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Diets based on Ayurvedic constitution--potential for weight management

Authors:

Abstract

Ayurveda, the traditional Indian medical system, is receivingincreasing attention worldwide. A retrospective study was conducted to determine the effectiveness ofAyurvedic constitution-based diets on weight loss patterns of obese adults. DESIGN, SETTING, SUBJECTS, AND INTERVENTION: Records of 200 obese adults, both male and female, who had completed 3 months of the diet therapy at Ayurvedic clinics, were examined and data collated. Techniques used included a checklist of personality traits, physical signs, and food likes and dislikes to determine the dosha. Based on the predominant doshas, diets were prescribed and closely monitored for a period of 3 months. Records of height and weight and chest, abdominal, waist, arm, and thigh circumferences noted initially and after each month for the period of 3 months were obtained. Among the 200 subjects, 55 (27.5%) were vatta-, 83 (41.5%) were pitta-, and 62 (31.0%) were kapha-predominant. At the beginning, kapha and pitta people were heavier than vatta people. After the 3 months of therapy, the pitta group lost the most weight (9.84%). The decrease in all the anthropometric measurements was higher in pitta and kapha people than in vatta individuals. Hence, diets based on Ayurvedic constitution may prove useful in promoting weight loss. Though these promising findings support traditional Indian Ayurvedic scriptures, more closely controlled trials are needed to substantiate these findings.
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2 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Table of Contents
TABLE OF CONTENTS
jan/feb 2009, VOL. 15, NO. 1
10 Change
David Riley,
MD
16 Improving the Science for Botanical and Dietary Supplements
Stacie E. Geller, PhD
20 The Map: Integrating Integrative Medicine
Mark A. Hyman
24 Confi rmation of the Effi cacy of ERr 731 in Perimenopausal Women With
Menopausal Symptoms
Marietta Kaszkin-Bettag,
PhD; Boris M. Ventskovskiy, MD, PhD; Sergey Solskyy, MD, PhD;
Sabine Beck,
PhD; Ilona Hasper, MD; Andrei Kravchenko, MD, PhD; Reinhard Rettenberger, PhD;
Andy Richardson,
PhD; Peter W. Heger
36 Clinical Observations and Seven-and-One-Half-Year Follow-up of Patients Using an
Integrative Holistic Approach for Treating Chronic Sinusitis
Robert S. Ivker, DO; William S. Silvers, MD; Robert A. Anderson, MD
44 Diets Based on Ayurvedic Constitution—Potential for Weight Management
Shikha Sharma,
MBBS, MD; Seema Puri, PhD; Taru Agarwal, MSc; Vinita Sharma, BAMS
50 Delivery of a Full-term Pregnancy After TCM Treatment in a Previously Infertile
Patient Diagnosed With Polycystic Ovary Syndrome
Jennifer A. M. Stone, LAc; Karmen K. Yoder, PhD; Elizabeth A. Case, MD
54 The Use of Botanicals During Pregnancy and Lactation
Tieraona Low Dog, MD
60 A Possible Central Mechanism in Autism Spectrum Disorders, Part 2: Immunoexcitotoxicity
Russell L. Blaylock, MD
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4 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Table of Contents
68 Frank Lipman, MD: Where Eastern Medicine Meets Western Medicine
78 American Holistic Medical Association January Newsletter
14 Letters to the Editor
14 Erratum
82 Resources
84 Classifi eds/Conference Calendar
84 Advertisers Index
Metabolic Cardiology: The Missing Link in Cardiovascular Disease
Understanding Diagnostic Reasoning in TCM Practice: Tongue Diagnosis
Cranberry Constituents Affect Fructosyltransferase Expression in Streptococcus mutans
The Effects of Distant Healing Performed by a Spiritual Healer on Chronic Pain
Does Valerian Improve Sleepiness and Symptom Severity in People With Restless Legs Syndrome?
• Effi cacy of Dried Cruciferous Powder for Raising 2/16 Hydroxyestrogen Ratios in Premenopausal Women
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It is generally known that Picasso’s paintings have exerted a great infl uence on the modern world, as have Oriental
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EDITOR in chief
David Riley, MD
Editorial Board
Sidney MacDonald Baker, MD
Co-Chairman of the DAN! Advisory Board
Elizabeth Ann Manhart Barrett, RN, PhD, FAAN
Hunter College of CUNY
Harriet Beinfi eld, LAc
Chinese Medicine Works
William Benda, MD
University of California San Francisco
Mark Blumenthal
American Botanical Council
Ian Coulter, PhD
RAND; UCLA; Samueli Institute;
Southern University of Health Sciences
Harley Goldberg, DO
Kaiser Permanente
Ellen Kamhi, PhD, RN
Stony Brook University
Ted Kaptchuk, OMD
Harvard Medical School
Stanley Krippner, PhD
Saybrook Graduate School and Research Center
George Lewith, MD, FRCP
University of Southampton
Peter Libby, MD
Brigham and Women’s Hospital
Harvard Medical School
Tieraona Low Dog, MD
University of Arizona
Victoria Maizes, MD
University of Arizona
Bill Manahan, MD
American Holistic Medical Association
Woodson C. Merrell, MD
Continuum Center for Health and Healing,
Beth Israel Medical Center
Pamela Miles, Reiki master
Institute for the Advancement of Complementary
Therapies (I*ACT)
Dean Ornish, MD
Preventive Medicine Research Institute,
University of California, San Francisco
Joseph E. Pizzorno, ND
President Emeritus, Bastyr University and
President, SaluGenecists, Inc
Anthony L. Rosner, PhD, LLD (Hon)
Parker College of Chiropractic
Robert B. Saper, MD, MPH
Boston University Medical Center
Betsy B. Singh, PhD
Medicus Research, LLC
Leanna Standish, ND, PhD, LAc
Bastyr University
Eugene Taylor, PhD
Saybrook Graduate School
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Roeland van Wijk, PhD
International Institute of Biophysics, Germany
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MISSION Alternative Therapies in Health and Medicine is an international scientifi c forum for the dissemination of peer-reviewed information to healthcare
professionals regarding the use of complementary and alternative therapies in promoting health and healing.
EDITORs
Christine L. Girard, NDJason Hao, DOMMichele Mittelman, RN, MPH
CONTRIBUTING EDITORs
Michael Balick, PhD
Jeffrey Bland, MD
Marc David
Mark A. Hyman, MD
Roberta Lee, MD
Melvyn R. Werbach, MD
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8 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Thank You
thank you
Lise Alschuler, ND, FABNO
Midwestern Regional Medical Center,
Cancer Treatment Centers of America
Belinda J. Anderson, PhD, LAc
Pacifi c College of Oriental Medicine
Robert Anderson, MD
Bastyr University
American Board of Holistic Medicine
Maira Bes-Rastrollo, PharmD, PhD
University of Navarra, Spain
Clement Bezold, PhD
Institute for Alternative Futures
Felicity L. Bishop, MA, MSc, PhD, CPsychol
University of Southampton School of
Medicine, UK
Jeffrey Bland, PhD, FACN, FACB
Synthesis
Jeffrey B. Blumberg, PhD, FAC N, CNS
Tufts University
Michelle Bowman, BSN, RNC, DiplAc
Health Center of Integrated Therapies,
A Service of Longmont United Hospital
William Braud, PhD
Institute of Transpersonal Psychology
Sarah Brien, PhD
University of Southampton, UK
Jane Buckle, RN, PhD
Thames Valley University, London, UK
Margaret Burkhardt, RN, PhD
West Virginia University School of Nursing
Etzel Cardeña, PhD
University of Lund, Sweden
Michael Carlston, MD
University of California, San Francisco
Lisa Conboy, MA, MS, ScD
Osher Institute, Harvard Medical School
J. K. Crellin, MD, PhD
Newfoundland, Canada
Jonathan Davidson, MD
Duke University
Robert M. Duggan, MA, MAc
Tai Sophia Institute
Charles Elder, MD, MPH, FACP
Kaiser Permanente NW
Henry Emmons, MD
Abbott Northwestern Hospital
Joan Engebretson, DrPH, AHN-BC, RN
University of Texas Health Science
Center at Houston
Joel M. Evans, MD
Albert Einstein College of Medicine
Tiffany Field, PhD
University of Miami
Peter Fisher, FRCP, FFHom
Royal London Homeopathic Hospital
Paula Gardiner, MD, PhD
Boston University
Tracy Gaudet, MD
Duke Integrative Medicine
Nicholas J. Gonzalez, MD
New York, New York
Gloria Andrea Gronowicz, PhD
University of Connecticut Health Center
Aviad Haramati, PhD
Georgetown University School of Medicine
Bethany Hays, MD
True North
Charles Nelson Ross Henderson
Palmer Center for Chiropractic Research
Martha R. Herbert, MD, PhD
TRANSCEND
Mark L. Hoch, MD
Partners in Healing of Minneapolis
Michael F. Holick, PhD, MD
Boston University Medical Center
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New York, New York
Randy A. Jones, PhD
University of Virginia School of Nursing
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Holistic Nursing Consultants
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Sleep & Human Health Institute
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University of Maryland
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Palmer Center for Chiropractic Research
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New York, New York
Karen Lesniak, PhD
Loma Linda University
Jacob Liberman, OD, PhD
Exercise Your Eyes, Inc
DeAnn Liska, PhD
Ocean Spray Cranberries, Inc
Patrick B. Massey, MD, PhD
Alexian Brothers Hospital Network
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Herb Research Foundation
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The Cancer Chronicles
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Nova Southeastern University
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BioScience Laboratories, Inc.
