Articles On Dr. Stephenson's Research
American Heart Association News Release to the press on Dr. Stephenson's research.
Medscape Medical News - AHA 2008
WebMD Health News - Hormone Creams Ease Menopause Symptoms
Family Practice News - Interview
Women in Balance - Update on the CHOIICE Study
Obstetrics and Gynecology News Interview
Bioidentical Hormone Research Shows Heart Benefits Interview
Dr. Stephenson's research on hormones in peri/postmenopausal women was one of 32 papers selected from over 4000 entries for a news release at the 2008 American Heart Association Scientific Sessions, the largest international meeting in the world, dedicated to cardiovascular disease research.
9 a.m. Abstract 5071/Poster P26 – Compound hormonal therapy may improve menopausal symptoms
Compound hormonal therapy, delivered through the skin via a lipophilic cream base, may relieve menopausal symptoms and provide anti-inflammatory effects before and during menopause, researchers said.
Researchers studied 150 perimenopausal and postmenopausal women, ages 30 to 70 years, who were either assigned to usual care or an interventional group that received the transdermal hormonal therapy for 12 months. Usual care was defined as the use of pharmacotherapy including: statins, cox-2-inhibitors, psychotropic drugs, oral hypoglycemic agents, and conventional hormone therapy of conjugated equine estrogens and medroxyprogesterone acetate to address signs and symptoms of mid-life and older women.
At 12 months, women in the compounded transdermal group experienced significant improvements in menopausal symptoms and cardiac risk factors.
Researchers found significant decreases in:
· systolic blood pressure, from an average at baseline of 133 mm Hg to 121 mm Hg;
· pulse pressure, from 52 mm Hg to 45 mm Hg;
· fasting glucose, from 110 mEq/L to 92 mEq/L; and
· fasting triglycerides, from 175 mg/dL to 120 mg/dL.
The women receiving the compounded estrogen, progesterone and androgen reported improvements in depression, anxiety and pain. But researchers found no significant differences from baseline to 12 months in nutrition, stress or body mass index. The noted benefits came without the therapy increasing blood clot formation. They also found no increase in inflammatory factors.
Larger clinical trials are needed to determine whether this therapy is a good alternative to conventional hormone replacement therapy, researchers said.
Kenna Stephenson, M.D.; University of Texas Health Science Center at Tyler, Texas
Karen Astle
Communications Manager
American Heart Association
7272 Greenville Ave.
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AHA 2008: Hormone Cream May Aid Menopausal Symptoms Without Increasing Thrombotic Risk
Marlene Busko
Medscape Medical News 2008. © 2008 Medscape
November 21, 2008 (New Orleans, Louisiana) — Custom-compounded plant-derived hormone cream may not only improve menopausal symptoms, including depression, anxiety, and pain, it may also provide an anti-inflammatory effect without increasing blood-clot formation, a small study suggests.
Researchers at the University of Texas Health Science Center, in Tyler, found promising 1-year safety and efficacy results in 75 peri- and postmenopausal women who received individually formulated hormone-replacement therapy applied as a cream to the skin.
"The 1-year findings are pretty encouraging," lead author Kenna Stephenson, MD, told Medscape Psychiatry. "We thought compounded transdermal hormones would relieve menopausal symptoms, but we didn't anticipate that they would also have a favorable effect on inflammatory, hemostatic, and cardiometabolic pathways."
The study was presented here at the American Heart Association 2008 Scientific Sessions.
Unproven Safety and Efficacy
In the United States, about 15 million women are currently peri- or postmenopausal and, as such, have an increased risk for cardiovascular disease, said Dr. Stephenson.
Since the Women's Health Initiative study showed an increased risk for breast cancer, stroke, and dementia with conventional hormone therapy, more women have been seeking alternative treatments for menopausal symptoms, such as hot flashes, night sweats, disrupted sleep, and irritability.
"We've seen an increase in the use of compounded transdermal hormone therapies among this population, but the safety and efficacy of these formulations have not been studied," she said.
To evaluate the hemostatic and anti-inflammatory effects of a compounded transdermal hormone-replacement therapy, the researchers recruited 150 peri- and postmenopausal women, aged 30 to 70 years.
Half were assigned to usual care and the rest were assigned to the compounded cream. Usual care was defined as conventional hormone therapy of conjugated equine estrogens and medroxyprogesterone.
