Estrogen therapy rediscovered

[GP24]

Before Lupron got FDA approval, prostate cancer was treated with orchiectomy or estrogens. The latter was done with diethylstilbestrol (DES) offered as fosfestrol and many further names. In India diethylstilbestrol is offered as Honvan and still used today against prostate cancer.

In men, the required estrogen is produced from testosterone. If you increase the level of estrogens, the body will start to reduce the level of testosterone to reduce the level of estrogens again. This is a very successful therapy for prostate cancer but it caused a high risk of cardiovascular events. This was demonstrated by several VACURG studies. When Lupron was approved, estrogen therapy was therefore replaced by hormone therapy with Lupron.

However, menopausal women treat hot flashes and bone loss with estrogens, knowing this has cardiovascular risks. Therefore estrogen patches and estrogen gels have been developed. When you add estrogens using a transdermal patch, the risk of cardiovascular events is much reduced. Transdermal administration bypasses first-pass hepatic metabolism and therefore avoids the vascular toxicity of oral oestrogen.

Within the STAMPEDE trial there is an arm which tests transdermal patches as a hormone therapy versus Lupron and similar drugs. This therapy starts with four 100 μg patches per 24 h, changed twice weekly. Then this is reduced to three patches twice weekly. This trial includes 904 patients using the transdermal patches while 790 are in the control group using LHRH injections. Recently an article was published which reports that no difference in the risk of cardiovascular events could be found between transdermal patches and Lupron. Both therapies reduced the testosterone level by 93% (0.4–1.1 nmol/L) after three months: thelancet.com/journals/lanc...

Why would you prefer to use patches versus Lupron? The side effects of ADT are mainly caused by the reduction of estrogen which is again caused by the reduction of testosterone. The patches, however, do not reduce estrogens and therefore avoid many of the side effects an ADT with Lupron has ncbi.nlm.nih.gov/pmc/articl... .

The side effects mainly caused by the reduction of testosterone are:

erectile dysfunction, loss of muscle mass and loss of muscle strength

The side effects mainly caused by the reduction of estrogens are:

hot flashes, bone loss (osteoporosis), increased insulin resistance, increased weight, memory loss, and lipid changes

In a previous article it was reported that there was no bone mineral density loss with the patch therapy: ncbi.nlm.nih.gov/pmc/articl...

The patients also reported a better quality of life using the patches: researchgate.net/publicatio...

On the other hand patches cause breast enlargement (gynecomastia). This can be mitigated by using Tamoxifen or breast radiation or surgery.

Details how to apply an estrogen patch therapy can be found in the STAMPEDE protocol: ctu.mrc.ac.uk/media/1282/c-...

However, not all patches work equally well. The STAMPEDE trial uses FemSeven patches. This abstract reports differences between these patches and different ones:

„On FemSeven [patches] all patients were castrate, serum T[testosterone] 0.4–1.1 nmol/L and Oe[estrogen] range 449–1226 pmol/L. After 4 weeks on the other brand: Oe range 166–591 pmol/L and 3/10 patients were not castrate (serum T 5.9, 3.5 and 4.9 nmol/L.) Back on FemSeven the 3 patients became castrate within 4 weeks and the Oe range of the group was 411–990 pmol/L.“ maturitas.org/article/S0378...

Dr. Myers recommends Vivelle patches, these work well.

An alternative to using patches is a Bicalutamide monotherapy with 150 mg which also does not reduce estrogens. You can also add low dose patches (0.1 mg twice a week) to a Lupron therapy to increase estrogens and mitigate side effects this way.

This topic has been discussed in this thread: healthunlocked.com/advanced...

You can also try to switch to an estrogen therapy when Lupron stops working and you become resistant. Before Abiraterone was approved, this switch was often done to reduce the PSA level again. In the following study, 79 % of the castration-resistant patients had a decline of more than 50% in their PSA value after switching to an estrogen therapy:

annalsofoncology.org/articl...

The median duration of the response was 3.5 months. However, 73% of the patients in the study were already symptomatic at treatment start while non-metastastic castration-resistant is common today. In that case a longer duration of the response is likely.

You can also add 0.5 mg Dexamethasone to reduce the testosterone level even further. Dexamethason blocks the testosterone production via the adrenal gland while the estrogen therapy reduces the testosterone production of the testis. Here is a report by Doug, a patient using transdermal patches together with Dexamethasone: web.archive.org/web/2016032...

