PremproCounsel Legal Team Articles and Publications
The rise and fall of hormone therapy
What began decades ago with promises of eternal youth for women ended last
year with troubling research findings that hormone therapy drugs cause
cancer, heart attacks, and other serious side effects. New litigation seeks
compensation for injured women.
On July 9, 2002, the National Institutes of Health sent shock waves
through the medical and scientific communities when it released a study on
the benefits and risks of so-called combination hormone replacement therapy
(HRT). After decades of promotional claims that long-term HRT use could
provide cardiovascular benefits to menopausal women and make them look and
feel “feminine forever,” the drugs’ mystique was shattered: The study
revealed that long-term HRT use increased the risk of cardiovascular
disease, invasive breast cancer, stroke, heart attack, pulmonary embolism,
and blood clots.1 Almost simultaneously, a separate study by the National
Cancer Institute reported that women who take estrogen alone—rather than in
combination with other hormones—over a long period are at significantly
increased risk of developing ovarian cancer.2
Immediately, sales of hormone therapy drugs plummeted,3 as doctors and
patients alike learned for the first time that long-held notions of the
drugs’ safety and efficacy were misguided. How could millions of women and
their doctors have believed for decades that long-term hormone therapy was a
prudent course of treatment, without being advised of the risks by the
companies that made the drugs? The answer lies in a remarkable marketing
campaign orchestrated by the manufacturers that convinced doctors and
patients that menopause is a medical disorder that must be treated with
prescription medication. As a result, countless women have suffered adverse
health effects, and today a new mass tort litigation is emerging.
HRT includes the use of conjugated (chemically modified) estrogens and
progesterone (or, more precisely, its synthetic form, progestin), and
sometimes androgen, a male hormone. The most prescribed HRT drug available
is Wyeth Laboratories’ Prempro. Estrogen used alone is known as ERT, or
estrogen replacement therapy. The most prescribed drug in this category is
Wyeth’s Premarin. In all, about 10 companies manufacture the more than two
dozen hormone therapy products currently available.
Combination HRT is generally prescribed for women who have made the natural
transition to menopause through aging; women who have experienced menopause
through surgical removal of their uterus generally use ERT. Despite the
terminology commonly used to describe them, hormone “replacement” drugs do
not actually replace the natural hormones produced in a woman’s body that
are lost during menopause. These synthetic alternatives are merely
substitutes, not replacements, for natural hormones.
During menopause, a woman’s estrogen level drops sharply, resulting in a
lower level of calcium in the skeleton. As a result, the risk of
osteoporosis and spinal, hip, and other fractures goes up. The rates of
heart disease, stroke, and cancer also increase in menopausal women.4
Menopause has been described in scientific literature since the late 1800s.
By the start of the 20th century, researchers had begun seeking an aid that
would help women maintain their youth, health, sexuality, and vitality.
Increasing awareness of the physical effects of menopause made a drug to
“cure” it a blockbuster waiting to happen. In 1942, Ayerst Laboratories
(which merged with Wyeth in the 1980s), received FDA approval to patent and
market that blockbuster.
The marketing blitz begins
Ayerst’s product was Premarin, a mix of estrogens extracted from the urine
of pregnant mares. Almost immediately, researchers began investigating the
effects of estrogen therapy on the women who used it. In 1952, an early
study showed that hormone treatment may help enhance verbal memory in
elderly women.5 In 1959, an article in the Journal of the American Medical
Association (JAMA) reported that a 25-year study of 292 women showed that
estrogen protects bones and relieves menopausal symptoms. The authors also
claimed that “fear that breast and cervical cancer may result from this
therapy appears to be unfounded.”6
In 1962, Robert Wilson, a Brooklyn gynecologist, went a step further,
claiming in a JAMA article that taking estrogen during menopause reduces the
risk of breast cancer and cancers of the reproductive organs.7 He followed
the article with his 1966 best-seller, Feminine Forever, in which he
recommended estrogen as the “cure” for “the tragedy of menopause.”8
Aside from keeping a woman sexually attractive and potent,” Wilson wrote,
“estrogen preserves the strength of her bones, the glow of her skin, the
gloss of her hair. . . . Estrogen makes women adaptable, even-tempered, and
generally easy to live with.”9 He again asserted that estrogen prevents
breast and other cancers, such as endometrial cancer.10
Soon after Wilson’s book was published, Ayerst sales representatives began
distributing it to doctors’ offices throughout the country. Estrogen sales
quadrupled. By the mid-1970s, more than 30 million prescriptions for
Premarin were being written every year, making it the fifth most frequently
prescribed drug in the United States.11
But by that time, it also became evident that women using estrogen were
showing a significant increase in the incidence of endometrial cancer.12
Soon doctors prescribed estrogen only for women who had undergone complete
hysterectomies and were therefore not at risk for endometrial cancer. In
1976, the first study showing a link between estrogen therapy and breast
cancer appeared in the New England Journal of Medicine.13
Estrogen sales dropped dramatically, and the pharmaceutical industry began
looking for ways to keep women who had undergone hysterectomies on the
In 1980, an article in the journal Obstetrics and Gynecology reported that
adding progestin to estrogen led to a decline in endometrial cancer.14
Doctors began prescribing Wyeth-Ayerst’s progestin product, Provera, along
with Premarin to protect a patient’s uterus. This development marked the
advent of the combination therapy known as HRT.
