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

In the first part of this article, we introduced some new information that is important to consider for patients who need bioidentical hormone replacement therapy (BHRT). Recent medical literature is shedding more light on the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. Specifically, we reviewed what the literature is showing and discussed compounded sublingual and buccal estrogen. Here, we will continue the discussion further with compounded topical estrogen.

Compounded Topical Estrogen
In addition to sublingual and buccal estrogen, 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.”1 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 we mentioned in part one, hormones are lipophilic, and a good base will enhance their diffusion through the stratum corneum.1 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.2 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 we listed in the first part of this article. 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, compounders should counsel their 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 in this article, 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 only form of estrogen replacement that we recommend for a postmenopausal woman.

Pamela W. 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.

1.    Allen, L. V., Jr., & Ansel, H. C. (2013). Ansel’s pharmaceutical dosage forms and drug delivery systems (10th ed.). Baltimore, MD: Lippincott Williams & Wilkins.
2.    Goodman, M. P. (2012). Are all estrogens created equal? A review of oral vs. transdermal therapy. Journal of Women’s Health, 21(2), 161–169.

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.