Brain steroid receptors and epigenetics

General Discussion
#1

I’m posting some interesting articles about steroid receptors in the brain. Sorry if they’ve been posted before by anyone else.

Hormonally mediated epigenetic changes to steroid receptors in the developing brain: implications for sexual differentiation.
Nugent BM, Schwarz JM, McCarthy MM.
Source
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA. bnuge001@umaryland.edu

Abstract
The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principal organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain.

#2

Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span.
Schwarz JM, Nugent BM, McCarthy MM.
Source
Program in Neuroscience, Department of Physiology, University of Maryland, Baltimore, 655 West Baltimore Street, 5-015, Baltimore, Maryland 21201, USA.

Abstract
Sexual differentiation of the rodent brain occurs during a perinatal critical period when androgen production from the male testis is locally converted to estradiol in neurons, resulting in masculinization of adult sexual behavior. Adult brain responses to hormones are programmed developmentally by estradiol exposure, but the mechanism(s) by which these changes are permanently organized remains poorly understood. Activation of steroid receptors plays a major role in organization of the brain, and we hypothesized that estradiol-induced alteration of steroid-receptor gene methylation is a critical component to this process. Estrogen receptor (ER)-α and ER-β and progesterone receptor are expressed at high levels within the preoptic area (POA) and the mediobasal hypothalamus, two brain regions critical for the expression of male and female sexual behavior. The percent methylation on the ER-α promoter increased markedly across development. During the critical period of sexual differentiation, females had significantly increased methylation than males or females masculinized with estradiol at two CpG sites. By adulthood, the neonatal sex difference and hormonal modulation of methylation were replaced with a new pattern at a different CpG site on the ER-α promoter. In contrast, the percent methylation on the progesterone receptor and ER-β promoter did not change developmentally but was modulated by hormones and exhibited only late emerging transient sex differences. These data indicate that sex differences in the methylation pattern of genes important for sexual behavior are epigenetically modified during development, but the specific changes observed do not endure and are not necessarily temporally associated with neonatal hormone exposure.

#3

Epigenetic setting for long-term expression of estrogen receptor α and androgen receptor in cells.
Imamura T.
Source
Laboratory for Biodiversity, Global COE Program, Division of Biological Science, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo-ku, Kyoto 606-8502, Japan. imamura@gcoe.biol.sci.kyoto-u.ac.jp

Abstract
Epigenetic regulation of the nuclear estrogen and androgen receptors, ER and AR, constitutes the molecular basis for the long-lasting effects of sex steroids on gene expression in cells. The effects prevail at hundreds of gene loci in the proximity of estrogen- and androgen-responsive elements and many more such loci through intra- and even inter-chromosomal level regulation. Such a memory system should be active in a flexible manner during the early development of vertebrates, and later replaced to establish more stable marks on genomic DNA. In mammals, DNA methylation is utilized as a very stable mark for silencing of the ERα and AR isoform expression during cancer cell and normal brain development. The factors affecting the DNA methylation of the ERα and AR genes in cells include estrogen and androgen. Since testosterone induces brain masculinization through its aromatization to estradiol in a narrow time window of the perinatal stage in rodents, the autoregulation of estrogen receptors, especially the predominant form of ERα, at the level of DNA methylation to set up the “cell memory” affecting the sexually differentiated status of brain function has been attracting increasing attention. The alternative usage of the androgen-AR system for brain masculinization and estrogenic regulation of AR expression in some species imply that the DNA methylation pattern of the AR gene can be established by closely related but different systems for sex steroid-induced phenomena, including brain masculinization.

#4

There was a member that recovered via the use of tamoxifen (SERM) and some people have reported feeling 100% normal following the use of a SERM, only to have their symptoms reverse. I wonder if a SERM will need to be combined with something in order to reverse some if not all our symptoms, for example, tamoxifen with deprenyl.

I also came across this:

Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells.
Shen F, Xue X, Weber G.
Source
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5119, USA.

Abstract
PURPOSE:
Tamoxifen and genistein were tested for synergism in estrogen receptor- negative human breast carcinoma MDA-MB-435 cells because the two compounds decrease signal transduction activity through different biochemical mechanisms and arrest the cell cycle at different phases.
MATERIALS AND METHODS:
The combination effect of tamoxifen and genistein on signal transduction was determined by measuring IP3 concentrations and on cell proliferation and colony formation by growth inhibition assay and clonogenic assay.
RESULTS:
In growth inhibition assays, for tamoxifen and genistein in the carcinoma cells the IC50s were (mean +/- SE) 17 +/- 0.9 and 27 +/- 1.6 microM; in clonogenic assays the LC50s were 0.9 +/- 0.4 and 12.5 +/- 1.1 microM, respectively. When tamoxifen and genistein were simultaneously added to the cells, synergism was observed in growth inhibition, in cytotoxicity and in the reduction of inositol 1,4,5-trisphosphate concentration.
CONCLUSION:
The synergistic down-regulation of signal transduction by tamoxifen and genistein may explain, in part at least, the synergistic antiproliferative and cytotoxic actions of the two compounds. The synergism of tamoxifen and genistein may be of interest in the clinical treatment of breast carcinoma.