In 1985, Wyeth developed a new spin on the marketing of ERT and HRT,
claiming that hormone therapy drugs helped prevent bone loss. The company
hired a public relations firm, which conducted research showing that 77
percent of women surveyed had never heard of osteoporosis. Wyeth launched a
campaign to educate women about the disease and promote its hormone drugs to
treat it. The campaign created support for a National Osteoporosis Week and,
eventually, a National Osteoporosis Foundation (to which the company
The golden goose for the pharmaceutical industry, however, would be a drug
to prevent cardiovascular disease, the number-one killer of American women.
Wyeth sought to claim that HRT could do just that. If this claim could be
substantiated, the therapy could be promoted as a recommended treatment for
Wyeth and other HRT drug makers touted a 1985 study of more than 32,000
postmenopausal nurses as coming to that very conclusion (although not
everyone agreed with the companies’ claim).16 Other research followed,
championing the use of HRT to prevent heart disease and bone loss without
the risk of cancer, stroke, or blood clots.17 From 1990 to 1995—no doubt
largely because of these impressive-sounding study results—Premarin was the
most frequently dispensed prescription drug in the United States.18
With Premarin’s patent nearly expired, the company began to develop a
product that would combine estrogen and progestin. In 1995, Wyeth introduced
Prempro, the first FDA-approved estrogen-plus-progestin pill. Soon, Wyeth
began funding a four-year study it hoped would show that HRT prevents heart
disease in high-risk women and in turn would lead the FDA to approve the
But in 1998, Wyeth’s researchers reported that HRT did not reduce the rate
of coronary heart disease in high-risk women, and that it increased serious
blood clots and gallbladder disease.19 Wyeth’s hopes were now pinned to an
important study then being conducted by the Women’s Health Initiative (WHI).
The honeymoon ends
The WHI is a branch of the National Institutes of Health focused on defining
the risks and benefits of strategies designed to reduce the incidence of
heart disease, breast and colorectal cancer, and fractures in postmenopausal
women. Its estrogen-plus-progestin trial involved 16,608 women ranging from
50 to 79 years old, each with an intact uterus. Some received Wyeth’s
Prempro, others a placebo. Important objectives of the trial were to examine
the effect of HRT on the incidence of heart disease and hÐp fractures and to
note any associated change in risk for breast and colon cancer. The study
did not initially address the short-term risks and benefits of hormones for
the treatment of menopausal symptoms.
In 2000 and again in 2001, WHI investigators complied with a recommendation
from the study’s Data and Safety Monitoring Board (DSMB) to inform
participants of a small increase in heart attacks, strokes, and blood clots
in women taking Prempro. The DSMB, an independent advisory committee charged
with reviewing results and ensuring participant safety, found that the
actual number of women experiencing any one of these events was small and,
to date, not statistically significant. Therefore, the board recommended
continuing the trial.
