HRT Medical References

The following are some of the medical references that I have relied upon in making informed decisions about my own treatment. And some conversely validate suppositions I reached on my own, based upon observations and logical thinking. Words in bold print have particular relevance to ideas put forth in the previous two pages. Words in green print are my own comments.

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FLAWS IN THE Women's Health Initiative (WHI) STUDY

Click on link entitled:
"HRT DOES NOT increase breast cancer risk.
Flaws in the Womens Health Initative Study."

at this webpage:
http://members.aol.com/natrajan9/content.htm
or go directly to:
http://members.aol.com/natrajan9/study.htm
for article by Murray A. Freedman, M.D., R. Don Gambrell, Jr., M.D. & P.K. Natrajan, M.D.

Also please see Website belonging to R. Don Gambrell, Jr., M.D.
Clinical Professor, Department of Obstetrics and Gynecology and Physiology and Endocrinology, Medical College of Georgia
http://members.aol.com/gambr999/content.htm


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Hormone researchers revolt
Criticizing recent negative studies of replacement therapy, some scientists are holding out for more data
By Tabitha M Powledge
http://www.biomedcentral.com/news/20030822/01

Dismayed at what they regard as an unreasoning and unwarranted backlash against long-term sex hormone replacement for middle-aged women, hormone researchers are planning a counterattack. The researchers are trying to organize new studies they hope will answer lingering questions about hormones' long-term benefits and risks arising from recent negative clinical investigations. Many believe the results would be different this time.
Would-be revisionist researchers acknowledge that they face enormous hurdles with funders, regulators, the media, and perhaps women themselves. "These things tend to be self-fulfilling prophecies," complained Frederick Naftolin, who directs the Yale University Center for Research in Reproductive Biology and has been a vigorous critic of the studies and the ways they have been interpreted. "You get people talking about how the issue has been settled and it becomes settled."
The current backlash against hormone replacement therapy (HRT) resulted from a cascade of large-scale studies reporting small increases in breast cancer, coronary heart disease, stroke, and pulmonary embolism in women on HRT. Revisionist researchers argue that the studies are mostly worthless for answering the most urgent questions: whether long-term HRT begun early, at the menopausal transition, could postpone at least some of the diseases of aging, and whether different hormone regimens would yield healthier results.
They point out that the average age of study subjects entering the massive US Women's Health Initiative (WHI) was 63, long past menopause, and note that many of those women would already have been on the road to heart disease and other disorders. The scientists also point out that much other research—observational human studies and animal research—suggests that different hormone formulations, such as lower doses of estrogen alone, or estrogen plus cyclical progesterone, might be beneficial. The WHI used Prempro, a pill taken daily that contains synthetic progesterone and conjugated horse estrogens.

