Study Findings Offer Doctors And Women A New Option

By Nancy K. Crevier

Women who are entering menopause or in the throes of menopause, that period of life when fertility ends due to a decrease in ovarian function, estrogen, and other hormone production, will find the recent study by Dr Jerilynn Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver, Canada, and Christine Hitchcock, PhD, University of British Columbia, interesting, if not hopeful.

Dr Prior is founder and scientific director of the Centre for Menstrual Cycle and Ovulation Research, has been published in journals including The New England Journal of Medicine and the Journal of the American Medical Association, and is a diplomate of the American Board of Internal Medicine, and a Fellow of the Royal College of Physicians and Surgeons, of Canada. In 1985, she was awarded a Nobel Peace Prize for her work with Physicians for the Prevention of Nuclear War.

The study, presented at the June Annual Meeting of the Endocrine Society in Sand Diego, Calif., suggests that oral micronized progesterone may be effective for the treatment of hot flashes and night sweats experienced by many women approaching or during menopausal years.

A hot flash is a sudden surge of heat swiftly followed by the dilation of blood vessels near the surface of the skin, as well as sweating, both of which serve to cool down the body. Hot flashes with sweating that occur at nighttime are called night sweats, and both hot flashes and night sweats lead to sleep disturbances and anxiety.

The Prior/Hitchcock study of 114 women receiving a 300-milligram dose of progesterone (sold in the US and Canada as Prometrium) or a placebo, followed the intensity and number of hot flashes experienced by those women. A swift and statistically significant improvement was observed in the women receiving the progesterone.

Prometrium has been approved in Canada since 1995 and in the US by the Federal Drug Administration since 1998, and is commonly prescribed in conjunction with the hormone estrogen. Estrogen/progesterone hormone therapy was linked to increased risk of heart disease and breast cancer in a 2002 Women’s Health Initiative Study, and resulted in many women opting to tough out the unpleasant symptoms of menopause rather than take on the risks associated with hormone replacement therapy, or menopausal hormone therapy, as it is now known. (Since then, studies suggest that the age at which women begin hormone therapy affects the outcome. Beginning hormone therapy shortly after the onset of menopause, between the ages of 50 and 59, may have many benefits. Risky side effects of hormone therapy, reintroducing hormones into the body after several years absence, may be more of a concern for women after age 60.) The study by Dr Prior and Dr Hitchcock is the first to suggest that the use of progesterone alone may decrease some of the most bothersome symptoms of menopause, without added risks.

“It makes me happy to have shown what many clinicians have known for some time,” said Dr Prior in a telephone interview, Thursday, June 24, “that progesterone is effective for hot flashes.” Prometrium has been used off-label by clinicians in Canada since it was first approved, said Dr Prior, and she herself used the progesterone-only therapy during premenopausal and menopausal years to successfully relieve symptoms of menopause.

While there have been studies of hormonal therapy to treat menopausal symptoms for years, said Dr Joshua Hurwitz, division director of reproduction, endocrinology, and fertility at Danbury Hospital, and a partner in Reproductive Medicine Associates of Connecticut, a leader in hormonal and infertility care in the area, studies have only been scientific and rigorous in the last ten years. “We know more in the last 15 years due to landmark studies,” said Dr Hurwitz, and he praised the study released by Dr Prior. “It’s a great study,” he said.

Because improving the quality of life for women experiencing menopausal symptoms is a number one goal for both Danbury Hospital and his private practice, said Dr Hurwitz, there may be “a place in our toolbox of things we use to treat menopause,” with the inclusion of Prometrium-only therapy. He welcomes the addition of this program to traditional estrogen/progesterone replacement therapy, the use of SSRIs such as Effexor or Prozac, and even practical interventions such as exercise, dietary changes, and simply layering clothing to alleviate hot flash symptoms. “It is always good to have lots of tools in the toolbox,” he said.

For those women wondering if they are opening a Pandora’s box through the use of Prometrium alone, Dr Hurwitz noted that the use of Prometrium is not a question of if it is “safe” or not. “Prometrium mimics exactly natural progesterone. The question is, we don’t know if having progesterone in the system for ten years after menopause is good, neutral, or bad. There might be consequences to having reproductive hormones in the body for an extended period of time, beyond when they would naturally occur,” he said. Still, he said the study by Dr Prior is a level one, gold study that indicates serious consideration for women and their doctors. “[Dr Prior’s] study allows us to use less hormones — one, rather than two — and there are patients who can’t use estrogen. Now we have an option,” Dr Hurwitz said.

