[Stevenator.]

I'm curious just how much it will change (?)
I dig PM's calming effects & breast growth.  
I've yet to see any long term before/after facial changes. 
Pharma changes are very obvious. I do get confused about
fat/muscle changes vs. bone, though 
That link/info you just posted sounds a bit on the scary side.

[The First Aria]

My GD claims it does not change bone structure..  But as T goes too low, you must have enough E to keep bone density up.  I wonder Steve, if you are stuck at the cross roads and therefore maybe loosing bone structure?

Another thing that my GD warned me about was the fact of some height loss, hands and feet due to the fact that connective tissue and cartilage soften and sometimes shrink.  So, maybe it has more to do with bone structure as anything else?

[Lotus]

Holy sh**........milk thistle inhibits testosterone (and rather big league-ly too).    


Time- and Concentration-Dependent Inactivation of Testosterone Metabolism of P450 3A4 by Silybin. 6 -Hydroxytestosterone was the major metabolite detected when testosterone was incubated with purified recombinant P450 3A4 in a reconstituted system in the presence of NADPH. Silybin inhibited the metabolism of testosterone by P450 3A4 in a time-, concentration-, and NADPH-dependent manner.   
http://dmd.aspetjournals.org/content/dmd...7.full.pdf

[Atom]

I have read that Silybin down-regulates and inhibits ERα in breast cancer cells in some studies, does this have any other meaning, e.g. how does Silybin affect ERα in general? Also I have read it has an anti-aromatase side as well. Is it like pumpkin seeds which while being potent anti-androgen (from what I have read) is also an anti-aromatase and ERα inhibitor? Is all this good or bad for NBE?

[Lotus]

Holy sh**... milk thistle inhibits testosterone.

Time- and Concentration-Dependent Inactivation of Testosterone Metabolism of P450 3A4 by Silybin. 6 -Hydroxytestosterone was the major metabolite detected when testosterone was incubated with purified recombinant P450 3A4 in a reconstituted system in the presence of NADPH. Silybin inhibited the metabolism of testosterone by P450 3A4 in a time-, concentration-, and NADPH-dependent manner.   
http://dmd.aspetjournals.org/content/dmd...7.full.pdf

I have read that Silybin down-regulates and inhibits ERα in breast cancer cells in some studies, does this have any other meaning, e.g. how does Silybin affect ERα in general? Also I have read it has an anti-aromatase side as well. Is it like pumpkin seeds which while being potent anti-androgen (from what I have read) is also an anti-aromatase and ERα inhibitor? Is all this good or bad for NBE?

This might go against logic (or maybe not lol), it is in my opinion that if we think of DHT as a precursor to aromatase we'd understand how powerful DHT is over aromatase, it certainly has a higher affinity for conversion to androgens over aromatase.

Milk Thistle inhibits testosterone:

Time- and Concentration-Dependent Inactivation of Testosterone Metabolism of P450 3A4 by Silybin. 6 -Hydroxytestosterone was the major metabolite detected when testosterone was incubated with purified recombinant P450 3A4 in a reconstituted system in the presence of NADPH. Silybin inhibited the metabolism of testosterone by P450 3A4 in a time-, concentration-, and NADPH-dependent manner.   

SILYBIN INACTIVATES CYTOCHROMES P450 3A4 AND 2C9 AND INHIBITS MAJOR HEPATIC GLUCURONOSYLTRANSFERASES 
http://dmd.aspetjournals.org/content/dmd...7.full.pdf

From the study, approximately 250mg of SILYBIN (milk thistle) was used to inhibit Testosterone, and metabolized in about 9 to 18 min. Here's the real find though:

silybin (milk thistle) inhibits both phase I and phase II enzymes which inactivates P450s 3A4. Additionally, Silybin was approximately 14- and 20-fold more selective at inhibiting UGT1A1 (aka-Glucuronidation) which is an important metabolic pathway in the liver such as steroid hormones.

Now, from my calculations using pseudofirst-order kinetics, milk thistle decreases T approximately 62% in 9-18min.

