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Update


UPDATE ON MENOPAUSE

Here is a roundup of the latest data on vitamin D requirements in women and how the route, timing, and duration of hormone therapy influence its safety and efficacy

May 2011 · Vol. 23, No. 5

IN THIS ARTICLE

RELATED ARTICLE

Dr. Kaunitz receives grant or research support from Bayer, Agile, Noven, Teva, and Medical Diagnostic Laboratories, is a consultant to Bayer, Merck, and Teva, and owns stock in Becton Dickinson.

Among the developments of the past year in the care of menopausal women are:

  • updated guidelines from the Institute of Medicine regarding vitamin D requirements—suggesting that fewer women are deficient in this nutrient than experts had believed
  • new data from Europe on hormone therapy (HT) that highlight the safety of transdermal estrogen in comparison with oral administration
  • a recent analysis from the Women’s Health Initiative (WHI), confirming a small elevated risk of breast cancer mortality with use of combination estrogen-progestin HT
  • confirmation that age at initiation of HT determines its effect on cardiovascular health
  • clarification of the association between HT and dementia
  • new data demonstrating modest improvement in hot flushes when the serotonin reuptake inhibitor (SRI) escitalopram is used
  • a brand new report from the WHI estrogen-alone arm that shows a protective effect against breast cancer.

The new data on HT suggest that we still have much to learn about its benefits and risks. We also are reaching an understanding that, for many young, symptomatic, menopausal patients, HT can represent a safe choice, with much depending on the timing and duration of therapy.

For more on how your colleagues are managing menopausal patients with and without hormone therapy, see “Is hormone therapy still a valid option? 12 ObGyns address this question,” on the facing page.


Menopausal women need less vitamin D than we thought

Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: IOM; December 2010. www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf. Accessed March 24, 2011.

In the 2010 Update on Menopause, I summarized recent findings on vitamin D requirements, including recommendations that menopausal women should take at least 800 IU of vitamin D daily. I also described the prevailing expert opinion that many North American women are deficient in this nutrient.

What a difference a year can make! In late November, the Institute of Medicine (IOM) released a comprehensive report on vitamin D. Here are some of its conclusions:

  • Vitamin D plays an important role in skeletal health but its role in other areas, including cardiovascular disease and cancer, is uncertain
  • An intake of 600 IU of vitamin D daily is appropriate for girls and for women as old as 70 years; an in-take of 800 IU daily is appropriate for women older than 70 years
  • A serum level of 25-hydroxy vitamin D of 20 ng/mL is consistent with adequate vitamin D status; this is lower than the threshold many have recommended
  • With few exceptions, all people who live in North America—including those who have minimal or no exposure to sunlight—are receiving adequate calcium and vitamin D
  • Ingestion of more than 4,000 IU of vitamin D daily can cause renal damage and injure other tissues.

The IOM report will likely prompt multivitamin manufacturers to increase the amount of vitamin D contained in their supplements to 600 IU daily. In addition, the report will probably discourage the common practice of checking serum 25-hydroxy vitamin D levels and prescribing a high dosage of vitamin D supplementation when the level is below 30 ng/mL.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

I continue to recommend multivitamin supplements that include calcium and vitamin D (but no iron) to my menopausal patients. However, I no longer routinely recommend that they take additional calcium and vitamin D or undergo assessment of serum vitamin D levels.

Is transdermal estrogen safer than oral administration?

Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol. 2010;30(2):340–345.

Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010;340:c2519. doi: 10.1136/bmj.c2519.

In the WHI, the combination of oral conjugated equine estrogen and medroxyprogesterone acetate more than doubled the risk of deep venous thrombosis and pulmonary embolism and modestly increased the risk of stroke, compared with nonuse.1

A year after publication of the initial findings of the WHI estrogen-progestin arm, the Estrogen and THromboEmbolism Risk Study Group (ESTHER) case-control study from France provided evidence that transdermal estrogen does not increase the risk of venous thrombosis.2 In France, many menopausal women use HT, and the transdermal route of administration is common.

In 2010, the E3N cohort study from France also assessed the risk of thrombosis associated with oral and transdermal HT. Investigators followed more than 80,000 postmenopausal women and found that, unlike oral HT, the transdermal route did not increase the risk of venous thrombosis.

More recent evidence also suggests a safety advantage for transdermal HT. The newest data come from the United Kingdom General Practice Research Database, which includes information on more than 870,000 women who were 50 to 70 years old from 1987 to 2006. Investigators identified more than 15,000 women who were given a diagnosis of stroke during this period and compared the use of HT in these women with that of almost 60,000 women in a control group. The risk of stroke associated with current use of transdermal HT was similar to the risk associated with nonuse of HT. Women who used a patch containing 0.05 mg of estradiol or less had a risk of stroke 19% lower than women who did not use HT.

In contrast, the risk of stroke in users of patches that contained a higher dosage of estradiol was almost twice the risk in nonusers of HT. Current users of oral HT had a risk of stroke 28% higher than that of nonusers of HT.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

The WHI assessed the risks and benefits of oral HT only. Although no randomized, clinical trial has compared cardiovascular risks among users of oral and transdermal HT, I believe that a preponderance of evidence points to a superior safety profile for the transdermal route, particularly at a dosage of 0.05 mg of estradiol or less.