The transdermal hormonal therapy consisted of plant-derived estrogen, progesterone, and sometimes testosterone and dehydroepiandrostenedione (DHEA).
Subjects in the transdermal-cream group were prescribed individualized therapy on the basis of their hormone levels. The women applied the cream to the skin once or twice daily to receive the target dose.
Although progesterone and DHEA are available over the counter in the United States, the doses of prescribed therapy, such as those used in the study, are much higher.
Encouraging Findings
At 12 months, the subjects who received the study treatment had:
* Significant decreases in depression and anxiety, as assessed by the Hamilton Depression Scale and the Hamilton Anxiety Scale
* Significant improvements in quality of life and menopausal symptoms, such as hot flashes and night sweats, as assessed by the Greene Climacteric Scale
* No harmful hemostatic effects, as indicated by significant decreases in fibrinogen and factor VII, and no significant changes in factor VIII or plasminogen activator inhibitor type I.
* No harmful anti-inflammatory effects, as shown by significant decreases in C-reactive protein (CRP), and no significant changes in interleukin-6
* Beneficial cardiometabolic effects, as shown by significant decreases in systolic blood pressure, pulse pressure, fasting glucose, and fasting triglycerides.
Still Early Days
"All hormones are not equal, and all hormone preparations are not equal," said Dr. Stephenson. "There are distinctly different risks and effects on inflammatory and thrombotic factors and cardiovascular biomarkers."
In this study, CRP and triglycerides decreased in women who received transdermal plant-derived compound hormones, whereas other studies have shown increased CRP and triglycerides in women receiving conventional equine and synthetic hormone therapy, she added.
However, "larger clinical trials are needed to determine whether this therapy is a good alternative to conventional hormone-replacement therapy," she said.
"Patients Like It"
"Many perimenopausal and postmenopausal women with mood symptoms may be given antidepressant therapy or antianxiety therapy, but by treating the underlying cause — hormonal changes — we see a statistically significant improvement in dysphoria," said Dr. Stephenson.
She added that patients in her clinical practice who receive compounded transdermal hormone-replacement therapy like it because it is easy, there are few adverse effects, it is very well tolerated, and it is effective for mood symptoms and hormone-related symptoms, such as vaginal dryness and night sweats."
It is important, she added, that a trained compounding pharmacist prepare transdermal hormone-replacement therapy. The International Academy of Compounding Pharmacists, which helped fund the study, lists such pharmacists on its Web site. Other information is available from the Professional Compounding Centers of America (PCCA) and the PCCA Canada Web sites.
The study was partly funded by the Progesterone Foundation and the International Academy of Compounding Pharmacists. The study authors have disclosed no relevant financial relationships.
American Heart Association (AHA) 2008 Scientific Sessions: Abstract 5071. Presented November 11, 2008.
Hormone Creams Ease Menopause Symptoms
Study Shows Custom-Compounded Preparations May Also Boost Heart Health
By Charlene Laino
WebMD Health News
Reviewed by Brunilda Nazario, MD
Nov. 12, 2008 (New Orleans) -- "Natural" hormone creams may help relieve hot flashes, night sweats, depression, and other symptoms of menopause, a new study suggests.
As an added benefit, they may also improve heart health, researchers say.
The researchers studied custom-compounded creams made from plant-derived hormones that are biochemically similar to those produced by the body. A preparation contains one or more various hormones in different amounts to meet each woman's individualized needs.
Custom-compounded hormones have been gaining favor ever since a large government-funded study known as the Women's Health Initiative linked the long-term use of conventional hormone replacement therapy in menopausal women to an increased risk of heart disease, stroke, and breast cancer.
But there have been few well designed studies showing the custom-compounded hormone preparations actually work.
The new research suggests that these compounds "can make remarkable changes in a woman's life," says Kenna Stephenson, MD, of the University of Texas Health Science Center at Tyler.
"Individualized hormonal treatments are just what women need," she tells WebMD.
Stephenson presented the new study at the American Heart Association's Scientific Sessions 2008.
Custom Creams Improve Menopause Symptoms
The 12-month study involved 150 perimenopausal and postmenopausal women 30 to 70. Half were given conventional hormone pills -- birth control pills for younger women and Prempro ( estrogen plus progesterone) or Premarin (estrogen only) for the menopausal women.