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Pebble Beach, California
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University of Minnesota
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New Mexico State University
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Castroville, California
Pamela G. Reed, RN, PhD, FAAN
University of Arizona
Susan W. Ryan, DO
Rose Medical Center
Alexander G. Schauss, PhD
AIBMR Life Sciences, Inc
Mark A. Schroll, PhD
Beatrice, Nebraska
Lai-Chu See, PhD
Chang Gung University, Taiwan
Anees A. Sheikh, PhD
Marquette University
Victor S. Sierpina, MD
University of Texas Medical Branch
Marc A. Silver, MD
Advocate Christ Medical Center
Jerry Solfvin, PhD
University of Massachusetts
Dartmouth
Suzanne Steinbaum, MD
Lenox Hill Hospital
Jacob Teitelbaum, MD
Fibromyalgia and Fatigue Centers
Noalani Terry
Whole Life Indexing & Energy Works
Vidette Todaro-Franceschi, PhD, RN
Hunter College of CUNY
Carolyn Torkelson, MD
University of Minnesota
Nancy Vuckovic, PhD
Intel Corporation/Digital Health Group
Diane Wind Wardell, PhD, RNC
The University of Texas Health Science
Center at Houston
Andrew Weil, MD
University of Arizona
Kristine Westrom, MD
Northwestern Health Sciences University
James Whedon, DC
Dartmouth-Hitchcock Medical Center
Eugene R. Zampieron, ND, (MH)AHG
Woodbury, Connecticut
Leonard Zegans, MD
University of California, San Francisco
Alternative Therapies in Health and Medicine is recognized as the premier journal in the fi eld of complementary and alternative medicine.
In 2006 and 2007, ATHM had the highest impact factor ranking of any independently published peer-reviewed CAM journal in the
United States—meaning that its research articles were cited more frequently than any other journal’s in the fi eld. These achievements
are due in large part to the dedication of the peer reviewers and other contributors who have joined us in our efforts to advance the fi eld
of CAM these last few years. Thank you.
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10 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 TK
David Riley, MD, is the editor in chief of Alternative Therapies in
Health and Medicine. (Altern Ther Health Med. 2009;15(1):10-11).
Change—and the images of transformation and
charting a different course—has certainly been a
powerful and motivating force for many during the
past year. In healthcare, what can we change? Can
we chart a course of healthcare reform that includes
health promotion and wellness and creates an integrative health-
care delivery system? Healthcare in the United States costs sub-
stantially more than anywhere else in the world. Shouldn’t we
consider our existing assumptions and strategies and contem-
plate including other approaches? The difficulties we face in
healthcare require us to expand our thinking in order to fi nd the
solutions that are inevitably hidden within our current challeng-
es. One key ingredient to consider is using a multidisciplinary
approach integrating a broader spectrum of healthcare provid-
ers. In our challenge to seek change, I am honored to introduce
our readers to 3 new editors of Alternative Therapies in Health and
Medicine who, through the diversity of their backgrounds, refl ect
elements of transformation.
Christine L. Girard, ND, is executive vice president of aca-
demic and clinical affairs for the Southwest College of
Naturopathic Medicine in Tempe, Arizona. Dr Girard complet-
ed her undergraduate degree at Goddard College, Plainfield,
Vermont, and received her doctorate in naturopathic medicine
from the National College of Naturopathic Medicine, Portland,
Oregon. She participated in and completed the fi rst hospital-
based residency for naturopathic physicians at Griffi n Hospital
in Derby, Connecticut. Dr Girard’s career has focused on hospi-
tal-based integrative medicine and leadership in undergraduate
and postgraduate naturopathic medical education. She is the
cofounder and past codirector of the Integrative Medicine
Center at Griffi n Hospital, where she created, in conjunction
with the University of Bridgeport College of Naturopathic
Medicine, an integrative medicine residency program for natur-
opathic physicians. Dr Girard served as a clinical research spe-
cialist at the Yale-Griffin Prevention Research Center and is
former director of naturopathic medicine at Southwestern
Regional Medical Center in Tulsa, Oklahoma, a Cancer
Treatment Centers of America hospital. Christine is a past board
member of the American Association of Naturopathic Medicine
and the Council on Naturopathic Medical Education. Her volun-
teer work includes support of the Sojourner Center, a domestic
violence shelter in the Greater Phoenix area, and the Leukemia
and Lymphoma Society.
Jason Hao, DOM, received his bachelor’s and master’s
degrees from the Heilongjiang University of Chinese Medicine in
China in 1982 and 1987 and received his master’s of business
administration in 2004 from the University of Phoenix. He is
president of the International Academy of Scalp Acupuncture,
chairman of the Acupuncture Committee at the National
Certification Commission for Acupuncture and Oriental
Medicine, and vice president of the Southwest Acupuncture
College Board in Santa Fe, New Mexico. Dr Hao is a well-known
professor and has been teaching, practicing, and researching
acupuncture and treatment with Chinese herbs for 26 years at
academic centers in both the United States and China. In 2006,
Dr Hao was invited to the Walter Reed Army Medical Center in
Washington, DC, where he achieved remarkable results using
scalp acupuncture to treat amputee veterans suffering from
phantom pain. Dr Hao has published numerous articles and cur-
rently serves as an editor of Chinese Acupuncture and Moxibustion,
a leading acupuncture journal in China. He is committed to using
his knowledge and experience to enhance the high professional
standards already set by Alternative Therapies in Health and
Medicine and pledges his highest level of service toward further-
ing its global mission.
Michele Mittelman, RN, MPH, has a background in nursing
from the University of Pennsylvania Hospital School of Nursing,
Rutgers University, and is a member of nursing’s national honor
society, Sigma Theta Tau International. She has worked as a reg-
istered nurse in intensive care, obtained a graduate degree in
public health from Columbia University, and worked as a health-
care consultant with Ernst & Young. After a hiatus from health-
care, Michele has been increasingly drawn to her roots in nursing
and is an advocate for the nursing profession, focusing on inte-
grative care. She has worked nationally to advance integrative
medicine through strategic philanthropic initiatives and is also
involved with the Dana Farber Cancer Institute in Boston.
Michele has worked in her local community, serving The
Catalogue for Philanthropy and Tenacre Country Day School,
and has been a trustee, docent, and active volunteer with the
New England Wildfl ower Society.
As evidence that our healthcare system as currently structured
Change
CHANGE
David Riley, MD
editorial
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TK ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 11
is fi nancially untenable continues to accumulate, we need inno-
vative and expansive thinkers who are committed to change—
like these 3 editors. If we “got what we paid for,” we would be the
healthiest nation in the world. Unfortunately, if we look at the
top 30 developed economies in the world, we rank at or near the
bottom in virtually every category, from infant mortality to life
expectancy. In 2006, the American College of Physicians warned
that “primary care, the backbone of the nation’s healthcare sys-
tem, [was in] grave risk of collapse.”1(p6) Nearly 50 million people
have no health insurance and limited access to care2; those who
do have insurance often face ever-shortening offi ce visits that
allow no time for comprehensive care for complex diagnoses,
much less health and wellness.
Today we fall short in prevention and instead focus on early
detection as an inadequate substitute. Access to services is limit-
ed, we have a shortage of a variety of healthcare providers, and
we offer little support or acknowledgement of the contributions
made by nurses, chiropractors, naturopaths, oriental medicine
practitioners, and other holistic healthcare providers. Nor have
we historically invested much energy envisioning on a policy
level what an integrative and holistic model of healthcare could
look like, how it might be designed, or how to track outcomes.
In fact, the actuarial data that track outcomes today and are
used to determine reimbursements from the insurance industry
are based on the CPT (Current Procedural Terminology) codes—
a proprietary product of the American Medical Association
(AMA) from which they earn millions of dollars every year.3 The
CPT codes ignore most of the services offered by the overwhelm-
ing majority of licensed healthcare providers, from nurses to
acupuncturists to naturopaths to chiropractors, making it virtu-
ally impossible to accurately track the outcomes associated with
their care. To make matters worse, the Centers for Medicare and
Medicaid Services has stifl ed innovation by basing its coding
policies almost exclusively on the AMA coding conventions.
