Pulse
Four Herbs and a Mushroom
Could an ancient Japanese formula ease menopause for American women?
Greg Plotnikoff, M.D., had no idea just how hot his study of an 1,800-year-old Japanese herbal formula that can cool hot flashes in menopausal women would be until a report on his research aired on Twin Cities television last November, and the phone in his office on the University of Minnesota campus began to ring.
“We got at least 500 phone calls in two days,” recalls the associate professor of internal medicine and pediatrics, who is splitting his time between Minneapolis and Tokyo, where he is a visiting associate professor at Keio University Medical School.
Plotnikoff and his colleagues were looking for volunteers to take part in a U.S. clinical trial of Keishi-bukuryo-gan (also known as TU-025), a formula consisting of four herbs and a mushroom that is prescribed in Japan for women wanting relief from hot flashes.
Plotnikoff learned about the formula while working alongside Japanese physicians in a clinic at the university. “We see about 40 patients a morning who have a wide variety of concerns, including menopausal concerns. I started seeing that women were having very good results from traditional Japanese herbal medicine,” he says.
In the United States, women had found relief in estrogen therapy, which proved to be 96 percent effective in reducing the frequency and severity of hot flashes. However, many stopped taking estrogen after the first randomized trial of hormone therapy for prevention of heart disease was discontinued in 2002 because it actually showed an increase in heart attacks, stroke, deep venous thrombosis and pulmonary embolism, and breast cancer. “Women who were going off estrogen wanted options,” Plotnikoff says, adding that use of antidepressants is often the only other choice for U.S. women. “This is something that’s been found to work in Japanese women, is widely used, and is known to be safe.”
More than 400 million doses of TU-025 have been prescribed in Japan since 1994. In addition, the compound is regulated as a pharmaceutical agent by the Japanese Ministry of Health and is covered by the country’s national health plan. According to Plotnikoff, the postmarketing surveillance conducted by Tsumura and Company, which manufactures TU-025, found few complications—seven cases of severe liver toxicity that were reversed with discontinuation and one serious rash that was alleviated after the patient stopped using the compound. “This compares very favorably with the other prescription options for hot flashes,” he says.
Although TU-025 isn’t an estrogen, Plotnikoff says it works in much the same way. Both estrogen and TU-025 affect calcitonin gene–related peptide (CGRP), a potent vessel dilator. Women going through menopause often experience spikes in CGRP. At the same time, the number of CGRP receptors on the walls of their blood vessels increases. Combine a sudden increase in concentration of CGRP with an increased number of receptors and the result is a hot flash. Both estrogen and TU-025 block this response. “Why and what ingredient or ingredients are doing it, we don’t know,” Plotnikoff says. (Cinnamon bark is one component in the herbal compound; Plotnikoff declined to name the others, saying that he’s concerned about people trying to recreate the formula on their own.)
In 2003, Plotnikoff and his co-investigators received FDA approval to conduct a Phase II clinical trial of TU-025 in U.S. women. They began recruiting 180 Minnesota women to take part in a 13-week randomized, double-blind study late last year. Of the participants, 60 will receive the dosage currently prescribed in Japan, 60 will get a higher dose, and the final group will receive a placebo. Participants are required to keep a “hot flash diary,” where they record information about the severity and duration of each episode.
According to Plotnikoff, this study is the largest and most scientifically rigorous trial of any traditional Japanese herbal medicine ever conducted. “We need to assess effectiveness in American women. We want to make sure we have evidence-based options for women to consider. That’s why we’ve put a lot of energy into making the trial happen,” he says.
Plotnikoff hopes to complete the clinical trial by the end of June. He explains that TU-025 would still need to go through Phase III trials to get FDA approval, and that it could be several years before the compound is on the shelves of U.S. pharmacies.
“I had heard women express concerns about menopause and hot flashes. But it wasn’t until we started advertising this study that I really heard incredible stories of the suffering women had been experiencing—the inability to sleep, being horrified by uncontrollable sweating even in the middle of winter. It was very humbling for me as a guy to hear those stories.”—Kim Kiser
A Man’s Problem, Too
A new antidepressant was found to be effective for alleviating hot flashes in men—men who are receiving hormone therapy for prostate cancer, that is. Mayo Clinic researchers followed 18 men who were receiving androgen ablation therapy, also known as hormonal deprivation therapy, for prostate cancer and were enrolled in a study of the antidepressant’s effectiveness between August 2001 and October 2003.
Participants were given paroxetine (Paxil), which is used to treat depression, obsessive-compulsive disorder, panic disorder, and anxiety. During the five-week study, the frequency of their hot flashes decreased from 6.2 to 2.5 per day on average. The men’s “hot-flash scores” (frequency multiplied by severity) fell from 10.6 to 3 per day.
A previous placebo-controlled trial found paroxetine reduced hot flashes in women.
The findings were published in the October 2004 issue of Mayo Clinic Proceedings.— K.K.
Having a hotto furasho
When McGill University medical anthropologist Margaret Lock reported in the 1980s that few Japanese women experienced hot flashes, she postulated that the reason was because they ate soy, which is rich in phytoestrogens. The soy industry in the United States used that argument to try to make their product the answer to one of menopausal women’s most frustrating problems.
What food manufacturers failed to understand was that Japanese women just didn’t have the words to describe what was happening to their bodies. “In Japan, the culture is very different. One does not share widely such concerns,” says Greg Plotnikoff, M.D., a University of Minnesota associate professor of internal medicine and pediatrics, who has been a visiting associate professor at Keio University Medical School in Tokyo for the past two years.
Plotnikoff recently conducted a study of nearly 1,100 women at a mature women’s clinic at Keio University. He gave them a list of 40 symptoms and asked which ones they’ve experienced and had them rate the severity. Among the top five symptoms: hot flashes.
“It’s clear that Japanese women have had hot flashes, but there was not societal permission to discuss these things,” he says. “It wasn’t until hotto furasho was imported into the Japanese language that women had permission to talk about them.”
Results of the study were reported in the November-December 2004 issue of Menopause. —K.K.