The other half received a cream that contained a customized blend of some combination of estrogen, progesterone, and the androgens testosterone and DHEA.
While androgens are often labeled "male hormones," they're necessary for women's health, too. A deficiency has been linked to menopausal symptoms, loss of libido, and other problems, Stephenson notes.
The pharmacist typically places the cream in plastic syringes that contain the precise amount a woman needs each day, she says.
By a year later, women who were taking compounded hormones reported significantly less depression, anxiety, and pain. They had fewer hot flashes and night sweats. Their quality of life improved. Blood pressure and triglyceride levels fell. Levels of C-reactive protein (CRP) and other markers of harmful inflammation in the arteries that can lead to blood clots dropped as well.
In contrast, conventional hormone pills have been shown to raise triglyceride and CRP levels, says Nieca Goldberg, MD, an American Heart Association spokeswoman and heart specialist at Lenox Hill Hospital in New York City.
"It appears this preparation could be protective against symptoms of menopause as well as heart disease, but clearly a larger study is needed," she tells WebMD.
Stephenson says women who want to use the hormonal blends need to make sure they choose a compounding pharmacist who is licensed and trained.
The International Academy of Compounding Pharmacists, which helped fund the research, maintains a list of members with specialized training, she says.
Transdermal Hormones Yield
CV Benefits in Menopause
BY BRUCE JANCIN
Denver Bureau
NEW OR L E A N S — Compounded transdermal hormone therapy relieves menopausal symptoms while improving cardiovascular risk factors and inflammatory and thrombotic biomarkers, according to a preliminary study.
“By replacing the hormone that’s deficient via transdermal dosing it may be possible to more closely mimic normal physiology and favorably impact cardiometabolic clinical biomarkers. Despite FDA concerns of dangers of compounded hormone use, our data suggest that transdermal compounded hormones may offer a safe and effective treatment for hormone- related symptoms when utilizing dosages targeting physiologic reference ranges and compounds, which meet USP standards for potency,” Dr. Kenna Stephenson, a family physician active in clinical research in women’s health at the University of Texas Health Science Center at Tyler, said at the annual scientific sessions of the American Heart Association.
Her study involves 150 women, mean age 51.9 years, with menopausal symptoms, who were randomized to usual care or individualized transdermal plant-derived estrogen, progesterone, testosterone, and dehydroandrostenidione therapy prepared by a compounding pharmacist.
After 12 months of follow-up, women on transdermal therapy showed significant reductions in triglycerides, blood pressure, fasting blood glucose, C-reactive protein, plasma fibrinogen, insulin-like growth factor–I, and factor VII along with significant symptomatic and quality of life improvements (see chart). The study will continue through 3 years of follow-up.
Ever since the Women’s Health Initiative linked oral hormone replacementtherapy to increased risks of breast cancer and cardiovascular events, women with menopausal symptoms have expressed growing interest in alternative forms of hormonal therapy.
As in the ongoing study, Dr. Stephenson’s clinical practice is to take a history of hormone-related symptoms such as hot flashes, night sweats, mood changes, sleep deprivation, and unexplained fatigue, measure the patient’s sex hormone levels, and then prescribe a low-dose transdermal hormone compounded specifically for her. Transdermal therapy avoids first-pass hepatic metabolism, thereby preventing buildup of atherogenic sex hormone metabolites, said Dr. Stephenson.
“What I see in clinical practice and my research studies is their biomarkers improve. They have adequate symptom relief, which is what’s most important to them. And once their symptoms are relieved they’re more likely to make positive nutritional and lifestyle changes: They feel like exercising; they feel like eating the way they’re supposed to,” she said.
Dr. Stephenson uses the university medical center’s compounding pharmacy. There are a growing number of such pharmacies as a result of increasing applications for compounded transdermal therapy in pain medicine, oncology, dermatology, and sports medicine, as well as hormone therapy. Physicians can locate a compounding pharmacist through the member registry maintained by the International Academy of Compounding Pharmacists (www.iacprx.org).
A home salivary specimen shipped to a CLIA-certified laboratory provides the most accurate way to assess a woman’s hormone status. “The reference ranges in serum testing for sex hormones are too broad,” Dr. Stephenson explained.