Paul Krugman, a Princeton economist and Nobel laureate,
recently said,
Our health care system is wildly inefficient, largely
because we have an insurance industry that devotes
enormous resources to try to identify who really needs
health insurance, so as not to give it to them. And we
have health care providers devoting enormous resources,
fighting with the insurance companies to actually get
paid. . . . It would be cheaper by far to just cover every-
body. We pay this huge price because we’ve managed to
convince ourselves or be convinced that somehow, some-
thing that every other advanced country does, and that
we do ourselves for the elderly, is impossible.4
The implicit assumption seems to be that we just need to do
more of what we are already doing, as if that will magically pro-
duce different results.
Other, more sustainable healthcare models are emerging,
such as the Wellness Initiative for the Nation from the Samueli
Institute, along with a move toward broader healthcare coverage.
Emerging research methods for evaluating more individualized
therapeutic approaches, ranging from bioregulatory medicine to
intercessory prayer to a systems biology approach, will help cre-
ate an evidence mosaic that can be incorporated into the health-
care roadmap for change. It appears that the forces that have
stymied the move toward innovations in healthcare for more
than 20 years may be shifting.
Meaningful healthcare delivery must support and track pre-
vention and health and value as one of its key principles the med-
ical narratives at the core of the partnership between patient and
provider. As participants in our healthcare system, we strive to
be a part of the transformation that will enhance health and
move us beyond our current disease-management model.
REFERENCES
1. American College of Physicians. Reform of the D ysfunctional Healthcare Payment and
Delivery System: A Position Paper. Philadelphia, PA: American College of Physicians;
2006. Available at: acponline.org/advocacy/where_we_stand/policy/dysfunctional_
payment.pdf. Accessed December 2, 2008.
2. DeNavas-Walt C, Proctor BD, Smith JC, US Census Bureau. Income, Poverty, and Health
Insurance Coverage in the United States: 2007. Washington, DC: US Government Printing
Offi ce; 2008. Current Population Reports, P60-235. Available at: http://www.census.
gov/hhes/www/hlthins/hlthin07.html. Accessed December 2, 2008.
3. American Medical Association. Helping Doctors Help Patients. 2007 Annual Report.
Chicago, IL: American Medical Association; 2008. Available at: http://www.ama-assn.
org/ama/pub/category/12528.html. Accessed December 2, 2008.
4. Rovner J. Is the government responsible for health care? NPR. September 24, 2008.
Available at: http://www.npr.org/templates/story/story.php?storyId=94812584&ft=1
&f=1027. Accessed December 2, 2008.
Change
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14 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Letters to the Editor/Erratum
PREGNANCY AND LABOR ALTERNATIVE THERAPY
RESEARCH
In a recent literature review in Alternative Therapies in Health
and Medicine, Tiffany Field reviews the most popular comple-
mentary and alternative (CAM) therapies research (from the last
5 years) used during pregnancy and labor and potential underly-
ing biological bases for their effects.1 We commend Dr Field on
her efforts. We are surprised and concerned, however, that the
literature review published by Field fails to discuss spinal manip-
ulative therapy (SMT) used by chiropractors, osteopaths, and
physical therapists.
The advantage of any systematic or narrative review is that it
provides a transparent, replicable approach to the subject area
through current and relevant references and an unbiased and
comprehensive view. This transparency is reflected through a
thorough methods section, possibly the most important aspect of
any research paper. It provides the information by which a study’s
validity is judged. It therefore requires a clear and precise descrip-
tion of how a study was done and the rationale for why specifi c
procedures were chosen.2 Like other study designs, the methods
section of a review paper (1) describes what was done to answer
the research question, (2) describes how it was done (eg, search
strategy, inclusion and exclusion criteria), (3) justifi es the design,
and (4) explains how the results were analyzed and interpreted.
Field states that “the most common alternative therapies rec-
ommended during pregnancy were massage therapy (61%), acu-
puncture (45%), relaxation (43%), yoga (41%), and chiropractic
(37%). Of the 5 therapies she references above, Field reviews 4
(massage therapy, acupuncture, yoga, and relaxation) as the most
frequently researched alternative therapies for pregnancy and
labor. Additionally, she also reviews exercise, hypnosis, music
therapy, and aromatherapy. It is not clear why she excluded chiro-
practic from her review and included other therapies. The lack of
a clear rationale for her inclusion and exclusion criteria presents a
bias in her review.
Raheleh Khorsan, MA
Research Associate
Military Medical Program and Integrative Medicine
Samueli Institute
Corona del Mar, California
Cheryl Hawk, DC, PhD
Vice President of Research and Scholarship
Cleveland Chiropractic College
Kansas City, Missouri, and Los Angeles, California
REFERENCES
1. Field T. Pregnancy and labor alternative therapy research. Altern Ther Health Med.
2008;14(5):28-34.
2. Kallet RH. How to write the methods section of a research paper. Respir Care.
2004;49(10):1229-1232.
Author Response
Many medical groups and professionals do not consider
chiropractic an alternative therapy at this point. That is the rea-
son I did not include chiropractic in the review.
Tiffany Field, PhD
Touch Research Institute
University of Miami Medical School
Florida
Fielding Graduate University
Santa Barbara, California
ERRATUM
In his guest editorial in the Nov/Dec 2008 issue (“Autism:
Asking the Right Questions to Find the Right Answers,”
2008;14(6):20-21), Dr Jeffrey Bland referred to a piece on autism
he wrote in what he called Autism Advances. The correct name of
the publication is Autism Advocate, published by the Autism
Society of America. Alternative Therapies in Health and Medicine
regrets the error.
letters to the editor
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16 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Improving the Science for Botanical and Dietary Supplements
Stacie E. Geller, PhD, is the G. William Arends Professor of
Obstetrics and Gynecology, College of Medicine; director of
the Center for Research on Women and Gender; and director
of the National Center of Excellence in Women’s Health at
the University of Illinois, Chicago. (Altern Ther Health Med.
2009;15(1):16-17.)
Millions of menopausal women use herbal medi-
cines and botanical dietary supplements (BDS)
on a regular basis to treat a variety of symp-
toms related to menopause and for other
aging-related issues. Despite their widespread
use, the regulatory framework of the Dietary Supplements Health
Education Act (DSHEA) allows most herbal medication to be
marketed (albeit without indications) without going through the
extensive testing and rigorous clinical trials required of pharma-
ceutical products. This is not the case in Germany, for example,
where herbal medicinal products are held to more rigorous stan-
dards and registered as pharmaceutical products. The absence of
rigorous scientifi c evidence for herbal products in this country
often makes it diffi cult for consumers to be fully informed about
the effi cacy and safety of the products they are using. I am pleased
to see a series of randomized controlled clinical trials on an herbal
extract of Rheum rhaponticum (Siberian rhubarb),1,2 reporting on
both effi cacy and safety. To date, however, all of these trials have
been carried out by one contract research organization, Health
Research Services (HRS), for the manufacturer of the product. It is
important for confi rmatory studies to be conducted as indepen-
dent clinical trials so that health consumers can be confi dent they
are receiving the most unbiased information on the safety and
effi cacy of herbal products, independent from organizations that
will profi t from their use.
How should this testing be done, and what sorts of issues
should be raised in menopause research? We already know that
60% to 75% of women report that they do not tell their providers
about these supplements, and providers seldom ask patients
about their use. What sorts of herb-drug interactions may be
going unreported? This means that scientists designing and con-
ducting clinical trials for BDS must be ever rigorous in their con-
duct of research, especially related to safety.
We also know from data of clinical trials in menopause that
there is a high placebo effect, ranging from 30% to 60%, especially
in studies of vasomotor symptoms in menopause. Exaggeration
of effectiveness can commonly occur if a clinical trial does not
have a placebo group and does not compare symptoms at entry
into the study to symptoms at the end of the study. Although it
was not the case in the trial reported by Kaszkin-Bettag,2 many
trials report only within-group comparisons and not between-
group comparisons.
Many trials are also designed with insufficient power to
address the outcome that is usually of greatest interest to wom-
en—reduction in hot fl ashes. For example, there have been at
least 8 clinical trials that have examined the efficacy of black
cohosh for relief of menopausal symptoms, and 6 of 8 have
shown a signifi cant reduction in vasomotor symptoms. It should
be noted, however, that 5 of these studies reported improvement
in menopause rating scales (MRS) where subjects report their
symptoms in diaries, noting the change in frequency and intensi-
ty of vasomotor symptoms. Even though the use of MRS is inter-
nationally validated and used in most conventional research on
menopause, the specifi c symptom of the reduction in hot fl ashes
may be lost in the fi nal analysis unless the reduction in hot fl ash-
es compared to placebo is calculated separately.