Maybe tamoxifen with genistein will cause the reversal of PFS symptoms to hold? This was seen as a more more effective treatment for breast cancer than just Tamoxifen alone.

#5

Regulation of striatal dopamine receptors by estrogen.
Lammers CH, D’Souza U, Qin ZH, Lee SH, Yajima S, Mouradian MM.
Source
Genetic Pharmacology Unit, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract
The ability of estrogen to modulate the expression of ventral and dorsal striatal dopamine receptors D(1), D(2,) and D(3) was examined in vivo using semi-quantitative in situ hybridization and ligand binding autoradiography. Two-week treatment with subcutaneous pellets of 17beta-estradiol (25 mg) downregulated D(2) dopamine receptor mRNA in both dorsal and ventral striatum (shell and core regions of nucleus accumbens). No significant changes in D(1) or D(3) mRNA expression were detected. Ligand binding autoradiography did not reveal changes in D(1), D(2,) or D(3) receptor protein expression. We also assessed the ability of 17beta-estradiol to regulate D(2) gene promoter activity in NB41A3 neuroblastoma cells that express this gene endogenously using co-transfections with an estrogen receptor expression vector. While a small fragment of the D(2) promoter could be activated 2.5-fold by estrogen, a larger portion of the D(2) gene was not regulated by this treatment. Estrogens do not appear to have a net effect on striatal dopamine receptor expression. The observed downregulation of D(2) receptor mRNA in the dorsal and ventral striatum in vivo could be secondary to the increased striatal dopamine release induced by estrogen. Synapse 34:222-227, 1999. Published 1999 Wiley-Liss, Inc.

This struck me… CDP choline up-regulates dopamine receptors in the brain…it also increases LH, FSH, GH, TSH… estrogen causes an increase in dopamine that down-regulates dopamine receptors in the brain…

#6

Yeah, there’s the guy that relapsed later by taking some other drug, and this guy viewtopic.php?f=3&t=6851 where the recovery appears to have stuck.

#7

I wonder if our crash somehow causes this…

come off finasteride feeling normal
because finasteride still in our symptoms estrogen is high? (may take many weeks to clear finasteride out of cells)
lots of sex/masterbation causes increase in dopamine (in addition to high dopamine because of estrogen)
down regulation of dopamine receptors messes up HPTA axis resulting in low LH, FSH, GH, TSH

this may explain our sex hormones and thyroid hormones

also, the crash caused such a hormonal roller coaster that it induced epigenetic changes that persist indefinitely

Now…how to reverse. I’m starting to agree with Finatruth in that the estrogen receptor in the brain is playing a large role in this… I’m betting SERMS are important here but they need to be combined with something else in order to reverse the epigenetic alterations. Dopamine? Up-regulate dopamine receptors?

I think people who have been able to recover via SERM, or dopamine alone were not as severely affected. I think the long persisting cases of PFS have more epigenetic alterations than the others.

#8

I wonder a lot about the catalyst myself. I was more or less fine for six weeks after stopping, even with almost daily sexual activity and some drug use. It was only when I had sudden and extreme stress/anxiety that I crashed and this whole mess began.

#9

The question is, how do we reverse PFS now. I want to see what the research shows this year, but I’m curious if combining tamoxifen, genistein, and cdp choline will help… Genistein and cdp choline are dietary supplements and can be bought over the counter, but tamoxifen can’t…

Cap…you were taking drugs you say…well many drugs elevate dopamine, thats why you feel so good on them, same with alcohol… you probably elevated your dopamine to extremely high levels. You also say you were stressed. Stress elevates cortisol. It may just be that combined with the stress at the time, your body just couldn’t handle it, and it sort of makes sense, imagine what a hormonal roller coaster we all went through when we crashed.

#10

Well the drug I was using was MDMA, which dumps your serotonin and makes you feel awesome, but it only lasts maybe 3-4 hours and after that you’re left with nearly zero. So if anything, I should have crashed then, but I didn’t until weeks later. I also used it two other times while on the drug. I doubt using them helped my situation, but I don’t think it had much of anything to do with the crash given how long after the fact it was. I also got what might have been the most drunk I’ve ever been in my life a week after stopping (birthday celebration) which had no impact. I’d say the daily jerking it or sex would have had more of an impact. That raises cortisol, then I flipped my shit which probably REALLY raised already high cortisol and tipped the scales. All just speculation, of course. Doesn’t really matter now, I guess.

#11

Cap - that guy that recovered via Tamoxifen took Blue Up. Blue Up has Tribulus Terrestris. Guess what Tribulus Terrestris is?..a MAO inhibitor. Thats probably how it increases LH.

So he recovered by antagonizing the estrogen receptor while also activating dopamine receptors…

#12

When I get my bloodwork back I’m going to start a similar protocol as him using Blue Up, so we’ll see. Unlike most PFS dudes my bloodwork isn’t fine, my T is actually tanked. So I’m going to try to focus on raising that first. If my T is normal and I’m still fucked then I can move on to other things. I’m still going to toss in that celebrosin or whatever for good measure.