Analysis: Estrogen therapy after hysterectomy may have saved lives



Thousands of women in their 50s who had a hysterectomy may have died prematurely since 2002 because they did not use estrogen-only therapy, according to a mathematical analysis of data from the Women’s Health Initiative.

The use of estrogen therapy (ET) has been on a steady decline since 2002, when the Women’s Health Initiative (WHI) halted its trial of estrogen plus progestin due to adverse events, which sent shockwaves among women and the medical community. The therapy’s decline has continued even after recent WHI studies showed mortality benefits from estrogen therapy.

Dr. David L. Katz

"We felt a sense of urgency about this project," said Dr. David L. Katz, director of the Yale University Prevention Research Center at Griffin Hospital, Derby, Conn., who developed the formula for the analysis.

"Our calculation is simple and robust, and there was really nothing aggressive about our assumptions. The urgency we feel is in getting the word out about the fact that women were dying every year as a result of unwillingness to talk about estrogen therapy," he said in an interview.

"The Mortality Toll of Estrogen Avoidance," part of the title of the study, is a mathematical analysis of the 2011 WHI-ET (Women’s Health Initiative Estrogen-Alone Trial) data, showing that a minimum of 18,600 and as many as 91,600 excess deaths occurred between 2002 and 2011 among hysterectomized women aged 50-59 years due to ET avoidance (Am. J. Public Health 2013 [doi: 10.2105/AJPH.2013.301295]).

In the 1990s, more than 90% of women in their 50s who had a hysterectomy used ET. It was the standard treatment. Research has consistently shown that ET is cardioprotective and bone protective, and relieves menopausal symptoms.

But all that came to a screeching halt in July 2002, when the WHI published the results of the Estrogen Plus Progestin Trial, and terminated the study because of the adverse effects of the therapy, which was the combination drug Prempro. The results were quickly generalized to all forms of hormone therapy, including ET, the authors of the analysis said.

In less than 2 years, half of the women who were using systemic hormone therapy stopped the treatment. Compared with 2001, use of oral estrogen-only among women aged 50-59 years with no uterus dropped by almost 60% in 2004, 71% by 2006, and 79% in 2010 and 2011, the authors noted.

The decline continued despite the positive findings of WHI-ET, first published in 2004, then in 2011, showing that the absolute total mortality risk was reduced by 13 per 10,000 women per year among hysterectomized women aged 50-59 years who were using estrogen during the 10-year follow-up (JAMA 2011;305:1305-14).

"I said to everyone that this is the most important paper in the last 10 years," said Dr. Philip M. Sarrel, one of the authors of the analysis, and emeritus professor of obstetrics and gynecology and psychiatry at Yale University, New Haven, Conn. "I said it’s got to have an impact. It hit the news, and 24 hours later it was gone. There was no impact. They came out and said here’s a lifesaving set of data, and the message just wasn’t heard."

The authors offered several reasons for why the study did not gain traction, but they pointed to clear communication as one of the main pitfalls.

"We’re not criticizing the WHI investigators," Dr. Sarrel said in an interview. "We’re critical of how the nuanced findings were presented."

"We believe that a mortality toll will better communicate the meaning and significance of the WHI-ET findings to women, health care providers, and the media," the authors wrote.

Dr. David M. Jaspan

Despite repeated requests, WHI investigators said they were not available to comment.

For their analysis, the researchers used the WHI’s 13 per 10,000 women per year as a point estimate for the mortality burden associated with not using estrogen among this specific group of women. Dr. Katz developed a formula that would apply the excess mortality in women aged 50-59 years who had a hysterectomy to the entire population of comparable women in the United States.

There were more than 49,000 excess deaths over 10 years when the researchers applied the lower estimate for hysterectomy rate in the population. The extreme low estimate showed nearly 22,700 deaths; a higher estimated rate showed almost 59,500 excess deaths, and the extreme high estimate approximately 91,600.

They also calculated the mortality toll of estrogen avoidance for women whose ovaries were retained. When the lower hysterectomy estimates were applied, the sum of excess mortality for both groups was 40,300, the low-end estimate was 18,600, the higher estimate 48,800, and the high-end estimate 75,100.

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