Additionally, there is very little understanding of the mecha-
nism of action of most botanicals. It is thought that the reduction
in hot fl ashes with treatment is due primarily to the binding of
medications with estrogen receptors in reproductive tissue. It
also has been known for more than a decade that some of these
effects are mediated via estrogen receptor (ER)–α and ER-β sys-
tems. Recent basic science studies with ER-α and ER-β have
shown that the activation of both receptors alleviates hot fl ashes.3
ER-β receptor activation seems to act as a negative regulator of
the ER-α receptors and probably protects against ER-α–mediated
breast cancer. And perhaps most interesting, it was shown by
Möller et al in Dresden that ERr 731—the special extract of
Siberian rhubarb—activates ER-β with high selectivity for this
estrogen receptor.4,5 It appears likely that ERr 731 may have bene-
cial effects on menopausal symptoms through its ER-β selective
properties without the negative risks associated with hormone
replacement therapy, which activates both receptors.
It is not common in herbal medicine to fi nd mechanism-of-
action studies for an herbal extract so consistent with known
physiological mechanisms of action. In fact, many clinical stud-
ies of plant extracts lack suffi cient detail as to the material being
evaluated, including how the extract was chemically and biologi-
cally standardized, as well as stability studies of the product over
the course of the study.
IMPROVING THE SCIENCE FOR BOTANICAL
AND DIETARY SUPPLEMENTS
Stacie E. Geller, PhD
guest editorial
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Studies of traditional hormonal therapies in menopause are
held to high standards, in part because of the reported risk of
adverse events associated with the Women’s Health Initiative (an
independent clinical trial), which came as a surprise to the medi-
cal community when it was fi rst reported in 2002.6 Clinical trials
of BDS—herbal medications—should be held to the same stan-
dards. We need not only randomized, placebo-controlled studies
to prove the effi cacy of these treatments for menopausal symp-
toms but also mechanism-of-action and safety studies, as well as
more detailed information on standardization so that reasonable
comparisons can be made among the many therapies from
which women can choose.
REFERENCES
1. Heger M, Ventskovskiy BM, Borzenko I, et al. Effi cacy and safety of a special extract of
Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints:
a 12-week randomized, double-blind, placebo-controlled trial. Menopause.
2006;13(5):744-759.
2. Kaszkin-Bettag M, Ventskovskiy BM, Kravchenko A, et al. The special extract ERr 731
of the roots of Rheum rhaponticum decreases anxiety and improves health state and
general well-being in perimenopausal women. Menopause. 2007;14(2):270-283.
3. Bowe J, Li XF, Kinsey-Jones J, et al. The hop phytoestrogen, 8-prenylnaringenin, revers-
es the ovariectomy-induced rise in skin temperature in an animal model of menopausal
hot fl ushes. J Endocrinol. 2006;191(2):399-405.
4. Wober J, Möller F, Richter T, et al. Activation of estrogen receptor-beta by a special
extract of Rheum rhaponticum (ERr 731®), its aglycones and structurally related com-
pounds. J Steroid Biochem Mol Biol. 2007;107(3-5):191-201.
5. Möller F, Zierau M, Jandausch A, Rettenberger R, Kaszkin-Bettag M, Vollmer G.
Subtype-specifi c activation of estrogen receptors by a special extract of Rheum rhapon-
ticum (ERr 731®), its aglycones and structurally related compounds in U2OS human
osteosarcoma cells. Phytomedicine. 2007;14(11):716-726.
6. Riley D, Moher D. When to disbelieve the believable. Altern Ther Health Med.
2002;8(5):36-37.
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20 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Integrating Integrative Medicine
Mark A. Hyman, MD, is a contributing editor of Alternative
Therapies in Health and Medicine. He recently launched the
Functional Medicine Foundation, based in New York, New
York, to promote awareness of, fund research on, and educate
the public about functional medicine. (Altern Ther Health Med.
2009;15(1):20-21.)
Everything should be made as simple as possible, but not simpler.
—Albert Einstein
The paradox and irony of integrative medicine is that
it is not integrated. A coherent scientifi c map for fi l-
tering a patient’s story into a personalized care plan
does not exist in clinical medicine, whether conven-
tional or “integrative”—at least not a science-based
method that enables us to decipher the causes of illness rather
than simply suppress symptoms. This leaves physicians frustrat-
ed and patients suffering unnecessarily. But a map does exist,
and contrary to prevailing notions, it is not integrating the best
of alternative and conventional medicine, which leads to mixed
metaphors, overlapping cosmologies, and a smorgasbord of
options without a menu.
The current approach of appending alternative therapies
onto conventional diagnoses leaves the patient with treatment
indigestion and the practitioner without a model of understand-
ing how to choose from many potentially benefi cial therapeutic
options—both alternative and conventional. At times this
approach will succeed but often in spite of itself, like a foreigner
in a strange city happening upon a particular restaurant for
which he or she was searching without a street map. Applying
wholly integrated therapeutic systems, such as traditional
Chinese medicine, Ayurvedic medicine, osteopathy, or homeopa-
thy, to conventional medical ICD-9 diagnoses mixes different
worlds without a common language.
A language does exist for a new medicine based on emerg-
ing scientifi c laws and biological principles, however. It provides
a framework and architecture for interpreting all the data held
within a patient’s story and biology, one that is patient-centered,
not paradigm-centered. This framework provides a clear direc-
tion and a distinct understanding that guides the practitioner to
choose the appropriate tool for the task of healing, whether it is a
drug, a nutrient, an herb, an acupuncture needle, a cranial
manipulation, a shamanic ritual, or a breathing technique.
Let us take a journey of the one and the many. One disease
with numerous potential causes and 29 “diseases” triggered by one
underlying precipitating cause. How might we assess them through
the lenses of “integrative medicine,” conventional medicine, and
the new “map”—a way of “integrating” integrative medicine?
Imagine a patient with a DSM-IV diagnosis of depression
entering an integrative healing center. This patient has a myriad
of emotional, cognitive, and physical symptoms. He also has a
number of “comorbid” and seemingly unrelated conditions.
After a thorough evaluation, a team of collaborative practitioners
reviews the case at a clinical case conference. Practitioners make
a diagnosis based on their perspective and worldview.
The psychopharmacologist diagnoses a serotonin defi ciency
and prescribes a serotonin reuptake inhibitor. The traditional
Chinese medical physician diagnoses spleen chi defi ciency and rec-
ommend herbs and acupuncture. The Ayurvedic physician diagno-
ses a pitta-kapha imbalance and recommends herbs and
Panchakarma. The homeopath determines the best remedy for
depression that is associated with the need to be hugged is
Pulsatilla. The energy healer believes the patient has a blocked
heart chakra from an old emotional trauma and recommends heal-
ing touch. The nutritionist diagnoses a folate or vitamin D defi cien-
cy and prescribes nutrients. The psychotherapist believes the
depression may be the result of deep childhood trauma that
requires psychoanalysis. The yoga therapist sees it as a result of
chronic stress and prescribes meditation and yoga. The spiritual
healer suggests unresolved past life experiences and rebirthing. The
herbalist recommends St John’s wort. The biomedically inclined
psychiatrist recommends transcranial magnetic stimulation. The
toxicologist suggests mercury poisoning and recommends chela-
tion. The virologist diagnoses a viral limbic system infection with
Bornavirus and prescribes 4 months of antiviral therapy.
Integrative medicine has become a way for conventionally
trained healthcare providers to incorporate alternative world-
views into their treatment plans. Though they often are trained
in some other healing modalities, most integrative physicians use
scientifi c lenses to assess and treat their patients. How then can a
primary care doctor of integrative medicine proceed, confused,
bewildered, searching through a broad collection of tools, to fi nd
the one or two that may help the patient “treat” his or her depres-
sion? What if it does not, as it often does not? What can he do
next? This presents a thoroughly disintegrating experience for
both doctor and patient.
So the question arises, is there a map that can serve as a
guide, is there a GPS to navigate the complex world of chronic
THE MAP: INTEGRATING INTEGRATIVE MEDICINE
Mark A. Hyman, MD
column
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Integrating Integrative Medicine
disease and apply the many tools beyond drugs and surgery we
have welcomed to medicine and healing?
Among the greatest discoveries of our lifetime are the new
laws of systems biology and the ways in which they help us
understand that a few common underlying causes result in the
more than 12 000 ICD-9 diagnoses that we have classifi ed and
named over the last 100 years of scientifi c medicine. As we can
see from the case of “depression” presented at an integrative
medicine case conference, however, the name of the disease has
nothing to do with the diagnosis. It describes symptoms, not eti-
ology. And the same symptoms may arise from a host of causes,
making the name of the disease increasingly meaningless. In a
recent JAMA editorial called “Shifts in Thinking About
Dementia,” the author says, “The concept of dementia is obso-
lete. It combines categorical misclassification with etiologic
imprecision.”1(p2173) This is true of all the labels we apply to com-
mon symptoms that may have many different causes.
And the opposite is true—just as depression may have 2
dozen causes, a patient presenting with 2 dozen “diseases” may,
in fact, have just 1 causal factor. Consider a recent patient who
had 29 different diseases, including depression, hypertension,
obesity, polycystic ovarian syndrome, migraines, menorrhagia,
asthma, sinusitis, irritable bowel syndrome, fibromyalgia,
osteoarthritis, and psoriasis. The cause of all of her diseases was
an autoimmune response to gluten leading to autoimmune thy-
roid disease and severe vitamin D defi ciency because of malab-
sorption. Six weeks after eliminating gluten, replacing thyroid
and vitamin D, her 29 diseases were completely gone, along with
21 lbs. She did not have separate “diseases” but a few simple
underlying imbalances in basic biological systems.
