KEEPS on Keeping On

Article taken from page 4 of November/December Newsletter 2015

By Adriane Fugh-Berman, MD

The myth that menopausal hormone therapy prevents heart attack and dementia should have died a swift death after the definitive results of the Women’s Health Initiative (WHI) a dozen years ago.  But the concept that hormones might prevent some disease —in some women, somewhere, sometime, somehow — just keeps rising from the grave.

The Kronos Early Estrogen Prevention Study (KEEPS) is the name of an unnecessary trial that was conducted by hormone enthusiasts after the WHI proved that the harms of menopausal hormone therapy (including increased risks of breast cancer, heart attacks, strokes and dementia) outweighed its only disease prevention benefit – a reduced risk of fractures.

The research question explored in KEEPS was based on the ludicrous “timing hypothesis.” This implausible hypothesis posits that, although healthy women given menopausal hormones experienced no disease prevention benefit, a benefit might be revealed if hormones were given to women who were close to the menopausal transition rather than to older women who went through menopause many years earlier. This was always a faulty foundation for a study because the average age of menopause is 51 and the WHI had already studied more than 5,000 women in their 50s — and found no such benefits. (For background on the claims made by KEEPS researchers, see “Two Years Too Late: Researchers Announce Hoped-For Results, Stall on Revealing Actual Data” at https://www.nwhn.org/two-years-too-late-researchers-announce-hoped-for-results-stall-on-revealing-actual-data.)

National Women’s Health Network (NWHN) members know that the NWHN has been the most important and effective force for questioning claims for hormone therapy’s benefits, and demanding that the right studies be done to assess the impact on women’s health. Our efforts helped launch the WHI, a large, long-term, federally-funded, randomized controlled trial that examined the risks and benefits of hormone therapy in more than 26,000 women.

Let’s review what the WHI found:

  • Starting in 1991, more than 16,000 women took either an estrogen/progestin combination (Prempro) or a placebo. In 2002, this study was stopped early because women taking the combined pills experienced harm, including higher rates of invasive breast cancer and heart attacks.[1]
  • Another arm of the WHI study tested an estrogen-only hormone therapy (Premarin) against placebo in more than 10,000 women. All of the women had had hysterectomies, so they did not need a progestin to protect their uterus from estrogen-induced cancers. In 2004, the WHI’s estrogen-only arm was stopped because an increased risk of stroke was found among women taking the hormones.[2]

These findings have been verified by other research. A systematic review of WHI and 22 other randomized controlled trials of menopausal hormone therapy use, involving a total of 42,830 women, found that estrogen-progestin combinations increased the risk of a cardiac event; blood clot; stroke; breast cancer; gallbladder disease; death from lung cancer; and, in women over 65, dementia.[3]

Although there was little point in doing a smaller, limited study after the large, comprehensive WHI study showed no benefit, the KEEPs researchers, many of whom had received payments from hormone manufacturers, randomized 727 recently menopausal women (with an average age of 52.6, and 1.4 years past their last menstrual period) to either a placebo or oral or transdermal (skin patch) estrogen with micronized progesterone. Notably, the progestin in this study was different than that used in the WHI — some alternative medicine practitioners have touted micronized progesterone as a better “bioidentical” hormone. These women were followed for four years. Hormone therapy failed to benefit measures of cardiovascular health and — in recent news — failed to have any benefit on cognition in a large substudy that included 693 women.[4]

All of the KEEPS findings are consistent with the results from the WHI and other randomized controlled trials — except that KEEPS found a minor mood-elevating effect in non-depressed women who took oral (but not transdermal) estrogen. There was no effect on real depression. (WHI, on the other hand, found no benefit of hormones on symptoms of depression or any other quality-of-life measures.)

When even the most loyal hormone enthusiasts can find no benefit of hormone therapy, it’s time to give up searching. The concept that hormones will benefit some woman, somewhere, if we just gave the right dose and mix of at some crucial — but elusive —moment is magical thinking. At this point, anyone who believes that menopause hormone therapy benefits women’s hearts or brains believes something that is inconsistent with science.

We’ve said it before and we’ll say it again: The risks of menopause hormone therapy overwhelmingly outweigh benefits for menopausal women — excepting those who have severe hot flashes or vaginal dryness, which estrogen helps.

The KEEPS results should drive the final nail in the coffin of the myth that menopausal hormone therapy has health benefits that outweigh its risks. So, why do we have the lurking sense that someday, the specter of hormone benefit will rise from the dead again to haunt us?

Alternative Approaches To Address Menopausal Symptoms

The most common complaint among women going through the menopausal transition is about hot flashes and night sweats. Given the risks of menopause hormone therapy, many women seek alternative approaches to controlling these problems. These include:

  • Following a low-fat diet, which has been found to help with menopausal symptoms and has the added benefit of reducing the risk of ovarian cancer.
  • Losing weight, regardless of what type of diet is used, helps reduce menopausal symptoms.
  • Getting enough exercise, which helps with symptom control (especially for very active women). Research indicates that physical activity, including yoga, helps with symptoms including hot flashes and pain. Exercise can also reduce stress and the risk of breast cancer, and improve mental health and bone density.
  • Try taking anti-depressants, which have been shown to help with hot flashes. It appears that venlafaxine (Effexor) and paroxetine (Paxil) are the most effective anti-depressants for treating hot flashes. Paroxetine is now available in a repackaged formula at a lower dose than used for treating depression.
  • Explore other drug therapies; potential hot flash treatments include the anti-seizure medication gabapentin and the blood pressure drug clonidine.

Lifestyle factors not only work for menopausal symptoms, but also have other health benefits as well. Non-hormonal drug therapies are also an option, but should be approached with caution until more is known about their long-term effects.

Finally, if you’re considering using hormone therapy for symptoms, start with the lowest dose possible, and make sure you’re familiar with the warning signs of complications, such as blood clots and stroke.  While rare, these complications are serious and even life-threatening. For references and more information, see our article from the November 2014 issue of the WHA, at https://www.nwhn.org/non-hormonal-alternatives-for-menopausal-symptoms.

Adriane Fugh-Berman, MD, is an associate professor in the Georgetown University Medical Center; a former chair of the NWHN Board of Directors; and director of PharmedOut, which educates prescribers about pharmaceutical marketing techniques.

References

[1] Writing Group for the Women’s Health Initiative Investigators, “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial,” JAMA 2002; 288(3):321–33.

[2] Hsia J, Langer RD, Manson JE, et al., “Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative,” Arch Intern Med 2006; 66(3):357-65.

[3] Marjoribanks J, Farquhar C, Roberts H, et al., “Long term hormone therapy for perimenopausal and postmenopausal women,” Cochrane Database Syst Rev. 2012; Jul 11;7:CD004143. doi: 10.1002/14651858.CD004143.pub4.

[4] Gleason CE, Dowling NM, Wharton W, et al., “Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study,” PLoS Med. 2015; 12(6):e1001833; discussion e1001833. doi: 10.1371/journal.pmed.1001833. eCollection 2015 Jun.