Estrogen and Mortality

Estrogen, avoiding replacement shortens lifespan.

Thirty years ago estrogen replacement was the standard of care in menopausal women after ysterectomy. clinical studies showed estrogen replacement was effective for treatment of menopausal symptoms and had good effects on bone and heart.

Then in 2002, the Women’s Health Initiative (WHI) published the results of the Estrogen Plus Progestin (NOT bio-identical progesterone and not natural estrogen) Trial and announced that the study was being stopped ahead of schedule because of problem with women receiving “hormones” compared with those receiving placebo.

The media went wild over this. The study’s treatment drug (“Prempro”), which is of course horse—not human—estrogen and progesterone was often referred to as “HT” (hormone therapy) or just “estrogen”. Because of this all forms of hormone replacement were lumped together and blamed.

I’m sure the media caused a lot of misery by their sensational hit job. Millions of women had the rug pulled out from under them. Hot flashes, night sweats, fatigue, memory loss, insomnia, vagina dryness, vaginal atrophy, no sex drive, sagging breasts, thin skin, hair loss….and now we know they would have actually lived longer had they stayed on hormones.

Prescriptions for menopausal hormone replacement dropped way off. Within 18 months, half of the women in the United States using “HT” stopped treatment. Included were almost 200,000 women who had no uterus who were using “ET” and not using the study drug (“Prempro”).

Subsequently, the findings of the WHI Estrogen-Alone Trial (WHI-ET) for women without a uterus were published for the intervention phase (2004) and the post-intervention long-term follow-up phase (2011).

These findings showed benefits (less mortality for “ET” compared with placebo). Preliminary subgroup analysis of the intervention phase data (2004) indicated reduced total mortality in the women aged 50 to 59 years. However, it is only in the post-intervention data (2011) that an absolute total mortality risk reduction of 13 per 10,000 women per year was reported for these women. The mortality decrease was almost entirely owing to a decrease in coronary heart disease (CHD), although reduced cancer mortality and other causes of mortality were also reported among the women who received “ET”.

Despite the positive findings for “ET”, prescriptions for all forms of systemic “HT” have continued to decline. Currently, less than one-third of women after uterine removal women are using “ET”. The decline in “ET” prescription and usage seems to reflect a generalized avoidance of any forms of “HT” (hormone therapy) not supported by the WHI data).

This raises the possibility that there has been and continues to be considerable resultant mortality toll. We therefore undertook analysis on the basis of published data to determine the likely toll of excess, premature death among hysterectomized (uterus removed) women aged 50 to 59 years in the United States following the WHI publication in 2002.

All-cause mortalities were also reported among the women who received “ET”. Despite the positive findings for “ET”, prescriptions for all forms of systemic “HT” have continued to decline. Currently, less than one-third of women who have had their uterus removed are using “ET”. The California Teachers Study, in which 97% of the oophorectomized (ovaries removed) women used “HT” (almost entirely “ET”), shows an all-cause mortality reduction similar to the WHI-ET results. The WHI-ET and the California Teachers Study results indicate that the decrease in CHD events and all-cause mortality are limited to hysterectomized women younger than 60 years or within 10 years of menopause. An analysis of 23 trials found that “HT” significantly reduced CHD events in these women. In fact, for CHD, the WHI-ET findings among women aged 50 to 59 years are in line with the reduced risks reported in the observational studies and support a “timing hypothesis” for “ET” heart protection when “ET” is started close to the time of menopause. The current thinking is that by age 60 years, pathological changes in vascular endothelial cells compromise the ability of estrogen to inhibit atherosclerosis and promote blood flow. Although prevention of cardiovascular mortality is by far the major benefit of “ET” in younger women, the WHI-ET and the California Teachers Study also show a reduction in cancer deaths. In 2012, the WHI-ET investigators reported a 63% reduction in mortality because of invasive breast cancer in the almost 12 years of follow-up in the post-intervention study of “ET” users versus placebo users.

Estrogen Therapy (“ET” and Mortality) “ET” reduces total mortality in women primarily through reducing CHD-related deaths. Since 1959 there have been many reports showing increased risk of CHD mortality after early surgical menopause and especially after oophorectomy (ovary removal). Estradiol inhibits the development of atherosclerosis and helps maintain normal arterial blood flow. Mortality is increased in younger women who have a hysterectomy and ovaries removed who do not use “ET”. Therefore, it is likely that nonuse of “ET” in women younger than aged 50 years has an additional mortality toll. For example, in the California Teachers Study, women aged 36 to 59 years show a 46% reduction in mortality among current “ET” users.

Our analysis suggests that between 2002 and 2011 a minimum of 18,601 and as many as 91,610 excess deaths occurred among hysterectomized women aged 50 to 59 years following the publication of the original WHI data. Decline in use of “ET” since 2002 has resulted in a significant increase in mortality for hysterectomized women aged 50 to 59 years. Avoidance of all forms of “HT” is persistent despite the positive findings for treatment with estrogen alone. Women, “HCPs” (“health care providers”), and the media should be offered clear and accurate information about the positive effects of estrogen alone therapy in these women. Our analysis suggests that failure to differentiate among populations of women and preparations of “HT” has cost thousands of lives.

This article was based on: https://ajph.aphapublications.org/doi/10.2105/AJPH.2013.301295