Oral vs. Topical Estrogen for Postmenopausal Women

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Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Providers and patients alike come to Pavilion Compounding Pharmacy, LLC for guidance about this, and our recommendations are based on knowledge about the available delivery options and their impact on safety.

In the area of BHRT, some new information has come to light in medical literature that is important to consider for patients. Therefore, we would like to review the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. VTE is a general term for a blood clot that forms in a vein. This can manifest as a deep vein thrombosis, wherein the clot forms in a deep vein of the leg, pelvis or arm.1 VTE also encompasses pulmonary embolism, which is when a blood clot reaches the lungs.2 According to the Centers for Disease Control and Prevention, these “are often underdiagnosed and serious, but preventable medical conditions” that can result in “serious illness, disability, and in some cases, death.”1 Symptoms of deep vein thrombosis include redness of the skin in the affected area as well as swelling, pain and tenderness to the touch. Pulmonary embolism symptoms include low blood pressure, lightheadedness, fainting, difficulty breathing, fast or irregular heartbeat, chest pain, or even coughing blood. Both conditions are treatable through immediate medical care.1 There are many risk factors for VTE, including recent surgery, long periods of immobilization and family history, among others.2


In recent years, there has been an enormous amount of discussion in the medical literature about estrogen and its route of administration for hormone replacement therapy. The overwhelming evidence has shown that oral estrogen replacement increases the risk of VTE in postmenopausal women with no previous thromboembolic events. Comparatively, non-oral estrogen use did not significantly affect their risk. In the medical literature examining the relationship between VTE and hormone replacement in menopausal women, the route of administration has been primarily oral. However, studies have revealed that oral estrogen therapy may exert a prothrombotic effect through hepatic induction.3,4 This is conceivably related to high concentrations of estrogen in the liver due to the liver’s “first-pass” effect. Likewise, a recent study revealed that compared with no hormone therapy, use of oral estradiol was associated with excess risk of VTE. In contrast, use of transdermal estradiol (most commonly used as a patch) was not associated with excess VTE. In addition, the study authors concluded that “transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.”5

Furthermore, in addition to an increase in prothrombotic effects, studies have shown that oral estrogen use is related to other possible side effects6–16:

• Increase in blood pressure • Increase in triglycerides • Increase in estrone • Increase in occurrence of gallstones • Increase in liver enzymes

• Increase in sex hormone binding globulin, which lowers available testosterone for the body to use  • Interruption of tryptophan metabolism and consequently serotonin metabolism

• Lower growth hormone levels • Increase in C-reactive protein • Increase in carbohydrate cravings

Other medical trials that have compared oral and transdermal estrogen replacement also discovered that transdermally administered estrogen has little or no effect in increasing prothrombotic substances. Furthermore, transdermal estrogen may have beneficial effects on proinflammatory markers (such as C-reactive protein and prothrombin activation peptide) as well as antithrombin activity. It may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity in contrast to oral estrogen as well, which would also be beneficial in many cases.4,14,17–20

Other study authors also examined the risk of transdermal estrogen use compared to patients that did not use hormone replacement therapy and showed that there was no increased risk compared to nonusers.21–25 Some research also suggested that transdermal estrogens may substantially improve the benefit/ risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.21 In fact, other studies revealed that women who were overweight8 and women who had prothrombotic mutations also had no increased risk of thrombosis with transdermal estrogen replacement therapy.26

Lastly, researchers have also investigated whether patients with a previous thromboembolism, family history of thromboembolism or prothrombotic mutation could take estrogen replacement therapy. The studies revealed that the above were a strong contraindication to oral hormone replacement therapy, but transdermal estrogen could be considered after careful individual evaluation of the benefits and risks. Furthermore, these studies suggested that transdermal estrogen should also be the first choice for overweight and obese women requiring hormone replacement therapy.27,28


When considering compounded estrogen delivery, there are several choices. The list includes multiple dosage forms, and two of the most common provide sublingual or buccal delivery and topical delivery (with or without permeation enhancement). While vaginal/ labial applications, injections and pellets are also treatment options, we are going to focus on the more common ones.

Sublingual and buccal delivery are similar and often used in medicine for patients who either can’t swallow a solid dosage form or for specific medical reasons, such as hyperemesis (severe nausea and vomiting). Sublingual administration involves placing medication under the tongue to absorb through the mucosa into the bloodstream. Buccal administration involves placing a medication between the gum and the cheek, where it absorbs through the mucosa and into the bloodstream. Absorption is generally considered rapid and efficient, and these routes avoid first-pass metabolism, though many dosage forms that are intended for sublingual or buccal delivery commonly also allow oral intake through normal salivary action. Sublingual absorption occurs in part through the ventral surface of the tongue or the floor of the mouth into the reticulated vein. The main mechanism for the absorption of a drug into oral mucosa is via passive diffusion into the lipoidal membrane.