Time- and Concentration-Dependent Inactivation of the 7EFC Activity of P450 2C9. As shown in Fig. 4, with P450 2C9 the silybin-mediated inactivation of the 7EFC O-deethylation activity was also time-, concentration-, and NADPH-dependent. Approximately 35% activity loss was seen in 15 min when 50 M silybin was used. The inactivation exhibited pseudofirst-order kinetics. The double- reciprocal plot of the values of the initial rate constants versus the silybin concentrations gave a KI of 5 M, a kinact of 0.14 min 1, and t1/2 of 7 min. 

Transcriptional regulation of human UDP-glucuronosyltransferase genes.
Hu DG1, Meech R, McKinnon RA, Mackenzie PI.
Author information

Abstract
Glucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3-1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of endogenous molecules that are primarily inactivated by UGTs. Deciphering the molecular mechanisms underlying tissue-specific UGT expression has been the subject of a large number of studies over the last two decades. These studies have shown that the constitutive and inducible expression of UGTs is primarily regulated by tissue-specific and ligand-activated transcription factors (TFs) via their binding to cis-regulatory elements (CREs) in UGT promoters and enhancers. This review first briefly summarizes published UGT gene transcriptional studies and the experimental models and tools utilized in these studies, and then describes in detail the TFs and their respective CREs that have been identified in the promoters and/or enhancers of individual UGT genes.

In this study DHT and EGF decreased the protein level of UGT2B17  by 75% ,  that was correlated with a decreased production of DHT-G by 73%. I take that to mean decreasing a protein like UGT2B17 it decreases (inhibits DHT) by 73%.

Differential Regulation of Two Uridine Diphospho-Glucuronosyltransferases, UGT2B15 and UGT2B17, in Human Prostate LNCaP Cells*
http://press.endocrine.org/doi/pdf/10.12...138.7.5226


I see Calcium D-Glucarate as an alternative to Milk Thistle, but the metabolism would be slower,  meaning a longer half life. I also have Calcium D-Glucarate as a pro-aromatase.


Calcium D-Glucarate - is an extract found in fruits and vegetables that has been found to be  beneficial in helping to remove toxins and excess used hormones, preventing them from being reabsorbed into the blood stream and deposited in the tissues of your body. Calcium D-Glucarate helps to support liver function and detoxification and boosts the immune system.

[Atom]

I guess you are saying that it is more important to squash the more potent DHT than whatever level of inhibition of aromatase is caused by Silybin? Also about the other thing you mentioned: how does its inactivation of P450 3A4 and inhibiting of Glucuronidation affect NBE? Thanx.

[Lotus]

I guess you are saying that it is more important to squash the more potent DHT than whatever level of inhibition of aromatase is caused by Silybin? Also about the other thing you mentioned: how does its inactivation of P450 3A4 and inhibiting of Glucuronidation affect NBE? Thanx.

Exactly, squash DHT by multiple means (pathways) and we'd see better gains. 

Re: Glucuronidation- think of Glucuronidation as a process to eliminate toxins (too detoxify) from tissues, (via excretion). see this attached study below as an example of using glucuronidation. As we know, GTE inhibits DHT.......it's all relative lol. 

Free Radic Res. 2004 Sep;38(9):1025-31.
Glucuronidation of the green tea catechins, (-)-epigallocatechin-3-gallate and (-)-epicatechin-3-gallate, by rat hepatic and intestinal microsomes.
Crespy V1, Nancoz N, Oliveira M, Hau J, Courtet-Compondu MC, Williamson G.
Author information


Abstract
The flavonoids (-)-epigallocatechin-3-gallate (EGCg) and (-)-epicatechin-3-gallate (ECg) are major components of green tea and show numerous biological effects. We investigated the glucuronidation of these compounds and of quercetin by microsomes. Quercetin was almost fully glucuronidated by liver microsomes after 3 h, whereas ECg and ECGg were conjugated to a lesser extent (12.2 +/- 0.2 and 7.5 +/- 0.2%, respectively). The intestinal microsomes also glucuronidated quercetin much more efficiently than ECg and EGCg. Although the rates were lower than quercetin, intestinal microsomes exhibited higher activity on the galloyl group of ECg and EGCg compared to the flavonoid ring, whereas hepatic glucuronidation was higher on the flavonoid ring of EGCg and ECg compared to the galloyl groups. The low glucuronidation rates could partially explain why these flavanols are present in plasma as unconjugated forms.

