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Thursday, April 29, 2010

My Take on Postmenopausal Hormone Replacement Therapy

During the past several months postmenopausal hormone replacement has resurfaced as a topic of discussion.

On April 12th The New York Times published an article written by Cynthia Goran reviewing current controversies in post-menopausal hormone replacement therapy, told from the point of view of patient-investigator.

The article, as discussed nicely by health blogger Margaret Polaneczky, tells of the so call “window hypothesis” of estrogen therapy. The premise is that reported risks of adverse effects from hormone replacement therapy (HRT) cannot be generalized from older menopausal women to younger menopausal woman. There may be some truth to this argument.

In March 2010 the North American Menopause Society (NAMS) revised its 2008 consensus statement. The 2010 evidence-based review was performed by an Advisory Panel of clinicians and researchers in the field of women’s health. The Position Statement on treatment of menopause generally looks similar to the 2008 recommendations.

Currently postmenopausal hormone replacement therapy is not advised for routine use for preventive purposes in postmenopausal women. These recommendations are in large part based on the largest randomized controlled trial (RCT) to date on hormone replacement therapy in postmenopausal women, the Women’s Health Initiative (WHI). Since the July 2002 press release from the estrogen and progesterone arm of this study reporting the negative effects of hormone replacement therapy, post-menopausal HRT use has declined substantially. This largest RCT of HRT to date of 16,000 postmenopausal women found that oral estrogen use combined with progesterone (required for women with a uterus) was associated with increased rates of carcinoma of the breast and cardiovascular risk, including increased risk of stroke. The magnitude of the breast cancer risk reported was 8 additional breast cancers per 10,000 women, or a 24% increase in breast cancer risk.

For a nice summary of the WHI findings and associated risks see Menopause Fact Sheet

In March 2004 the estrogen alone trial of the WHI was reported. This study looked at oral estrogen use (.625 mg daily) in women who did not require progesterone, as they had undergone hysterectomy. “Unopposed” estrogen (without progesterone) is a known clear risk factor for uterine cancer. This arm reported on 11,000 women who were noted to have increased stroke risk, though were not found to have increased breast cancer risk.

The dispute over the applicability of the WHI findings stems from the fact that the average age of women studied was 63 years and the average time from menopause was >10 years. More recent analysis of younger subgroups of women, closer to the time of menopause, have in fact shown decreased cardiovascular risk with HRT. Additional study has shown that younger menopausal women treated with HRT have less coronary calcium build-up (linked to cardiovascular risk) than those randomized to placebo. These data form the basis for the “window,” or timing hypothesis that HRT may be cardioprotective when initiated earlier.

Needless to say this does not negate the finding that the combination of oral conjugated estrogen (.625 mg) and oral progesterone, medroxy-progesterone (2.5-5 mg), has been found to increase breast cancer risk in postmenopausal users, regardless of timing, when used for more than 3 to 5 years. In addition, HRT, both estrogen alone and estrogen with progestin, puts women at risk for abnormal mammograms and breast procedures.

Currently, the main indication for postmenopausal HRT is for treatment of vasomotor symptoms (hot flashes and night sweats). For this purpose HRT is the most effective treatment available and is recommended for no more than 5 years of use. HRT is also effective for treatment and prevention of osteoporosis, though is not recommended for either as first line therapy given its known risks.

Other news of interest on postmenopausal hormone replacement:
  • Transdermal estrogen has different biochemical effects, and therefore may have a better safety profile than oral estrogen.
  • There is not evidence to support the use of progesterone based intrauterine devices (Mirena) to prevent the endometrial hyperplasia related to estrogen use.
  • There is also not evidence to support the use of progesterone cream as adequate to prevent the endometrial hyperplasia related to estrogen therapy.
  • An association between post-menopausal hormone replacement and improvement in depressive symptoms has not been shown.
  • There is not evidence to support an association between post-menopausal hormone replacement and prevention of Alzheimer’s disease.
  • The touted improved safety and better efficacy of “bio-identical” hormonal products over standard hormone replacement therapy is very suspect.
While the term “bio-identical” may refer to standard brand name and tested hormonal products, such as 17B-estradiol or micronized progesterone, the terminology more commonly refers to custom compounded products that have not been tested and are not approved. Furthermore, the dosing of such products on the basis on salivary testing has not been shown to be either reliable or accurate.