His success is not accidental, the effect of adding Dexamethasone to Lupron when patients become castration-resistant is demonstrated in this trial: acsjournals.onlinelibrary.w...

GP

[noahware]

Great summary. Thank you!

[Tall_Allen]

Really bad idea to take dexamethasone. Steroids carry a lot of side effects. Also, I'm not sure about tamoxifen with estrogen - it may block its effects. Breast radiation works poorly.

[dhccpa in reply to Tall_Allen]

Yes, trading side effect for side effect.

[TeleGuy]

GP, thank you for the thorough and well-documented post! The dexamethasone aspect of this really intrigues me because of what is happening in my case. When my PSA started rising while on abiraterone+prednisone, I switched to to AA+dex in November 2019. My PSA plummeted. I started 177Lu-PSMA therapy in December 2019 and was asked to stop AA while on treatment. I continued on dex for a month and then slowly tapered off. As I tapered off the downward slope of my PSA started to flatten and then it actually rose while I was doing the 177Lu-PSMA every 6 weeks. At that point (April 2020) I went back on 0.5mg of dex and my PSA has been undetectable since July 2020. I'm now past the 7 month median to 177Lu-PSMA rechallenge (anecdotal from TUM in Munich) and no sign of a PSA. At this point I have to wonder how much of my current success is due to the dex and how much is due to the 177-Lu PSMA treatment! I'm continuing to cross my fingers as every blood test rolls around.

[GP24 in reply to TeleGuy]

Teleguy,

Lupron, Firmagon or the estrogen patches reduce the testosterone production of the testis but not the production by the adrenal gland. Abiraterone reduces the testosterone production by the testis, the adrenal gland plus the testosterone production by the tumor itself. Dexamethasone reduces the testosterone production of the adrenal gland only.

So if you combine Lupron with Dexamethasone, this will work almost as well as Abiraterone. It will stop testosterone production of the testis and the adrenal gland. Just the testosterone production by the tumor is not stopped. This is the logic that explains why Lupron plus Dexamethasone works better than Lupron alone.

Dexamethasone has further effects. It will reduce inflammation and the tumor causes inflammation to support its growth. Therefore you can sometimes observe that Dexamethasone reduces the Interleukin-6 inflammation marker. To what extend this helps to fight the cancer is unknown.

I know another patient who has been using low-dose Dexamethasone for almost ten years now. He does intermittent ADT and in each cycle reduces his PSA value to undetectable. He uses even lower doses of Dexamethasone 0.25 or 0.125 mg. He says this dose still works for him.

I think the Lu177 therapy just debulked the tumor and this helped to make ADT (+Dexa) more effective. ADT will last longer when there are fewer tumor cells to fight against. (Studies by Klotz and Morote)

GP

[TeleGuy in reply to GP24]

I'm encouraged to hear about the other patient you know. I don't expect anything intermittent with the mCRPC I have now. But I am still amazed at a) the strong evidence that abiraterone was not failing, it was the prednisone, and b) that something as simple as 0.5mg of dexamethasone can suppress my adrenals enough to keep the cancer at bay without abiraterone. I don't have a lot of bulk, just a collection of several LN. I am also pleasantly surprised that in the 3 months after my last 177Lu treatment they continued to shrink. So I'm just maintaining with goserelin+dex.

[Hidden]

Thanks for the information. I have benefited from the Zytiga + steroid switch with 2 years of undetectable PSA so far.

I just read the ACS Journals article you linked and found it very interesting and informative. Many of the patients who took Dexamethasone also had an improvement in their anemia. I've been anemic since I started ADT, but just noticed recently that my numbers have slowly been improving and was wondering what was going on. I'm almost in range on the Hemoglobin now, quite an improvement from even 6 months ago.

[GP24 in reply to Hidden]

Thank you Gregg, since I do not have anemia I did not take notice of this effect of Dexamethasone. Just read that the most common side effect of Olaparib is anemia. Maybe one should try to add low-dose Dexamethasone to Olaparib.

[Hidden in reply to GP24]

My HGB was 12.8 before the switch and 13.8 at the last blood test. RBC is also up.