In January 2008, the Food and Drug Administration announced a new policy of restricted access to medications containing estriol that could have a negative impact on compounded transdermal hormone therapy for women, since prescribing physicians are required to fill out an Investigational New Drug application. Resolutions have been introduced in both the Senate (S.Con.Res. 88) and House of Representatives (H.Con. Res. 342) calling on the FDA to reverse this policy.
To watch a video interview with Dr. Stephenson, go to http://www.youtube. com/familypracticenews.
Download a PDF of this article here.
update on the CHOIICE study
Bioidentical Hormones May Help Prevent Heart Disease and Stroke
Women have been using natural hormones for well over a decade, but until fairly recently there hasn’t been good, solid scientific research showing that it is safe and effective. Yes, there are hundreds of studies that point indirectly to how well natural hormones work, and yes, there are hundreds of thousands, if not millions of women who can attest to how much better they feel using natural hormones. But we would like to see all women have the choice of using natural hormones. The way to get more doctors on the natural hormone bandwagon is to have more clinical research, which means doctors prescribing natural hormones to women and formally tracking the results.
In France and other parts of Europe, women have been using natural progesterone and estradiol (a natural estrogen) in pill form, for about a decade. There are several large and excellent studies of these women which provide solid evidence that it is a safe and effective combination. In contrast, these same studies show that the synthetic progestin hormone replacement (HRT) combinations have numerous harmful side effects, including an increase in stroke, breast cancer and heart disease.
Bioidentical Hormone Heroes
Clinical studies are very expensive, and as a result nearly all published clinical research done in the U.S. is funded by pharmaceutical companies. The drug companies are not sponsoring natural hormone research because they have no interest in selling natural hormones, which cannot be patented. In the U.S. most natural hormones use is transdermal, meaning they are in creams that are applied to the skin. Clinical research on transdermal hormones has fallen to a few courageous and inspired doctors who are willing to devote enormous time, money and energy to conduct small studies. They have to overcome the resistance of their local hospital boards, scrounge up funds, and ask for free testing and materials. They have to interview hundreds of women to find a few dozen to qualify for a small study, and talk them into participating for free. They convince staff and students to help them make phone calls, keep records and crunch data in their off hours. These devoted doctors are indeed true pioneers and heroes whose hard work and dedication will ultimately benefit millions of women for decades to come.
One of those courageous and inspired researchers is Dr. Kenna Stephenson, who recently presented the first-year results of her CHOIICE (Compounded Bioidentical Hormones: Immune, Inflammatory, and Cardiovascular Biomarker Effects) study to the American Heart Association 2008 Scientific Sessions. Dr. Stephenson did her research under the auspices of the University of Texas Health Science Center. She is currently an Associate Professor of Family Medicine at The University of Texas Health Science Center in Tyler, Texas.
The CHOIICE Study Will Give Women More Options
The goal of Stephenson’s three-year CHOIICE study is to measure some important thrombotic (stroke) risk factors in women using transdermal estrogen, progesterone, and androgen (DHEA, testosterone) therapy in peri/postmenopausal women. We already know that conventional HRT (e.g. PremPro) increases the risk of stroke, and the question is, do natural hormones have the same effect?
The CHOIICE study is particularly unique because it does not administer a one-dose-fits-all strategy, which is typical of most studies. Rather, each women’s hormone levels were evaluated at the beginning of the study with saliva tests, and hormones were prescribed accordingly.
What the CHOIICE Study Measured
Hormone Levels, including progesterone, estrogen, testosterone, DHEAS, and cortisol.
Fibrinogen, a protein found in the blood that plays an important role in blood clotting. High fibrinogen levels increase the risk of stroke, atrial fibrillation (rapid heartbeat), intermittent claudication (pain in the legs when walking), and high blood pressure.
Factors V, VII and VIII, blood clotting factors. High levels are a well-established risk factor for stroke.
C-Reactive Protein (CRP), an indicator in the blood of inflammation. High CRP levels are strongly associated with an increased risk of heart disease and stroke.
Clinical parameters, including blood pressure, pulse pressure and body mass index (BMI).
Indicators of Metabolic Syndrome, including fasting glucose, fasting insulin and fasting triglycerides.
Indicators of mood, including the Hamilton Depression/Anxiety Score, the Greene Climacteric Scale and a Pain Scale.
