-term hormone therapy for perimenopausal and postmenopausal women were thought to be numerous. However, the results of two large randomized controlled trials-the Heart and Estrogen/progestin Replacement (HER) study and the Women's Health Initiative (WHI) study-showed there were significant risks to this approach. The Cochrane authors reviewed 15 double-blind, randomized trials comparing the effects of hormone therapy with placebo for at least one year.1 Nearly 50,000 women 41 to 91 years of age who were perimenopausal or postmenopausal participated in the studies. The two largest randomized controlled trials were the HER and the WHI studies.

The reviewers found that statistically significant benefits of long-term hormone therapy include the prevention of fractures in healthy women with no other previous osteoporosis risk factors (risk ratio [RR] = 0.78; 95% confidence interval [CI], 0.71 to 0.85) and the prevention of colon cancer. These benefits were noted only after five years of continuous use and were reported in the WHI study, but not the HER study.

The WHI study's combined estrogen-progesterone arm showed a reduced incidence of colon cancer (RR = 0.62; 95% CI, 0.43 to 0.89); however, those in the treatment arm who subsequently were diagnosed with cancer showed evidence of more advanced disease at the time of diagnosis, offsetting the positive findings of possible prevention.

The HER and WHI studies also yielded information about the negative outcomes of long-term hormone therapy. Combined continuous hormone therapy increased coronary events (after one year: RR = 1.74; 95% CI, 1.05 to 2.89; after four years: RR = 1.37; 95% CI, 1.05 to 1.79). Women taking hormone therapy had a higher risk of stroke after three years (RR = 1.47; 95% CI, 1.02 to 2.11).2 The risk of venous thromboembolism was more than three times greater in women taking hormone therapy at one year, and the risk remained increased for more than five years. However, according to the WHI study, after five years of taking the medication, the absolute risk of venous thromboembolism for women 50 to 59 years of age was 0.5 percent for women of normal weight and 1.4 percent for women who were obese. Risk of breast cancer after five or more years of hormone therapy was increased (after a mean of 5.6 years: RR = 1.26; 95% CI, 1.02 to 1.56). There are no known benefits or risks from long-term hormone therapy with respect to the prevention of cognitive decline or dementia, quality-of-life assessments, or mortality. Rates of endometrial cancer and quality-of-life scores were similar for those taking hormone therapy and those taking placebo.

Data are more limited regarding the use of hormone therapy for relieving the symptoms of menopause in younger perimenopausal patients. However, in the WHI study, the subgroup of women 50 to 59 years of age taking combined continuous hormone therapy for five years had no adverse outcomes other than a slightly higher risk of venous thrombosis. The absolute risk of venous thrombosis for those taking hormone therapy is 19 per 10,000 women per year, compared with eight per 10,000 in women not taking therapy. Therefore, short-term use of hormone therapy in younger women is relatively safe. Because the WHI and HER studies reported an increased risk of cardiovascular events at one year, it is difficult to advise patients to take hormone therapy for longer than this. Future studies must assess the relationship between short-term hormone therapy use (i.e., three to six months) and perceived benefits in terms of quality of life for those with menopausal symptoms.3

Address correspondence to Susanna R. Magee, M.D., M.P.H., at Susanna_Magee@mhri.org. Reprints are not available from the authors.

REFERENCES

1. Farquhar CM, Marjoribanks J, Lethaby A, Lambets Q, Suckling JA, and the Cochrane HT Study Group. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2005;(3):CD004143.

2. NHLBI advisory for physicians on the WHI trial of conjugated equine estrogens versus placebo. Accessed September 27, 2006, at: http://www.nhlbi.nih.gov/whi/e-a_advisory.htm.

3. LaCroix AZ. Estrogen with and without progestin: benefits and risks of short-term use. Am J Med 2005;118(12 suppl 2):79-87.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See Clinical Quiz on page 1475.

Cochrane Briefs

Antidepressants in Older Persons

Clinical Question

Which antidepressants are effective and well tolerated in older persons with depression?

Evidence-Based Answer

In older persons with depression, three classes of antidepressants are equally effective: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and tricyclic-like compounds. More patients taking classic tricyclic antidepressants stopped their medications because of adverse events than did those taking SSRIs. Tricyclic-like medications had withdrawal rates similar to SSRIs, but the studies were small. The strongest evidence supports using SSRIs as first-line pharmacotherapy in older patients with depression.

Practice Pointers

Depression is estimated to affect 17 to 37 percent of the population older than 55 years.1 Despite its high prevalence in a rapidly growing segment of the U.S. population, depression still is underdiagnosed.2 In older persons, it can be difficult to diagnose because medical illnesses and dementia can cause symptoms of depression. In 2001, a Cochrane review concluded that antidepressant medications are effective in older patients and those with severe medical illness.1 However, choice of medication in older patients must account for decreased renal and hepatic function and the potential for adverse reactions and drug interactions,2 and it depends on medical comorbidities and patient and physician preference.