But on May 31, 2002, the data revealed for the first time that the number of
invasive breast-cancer cases in the Prempro group had crossed the threshold
of acceptable risk, and the board changed its conclusion and recommended
that the clinical trial be stopped. When all the data were tallied, the
results, published in JAMA, showed that women taking Prempro experienced a
41 percent increase in strokes, a 29 percent increase in heart attacks, a 22
percent increase in cardiovascular disease, and a 26 percent increase in
breast cancer. Their incidence of blood clots doubled.20
There were some positive findings: The Prempro group had a 37 percent
reduction in colorectal cancer, a 33 percent reduction in hip and vertebral
fractures, and a 24 percent reduction in total fractures. The study found no
difference in mortality (from all causes) between the two groups.21
The researchers concluded that the “overall health risks exceeded benefits”
of HRT22 and that the results “indicate that the combined postmenopausal
hormones . . . should not be initiated or continued for primary prevention
of [heart disease].”23
The same issue of JAMA also reported the results of a National Cancer
Institute (NCI) study that investigated the risk of long-term use of
estrogen-only therapy. Involving more than 44,000 postmenopausal women whose
health had been tracked for nearly 20 years, it found that long-term ERT use
significantly increased the risk of ovarian cancer.24 A parallel WHI study
on estrogen is ongoing and scheduled to end in March 2005.25
Redemption for Wyeth and other makers of HRT drugs seemed possible when, in
November 2002, JAMA published a study suggesting that Prempro might help
prevent Alzheimer’s disease.26 Although the study was not conclusive and did
not recommend HRT as a preventative treatment, the researchers said further
testing was warranted. But three months later, Wyeth reported that initial
data from an arm of the WHI study showed that Prempro may worsen memory and
understanding of surroundings and events among women 65 and older.27
But what about quality of life? Despite HRT’s risks, doesn’t it diminish the
unpleasant symptoms of menopause and enhance women’s overall sense of
well-being during this time of life? The New England Journal of Medicine
offered more bad news for HRT drug makers in its May 28, 2003, issue: New
findings from the WHI study group suggested that the drugs do not achieve
even those results. The women who took Prempro did not report improved
sleep, greater vitality, more sexual satisfaction, or less depression.28
T he author of an accompanying commentary wrote that the message from the
research is clear: Women who are not experiencing debilitating menopausal
symptoms should not take HRT, and those who do should take the lowest
possible dose for the shortest possible time.29
The fallout from this growing body of research continues. In December 2002,
the National Institute of Environmental Health Sciences, a branch of the
U.S. Department of Health and Human Services, decided to place estrogen on
the government’s roster of known human carcinogens.30
A second development soon followed. On January 6, 2003, Wyeth wrote to
health care professionals around the country, explaining that it would adopt
new labeling for Premarin and Prempro in light of the research findings. The
changes include boxed warnings stating that “estrogens and
estrogen-plus-progestin therapies should not be used for prevention of
cardiovascular disease” and that the drugs “should be prescribed for the
shortest duration consistent with treatment goals.” Other manufacturers,
such as Pharmacia, followed with their own letters announcing labeling
changes that would include similar warnings.
In recent months, more bad news has come to light:
• In May, JAMA reported that hormone therapy nearly doubles the risk of
Alzheimer’s disease and other types of dementia in women who began treatment
at age 65 or older.31 The study focused only on the effect of combination
HRT; another part of the WHI study addressing the effect of estrogen alone
on brain cells, still in progress, is due in 2005. Wyeth plans to add a new
warning to its label to reflect the results of this research.32
• In June, another study published in JAMA reported that even short-term use
of combination HRT increases the risk of breast cancer and may make the
disease harder to detect. After an in-depth review of statistics from the
WHI study, researchers found that abnormal mammograms and increased breast
cancer rates occur in women who have used the therapy for as little as one
to three years.33 Even though most of the patients with abnormal mammograms
did not have cancer, the researchers noted that patients bore emotional,
financial, and psychological costs that stem from facing a potentially
serious disease. In light of these findings, manufacturers must now decide
whether they can continue to recommend even the short-term use of HRT to
alleviate the effects of menopause.
The litigation gears up
Class actions filed over the past year against Wyeth seek damages for
injuries and death among women who took Prempro. Although no cases alleging
adverse health effects from estrogen-only therapy had yet been filed at
press time, Premarin litigation is likely to begin soon.
In addition to compensating women harmed by combination HRT, goals of the
litigation include informing the public that users are at increased risk of
injury, establishing a medical-monitoring fund so that users can be tested
and treated for the drug’s adverse effects, and reimbursing users for the
cost of the product.