Who Participated in the Study and What They Were Treated With
According to Dr. Stephenson, “The women chosen to be in the study were perimenopausal and postmenopausal, between the ages of 30 and 70, and were free of any severe chronic diseases. They could not be on a statin or other cholesterol-lowering drugs, they could not be on a COX-2 inhibitor, they could not be on any hormones, and had to be cancer-free for five years.” There were 70 women in the study group, and 75 women in the control group (were not treated).
The women’s hormone levels were measured with saliva tests when they entered the study, and those in the treatment group were given bioidentical hormones according to their individual needs. A compounding pharmacy made up a hormone cream for each woman. You can read in more detail about Dr. Stephenson’s approach to testing hormones and prescribing them in her book Awakening Athena, which is available on amazon.com.
CHOIICE Results Point to New Approaches in Women’s Health
The results of Dr. Stephenson’s research should give doctors and women more confidence about using bioidentical hormones. All of the parameters measured either stayed the same or improved, especially in the postmenopausal women.
Dr. Stephenson emphasizes that, “The most compelling thing about the study results that I can share as it relates to women’s health and assessing women in this age group, is that when they visit a doctor with complaints that point to heart disease and stroke, it is vital to know their hormone profile. Starting treatment with pharmacotherapy [drugs] to lower blood pressure, triglycerides or blood sugar may create problems with drug interactions or side effects, or not have global protective effects. By knowing a woman’s hormone profile and her hormone status, and by testing and treating that first, you may see a significant improvement in her blood pressure, her lipids and her glucose.”
We’ll report back next year when Dr. Stephenson has more results from the third year of the CHOIICE study! In the meantime, if you’re interested in the details of the current round of results, you might enjoy this Women In Balance Interview with Kenna Stephenson, M.D.
You can also view this article online here.
Obstetrics and Gynecology News Interview
Early Data on Compounded Transdermal HT
BY BRUCE JANCIN
Denver Bureau
NEW ORLEANS — Compounded transdermal hormone therapy relieves menopausal symptoms while improving cardiovascular risk factors and inflammatory and thrombotic biomarkers, according to a preliminary study.
“By replacing the hormone that’s deficient via transdermal dosing it may be possible to more closely mimic normal physiology and favorably impact cardiometabolic clinical biomarkers.
“Despite FDA expressed concerns of dangers of compounded hormone use, our data suggest that transdermal compounded hormones may offer a safe and effective treatment for hormone-related symptoms
when utilizing dosages targeting physiologic reference ranges and compounds, which meet USP standards for potency,” Dr. Kenna Stephenson said at the annual scientific sessions of the American Heart Association.
“Our study would suggest this is a superior way to treat women. Sure, Premarin [conjugated estrogens] gets rid of hot flashes, but it also increases C-reactive protein and increases thrombotic risk,” added Dr. Stephenson, a family physician active in clinical research in women’s health at the University of Texas Health Science Center at Tyler.
Her group’s ongoing study involves 150 women, mean age 51.9 years, with menopausal symptoms, who were randomized to usual care or individualized transdermal plant-derived estrogen, progesterone, testosterone, and dehydroandrostenidione therapy prepared by a compounding pharmacist. After 12 months of follow-up, the women on transdermal therapy showed significant reductions in triglycerides, blood pressure, fasting blood glucose, C-reactive protein, plasma fibrinogen, insulinlike
growth factor–I, and factor VII along with significant symptomatic and quality of life improvements (see chart). The study will continue through 3 years of follow-up.
 Ever since analysis of data from the Women’s Health Initiative linked oral hormone replacement therapy to increased risks of breast cancer and cardiovascular events, women with menopausal symptoms
have expressed growing
interest in alternative forms of hormonal therapy.
“In my clinical practice I would say every week I see a patient who’s already had an MI or a stroke, she’s in her 50s or maybe her 40s, and she’s been told she can never have hormones again,” Dr. Stephenson observed in an interview.
As in the ongoing study, her clinical practice is to take a history of hormone-
related symptoms such as hot flashes, night sweats, mood changes, sleep deprivation, and unexplained fatigue, measure the patient’s sex hormone levels, and then prescribe a low-dose transdermal hormone compounded specifically for her. Transdermal therapy avoids first-pass hepatic metabolism, thereby preventing buildup of atherogenic sex hormone metabolites, Dr. Stephenson explained.
