Estradiol?

[JolleySprings]

Has anyone taken a low dose Estradiol along with ADT? If so, any benefits or harm??

Thank you all!!!

[pjoshea13]

Low-dose estradiol [E2] will cause no harm provided that E2 is maintained in the 20-30 pg/mL range - according to Life Extension this is the ideal range.

ADT will likely drive E2 below 12 pg/mL, resulting in bone loss. Add-back E2 is an attractive & logical way to counter this.

If low-dose E2 gets E2 into the 12-20 pg/mL range, any subsequent bone loss will not be due to E2 deficiency IMO. Don't forget vitamins K2 and D & the usual bone minerals - not just calcium & certainly not high-dose calcium.

I would aim for E2 = ~20 pg/mL.

-Patrick

[maley2711 in reply to pjoshea13]

Take D if D test is in normal range? Estradiol is not a prescription is it? Are most ROs & MOs OK with the patient using estradiol patches or gel while on ADT.? Did I read somewhere about estradiol being used as an ADT? I believe the pills caused unacceptable cardiac problems? But not the case with patch or gel?

[pjoshea13 in reply to maley2711]

Estradiol [E2] patches require a prescription in the U.S.

A blood test will verify deficiency - <12 pg/mL

The lowest dose Vivelle-Dot estradiol patch is all that is required: 0.025 mg/day.

You can go to your doctor armed with papers on the impotance of E2 to male bone health. but I don't see how any doctor could object to a patient wanting E2 to be in the 12-29 range.

There are no health concerns at the low dose.

Not to be confused with E2 for castration, which requires a massive dose to halt testosterone production.

Regarding vitamin D, someone recently posted that "serum level at 20 ng/ml ... is adequate".

While <20 is often the definition of deficiency, it to common to see 20 -32 described as 'insufficiency'.

The Vitamin D Council advises that we get above 50.

I have no specific target, but a recent blood test showed 73.2 ng/mL, which is fine with me.

When using an E2 patch, verify that it is doing the job. If E2 goes above 30 pg/mL, cut back to every other day (for example.)

-Patrick

[maley2711 in reply to pjoshea13]

Thank you....apparently estradiol not currently used for ADT......any chance of that happening in the future??

[pjoshea13 in reply to maley2711]

Not sure when the UK 'PATCH' trial will end, but it has been going on a long, long time - so things are looking good for E2 as a non-inferior approach.

Ironic, since before Lupron was approved for ADT in 1985, the synthetic estrogen diethylstilbestrol [DES] had been used for decades.

A number of men here are using E2 already.

See the latest PATCH paper (2021), below.

-Patrick

pubmed.ncbi.nlm.nih.gov/335...

Clinical Trial Lancet

. 2021 Feb 13;397(10274):581-591. doi: 10.1016/S0140-6736(21)00100-8.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme

Ruth E Langley 1 , Duncan C Gilbert 2 , Trinh Duong 2 , Noel W Clarke 3 , Matthew Nankivell 2 , Stuart D Rosen 4 , Stephen Mangar 5 , Archie Macnair 2 , Subramanian Kanaga Sundaram 6 , Marc E Laniado 7 , Sanjay Dixit 8 , Sanjeev Madaan 9 , Caroline Manetta 10 , Alvan Pope 11 , Christopher D Scrase 12 , Stephen Mckay 13 , Iqtedar A Muazzam 14 , Gerald N Collins 15 , Jane Worlding 16 , Simon T Williams 17 , Edgar Paez 18 , Angus Robinson 19 , Jonathan McFarlane 20 , John V Deighan 2 , John Marshall 2 , Silvia Forcat 2 , Melanie Weiss 2 , Roger Kockelbergh 21 , Abdulla Alhasso 22 , Howard Kynaston 23 , Mahesh Parmar 2

Affiliations collapse

Affiliations

1 Medical Research Council (MRC) Clinical Trials Units at University College London (UCL), London, UK. Electronic address: [e-mail].

2 Medical Research Council (MRC) Clinical Trials Units at University College London (UCL), London, UK.

3 The Christie and Salford Royal Hospitals, Manchester, UK.

4 National Heart and Lung Institute, Imperial College, London, UK.

5 Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.