I encourage my patients who are initiating HT to consider the transdermal route—particularly women who have an elevated risk of cardiovascular disease, including those who are overweight, smoke cigarettes, or who have hypertension or diabetes. I suggest the transdermal route despite its higher cost (oral micronized estradiol can be purchased for as little as $4 for a month’s supply at a chain pharmacy).

When a patient prefers to avoid a patch (because of local irritation), I offer her estradiol gel or spray or the vaginal ring. (Femring is systemic estradiol, whereas Estring is local.) These formulations should provide the same safety benefits as the patch.

Estrogen-progestin HT raises the risk of death from breast cancer

Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–1692.

Toh S, Hernandez-Diaz S, Logan R, Rossouw JE, Hernan MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin: does the increased risk ever disappear? Ann Intern Med. 2010;152(4):211–217.

In the estrogen-progestin arm of the WHI, initially published in 2002, the risk of invasive breast cancer was modestly elevated (hazard ratio [HR], 1.26) among women who had used HT longer than 5 years.3

In 2010, investigators reported on breast cancer mortality in WHI participants at a mean follow-up of 11 years. They found that combination HT users had breast cancer histology similar to that of nonusers. However, the tumors were more likely to be node-positive in combination HT users (23.7% vs 16.2%). In addition, breast cancer mortality was slightly higher among users of HT (2.6 vs 1.3 deaths in every 10,000 woman-years) (HR, 1.96; 95% confidence interval, 1.00–4.04).

Earlier observational studies had suggested that the death rate from breast cancer is lower in users of combination HT than in nonusers. Consistent with the UK Million Women Study, however, a 2010 report from the WHI found a higher mortality rate among women who have used HT.4

These new WHI findings reinforce the importance of assessing whether micronized progesterone combined with estrogen might lower the risk of death from breast cancer—a possibility suggested by findings of the French E3N cohort study.5

In addition, given the possibility that HT may be cardioprotective when it is initiated within 10 years after the onset of menopause, a WHI report that addresses long-term all-cause mortality would allow us to better counsel our menopausal patients who are trying to decide whether to start or continue HT. See, for example, the data from the California Teachers Study (below) and the estrogen-alone arm of the WHI (page 46).

WHAT THIS EVIDENCE MEANS FOR PRACTICE

The findings of this important WHI publication have strengthened the resolve of some clinicians to stop prescribing HT for menopausal women. I continue to prescribe HT to patients who have bothersome vasomotor and related symptoms, however. I also counsel women about the other benefits of HT, which include alleviation of genital atrophy and prevention of osteoporotic fractures. For patients considering or using estrogen-progestin HT, I include discussion of the small increase in their risk of developing, and dying from, breast cancer.

Age at initiation of HT determines its effect on CHD

Stram DO, Liu Y, Henderson KD, et al. Age-specific effects of hormone therapy use on overall mortality and ischemic heart disease mortality among women in the California Teachers Study. Menopause 2011;18(3):253-261.

Allison MA, Manson JE. Age, hormone therapy use, coronary heart disease, and mortality [editorial]. Menopause. 2011;18(3):243-245.

The initial findings of the WHI estrogen-progestin arm suggested that menopausal HT increases the risk of CHD. Since then, however, further analyses from the WHI and other HT trials, as well as reports from the observational Nurses’ Health Study, have suggested that the timing of initiation of HT determines its effect on cardiovascular health.

In this study from the California Teachers Study (CTS), investigators explored the effect of age at initiation of HT on cardiovascular and overall mortality. The CTS is a prospective study of more than 133,000 current and retired female teachers and administrators who returned an initial questionnaire in 1995 and 1996. Participants were then followed until late 2004, or death, whichever came first. More than 71,000 participants were eligible for analysis.

Current HT users were leaner, less likely to smoke, and more likely to exercise and consume alcohol than nonusers were. The analysis was adjusted for a variety of potential cardiovascular and other confounders.

Youngest HT users had the lowest risk of death

During follow-up, 18.3% of never-users of HT died, compared with 17.9% of former users. In contrast, 6.9% of women taking HT at the time of the baseline questionnaire died during follow-up.

Overall, current HT use was associated with a reduced risk of death from CHD (hazard ratio [HR], 0.84; 95% confidence interval, 0.74–0.95). This risk reduction was most notable (HR, 0.38) in the youngest HT users (36 to 59 years old). The risk of death from CHD gradually increased with the age of current HT users, reaching a hazard ratio of approximately 0.9 in current users who were 70 years and older. However, the CHD mortality hazard ratio did not reach or exceed the referent hazard ratio (1.0) assigned to never users of HT of any age.

The overall mortality rate was lowest for the youngest HT users (HR, 0.54) and approached 1.0 in the oldest current HT users.

The associations between overall and CHD mortality were similar among users of estrogen-only and estrogen-progestin HT.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

As Allison and Manson point out in an editorial accompanying this study, the findings from the CTS are congruent with an extensive body of evidence from women and nonhuman primates. These data provide robust reassurance that HT does not increase the risk of death from CHD when it is used by recently menopausal women who have bothersome vasomotor symptoms.

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