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Blocking Estrogen In Brain Strikingly Anabolic For Female Muscles / Bones

Discussion in 'Scientific Studies' started by haidut, Jan 18, 2019.

  1. haidut

    haidut Member

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    In yet another great example of "synchronicity" (Synchronicity - Wikipedia), just a few days after posting the study on lack of estrogen and muscle growth, another fascinating study popped into my mailbox.
    Estrogen Is NOT Needed For Either Muscle Or Bone Growth / Anabolism

    Now, the study below add to the evidence that estrogen is not only not needed for muscle growth and bone health, but blocking its effects (in the brain) leads to such remarkably dense/strong bones in females (mice) that no other known model can even come close to. Simultaneously, the muscle mass of those females also increased dramatically and the authors think the two effects are not a coincidence. I don't know why the effects of blocking estrogen in males were much less pronounced than in females, but I suspect it is due to surges in progesterone activity. Progesterone is highly anabolic in females, but not so much in males. Be that as it may, hopefully this study will lead to serious reconsideration of estrogen therapy in females. The authors think that the anabolism from blocking estrogen in the brain reduces mating and physical activity in the females, and the resulting surplus of energy was diverted towards bone/muscle building. I guess it is another way of saying that stress is bad for women's bones/muscles and blocking the stress hormone (estrogen) allowed the females to grow as much as there is food available. I really see no reason why the same would not be true in males and the authors clearly state that blocking estrogen in brain would be therapeutic for both sexes even if this specific study did not find much anabolism for males.
    @Blossom @tara @Sheila @AretnaP @Wagner83 @Lokzo @RisingSun @jb116 @tankasnowgod
    @opethfeldt

    Estrogen signaling in arcuate <i>Kiss1</i> neurons suppresses a sex-dependent female circuit promoting dense strong bones

    "...Esr1Nkx2-1Cre females exhibited a sex-dependent change in energy balance that was entirely absent in male mice. The lean mass of mutant females was significantly higher than control floxed (Esr1fl/fl) littermates (Fig. 1d) and was accompanied by decreased physical activity during the dark phase (Fig. 1e and Supplementary Figure 2C). Although highly significant, increased lean mass observed in mutant females failed to change their overall mobility and muscle strength as measured by rotarod and grip strength assays, respectively (Supplementary Figure 2D, E). Blunted BAT thermogenesis was observed in mutant females as evidenced by whitening of BAT and decreased Ucp1 levels; circulating catecholamines were not lower (Fig. 1f and Supplementary Figures 2F, G). Serum leptin levels were also unchanged (Fig. 1g). Thus, these data reveal that central estrogen signaling in this brain region promotes a sex-dependent negative energy state in females in the absence of any change in feeding behavior. This unexpected finding implies that the hyperphagia reported for Esr1POMC-Cre mice might result from selective or ectopic activity of POMC-Cre in non-ARC neurons8."

    "...Strikingly, bone mineral density (BMD), as determined by dual X-ray absorptiometry (DEXA), was significantly elevated in Esr1Nkx2-1Crefemales, but not males (Fig. 1h), consistent with the sex-dependent significant increases in lean mass. Further analyses of femoral bone, using three-dimensional high resolution micro-computed tomography (µCT), confirmed a striking increase in trabecular bone mass and microarchitecture in older Esr1Nkx2-1Cre females compared to control littermates (Fig. 2a). Mutant females exhibited a ~500% increase in fractional bone volume in the distal femur, rising from 11 to 52 bone volume/tissue volume (BV/TV) (%) (Fig. 2a). A similar trend was found for vertebral bone (Supplementary Figure 3A). Accompanying structural changes included increases in trabecular number and thickness and reduced trabecular separation (Fig. 2a). Mutant females also exhibited a significant increase in cortical thickness but a modest decrease in tibial and femoral length (Supplementary Figure 3B). This striking skeletal phenotype is sex-dependent, as no changes in bone mass were observed in Esr1Nkx2-1Cre males (Fig. 2b). Further, unlike the 20% increase in femoral bone mass reported for Esr1POMC-Cre and Esr1Nestin-Cre mice that vanishes in OVX females, bone parameters in Esr1Nkx2-1Crefemales remained elevated 5 weeks following ovariectomy (Fig. 2c). In fact, no significant changes in serum sex steroids (E2, T) were detected in 4–5-week-old mutant females when the high bone mass phenotype is clearly present (Fig. 2d, f)."

    "...Pituitary and thyroid hormones in mutant females were also unchanged at 7–8 weeks of age (Supplementary Figure 3C). Removing circulating androgens in juvenile Esr1Nkx2-1Cre males by castration failed to elevate their bone mass, implying that male gonadal hormones are unable to account for the lack of high bone mass in Esr1Nkx2-1Cre males (Supplementary Figure 3D). These data imply that while the high BMD in Esr1Nkx2-1Crefemales is partially maintained by ovarian steroids, elevated levels of circulating E2 or pituitary hormones are not the primary drivers of this sex-dependent bone phenotype."

