Wulf H. Utian, MD, PhD

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Medical evidence accumulates at a pace too fast for the individual mortal to absorb. Inevitably, trustworthy guidelines became essential to day-to-day decision-making, particularly regarding the use of estrogen and progestogen in peri- and postmenopausal women.

Frequent updates help interpret proliferating data

A Hormone Therapy Panel of experts in many fields was convened in each of the last 3 years by the North American Menopause Society (NAMS), to review new studies and determine whether recommendations need to be changed, in light of new issues and new evidence. These Position Statements have become the internationally recognized standard of care.

October 6, 2004, a new Position Statement was announced at the annual NAMS meeting in Washington, DC.

In theory, developing a Position Statement according to the principles of evidence-based medicine would seem simple. Identical databases and published evidence should lead to identical consensus statements and clinical guidelines, should they not? Why then do different organizations, after scrutinizing identical evidence, come out with different interpretations and recommendations?

For example, one of the most enduring debates is to what extent evidence based on a select population can be extrapolated to another select population or to the general population. Argument about the populations studied in the Women’s Health Initiative and the Nurses Health trials rages vociferously. Neither study is able to consider all the combinations and variations we encounter in practice.

We will always lack a complete database. It is impossible to undertake and complete evidence-based clinical research that incorporates all populations, subpopulations, conflicting and confounding factors, comorbidities, risk factors, and medication permutations.

Practical experience, judgment called into play

What’s more, guideline development would be flawed were it to rely entirely on the existing base of evidence at any one time. Development of guidelines must accommodate the clinical and scientific judgment of both the developer and the clinicians who will put the recommendations into practice. The judgment element explains the differing guidelines, in considerable part.

We considered all of these issues as we wrote the new NAMS Position Statement on peri- and postmenopausal estrogen and progestogen usage. Like previous reports, the latest one identifies issues that cannot be resolved now because of insufficient data.

We invite you to scrutinize our latest Position Statement. But translating these positions into practice still necessitates taking into account the complete health profile of the individual woman as well as her personal preferences and beliefs. This Position Statement is intended to enhance the quality of patient care and modulate clinical practice. NAMS believes the positions we have taken are fair and credible, and we hope that both you and your patients will find them practical and acceptable.

Ultimately, we have to do the best we can with what we know at the moment.

Medical evidence accumulates at a pace too fast for the individual mortal to absorb. Inevitably, trustworthy guidelines became essential to day-to-day decision-making, particularly regarding the use of estrogen and progestogen in peri- and postmenopausal women.

Frequent updates help interpret proliferating data

A Hormone Therapy Panel of experts in many fields was convened in each of the last 3 years by the North American Menopause Society (NAMS), to review new studies and determine whether recommendations need to be changed, in light of new issues and new evidence. These Position Statements have become the internationally recognized standard of care.

October 6, 2004, a new Position Statement was announced at the annual NAMS meeting in Washington, DC.

In theory, developing a Position Statement according to the principles of evidence-based medicine would seem simple. Identical databases and published evidence should lead to identical consensus statements and clinical guidelines, should they not? Why then do different organizations, after scrutinizing identical evidence, come out with different interpretations and recommendations?

For example, one of the most enduring debates is to what extent evidence based on a select population can be extrapolated to another select population or to the general population. Argument about the populations studied in the Women’s Health Initiative and the Nurses Health trials rages vociferously. Neither study is able to consider all the combinations and variations we encounter in practice.

We will always lack a complete database. It is impossible to undertake and complete evidence-based clinical research that incorporates all populations, subpopulations, conflicting and confounding factors, comorbidities, risk factors, and medication permutations.

Practical experience, judgment called into play

What’s more, guideline development would be flawed were it to rely entirely on the existing base of evidence at any one time. Development of guidelines must accommodate the clinical and scientific judgment of both the developer and the clinicians who will put the recommendations into practice. The judgment element explains the differing guidelines, in considerable part.

We considered all of these issues as we wrote the new NAMS Position Statement on peri- and postmenopausal estrogen and progestogen usage. Like previous reports, the latest one identifies issues that cannot be resolved now because of insufficient data.

We invite you to scrutinize our latest Position Statement. But translating these positions into practice still necessitates taking into account the complete health profile of the individual woman as well as her personal preferences and beliefs. This Position Statement is intended to enhance the quality of patient care and modulate clinical practice. NAMS believes the positions we have taken are fair and credible, and we hope that both you and your patients will find them practical and acceptable.

Ultimately, we have to do the best we can with what we know at the moment.

Medical evidence accumulates at a pace too fast for the individual mortal to absorb. Inevitably, trustworthy guidelines became essential to day-to-day decision-making, particularly regarding the use of estrogen and progestogen in peri- and postmenopausal women.

Frequent updates help interpret proliferating data

A Hormone Therapy Panel of experts in many fields was convened in each of the last 3 years by the North American Menopause Society (NAMS), to review new studies and determine whether recommendations need to be changed, in light of new issues and new evidence. These Position Statements have become the internationally recognized standard of care.

October 6, 2004, a new Position Statement was announced at the annual NAMS meeting in Washington, DC.

In theory, developing a Position Statement according to the principles of evidence-based medicine would seem simple. Identical databases and published evidence should lead to identical consensus statements and clinical guidelines, should they not? Why then do different organizations, after scrutinizing identical evidence, come out with different interpretations and recommendations?

For example, one of the most enduring debates is to what extent evidence based on a select population can be extrapolated to another select population or to the general population. Argument about the populations studied in the Women’s Health Initiative and the Nurses Health trials rages vociferously. Neither study is able to consider all the combinations and variations we encounter in practice.

We will always lack a complete database. It is impossible to undertake and complete evidence-based clinical research that incorporates all populations, subpopulations, conflicting and confounding factors, comorbidities, risk factors, and medication permutations.