“What I see in clinical practice as well as in my research studies is their biomarkers improve. They have adequate symptom relief, which is what’s most important to the patients. And once their symptoms are relieved they’re more likely to make positive nutritional and lifestyle changes: They feel like exercising; they feel like eating the way they’re supposed to,” the family physician continued.
She uses the university medical center’s compounding pharmacy. There are a growing number of such pharmacies around the country as a result of increasing applications for compounded transdermal therapy in pain medicine, oncology, dermatology, and sports medicine, as well as hormone therapy. She noted that interested physicians can locate a compounding pharmacist
through the member registry maintained by the International Academy of Compounding Pharmacists (www.iacprx.org).
A home salivary specimen shipped to a CLIA-certified laboratory provides the most accurate way to assess a woman’s hormone status. “Traditional blood tests are not helpful, in my clinical experience. The reference
ranges in serum testing for sex hormones are too broad,” Dr. Stephenson said.
She is the author of “Awakening Athena: Resilience, Restoration, and Rejuvenation for Women” (Hallsville, Texas: Health, Heart, and Mind Institute, 2004) a book that goes into the details of individualized transdermal compounded hormone therapy.
In January 2008, the Food and Drug Administration announced a controversial new policy of restricted access to medications containing estriol that could have a negative impact on compounded transdermal hormone therapy for women, since prescribing physicians are required to fill out an Investigational New Drug application. Resolutions have been introduced in both the Senate (S.Con.Res. 88) and House of Representatives (H.Con.Res. 342) calling on the FDA to reverse this policy.
A video interview of Dr. Stephenson discussing her study is available at
www.youtube.com/watch?v=IXDCo4nw86Q.
You can get a PDF of this article here.
Bioidentical Hormone Research Shows Heart Benefits
by Kenna Stephenson MD on 7/11/09 at 5:06 pm
Interview with KENNA STEPHENSON, M.D.
Dr. Kenna Stephenson presented the first-year results of her CHOIICE (Compounded Bioidentical Hormones: Immune, Inflammatory, and Cardiovascular Biomarker Effects) study to the American Heart Association Scientific Sessions. Dr. Stephenson did her research under the auspices of the University of Texas Health Science Center. She has had a distinguished academic career that includes clinical research and professional publications on women’s health, cardiovascular pharmacology, aging, prevention, and holistic medicine. She is a Fellow in the American Academy of Family Physicians, and is board certified in Family Medicine. She appears as the health expert for the local CBS television affiliate, KYTX, in Eye on Health and is a sought after speaker on the subject of natural hormones in clinical practice. Stephenson is currently an Associate Professor of Family Medicine at The University of Texas Health Science Center in Tyler, Texas.
The following is an interview done by Virginia Hopkins for Women in Balance with Dr. Kenna Stephenson about her research with bioidentical hormones and their effects on heart health, and is republished here with permission of Women in Balance.
WIB: Taking on a study like this involves an enormous commitment of time, energy and fund raising. What inspired you to take on this task?
KS: I started using compounded [bioidentical] hormones in clinical practice about a decade ago and observed an oftentimes dramatic benefit and very few side effects or problems. I wasn’t entirely comfortable prescribing them because of the paucity of clinical studies, especially long term, with specifically compounded hormones. I wanted to make up for that deficit in the U.S. research literature in a prospective, 36-month, long-term study to look at clinical outcomes with the compounded hormones as well as potential for harm.
I was really spurred on after the Women’s Health Initiative [WHI] when all hormones were condemned equally. My thinking in looking at the clinical literature, epidemiological studies and experimental studies is that hormones are not all equal as it relates to their pharmacology and physiology, and that there are distinct differences with the compounded hormones. This needed to be explored further instead of just saying, “Hormones are dangerous, hormones are bad, we can’t use them anymore, we’ve got to look at non-hormone therapies for hormone-related symptoms.”
We started recruiting for the CHOIICE study in 2005. The second arm of the WHI, the Premarin-only study, was halted in 2004. I think the timing was good in that there were women who had been off hormones for awhile because of the fear-based knee jerk response by a lot of physicians and patients, and yet women were suffering and looking for relief.
WIB: What were the criteria for women entering the study? Did you choose women suffering from specific menopausal symptoms?