6 Mid Yorkshire NHS Trust, Wakefield, UK.

7 Wexham Park Hospital, Frimley Health Foundation Trust, Slough, UK.

8 Scunthorpe General Hospital, Scunthorpe, UK.

9 Department of Urology & Nephrology, Dartford and Gravesham NHS Trust, Dartford, UK.

10 Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.

11 The Hillingdon Hospitals NHS Foundation Trust and Imperial College Healthcare NHS Trust, London, UK.

12 Ipswich Hospital, East Suffolk North Essex NHS Foundation Trust, Ipswich, UK.

13 Forth Valley Royal Hospital, Larbert, UK; Beatson West of Scotland Cancer Centre, Glasgow, UK.

14 Castle Hill Hospital, Hull University Teaching Hospitals NHS Trust, Cottingham, UK.

15 Macclesfield District General Hospital, East Cheshire NHS Trust, Macclesfield, UK.

16 University Hospital Coventry, Coventry, UK.

17 Royal Derby Hospital, Derby, UK.

18 Newcastle Urology, Freeman Hospital, Newcastle upon Tyne, UK.

19 Sussex Cancer Centre, Brighton, UK.

20 Royal United Hospitals, Bath NHS Foundation Trust, Bath, UK.

21 Department of Urology, University Hospitals of Leicester, Leicester, UK.

22 Beatson West of Scotland Cancer Centre, Glasgow, UK.

23 Division of Cancer and Genetics, Cardiff University Medical School, Cardiff, UK.

PMID: 33581820 DOI: 10.1016/S0140-6736(21)00100-8

Abstract

Background: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

Methods: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive.

Findings: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001).

Interpretation: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer.

Funding: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Copyright © 2021 Elsevier Ltd. All rights reserved.

[Carlosbach in reply to pjoshea13]

Extremely helpful info Patrick. Thank you

[E2-Guy in reply to pjoshea13]

Patrick, You are adamant about keeping E2 levels below the 30 pg/mL level. Richard Wassersug has been using tE2 gel for over 20 years (I'm in my forth year on it), and we both have E2 levels in the range of premenopausal women without any side effects other than some gynecomastia. Can you please explain why you are so against having higher levels?

Thanking you in advance,

Ron

[pjoshea13 in reply to E2-Guy]

For a man not on ADT, 20-30 pg/mL appears to be optimal. Above 30, there is increased risk of various health conditions.

I think of this as a state of estrogen dominance over testosterone, & there are studies that found the E2:T ratio to be more significant than either variable alone.

With ADT using E2 (or DES), T is no longer in the picture.

A huge level of E2 is required for castrate T. In the PATCH trial:

"The median (range) serum oestradiol levels was 442 (52.1–1542) pmol/L" [1]

Note that 442 pmol/L is 120 pg/mL (1542 pmol/L is 420 pg/mL!!!)

Classic ADT mostly results in E2 deficiency, causing rapid bone loss. So far as I can tell, most doctors don't even test E2, let alone treat deficiency with low-dose patches. Better to have E2=120 pg/mL than zero.

***

The E2:T Ratio.

"Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19" [2]

"Lower serum total T and PRL levels and higher total E2/T are independently associated with presence of hepatic steatosis in male patients with CHB." [3]

"The International Index of Erectile Function questionnaire (IIEF-EF) score correlated negatively with estradiol/testosterone ratio (E2/T)" [4]

"our study demonstrated a negative relationship between E2/T ratio and penile erection, particularly at the root of the penis" [5]

"Patients with significant depressive showed higher levels of estradiol (136 ± 48 versus 103 ± 48 pg/ml ... and E2/T" [6]

"a lower E2/T ratio was associated with a lower risk of incident MetS" [7]

"E2/T, was higher for prevalent CVD" [8]

"The ratio of E₂/T of male patients with lung cancer was also remarkably higher than that of control" [9]

"The elevated estradiol/testosterone (E2/T) ratio had been proved to be a risk factor for coronary heart disease (CHD) in elderly men."

etc.

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] pubmed.ncbi.nlm.nih.gov/346...

[3] pubmed.ncbi.nlm.nih.gov/341...

[4] pubmed.ncbi.nlm.nih.gov/340...

[5] pubmed.ncbi.nlm.nih.gov/325...

[6] pubmed.ncbi.nlm.nih.gov/264...

[7] pubmed.ncbi.nlm.nih.gov/256...

[8] pubmed.ncbi.nlm.nih.gov/201...

