My general sense about this is that if HRT is started greater than 10 years post-meno, there are possibilities for increased risks. 10 years post and beyond, arteries have started to perhaps harden/calcify more, any inherent genetic risk factors toward CHD have likely become more pronounced from cellular aging alone and the body has downregulated or adapted physiologically to the very low estradiol levels. Arteries lacking as much elasticity, changes in the way receptors now respond to exogenous hormones, physiological aging, etc., may all impact the way the exogenous estradiol is processed and handled by the body. These are only my own thoughts after reading what I have on HRT and the 'timing' hypothesis.
It would make sense to me if the body has adjusted (to a great degree physiologically) to the decreased estradiol, perhaps reinstating it is some form 'shock' to the body?? As far as any risk factors in long-term continued use, it really bothers me that no new, randomised, LARGE studies have been done using current generation bioidentical HRT - transdermals specifically, and natural progesterone (not a progestagen). Studies of long-term use via transdermal estradiol administration (oral progesterone) may yield different, long-term risk/use data. So much of even the current recommendations are still based on the WHI study - which we all know has been seriously picked apart, reanalyzed and debated in terms of the validity of its conclusions for those in peri or recently post-menopausal seeking HRT.
I am not in this industry, but with women representing 50% of our population, and ALL women going through menopause, why are larger, newer studies not being pursued??