I have been conducting a long-term n of 1 trial since January 23, 2021 using lose dose estradiol (E2) gel to counteract the effects of androgen deprivation therapy (ADT) on bone mass density (BMD). I believe that I now have sufficient data to report that low dose transdermal E2, along with exercise and diet, appears to be sufficient to stabilize BMD.
ESTROGEL®, a transdermal gel manufactured by Merck containing 0.06% E2, was used for the add-back trial. A product monogram for ESTROGEL® is available on the internet (1). According to the monograph, each depression of the metered-dose pump delivers 1.25 g of gel or 0.75 mg of E2. The gel was initially applied to both inner thighs over a consistent area (~264 cm2 per inner thigh) before bedtime and allowed to dry. Later in the trial I switched from applying 1.25 grams of gel to both inner thighs to one thigh, alternating thighs every other night. Applying the same dosage to a smaller area increases the dosage delivered (2), but surprisingly the circulating E2 concentration did not change as a consequence of the change.
The desired target range for E2 circulating concentration at 12 hours was 15 to 25 pg/ml. This target range was selected based on the need to be moderately above the minimum value of 11 pg/ml required to maintain bone density according to Russell, et al (3). Russell, et al further state that the average concentration of E2 in healthy older males is ~25 pg/ml, hence the rationale for selecting a maximum E2 concentration of 25 pg/ml. This range is similar to what our illustrious POShea has been recommending in his posts on HealthUnlocked. The actual average 12 hour (+/- 1 hour) circulating E2 concentration has been 14.7 pg/ml.
Bone density scans were performed 2 months after initiation of ADT with leuprolide in March 2016 and at 12, 24, 38 and 78 months afterwards. The time difference from initiation of transdermal E2 and the last DEXA scan was 20 months. There were two switches in testing laboratories, which were beyond my control that may have contributed to some variability in the data. The results are summarized in the attached figure.
It should be noted that abiraterone + prednisone, as a second line therapy, was initiated in August 2020, ~58 months after ADT with leuprolide was started. The dosage of abiraterone was initially 1000 mg/day without food, but was reduced to 250 mg/day with food (and prednisone reduced from 5 mg to 2.5 mg) – see NCCN guidelines. Furthermore, five+ hours of exercise (weight and cardio) per week and a Mediterranean type diet, on a time restricted feeding basis, doubtlessly contributed to the maintenance of the BMD. Calcium supplements (300 mg calcium citrate) were taken irregularly because of the consumption of cheese and soya based products. Vitamin D was initially 4000 IU but reduced to 2500 IU on August 2022 in order to reduce circulating levels of 1, 25 hydroxy VD. Lastly, I also take 10 mg slow release melatonin every night, which may have contributed to the maintenance of BMD (search PubMed for references), although this may be controversial.
With regard to side effects there was an initial nipple tenderness when starting transdermal E2 and a slight increase in breast size. When the same dosage of E2 was applied to one inner thigh, the nipples became tender again confirming exposure to a higher peak E2 concentration. Hot flashes appeared to decrease, but the frequency and severity of these were already waning after 5 years of ADT. There have been no adverse side effects to speak of. Quality of life has been very good during the trial.
Conclusion
At least in my case, low dose transdermal E2, exercise and diet was able to maintain BMD. For men with an initial BMD in the normal range (before or soon after initiation of ADT) and who see a significant decrease in BMD after a couple of years and would like to avoid taking bisphonates, then low dose transdermal E2 may be an option. It requires monitoring circulating E2 initially every 6 weeks until a target value is obtained, then decreasing testing to once every 3 months. A consistent application method, time of application and time of testing must be followed.
Obtaining a prescription through an oncologist may be difficult, or impossible. I was fortunate that my family doctor is open minded and prescribes E2 gel for many of his female patients. I guess a biochemically castrated male qualified (sorry, I could not resist).
There is abundant information in PubMed indicating that transdermal E2 is safe for men on ADT. It is truly unfortunate that there is no published literature that discusses bone medications for maintaining bone density that includes add-back E2 as an option. There is no profit in this alternative method for avoiding fractures.
References
1. merck.ca/static/pdf/ESTROGE...
2. en.wikipedia.org/wiki/Pharm...
3. Russell N, Cheung A, Grossmann M. Estradiol for the mitigation of adverse effects of androgen deprivation therapy. Endocr Relat Cancer. 2017 Aug;24(8):R297-R313. doi: 10.1530/ERC-17-0153. Epub 2017 Jun 30. PMID: 28667081.
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