Practical experience, judgment called into play

What’s more, guideline development would be flawed were it to rely entirely on the existing base of evidence at any one time. Development of guidelines must accommodate the clinical and scientific judgment of both the developer and the clinicians who will put the recommendations into practice. The judgment element explains the differing guidelines, in considerable part.

We considered all of these issues as we wrote the new NAMS Position Statement on peri- and postmenopausal estrogen and progestogen usage. Like previous reports, the latest one identifies issues that cannot be resolved now because of insufficient data.

We invite you to scrutinize our latest Position Statement. But translating these positions into practice still necessitates taking into account the complete health profile of the individual woman as well as her personal preferences and beliefs. This Position Statement is intended to enhance the quality of patient care and modulate clinical practice. NAMS believes the positions we have taken are fair and credible, and we hope that both you and your patients will find them practical and acceptable.

Ultimately, we have to do the best we can with what we know at the moment.

The past 2 years have witnessed a flurry of scientific publications on menopause and related therapies, particularly use of the sex steroid hormones. In turn, attitudes about menopause and hormone therapy have changed. Perhaps the greatest consequence of all the attention is the confusion about what to do, on the part of both provider and patient.

Many organizations responded with considered, evidence-based, practical guidelines. The most detailed and practice-oriented of these guidelines is the North American Menopause Society’s (NAMS’s) September 2003 Position Statement on use of estrogen and progestogen in peri- and postmenopausal women (www.menopause.org). Even as this Update on Menopause is being written, the report of the terminated estrogen-only arm of the Women’s Health Initiative (WHI) is in press and may further change clinical practice. NAMS will present an updated report on all these developments at the 2004 scientific meeting in Washington, DC, October 6 to 9, 2004. In the interim, the current recommendations hold, and the following publications are of clinical relevance.

WHIHigher levels of exercise reduce breast cancer risk

McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA. 2003;290:1331–1336.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED TRIAL
  

A total of 74,171 postmenopausal women aged 50 to 79, with no history of breast cancer, were enrolled. At a mean follow-up of 4.7 years, an increasing total current physical activity score was associated with a statistically significant reduced risk for breast cancer (P = .03 for trend). The women in whom the 18% (95% confidence interval [CI], 0.68-0.97) reduced risk of breast cancer was observed exercised the equivalent of 1.25 to 2.5 hours per week of brisk walking (5.1-10.0 metabolic hours). Women who exercised the equivalent of 10 or more hours of brisk walking per week had slightly greater reductions.

The greatest benefit was in women with a body mass index (BMI) below 24.1, but benefits were seen in women with BMIs ranging from 24.1 to 28.4. In evaluating the effect of previous strenuous-intensity exercise, a statistically significant decreased risk of breast cancer was seen for women who had engaged in strenuous exercise at age 35 (relative risk [RR], 0.86; 95% CI, 0.78-0.95); no significant associations were found for strenuous exercise at ages 18 or 50.

COMMENT
Modest protection, but encourage exercise anyway

This large, prospective cohort study performed in the mid-1990s strengthens the growing body of evidence that higher levels of physical activity afford modest protection against breast cancer. Recreational physical activity appears to be associated with reduced risk for breast cancer in postmenopausal women; longer exercise durations showed only slightly greater reduction in risk.

The strengths of this study are its large numbers, prospective nature, and detailed reporting of breast cancer outcomes. Limitations include possible confounders such as prior oral contraceptive use, and use of self-administered questionnaires to estimate physical activity.

One very important question is raised by this study: Given the low increase in absolute risk of breast cancer reported by the WHI with estrogen plus progestin¹—which barely reached statistical significance (total breast cancer RR, 1.24; 95% CI, 1.02-1.50)—and given the statement in the McTiernan study that “the reduced risk associated with increased levels of total physical activity was seen across all the categories of these variables” (including current or past use, or no previous use of hormone therapy), does the reduction of incidence with physical activity in hormone therapy users lower the level of risk to non-significance or to that of nonexercisers in the placebo group? The answer cannot be determined from this report, but it would be illuminating.

These findings are preliminary, and confirming studies are needed. There is little harm in encouraging women to exercise, however.

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.

WHIEstrogen-progestin has no significant effect on gynecologic cancers

Anderson GL, Judd HL, Kaunitz AM, et al, for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–1748.

• LEVEL I EVIDENCE: RANDOMIZED, CONTROLLED TRIAL
  

In this randomized, double-blind, placebo-controlled trial, 16,608 women were assigned to either EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate) or placebo; none of the women had undergone a hysterectomy.

After an average follow-up of 5.6 years:

• There were 20 cases of invasive ovarian cancer in the EPT group (n = 8,506) and 12 cases in the placebo group (n = 8,102). Compared with placebo, the hazard ratio (HR) for invasive ovarian cancer among EPT recipients was a nonsignificant 1.58 (95% CI, 0.77-3.24 [adjusted 95% CI, 0.59-4.23]).
  
• For endometrial cancer, 27 and 31 cases occurred, respectively, which translated statistically to a nonsignificant hazard ratio for EPT recipients of 0.81 (95% CI, 0.48-1.36).
  
• For cervical cancers, 8 and 5 cases were reported, respectively, with a nonsignificant HR of 1.44 (95% CI, 0.47-4.42).
  

COMMENT
Bias against hormone therapy?

The authors concluded that EPT may increase the risk of ovarian cancer but has no significant effect on the risk of endometrial cancer. They commented, however, that, since the EPT arm of the trial was prematurely stopped, the precision of the results is limited and examination of longer-term exposure is precluded.