Alternative therapies and conventional treatments are tools.
We need a new map that can teach us how to skillfully use those
tools. That map is functional medicine, a system of thinking
about patterns, connections, and systems that helps us fi lter a
patient’s story and emerge with a clear map of how to use all the
tools of medicine and healing. In fact, it encompasses all modali-
ties and therapies because it is not a treatment or a test but a way
of interpreting the natural laws of biology. It is the map that can
guide us through the puzzle of chronic, complex, persisting ill-
nesses that is at the root of our healthcare crisis. It is heartening
that science has uncovered these basic laws of biology that can
now be used to guide practitioners and patients. This is the new
map that can integrate integrative medicine.
REFERENCE
1. Hachinski V. Shifts in thinking about dementia. JAMA. 2008;300(18):2172-2173.
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24 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Effi cacy of ERr 731 in Perimenopause
Marietta Kaszkin-Bettag, PhD, is professor of Pharmacology,
Toxicology, and Phytotherapy, University of Frankfurt Medical
School, Germany (mkbrhubarb@yahoo.de). Sabine Beck, PhD,
is a medical writer, Ilona Hasper, MD, is a medical writer, and
Peter W. Heger is director, all at Health Research Services Ltd,
St Leon-Rot, Germany. Boris M. Ventskovskiy, MD, PhD, is
chair of obstetrics and gynecology N1 and Sergey Solskyy, MD,
PhD, is chair of obstetrics and gynecology N2 at National
Medical University A.A. Bogomolets, Kiev, Ukraine. Andrei
Kravchenko, MD, PhD, is head of offi ce at Health Research
Services Ltd, Kiev, Ukraine. Reinhard Rettenberger, PhD, is
director of Chemisch-Pharmazeutische Fabrik Göppingen, Carl
Müller, Apotheker, GmbH & Co KG, Göppingen, Germany.
Andy Richardson, PhD, is director of Health Research Services
Ltd, Hungerford, Berkshire, UK.
Corresponding author: Peter W. Heger, peter.heger@h-r-s.biz.
The conventional therapy for the relief of moderate to
severe menopausal symptoms is hormone therapy
(HT). In March 2007, the North American Menopause
Society (NAMS) recommended HT as the preferred
therapy but with the caveat that it should be weighed
carefully against the potential risk of breast cancer and thromboem-
bolism.1 A recent comment on the NAMS statement recommended
that postmenopausal HT should be used only for bothersome
symptoms, using the lowest effective HT dose for the shortest possi-
ble time and should not be used to prevent disease (eg, osteoporo-
sis).2 Lower HT doses or even ultra-low doses appear to be better
tolerated than standard doses and may have a better safety profi le.3,4
The risks of the long-term use of low-dose HT over extended peri-
ods (ie, several years), however, has not been clarifi ed. The European
Medicines Agency (EMEA) guidance for HT recommends the use of
HT only for the treatment of menopausal symptoms in postmeno-
pausal women,5 and the risks of breast cancer, coronary heart dis-
ease, stroke, and thromboembolism in perimenopausal women
with moderate to severe menopausal symptoms taking HT have not
been established in randomized controlled trials (RCTs).
The problems with HT therefore limit the spectrum of effective
measures available for women in perimenopause suffering from
menopausal symptoms, and often their only option is to use herbal
preparations. The special extract ERr 731 from the roots of rhapon-
tic rhubarb (Rheum rhaponticum) (trade name Phytoestrol N,
rebranded since September 1, 2007, Phyto-Strol and Phyto-Strol
Loges, Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller,
Apotheker, GmbH & Co KG, Göppingen, Germany) has been used
in Germany since 1993 for the treatment of women with menopau-
sal symptoms in both perimenopause and postmenopause.6 The
extract ERr 731 contains rhaponticin, desoxyrhaponticin, and their
CONFIRMATION OF THE EFFICACY OF ERr 731
IN PERIMENOPAUSAL WOMEN WITH
MENOPAUSAL SYMPTOMS
Marietta Kaszkin-Bettag, PhD; Boris M. Ventskovskiy, MD, PhD; Sergey Solskyy, MD, PhD; Sabine Beck, PhD; Ilona Hasper, MD;
Andrei Kravchenko, MD, PhD; Reinhard Rettenberger, PhD; Andy Richardson, PhD; Peter W. Heger
original research
Objective • In a previous study, the special extract ERr 731 of
Rheum rhaponticum signifi cantly reduced vasomotor and other
menopausal symptoms associated with perimenopause. This
trial was conducted to confi rm the effi cacy of ERr 731.
Design • A multicenter, randomized, placebo-controlled, clini-
cal trial with 112 perimenopausal women with menopausal
symptoms receiving either 1 enteric-coated tablet of ERr 731
(n=56) or placebo (n=56) daily for 12 weeks. Primary outcome
criterion for effi cacy of ERr 731 compared to placebo was the
change of the Menopause Rating Scale (MRS) total score from
day 0 to day 84. Other effi cacy assessments analyzed included
the number and severity of hot fl ushes, individual symptoms of
the MRS, treatment outcome, and various safety parameters.
Results • By 12 weeks, ERr 731 caused a highly signifi cant
reduction of the MRS total score from 27.0 ± 4.7 points to 12.4
± 5.3 points when compared to the placebo-induced decrease
from 27.0 ± 5.3 points to 24.0 ± 6.2 points (P<.0001). A signifi -
cant reduction in each individual MRS item score, in hot
ushes and the hot fl ush weekly weighted score, together with
a marked improvement in treatment outcome were also
observed (P<.0001). These results confi rm the effi cacy of ERr
731 in alleviating menopausal symptoms in perimenopausal
women. Fourteen adverse events were reported in total: 11 by 5
women receiving ERr 731 and 3 by 3 women receiving placebo.
ERr 731 was well tolerated by the majority of the women.
Conclusion • ERr 731 was confi rmed to be effective for the
treatment of menopausal symptoms in perimenopause. (Altern
Ther Health Med. 2009;15(1):24-34.)
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ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 25
Effi cacy of ERr 731 in Perimenopause
aglycones, rhapontigenin and desoxyrhapontigenin.6 Neither
rhapontic rhubarb nor the special extract ERr 731 contains any of
the anthraquinones such as emodin or rhein that are found in
other rhubarb species.7 Thus, this extract has no laxative effect.
The absence of anthraquinones, of which some are known to be
potent activators of estrogen receptors (ERs) and therefore may
increase the risk of unwanted side effects in the endometrium and
breast,8 supports the use of ERr 731 in menopausal women.
It is thought that part of the reduction of menopausal com-
plaints by HT is due to the replacement of estradiol levels, and this
is consistent with the known role of estrogens in the development
and functioning of the female reproductive system and their
important role in the maintenance of structure and function in
nonreproductive tissues and systems (eg, vasculature, smooth
muscle, central nervous system, immune system).9 It is also known
that some of these effects are mediated with high specifi city via the
structurally and functionally different estrogen receptor-α (ERα)
and ERβ systems. A recent study with ERα- and ERβ-specifi c acti-
vators has shown that both ERs need to be activated to alleviate
hot fl ushes.10 Additionally, through the use of ERβ-defi cient mice,
an involvement of this receptor subtype in the etiology of anxiety
and depression has been demonstrated.11 Most importantly, ERβ
seems to act as a negative regulator of ERα and, where the recep-
tors are coexpressed, protect against ERα-mediated tissue hyper-
proliferation and carcinogenesis.12-15
Recent investigations with ERr 731 and its hydroxystilbene
constituents have shown that they bind and activate the ERβ with
high specifi city in a variety of cell lines.16,17 In contrast, neither ERr
731 nor its aglycones rhapontigenin and desoxyrhapontigenin nor
the structurally related compounds resveratrol and piceatannol acti-
vate the ERα in Ishikawa cells naturally expressing ERα. Similarly,
ERr 731 showed no agonist activity when tested in the HEC-1B
endometrial cancer cells transfected with ERα.16 On ERβ, the activi-
ty of ERr 731 is comparable to that of 10-8 M E2, and thus, it appears
likely that ERr 731 mediates its benefi cial effects on menopausal
symptoms such as hot fl ushes, depression, and anxiety at least in
part via its ERβ-selective properties. Preliminary results from an
uterotrophic assay in ovariectomized rats have shown that ERr 731
up to 100 mg per kg body weight per day did not display any prolif-
erative and uterotrophic effects (submitted for publication).