[9] pubmed.ncbi.nlm.nih.gov/213...

[10] pubmed.ncbi.nlm.nih.gov/822...

[E2-Guy in reply to pjoshea13]

Patrick,

Thank you so much for the extremely detailed reply to my questions. I didn't expect you to spend this much time to answer. You certainly are a PCa guru...I believe you know more than most urologists about PCa! After reading all of the papers that you have listed, I may be afraid to continue my unconventional tE2 regimen; however, Lupron injections are out of the question due to the numerous side effects. I also have no insurance in Thailand since Medicare pays for nothing.

In appreciation,

Ron

[pjoshea13 in reply to E2-Guy]

Hi Ron,

Richard has done extremely well on high-dose E2 & the PATCH trial will likely show non-inferiority to Lupron, etc. Note that I'm using DES (diethylstilbestrol) - back to the future, lol. Here in the US I am paying ~$50 for a 3 month supply.

The PATCH paper has this on DES:

"The oral oestrogen diethylstilbestrol (DES) is used in the UK to treat men with prostate cancer whose disease has progressed during first-line hormonal therapy, usually with LHRH analogues. The observation that DES produces and maintains a clinical response in patients with prostate cancer who are thought to already have castrate levels of testosterone is unexpected, and not fully explained. In 2003 DES became temporarily unavailable due to lack of production and some UK clinicians prescribed oestrogen patches instead. Kandola et al. [7] recently published a report documenting their centre's concerns with transdermal oestrogen therapy as a second-line hormonal intervention in prostate cancer."

"One of the reasons for releasing these data was to respond to an article which reported on the substitution of DES with transdermal oestrogen patches in men with prostate cancer who had progressed during first-line hormonal manipulation [7]. In that study, two Evorel-100 patches were administered twice weekly. No data were given on the oestradiol levels obtained or the effect on serum testosterone level. However, two interesting questions are raised by these second-line data. First, what is the mechanism by which DES produces clinical responses in testosterone-suppressed men who have developed androgen-independent prostate cancer; and second, would patches that release oestradiol be expected to act in the same way as DES? Of the several small published studies documenting the use of DES as second- or third-line therapy, PSA responses appear to occur in 30–40% of patients and last for ≈6 months, with a cardiovascular complication rate of 5–28% [16].

"DES is thought to act primarily by producing negative feedback on the hypothalamus and anterior pituitary, resulting in down-regulation of LH and a decrease in testosterone to castrate levels. Although castrate levels of testosterone have been defined as <1.7 nmol/L, recent data from Oefelein et al. [8] using current assays show that median testosterone levels after orchidectomy (in 35 men) were 0.5 nmol/L and that for most patients on LHRH therapy (33/38) testosterone levels were <0.7 nmol/L (20 ng/dL) [14]. Thus it is possible that DES could be providing additional down-regulation of LH in patients whose testosterone levels have not reached these lower levels. However, data from the original studies [3] of orchidectomy plus DES (5 mg daily) compared to orchidectomy plus placebo resulted in fewer deaths from prostate cancer in patients with Stage III and IV disease, at 107/473 (23%) vs 132/469 (28%), respectively, suggesting that DES might have additional mechanisms of action.

"Additional mechanisms of action that have been postulated for DES include direct cytotoxicity, androgen inactivation, and direct suppression of Leydig cell function in the testis [17]. There are also some in vitro data that question whether DES and other oestrogens would always be expected to have similar clinical effects. Robertson et al. [18] showed that DES inhibits growth and can induce apoptosis in prostate cancer cell lines at physiological concentrations, regardless of androgen sensitivity or oestrogen-receptor status, while oestradiol promoted growth of one of the cell lines positive for oestrogen receptors. Kalach et al. [19] also reported divergent biological effects of oestradiol and DES on a prostate cancer cell line. Oestradiol inhibits the growth of the MOP cell line whereas DES does not, and they suggested that this is due to oestradiol binding to mutated androgen receptors."

ncbi.nlm.nih.gov/pmc/articl...

Best, -Patrick

[E2-Guy in reply to pjoshea13]

Good morning Patrick,

I can't even begin to thank you enough for your in depth replies! I thought that I knew something about PCa; however, compared to you, I know nothing. I actually have difficulty even understanding some of them since they are so complex and I don't have the chemistry background.