This paper once again raises the question of whether the writers of the WHI trial have a bias against hormone therapy. In this report, the EPT arm of the WHI trial had an observed annual incidence of 34 ovarian cancer cases per 100,000 person-years—somewhat less than the anticipated population-based rate of 45 per 100,000 person-years. In the authors’ words, the ovarian cancer rate in the EPT group “was elevated (HR 1.58; 95% CI 0.77-3.24 [adjusted 95% CI, 0.59-4.23]) but not statistically significant.” The Kaplan-Meier estimates of cumulative hazards also did not reach statistical significance. Yet in the conclusion of the abstract, the authors state that continuous combined EPT “may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.”

Regarding the conclusion on endometrial cancer risk, the observed incidence for EPT users was 62 per 100,000 person-years, which is also lower than the anticipated population-based rate of 83 per 100,000 person-years. The authors state that this was a “small, nonsignificant reduction” in endometrial cancer risk (HR 0.81; 95% CI, 0.48-1.36). Yet, in the conclusion, while claiming that the nonsignificant difference in ovarian cancer suggests an increased risk, the authors do not state that the nonsignificant reduction in endometrial cancer suggests a decreased risk.

What do the authors expect us to believe, their data or their conclusions? My interpretation of the data in this article is that ovarian and uterine cancers need not be of major concern when determining a woman’s risk-benefit ratio for hormone therapy.

A retraction. Of interest, when this issue was raised in subsequent JAMA correspondence, the WHI authors agreed—representing perhaps the first time that a WHI report publicly retracted a potentially biased conclusion.^1,2

Fewer biopsies will be needed with lower dosage. It is not surprising that women taking hormonal therapy containing estrogen had more bleeding and, therefore, more endometrial biopsies than women taking placebo, because a known effect of estrogen is proliferation of the endometrial lining. With the lower-dose hormonal preparations currently available (which result in lower systemic estrogen levels and less endometrial stimulation), uterine bleeding episodes in menopausal hormone therapy users should diminish, along with the number of endometrial biopsies.

1. Utian WH. Hormone therapy and risk of gynecologic cancers [letter]. JAMA. 2004;291:42.-

2. Anderson GL, Judd HL, Kaunitz AM, et al. Hormone therapy and risk of gynecologic cancers—Reply. JAMA. 2004;291:43.-

MILLION WOMEN STUDYBreast cancer risks increased by estrogen plus progestogen

Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED
  

A total of 1,084,110 women aged 50 to 64 were enrolled between May 1996 and March 2001 and followed to the study finish (end of 2002). Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Nearly half of the women had used postmenopausal hormone therapy, either estrogen therapy alone (ET) or EPT. Primary endpoints were diagnosis of breast cancer and death from breast cancer.

Current ET or EPT use (compared with nonuse) was associated with a statistically significant increased risk of both breast cancer incidence (RR, 1.66; 95% CI, 1.58-1.75) and breast cancer mortality (RR, 1.22; 95% CI, 1.00-1.48). Past use did not increase the risk of incident (RR, 1.01; 95% CI, 0.94-1.09) or fatal disease (RR, 1.05; 95% CI, 0.82-1.34), and the risk decreased with time since last use.

The risks associated with ET and with EPT differed significantly. Current ET users had a 30% increased risk for breast cancer (95% CI, 1.21-1.40) while current EPT users had a 100% increased risk (95% CI, 1.88-2.12). However, vaginal or other local EPT formulations did not increase the risk (RR 0.67, 95% CI, 0.30-1.49). No significant differences in risk were found between specific types or doses of EPT or between continuous combined and continuous cyclic regimens.

COMMENT
Limitations of observational studies

This extremely large observational study found levels of breast cancer risk associated with ET and EPT similar to those reported by the WHI and as predicted in 1997 by the Collaborative Group on Hormonal Factors in Breast Cancer study.¹ The Million Women Study implicates an expanded number of ET and EPT products and routes of administration.

Acting as devil’s advocate, I will point out that this is an observational study with large potential for error. The major weakness is that it is a snapshot of hormone therapy use taken at the time of the women’s entry into the study, which was at the time of their 3-year mammogram. No further information was gleaned from the women regarding subsequent changes in hormone therapy use, such as whether they terminated use or changed the dose or route.

Also, the patient-provided data at entry showed a 96% agreement with the actual prescription written by the physician. The 4% variance, although it seems small, is of some concern given the narrow difference in relative risks and the large number of study participants. This is a weakness of any observational study; even if the prescription is filled, evidence that it was actually taken is inadequate.

Finally, the authors report that current use of hormone therapy at baseline increased the risk of breast cancer, although the relative risk was not as large as for disease incidence. They were not able to come up with reliable estimates of mortality attributable to breast cancer.

“Million Women” can be accepted only as an observational confirmation of a small increase in absolute risk of breast cancer.

In conclusion, the Million Women Study can be accepted only as an observational study providing confirmation of a small increase in the absolute risk for breast cancer in women on hormone therapy.

Further implications. The suggestion that these results apply to products beyond those tested in the WHI is in agreement with the NAMS Advisory Panel’s 2003 statement on Postmenopausal Hormone Therapy, which supports the view that although it is not possible to make general conclusions about all members of the estrogen and progestogen families, an improved benefit-risk profile of other EPT agents cannot be assumed.

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-1059.

Transdermal estrogen/progestogen had no effect on risk of venous thromboembolism in postmenopausal women.

ESTHER STUDYOral and transdermal EPT have different effects on risk of thromboembolism

Scarabin PY, Oger E, Plu-Bureau G, for the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–432.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED STUDY
  

Investigators enrolled 155 women aged 45 to 70 years who had been diagnosed with VTE, defined as either pulmonary embolism or deep vein thrombosis, and 381 matched controls. In women with VTE, 21% were using oral EPT and 19% were using transdermal EPT. In controls, 7% and 24% were using oral or transdermal EPT, respectively. An adjusted analysis showed that, compared with nonuse, current use of oral EPT significantly increased the VTE risk (adjusted odds ratio, [OR] 3.5; 95% CI, 1.8-6.8); transdermal EPT did not increase the VTE risk (OR, 0.9; 95% CI, 0.5-1.6). A between-group comparison showed that current oral EPT users had a significantly increased VTE risk (OR, 4.0; 95% CI, 1.9-8.3) over transdermal EPT users.