Wulf Utian, executive director of the North American Menopause Society (NAMS), told The Scientist that a committee from his group is putting together a list of urgent research that remains to be done on HRT. "There is a recognition by the committee that hormones have potential risks but certainly have potential benefits," he said. Committee members are drawn from both critics and supporters of the controversial human studies, and the report is expected in September, he said.
Among the questions the NAMS group wants answered are whether hormones could help postpone diseases of aging with tolerable risks if women began long-term HRT at the menopausal transition, when their sex hormones decline, rather than years later. They also believe hormone formulations and routes of administration different from those most commonly used now need investigating. There is evidence that these strategies might lead to better results not just from other research but also from the big recent studies themselves.
"But the dilemma, given the extremely negative spin that the media have taken on the whole subject, and the decline in sales throughout the pharmaceutical industry, is whether those companies would step to the plate and put money into expensive projects," Utian said.
Naftolin and other researchers have joined with the Kronos Longevity Research Institute to seek funding for a clinical trial of transdermal and oral hormone replacement for prevention of cardiovascular disease with study subjects who are perimenopausal. If support is forthcoming and regulatory issues can be settled, the multicenter trial might begin as early as next year.
The researchers plan to examine surrogate indications of disease progression, such as thickening of the carotid artery wall, rather than clinical events like heart attacks or strokes. Kronos's Mitchell Harman acknowledges that surrogate endpoints will not satisfy all critics, but notes that looking for statistically significant differences in clinical events among placebo and treatment groups of younger women would take ten years and 50,000 subjects.
The WHI, which involved well over 16,000 postmenopausal women, reported small increases in invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism in women taking Prempro, which has been by far the most commonly prescribed HRT in the United States. Because of these risks, the National Institutes of Health shut down the study in July 2002, two years early, even though there were observed benefits, among them a reduced incidence of hip fracture and colon cancer.
The WHI, a randomized double-blind clinical trial, issued final reports on cardiovascular data in the August 7 issue of the New England Journal of Medicine; they confirmed that Prempro does not protect the heart. The same week, Lancet published the United Kingdom's Million Women observational study, which confirmed once more a link between HRT and breast cancer, but also revealed risk differences that appeared to be related to hormone formulation and route of administration. The largest risk was in women on combination oral HRT like Prempro.
Marcia Stefanick of Stanford, one of the WHI principal investigators, concedes readily that many scientific questions about HRT remain up in the air, but she's dubious about getting them all resolved. A study that was big enough and lengthy enough to evaluate the long-term effects of different hormone regimens on perimenopausal women's liability to cardiovascular disease, cognitive decline, decreased quality of life, and other burdens of aging would soon encounter unacceptable increases in breast cancer, she said.
The specter of breast cancer would keep institutional review boards (IRBs)—local regulatory bodies that oversee and must approve human subjects research at US institutions—from allowing them. "There's just no IRB in this country that would accept that risk even if 30 years down the road you're going to show that you've saved more women from heart disease," she predicted.
On the subject of more HRT research, Stefanick is voting with her feet. "I think we've answered the estrogen and progestin question for the areas that I'm interested in studying, so for me personally I'm going in a different direction," she said. Stefanick is turning her research attention to topics she regards as far more vital for women's health: obesity and exercise.
Frederick Naftolin
http://www.biology.yale.edu/facultystaff/naftolin.html
North American Menopause Society
http://www.menopause.org/
Kronos Longevity Research Institute
http://www.kronosinstitute.org/home.html
S. Mitchell Harman
http://www.kronosinstitute.org/Biographies/harman.html
J.E. Manson et al., "Estrogen plus Progestin and the Risk of Coronary Heart Disease," New England Journal of Medicine 349:523-534, August 7, 2003. [PubMed Abstract]
V. Beral, "Breast cancer and hormone-replacement therapy in the Million Women Study," Lancet 362:419-27, August 9, 2003. [PubMed Abstract]
Stanford School of Medicine
http://www.med.stanford.edu/
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Testosterone may counter HRT's cancer effects (excerpts)
Last Updated: 2004-09-14 16:46:32 -0400 By Karla Gale (Reuters Health)
SOURCE: Menopause, September/October 2004.
http://www.reutershealth.com/archive/2004/09/14/eline/links/20040914elin023.html

Before menopause, the ovaries produce both testosterone and estrogen, co-author Dr. Robert A. Jones, at Memorial Medical Center in North Adelaide, South Australia, explained in an interview with Reuters Health. Conventional HRT "tends to interfere with the protective effect of testosterone," thus increasing the risk of breast cancer.
"If testosterone had been used by subjects in the Women's Health Initiative study, it may have stopped the rise in breast cancer risk," he added. "It's possible the trial would not have needed to be stopped early."

When added to conventional hormone replacement therapy (HRT), testosterone may reduce the risk of breast cancer in postmenopausal women, results of a small study suggest.
"I hope that this paper stimulates interest in the question of whether a more physiological HRT regimen might have better effects," senior author Dr. Carolyn A. Bondy told Reuters Health.
But, she emphasized, "I do not recommend any changes in HRT treatment until we're convinced it's safe and efficacious."

The Women's Health Initiative and the "Million Women" Study, large clinical trials of combined estrogen and progestin HRT, were terminated early when they showed an increased risk of breast cancer. However, these studies did not evaluate combined treatment that included testosterone.

Bondy, with the National Institutes of Health in Bethesda, Maryland, and colleagues report the results of a look-back study of 508 postmenopausal women given testosterone and estrogen, with or without progestin, for an average of about 6 years. Their findings are published in the medical journal Menopause.
During follow-up there were seven cases of invasive breast cancer. One case occurred in the group using estrogen and testosterone only, while six cases occurred in the group that was also using progestins -- which translates to about twice the incidence.
His group's findings also confirm the suspected increased risk when oral progestin is added to estrogen HRT. That issue could possibly be circumvented by administering the progestin via an intrauterine device rather than orally, Jones said. After all, he commented, "Why give progestin to the breast when all you want to do is give it to the uterus?"

In comparison, the incidence of breast cancer was 2- to 3- times higher among women taking estrogen and progestin arm of the Women's Health Initiative.
He noted that testosterone has the added bonus of improving a woman's mood, reducing breast soreness, increasing bone density, as well as restoring energy, stamina, and sex drive.
In the end, though, these findings do not prove that testosterone is protective, Jones added.
Bondy agreed. "I would love to see a clinical trial, especially for younger women who've had their ovaries surgically removed or who have ovarian failure for some other reason, who have to take HRT. Otherwise, they get terrible osteoporosis and their sexual characteristics disappear at a young age."
Until such studies have been completed, she reiterated, "I do not want people to jump on the bandwagon and do something that is unproven."