I forward many of your posts/replies to my daughter and her husband (she is a pathologist and he is a neurosurgeon), and they are amazed at your vast chemistry, med, and PCa knowledge! They are wondering if you are an MD, or what your background is? If you are not a doctor, you would make one hell of a good one with your 'thorough' replies...$2000/hour would be a reasonable fee!

Regarding DES, I have previously mentioned that my father and his two brothers all had 'failed' RPs in their early sixties, and did extremely well on DES until it was banned and replaced with Lupron in 1985. They never felt the same on Lupron, but all lived into their late 80s (dad was 89, and his brothers died at 87 and 86).

You obviously have done your homework, and I appreciate the hundreds of posts that you have contributed in your efforts to helping all of us warriors. I don't find much on you as to your age, diagnostic info, how long you've been dealing with this shit, etc, but I wish you many more years of good health, and success with your somewhat unconventional regimens.

Ron

[dhccpa in reply to pjoshea13]

Estradiol is an Rx drug?

[pjoshea13 in reply to dhccpa]

Yes: "Vivelle-Dot is a prescription medicine ..." [estradiol transdermal system]

rxlist.com/vivelle-dot-drug...

[dhccpa in reply to pjoshea13]

Thanks

[MrG68 in reply to pjoshea13]

You can get vitamin K2 from grass dairy. Has to be grass fed though. I found that Kerrigold to be very good as a grass fed butter. I actually eat natto. It’s a fermented soy. I get a brand imported from Japan. If you decide to try it, try to get an organic soy because of GMOs.

Natto is the best form of K2 on the planet. It’s has other health benefits as well. Research it though because it is also a potential blood thinner.

Be warned - natto is an EXTREME acquired taste.

[pjoshea13 in reply to MrG68]

Natto, of course, is the original source of nattokinase. Nattokinase products derived from natto have had the K2 removed.

"One tablespoon of Natto contains 150 micrograms of vitamin K2, about twice the recommended intake."

Speaking of Japanese menus, unagi (eel) has 63 micrograms in a 100-gram serving, but I believe that is menaquinone-4.

"cheeses with the highest amount of vitamin K2 (menaquinone-7) per 50-gram serving include:

50 micrograms in Munster

34 micrograms in Camembert

About 32 micrograms in Edam and aged Gouda

12 micrograms in cheddar"

-Patrick

see also: intechopen.com/chapters/51024

[GP24]

E2 will also mitigate hot flushes.

[EdBar]

I’ve used estradiol patches for over 7 years now to help with hot flashes etc. They work like a charm. Several YouTube videos out there by Snuffy Myers on them.

Ed

[PBnative in reply to EdBar]

Thanks fo the reminder about Snuffy videos. I’m going to ask my MO for patches for hot flashes and bone strength

[Exrunner]

From my perspective doctors do the prostate cancer patient a disservice if they do not prescribe estradiol when they prescribe ADT. The side effects (bone loss, hot flushes, brain fog, etc.) of extended ADT are well documented (and should be well known by doctors). Since it is not standard of care (SOC) I have yet to find a doctor that will prescribe it or provide an explanation as to why it shouldn't be used. I have found plenty of articles that suggest that Estradiol patches or creams can be used to mitigate the side effects of extended ADT. I have not found any articles that indicates that it may be harmful to the patient if the levels are maintained in the 12-30 pg/ml. While the estradiol patches required a prescription bioidentical cream can be purchased OTC. Use of OTC estradiol requires the PCa patient to monitor his estradiol levels through regular lab test to ensure they stay in the recommended 12-30 pg/ml range. If the doctor won't order the estradiol test it can be purchased online at a reasonable rate.

Studies are underway, I believe in the UK and India using high levels of Estrogen patches to bring men to castrate levels. The side effects are less severe that current ADT used in the U.S.

Good Luck!

