Return to Estrogen?

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Remarkably, estrogen was discovered to be a cancer driver for breast cancer by surgeons in the late 1800’s but it was 5 decades before the relationship of hormones to prostate cancer was discovered. George Beatson had considered performing oophorectomy for women with breast cancer because the procedure was successful in prolonging lactation in cattle. His first patient experienced a complete remission from soft tissue breast ca metastases and lived another 4 years. He later said that he thought this treatment would induce “fatty degeneration” of malignant cells.

The relationship of testosterone as a driver of prostate cancer is credited to Huggins and Hodges, who found that either surgical castration or administration of estrogen to men with prostate cancer could reduce what was then the only known marker of prostate cancer, acid phosphatase. Additionally, if they administered testosterone to these patients, the acid phosphatase would increase. This built on observations that the enzyme was present in the prostate gland and would go up in patients as they developed metastases, usually in the bones. For this work, Huggins was awarded the Nobel prize in 1966. The use of surgical castration or estrogen administration remained the mainstay of treating metastatic prostate cancer until the introduction of leuprolide in the early 1980’s. I had the extraordinary opportunity to participate in those trials, which we published in 1984. We compared leuprolide to DES, an oral form of estrogen that works on the same endocrine axis as leuprolide, causing the pituitary gland signaling hormone, LH to drop, and subsequently the testicles stop making testosterone. Leuprolide worked as well as DES, but oral estrogen is dangerous – leading to blood clots and increased risk for heart attacks or strokes. Thus, leuprolide (and other GnRH analogs…including the recently approved oral GnRH antagonist, relugolix) became the standard for ADT therapy of prostate cancer.

But estrogen still works. In fact, it may have some significant advantages over surgical castration or GnRH therapy. Our team found that DES could still produce meaningful responses in patients with rising PSA’s who had failed GnRH even though we did see blood clots. But, you can also give estrogen via transdermal patches which avoids many of the problems of oral DES. This week, the PATCH trial program in the UK reported the safety results of using estradiol patches (E) to treat prostate cancer patients compared to GnRH agonists. The ability to produce therapeutic (castrate level) testosterone was the same, but the E treated patients had lower cholesterols, lower blood pressure, less diabetic tendencies, and far fewer hot flushes. Previous study analyses have shown that E is better for bone health with no calcium loss. The only thing that was worse was breast enlargement (gynecomastia) which was seen in 86% of E patients compared to 38% in the GnRH agonist patients. To some extent, gynecomastia can be treated by radiating the breast tissue. The efficacy of E in treating the prostate cancer in these patients will be reported in 2023 and 2024. The cost of E treatment (4x .025mg/24h patches every 3.5 days) is about $62/week ($750/3 months) which is definitely less than any of the GnRH agonists or antagonists. It will be terrific if this “old fashioned” treatment can again join the treatment options for men with advanced prostate cancer. I think it would also be reasonable to try in patients who are failing the newer second generation agents before trying the more expensive/complicated/toxic alternatives like taxane chemotherapy or radionuclide agents (Radium 223, Lu177-PSMA, etc.) With PSA monitoring, it should be relatively easy to find patients who benefit from such treatment.


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7 responses to “Return to Estrogen?

  1. Robert Taylor

    Hi Dr G
    Would it make sense for someone like me to start E on top of ADT?

  2. Unknown and would require a trial. It could make sense biologically, but it could also simply add toxicity with no benefit. We need to know how often it would work in anyone who has progressed on 2nd gen ADT first, then it would require 100’s of patients in a randomized trial, then another trial of combined therapy “up front” to definitively answer your very reasonable question.

  3. Thomas Remenick

    Quite interesting. Another bit of evidence to support the adage “everything old is new again”.

  4. Jeff Dwyer

    Dear Dr. Glode,

    I’m curious what you’d recommend to PCa gents who would like to use tE2 for their primary ADT and monitor their T, E and PSA using LabCorp testing but they have no source to obtain the tE2? It has been my experience that COE will not allow their MOs to prescribe tE2 for primary ADT since the financial settlements of the class action lawsuits against the drug makers of DES and the accompanying malpractice suits against the medical establishments that resulted from the use of the oral DES pill. As a result, getting tE2 has become a challenge, and finding a MO to even discuss the use of tE2 is difficult. Presently, men with PCa exchange information about tE2 use and sourcing anonymously using online PCa health forums.


    • I don’t have much experience with using transdermal E2 in prostate cancer. As my blog pointed out, it seems to be safe (compared to GnRH analogs) with fewer hot flashes, probable better bone preservation, but gynecomastia. We published on low dose DES which was an interesting option for CRPC before the 2nd gen ADT agents were developed, but we did see blood clots, even with the low dose approach.

  5. Richard Wassersug

    Dear Dr. Glode,

    I am both a PCa patient and psycho-oncology research with particular interest in transdermal E2. I have, for example, been a coauthor with PATCH team on their one paper look at QoL for patients on transdermal E2.

    I just learned of your blog from another PCa patient and just read this posting from some 4 months ago. on the PATCH study.

    As a personal tag to your summary of the latest PATCH paper, I personal find that the gel product Estrogel is easier to use than the patches. I can fill you in on that in greater detail, if you are in fact prescribing tE2 to patients who need androgen suppression and wish to avoid the LHRH drugs.

    Feel free to email me directly.

    Richard Wassersug, PhD
    Honorary Professor
    Faculty of Medicine
    University of British Columbia

    Twitter: @LifeOnADT

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