SOURCE: Menopause, September/October 2004.
http://www.dental.am/more.php?id=3104_0_1_12_M66
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Health News for Mid-Life Women: Testosterone Therapy
by Judith Paley, MD

This information is intended to be general in nature and should not be relied upon for specific treatment. If you need medical attention, please contact your personal physician's office for an appointment.

T for two--it's also in you!

Androgens are the sex steroids responsible for the development and maintenance of male sexual characteristics. Testosterone (T) is the most potent circulating androgen and, in fact, women produce much more T than estrogen--their blood levels of T are roughly 1,000 times higher than those of estrogen. Androgens are essential biochemical building blocks in a woman's body, manufactured in the ovaries and adrenal glands, and converted into estrogen in these organs and peripheral tissues such as breast, muscle, fat, and skin. Testosterone is also known to directly enhance female mood, sexuality, muscle and bone mass, and strength. Interestingly, there is a mid-cycle surge of T coinciding with ovulation, which increases sex drive during the most fertile time of the month.
The ovaries produce a significant portion of the circulating testosterone. After menopause, when the ovaries cease to produce estrogen, they can actually increase T secretion to levels greater than ever! Unfortunately, other body sources of androgens start to falter in the decade after menopause, causing tiny T levels and a possible deficiency. If a woman undergoes surgical removal of her ovaries (oophorectomy), T levels abruptly topple by as much as 70% within 24 hours of surgery.
Postmenopausal estrogen therapy can also cause a drop in available testosterone because it causes the liver to increase production of a protein that tightly binds up T--and estrogen--making the hormones less accessible to the cells. When women begin to have recurrent menopausal symptoms, fatigue, and diminished libido after years of hormone therapy, the problem often lies in dwindling "bioavailable" estrogen and testosterone. Increasing estrogen supplementation actually worsens the problem because it causes levels of binding proteins to rise even more. On the other hand, supplemental T decreases the hormone binding protein production and improves the overall situation.
Testosterone therapy is available in a combination product with estrogen called Estratest, which also comes in half-strength tablets as Estratest HS. Supplemental T can also be ordered from compounding pharmacies as methyltestosterone. Pure testosterone cannot be taken orally (it would be destroyed by the liver); it's available as a gel or patch for men and as a compounded cream or dissolve-in-the-mouth tablets for women (these are absorbed directly through the inner surfaces of the mouth).

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Testosterone and our aging hearts

Since coronary artery disease is more prevalent in men than premenopausal women, estrogen has been assumed to be heart-protective and concerns existed that testosterone (T) was detrimental to cardiovascular health. Several studies provide reassuring evidence that this is not the case.
A group of menopausal women from Maryland were recruited for this four-month study. One group downed estrogen alone and the other group took estrogen plus testosterone (the equivalent of estra-test). The primary outcomes of interest were changes in plasma viscosity (a measure of how gooey blood is which correlates with stroke and heart attack risk) and fibrinogen levels (a clotting factor). In addition, cholesterol and triglyceride levels were checked.
Women on Estratest had lower total cholesterol, triglycerides, sex hormone binding globulin, and plasma viscosity--all good things. Conversely, they had lower HDL-cholesterol and higher fibrinogen--not so good. The estrogen-only group had higher fibrinogen, but nothing much else changed. Study authors enthused that they now felt warm and good about administering low-dose testosterone to menopausal women.
In another study, lower testosterone levels correlated with the incidence of coronary artery disease in women, independent of other metabolic risk factors. In other words, no matter what sort of cholesterol or other blood fat abnormalities these ladies had, the lower the testosterone, the more likely they were to have a heart attack. .....Dr. Alan Altman, a Boston gynecologist.....
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HRT patches 'boost libido'
Libido can be affected by the menopause
http://news.bbc.co.uk/1/hi/health/2038376.stm

Hormone replacement patches may increase the libido of postmenopausal women, a study has found. HRT pills, combining oestrogen and a synthetic progesterone, are traditionally given to women to treat the physical symptoms of the menopause, such as hot flashes and vaginal dryness.
But they suppress "male" sex hormones such as testosterone, which are needed for both male and female libido.
HRT users had a greater degree of sexual satisfaction
Research presented to the 10th World Congress on the Menopause in Berlin carried out by researchers from the University of Southern California suggests giving HRT via patches can stimulate these hormones.
There is currently no treatment to boost low libido for the millions of postmenopausal women affected, though some research has suggested the male hormones may help.
But there can be problems finding the right dose, and women can suffer side effects such as excessive hair growth and acne.
The team say HRT patches allow the woman's body to use the hormones, including the testosterone, already in her body, more effectively.
First step

