By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Colleagues and patients alike come to us for guidance about this, and our recommendations should be based in part 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. In the first part of this article, we will review what the literature is showing and discuss compounded sublingual and buccal estrogen. In the second part of this article, which we will publish on The PCCA Blog soon, we will discuss compounded topical estrogen.

VTE is a general term for a blood clot that forms in a vein. This can manifest as a deep vein thrombosis, where 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

What the Literature Says
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 risk of 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-creative 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

Compounded Sublingual and Buccal Estrogen
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 for postmenopausal women.

Pamela Wartian Smith, MD, MPH, MS, spent 20 years as an emergency room physician with the Detroit Medical Center and then 24 years as an anti-aging/functional medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of metabolic, anti-aging and personalized medicine. She has been featured on CNN, PBS and many other television networks; has been interviewed in numerous consumer magazines; and has hosted two of her own radio shows. She is currently the Director of the Center for Personalized Medicine and the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine. Dr. Smith is also the co-director of the Master’s Program in Metabolic and Nutritional Medicine at the Morsani College of Medicine, University of South Florida. Additionally, she is the Director of Medical Education for the American Academy of Anti-Aging Medicine. She is the author of the best-selling books HRT: The Answers, What You Must Know about Women’s Hormones, and many others.

Nat Jones, RPh, FIACP, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.

Sara Hover, RPh, FAARM, has been a compounding pharmacist for over 20 years and joined the PCCA Clinical Services team in June 2013. Before joining the PCCA staff, she was the owner and pharmacist of Creative Compounds in Prosper, Texas, an independent, compounding-only pharmacy that focused on women’s health and nutrition. In addition to her expertise in hormone replacement therapy, Sara possesses a vast knowledge of homeopathics as well as herbal and vitamin supplements. Sara obtained her Bachelor of Science degree from the University of Texas at Austin in 1994. She is a lifetime member of the University of Texas College of Pharmacy Alumni Association.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

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These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.