COMMENT
More studies needed but unlikely

A prime consideration for nonoral EPT for postmenopausal women is avoidance of the first-pass hepatic effect of oral medications, thereby reducing potential for the adverse effects associated with oral therapies. This study demonstrates a difference between oral and transdermal therapy, but the number of patients is small and, while promising, it is probably not a final answer to the problem.

The reduced incidence of VTE in postmenopausal women on transdermal EPT does justify further randomized controlled clinical trials; however, given the low prevalence of VTE, conducting such a study would be nearly impossible. It would be interesting if data from the Million Women Study were analyzed for effects of different routes of ET/EPT administration on VTE.

3 RANDOMIZED, CONTROLLED TRIALSIsoflavones are no better than placebo for hot flashes

Soy 40%, placebo 40%

Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Effects in women with breast cancer

Nikander E, Kikkinen A, Metsa-Heikkila M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Menopause-related symptoms, including hot flashes, were recorded on the Kupperman index. At study end, the overall Kupperman index score was reduced by 15.5% in the phytoestrogen group (mean drop, 4.2) and by 14.7% in the placebo group (mean, 4.0); the between-group difference was not statistically significant.

When evaluated separately from the rest of the Kupperman index, the hot flash component was reduced more in the placebo group (14.3%) than in the study group (10%), although the difference was not statistically significant.

The quality of life parameters measured—capacity to work and mood changes—were not affected by phytoestrogen therapy.

Phytoestrogen treatment was well tolerated and caused no significant changes in liver enzymes, creatinine, body mass index, or blood pressure. In a subset analysis, investigators evaluated results based on high and low levels of endogenous equol; results did not differ between the groups.

Red clover vs placebo

Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–214.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

COMMENT
The clinical implications

These 3 negative trials of isoflavones (2 extracted from soy, 1 from red clover) confirm previous reports of their essential inefficacy. The clinical implications:

• Women with mild hot flashes might consider either no pharmacotherapy or low-dose selective serotonin-reuptake inhibitors.
  
• Women with moderate to severe hot flashes that disrupt quality of life may continue to benefit from short-term, low-dose hormone therapy.
  

The past 2 years have witnessed a flurry of scientific publications on menopause and related therapies, particularly use of the sex steroid hormones. In turn, attitudes about menopause and hormone therapy have changed. Perhaps the greatest consequence of all the attention is the confusion about what to do, on the part of both provider and patient.

Many organizations responded with considered, evidence-based, practical guidelines. The most detailed and practice-oriented of these guidelines is the North American Menopause Society’s (NAMS’s) September 2003 Position Statement on use of estrogen and progestogen in peri- and postmenopausal women (www.menopause.org). Even as this Update on Menopause is being written, the report of the terminated estrogen-only arm of the Women’s Health Initiative (WHI) is in press and may further change clinical practice. NAMS will present an updated report on all these developments at the 2004 scientific meeting in Washington, DC, October 6 to 9, 2004. In the interim, the current recommendations hold, and the following publications are of clinical relevance.

WHIHigher levels of exercise reduce breast cancer risk

McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA. 2003;290:1331–1336.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED TRIAL
  

A total of 74,171 postmenopausal women aged 50 to 79, with no history of breast cancer, were enrolled. At a mean follow-up of 4.7 years, an increasing total current physical activity score was associated with a statistically significant reduced risk for breast cancer (P = .03 for trend). The women in whom the 18% (95% confidence interval [CI], 0.68-0.97) reduced risk of breast cancer was observed exercised the equivalent of 1.25 to 2.5 hours per week of brisk walking (5.1-10.0 metabolic hours). Women who exercised the equivalent of 10 or more hours of brisk walking per week had slightly greater reductions.

The greatest benefit was in women with a body mass index (BMI) below 24.1, but benefits were seen in women with BMIs ranging from 24.1 to 28.4. In evaluating the effect of previous strenuous-intensity exercise, a statistically significant decreased risk of breast cancer was seen for women who had engaged in strenuous exercise at age 35 (relative risk [RR], 0.86; 95% CI, 0.78-0.95); no significant associations were found for strenuous exercise at ages 18 or 50.

COMMENT
Modest protection, but encourage exercise anyway

This large, prospective cohort study performed in the mid-1990s strengthens the growing body of evidence that higher levels of physical activity afford modest protection against breast cancer. Recreational physical activity appears to be associated with reduced risk for breast cancer in postmenopausal women; longer exercise durations showed only slightly greater reduction in risk.

The strengths of this study are its large numbers, prospective nature, and detailed reporting of breast cancer outcomes. Limitations include possible confounders such as prior oral contraceptive use, and use of self-administered questionnaires to estimate physical activity.

One very important question is raised by this study: Given the low increase in absolute risk of breast cancer reported by the WHI with estrogen plus progestin¹—which barely reached statistical significance (total breast cancer RR, 1.24; 95% CI, 1.02-1.50)—and given the statement in the McTiernan study that “the reduced risk associated with increased levels of total physical activity was seen across all the categories of these variables” (including current or past use, or no previous use of hormone therapy), does the reduction of incidence with physical activity in hormone therapy users lower the level of risk to non-significance or to that of nonexercisers in the placebo group? The answer cannot be determined from this report, but it would be illuminating.

These findings are preliminary, and confirming studies are needed. There is little harm in encouraging women to exercise, however.