The study involved 23 postmenopausal women who were given a combination oestrogen/progesterone patch.
The researchers admit their results are only preliminary.
Subir Roy, professor of obstetrics and gynaecology at the Keck School of Medicine of the University of Southern California, led the research.
He said it was the first step in showing HRT patches should be the first choice for treating postmenopausal women, before trying male hormone therapies.
Further research, partially backed by Novogyne Pharmaceuticals, which markets the CombiPatch used in the study, is underway.
Professor Roy added: "The results presented today might be the first step in providing a new solution for post-menopausal women, since preliminary results show that HRT from a patch had positive effects on mood and libido, leading to more orgasms.
"The results of our study showed that patch users, in comparison to oral HRT users, have higher levels of androgens (male sex hormones), including free testosterone, and a greater degree of sexual satisfaction."
"Female sexual dysfunction - low libido, slow arousal, difficulty reaching orgasms and painful intercourse - is a problem that many menopausal women view as a normal part of ageing and have simply decided to accept.
"Where men have the choice of the little blue pill, there is a lack of treatment options for women.
Terry Linehan, from Los Angeles, California, who took part in the study, said: "The stereotype of older people not being interested in having good sex just isn't true.
"A satisfying sex life is very important to most marriages, no matter what your age.
"I wasn't looking for a miracle pill or a quick fix. I just hoped that if the reason behind my low libido was due to my hormone levels that I could help find a way to regulate the problem."
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P&G female sexual desire patch effective in trial
http://www.reutershealth.com/archive/2004/06/16/eline/links/20040616elin007.html
By Bill Berkrot Last Updated: 2004-06-16 10:58:48 -0400 (Reuters Health)

NEW YORK (Reuters) - Procter & Gamble Co. on Wednesday moved a step closer to becoming the first company with a drug on the market to treat sexual dysfunction in women after releasing data from a pivotal late-stage clinical trial that backs up its previous findings.
The testosterone skin patch, to be called Intrinsa, significantly improved sexual desire and satisfaction in women whose ovaries had previously been removed, according to data to be presented on Friday at the Endocrine Society of America annual meeting in New Orleans.
Armed with data from two large phase III clinical trials that appear to demonstrate safety and efficacy of Intrinsa, P&G believes it now has the information needed to seek approval from U.S. regulators.
Although the company declined to discuss when it would file its new drug application with the Food and Drug Administration, P&G spokeswoman Mary Johnson said if approved they hope to have Intrinsa available by prescription sometime next year.

The drug would be prescribed to increase sexual desire in menopausal women who have experienced loss of desire and are distressed by that loss.
"This is huge," said Sheryl Kingsberg, an associate professor of reproductive biology at Case Western Reserve University and one of the lead investigators of the trial.
"It's important to get it out there because we don't have any approved medical treatment on the market for female sexual dysfunction that clinicians can look at as safe and effective," Kingsberg said.
In P&G's latest 24-week trial of 533 women, patients taking Intrinsa reported a 51 percent increase in frequency of "satisfying sexual activity" and a 49 percent increase in sexual desire, compared with their previous experience.
The response rate was lower than in a previous trial, but researchers said the findings were statistically significant.
In a similar study of 562 women released in May, women receiving the patch had a 74 percent increase in frequency of satisfying sexual activity and a 56 percent increase in sexual desire.
P&G, best known for consumer products such as Tide laundry detergent and Crest toothpaste, said it is currently conducting two more late-stage clinical studies of the testosterone patch in menopausal women who have not had surgery to remove their ovaries, Johnson said.
The search for a so-called female Viagra has so far proved elusive. Even Viagra-maker Pfizer Inc. abandoned their program of testing the drug for women, whose sexual dysfunctions are more varied and complicated than men.
"In any area of research, women's research always lags behind men," Kingsberg said.
Analysts have said drugs for female sexual dysfunction that prove effective in treating problems with desire, arousal or ability to achieve orgasm could garner sales in excess of $1 billion a year.
Vivus Inc. is developing a drug to treat the arousal component of female sexual disorder that it hopes to submit to the FDA in 2006. It also acquired rights to a female sexual desire treatment that may compete with Intrinsa.
"The launches of these drugs, starting with Intrinsa, will prompt a wave of marketing that will likely raise awareness of Female Sexual Dysfunction," David Lapidus, analyst at Decision Resources, said in a report.
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ORAL vs OTHER DELIVERY METHODS of DHEA

http://groups.google.com/groups?q=oral+group:alt.support.impotence.*&hl=en&lr=&ie=UTF-8&group=alt.support.impotence.*&selm=23CI7.170066%243d2.6990341%40bgtnsc06-news.ops.worldnet.att.net&rnum=5
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11694019&dopt=Citation