The sublingual area is more permeable than the buccal area, which is more permeable than the palatal area (top of the mouth). These differences are generally related to the relative thickness, blood supply and degree of keratinization of these membranes. For a drug to be absorbed completely through the sublingual route, it must have slightly higher lipid solubility for passive permeation, and luckily, estrogens are lipophilic (fat soluble).29 Notably, sublingual BHRT seems to be effective in reducing vasomotor, mood and quality-of-life symptoms experienced in postmenopausal women.30

While compounders have prepared sublingual hormone drop formulas for years,31 troches are the most popular sublingual and buccal dosage form for BHRT. There is a lot of older pharmacokinetic data published on sublingual use from manufactured oral estradiol tablets.32–34 This data clearly shows sublingual administration resulted in rapid absorption with significantly higher estradiol levels than did comparable oral dosing, and these increased levels fell rapidly over the first six hours, indicating the need for multiple daily doses considering the half-life of oral estradiol is approximately one to two hours at steady state. There are no similar pharmacokinetic studies for comparable compounded dosage forms (rapid dissolve tablets or tablet triturates), but assuming extremely close dissolution times, one could expect similar outcomes.

Even though sublingual and buccal absorption of estrogen is relatively rapid, troches dissolve more slowly than tablets (from 20 minutes to an hour depending on the formulation). Additionally, more than 50% of the troche is swallowed by the normal mechanism of saliva formation, and the remainder is absorbed transmucosally.35 Because over half of the troche is swallowed, prescribers and compounders must be aware that estrogens given in this manner may have a similar risk of VTE as oral administration, and we therefore do not recommend estrogen troches.


Another common route for compounded hormone replacement is topical. Many times, the terms “topical” and “transdermal” are used interchangeably. Strictly speaking, topical refers to the delivery of a drug into the skin to treat a dermal disorder, with the skin as the target tissue. In contrast, transdermal, or percutaneous, absorption refers to the delivery of a drug through the skin for systemic effect. However, we often refer to BHRT compounds as topical because they are topically applied. So when we talk about topical BHRT here, these compounds are intended for hormone delivery through the skin.

There are many factors to consider with absorption through the skin: physical and chemical properties of the drug, molecular weight, solubility, partition coefficient and dissociation constant, the nature of the carrier vehicle, and the condition of the skin. With hormones, the most important factors are the molecular weight and the vehicle or base.

The low molecular weight of hormones definitely lends them to topical delivery as an excellent option. However, we also have to consider the size of the drug particle. When a drug is reduced to a number of smaller particles, or micronized, the total surface area is greater, which results in an increased rate of dissolution. As Allen and Ansel point out, “Due to the different rates and degrees of absorption obtainable from drugs of various particle size, it is conceivable that products of the same drug substance prepared by two or more reliable pharmaceutical manufacturers may result in different degrees of therapeutic response in the same individual.”36 In other words, the particle size of a hormone can make a clinical difference, so it’s an important consideration in compounding for BHRT.

The base of the compounded preparation is also critical. The type of base and permeation enhancers used can affect absorption of hormones, and the delivery system must be able to release the drug in a reproducible way. As mentioned, hormones are lipophilic, and a good base will enhance their diffusion through the stratum corneum.36 In-depth discussion of the importance of a proper base is outside the scope of this article, but we mention this aspect of hormone absorption to stimulate thought.

The main advantage of topical administration is bypassing the first-pass effect.37 Estrogen that is absorbed orally passes through the portal vein into the liver, where it is heavily conjugated before being released into the systemic circulation, which may account for the negative effects mentioned above. Since this is only seen with oral administration, it is reasonable to hypothesize that this is related to first-pass hepatic metabolism.

One of the disadvantages of topical delivery is the potential for transference to family members and pets. Therefore, Pavilion’s pharmacists counsel our patients to be aware of contact with others and identify areas to apply creams that will minimize exposure to others. Another perceived disadvantage to topical hormone delivery relates to the limitations of different types of lab testing. The gold standard is serum testing, for example, but topical hormone application does not typically show up in blood serum results. It shows in the saliva. We could write an entire book explaining and debating the differences between serum testing and saliva testing. Each type of testing is looking at a specific compartment of the body and provides different information. We will leave this topic for a future article. Despite the disadvantages of transference or the debate over testing, topical delivery of estrogen is a practical, proven compounding option, and as we have seen here, it is safer than oral delivery for postmenopausal women.

The risk of VTE is a very important consideration for choosing the route of estradiol administration, and being cognizant of the possibility of oral absorption from other dosage forms, such as troches, is an important factor to be aware of as well. While a certain type of compound may be popular, the risk of potential harm must take precedence over convenience when making a dosage form recommendation. Consequently, after review of the medical literature, topically applied estrogen is the form of estrogen replacement that Pavilion’s compounding pharmacists recommend for a postmenopausal woman. Please contact one of our clinical pharmacists today with any questions or concerns. We typically recommend Versabase cream for topical or vaginal Estrogen therapy. See the video below regarding Versabase cream.



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27. PCCA Apothagram Fall 2019 By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist. Accessed 11/5/2019