[PhilipSZacarias]

Hello JolleySprings, I have been on Lupron since 2016 and abiraterone since 2020. I was becoming concerned about the loss of bone density and possible fractures so I decided to add-back the missing estradiol (E2) to maintain (not gain) density. I started applying estradiol gel last April, 2021. I use EstroGel manufactured by Merck. It contains 0.06% estradiol (E2) and I apply 1.25 grams (1 pump) = 0.75 mg E2 at bedtime which results in an average E2 concentration of about 13.5 pg/ml 12 hours after application. The surface area that a given amount of E2 gel is applied affects the concentration in the blood - the smaller the area the higher the concentration (go to Wikipedia's "Estradiol Pharmacokinetics" page). I apply the gel to my inner thigh over an area of approximately 265 cm2. I initially experienced an increased sensitivity of the nipples, which subsided over time. There has been no significant breast enlargement over that caused by ADT alone. I have experienced a slightly greater sense of well being and appear to have gained maybe some muscle mass in the arms. Hot flashes were already on the decline when I started applying E2, but I believe they are definitely less frequent and minimally bothersome. I was very fortunate to find a family doctor who understood what I was trying to (he happened to prescribe EstroGel to many women) - no oncologist would prescribe it. A bone density scan will be performed this year. Fingers crossed. I hope this is helpful. Cheers, Phil

[MateoBeach]

Yes I have used estradiol patch with ADT and found it beneficial. I used the generic for the expensive Vivelle Dot patch called Dotti. I tried the PATCH trial protocol with four 0.10 mg/24 hrs patches at a time, without an ADT shot. But not getting to Castrate T level so I went for a Firmagon shot, but kept with just one patch changed twice weekly. Not only protecting my bones (also on Prolia, calcium 500, D3 with K2). But also no hot flushes at all and much less brain fog and fatigue than I had experienced previously on ADT. Worth it and proven safe in the PATCH Trial. Search that and print out for your MO. If still a no go, try a local naturopath to prescribe it. Paul

[Hidden]

I have used it two ways:In 2019 I did 5 months of ADT. I used high-dose estrogen patches (0.3-0.4 mg/day) to drop my testosterone to zero. During this time, DEXA scans revealed that I had a small amount of bone growth in one area, I did not have hot flashes, and I did not have depression.

Late last year I started bipolar androgen therapy. On the low T phases, I replace some estrogen using 0.05-0.1 mg/day patches. I experimented one time (never again) and did not use a patch. Within 2 weeks my mind went to a very dark, depressed, paranoid place. I did some Androgel later that night and within hours I was normal. I do not anticipate ever going low T with low E again.

3. The Importance of Estrogen (Estradiol) in Men’s Health

tctmed.com/estrogen-in-men/

10. Estrogen patch ADT

a. PATCH Results: Consider Transdermal Estrogen for Advanced Prostate Cancer - Physician's Weekly

physiciansweekly.com/patch-...

b. PCa Commentary | Volume 126 - September 2018 - Grand Rounds in Urology

grandroundsinurology.com/pc...

43. Estrogens for or during ADT (or reduction of estrogens)

a. The resurgence of estrogens in the treatment of castration-resistant prostate cancer – PMC

ncbi.nlm.nih.gov/pmc/articl...

b. Estrogen Patch Treats Prostate Cancer with Fewer Adverse Events

cancernetwork.com/view/estr...

c. Transdermal estradiol therapy for advanced prostate cancer--forward to the past? – PubMed

pubmed.ncbi.nlm.nih.gov/126...

d. (I have not tried this) A possible method to use for low dose estrogen replacement if it isn’t possible to obtain estrogen patches: The pros and cons of phytoestrogens - PMC

ncbi.nlm.nih.gov/pmc/articl...

e. Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy | Nature Reviews Clinical Oncology

nature.com/articles/ncponc0602

f. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first‐line hormonal therapy in patients with locally advanced or metastatic prostate cancer - Langley - 2008 - BJU International - Wiley Online Library

bjui-journals.onlinelibrary...

g. Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer - PMC

ncbi.nlm.nih.gov/pmc/articl...

h. Estradiol for the mitigation of adverse effects of androgen deprivation therapy in: Endocrine-Related Cancer Volume 24 Issue 8 (2017)

erc.bioscientifica.com/view...

i. Concurrent Androgen and Estrogen Ablation and Inhibition of Steroid Biosynthetic Enzyme Treatment for Castration-resistant Prostate Cancer | Anticancer Research

ar.iiarjournals.org/content...

My MO supports the use of estrogen during ADT. My urologist did not but when I flat out asked him "does it make ADT less effective?", he admitted no. I followed up with "is it beneficial to have zero estrogen?", he admitted no. Then I stated, "so a low dose estrogen replacement does not make ADT less effective and it is beneficial to have some estrogen." He agreed.