KS: We did not seek out women that were having menopausal symptoms. We looked at women who were perimenopausal and postmenopausal, between the ages of 30 and 70, and who were free of any severe chronic diseases. They could not be on a statin or other cholesterol-lowering drugs, they could not be on a COX-2 inhibitor, they could not be on any hormones, and had to be cancer-free for five years. Those are the inclusion/exclusion criteria. We documented their symptoms at baseline and on followup. There were a few women that did not have hormone-related symptoms because that was not an inclusion criteria, but part of our hypothesis is that if women have depleted levels of sex steroid hormones, and those levels are vital to multiple systems in the body, then it would benefit them to have those levels restored. Maybe they don’t feel it as it relates to having a hot flash or a night sweat, but does it reflect on say, cardiovascular markers? Does it behoove them perhaps in a preventive way, in a proactive way, to have their hormones evaluated and then restored if they’re deficient?
WIB: How many women total are in the study?
KS: Seventy-five in the interventional group, and then 75 in the control group. The control group are women in the clinics at our facility that are receiving conventional care. They’re ethnic and age-matched controls. Those women are receiving, let’s say, statins, antidepressants, anxiolytics [drugs for anxiety] and conventional hormone therapy from their providers. This is a three-year study. The data that we reported at American Heart Scientific Sessions last month [November 2008] was the 12-month data.
WIB: What were the markers that you chose to measure?
KS: Our high interests were in thrombotic [stroke/blood clot] factors because there is a large body of clinical and experimental evidence demonstrating that conventional hormone therapy does increase thrombotic risk when given orally. Then there have been statements by entities such as the North American Menopause Society that progesterone should be inferred to have the same thrombotic risk as medroxyprogesterone acetate [e.g. Provera], yet there’s not evidence of that—but again there was no lack of evidence either.
We had a high interest in what was happening with hemostatic [blood clotting] factors. We looked at factor VII, factor V, factor VIII, antithrombin III, fibrinogen activator inhibitor and fibrinogen. These factors may be reduced or elevated in patient populations and then lead to risk of stroke or heart attack, pulmonary embolism or venous thrombosis.
Both the PremPro arm and the Premarin arm of the WHI were stopped early because of increased thrombotic risk, so we measured all of these factors and did not see any significant changes that would be pro-thrombotic, and we saw, with several of the factors, a statistically significant beneficial change. That change was most pronounced in the postmenopausal women.
We also looked at other biomarkers for cardiovascular disease: the inflammatory factors such as C-reactive protein [CRP] and we looked at clinical measures of systolic blood pressure, diastolic blood pressure, pulse pressure, fasting blood glucose, fasting insulin, fasting triglycerides.
Then we looked at a mood scale for depression, anxiety, as well as the Greene Climacteric Scale, a numerical index that scores 21 menopausal symptoms. We looked at a depression and anxiety scales scale because of data from the POWER study and the ATTICA study—both demonstrate that when women have a mood state of anxiety or depression, they have an increase in both pro-thrombotic and proinflammatory factors irrespective of whether they’re on psychotropic drugs, they smoke, or their BMI [body mass index, or weight]. A woman’s emotional state will affect these biomarkers, so it was important for us to quantify that.
WIB: How did you decide which hormones to put the women on?
KS: For each patient that met the strict inclusion/exclusion criteria and entered the study, we performed baseline hormone profiles. We looked at estrogen, progesterone, testosterone, DHEAS, and we also looked at their cortisol circadian rhythms. We used saliva testing, which our research team feels is the best measure of bioavailable hormones. Then, if the patients had sub-optimal levels of progesterone they were given progesterone during the first eight weeks. If they had sub-optimal levels of both estrogen and progesterone they were given both of those for the first eight weeks. The first eight weeks did not include any androgens [male hormones].
Then we retested the patients and at that point if they had low androgens we added in androgen therapy. All of our hormones were given transdermally [through the skin, via cream]. There is a myth out there that androgens are harmful to women, but some of that may come from the fact that very high doses of oral synthetic androgens have been shown to have adverse effects. And of course that’s distinctly different than the transdermal low dose compounded androgens that were given to our patients.
WIB: How did you decide the amounts of hormones to give them?
