Estrogens in menopause, time to change the recommendations?

Translation from an article by E.F.Eriksen, M.H.Moen, O.L. Iversen,

This is a translation of an article published in the Norwegian Journal for Physicians, Tidsskriftet, https://tidsskriftet.no/2018/03/kronikk/ostrogener-i-menopausen-p%C3%A5-tide-endre-anbefalingene

New studies show, that  treatment with estrogen with start before age 60, are for the most part positive.  It’s time to change the recommendations.

Why did we become scared of Estrogen?

The Women’s Health Initiative was a big, American study initiated by the National Institute of Health in 1991. More than 27 000 women between the age 50 to 79 were assigned to either hormone treatment or placebo. Women who had their uterus intact were given a combination of conjugated equine Estrogens, o,625 mg and Gestagen 2,5 mg (medroksyprogesteronacetat). Women who had had a hysterectomy were given conjugated estrogens, 0,625 mg, as mono therapy.

The study on the group on both Estrogen and Gestagen were halted before time, after 5,2 years. The plan was 8,5 years. This was because there was an increased incidence of coronary disease and breast cancer. There were also increases in strokes and pulmonary embolism. Cancer of the colon and hip fractures had decreased.

The group on estrogen only was also stopped before planned.  One found an increase in stroke. There also a significant amount of hip fractures in this group. There was no increase in death rate though. Link to the study, https://escholarship.org/content/qt3mr6f93p/qt3mr6f93p.pdf

In the following years, hormone replacement went down by 2/3 all over the world. Expert committees published new, restrictive guidelines, recommending hormone replacement therapy (HRT) only for very severe menopausal issues, and for 5 years only.

Risks for the group 50 to 59

Women’s Health Initiative has since published many smaller studies and ad hoc studies, ad hoc is when you design a study for a purpose. These have all shown, women who start HRT before the age of 59 have a different risk profile than the studied group of women aged 60-79, The timing hypotheses. Among women 50-59, one saw only 6 extra cases of breast cancer and 5 extra cases of stroke pr 10 000 women in the group treated with both estrogen and Gestagen. This is a very small risk factor. When one took a look at the group 50-59 one estrogen only therapy, one saw no increased risk of breast cancer or stroke.

Both groups had less osteoporosis fractures, colon cancer and diabetes. Both groups aslo had decreased death rate. The pro’s of HRT have been neglected in the debate about this study, where almost all focus has been on the small increased risk of breast cancer and stroke.

Several randomized studies started in the 1990 ies (the Heart and Estrogen/Progestin Replacement Study), The Women’s International Study of long-duration Estrogen after Menopause and Women’s Health Initiative Memory studies) confirmed that HRT had differing effect on women over and under 60.

In newer studies, one has concluded that early intervention even has a positive influence on the thickness of arterial intima. I don’t know how to translate that. But it means the thickness of the innermost layer of arteries and veins. In the Danish Osteoporosis Prevention Study  1000 women early in menopause, age 45 to 58, randomized to either HRT or placebo, the study. There was no increase in breast cancer during the study. After 10 years, there were only half as many cardiovascular incidences in the HRT group. And the reduction was still there after 18 years. The risk for stroke and blood clots were the same in the two groups.

A new study, a 18 year follow up of the Women’s Health Initiative study showed no higher death rate for ALL participants in the original study. The follow up also confirmed the importance of early upstart on hormone. Women who were treated with Estrogen only aged 50 to 59 had a lower death rate in the intervention periode, and in the following 18 years. Breast cancer and dementia related deaths were significantly lower than in the age group 70-79.