DHEA shows a low oral bioavailability; taking the bioavailability obtained by the subcutaneous route as 100%, it was estimated that the potencies of DHEA by the percutaneous and oral routes were approximately 33% and 3%, respectively.
Oral DHEA Absorbtion 3% Transdermal DHEA Absorbtion 33%


Drug Dev Ind Pharm 2001 Aug;27(7):711-7 Books
Development of patches for the controlled release of dehydroepiandrosterone.
Minghetti P, Cilurzo F, Casiraghi A, Montanari L, Santoro A. Istituto di Chimica Farmaceutica e Tossicologica, Universita degli Studi di Milano, Italy. paola.minghetti@unimi.it

Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the major secretory steroidal products of the adrenal gland. Some epidemiologic studies have found an association between low DHEA serum levels in patients and many important diseases. To prevent all such pathological conditions and, in any case, in aging, a DHEA supplementation has been proposed. DHEA shows a low oral bioavailability; taking the bioavailability obtained by the subcutaneous route as 100%, it was estimated that the potencies of DHEA by the percutaneous and oral routes were approximately 33% and 3%, respectively. Thus, transdermal patches could be considered a promising formulation as a continuous and controlled delivery of DHEA in replacement therapy is desired. With the aim of evaluating the effect of the matrix composition in terms of polymers and enhancers on the DHEA skin permeation flux, 10 types of monolayer self-adhesive patches containing 0.25mg/cm2 of active ingredient were designed. The matrices were based on three different acrylic copolymers: an acrylate-vinylacetate copolymer, a polyaminomethylmethacrylate (PAMA), and a polymethylmethacrylate. Transcutol (TR), mint essential oil, Lauroglycol, Brij 58, and propylene glycol (PG) were evaluated as DHEA skin permeation enhancers. All prepared patches were characterized by drug content, light microscopy, and in vitro skin permeation, performed using a modified Franz-type diffusion cell and human stratum corneum and epidermis as a membrane. The in vitro skin permeation studies are particularly significant in the development studies of DHEA patches as the in vivo determination of DHEA is affected b the fact that the endogen substance in the plasma is not constant over time. Among the testedpatches, highest DHEA fluxes were obtained using the formulation based on PAMA. Moreover, the introduction in the matrix of binary mixtures of TR and PG, used also for their plasticizer properties, permitted enhancing DHEA skin permeation. On the basis of these studies, the transdermal administration of DHEA using patches seems feasible.
PMID: 11694019 [PubMed - in process]
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How does route of delivery affect the risk/benefit ratio of hormone therapy?
http://www.unboundmedicine.com/medline/mlc?cmd=medCit&login=true&username=che1&password=che1&m=full&id=15251108
Title The menopausal transition: How does route of delivery affect the risk/benefit ratio of hormone therapy? Author(s) Shulman LP
Institution Northwestern University, Feinberg School of Medicine, Chicago, IL USA.
Source J Fam Pract 2004 Jul;53 (7) :S13-7.
Abstract Despite concerns about the risks of HT, relief of menopausal symptoms is an important goal. Clearly, HT remains an important option to improve the quality of life for menopausal women. Administration should be at the lowest possible dosage and for the shortest duration required to provide symptom relief.
Route of HT administration also should be considered. Non-oral formulations typically administer lower doses than do oral products and provide dosing over extended periods of time, avoiding the peak-to-trough fluctuations associated with daily oral administration.
Language eng Pub Type(s) Journal Article
PubMed ID 15251108
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HERBAL REMEDIES ... AREN'T!

Women reverting to HRT?
04/10/2004 - Women are going back onto hormone replacement therapy because it is significantly more effective against menopausal symptoms than herbal remedies, an organisation of American gynecologists said on Friday.