[Lotus]

Greetings, 


Steroidal lactones as inhibitors of 17beta-hydroxysteroid dehydrogenase type 5: chemical synthesis, enzyme inhibitory activity, and assessment of estrogenic and androgenic activities.
Bydal P1, Luu-The V, Labrie F, Poirier D.
Author information

* 1Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and University Laval, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
Abstract
Androgens are well known to play a predominant role in prostate cancer and other androgen-dependent diseases. To decrease the level of androgen testosterone in the prostate, we are interested in developing inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5). This enzyme expressed in the prostate is one of the two enzymes able to convert 4-androstene-3,17-dione into testosterone. From a screening study, it was found that a series of steroid derivatives bearing a lactone on D-ring demonstrated potent inhibition of 17beta-HSD5 over-expressed in HEK-293 cells. The results of enzymatic assays using intact cells indicated that a C18-steroid (estradiol or 3-deoxyestradiol) backbone and a spiro-delta-lactone (six-member ring) are important for a strong inhibitory activity. Moreover, the presence of a dimethyl group at the alpha-position of the lactone carbonyl increases the selectivity of the inhibitor toward 17beta-HSD5. Compound 26, a 3-deoxyestradiol derivative with a dimethylated spiro-delta-lactone at position 17, possesses the most potent inhibitory activity for 17beta-HSD5 (IC(50)=2.9 nM). It showed no binding affinity for estrogen, androgen, progestin and glucocorticoid receptors (ER, AR, PR and GR). A weak proliferative effect was, however, observed on ZR-75-1 (ER+) cells in culture at high concentration (1 microM), but not at 0.03 microM. Interestingly, no significant proliferative effect was detected on Shionogi (AR+) cells in culture in the presence of 0.1 and 1 microM of lactone 26.


So check this out:

C18-steroid (estradiol or 3-deoxyestradiol) backbone and a spiro-delta-lactone (six-member ring) are important for a strong inhibitory activity.

My translation?, estradiol with spiro demonstrated a potent inhibition of 17beta-HSD5 in the prostate ( inhibiting DHT). Now when a dimethyl group (e.g. MSM) was added it had the strongest inhibiting effect. 

even more loosely translated    E2 + spiro + MSM has an effective inhibiting effect over DHT, and thus boosting spiro's ability (or bioavailability). 

[Atom]

Do you think MSM with other anti-androgens or with PM will have a similar effect?

[Lotus]

Do you think MSM with other anti-androgens or with PM will have a similar effect?

Yes, it seems quite possible......meaning the science is there, although yet to be deciphered on our part....lol the world is our oyster. 

I sought to find a natural (herbal) derivative of " Lactone " to Spirolactone, and wow I wasn't disappointed, it's like peeling an onion (the jumbo colossal types they use for awesome blossoms or bloomin' onion, lmao). I used wiki to help explain this process I see, though sources need to be confirmed ( I feel confident we're on the right track though). I'll have to break all this down in the coming New Years.........thank you Atom for the query. So, the CYP2C9 enzyme pathway we'll help us to incorporate a theory of " PM + CYP2C9 + MSM " . And that's only the beginning, meaning other variations will certain be gained from exploring this alternative. 