In summary, the most current expert advice is that the lowest dose of HRT required should be used to treat symptoms of menopause if needed and continued for ideally less than 5 years. The doses of HRT on the market currently are lower than those studied in the WHI and may be safer, though this still remains unproven. Transdermal therapy may be preferable over oral therapy. There is no standard procedure for the discontinuation of HRT.

The assessment of a patient's personal risk profile and preferences and clinical flexibility are key to treating postmenopausal women with HRT. We all take risks in life. Some women feel better on perpetual hormone replacement therapy and that’s ok, but I personally feel more confident prescribing formulations that are better understood.

Wednesday, April 14, 2010

The Health Benefits of Chocolate

Recently I returned home from the grocery store with my weekly groceries, including my typical purchase of two 43 gram Hershey’s Milk Chocolate Bars with Almonds. As I munched on chocolate, consuming 210 calories and 8 gm of saturated fat, which virtually negated my morning run, I pondered the possible health benefits of chocolate, which have been reported recently.

In February, 2010 a press release from the American Academy of Neurology reported on several studies authored by Sarah Sahib (McMaster University, Hamilton, ON) demonstrating the effectiveness of chocolate in preventing and reducing the risk of stroke in prospective cohorts of patients. These studies respectively showed a reduction in first-time stroke risk in those who consumed chocolate by 22%, and a reduction in death risk for patients with previous stroke by 47% in patients who consumed 50 gm of chocolate rich in flavonoids once weekly. A third study showed no benefit. These studies will be presented at this week’s annual session of the American Academy of Neurology.

There is mounting evidence for the health benefits of chocolate, which is attributed to the high levels of flavonoids contained in cacoa. Flavonoids appear to have anti-inflammatory and anti-oxidative properties. However, the more highly processed the chocolate, the more these healthful flavonoids may be lost. In particular, roasting, fermentation and “alkalization” (Dutch processing) may contribute to the loss. Dark chocolate tends to be less processed and may contain fewer unhealthy ingredients (saturated fat and sugar) than milk chocolate. In addition, dark chocolate, compared with milk chocolate, has a higher content of cacao (>50%, compared with the 10 to 30% found in most milk chocolate).

There are three kinds of fat is chocolate: oleic acid, stearic acid and palmitic acid. Of the three, oleic acid is monounsaturated (as is olive oil) and considered healthy. Stearic and palmitic acid are saturated fats. While palmitic acid does increase LDL cholesterol (as do most saturated fats), stearic acid appears to be neutral in its cholesterol effect.

Evidence for the anti-inflammatory properties of chocolate include studies that have shown that the consumption of dark chocolate may reduce C-reactive protein (CRP) levels. (Di Giuseppe,J Nutr.2008;138:1939–1945) Clinical trials have also indicated that the consumption of dark chocolate reduces platelet dysfunction and improves endothelial function. (Flammer AJ et al. Dark Chocolate Improves Coronary Vasomotion and Reduces Platelet Reactivity. Circulation. 2007;116:2376–2382) Finally, the consumption of chocolate has been linked to a reduction in blood pressure as well as serum markers of oxidative stress (Taubert D et al. Effects of Low Habitual Cocoa Intake on Blood Pressure and Bioactive Nitric Oxide. A Randomized Controlled Trial. JAMA. 2007;298(1):49–60). This evidence all makes the findings of the prospective cohort study demonstrating a reduction in stroke risk with chocolate consumption seem more likely. However, further study with randomized controlled trials is needed to confirm these findings.

What "dose" of chocolate do I recommend for health? In most of the studies finding benefit, between 30 and 100 grams of chocolate containing 60 to 70 percent cacao were consumed weekly. My Hershey’s Milk Chocolate Bar with its lower cacao content (11%) may or may not apply. I think I’ll continue to indulge in my late afternoon snack of chocolate, but maybe I’ll try dark chocolate with a higher percent of cacao instead, and just maybe I’ll throw in a cup of coffee with it to prevent diabetes, but that’s a separate discussion.