The American College of Obstetricians and Gynecologists (ACOG) says that about a quarter of US women who stopped taking hormone replacement therapy after it was found to raise the risk of heart disease and some cancers have gone back on it. New guidelines on HRT drawn up for the association by a task force of 21 national experts also concluded that herbal supplements do not relieve hot flushes.
"Treatment with wild yam extract, black cohosh, or dietary phytoestrogen supplements derived from the isoflavone red clover has no significant effects on vasomotor symptoms," the guidelines said.
“A very few limited studies have suggested that soy helps with vasomotor symptoms in the short-term (less than two years), while other studies show little difference between soy beverages or extracts and placebos,” they continued.
However the number three soy isoflavone maker Solbar says it has seen no decline in demand for its products. The Israeli firm reported last year that its sales were up 30 per cent on the back of this research and marketing manager Gary Brenner says sales will be at a similar level this year.
“There has been no drop in sales or in enquiries from customers looking at this application,” he told NutraIngredients.com.
But the firm's scientific adviser Tova Arditi noted that it is a false assumption to expect herbal remedies to achieve the same benefit as HRT.
"Soy isoflavones are believed to reduce frequency of hot flushes but in severe cases, they don't really help," she told us. "It is wrong to view these supplements as an alternative to HRT. There have been huge expectations from women who take them but the small effect is evident only after a period of time and many women are looking for a quick remedy."
The major Women’s Health Initiative study released in 2002 found that hormone therapy could actually increase the risk of certain conditions it was previously believed to prevent, including heart attack. A further study on combination hormone therapy also found that it increased the risk of death from breast cancer.
Following the findings, sales of soy isoflavones have surged. However the US guidelines suggest that further research to prove the efficacy of herbal remedies for hot flushes may be needed to support their longevity on the marketplace.
"Approximately 65 per cent of women on hormone therapy stopped therapy after the (Women's Health Initiative)," said Dr Isaac Schiff, chair of the ACOG Task Force on Hormone Therapy. "Two years later, reports suggest that about one in four women who stopped (the therapy) went back on it because it still offers the best relief for menopausal symptoms.”
He added that this trend could be seen as normal. "So we're moving back to an appropriate balance - accepting that (hormone therapy) has risks, but recognizing that it can be appropriate for conditions like hot flushes so long as women are informed about the risks and weigh their decision with their doctor.”
The report calls for more research into whether hormone replacement therapy may be safer for younger women, as the average age of those studied in the Women’s Health Initiative trial was 63.
It also warns that since soy and dietary isoflavones appear to affect oestrogen receptors, they may not be safe for women with oestrogen-dependent cancers such as breast cancer.
A conference in Bruges this week will focus on all of the latest research on soy and health, including its benefits for menopausal women.
_____________________________________________



"For those who still subscribe to the menopause-is-natural philosophy this question is posed, 'why does the brain naturally have sex hormone receptors if they are not necessary?'"
-----Dr. R.Greene, UC-Davis, Medical School


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SOY shows no evidence of efficacy in treatment of menopausal symptoms

Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women
A Randomized Controlled Trial
Sanne Kreijkamp-Kaspers, MD, PhD; Linda Kok, MD, PhD; Diederick E. Grobbee, MD, PhD; Edward H. F. de Haan, PhD; André Aleman, PhD; Johanna W. Lampe, PhD, RD; Yvonne T. van der Schouw, PhD
JAMA. 2004;292:65-74.

Context
Postmenopausal estrogen therapy has been posited to have some beneficial effects on aging processes, but its use has risks. Isoflavones, estrogenlike compounds naturally occurring in plant foods, might confer positive effects with fewer adverse effects.
Objective
To investigate whether soy protein with isoflavones improves cognitive function, bone mineral density, and plasma lipids in postmenopausal women.
Design, Setting, and Participants
Double-blind, randomized, placebo-controlled trial of 202 healthy postmenopausal women aged 60 to 75 years, recruited from a population-based sample in the Netherlands, conducted between April 2000 and September 2001.
Intervention
Participants were randomly assigned to receive 25.6 g of soy protein containing 99 mg of isoflavones (52 mg genistein, 41 mg daidzein, and 6 mg glycetein or total milk protein as a powder on a daily basis for 12 months.
Main Outcome Measures
Cognitive function was assessed using the following instruments: dementia, Mini-Mental State Examination; memory, Rey Auditory Verbal Learning Test, immediate recall, delayed recall, and recognition, the Digit Span forward and reversed, and the Doors test; complex attention tasks, Digit Symbol Substitution and Trailmaking, A1, A2, and B; and verbal skills, Verbal Fluency A and N, animals and occupations, and the Boston Naming Task. Bone mineral density of the hip and lumbar spine was assessed using dual-energy x-ray absorptiometry scanning. Lipid assessment included lipoprotein(a), total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides.
Results
A total of 175 women completed the baseline and at least 1 postintervention analysis and were included in the modified intent-to-treat analysis. Adherence was good (median plasma genistein levels, 17.2 and 615.1 nmol/L for placebo and soy group, respectively). Cognitive function, bone mineral density, or plasma lipids did not differ significantly between the groups after a year.
Conclusion
This double-blind randomized trial does not support the hypothesis that the use of soy protein supplement containing isoflavones improves cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women when started at the age of 60 years or later.
Author Affiliations: The Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (Drs Kreijkamp-Kaspers, Kok, Grobbee, and van der Schouw), Division of Psychonomics, Helmholz Research Institute, Utrecht University (Dr de Haan), and Department of Neuroscience, University Medical Center Utrecht (Dr Aleman), Utrecht, the Netherlands; and Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr Lampe).
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'Bioidentical’ Hormones

