Unmetabolized Estrogen (Depurinated Adducts) How I got PCa and how to prevent and detect it.

[KocoPr]

3 months before I got diagnosed with PCa in May of 2013 I had been feeling tired with no libido. I will bypass my health care profession system failures as it will take up to much space.

In Feb 2012-13 I ordered several tests through Genova Diagnostics (detox genomic and complete male hormone, nutra eval, organic acid comprehensive profile). I will reference the first two with a few of so many articles wirtten on the subject of unmetabolized estrogens and their very carcinogenic DNA depurinating adducts.

Just Some of the many articles in chronological order:

A unifying mechanism in the initiation of cancer and other diseases by catechol quinones (2004)

Abstract

The first step in cancer initiation is the reaction of chemical carcinogens with DNA to form stable adducts, which remain in DNA unless removed by repair, and depurinating adducts, which detach from DNA following destabilization of the glycosyl bond. Following these results, experiments on the metabolism of estrogens, formation of depurinating DNA adducts, carcinogenicity, mutagenicity, and cellular transformation have led us to the hypothesis that certain metabolites of endogenous estrogens--in particular, estradiol(estrone)-3,4-quinones--can react with DNA to form depurinating adducts at the N-3 of Ade and the N-7 of Gua. Depurination of these adducts can generate critical mutations by error-prone repair to initiate breast, prostate, and other cancers.

pubmed.ncbi.nlm.nih.gov/156...

Potential biomarker for early risk assessment of prostate cancer (2006)

Abstract

Background: Catechol estrogen quinones (CEQ) derived from 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2) react with DNA to form depurinating--N7Gua and--N3Ade adducts. This damage leads to mutations that can initiate breast and prostate cancer. To determine whether this damage occurs in humans, urine samples from men with prostate cancer and benign urological conditions, and healthy controls were analyzed. The objective was determining whether any of the cancer patients had formed the depurinating 4-OHE1(E2)-1-N3Ade adducts.

pubmed.ncbi.nlm.nih.gov/168...

Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention (2016)

Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma.

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

The 3,4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers (2021)

Abstract:

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.

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

Very Very good 2023 article on subject: I find the bolded text fascinating for monitoring our progression to castrate resistance as an early marker.

To block or not to block—hormonal signaling in the treatment of cancers

In the cell culture models of prostate cancer, it has been observed that local steroid metabolism is different in androgen-sensitive vs. Androgen-resistant cells (36). In LNCaP prostate cancer cells, as they progress toward an androgen refractory state, there are a decrease in oxidative activity and an increase in the reductive activity of 17-beta hydroxysteroid dehydrogenase 3 (17-βHSD). This results in the accumulation of bioactive estrogen (estradiol) in androgen refractory cells. Meanwhile, androgen-sensitive cells show a predominance of oxidized estrogens such as estrone (36).

Androgen-responsive LNCaP cells produce bioactive DHT and its derivatives as well as estrogen, while androgen-insensitive PC3 cells mainly produce oxidized androgen and estrogen derivatives such as androstenedione and estrone. This observation of altered steroid metabolism is crucial to the biological impact on the target cells (37).

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

You get the picture. I could list a thousand articles on this subject, but let me show you my two Genova Diagnostic tests (above and next post) pointing directly to why my specific cyp1A1, Cyp1B1, COMT, and GST caused me to have a very unbalanced and excees 3,4 Quinones which I think is why I have no detected "cancer sequencing mutations" but have somatic MSH6-loss which does point to a germline mutation/s. (The cancer genetic sequencing does not test for CYP1A family, COMT, GSTM1

[KocoPr]

Sorry I just realized i posted a duplicate and wrong image. above is the correct image of my Genomic mutations in the detox pathways.

My mutations greatly effected my estrogen metabolism causing DNA mutations and my cancer.

Genova Diagnostics Detox Genomic test

[No_stone_unturned]

I’m feeling stupid right now, but what does this mean layman’s terms…. Estrogen gel bad?

[PCaWarrior in reply to No_stone_unturned]

AI use is good. Reduces tumoral estrogen. Gel and patches replace SYSTEMIC estrogen. Redirect it.

[KocoPr in reply to PCaWarrior]

what do you mean by AI in this context?

[PCaWarrior in reply to KocoPr]

Aromatase Inhibitor

[KocoPr in reply to PCaWarrior]

oh yes, correct I will be asking for letrozole once I start BAT

[KocoPr in reply to No_stone_unturned]

It all depends on what your estrogen metabolites status/levels, your gene mutations, your PCa status (HSPC or CRPC).

In my case I have obviously known I have a bad estrogen metabolite issue so i am concerned on going on BAT or since im still HSPC and have been on Orgovyx and darolutamide for a year now I know my E2 will be dropping sometime and I want to do E2 gell adback.

I am also seriously considering stopping Orgovyx but I am highly concerned about all the unused testosterone from either that or BAT going down the aromatase pathway to create large amounts of estrogen and since I have all those mutations in this path (cyp1a1 cyp1b1,comt, gstm1) I will be producing high 3,4 quinones by (COMT) and it will also not be metabolized through a failsafe pathway (GSTM1) so it will create depurinated adducts that will create bad DNA mismatch repairs (cancer).

From what i have studied on this subject this is a major cause for breast, prostate, non Hodgkin’s lymphoma, renal cell carcinoma.

[NPfisherman]

KocoPr,

Thanks for the post...Can controlling hormones help to control our destinies?? I believe that such control may play a large role in prolonging vacations. I am starting Mucuna Pruriens for elevated Prolactin.. When I asked my MO for cabergoline, he said people shouldn't try to manage hormones, since some other hormone will go up in response. I disagree. I believe that controlling hormones, cholesterol, and inflammation can help control our disease.

All the best,

DD

[KocoPr]

Are you on vacation now?

If so you should test your estrogen panel. before taking any hormone blockers.

did you check out my the genova diagnostics estrogen metabolites above?

You can see the great disparity between good to bad estrogens.

you should either see if your doctor can order a male estrogen panel or try the complete male hormone panel at genova diagnostics.

[NPfisherman]

Not on vacation yet, but hopefully starting in July... I have been following my estrogen level for some time...was elevated in the beginning, and during abiraterone, it is normal or below, but no breakdown of estrogen levels...Time to do some other testing... Thanks for the advice... We learn from each other...

Have a great weekend...

DD

[KocoPr in reply to NPfisherman]

I had posted the wrong image in my second post so now it has the correct image of my mutations in the estrogen detox pathway. We certainly do learn from each other that's what is great about collaboration and the internet is the key.