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dr. frankenstein

Nandrolone and Stanozolol can be directly estrogenic/progestagenic

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Effects of Acute Stanozolol Treatment on Puberty in Female Rats

http://www.biolreprod.org/content/64/5/1460.full

"The data presented here provide only indirect evidence that stanozolol is acting at the ER. Additional analyses of binding of stanozolol to the ER or evaluation of stanozolol action in ER knockout mice are essential to confirm this hypothesis"

 

 

Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens.

 

http://www.sciencedirect.com/science/article/pii/S0960076006000641

The binding of estradiol (E(2)) to estrogen receptors (ER) is followed by conformational changes resulting in coactivator or corepressor recruitment that influences gene transcription. A series of synthetic A-ring reduced 19-nortestosterone-derived progestins has the capacity to selectively bind and activate transcription through the ERalpha. Herein, the molecular mechanisms involved in ER subtype-selective interactions of these compounds as assessed by their effects upon both ERalpha and ERbeta structural conformation and their ability to induce recruitment of steroid receptor coactivator-1 (SRC-1) to ERalpha were investigated. The results demonstrated that all synthetic A-ring 3beta,5alpha-tetrahydro-reduced derivatives of 19-nortestosterone induced an ERalpha trypsin digestion pattern similar to that seen with E(2), without effects upon ERbeta. In addition, these compounds had the ability to recruit SRC-1 to the ligand-binding domain of ERalpha similar to E(2). Our data indicate that A-ring 3beta,5alpha-tetrahydro-reduced 19-nortestosterone-derived progestins behave as selective ERalpha agonists with ligand-receptor structural and functional responses similar to those induced with natural E(2).

 

 

 

Estrogenic and progestagenic activities of physiologic and synthetic androgens, as measured by in vitro bioassays.

Markiewicz L, Gurpide E.

Mount Sinai School of Medicine (CUNY), Department of Obstetrics, Gynecology and Reproductive Science, NY, USA.

Estrogenic activities of testosterone (T) and 5a-dihydrotestosterone (DHT) were detected and measured by using their specific stimulatory effects on alkaline phosphatase (AP) activity in human endometrial adenocarcinoma cells of the Ishikawa Var-1 line. These two physiologic androgens were able to induce, at microM concentrations, estrogenic effect believed to be mediated by the estrogen receptor (ER) since the antiestrogens ICI-164384 and 4-hydroxytamoxifen (OHTam), but not the antiandrogens hydroxyflutamide (OHFl) or cyproterone acetate (CPA), reversed that effect. By using another in vitro bioassay, based on the progestin-specific stimulation of AP activity in cells of the T47D human breast cancer line, progestagenic activity was detected and measured in T, DHT and three synthetic androgens: nandrolone (19-nortestosterone). 7 alpha-methyl 19-nortestosterone (MENT) and mibolerone (7 alpha, 17 alpha-dimethyl 19-nortestosterone) (DMNT). While progestagenic effects of T and DHT required relatively high concentrations (microM levels), the synthetic androgens stimulated AP activity at nM or pM levels. These effects seem to be mediated by the progesterone receptor (PR), since they are completely abolished by the antiprogestins RU-486, ZK-98299 and ZK-112993, but not by the antiandrogen OHFl. These simple in vitro bioassays, expressing biological effects of the test compounds in human cells in culture, revealed dual or multiple hormonal activities coexisting in a single compound and provide quantitative information of considerable pharmacological importance concerning the complex actions of drugs.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837307/

 

..Nandrolone itself shows significant binding affinity and full agonist activity with the alpha-estrogen receptor...

 

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https://www.sciencedirect.com/science/article/pii/S096007600400216X?via%3Dihub

 

...19-nortestosterone showed a clear dose-related response with estrogen receptor α....

 

 

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I've always wanted to try nandrolone but never did because I'm prone to gyno sides.  =/  Good to know that an AI wouldn't help.

 

I wonder what other AAS/DS share this attribute.

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stanozolol 

 

https://www.ncbi.nlm.nih.gov/pubmed/8079819

 

...indicating that stanozolol binds to the progesterone receptor...

...These results indicate that the inhibition of DNA synthesis by stanozolol is elicited through the progesterone receptor...

 

https://www.sciencedirect.com/science/article/pii/S0034528812003797

... hindering progesterone activity...

 

 

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a very interesting article about AASs binding

albeit a theoretical article,

it reproduces various experimental findings.

 

stanozolol a tripetiae steroid ??

 

 

Synthetic anabolic steroids binding to the human androgen receptor

http://www.nipne.ro/rjp/2015_60_7-8/RomJPhys.60.p1112.pdf

 

 

Within this study we assess the affinity binding of a few synthetic anabolic oral administrable steroids: oxymetholone, oxandrolone, methandrostenolone and stanozolol to the human androgen receptor (hARLBD) and a few nonspecific receptors. Molecular docking studies reveal that all these steroids are able to bind to the hARLBD and other nuclear and hormone receptors, despite the law sequence similarity between these receptors. The highest binding energy is registered for methandrostenolone binding to hARLBD, its molecular properties being the most similar to those of the natural ligand, testosterone. Stanozolol provides higher interaction energies for nonspecific receptors in comparison to its interaction with hARLBD.

