Back to the future?

Following on from Alfred, we had another great session on “Back to the future”.  Starting in the past we heard about how vertebrate steroid hormone receptors evolved from a common ancestor that existed 600-800 million years ago. 

Estrogen receptors, often labelled as “sex steroids” actually have a number of other physiological implications impacting; breast epithelial cells physiology, endometrial cells proliferation, ovarian physiology, colorectal and prostate physiology, bone osteoclasts and oesteoblasts function, glucose and lipid metabolism, cardiovascular protection, neuroprotection and immunity.

It is thought that natural estrogens may have the ability to meet many unmet medical needs including delaying memory loss, protecting from myocardial infraction, stimulating maturation of the follicles of the uterus to reduce ovarian and endometrial cancer risk and improving glucose tolerance to reduce the risk of diabetes. So why aren't we targeting these conditions with natural estrogen? Any clinical use of a new drug must be based on extensive pre-clinical knowledge of its targets, mode of action and evaluation of balance of risks/benefits in healthy individuals and diseased women. In order to progress with natural estrogen we must master its mode of action.

In 1929 Butenandt and Doisy discovered the first estrogen, one year later Estriol was produced and in 1926 Estradiol was marketed followed by Ethinylestradiol in 1943. But there have been no significant improvements since over the last 90 years. We haven’t identified the proper mode of action in vitro because of the complications resulting from the presence of different types of estrogen receptors (ERs) , and estrogen (ER)  binding to estrogen response elements (ERE). There’s also differential binding to different classes of ERs. The situation is further confused by the fact that estrogen receptors are not just present in the nucleus but there is also a receptor present at the cell surface. It has been found that E4 blocks this membrane receptor and impedes the binding of E2 and E4. This is important as the nuclear receptor is more active in the uterus whilst the membrane receptor is most active in the endometrium.

Natural hormones have been selected through millions of years of evolution but we are still unable to predict the long term outcomes due to the multiple potential pathways and interactions and it’s not just estrogens that are causing issues, we heard in the last session that types of estrogen is linked to potential VTE risk, but type of progesterone also has an impact. For example with the risk of invasive breast cancer, as we heard yesterday dydrogesterone doesn’t significantly increase risk if used for 10 years but use of testosterone does. A recent study (JE Marson et al. JAMA. 2017; 318 (10): 927-938) showed MHT with natural CE used for 5-7 years is not associated with long term or all-cause mortality.

Despite the extensive research done in the 90 years since the first estrogens were discovered, we are still unable to reliably anticipate the pharmacological properties, clinical features and benefit/risk ratio...more work needs to be done!