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.

WHIEstrogen-progestin has no significant effect on gynecologic cancers

Anderson GL, Judd HL, Kaunitz AM, et al, for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–1748.

• LEVEL I EVIDENCE: RANDOMIZED, CONTROLLED TRIAL
  

In this randomized, double-blind, placebo-controlled trial, 16,608 women were assigned to either EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate) or placebo; none of the women had undergone a hysterectomy.

After an average follow-up of 5.6 years:

• There were 20 cases of invasive ovarian cancer in the EPT group (n = 8,506) and 12 cases in the placebo group (n = 8,102). Compared with placebo, the hazard ratio (HR) for invasive ovarian cancer among EPT recipients was a nonsignificant 1.58 (95% CI, 0.77-3.24 [adjusted 95% CI, 0.59-4.23]).
  
• For endometrial cancer, 27 and 31 cases occurred, respectively, which translated statistically to a nonsignificant hazard ratio for EPT recipients of 0.81 (95% CI, 0.48-1.36).
  
• For cervical cancers, 8 and 5 cases were reported, respectively, with a nonsignificant HR of 1.44 (95% CI, 0.47-4.42).
  

COMMENT
Bias against hormone therapy?

The authors concluded that EPT may increase the risk of ovarian cancer but has no significant effect on the risk of endometrial cancer. They commented, however, that, since the EPT arm of the trial was prematurely stopped, the precision of the results is limited and examination of longer-term exposure is precluded.

This paper once again raises the question of whether the writers of the WHI trial have a bias against hormone therapy. In this report, the EPT arm of the WHI trial had an observed annual incidence of 34 ovarian cancer cases per 100,000 person-years—somewhat less than the anticipated population-based rate of 45 per 100,000 person-years. In the authors’ words, the ovarian cancer rate in the EPT group “was elevated (HR 1.58; 95% CI 0.77-3.24 [adjusted 95% CI, 0.59-4.23]) but not statistically significant.” The Kaplan-Meier estimates of cumulative hazards also did not reach statistical significance. Yet in the conclusion of the abstract, the authors state that continuous combined EPT “may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.”

Regarding the conclusion on endometrial cancer risk, the observed incidence for EPT users was 62 per 100,000 person-years, which is also lower than the anticipated population-based rate of 83 per 100,000 person-years. The authors state that this was a “small, nonsignificant reduction” in endometrial cancer risk (HR 0.81; 95% CI, 0.48-1.36). Yet, in the conclusion, while claiming that the nonsignificant difference in ovarian cancer suggests an increased risk, the authors do not state that the nonsignificant reduction in endometrial cancer suggests a decreased risk.

What do the authors expect us to believe, their data or their conclusions? My interpretation of the data in this article is that ovarian and uterine cancers need not be of major concern when determining a woman’s risk-benefit ratio for hormone therapy.

A retraction. Of interest, when this issue was raised in subsequent JAMA correspondence, the WHI authors agreed—representing perhaps the first time that a WHI report publicly retracted a potentially biased conclusion.^1,2

Fewer biopsies will be needed with lower dosage. It is not surprising that women taking hormonal therapy containing estrogen had more bleeding and, therefore, more endometrial biopsies than women taking placebo, because a known effect of estrogen is proliferation of the endometrial lining. With the lower-dose hormonal preparations currently available (which result in lower systemic estrogen levels and less endometrial stimulation), uterine bleeding episodes in menopausal hormone therapy users should diminish, along with the number of endometrial biopsies.

1. Utian WH. Hormone therapy and risk of gynecologic cancers [letter]. JAMA. 2004;291:42.-

2. Anderson GL, Judd HL, Kaunitz AM, et al. Hormone therapy and risk of gynecologic cancers—Reply. JAMA. 2004;291:43.-

MILLION WOMEN STUDYBreast cancer risks increased by estrogen plus progestogen

Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED
  

A total of 1,084,110 women aged 50 to 64 were enrolled between May 1996 and March 2001 and followed to the study finish (end of 2002). Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Nearly half of the women had used postmenopausal hormone therapy, either estrogen therapy alone (ET) or EPT. Primary endpoints were diagnosis of breast cancer and death from breast cancer.

Current ET or EPT use (compared with nonuse) was associated with a statistically significant increased risk of both breast cancer incidence (RR, 1.66; 95% CI, 1.58-1.75) and breast cancer mortality (RR, 1.22; 95% CI, 1.00-1.48). Past use did not increase the risk of incident (RR, 1.01; 95% CI, 0.94-1.09) or fatal disease (RR, 1.05; 95% CI, 0.82-1.34), and the risk decreased with time since last use.

The risks associated with ET and with EPT differed significantly. Current ET users had a 30% increased risk for breast cancer (95% CI, 1.21-1.40) while current EPT users had a 100% increased risk (95% CI, 1.88-2.12). However, vaginal or other local EPT formulations did not increase the risk (RR 0.67, 95% CI, 0.30-1.49). No significant differences in risk were found between specific types or doses of EPT or between continuous combined and continuous cyclic regimens.

COMMENT
Limitations of observational studies

This extremely large observational study found levels of breast cancer risk associated with ET and EPT similar to those reported by the WHI and as predicted in 1997 by the Collaborative Group on Hormonal Factors in Breast Cancer study.¹ The Million Women Study implicates an expanded number of ET and EPT products and routes of administration.

Acting as devil’s advocate, I will point out that this is an observational study with large potential for error. The major weakness is that it is a snapshot of hormone therapy use taken at the time of the women’s entry into the study, which was at the time of their 3-year mammogram. No further information was gleaned from the women regarding subsequent changes in hormone therapy use, such as whether they terminated use or changed the dose or route.

