Mirror, Mirror on the wall:Which is the safest of them all??
This article is a discussion of a complex subject that does not lend itself to a fifteen minute office visit. It is not designed to give the reader personal medical advice
The Harvard Nurses Study had its start in 1976; it examined the effect of hormone replacement therapy (HRT) in 60.000 nurses. It reported in 1985 that there was a 37% reduction in the rate of heart related events in the subjects who used HRT.
The adherents of HRT treatment were also further convinced by a pronouncement several years earlier by Dr Robert Wilson the author of Feminine Forever where he proclaimed "menopause is a hormone deficiency and totally preventable".
Drs. E. L. Severinghaus and J. Evans in 1929 were the first physicians to attempt to treat the symptoms of menopause. Their treatment was a derivative from the amniotic fluid of cattle. A German , Bernhard Zondek found that urine from pregnant mares contained water-soluble estrogens. Emmenin a product of the urine of pregnant women in 1933 became the first estrogen replacement product marketed in the United States.
Work soon started on producing a less expensive version from pregnant mare’s urine.
Diethylstilbestrol (DES) was marketed in 1942 as a more potent form of estrogen than Emmenin. By 1948, it was advertised as having therapeutic value for the prevention of pregnancy complications, such as toxemia, low birth weight, and early pregnancy loss. Approximately two million women in those years were exposed to DES.
The text in major medical journals in the 1950s describing DES read, “Recommended for routine prophylaxis in ALL pregnancies . . . Bigger and stronger babies . . . No gastric or other side effects.” It wasn’t until 1953 that a controlled trial using DES showed it had no clinical benefit in preventing complications during pregnancy.
By 1942 the higher-dose Premarin—1.25milligrams a product of mares urine—was introduced. Six years later, lower doses of Premarin—0.625 milligram and 0.3 milligram—were made available.
Ayerst Laboratories in the 1950s funded a massive campaign to educate doctors on menopause, menopausal symptoms, and the consequences of estrogen loss—and on the use of its product Premarin to treat menopausal symptoms.
By the 1960s the use of hormone (estrogen) replacement therapy (ERT) included 12 percent of all postmenopausal women.
Premarin sales grew 170 percent between 1963 and 1966, making it the most dispensed drug in America.
The spurt in HRT use was given a boost in particular when Dr. Robert A. Wilson published his article “No More Menopause” in Newsweek magazine in January 1964.
Ronald the son of Dr. Wilson in 2002 revealed to the New York Times that his father’s research foundation, book, and speaking tours were funded by Wyeth-Ayerst, the makers of Premarin. The father had earlier to himself as a “gallant knight” on a mission to help women through their “loss of womanhood “even suggesting Premarin would prevent their husbands from having extramarital affairs. His opinion: “In truth, an extramarital affair may not, in the literal sense of the term, involve any infidelity at all. For a man may loyally maintain a deep love for his wife and yet feel the need for a kind of thrill that a wife with her aura of comfortable domesticity cannot give.” There was a hint that the hot flashes of menopause would be replaced the fires of a new sexuality.
Dr. Susan Love a pioneer in the treatment of breast cancer at UCLA has been a critic of the menopause industry stating “If estrogen deficiency’s a disease, all men have it!”
There was a decrease in the popularity of HRT in the 1970s when it became apparent that there was an increase in the incidence of uterine cancer when HRT involved estrogens alone. This waning in popularity was soon overcome by a finding that this effect could be overcome if the estrogen were combined with another hormone progestin.This combination rapidly became one of the most prescribed therapies for American women.
The benefits of hormone therapy in preventing some of the accompanying symptoms of menopause such as the vasomotor symptoms (hot flashes) and vaginal dryness have never been disputed.
The American Heart Association, the American College of Physicians and the American College of Obstetricians and Gynecologists had all concluded by the mid 1990s that H.R.T. could be recommended to older women as a means of warding off heart disease and osteoporosis. By 2001, 15 million women were filling H.R.T. prescriptions annually; perhaps 5 million were older women, taking the drug with the sole belief that it would allow them to lead a longer and
healthier life.
Despite these endorsements there were physicians who remained unconvinced of the ability of HRT to prevent heart disease and were yet concerned about their ability to increase the incidence of breast cancer and blood clots. Others were convinced of the efficacy of this treatment based on earlier reports from the Harvard Nurse Study and other anecdotal evidence and believed that further studies were not only unnecessary but may be morally inappropriate.
This uncertainty and Wyeth’s need to expand the indications for use of its prize products, to indications beyond hot flashes drove studies to evaluate these hypotheses The National Institutes of Health funded a study the Womens Health Initiative (WHI) and a parallel study was funded by Wyeth, the Heart and Estrogen/Progesterone Study (HERS).
