Oral estrogens are quickly broken down by the liver, and this "first pass" through the liver seems to be responsible for certain side effects as well as for the positive effects of oral estrogen on cholesterol levels, lowering LDL (the "bad" cholesterol) and raising HDL (the "good" cholesterol). Oral estrogen sometimes raises triglycerides (another type of blood fat) and women who have high triglyceride levels should be aware of this.

Transdermal estrogen (estrogen delivered by patch) does not raise HDL and usually does not lower LDL cholesterol as much as oral estrogen, and it does not affect triglycerides, so it may be a better choice in women with elevated triglyceride levels. Avoiding the first pass through the liver also may prevent the increased risk of blood clots and gallbladder problems associated with oral estrogens.

Transdermal estrogen and oral estrogen have differing effects on androgens in the body. Oral estrogen lowers free testosterone and can lead to androgen deficiency (affecting libido among other things), while transdermal estrogen has little effect on testosterone levels.