Vagifem is estradiol. Estriol is a by product of estradiol and far weaker. I do not think estriol is prescribed in US for anything as is considered so weak in its effect on estrogen receptors in the vag and bladder and urethra. So it probably is the safest, but the least effective.
If used correctly Vagifem and estradiol creams have very little absorption. Used correctly means one to two weeks nightly to build up cells that prevent or reduce systemic absorption to nearly nothing. Then it must be used two or three times a week per your doctor to maintain this wall of protective cells. Once a year many doctors suggest another one week of nightly use. Every time I do the nightly routine my prolapse lessens so much.
Dr. Currie commented on the safety of Vagifem once and I dare not quote her. Studies have shown that Vagifem does not effect the uterine lining or increase any of the things mentioned on the black box warning that must go on ALL estrogen products in the US even though each product is totally different in side effects-- this is so stupid and misleading.
The studies done about three years ago, not sure exactly when now, showed that Vagifem was absorbed at approximately a few milligrams a year. Again, we all are different, have different histories and our bodies react differently to meds. So nothing is exact or true for everyone.