Hormone Therapy

Questions

The book is not finished yet on hormone therapy, emphasized Dr Hurwitz, in a world really just starting to look at those questions. “We have learned over many years that hormone therapy has a foremost role in treating menopausal symptoms. What we have learned from the Women’s Health Initiative study is to use the lowest effective dose for the shortest period of time to help patients through those symptomatic periods of their lives,” he added.

While the Prior/Hitchcock study focused on the efficacy of Prometrium in treating hot flashes and night sweats, there are other randomized trials that show progesterone-only treatment for premenopausal and menopausal women can increase the rapid eye movement stage of sleep, during which people gain the most restful sleep, and decrease fragmented sleep and anxiety. Poor sleep and daytime fatigue are common complaints, along with hot flashes, among women in menopause, said Dr Prior.

Prometrium should not be confused with progestin, stressed Dr Prior. Porgestin is a synthetically produced form of progesterone. Prometrium is manufactured from a wild yam steroid molecule that has been converted into the natural form of progesterone. It is also because Prometrium is conveyed as an oral micronized form (small particles dissolved in peanut oil) that makes it more effective than other forms of progesterone, said Dr Prior.

Confusion could be avoided if the name “progesterone” were saved for only the molecularly identical hormone manufactured from the wild yam, as is Prometrium, Dr Prior said.

And although Prometrium is manufactured from wild yam, women must beware of the wild yam products sold over the counter. “Wild yam creams are a scam. We can’t turn the wild yam in creams into natural progesterone in our bodies,” said the doctor. Synthesized progesterone creams typically contain a lower dose of the hormone, and have not been that well studied, she added.

Despite Prometrium having been prescribed off label for more than a decade by many clinicians, it is still not commonly suggested by doctors when women complain of hot flashes. And Googling “Prometrium” brings up a laundry list of side effects that will give any woman second thoughts about taking the hormone, including increased risk of clot-related disorders, fluid retention, and depression.

For medical and legal reasons, any product with progestin in it, or Prometrium in a combined therapy, must show all of the side effect warnings, even though it is more likely the estrogen aspect of the product that contributes to the side effects, explained Dr Prior.

A Cultural Bias

There is a systemic and cultural bias that makes progesterone the bad guy in hormone therapy, said Dr Prior, when it is estrogen that should be equally villainized. “It has been well known since the 1500s that there are two different types of cells in the ovary. When estrogen was synthesized for therapy in the 1900s,” she said, “estrogen became the female hormone. Progesterone became the forgotten and maligned hormone, and a lot of negative attribution has been given it that is not warranted. The current belief is that estrogen is what makes a girl a girl. But there is evidence-based information that says it is estrogen and progesterone that makes a girl a woman. You only acquire progesterone as you mature.”

The use of Prometrium alone to treat menopausal symptoms is extremely safe, said Dr Prior, when taken as prescribed. Because it is a natural and effective sleep aide, she tells her patients to take it only immediately before getting into bed. Some morning drowsiness was experienced by six of the study patients, she said, who were taking Prometrium, but was not experienced after being on the hormone for a couple of weeks. Because most women starting therapy are sleep deprived, she believes that the initial lethargy is due to the body trying to catch up on needed sleep. Once several peaceful nights have restored rest, morning sleepiness is relieved.

Oral micronized progesterone has been shown in careful studies to decrease the proliferation of breast cancer cells, said Dr Prior, making it a safe choice for women who fear hormone therapy will cause breast cancer. Observational data from a study in France, where Prometrium has been available for more thantwo decades, show no increased risk of breast cancer, out to eight years, with oral micronized progesterone, she said.

She believes that progesterone-only therapy works for women because it calms the brain’s reaction to estrogen “withdrawal” that occurs during menopause. If hot flashes are estrogen “addiction,” it makes sense to use progesterone for treatment she said. She elaborates on that theory in her book, Estrogen Errors: Why Progesterone Is Better For Women’s Health, co-authored with Susan Baxter, PhD.

“Currently, women are in a rough choice: take estrogen combination therapy and run the risks of heart disease and breast cancer, or take nothing and suffer. Women need alternatives that don’t carry these risks,” stressed Dr Prior. She is hopeful that the release of the study will mean doctors will be more willing to offer effective treatment of menopausal symptoms through the use of oral micronized progesterone to their patients.

The trial was funded strictly through private donations, said Dr Prior. “This is going to be driven by women, of course,” said Dr Prior, “as are most women’s health initiatives.”