Most medicine comes in the form of a pill. This delivery method is familiar and easy to use. However, in the case of estrogens, oral delivery has been shown to have negative physiological effects such as increased inflammation, cardiovascular sequelae including increased blood pressure, blood clots and deep vein thrombosis, weight gain, altered thyroid function, and gallstones. Isomolecular, or bioidentical, estradiol has the same biochemical structure as endogenously produced estrogen giving it the ability to avert some of these issues, and transdermal estradiol avoids these adverse effects altogether.
Why do oral and transdermal estrogens have different effects? During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in systemic circulation. This supraphysiologic estrogen concentration can upregulate the expression of many hepatic-derived inflammatory proteins that are typically not seen in premenopausal women. Bypassing hepatic metabolism by delivering estradiol transdermally has been shown to contribute to more stable serum estradiol levels without contributing to problematic supraphysiologic concentrations in the liver.
While oral conjugated equine estrogens have a more prothrombotic hemostatic profile than estradiol, oral isomolecular estradiol (E2) is not without issue. Oral E2 has been shown to decrease IGF-1, and insufficient levels are associated with increased cardiovascular and cerebrovascular risk because IGF-1 improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. Oral estradiol also can increase thyroid markers total T4 and thyroid binding globulin (TBG), increase sex hormone binding globulin (SHBG); and render some hypothyroid medications less effective. Compare these effects to transdermal estradiol gel, which has no significant impact on thyroid markers. Interestingly, studies have shown that when oral micronized progesterone is added, TSH decreases and T4 increases.
Oral estrogens have been shown to have some benefits in treating hot flashes, preventing osteoporosis, and lowering total cholesterol, LDL, and lipoprotein-a. Adding oral progesterone to the hormone replacement regimen diminishes some of the effects of oral estrogens on the lipid profile (In contrast to oral estrogen, oral progesterone is not associated with significant adverse effects). Even so, transdermal estradiol is a better choice because it can effectively reduce hot flashes, improve insomnia, and prevent osteoporosis without causing all the problems associated with oral estrogen. Other safe, non-oral options include vaginal suppositories, creams, and nasal gel.
Because menopause is a time of increased cardiovascular and metabolic risk, besides choosing the safest form of hormone replacement, providers can be even more proactive by measuring biomarkers of metabolic and cardiovascular risk. A traditional lipid profile only provides a limited view of patient’s health. Doctors’ Data’s CardioMetabolic Profile includes more clinically sensitive atherogenic lipoprotein sub-species (such as apolipoproteins A1 and B and small dense LDL) as well as Glycomark®, a better indicator of hyperglycemic response than HgA1c.