 

Four oral administrable synthetic anabolic steroids are considered in this study: oxymetholone (OXY), oxandrolone (OXA), methandrostenolone (MAS) and stanozolol (STA).

 

interesting thing, can bind to thyroid receptor (less fat ?)

 

binding domains of such possible nonspecific receptors: 1UOM for human estrogen receptor, 2BAW for human nuclear receptor, 2PIN for thyroid receptor and 3L0J for orphan nuclear receptor. We assessed the interactions of considered anabolic steroids with these targets and the results are presented in Table 4. All considered anabolic steroids are able to bind to these targets, some predicted interactions being stronger than their interaction with the human androgen receptor binding domain.

 

No hay texto alternativo automático disponible.

 

The results obtained within this study indicate that synthetic anabolic steroids are able to bind to the active site of hARLBD and also to another human nuclear and hormone receptors.

 

Among the synthetic anabolic steroids, the methandrostenolone possesses the highest binding affinity for hARLBD. Moreover, its molecular properties are the most similar to those of testosterone and this outcome illustrates that even small differences in the ligand properties significantly influences the interaction strength. For the nonspecific interactions, stanozolol possesses the highest binding energies for almost all the nonspecific targets, these energies being even higher than its interaction energy with hARLBD.

 

 

 

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Blocks Glucocorticoids Receptors

 

https://www.vin.com/apputil/content/defaultadv1.aspx?id=3846454&pid=11147&

 

...stanozolol shows a higher affinity for the glucocorticoid receptors than for those of the androgens. The glucocorticoid receptor block is carried out for low Stanozolol doses and it reduces the tissue catabolic activity...

 

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Why the binding of androgens to ERs

 

 

Determinants of Ligand Specificity of Estrogen Receptor-α: Estrogen versusAndrogen Discrimination

http://www.jbc.org/content/273/2/693.long

 

We have been interested in understanding how the estrogen receptor (ER) binds estrogens and discriminates between different classes of steroids with closely related structures. Using insights from our prior studies on ER and from sequence comparisons of steroid receptors, we identified three residues in the hormone-binding domain of the human ER, Leu345, Thr347, and Glu353, that we considered were likely to be involved in steroid A-ring recognition and therefore estrogen versusandrogen discrimination. We then tested the effect on ER activity of mutating these ER residues to the corresponding androgen receptor residues. Specifically, we examined the ability of the mutant receptors to bind and be activated by 17β-estradiol and three different androgens. No change in receptor activity was observed with the T347N mutation, while the L345S mutation greatly reduced ER activity in response to all ligands. Interestingly, the E353Q substitution behaved as expected, causing a 9-fold reduction in the transactivation potency of estradiol and a concomitant 10–140-fold increase in the transactivation potency of different androgens. These reciprocal changes in the transcriptional effectiveness of estrogens and androgens correlated with a decreased affinity of the E353Q ER for estradiol binding and an increased affinity for androgen binding. Therefore, amino acid Glu353 appears to be playing a significant role in binding the A-ring phenolic group of estradiol and in receptor discrimination between estrogens and the most closely structurally related steroids, androgens. 

 

 

Directed Evolution of Human Estrogen Receptor Variants with Significantly Enhanced Androgen Specificity and Affinity

http://www.jbc.org/content/279/32/33855.long

 

Human estrogen receptor α (hERα) and human androgen receptor exhibit exquisite ligand specificity, which underlies their remarkable ability to effect ligand-regulated gene transcription in a highly distinctive and specific manner. Here we used a directed evolution approach to create hERα variants with enhanced androgen specificity and affinity with the goal to better understand the molecular basis of ER ligand specificity and the evolutionary mechanism of nuclear receptors. We developed a sensitive yeast two-hybrid system to screen for hERα variants with increased transactivation potency toward testosterone. After two rounds of directed evolution, we identified five hERα variants with dramatically improved transactivation potency toward testosterone in both yeast and mammalian cells. These variants showed up to 7,600-fold improvement in the binding affinity for testosterone and only slightly reduced affinity toward 17β-estradiol. Detailed analysis of these evolved variants and a few site-directed mutants generated de novo led to several unexpected findings including the following. 1) Only two beneficial mutations were needed to create hERα variants with near nanomolar affinity for testosterone. 2) Some beneficial mutations were synergistic, context-dependent, or non-additive. 3) Of the five identified beneficial mutations, four of them were not in the ER ligand binding pocket and yet exerted important action on ligand specificity. 4) The single ligand-contacting mutation E353Q plays a dominant role in discriminating androgens and estrogens. These results, viewed in conjunction with the ligand exploitation model of nuclear receptor evolution, suggest that the mutation E353Q may represent a key event in the evolution of androgen receptors from an ancestral estrogen receptor and that ligand promiscuity may play an important role in the creation of new nuclear receptors via divergent evolution.

 

 

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