In 4-week and 13-week toxicity studies in male and female
dogs with continuing intake of 100 mg, 300 mg, and 1000 mg ERr
731 per kg body weight per day, it was demonstrated that even at
the highest doses, ERr 731 (1000 mg per kg body weight per day)
did not affect viability, induce any signs of toxicity or signifi cant
pathological changes in any organs in either male or female ani-
mals which might be related to the intake of the extract.18 Of par-
ticular importance is the observation that the uterine weight was
not changed when compared to the control animals, indicating
that ERr 731 even in these high dosages given continuously had
no uterus-stimulating effect. Also, no other abnormalities in the
genital tracts of either female or male dogs were detected macro-
scopically or microscopically. Based on the animal study reports,
the no-observed-adverse-effect-level has been determined to be
1000 mg per kg body weight per day.
The recommended therapeutic dose of ERr 731 for menopau-
sal women is 4 mg extract per day (taken as 1 tablet once daily).
This dose has been demonstrated to be effective in reducing meno-
pausal symptoms in a 12-week RCT in 109 perimenopausal
women6,19 and in a 6-month postmarketing surveillance study with
252 perimenopausal and postmenopausal women.20
In these and other long-term (48-week and 96-week) observa-
tional studies with continuous intake of ERr 731, no clinically rele-
vant changes due to ERr 731 in endometrial biopsies, bleeding,
weight, blood pressure, pulse, and laboratory parameters were
seen, whilst sustained alleviation of the menopausal symptoms
was present, and there were no adverse events associated with the
intake of the extract.21 The results have confi rmed that ERr 731 is a
safe and effective alternative to HT in perimenopausal women for
the alleviation of menopause symptoms.
In order to provide confi dence to physicians, consumers, and
regulatory authorities that ERr 731 is of value in alleviating the cardi-
nal menopausal complaints such as vasomotor, psychological, and
physical symptoms, the effi cacy and safety of ERr 731 has been fur-
ther examined using an extended battery of symptom scores and
including additional safety parameters. These results are reported
here. The primary outcome criterion for effi cacy used was the change
of the Menopause Rating Scale (MRS) total score under ERr 731
when compared with placebo after 12 weeks of treatment.
Menopausal symptoms were assessed using an international version
of the validated MRS score, with the subjects reporting their experi-
ences directly using subject diaries to record the MRS, hot fl ushes,
and other effi cacy parameters independently of the investigators.22
METHODS
Trial Design, Participants, and Treatment
This was a 12-week, multicenter, prospective, randomized,
double-blind, parallel-group, placebo-controlled, phase III clinical
trial using a multistage adaptive-sequential design with 2 interim
analyses to compare the effi cacy and safety of ERr 731 with placebo
in women with menopausal complaints in perimenopause. The
trial and the subsequent 52-week observational study were con-
ducted at 8 gynecological outpatient departments with a Russian-
speaking trial population in the Ukraine from February 2004 to
April 2007. Trial and study were conducted in accordance with the
ethical requirements of the Declaration of Helsinki, ICH GCP guide-
line, and the legal provisions of the Ukraine. Approval by the Ethics
Committee, Kiev, Ukraine, and the State Pharmacological
Committee of the Ministry of Health, Kiev, Ukraine, was obtained
in December 2003.
Inclusion and Exclusion Criteria
Inclusion criteria were (1) females aged 45 to 55 years; (2)
perimenopause defi ned as a break in cycle regularity during the
past 12 months or last menstruation at least 3 but no longer than
12 months ago; (3) MRS total score ≥18 points, refl ecting moder-
ate to severe menopausal symptoms23; (4) capability of providing
written informed consent; (5) accessibility by telephone; and (6)
26 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Effi cacy of ERr 731 in Perimenopause
willingness and ability to comply with all procedures of the trial
and attend all scheduled contacts at the investigational site.
Exclusion criteria included abnormalities in the endometrium
and breast, presence of concomitant diseases, the concomitant use
of predefi ned medications, pretreatment of menopausal symptoms
with hormone therapies, semi-luxuries (alcohol, smoking, caf-
feine), and a body mass index <18kg/m2 or >30kg/m2.
Women who met all inclusion and no exclusion criteria and
gave informed consent were enrolled into the trial and allocated to
one of the treatment groups.
Trial Conduct
Baseline and all assessment parameters were recorded by the
investigator in electronic case report forms. In addition, every
woman was required to keep a diary during the course of the trial
recording her hot fl ushes, menstrual bleeding, MRS, and the con-
sumption of investigational medication. Other assessments
including anxiety, depression, state of health, and quality of life
also were recorded (not reported here; they will be the subject of a
separate publication).
Subjects visited the investigator on days 28, 56, and 84, where
the clinical status was checked, the diary reviewed, and blood and
urine samples taken for laboratory analyses. The intake of investi-
gational medication was also documented, as were any changes in
concomitant medications and the appearance of any adverse
events (AEs).
On day 84 (and also in the case of premature withdrawal
from the trial), each participant underwent a fi nal investigation
including determination of laboratory blood and urine parame-
ters, a tobacco test, a clinical breast examination, breast tender-
ness assessment, mammography, PAP and vaginal smears, a
transvaginal ultrasound examination, a pelvic examination, and
endometrial biopsy. Women were free to discontinue their partici-
pation in the trial at any time without any prejudice to their fur-
ther treatment. In contrast to a previous RCT,6 the protocol for the
present trial did not permit nonresponders to withdraw from the
trial or cross over to open active treatment during the 12-week
period of the double-blind phase due to lack of effi cacy of the
investigational medication.
Investigational Medication
The investigational medication was administered as enteric
coated tablets (400 mg) containing 4 mg Rheum rhaponticum dry
extract as the only active ingredient (drug:extract ratio 16-26:1,
extraction solvent calciumoxide:water, 1:38 [m/m]). Placebo was
matched to a formulation of ERr 731 with regard to color, smell
and taste, and viscosity. The medication was manufactured by
Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller,
Apotheker, GmbH & Co KG, Göppingen, Germany. On day 0, day
28, and day 56, women received 30 enteric coated tablets of either
ERr 731 or placebo over a maximum time period of 12 weeks,
according to their treatment group. Tablet intake started on day 1.
Participants documented the consumption of investigational med-
ication every day in their diaries.
Outcome Criteria
Primary outcome criterion for the effi cacy of ERr 731 com-
pared to placebo was the change of the MRS total score from day 0
to day 84:
ΔMRSday 84 = MRSday 0 – MRSday 84.
The Menopause Rating Scale (MRS) consists of 11 symptoms
typically associated with the menopausal transition.22 The individ-
ual MRS items recorded were (1) hot fl ushes, sweating; (2) heart
complaints; (3) sleep problems; (4) depressive mood; (5) irritabili-
ty; (6) anxiety; (7) physical and mental exhaustion; (8) sexual prob-
lems; (9) bladder problems; (10) vaginal dryness; and (11) joint
and muscular discomfort.
These items were further categorized for analysis as “psycho-
logical,” “somatic,” and “urogenital.” Subscales were calculated
from the following item groups23:
• Psychological subscale: symptoms number 4, 5, 6, and 7;
• Somatic subscale: symptoms number 1, 2, 3, and 11; and
• Urogenital subscale: symptoms number 8, 9, and 10.
The MRS was recorded by both the investigators (in the
eCRFs at each visit on day 0, day 28, day 56, day 84) and by the trial
subjects in their diaries every week, using the following rating
scale: 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe. The
value of the total MRS score is between 0 and 44 points, with lower
scores indicative of less severe menopausal symptoms.
Secondary outcome criteria used to determine effi cacy were
(1) the individual symptoms of the MRS, (2) the number and
severity of hot fl ushes, (3) the Hot Flush Weekly Weighted Score
(HFWWS), (4) the time until onset of treatment effect, and (5)
treatment outcome according to Integrative Medicine Outcomes
Scale (IMOS).24
The HFWWS was calculated from the daily assessment of the
number and severity of hot fl ushes during the last week as follows:
total number of slight hot fl ushes per week multiplied by 1, plus
total number of moderate hot fl ushes per week multiplied by 2,
plus total number of severe hot fl ushes per week multiplied by 3.25
Outcome criteria for safety were endometrial biopsy fi ndings,
transvaginal ultrasound, PAP smear, vaginal smear, mammography,
breast tenderness, vital parameters, tolerability of investigational
medication, adverse events, and laboratory safety parameters.
Response Criteria
The following 3 response criteria were used to determine
which subjects had responded to treatment:
1. MRS total score < 24 points by the end of the trial (day 84);
2. Decrease of ≥10 points in MRS total score from baseline
(day 0) to the end of the trial (day 84); and
3. Women fulfi lling criterion number 1 and criterion number 2.
Trial Objective
This was a confi rmatory trial to prove the superiority of ERr 731
when compared to placebo as determined using the primary outcome
variable “change of the MRS from day 0 to day 84 (ΔMRSday 84 =
MRSday 0 – MRSday 84).” For women who discontinued the trial, the
ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 27
Effi cacy of ERr 731 in Perimenopause
clinical fi ndings at the time of discontinuation were used for the
analysis of the primary outcome variable using the last observation
carried forward (LOCF) method.