Also, the patient-provided data at entry showed a 96% agreement with the actual prescription written by the physician. The 4% variance, although it seems small, is of some concern given the narrow difference in relative risks and the large number of study participants. This is a weakness of any observational study; even if the prescription is filled, evidence that it was actually taken is inadequate.

Finally, the authors report that current use of hormone therapy at baseline increased the risk of breast cancer, although the relative risk was not as large as for disease incidence. They were not able to come up with reliable estimates of mortality attributable to breast cancer.

“Million Women” can be accepted only as an observational confirmation of a small increase in absolute risk of breast cancer.

In conclusion, the Million Women Study can be accepted only as an observational study providing confirmation of a small increase in the absolute risk for breast cancer in women on hormone therapy.

Further implications. The suggestion that these results apply to products beyond those tested in the WHI is in agreement with the NAMS Advisory Panel’s 2003 statement on Postmenopausal Hormone Therapy, which supports the view that although it is not possible to make general conclusions about all members of the estrogen and progestogen families, an improved benefit-risk profile of other EPT agents cannot be assumed.

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-1059.

Transdermal estrogen/progestogen had no effect on risk of venous thromboembolism in postmenopausal women.

ESTHER STUDYOral and transdermal EPT have different effects on risk of thromboembolism

Scarabin PY, Oger E, Plu-Bureau G, for the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–432.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED STUDY
  

Investigators enrolled 155 women aged 45 to 70 years who had been diagnosed with VTE, defined as either pulmonary embolism or deep vein thrombosis, and 381 matched controls. In women with VTE, 21% were using oral EPT and 19% were using transdermal EPT. In controls, 7% and 24% were using oral or transdermal EPT, respectively. An adjusted analysis showed that, compared with nonuse, current use of oral EPT significantly increased the VTE risk (adjusted odds ratio, [OR] 3.5; 95% CI, 1.8-6.8); transdermal EPT did not increase the VTE risk (OR, 0.9; 95% CI, 0.5-1.6). A between-group comparison showed that current oral EPT users had a significantly increased VTE risk (OR, 4.0; 95% CI, 1.9-8.3) over transdermal EPT users.

COMMENT
More studies needed but unlikely

A prime consideration for nonoral EPT for postmenopausal women is avoidance of the first-pass hepatic effect of oral medications, thereby reducing potential for the adverse effects associated with oral therapies. This study demonstrates a difference between oral and transdermal therapy, but the number of patients is small and, while promising, it is probably not a final answer to the problem.

The reduced incidence of VTE in postmenopausal women on transdermal EPT does justify further randomized controlled clinical trials; however, given the low prevalence of VTE, conducting such a study would be nearly impossible. It would be interesting if data from the Million Women Study were analyzed for effects of different routes of ET/EPT administration on VTE.

3 RANDOMIZED, CONTROLLED TRIALSIsoflavones are no better than placebo for hot flashes

Soy 40%, placebo 40%

Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Effects in women with breast cancer

Nikander E, Kikkinen A, Metsa-Heikkila M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Menopause-related symptoms, including hot flashes, were recorded on the Kupperman index. At study end, the overall Kupperman index score was reduced by 15.5% in the phytoestrogen group (mean drop, 4.2) and by 14.7% in the placebo group (mean, 4.0); the between-group difference was not statistically significant.

When evaluated separately from the rest of the Kupperman index, the hot flash component was reduced more in the placebo group (14.3%) than in the study group (10%), although the difference was not statistically significant.

The quality of life parameters measured—capacity to work and mood changes—were not affected by phytoestrogen therapy.

Phytoestrogen treatment was well tolerated and caused no significant changes in liver enzymes, creatinine, body mass index, or blood pressure. In a subset analysis, investigators evaluated results based on high and low levels of endogenous equol; results did not differ between the groups.

Red clover vs placebo

Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–214.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

COMMENT
The clinical implications

These 3 negative trials of isoflavones (2 extracted from soy, 1 from red clover) confirm previous reports of their essential inefficacy. The clinical implications:

• Women with mild hot flashes might consider either no pharmacotherapy or low-dose selective serotonin-reuptake inhibitors.
  
• Women with moderate to severe hot flashes that disrupt quality of life may continue to benefit from short-term, low-dose hormone therapy.
  

The past 2 years have witnessed a flurry of scientific publications on menopause and related therapies, particularly use of the sex steroid hormones. In turn, attitudes about menopause and hormone therapy have changed. Perhaps the greatest consequence of all the attention is the confusion about what to do, on the part of both provider and patient.

Many organizations responded with considered, evidence-based, practical guidelines. The most detailed and practice-oriented of these guidelines is the North American Menopause Society’s (NAMS’s) September 2003 Position Statement on use of estrogen and progestogen in peri- and postmenopausal women (www.menopause.org). Even as this Update on Menopause is being written, the report of the terminated estrogen-only arm of the Women’s Health Initiative (WHI) is in press and may further change clinical practice. NAMS will present an updated report on all these developments at the 2004 scientific meeting in Washington, DC, October 6 to 9, 2004. In the interim, the current recommendations hold, and the following publications are of clinical relevance.

WHIHigher levels of exercise reduce breast cancer risk

McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA. 2003;290:1331–1336.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED TRIAL
  

A total of 74,171 postmenopausal women aged 50 to 79, with no history of breast cancer, were enrolled. At a mean follow-up of 4.7 years, an increasing total current physical activity score was associated with a statistically significant reduced risk for breast cancer (P = .03 for trend). The women in whom the 18% (95% confidence interval [CI], 0.68-0.97) reduced risk of breast cancer was observed exercised the equivalent of 1.25 to 2.5 hours per week of brisk walking (5.1-10.0 metabolic hours). Women who exercised the equivalent of 10 or more hours of brisk walking per week had slightly greater reductions.