Natural sources
Edit
Naturally occurring lactones are mainly saturated and unsaturated γ- and δ-lactones, and to a lesser extent macrocyclic lactones. The γ- and δ-lactones are intramolecular esters of the corresponding hydroxy fatty acids. They contribute to the aroma of butter, cheese and various foods and fruits. Cyclopentadecanolide is responsible for the musklike odor of angelica root oil. Of the naturally occurring bicyclic lactones, phthalides are responsible for the odors of celery and lovage oils, and coumarin for woodruff.[3] Lactone rings occur widely as building blocks in nature, such as in ascorbic acid, kavain, nepetalactone, gluconolactone, hormones (spironolactone, mevalonolactone), enzymes (lactonase), neurotransmitters (butyrolactone, avermectins), antibiotics (macrolides like erythromycin; amphotericin B), anticancer drugs (vernolepin, epothilones), phytoestrogens(resorcylic acid lactones, cardiac glycosides).
https://en.m.wikipedia.org/wiki/Lactone

Natural sesquiterpen lactones as acetylcholinesterase inhibitors
Abstract
Background and the purpose of the study: The amount of elder people who suffer from Alzheimer disease is continuously increasing every year. Cholinesterase inhibitors have shown to be effective in alleviating the symptoms of the disease, thus opening a field of research for these treatments. Herbal products, owning a reputation as effective agents in many biological studies are now drawing attention for inhibiting acetylcholinesterase, in other words, Alzheimer disease. In the present study, the ability of three sesquiterpene lactones from Inula oculus-christi and I. aucheriana to inhibit AChE has been evaluated through Ellman assay. Materials and Methods: Gaillardin and pulchellin C were obtained from I. oculus-christi and britannin from I. aucheriana by chromatographic methods. They were dissolved in methanol in concentration of 3 mg/mL and the AChEI activity of the compounds was determined by Ellman method using Acethylthiocholine iodide as the substrate and 5, 5'-dithiobis-2-nitrobenzoic acid as the reagent, in 96-well plates at 405 nm. Results: AChEI activity of the examined compounds was obtained as 67.0, 25.2 and 10.9% in concentration of 300 µg/L for gaillardin, britannin and pulchellin C, respectively. Conclusion: Among the three sesquiterpene lactones, gaillardin with 67% inhibition of AChE could be considered a good candidate for future Alzheimer studies.
https://www.researchgate.net/publication...inhibitors

https://en.m.wikipedia.org/wiki/Sesquiterpene_lactone

https://en.m.wikipedia.org/wiki/Apigenin

https://en.m.wikipedia.org/wiki/CYP2C9



Mechanism of CYP2C9 inhibition by flavones and flavonols.
Si D1, Wang Y, Zhou YH, Guo Y, Wang J, Zhou H, Li ZS, Fawcett JP.
Author information

Abstract
This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4'-hydroxylation in the CYP2C9 RECO system, with K(i) value https://www.ncbi.nlm.nih.gov/pubmed/19074529



Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism.
Spector AA1, Kim HY2.
Author information

Abstract
Polyunsaturated fatty acids (PUFA) are oxidized by cytochrome P450 epoxygenases to PUFA epoxides which function as potent lipid mediators. The major metabolic pathways of PUFA epoxides are incorporation into phospholipids and hydrolysis to the corresponding PUFA diols by soluble epoxide hydrolase. Inhibitors of soluble epoxide hydrolase stabilize PUFA epoxides and potentiate their functional effects. The epoxyeicosatrienoic acids (EETs) synthesized from arachidonic acid produce vasodilation, stimulate angiogenesis, have anti-inflammatory actions, and protect the heart against ischemia-reperfusion injury. EETs produce these functional effects by activating receptor-mediated signaling pathways and ion channels. The epoxyeicosatetraenoic acids synthesized from eicosapentaenoic acid and epoxydocosapentaenoic acids synthesized from docosahexaenoic acid are potent inhibitors of cardiac arrhythmias. Epoxydocosapentaenoic acids also inhibit angiogenesis, decrease inflammatory and neuropathic pain, and reduce tumor metastasis. These findings indicate that a number of the beneficial functions of PUFA may be due to their conversion to PUFA epoxides. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". 
Published by Elsevier B.V.
https://www.researchgate.net/publication...metabolism