Mottram and colleagues reviewed the literature to determine which antidepressants are effective and well tolerated in older patients. They found 29 trials. Six trials, with a total of 843 participants, compared all tricyclic antidepressants with all SSRIs. There was no difference in effectiveness. Eleven trials (with 1,091 patients) measuring withdrawal rates showed that patients taking SSRIs were less likely to withdraw than patients taking tricyclic antidepressants, in general (relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04 to 1.47) and because of side effects (RR = 1.30; 95% CI, 1.02 to 1.64). Patients taking SSRIs also were less likely to withdraw than patients taking tricyclic-like compounds, but the studies were small.

When starting antidepressant treatment in older patients, most family physicians make a medication choice based on effectiveness and tolerability. In most situations, SSRIs are the initial medication chosen for major or minor depression because of their good effectiveness and tolerable side-effect profile. In some situations, such as treatment resistance or medical conditions that would benefit from a different class of medications, comorbidities may dictate another choice (e.g., use of a tricyclic antidepressant in a patient with peripheral neuropathy).

The Cochrane study reaffirms that patients will benefit from SSRIs, but also that, if the situation is appropriate, tricyclic and atypical antidepressants will benefit patients as well. If a patient is warned in advance about potential side effects, withdrawal because of the side effects may be less likely.

Avril Swan, M.D.

Source: Mottram P, et al. Antidepressants for depressed elderly. Cochrane Database Syst Rev 2006;(1):CD003491.

REFERENCES

1. Wilson K, Mottram P, Sivanranthan A, Nightingale A. Antidepressants versus placebo for the depressed elderly. Cochrane Database Syst Rev 2001;(1):CD000561.

2. Institute for Clinical Systems Improvement. Major depression in adults in primary care. Bloomington, Minn.: Institute for Clinical Systems Improvement, 2006.

Interventions for Molluscum Contagiosum

Clinical Question

Is there an effective treatment for molluscum contagiosum?

Evidence-Based Answer

There is insufficient evidence to determine whether treatments for molluscum are effective.

Practice Pointers

Molluscum contagiosum, a poxvirus skin infection that largely affects children and adolescents, presents as single or multiple painless white papules with a central dimple. Lesions enlarge slowly and may reach a diameter of 0.2 to 0.4 inches (5 to 10 mm) in six to 12 weeks. After trauma, or spontaneously after several months, inflammatory changes result in the production of pus, crusting, and eventual destruction of the lesions. Most cases are self-limited and resolve within six to nine months. Treatments include cryotherapy, expression or pricking with a sterile needle, topical preparations (e.g., podofilox [Condylox], liquefied phenol, tretinoin [Retin-A], cantharidin, potassium hydroxide), and systemic treatment (e.g., cimetidine [Tagamet]).1

Five randomized controlled trials addressing the effectiveness of different topical treatments for raised molluscum lesions were identified. The participants included children, adolescents, and adults with molluscum. Immunocompromised patients and those with genital molluscum were excluded. The studies reported medium and long-term cure rates, time to cure, and adverse effects for the following treatments: povidone iodine plus salicylic acid (Keralyt); sodium nitrite plus salicylic acid; potassium hydroxide; systemic cimetidine; and calcarea carbonica (a homeopathic and impure form of calcium carbonate). No studies examined cryotherapy or needle expression. The included studies followed a total of 137 participants, with numbers of participants in each study ranging from 20 to 38. Overall, these studies were limited by small size and high drop-out rates, and some did not include an intention-to-treat analysis.

Only one study showed a statistically significant difference in the rate of complete cure in the treatment group. This study (n = 30) demonstrated that treatment with 5% sodium nitrite coapplied daily with 5% salicylic acid under occlusion resulted in a significantly higher rate of lesion cure after three months than treatment with salicylic acid alone (12 out of 16 participants [75 percent] compared with three out of 14 participants [21 percent], respectively [number needed to treat = 2]). The mean number of treatment days was lower in the treatment group than in the control group (38 versus 49 days, respectively). Adverse effects of the sodium nitrite plus salicylic acid treatment included brown staining of skin and irritation.

Another study (n = 35) found a shorter mean time to cure in the group treated with iodine plus salicylic acid plaster compared with iodine alone or salicylic plaster alone (26, 86, and 47 days, respectively). There was no significant difference in complete cure rates between the groups treated with 10% povidone iodine solution plus 50% salicylic acid plaster compared with povidone iodine alone (100 versus 60 percent [risk ratio = 1.67; 95% confidence interval, 0.81 to 3.41]). All participants developed redness of the skin at the treatment site within three to seven days after the start of the treatment.

The other three studies included in the review showed no significant difference in complete cure or lesion improvement with the use of topical 10% potassium hydroxide, systemic cimetidine, or calcarea carbonica compared with the placebo groups.

In the absence of evidence about treatment effectiveness, many experts recommend watchful waiting.1

janelle Guirguis-Blake, M.D.

Source: van der Wouden JC, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev 2006;(2):CD004767.

REFERENCE

1. Sladden MJ, Johnston GA. Common skin infections in children. BMJ 2004;329:95-9.

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