The greatest benefit was in women with a body mass index (BMI) below 24.1, but benefits were seen in women with BMIs ranging from 24.1 to 28.4. In evaluating the effect of previous strenuous-intensity exercise, a statistically significant decreased risk of breast cancer was seen for women who had engaged in strenuous exercise at age 35 (relative risk [RR], 0.86; 95% CI, 0.78-0.95); no significant associations were found for strenuous exercise at ages 18 or 50.

COMMENT
Modest protection, but encourage exercise anyway

This large, prospective cohort study performed in the mid-1990s strengthens the growing body of evidence that higher levels of physical activity afford modest protection against breast cancer. Recreational physical activity appears to be associated with reduced risk for breast cancer in postmenopausal women; longer exercise durations showed only slightly greater reduction in risk.

The strengths of this study are its large numbers, prospective nature, and detailed reporting of breast cancer outcomes. Limitations include possible confounders such as prior oral contraceptive use, and use of self-administered questionnaires to estimate physical activity.

One very important question is raised by this study: Given the low increase in absolute risk of breast cancer reported by the WHI with estrogen plus progestin¹—which barely reached statistical significance (total breast cancer RR, 1.24; 95% CI, 1.02-1.50)—and given the statement in the McTiernan study that “the reduced risk associated with increased levels of total physical activity was seen across all the categories of these variables” (including current or past use, or no previous use of hormone therapy), does the reduction of incidence with physical activity in hormone therapy users lower the level of risk to non-significance or to that of nonexercisers in the placebo group? The answer cannot be determined from this report, but it would be illuminating.

These findings are preliminary, and confirming studies are needed. There is little harm in encouraging women to exercise, however.

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.

WHIEstrogen-progestin has no significant effect on gynecologic cancers

Anderson GL, Judd HL, Kaunitz AM, et al, for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–1748.

• LEVEL I EVIDENCE: RANDOMIZED, CONTROLLED TRIAL
  

In this randomized, double-blind, placebo-controlled trial, 16,608 women were assigned to either EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate) or placebo; none of the women had undergone a hysterectomy.

After an average follow-up of 5.6 years:

• There were 20 cases of invasive ovarian cancer in the EPT group (n = 8,506) and 12 cases in the placebo group (n = 8,102). Compared with placebo, the hazard ratio (HR) for invasive ovarian cancer among EPT recipients was a nonsignificant 1.58 (95% CI, 0.77-3.24 [adjusted 95% CI, 0.59-4.23]).
  
• For endometrial cancer, 27 and 31 cases occurred, respectively, which translated statistically to a nonsignificant hazard ratio for EPT recipients of 0.81 (95% CI, 0.48-1.36).
  
• For cervical cancers, 8 and 5 cases were reported, respectively, with a nonsignificant HR of 1.44 (95% CI, 0.47-4.42).
  

COMMENT
Bias against hormone therapy?

The authors concluded that EPT may increase the risk of ovarian cancer but has no significant effect on the risk of endometrial cancer. They commented, however, that, since the EPT arm of the trial was prematurely stopped, the precision of the results is limited and examination of longer-term exposure is precluded.

This paper once again raises the question of whether the writers of the WHI trial have a bias against hormone therapy. In this report, the EPT arm of the WHI trial had an observed annual incidence of 34 ovarian cancer cases per 100,000 person-years—somewhat less than the anticipated population-based rate of 45 per 100,000 person-years. In the authors’ words, the ovarian cancer rate in the EPT group “was elevated (HR 1.58; 95% CI 0.77-3.24 [adjusted 95% CI, 0.59-4.23]) but not statistically significant.” The Kaplan-Meier estimates of cumulative hazards also did not reach statistical significance. Yet in the conclusion of the abstract, the authors state that continuous combined EPT “may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.”

Regarding the conclusion on endometrial cancer risk, the observed incidence for EPT users was 62 per 100,000 person-years, which is also lower than the anticipated population-based rate of 83 per 100,000 person-years. The authors state that this was a “small, nonsignificant reduction” in endometrial cancer risk (HR 0.81; 95% CI, 0.48-1.36). Yet, in the conclusion, while claiming that the nonsignificant difference in ovarian cancer suggests an increased risk, the authors do not state that the nonsignificant reduction in endometrial cancer suggests a decreased risk.

What do the authors expect us to believe, their data or their conclusions? My interpretation of the data in this article is that ovarian and uterine cancers need not be of major concern when determining a woman’s risk-benefit ratio for hormone therapy.

A retraction. Of interest, when this issue was raised in subsequent JAMA correspondence, the WHI authors agreed—representing perhaps the first time that a WHI report publicly retracted a potentially biased conclusion.^1,2

Fewer biopsies will be needed with lower dosage. It is not surprising that women taking hormonal therapy containing estrogen had more bleeding and, therefore, more endometrial biopsies than women taking placebo, because a known effect of estrogen is proliferation of the endometrial lining. With the lower-dose hormonal preparations currently available (which result in lower systemic estrogen levels and less endometrial stimulation), uterine bleeding episodes in menopausal hormone therapy users should diminish, along with the number of endometrial biopsies.

1. Utian WH. Hormone therapy and risk of gynecologic cancers [letter]. JAMA. 2004;291:42.-

2. Anderson GL, Judd HL, Kaunitz AM, et al. Hormone therapy and risk of gynecologic cancers—Reply. JAMA. 2004;291:43.-

MILLION WOMEN STUDYBreast cancer risks increased by estrogen plus progestogen

Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED
  

A total of 1,084,110 women aged 50 to 64 were enrolled between May 1996 and March 2001 and followed to the study finish (end of 2002). Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Nearly half of the women had used postmenopausal hormone therapy, either estrogen therapy alone (ET) or EPT. Primary endpoints were diagnosis of breast cancer and death from breast cancer.