The results of the HERS study when first available were worrisome, though HRT did in fact reduce the bad cholesterol (LDL) and increase the good cholesterol (HDL) this study where nearly 2700 women (average age 67)with heart disease were randomly assigned to receive HRT or a placebo (inactive pill) HRT did not reduce the incidence of heart disease. In women treated with HRT an increased incidence of blood clots in veins and the lungs was also noted.
It was postulated that the adverse effects of HRT wee an early treatment result, but if treatment was continued the positive effect on blood fats would negate the earlier effects and the net effect would be positive.
The reports of this study though widely cited were generally ignored, though a recommendation was made that women with heart disease not be given HRT.
But the perfect storm was brewing. Women in the HERS study receiving HRT for an additional three years were reported to have no reduction in heart disease but had a persisting trend of increasing rates of breast cancer.
The results of the WHI became available at the same time as the extended results of the HERS study.
The WHI though similar to HERS tested two forms of HRT, estrogen alone and estrogen combined with progesterone (believed to protect against uterine cancer) comparing both with placebo.
The WHI was different from HERS in two features, the women studied had no evidence of heart disease, this study also involved more than 16,000 women. This number believed by statisticians to be large enough to detect small differences in outcomes between the treatments.
The results supported those of the earlier published HERS study.
When estrogen was combined with progesterone it did reduce the incidence of uterine cancer but disturbing increases in coronary heart disease, blood clots to the lung, stroke and breast cancer were recognized. These negative effects outweighed diminished incidences of colon cancer and osteoporosis also observed. An increase in dementias was noted in women over 65 treated with hormones.
Two years later a subgroup of women with prior hysterectomies who received estrogen alone were evaluated. The incidence of strokes, dementias were yet noted in alarming numbers, the occurrence of coronary heart disease and breast cancer decreased when compared with the combination hormone treatment group the decrease had no statistical significance.
In real life how should a woman facing the dilemma of HRT consider her options?
Beyond the age of sixty the options are clear, HRT either estrogen or estrogen combined with progesterone are associated with an increase in the incidence of heart disease, breast cancer, blood clots and dementias.
The combination therapy has greater hazards than the estrogen alone.
The HERS and the WHI have one significant flaw, the women studied were above the age of 60, data evaluating women between the ages of 50 and 59 noted more favorable effects against coronary heart disease than in older women though the risk of stroke, blood clot, uterine and breast cancer remain unchanged.
One must realize that the results of these studies have often been trivialized, detractors of these studies have flawed mathematical reasoning they argue
Example:
If a treatment increased the incidence of breast cancer by 5 women in every 10,000 who received it the figure may seem inconsequential
But if this treatment is given to 2 million women it would result in 1000 breast cancers that could otherwise have been avoided.
If an automobile defect was known to result in a 1000 extra deaths each year would you buy one for its GPS feature?
Relevant practical considerations:
1) The absolute magnitudes of the risks are small but sufficiently concerning for a treatment given to women with NO preexisting disease.
The Food and Drug Administration has a special prescribing warning advising that these drugs
2) HRT administration is yet appropriate for bothersome symptoms of early menopause but should be used in the smallest dose that relieves symptoms and their need periodically assessed.
The acceptance of this recommendation is already apparent. It has resulted in a decrease in prescription of these agents and a parallel decrease in the incidence of breast cancer
3) Heart disease and breast cancer are more lethal than hot flashes, the risks for the former should be evaluated and if present high blood pressure, diabetes and elevated levels of cholesterol treated with drugs specifically targeted for these conditions.
4) Medications that alleviate hot flashes and vaginal dryness with no increased risk should be used and are available.
5) Transdermal (skin patch) preparations of estradiol have been shown to reduce hot flashes and progression of osteoporosis with a reduced risk for breast cancers when compared with hormones taken by mouth. Compounded hormones sold by pharmacies that are advertised as being "natural" have a capricious absorption through the skin and may possess all the all the harmful effects of those taken by mouth while not offering any advantages.
6) One size does not fit all and each menopausal subject must be evaluated, the use of hormones if needed combined with other proven necessary health interventions
A link to a breast cancer assessment tool is provided for a personal risk analysis
http://www.cancer.gov/bcrisktool/Default.aspx
Finally why was the Harvard Nurses Study flawed? Retrospective analysis noted that only those without significant health problems and model lifestyles took the hormones. Lifestyles not hormones were the answer.
This conclusion has a message for all of us.