The plaintiffs’ negligence claims include that Wyeth failed to
• use due care in designing and manufacturing Prempro to prevent health
• conduct adequate clinical testing and postmarketing surveillance to
determine the drug’s safety
provide proper warnings to consumers and health care providers about
possible adverse side effects, including strokes, heart attacks, blood
clots, cardiovascular disease, and breast cancer, as well as the need for
medical monitoring to ensure early discovery of these effects.
A major focus in the litigation will be the products’ written warnings. The
warning labels on Prempro and Premarin have been changed twice—in August and
December 2002—reflecting the results of the WHI and NCI studies. Case
investigation should concentrate on clients who used the drugs before August
2002, when the warnings were arguably inadequate.
For example, the Prempro warning label explained the risk of breast cancer
associated with conjugated estrogens (the Premarin component of Prempro),
but added that “the effect of added progestins on the risk of breast cancer
is unknown. . . . The overall incidence of breast cancer does not exceed
that expected in the general population.” The Premarin warning label made no
mention of ovarian cancer. Clearly, in light of the WHI and NCI studies,
these warnings are insufficient.
As for cardiovascular disease, the Prempro warning said that the risks “have
not been adequately studied. . . . [P]reliminary observations suggest that
there is a small increase in the number of heart attacks, stroke, and [blood
clots] in women without established [heart disease] on estrogen alone or
estrogen plus progestin. . . .”
As in all mass tort cases, a key question in the hormone therapy litigation
is whether there is enough epidemiological evidence to establish causation.
Certainly, the WHI and NCI studies provide compelling support for
Class actions have been filed in Arkansas, California, Illinois, Louisiana,
and Pennsylvania.34 Individual cases have been filed in several other
states. In March, the Judicial Panel for Multidistrict Litigation granted a
petition to consolidate the federal actions in the Eastern District of
Arkansas before Judge William Wilson Jr.35 A hearing on class certification
is scheduled for June 2004.
Other individual cases are expected to be filed in state and federal courts
around the country. Because Wyeth has divisions in New Jersey and
Pennsylvania, it is likely that much of the state litigation will take place
in those jurisdictions.
The future medical uses of hormone therapy remain uncertain. Clearly, the
marketing blitz is over, and drug makers have begun to concede not only the
risks of the drugs, but also their limited effectiveness in achieving their
original purpose: to alleviate the symptoms of menopause. The courts remain
the next forum for the continuing investigation into the adverse effects of
combination HRT and estrogen-only therapy—and the responsibility of the
manufacturers for the harm the drugs have caused.
1. Writing Group for the Women’s Health Initiative Investigators, Risks and
Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women, 288
JAMA 321 (2002).
2. James V. Lacey Jr. et al., Menopausal Hormone Replacement Therapy and
Risk of Ovarian Cancer, 288 JAMA 334 (2002).
3. IMS Health reports that in 2001, sales of Wyeth Laboratories’ Premarin
(estrogen only) reached $1.3 billion, and sales of the company’s Prempro
(estrogen plus progestin) were at $733 million. By the end of 2002, Premarin
sales dropped to $957 million, and Prempro sales were down to $489 million.
4. Bernardine Healy, The Mysteries of Menopause, U.S. NEWS & WORLD REP.,
Nov. 18, 2002, at 39, 41.
5. B.M. Caldwell & R.I. Watson, An Evaluation of Psychologic Effects of Sex
Hormone Administration in Aged Women: Results of Therapy After Six Months, 7
J. GERONTOLOGY 228 (1952).
6. Stanley Wallach & Philip H. Henneman, Prolonged Estrogen Therapy in
Postmenopausal Women, 171 JAMA 1637 (1959).
7. Robert A. Wilson, The Roles of Estrogen and Progesterone in Breast and
Genital Cancer, 182 JAMA 327 (1962).
8. ROBERT A. WILSON, FEMININE FOREVER (1966).
11. Amanda Spake, The Menopausal Marketplace, U.S. NEWS & WORLD REP., Nov.
18, 2002, at 42, 45.
12. Id. at 46.
13. Robert Hoover et al., Menopausal Estrogens and Breast Cancer, 295 NEW
ENG. J. MED. 401 (1976).