Current ET or EPT use (compared with nonuse) was associated with a statistically significant increased risk of both breast cancer incidence (RR, 1.66; 95% CI, 1.58-1.75) and breast cancer mortality (RR, 1.22; 95% CI, 1.00-1.48). Past use did not increase the risk of incident (RR, 1.01; 95% CI, 0.94-1.09) or fatal disease (RR, 1.05; 95% CI, 0.82-1.34), and the risk decreased with time since last use.

The risks associated with ET and with EPT differed significantly. Current ET users had a 30% increased risk for breast cancer (95% CI, 1.21-1.40) while current EPT users had a 100% increased risk (95% CI, 1.88-2.12). However, vaginal or other local EPT formulations did not increase the risk (RR 0.67, 95% CI, 0.30-1.49). No significant differences in risk were found between specific types or doses of EPT or between continuous combined and continuous cyclic regimens.

COMMENT
Limitations of observational studies

This extremely large observational study found levels of breast cancer risk associated with ET and EPT similar to those reported by the WHI and as predicted in 1997 by the Collaborative Group on Hormonal Factors in Breast Cancer study.¹ The Million Women Study implicates an expanded number of ET and EPT products and routes of administration.

Acting as devil’s advocate, I will point out that this is an observational study with large potential for error. The major weakness is that it is a snapshot of hormone therapy use taken at the time of the women’s entry into the study, which was at the time of their 3-year mammogram. No further information was gleaned from the women regarding subsequent changes in hormone therapy use, such as whether they terminated use or changed the dose or route.

Also, the patient-provided data at entry showed a 96% agreement with the actual prescription written by the physician. The 4% variance, although it seems small, is of some concern given the narrow difference in relative risks and the large number of study participants. This is a weakness of any observational study; even if the prescription is filled, evidence that it was actually taken is inadequate.

Finally, the authors report that current use of hormone therapy at baseline increased the risk of breast cancer, although the relative risk was not as large as for disease incidence. They were not able to come up with reliable estimates of mortality attributable to breast cancer.

“Million Women” can be accepted only as an observational confirmation of a small increase in absolute risk of breast cancer.

In conclusion, the Million Women Study can be accepted only as an observational study providing confirmation of a small increase in the absolute risk for breast cancer in women on hormone therapy.

Further implications. The suggestion that these results apply to products beyond those tested in the WHI is in agreement with the NAMS Advisory Panel’s 2003 statement on Postmenopausal Hormone Therapy, which supports the view that although it is not possible to make general conclusions about all members of the estrogen and progestogen families, an improved benefit-risk profile of other EPT agents cannot be assumed.

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-1059.

Transdermal estrogen/progestogen had no effect on risk of venous thromboembolism in postmenopausal women.

ESTHER STUDYOral and transdermal EPT have different effects on risk of thromboembolism

Scarabin PY, Oger E, Plu-Bureau G, for the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–432.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED STUDY
  

Investigators enrolled 155 women aged 45 to 70 years who had been diagnosed with VTE, defined as either pulmonary embolism or deep vein thrombosis, and 381 matched controls. In women with VTE, 21% were using oral EPT and 19% were using transdermal EPT. In controls, 7% and 24% were using oral or transdermal EPT, respectively. An adjusted analysis showed that, compared with nonuse, current use of oral EPT significantly increased the VTE risk (adjusted odds ratio, [OR] 3.5; 95% CI, 1.8-6.8); transdermal EPT did not increase the VTE risk (OR, 0.9; 95% CI, 0.5-1.6). A between-group comparison showed that current oral EPT users had a significantly increased VTE risk (OR, 4.0; 95% CI, 1.9-8.3) over transdermal EPT users.

COMMENT
More studies needed but unlikely

A prime consideration for nonoral EPT for postmenopausal women is avoidance of the first-pass hepatic effect of oral medications, thereby reducing potential for the adverse effects associated with oral therapies. This study demonstrates a difference between oral and transdermal therapy, but the number of patients is small and, while promising, it is probably not a final answer to the problem.

The reduced incidence of VTE in postmenopausal women on transdermal EPT does justify further randomized controlled clinical trials; however, given the low prevalence of VTE, conducting such a study would be nearly impossible. It would be interesting if data from the Million Women Study were analyzed for effects of different routes of ET/EPT administration on VTE.

3 RANDOMIZED, CONTROLLED TRIALSIsoflavones are no better than placebo for hot flashes

Soy 40%, placebo 40%

Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Effects in women with breast cancer

Nikander E, Kikkinen A, Metsa-Heikkila M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

Menopause-related symptoms, including hot flashes, were recorded on the Kupperman index. At study end, the overall Kupperman index score was reduced by 15.5% in the phytoestrogen group (mean drop, 4.2) and by 14.7% in the placebo group (mean, 4.0); the between-group difference was not statistically significant.

When evaluated separately from the rest of the Kupperman index, the hot flash component was reduced more in the placebo group (14.3%) than in the study group (10%), although the difference was not statistically significant.

The quality of life parameters measured—capacity to work and mood changes—were not affected by phytoestrogen therapy.

Phytoestrogen treatment was well tolerated and caused no significant changes in liver enzymes, creatinine, body mass index, or blood pressure. In a subset analysis, investigators evaluated results based on high and low levels of endogenous equol; results did not differ between the groups.

Red clover vs placebo

Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–214.

• LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
  

COMMENT
The clinical implications

These 3 negative trials of isoflavones (2 extracted from soy, 1 from red clover) confirm previous reports of their essential inefficacy. The clinical implications:

• Women with mild hot flashes might consider either no pharmacotherapy or low-dose selective serotonin-reuptake inhibitors.
  
• Women with moderate to severe hot flashes that disrupt quality of life may continue to benefit from short-term, low-dose hormone therapy.