Transdermal estradiol reduced hot flashes and bone resorption in men with prostate cancer

Transdermal estradiol (E2) treatment reduced the frequency and severity of hot flashes as well as reduced a marker of bone resorption in men with prostate cancer undergoing androgen deprivation therapy (ADT). The results of the study were published in the European Journal of Endocrinology.

High-dose oral estrogen therapy, previously used to achieve medical castration, is associated with increased thromboembolic events due to hepatic first pass metabolism of ingested estrogens leading to up-regulation of liver-derived clotting factors.

The study, led by Nicholas Russell, University of Melbourne, Heidelberg, Australia, evaluated the effects of low-dose daily transdermal E2 therapy and the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production due to ADT.

A total of 37 participants were randomized to 28 days of treatment with transdermal 0.1% E2 gel at a dose of either 0.9 mg or 1.8 mg daily, or a placebo gel matched for color, smell, and consistency. Serum hormones, quality of life (QoL), adverse events (AEs), hot flash diaries, and other biochemical measurements were evaluated.

Participants were seen at baseline and at days 14 and 28. At each visit, AEs were recorded and men completed the FACT-P, a questionnaire which grades QoL. The patients also completed a hot flash diary seven days prior to starting the gel and during days 21-28 of the intervention.

At baseline and day 28, hematology and biochemistry values were measured, including hemoglobin, hematocrit, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin, glucose, c-peptide, insulin-like growth factor 1 (IGF-1), triglycerides, and total and high-density lipoprotein (HDL) cholesterol.

In addition, biomarkers for bone remodeling were measured, including serum beta carboxyl-terminal type 1 collagen telopeptide (CTX), a marker for osteoclastic activity, and procollagen type 1 amino-terminal propeptide (P1NP), which reflects osteoblastic bone formation.

The primary outcomes were the serum E2 concentration change from baseline to day 28, as well as the change in the daily hot flash score. Secondary outcomes were changes from baseline to study end in other serum sex steroids, gonadotropins, updated homeostatic model assessment of insulin resistance (HOMA2-IR), IGF-1, bone remodeling markers, hot flashes, and prostate cancer-related QoL.

The age range of participants was 60 to 83 years, with 18 participants (49%) receiving ADT for more than 3 months (median: 3 months). Seven of the men (19%) were receiving medication to treat hot flashes, but doses were not altered during the study.

Both doses of E2 significantly increased serum E2 levels from baseline to day 28 when compared to placebo. The median serum E2 level was 208 pmol/L in the 0.9 mg dose group, and 220 pmol/L in the 1.8 mg group.

The average daily hot flash scores declined in the E2 group when compared to the placebo group (P=0.02). However, this did not translate into an improvement of QoL, as there were no significant changes in the FACT-P total score or any of the subscale scores in any group at day 28.

For hematological and biochemical secondary endpoints, changes from baseline to day 28 were not different between combined E2 and placebo groups for testosterone (TS) and dihydrotestosterone (DHT). Treatment with E2 led to increased serum estrone and sex hormone binding globulin (SHBG) and decreased serum FSH, as well as a slight increase in serum LH. There was no change in hemoglobin, glucose, insulin, HOMA2-IR, IGF-1, or lipids.

In the E2 group, CTX decreased significantly when compared to placebo; a smaller relative increment in P1NP was also observed. The researchers noted that studies that evaluate longer-term treatment will be necessary to determine whether this strategy will improve or preserve bone density.

None of the participants reported breast swelling. Grade 1 nipple tenderness by day 14—which persisted until day 28—was reported by one (8%), two (17%), and zero participants in the E2 0.9 mg, E2 1.8 mg, and placebo groups, respectively. No cardiovascular or thromboembolic events were reported.

The investigators noted that the primary limitations of the study were the short duration and the small sample size.

“In men who have castrate levels of both E2 and TS, daily transdermal E2 0.9-1.8 mg increases median serum E2 concentrations into the reference range reported for healthy young or older men, but with substantial variability,” the authors wrote. “E2 gel treatment reduces vasomotor symptoms and bone remodeling in older men with prostate cancer, and further suppresses partially suppressed serum FSH in the absence of TS.”

In addition, they point out that E2 add-back may have other benefits, such as mitigating metabolic effects of ADT as well as bone loss.

To read more about this study, click here.