Validity for women in Norway

There are many published articles on the whether The women’s health Initiative study is valid for the clinical treatment with hormone for actual women. Treatment that typically starts between the ages of 45 and 55. The mean up start age in the study was 63. No risk factor was statistically significant after correction for covariates (must mean other variables influencing the outcome )and multiple  analysis of the data at different timings. Plus, the Estrogen used, conjugated ekvind estrogen, not quite sure of that translation. This form of Estrogen is not in use in Norway, and it is not similar to 17-β-estradiol.  Which is the form of Estrogen used in Europe. The Gestagen used, Medroksyprogesteronacetat has also a different risk profile than Noretisteronacetat, which is the most used Gestagen in Europe. My comment on this, I believe natural plant derived progesterone is much better for us.

So what is the verdict, HRT good or bad?

The following is a discussion of HRT in menopause based on analysis after 2002, including the follow up study from The Women’s Health Initiative.

The primary studies in the Women’s Health Initiative studies, showed, it’s the combination of Estrogen and Gestagen that increases the risk for breast cancer. As it was only the women in this group that had an increased risk. While women on Estrogen only had nearly an decreased risk. Later analysis have shown, that it is likely that the increased breast cancer risk in the combination group was caused by the decreased incidence of breast cancer in the placebo group.  Some of the women in the placebo group had been on post menopausal HRT, and had less breast cancer than in the average population. The fact that the incidence of breast cancer 18 years later was reduced by 50% , is striking. See this study

The incidence cancer of the uterus as well as cancer of the ovaries did not increase after HRT therapy in the study. the incidence of cancer of the colon decreased. But this fact has been largely ignored.

Consequences of the study

Those first results from the Women’s helath Initiative, was an advice against HRT for women with cardivascular issues or increased risk of getting it. This advice still stands. But the negative findings were a result of including 79 years old women in the study, and one is getting different results in more recent studies.

En Cochrane analysis, link to the study, showed that the incidence of heart issues were halved and cardiovascular death 30% less when women were treated with HRT starting before the age of 60. For women aged between 50 and 59, the Women’s Health Initiative study also showed reduced cardiovascular morbidity. En Cochrane analysis is a kind of a Meta study. That is, results from several studies are analysed together.

Almost all studies where hormone has been administered orally, one sees an increase in stroke, deep vein thrombosis and lung embolism.  but the same risks have not been observed with transdermal treatment with Estradiol, link to article. 

Women’s health Initiative study was the first randomized study (people being assigned to the experimental conditions in an arbitrary fashion)showing less risk for both fractures in the vertebrates(35%)  and in the rest of the body (25%) with HRT treatment.  25 less fractures pr 10 000 women in the combination group, and 16 less in the Estrogen only group.

One result there has been little or no focus on, is the fact that one saw reduction of diabetes in both treatment groups. this result has been demonstrated also in other studies, by as much as 35%.

On dementia related tests, the Women’s Initiative Memory studies, showed negative effects . for the women who started HRT after the age of 65. for those starting before 60, one saw no negative effects. That is why, it is surprising that one on the 18 year follow up found reduced mortality from dementia related deaths.

Increased use of HRT treatment

According to The National Institute of Health in Norway, did 50 000 women use HRT in Norway in 2016. the number prior to 2002 was 170 000. As we can see, studies show that women starting HRT in their fifties have mostly positive results.

Under the debate, one forgot that HRT reduces prevalent conditions like osteoporosis, colon cancer and diabetes. In addition, one transferred the US result with conjugated Estrogens and Medroksyprogesteronacetat given to women over 65 without reservations to European conditions.Which were HRT treatment to women between 45 -55 treated with 17-β-estradiol and Noretisteronacetat.

Conclusion

Women starting HRT before the age of 60 have reduced risk of osteoporosis, cardiovascular disease, colon cancer and diabetes without higher risk of other cancer diseases or higher mortality.

In the last 15 years, one has also totally forgotten the positive impact HRT can have on quality of life. Like less hot flushes, better sleep and better sex life. the use of transdermal (cremes , gels and patches) administration and micronized  progesterone can most likely reduce the risk of side effects even more. That is why, more women should be offered HRT than what is the case at present.