KS: We used the formulary for health care professionals that’s published in my book, Awakening Athena. I used that formulary in clinical practice for nearly a decade. Then the prescriptions were titrated to physiologic reference ranges because women have different responses to hormone therapy. Some women may be rapid metabolizers, some slow metabolizers, so that’s why it was important that we monitor and retest them. One patient may need 20 mg of progesterone to get her to target, and another may need 40 mg or 60 mg. We’ve looked at the patients collectively as it relates to risk and benefit and the type of hormone therapy. But as far as the dosing, women have to be treated individually, and they need individual dosing. It is not good enough to just categorize them based on their uterine status or symptoms. Each patient received her specific hormone dose based on her saliva test profile results. It sounds complex but it’s really not, and it sure saves a lot of time in the long run.
WIB: And the women sure feel better!
KS: We proved that I think. Our hypothesis was that we would not see the elevated thrombotic factors, but we were very surprised to see this global benefit in all domains. We felt that we would see some, but it was quite surprising to us to see the statistically significant beneficial changes across the board.
WIB: Very exciting. Would you give us a general overview of the results?
KS: Cardiovascular disease is the leading cause of death and disability in American women. Our concern is that there are hormonal factors involved, and our research suggests that if we address those hormonal factors primarily, then there’s a downstream effect on the cardiovascular biomarkers showing a benefit. The WISE [Women and Ischemic Events] studies by the NIH Heart, Lung and Blood Institute and others over the last decade suggest that there is a gender-specific pathophysiology as it relates to cardiovascular disease. This clustering effect in peri-menopausal and post-menopausal women of an elevated fasting glucose, elevated triglycerides, elevated CRP and elevated pulse pressure, all contribute strongly to cardiovascular disease risk, along with psychosocial factors of anxiety and depression. We saw benefit in all of these domains both at eight weeks and at 12 months. We saw improvement in their depression and anxiety scores, we saw a decrease in fasting glucose and fasting triglycerides, we saw a decrease in CRP, we saw a decrease in systolic pressure and pulse pressure.
WIB: Do you plan to continue to follow these women when the study is over?
KS: Funding is the issue. It’s been quite a struggle to do this study on a shoestring. We’re competing with Big Pharma studies that are very generously funded, where there’s want of nothing. We’ll probably survey the women, but I don’t know that we’ll be able to afford much more than that.
WIB: Do you have any insights that you can share from your own clinical practice?
KS: I think the most compelling thing that I can share as it relates to women’s health and assessing women in this age group, is that when they are pre-hypertensive and prediabetic, by clinical criteria, it is vital to know their hormone profile. Starting treatment with pharmacotherapy [drugs] to lower blood pressure, triglycerides or blood sugar may create problems with drug interactions or side effects, or not have a global protective effects. By knowing a woman’s hormone profile and her hormone status, and by testing that first, you may see a significant improvement in her blood pressure, her lipids and her glucose.
WIB: So doctors can use a treatment that’s safe and effective, is replacing what’s depleted, and addresses the whole body, rather than treat specific symptoms with a pharmaceutical drug approach. You’re treating an underlying cause rather than a symptom.
KS: Yes. That is what I try to emphasize with the medical students and the residents. Metabolic syndrome is so prevalent and is increasing in this patient population. Hormone factors are the priority.
WIB: How do you treat women whose cortisol is out of balance and indicating tired adrenals?
KS: First I want to know what’s happening with her progesterone. If the progesterone is low, then I prescribe transdermal progesterone along with nutritional and lifestyle counseling. That’s my primary approach.
WIB: Does the nutritional/lifestyle counseling include getting more sleep, eating less sugar, stress management and exercise?
KS: Yes. We counsel women with low adrenal function to pay attention to the glycemic indices of food, to take the time to restore and recharge. Even if she’s working two jobs. Some of my patients are working three jobs. They need to find somewhere, even if it’s just a twenty-minute break, to help de-stress. Maybe she can take 30 minutes on an hour lunch break to do some yoga work or aerobic type exercise. That’s what I counsel the patients initially. And then if the adrenal depletion is more profound or severe, I will oftentimes have them take supplements.
WIB: What types of supplements do you recommend?
KS: I primarily use James Wilson’s protocols and supplements.
WIB: Thanks so much for your time and attention, Dr. Stephenson. This is a beautifully thought-out and executed study, and it will change how doctors approach women’s health.
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