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 treatment.

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 contributes). (15)

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 all women.

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 drug's use.

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 hip 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 HRT (22) 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 Will 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)

The 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 risks

* 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 plaintiffs.

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.

Notes

(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).

(9.) Id.

(10.) Id.

(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., Use of the Progestrogen Challenge Test to Reduce the Risk of Endometrial Cancer, 55 OBSTETRICS & GYNECOLOGY 732 (1980).

(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.

(21.) Id.

(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 (2002).

(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 at., Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women, 289 JAMA 2651 (2003).

(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 (2003).

(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, 2003).

Tobias Millrood manages the mass tort department at Schiffrin & Barroway in Bala Cynwyd, Pennsylvania.