Introduction
Women and health professionals are constantly being given information about 'hormone imbalance' and how to deal with menopause 'naturally'.
Many women are turning away from approved pharmaceutical postmenopausal hormone therapy (HT) currently available as a tablet, patch, gel, intranasal spray and/or implant and are using instead hormonal preparations, made up as lozenges or troches. These hormonal preparations are sucked in the cheek and are absorbed through the lining of the cheek.
The makers of these lozenges have named these 'bio-identical' hormones.


(NOTE: This article is published in Australia - in the United States compounding pharmacists use the catch phrase "bioidentical" to promote the hormones that they add to their creams and gels, hormones that are no different or more natural than hormones supplied by gyns.)

This term is misleading as the hormones used are made in a factory and are the same hormones used in prescription hormone therapy.

Compounded Preparations

Compounded hormone preparations require a doctor's prescription and are made up by pharmacists who may call themselves compounding pharmacists. There are no further training requirements for a compounding pharmacist who may have exactly the same training as your usual pharmacist.
The pharmacists making the lozenges are not required to adhere to any of the codes of conduct of the professional pharmaceutical body, Medicines Australia, as these codes apply only to pharmaceutical companies. This means that there is no formal quality control or quality assurance of what the pharmacists formulate. There has also been no formal research into dosage used, so the dose prescribed is the responsibility of the prescribing doctor.
Hormone formulations made in a pharmacy are expensive and are no more 'bio-identical' than oestrogen therapy available as government approved oral and non-oral hormone therapies (such as patches, implants and gels). The government department responsible for the approval of medicines is the Therapeutic Goods Administration (TGA).

About Oestrogen

The oestrogen present in many oral and all non-oral hormone therapies is exactly the oestrogen that occurs naturally in the human body - oestradiol. It is therefore misleading to suggest that these troches and lozenges have advantages over TGA approved pharmaceutical therapies.
It has also been suggested that these hormone preparations made in a pharmacy may contain a unique mix of the three major classes of oestrogen in the female body: oestradiol, oestrone and oestriol. While sounding important, there is no evidence to support that giving oestrogen in this way is better than giving oestradiol. Our bodies automatically make the other two oestrogens from oestradiol as required anyway.
Oestrogen mixes are sometimes combined with testosterone or DHEA (a hormone made by the adrenal glands) or each prescribed alone. Of note, DHEA is not approved for use in Australia.

Safety and Efficacy

The hormone preparations made in pharmacy have no evidence that the doses recommended are safe or even effective. Currently there is no published data for these products, yet some of the compounding pharmacies have issued documents recommending various doses and equivalent doses to TGA-approved oestrogen therapies.
For the oestrogen doses commonly recommended, there have been no studies conducted to show what is the lowest dose needed to treat symptoms. Similarly no data exists to show what dose of progestin (progesterone) is necessary to protect the lining of the uterus (endometrium). No evidence is available from any published study to show that transdermal (skin) or buccally (mouth) absorbed progesterone will protect the lining of the uterus from conditions such as uterine cancer.
Summary

Prescription of so-called 'bio-identical' hormones cannot be recommended until there is sound pharmacokinetic, efficacy and safety data.

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WHY TESTING FOR HORMONE LEVELS IS INEFFECTIVE

Hormones and neurotransmitter levels are in a constant state of flux, along with each individual's unique chemical makeup, and the amount of usable hormones at any given time simply cannot be quantified.

These tests exist for two reasons, IMO:
1) Profit
2) Protection against litigation for practitioners, in the event a patient on HRT develops cancer and decides to sue.

The psychiatric community knows better than to try measuring seratonin levels as an aid in prescribing anti-depressants. There are just too many influencing factors involved. They use their patients' mental health as a barometer, since this is the only accurate measuring tool.