The null hypothesis was as follows:
H0: Decrease of the MRS in the ERr 731 group is less than or
equal to the decrease in the placebo group.
The alternative hypothesis was as follows:
H1: Decrease of the MRS in the ERr 731 group is larger than
the decrease in the placebo group.
Statistical Methods
The trial was conducted according to a 3-stage group sequen-
tial design with adaptive sample size adjustments at the 2 interim
analyses.26 The adjusted 1-sided signifi cance limits for the fi rst, sec-
ond, and third stages were αi=0.00026, 0.00710, and 0.02253 (i=1,
2, 3) with the corresponding critical values 3.471, 2.454, and 2.004
and the information rates 0.333, 0.667, and 1, respectively.
The statistical evaluation was performed using the statistical
software package SAS (release SAS 9.1.3, SAS Institute Inc, Cary,
North Carolina). The primary effi cacy comparison of the treatment
groups was performed using a 2-factorial analysis of covariance
with the 2 factors treatment and study site, and the baseline value
as covariate. Study sites with less than 6 women (4 of 7 study sites)
were pooled. Descriptive statistical methods were used to analyze
baseline, secondary effi cacy, and safety variables. Explorative P val-
ues were calculated for the comparison of ERr 731 with placebo on
day 0 and day 84 (LOCF) using the 2-sample t-test. The data are pre-
sented as mean and standard deviation (SD) and [median] if not
otherwise indicated.
RESULTS
Baseline Characteristics
In this trial, 171 women were screened for participation;
112 women were enrolled in the trial at 7 of 8 investigational sites (1
site failed to recruit any trial subjects). All enrolled trial subjects
were randomized to treatment with ERr 731 (56 women) or placebo
(56 women). All women in the ERr 731 and the placebo group were
included in the intention-to-treat (ITT) analysis (Figure 1). Three
(5.4%) women in the ERr 731 group and 2 (3.6%) women in the pla-
cebo group were excluded from the per-protocol (PP) analysis due
Screened (N=171)
Randomized (n=112)
Allocated to ERr731 (n=56)
• received ERr731 as randomized (n=56) Allocated to placebo (n=56)
• received placebo as randomized (n=56)
Trial termination/withdrawal (n=9)
• Adverse events (n=1)
• Noncompliance (n=5)
• Other reasons and noncompliance (n=1)
• Withdrawal of informed consent (n=1)
• Noncompliance and withdrawal of
informed consent (n=1)
Follow-up on
• Day 28 (n=56)
• Day 56 (n=55)
Follow-up on
• Day 28 (n=55)
• Day 56 (n=54)
Termination as planned
at FAI (n=46)*
Termination as planned
at FAI (n=47)*
ITT analysis: n=56
ITT analysis: n=56
Excluded
• no regular intake of medication (n=3)
Excluded
• no regular intake of medication (n=2)
PP analysis: n=53 PP analysis: n=54
Trial termination/withdrawal (n=10)
• Adverse events (n=1)
• Noncompliance (n=7)
• Other reasons and noncompliance (n=1)
• Violation of inclusion/exclusion criteria (n=1)
Screening failures (n=59)
• inclusion criteria not met/
exclusion criteria present
• other reasons
FIGURE 1 Participant Flow Chart
Individuals may have discontinued for more than one reason. For these trial subjects, all examinations and assessments were available at the Final Assessment I (FA I). Eighty-
nine women who terminated the double-blind phase of the trial entered into a 52-week observational study with ERr 731. ITT indicates intention to treat.
28 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Effi cacy of ERr 731 in Perimenopause
to major protocol deviations. All planned examinations and assess-
ments were available for 93 of 112 women at the end of the double-
blind trial (FA I, Figure 1).
None of the baseline characteristics differed markedly
between the treatment groups (Table 1). All women were peri-
menopausal when included in the trial, with their serum hormone
levels showing large variations as expected during perimeno-
pause. All women reported menstrual cycle irregularities during
the previous 12 months. The time since last menstrual bleeding
was slightly longer in the ERr 731 group (4.1 ± 3.6 [3.0] months)
than in the placebo group (3.6 ± 3.5 [2.0] months). Previous gyne-
cological diseases and surgeries were distributed similarly among
the treatment groups (Table 1). The most frequently reported dis-
eases and surgeries were salpingitis, uterine leiomyoma, and cer-
vical diathermy.
Duration of Treatment
The duration of treatment was comparable between the 2 treat-
ment groups (ERr 731: 81.5 ± 9.7 [84.0] days, placebo 81.3 ±
12.4 [84.0] days).
Primary Outcome Criterion
At baseline (day 0), the MRS total score was 27.0 ± 4.7 [26.0]
points in the ERr 731 group (n=56) and 27.0 ± 5.3 [26.0] points in
the placebo group (n=56) (not signifi cant, P=1.00, 2-sided t-test).
From baseline to day 84 (LOCF), the MRS total score decreased
by -14.6 ± 5.1 [-15.0] points in the ERr 731 group (n=56) and -2.9 ±
4.3 [-2.0] points in the placebo group (n=56). The difference in the
MRS total score between the 2 treatment groups on day 84 was high-
ly significant (P<.0001; 95% confidence interval [-13.8 to -9.5],
LOCF). The results from the PP analysis were consistent with the ITT
analysis (data not shown). Figure 2 shows the change in the MRS
total score in the ERr 731 group compared with the placebo group
from day 0 to day 84 for those trial subjects for whom MRS assess-
ments were available on day 84 (n=105, no LOCF).
Response Criteria
Using the response criteria defined earlier, the number of
responders in the ERr 731 group (n=56, LOCF) was higher than in
the placebo group (n=56, LOCF) in each category:
• response criterion 1: 54 (96.4%) women with ERr 731 vs 27
(48.2%) women with placebo;
• response criterion 2: 47 (83.9%) women with ERr 731 vs 2
(3.6%) women with placebo; and
TABLE 1 Demographic Data and Gynecological Findings at Screening*
Screening
ERr 731
(n=56)
Placebo
(n=56)
Age, yrs
(mean ± SD [median]) 49.4 ± 3.6 [49.0] 49.6 ± 3.0 [49.0]
Height, cm
(mean ± SD [median]) 163.7 ± 5.3 [164.0] 164.0 ± 5.5 [165.0]
Weight, kg
(mean ± SD [median]) 68.9 ± 9.3 [70.0] 71.3 ± 8.9 [72.0]
Body mass index, kg/m2
(mean ± SD [median]) 25.7 ± 3.2 [26.0] 26.4 ± 2.7 [27.5]
Serum hormone levels
(mean ± SD [median])
17β-Estradiol, ng/L 110.3 ± 127.9 [49.4] 138.6 ± 159.2 [76.0]
FSH, IU/L 44.5 ± 36.7 [42.5] 36.2 ± 32.6 [19.3]
Polymenorrhea, n (%) 6 (10.7) 8 (14.3)
Oligomenorrhea, n (%) 20 (35.7) 23 (41.1)
Amenorrhea, n (%) 30 (53.6) 25 (44.6)
Intermenstrual bleeding, n (%)
yes
no
0 (0)
56 (100.0)
1 (1.8)
55 (98.2)
Spotting, n (%)
yes
no
0 (0)
56 (100.0)
1 (1.8)
55 (98.2)
Dysmenorrhea, n (%)
yes
no
6 (10.7)
50 (89.3)
7 (12.5)
49 (87.5)
Complications concerning
pregnancies, births, or
abortions, n (%)
yes
no
25 (44.6)
31 (55.4)
20 (35.7)
36 (64.3)
Previous gynecological
diseases and surgeries, n (%)
yes
no
38 (67.9)
18 (32.1)
39 (69.6)
17 (30.4)
Pretreatment of menopaus-
al symptoms (during the
past 6 months), n (%)
yes
no
1 (1.8)
55 (98.2)
1 (1.8)
55 (98.2)
*Intention-to-treat population (N=112); FSH indicates follicle-stimulating hormone.
44
40
36
32
28
24
20
16
12
8
4
00 28 56 84
MRS Points
Days
ERr731
Placebo
n=56
n=56
n=56
n=55
n=55
n=54 n=53
n=52
**
**
*
FIGURE 2 Change in the MRS Total Score
Presented is the decrease in the Menopause Rating Scale (MRS) total score from
baseline to the third follow-up contact on day 84. The number of trial subjects, for
whom MRS assessments in the electronic case report forms were available, is
indicated for each time point. The signifi cances were calculated for the differences
between the treatment groups: *P<.001, **P<.0001.
ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 29
Effi cacy of ERr 731 in Perimenopause
• response criterion 3: 46 (82.1%) women with ERr 731 vs 2
(3.6%) women with placebo.
