As women reach menopause, ovarian hormone production declines and estradiol levels fall resulting in symptoms commonly associated with menopause such as hot flashes, vaginal dryness, and mood swings. Bioidentical estrogen replacement is a therapy option when testing confirms low hormone levels. Often overlooked, the route of administration of estradiol or bi-est should be considered carefully in order to minimize health risks. To explore the differing physiological effects of oral versus topical estradiol delivery, read on.
A growing body of evidence reveals a significant difference between oral and transdermal estrogens in terms of bioavailability and metabolism, as well as implications for clinical efficacy, potential side effects, and varying risk profiles. Oral hormone therapy, while effective for menopausal symptoms, is subject to first-pass metabolism in the liver resulting in undesirable effects on hepatic protein synthesis, such as inflammatory markers, markers of coagulation and fibrinolysis, and steroid binding proteins. In bypassing first-pass metabolism, transdermal hormone therapy may avoid precipitating these harmful changes. Additionally, topical bioidentical estradiol therapy confers potential benefits beyond relief of hot flashes that oral estrogens cannot provide. Some of the most important known risks of oral estrogen therapy and proven advantages of transdermal estradiol are discussed below.
Disadvantages of oral estrogen therapy
The primary dangers of oral estrogen therapy appear to be increased risk of inflammation and clotting, and unfavorable effects on lipid profiles. Additional disadvantages include impacts on thyroid and adrenal hormone levels.
Oral—but not transdermal—estrogen therapy has been associated with increased inflammatory markers, specifically a rise in acute phase proteins such as C-reactive protein and serum amyloid A. As well, the anti-inflammatory growth factor IGF-1 decreases with oral estrogen use, but not with transdermal estrogen.
Oral estrogens have been shown to be prothrombotic, meaning their use increases the likelihood of developing blood clots. Procoagulant factors such as Factor VII antigen and prothrombin fragments 1 and 2 rise, along with several key enzymes involved in plaque disruption. Oral estrogen therapy has been associated with an increased risk of first episode venous thromboembolism, deep vein thrombosis, and possibly stroke. Research has found no association between transdermal estradiol and these adverse effects.
Effects on the lipid profile
Oral estrogen use has been shown to increase total cholesterol. It is true that both oral and transdermal estrogens increase HDL and reduce LDL; however, transdermal estradiol (E2) produces larger, more oxidation-resistant LDL particles and decreases triglycerides, whereas oral E2 does not have this antioxidant effect. These effects on lipids are important because less oxidation of LDL decreases cardiovascular risk, and having lower triglycerides reduces their contribution to arteriosclerosis. Herein lies an opportunity for healthcare providers to provide true preventive medicine while addressing the menopausal symptoms that brought the patient to the office in the first place.
Sex hormone binding globulin and total testosterone increase with oral conjugated equine estrogen (CEE) use, while free testosterone levels decrease. Lower levels of free testosterone contribute to decreased bone density, declining memory, weight gain, and increased risk of heart disease. Similarly, oral CEE can affect thyroid function, increasing thyroxine binding globulin and total thyroxine (T4) while decreasing free T4 (fT4). This increases the likelihood for weight gain, constipation, and fatigue. Oral CEE also increases cortisol levels, which may contribute to blood sugar dysregulation, fatigue, hypertension, and weight gain. Transdermal estrogens are not associated with these negative impacts on health as they have been shown to have minimal effects on these hormones.
Transdermal estradiol advantages
Choosing transdermal estradiol may impart benefits not found with oral estrogen, specifically improvements in sexual and cognitive function.
Topical estradiol has been evidenced to improve postmenopausal sexual function, while oral estradiol has not demonstrated these effects. Specifically, topical estradiol can increase lubrication and decrease pain. Oral estrogens have been shown to negatively impact sex drive and sexual responsiveness, a disadvantage for patients who value sexual function as an important determinant of quality of life.
Topical estradiol has been demonstrated to impart important benefits for brain health, namely improved cognition and prevention of beta-amyloid deposition. A small randomized controlled trial found improved cognition in postmenopausal women with Alzheimer’s Disease who were given transdermal estradiol. Both verbal and semantic memory showed significant gains after 3 months of treatment. According to a placebo-controlled pilot study, topical estradiol administration, but not oral estradiol, may reduce beta-amyloid deposition (one of the factors presumed to contribute to the development of Alzheimer’s Disease) in post-menopausal women, particularly if they are a carrier of the APOEɛ4 gene. On the other hand, the Women’s Health Initiative showed that oral CEE given to women over age 65 increased the risk of cognitive decline and all-cause dementia, a wake-up call for providers treating women in this demographic currently on or considering oral estrogens.
Menopausal symptoms bring patients to their providers’ offices. This can be a great opportunity to provide true preventive care by not only helping patients feel better, but also providing solutions that could improve their overall health and prevent future disease. Proper consideration of hormonal route of delivery can significantly impact outcomes, as the topical route has been shown to be safe and effective. Considering transdermal estradiol provides an opportunity to step beyond symptom relief and offers many documented potential benefits to your patients, including a decrease in inflammation, and overall improvement in cardiovascular and hormonal health. Testing salivary hormones before and after initiating bioidentical hormone replacement therapy can ensure proper dosing. A tool to consider is the Comprehensive Plus Profile, which provides a measure of estrogens, including estrone, estradiol and estriol, as well as progesterone, testosterone, DHEA, and four diurnal cortisol levels, so that you have the information you need to help select the best hormone balancing options for your patients.