14. R. Don Gambrell Jr. et al., Ose of the Progestrogen Challenge Test to
Reduce the Risk of Endometrial Cancer, 55 OBSTETRICS & GYNECOLOGY 732
15. SANDRA CONEY, THE MENOPAUSE INDUSTRY: HOW THE MEDICAL ESTABLISHMENT
EXPLOITS WOMEN 201-02 (1994).
16. Gina Kolata, Hormone Studies: What Went Wrong?, N.Y. TIMES, Apr. 22,
2003, at F1.
17. See, e.g., R.L. Prince et al., Prevention of Postmenopausal
Osteoporosis: A Comparative Study of Exercise, Calcium Supplementation, and
Hormone-Replacement Therapy, 325 NEW ENG. J. MED. 1189 (1991); The Writing
Group for the PEPI Trial, Effects of Estrogen/Progestin Regimens on Heart
Disease Risk Factors in Postmenopausal Women, 273 JAMA 199 (1995).
18. Spake, supra note 11, at 49.
19. Stephen Hulley et al., Randomized Trial of Estrogen Plus Progestin for
Secondary Prevention of Coronary Heart Disease in Postmenopausal Women, 280
JAMA 605 (1998).
20. Writing Group for the Women’s Health Initiative Investigators, supra
note 1, at 321.
22. Id. at 331.
23. Id. at 332.
24. Lacey Jr. et al., supra note 2, at 334.
25. Writing Group for the Women’s Health Initiative Investigators, supra
note 1, at 321. At least two other studies reported last year found
increased risk of breast cancer from hormone therapy. See Rui Li et al.,
Hormone Replacement Therapy and Breast Carcinoma Risk in Hispanic and
Non-Hispanic Women, 95 CANCER 960 (2002); Clive Cookson, HRT Study Abandoned
Amid Health Concerns, FIN. TIMES, Oct. 25, 2002, at 6.
26. Peter P. Zandi et al., Hormone Replacement Therapy and Incidence of
Alzheimer’s Disease in Older Women: The Cache County Study, 288 JAMA 2123
27. Wyeth Pharms., News and Announcements, Wyeth Receives Draft Manuscripts
from the Women’s Health Initiative Memory Study (WHIMS) (Feb. 28, 2003)
available at www.wyeth.com/news/Pressed_and_Released/pr02_28_2003_09_18_09.asp
(last visited June 28, 2003).
28. Jennifer Hays et al., Effects of Estrogen Plus Progestin on Health-
Related Quality of Life, 348 NEW ENG. J. MED. 1839 (2003).
29. Deborah Grady, Postmenopausal Hormones: Therapy for Symptoms Only, 348
NEW ENG. J. MED. 1835 (2003).
30. NATIONAL TOXICOLOGY PROGRAM, U.S. DEP’T OF HEALTH & HUMAN SERVS., REPORT
ON CARCINOGENS (10th ed. 2002).
31. Sally A. Shumaker et al., Estrogen Plus Progestin and the Incidence of
Dementia and Mild Cognitive Impairment in Postmenopausal Women, 289 JAMA
32. Denise Grady, Hormone Use Found to Raise Dementia Risk, N.Y. TIMES, May
28, 2003, at A1.
33. Rowan T. Chlebowski et al., Influence of Estrogen Plus Progestin on
Breast Cancer and Mammography in Healthy Postmenopausal Women, 298 JAMA 3243
34. Cook v. Wyeth, Inc., No. 2:02cv0529 (E.D. Ark. filed Aug. 22, 2002);
Favela v. Wyeth, Inc., No. 2:02cv5893 (C.D. Cal. filed July 26, 2002);
Krznaric v. Wyeth, Inc., No. 2:02cv7692 (C.D. Cal. filed Sept. 22, 2002);
Szabo v. Wyeth, Inc., No. 2:02cv7628 (C.D. Cal. filed Aug. 11, 2002); Lewers
v. Wyeth, Inc., No. 1:02cv04970 (N.D. Ill. filed July 15, 2002); Attuso v.
Wyeth, No. 02-852 (M.D. La. filed Aug. 29, 2002); Bloch v. Wyeth &
Wyeth-Ayerst Research , No. 01542 (Pa., Philadelphia Ct. Common Pleas filed
July 11, 2002).
35. In re Prempro Prods. Liab. Litig., MDL 4:03cv01507 (E.D. Ark. Mar. 4,
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