HRT Safety

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:
or go directly to:
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


Hormone researchers revolt

Criticizing recent negative studies of replacement therapy, some scientists are holding out for more data

By Tabitha M Powledge

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
North American Menopause Society
Kronos Longevity Research Institute
S. Mitchell Harman
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

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.

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.

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).


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.....