Diary-reported MRS
The diary-reported MRS total score in the ERr 731 group
decreased continuously over the 84-day period, whereas the scores in
the placebo group displayed a small decrease during the fi rst week
and then remained constant. This decrease (a mean of -2.4 points)
was observed over the fi rst week; scores then remained generally
constant but returned to their original value before the next follow-
up contact. This pattern was repeated over the next assessment peri-
ods (decreases of -1.5 points after day 28, -1.3 points after day 56,
respectively [Figure 3]). The treatment success reported by the
women in their diaries was consistent with that reported by the phy-
sicians at the follow-up contacts (Figure 2).
At the end of the RCT, the severity of the menopausal symp-
toms was signifi cantly different in the 2 groups. The majority of the
ERr 731 women reported to have no/mild (0-8 points) or moderate
(9-16 points) symptoms on Day 84, while more than 80% of the pla-
cebo women still had severe (>17 points) symptoms (Figure 3).
Individual Symptoms of MRS
Analysis of the individual MRS symptoms showed that the
majority of women in both treatment groups had moderate to very
severe symptoms at baseline (Table 2). After 12 weeks, ERr 731 was
effective in reducing symptoms, whereas the placebo group contin-
ued to report high incidences of each symptom. The difference
between the groups on day 84 is highly signifi cant for all MRS items.
The analysis of the combined MRS items into the “psychologi-
cal,” “somatic,” and “urogenital” subgroups showed that ERr 731
TABLE 2 Changes in the Individual Menopause Rating Scale (MRS) Items*
MRS Item
ERr 731
(n=56)
mean ± SD [median]
Placebo
(n=56)
mean ± SD [median]
Day 0 Day 84 Δ Day 0 to Day 84 Day 0 Day 84 Δ Day 0 to Day 84
1. Hot fl ushes/sweating‡ 2.8 ± 0.9 [3.0] 1.0 ± 0.7 [1.0] -1.7 ± 0.8 [-2.0] 2.9 ± 0.8 [3.0] 2.5 ± 1.1 [3.0] -0.4 ± 0.9 [0.0]
2. Heart complaints‡ 2.3 ± 0.9 [2.0] 1.2 ± 0.9 [1.0] -1.1 ± 0.9 [-1.0] 2.4 ± 0.9 [2.0] 2.2 ± 0.9 [2.0] -0.2 ± 0.9 [0.0]
3. Sleep problems‡ 2.5 ± 1.1 [3.0] 1.0 ± 0.8 [1.0] -1.5 ± 0.9 [-2.0] 2.4 ± 1.0 [2.0] 2.1 ± 0.8 [2.0] -0.4 ± 0.9 [0.0]
4. Depressive mood‡ 2.5 ± 1.1 [3.0] 0.8 ± 0.9 [1.0] -1.8 ± 1.2 [-2.0] 2.7 ± 0.8 [3.0] 2.1 ± 0.8 [2.0] -0.5 ± 0.7 [0.0]
5. Irritability‡ 2.7 ± 0.8 [3.0] 1.1 ± 0.7 [1.0] -1.6 ± 1.1 [-2.0] 2.9 ± 0.8 [3.0] 2.2 ± 0.7 [2.0] -0.6 ± 0.8 [-1.0]
6. Anxiety‡ 2.7 ± 1.0 [3.0] 1.1 ± 0.7 [1.0] -1.6 ± 1.0 [-2.0] 2.7 ± 0.9 [3.0] 2.3 ± 0.9 [2.0] -0.4 ± 0.9 [0.0]
7. Physical and mental exhaustion‡ 2.7 ± 0.9 [3.0] 1.4 ± 0.6 [1.0] -1.3 ± 0.9 [-1.0] 2.6 ± 0.9 [3.0] 2.5 ± 0.9 [3.0] -0.1 ± 0.7 [0.0]
8. Sexual problems‡ 2.4 ± 0.9 [2.0] 1.5 ± 0.7 [1.5] -0.9 ± 1.0 [-1.0] 2.4 ± 1.0 [2.0] 2.3 ± 1.1 [2.0] -0.1 ± 0.7 [0.0]
9. Bladder problems‡ 1.9 ± 1.1 [2.0] 0.9 ± 0.8 [1.0] -1.0 ± 0.9 [-1.0] 1.9 ± 1.0 [2.0] 1.7 ± 1.0 [2.0] -0.2 ± 0.8 [0.0]
10. Vaginal dryness† 1.8 ± 1.2 [2.0] 1.1 ± 0.7 [1.0] -0.7 ± 1.1 [-0.5] 1.7 ± 0.7 [2.0] 1.6 ± 0.8 [2.0] -0.1 ± 0.6 [0.0]
11. Joint and muscular discomfort‡ 2.8 ± 0.9 [3.0] 1.5 ± 0.9 [1.0] -1.3 ± 1.1 [-1.0] 2.5 ± 0.8 [3.0] 2.6 ± 0.8 [3.0] 0.1 ± 0.6 [0.0]
*Intention-to-treat population (n=112). The signifi cances were calculated for the difference between both treatment groups on Day 84: †P<.001, ‡P<.0001 (t-test,
2-sided, last observation carried forward).
44
40
36
32
28
24
20
16
12
8
4
00 7 14 21 28 35 42 49 56 63 70 77 84
MRS Points (Mean ± 95% CI)
Days Day 0
ERr 731 Placebo
Day 84 Day 0 Day 84
MRS Total Score
ERr731
Placebo
1. FU 2. FU FA I
100
80
60
40
20
0
Subjects (%)
Severe > 17
Moderate 9-16
Mild 5-8
No/little 0-4
FIGURE 3 Change in the MRS Total Score as Assessed by the Women in Diary I
The Menopause Rating Scale (MRS) total score was assessed weekly by the women in diary I. Presented is the change from baseline to the third follow-up contact on day 84. The
arrows indicate the time point of the scheduled visits of the women at their gynecological centers on day 28, day 56, and day 84. FU indicates follow-up contact; FA I, fi nal assessment I.
30 ALTERNATIVE THERAPIES, jan/feb 2009, VOL. 15, NO. 1 Effi cacy of ERr 731 in Perimenopause
was most effective in reducing symptoms in the “psychological”
and “somatic” subscales (Figure 4).
Hot Flushes
On entry to the study, all women were experiencing an aver-
age of 12 hot fl ushes per day (Figure 5), and there was no differ-
ence between the treatment groups (ERr 731: 11.4 ± 5.8 [12.0] hot
ushes, placebo: 12.1 ± 6.0 [12.0] hot fl ushes, Table 3).
By day 84, a signifi cant reduction in the number of hot fl ush-
es was observed in women in the ERr 731 group when compared
to placebo (Figure 5). Moderate and severe hot fl ushes decreased
to a larger extent with ERr 731 than with placebo (Table 3). One
woman did report an increase in hot fl ushes following ERr 731
intake, but on average, women taking ERr 731 were experiencing
2.8 ± 2.8 [2.0] hot fl ushes per day after 12 weeks.
In contrast, women in the placebo group experienced vari-
able changes in hot fl ushes: some reduction, some not changing,
and some deterioration (Figure 5). By 12 weeks, the women in the
placebo group still had an average of 11.4 ± 6.8 [13.0] hot fl ushes
per day, most of them being moderate to severe (Table 3).
On entry to the trial, women had an average of 84 hot fl ush-
es per week, with most of the trial subjects reporting >60 moder-
ate to severe hot fl ushes in this period. Thus, the HFWWS on
entry was 121.83 ± 75.9 [120.5] points in the ERr 731 group and
144.96 ± 81.6 [158.0] points in the placebo group. The difference
between the groups is not signifi cant (P=.13, 2-sided t-test).
In the ERr 731 group, the HFWWS decreased to 23.9 ± 27.5
[13.0] points from day 1 to day 84, but it remained high in the
placebo group (137.6 ± 95.9 [147.0] points, LOCF). The 95% CI
for the differences in HFWWS between the 2 treatment groups
(ERr 731 minus placebo) on day 84 (LOCF) was calculated as
[-140.3 to -87.0] (P<.0001, 2-sided t-test).
Treatment Outcome
On day 84 (LOCF), 44 (78.6%) women in the ERr 731 group
but only 2 (3.6%) women in the placebo group reported a major
improvement. Ten (17.9%) women in the ERr 731 group and
5 (8.9%) women in the placebo group reported slight to moderate
improvement, and the majority of women in the placebo group
(47 of 56 [83.9%]) reported no change. In the ERr 731 group, 2 of
56 (3.6%) women reported no change following treatment. One
woman in the placebo group (1.8%) and no women from the ERr
731 group reported a deterioration of their condition. The investi-
gator-reported changes of treatment outcome confi rmed the rat-
ings given by the women themselves (data not shown).
Adverse Events
Fourteen adverse events and no serious AEs were reported
during the study. Eleven AEs were reported by women in the ERr
731 group (all assessed as “moderate”) and 3 by women in the pla-
cebo group (2 mild and 1 moderate, Table 4). Three AEs in the ERr
MRS Points
MRS Points
Psychological Somatic
Day 0
Day 84
Day 0