[MateoBeach]

Good summary GP and much to consider. Especially the low dose dexamethasone. I tried straight E2 patches for ADT with RT. 4X 0.10 of Dotti which is generic for Vivelle. Added tamoxifen 10 for breast swelling which resolved promptly. Was still a bit above castrate after 3 weeks so I punted by getting a little Firmagon shot (120 mg). Was castrate the next day. Reduced the E2 to two patches changed every two days as most is released in the first 48 hrs, whether 4 or 7 day patches. Stayed castrate for four more months without further Firmagon. Tamoxifen continued to work well never felt so wonderful on ADT.

[bluesnjazz]

The research I've done shows estrogen therapy among the highest risk for causing heart trouble. And you'll almost certainly get large, painful breasts (I did).

[GP24 in reply to bluesnjazz]

I discussed this in my post:

This is a very successful therapy for prostate cancer but it caused a high risk of cardiovascular events. This was demonstrated by several VACURG studies.

[However,] When you add estrogens using a transdermal patch, the risk of cardiovascular events is much reduced. Transdermal administration bypasses first-pass hepatic metabolism and therefore avoids the vascular toxicity of oral oestrogen.

[AlmostnoHope]

Fantastic post. I know 6 guys with serious CRPC after Xtandi, Orgovyx, etc. that have lowered their PSA's to single digits in a month using HONVAN. It's amazing.

[ragnar2020 in reply to AlmostnoHope]

In my opinion, HONVAN the oral estrogen med can be extremely dangerous if taken orally for ADT use with PCa especially if the man has any cardiac issues. There is a reason why oral estrogen is not easily available in the US. Transdermal estrogen tE2 using patches or gel is an ADT med for reducing testosterone, and it is used successfully around the world as an ADT med. Simplistically, tE2 has proven to cause fewer cardiac events than do oral estrogen meds. Just be very careful with oral estrogen and explore the use of tE2 before you proceed with DIY ADT treatments. Richard Wassersug offers expert advice in the use of tE2 for those men seeking some guidance.

[GP24 in reply to AlmostnoHope]

Hello AlmostnoHope,

thank you for your message! Do you know the dose of Honvan these patients got and how long it worked to keep the PSA value below 10?

GP24

[ragnar2020 in reply to GP24]

Hello GP24,

No, I do not know anything about Honvan oral estrogen. From researching about estrogen on the web, I learned that oral estrogen has a long complex history. There was a class action lawsuit filed in Boston about the use of oral estrogen that was settled prior to trial. The suit was about the use of oral estrogen given to mothers that accused the drug companies, docs, and hospitals of administering estrogen leading to birth defects and cardiac deaths. Almost immediately following the settlement of that lawsuit, the sale of oral estrogen disappeared from the marketplace in the US. There is a complete history of all this on Wikipedia.

Administration of estrogen using dermal patches and gels through the skin is still used for ADT because as I understand it, the estrogen does not get processed through the liver which has been attributed to the cause of the cardiac issues. Men use dermal estrogen - tE2 - in other countries that have national health care for ADT. Those foreign countries do not have attorneys waiting to file medical malpractice lawsuits against the tE2 prescribing docs and suppliers of tE2.

Search on the HealthUnlocked portal for "tE2" and "estrogen for ADT" and you'll find postings explaining this in much more detail.

Good luck,

Jeff

[AlmostnoHope in reply to GP24]

I know guys it has held PSA under 1.0 for 10 years using it intermittently 1 month and off 3-5 months all had PSA above 100.

[GP24]

Jeff,

I did mention the risks of estrogen therapy in my post:

"This is a very successful therapy for prostate cancer but it caused a high risk of cardiovascular events. This was demonstrated by several VACURG studies. When Lupron was approved, estrogen therapy was therefore replaced by hormone therapy with Lupron."

I also mentioned that you should use patches instead:

"When you add estrogens using a transdermal patch, the risk of cardiovascular events is much reduced. Transdermal administration bypasses first-pass hepatic metabolism and therefore avoids the vascular toxicity of oral oestrogen. "

Next year the results of the STAMPEDE trial's patch arm will be published and I expect this to be "practice changing".

GP24

[ragnar2020 in reply to GP24]

Yep, I failed to return and read the numerous posts from the beginning. Like you and others, I hope the Stampede and Patches trial in UK results in enough support for tE2 to become SOC in the US so PCa care can move away from overpriced ADT drugs to other ways of regulating testosterone.