A systematic review published in 2023 screened 1,369 papers and included 51 that directly compared the two routes in postmenopausal women. Across all of them, the clearest and most consistent difference was venous clot risk.
In the Women's Health Initiative, using oral combined therapy, the relative risk of venous thromboembolism against placebo was 2.03. That is the number the route conversation is about.
Same hormone. Same molecule. Two entirely different journeys through your body, and two different risk profiles at the end of them.
Why the route changes anything at all
Swallow estrogen and it is absorbed from the gut and goes straight to the liver before it reaches the rest of you. The liver, seeing a large arriving dose, alters its output of the proteins involved in clotting. That is called first pass metabolism, and it is the entire mechanism.
Deliver the same hormone through the skin, as a patch, gel or spray, and it enters the bloodstream directly. The liver sees ordinary circulating levels rather than a bolus. The clotting protein shift is largely avoided.
Everything else in this piece follows from that one difference.
What the comparison actually found
- Clots. The clearest difference and the reason route is discussed at all. Oral carries the higher risk; transdermal largely avoids it.
- Triglycerides. Oral estrogen raises them. If yours are already high, that matters, and it points firmly to the skin.
- Cholesterol. Here oral has an advantage. It lowers LDL cholesterol and lipoprotein(a) and raises HDL more than the transdermal route does. This is the honest counterpoint and it belongs in the conversation.
- Blood pressure and gallbladder disease. Both track with the oral route.
- Symptom relief. Both routes work. This is not a choice between effective and ineffective.
Where the guideline stops hedging
The 2025 European Society of Endocrinology clinical practice guideline is direct about the situations where transdermal is preferred rather than merely acceptable. Those include women with, or at raised risk of, clotting problems, and women with high triglycerides. It also names transdermal as the preferred route in women with well controlled diabetes, and states that well controlled diabetes is not in itself a reason to withhold treatment.
For a woman with dyslipidemia and high cardiovascular risk the guidance is different again, and that is exactly the sort of individual judgment that cannot be made from a page.
The other half of the regimen, which also has a route
If you still have a uterus, estrogen is not given alone, because unopposed estrogen stimulates the lining of the womb. Something has to protect it, and what is chosen matters too.
The 2025 Cochrane review found that the combined oral regimen used in the WHI probably increased breast cancer risk with a relative risk of 1.27, may have increased stroke, and increased clot risk. In the estrogen only arm, in women who had had a hysterectomy, the picture was gentler across the board.
The guideline also notes that some progestogens partly offset estrogen's metabolic benefit, that women on estrogen alone had a lower risk of developing diabetes than women on the older combined regimens, and that micronized progesterone and dydrogesterone may not adversely affect glucose metabolism in the same way.
None of that means one option is right for everyone. It means there are several decisions inside what most women experience as a single yes or no, and each one is being made on your behalf.
If nobody discussed route with you, a decision was still made. It was just made without you, and possibly on habit rather than on your clot history, your triglycerides and your blood pressure.
What about dose
Also part of it. On bone specifically, the guideline notes that transdermal estradiol at 25 micrograms a day or more, or oral estradiol at 0.5 mg a day or more, is generally enough that a separate bone medicine is not required. Even ultra low dose transdermal at 14 micrograms shows skeletal benefit, though bone density is worth monitoring at that dose in a woman at high fracture risk.
The lowest dose that controls your symptoms is not automatically the best dose if you also have bone at stake. That trade off is individual.
The three things to bring to the conversation
Your personal and family history of blood clots. Your most recent lipids, particularly triglycerides. Your blood pressure, and whether you still have a uterus.
With those four facts a specialist can tell you which route is appropriate for you and why, rather than which one was in the drawer.
If you are already on something and nobody ever explained why it was that one, that is worth checking rather than assuming. Take it to the specialist and have your own regimen read properly, in English or Dutch.