1) Exerpt from: Official Recommendations of ISSAM (The International Society for the Study of the Aging Male) http://www.issam.ch/ The accepted value for testosterone in andropause is defined to be 2 standard deviations below normal values for young men (317 ng/dLtotal testosterone, 7.34 ng/dL freetestosterone,15and 86–231 ng/dL forbioavailable testosterone). The normal ranges and methods vary widely, and physicians are urged to consult with their local laboratories for the applicable values in their clinical practice environment. The actual value in an individual does not tell the whole story, for the following reasons: the history of what has been a normal continued testosterone level for a given patient in previous years is almost always unknown; the sensitivity of different target organs (brain, muscle, bone, etc) varies; there are other, unmeasured hormones contributing to the condition (testosterone is a major factor but not the only one); and there may be unrecognized molecules (endocrinedisruptors) blocking the normal action of testosterone

Factors Influencing Variability in Presentation of Andropause & Attendant Testosterone Values

Normal ranges vary widely
History of individual normal testosterone is unknown
Sensitivity of target organs (brain, muscle, bone, etc) varies
Other unmeasured hormones contribute
Potential, unrecognized endocrine disruptors
This variability in symptoms presents difficulties in giving a simple clinical picture


Despite these findings ISSAM's Official Recommendations are to do hormone tests! Go figure - they largely discredit the tests, then recommend using them!

I first became aware of the gross inaccuracy of panel hormone tests 10 years ago when my dog developed chronic skin lesions, brittle falling hair, lethargy and weight loss. His thyroid panel test (same test as used in human medicine) came back in the normal range, but my astute vet said "no wait, these tests can be VERY ambiguous. Let's try him on thyroid hormone replacement first." The poor creature by now looked like a concentration camp victim, but on thyroxine recovered permanently from his skin problems, grew a new shiney coat, gained weight, and was infused with energy.

I have also read that a quite large percentage of people, esp women, go undiagnosed or are wrongly diagnosed, but suffer from hypothyroidism.

This from a last year veterinary student:
Thyroid question
Our dermatology professor calls this "the blonde frizzies" :-) A couple of her dogs tested in the normal range for thyroid BUT she put them on thyroid supplementation and their skins and coats improved (they had some hair loss and skin problems). . . RESPONSE TO TREATMENT *IS* a way to diagnose hypothyroidism if the blood tests are not conclusive. I know someone else . . . Her dogs have a problem but since their *bloodwork* is normal, she says it must be OK . .. that's probably another reason that vets are a bit reluctant to go through the testing . . . the results can be extremely variable and influenced by so many other factors that the test might not give you anything you can "hang your hat on."


A more on-topic example - my own bi-weekly blood tests during my fight for a prescription for t-gel. The results flew in the face of all reason. When I was amply estrogenated, the tests claimed I was low in estrogen but high in freeT (yeah right! I had yet to gain access to testosterone and menopause with oral hrt had depleted my supply.) I was taking the same amount of E and P throughout, but over the months the results would proclaim one high and the other deficient. Then the next test would claim the reverse. Finally a test randomly supplied the result I was waiting for - low in free T. I got my T-gel and left. I will *never* put myself in a position of being held hostage by these bogus tests again!

That was over a year ago. I went back last month for an annual exam and pap smear, and to hand the doctor a written dissertation
(The contents of PAGE 1 of this web site, in fact!)
on exactly what is wrong with HRT research to date and the current protocol that the research community has handed down to practitioners for prescribing HRT. It listed sources, as well as information about the new topical HRT products currently undergoing final testing, which include the androgen group.

Her 3 most relevant comments were that
1) My vaginal tissues resemble those of a 20 yr old
2) She planned to photocopy and share the document I handed her with her associates
3) Research in Europe (where most of the new topicals were conceived and tested) is far more advanced than here in the states.

Some blood tests are good diagnostic tools, tests for cancer, diabetes, mineral deficiences etc, but it is my opinion that hormonal levels simply cannot be measured in this way with any accuracy. I would at least suggest that if you have hormone test results in front of you saying one thing, and your body is telling you something entirely different, trust the latter!


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to Page 1 Inadequacies of Current Methods of HRT
http://infowomanhrt.tripod.com/index.htm

to Page 2 The Current GYN Protocol For HRT
How To Opt For Safer, More Effective Treatment
http://infowomanhrt.tripod.com/HRT.html

Page 3 Medical References
http://infowomanhrt.tripod.com/HRTreferences.html


Any questions, suggestions, complaints, or other input...
email me at: rsummers@emailaccount.com