    "...Mechanical bone strength tests established that femora and L5 vertebrae in older Esr1Nkx2-1Cre females were substantially stronger than controls (Fig. 2e). The dense skeletal phenotype in Esr1Nkx2-1Cre females observed in femoral and vertebral trabecular bone emerged early and continued to persist in older females (54–74 weeks), exceeding values found for OVX mutant females (Fig. 2c, f, g). Thus, trabecular bone, which becomes porous and more fragile in osteoporosis, is remarkably dense and durable in older Esr1Nkx2-1Cre females. Upregulation of bone metabolism in Esr1Nkx2-1Cre females was not associated with ectopic Cre expression in femoral bone (Supplementary Figure 3F). Representative H&E stained femoral bone sections from juvenile female mice illustrate the striking increase in bone density accompanied by a marked decrease in bone marrow space (Fig. 2h). Despite a narrowing of the bone marrow cavity, no differences in spleen weights were observed in mutant females compared to controls at all ages examined (Supplementary Figure 3E)."

    "...Our investigation to understand the complex role of estrogen signaling in the MBH establishes that ERα-expressing Kiss1 ARC neurons are central to restraining a powerful brain–bone axis in female mice. This assertion stems from the sex-dependent, high bone mass phenotype that emerged from three independent, intersectional strategies that target central ERα signaling. When compared with other mouse models that alter bone remodeling, several prominent features emerge from our results. In particular, the only model that, to our knowledge, rivals the magnitude of volumetric bone density increase observed in Esr1Kiss1-Cre and Esr1Nkx2-1Cre females is the sclerostin null (Sost−/−) mouse40,41. However, the Sost−/− bone phenotype is observed in both sexes and the connectivity density is substantially lower40. Moreover, we find that selectively removing ERα in the ARC of older, estrogen depleted females results in an impressive ~50% increase in bone density, indicating a potential therapeutic value in manipulating this female neuroskeletal circuit. Disrupting this neuroskeletal circuit enhances genetic pathways associated with osteogenesis and results in fully functional mature bones with exceptional strength. When considered alongside the well-established role of peripheral estrogen in the prevention of bone loss42, our findings illustrate that the same hypothalamic neurons used to restrain the onset of puberty also inhibit anabolic bone metabolism in females. We speculate that once this female ERα-dependent brain-to-bone pathway is disturbed, energetic resources are funneled into bone and diverted away from reproduction and energy expenditure (Fig. 6f)."

    "...Given that prodynorphin, a marker of KNDy ARC neurons is suppressed by estrogen, but not by tamoxifen46, one might also speculate that some of the bone-sparing effects of this selective ERα modulator47 stem from its antagonist activity in the ARC."

    "... That sclerostin, a known repressor of bone metabolism is elevated in Esr1Nkx2-1Cre mutants implies that their massive increase in female volumetric bone mass is independent of sclerostin. Thus, we conclude that the high bone mass in our mouse models results from activation of a potent signaling pathway that promotes bone formation by a humoral mechanism and is initiated in the brain."

    "...In summary, our work reveals an unprecedented sex-dependent bone phenotype and provides unequivocal proof of brain-to-bone signaling55. Furthermore, our findings demonstrate the importance of central estrogen signaling (which exists in a coregulatory system with peripheral estrogen) in the maintenance of bone homeostasis in females. Breaking this neuroskeletal homeostatic circuit in young and old females promotes anabolic bone metabolism and provides a model for further mechanistic investigations that might eventually provide opportunities to counteract age-related osteoporosis in both women and men."
     
  2. miki14

    miki14 Member

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    Nicotine acts like an anti estrogen in the brain. Girls between the age of 12-25 years smoke disproportionately a lot.
     
  3. OP
    haidut

    haidut Member

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    Not surprised, as nicotine is an aromatase inhibitor. I think these effects are systemic though, not just in the brain, but this would be even better as per the other thread on AI and muscle/bone growth.
    Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    It also inhibits the enzyme 3a-HSD, which degrades DHT into weaker metabolites. So, consuming nicotine both lowers estrogen and raises androgens (at least DHT).
    Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate. - PubMed - NCBI
     
  4. miki14

    miki14 Member

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    It also inhibits the enzyme 3a-HSD, which degrades DHT into weaker metabolites. So, consuming nicotine both lowers estrogen and raises androgens (at least DHT).

    Smoking was considered a 'manly' product until the 60s.
     
  5. Captain_Coconut

    Captain_Coconut Member

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    What is the dose range for nicotine to achieve estrogen blocking? Is not the half life of nicotine fairly short, or is it substantial enough to be practical method of increasing dht?
     
  6. tankasnowgod

    tankasnowgod Member

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    The health issues with smoking aren't mainly to do with nicotine. There are many harmful compounds in cigarette smoke, and I would think regularly inhaling any sort of smoke would be damaging to the lungs.

    Iron researcher E.D. Weinberg has suggested that the main harm caused by cigarette smoking is inhaling excess iron, and I believe has suggested that iron free cigarettes would be safe to smoke (or at least much safer)

    https://www.ncbi.nlm.nih.gov/pubmed/18704272

    https://www.ncbi.nlm.nih.gov/pubmed/10527070

    The drug buproprion has enjoyed quite a bit of success as an anti-smoking aid, sold under the name Zyban. One of it's actions is as a Dopamine Re-Uptake Inhibitor. It looks like there is some research to suggest that Bromocriptine could also do the same thing-

    https://www.ncbi.nlm.nih.gov/pubmed/11092065

    https://www.ncbi.nlm.nih.gov/pubmed/12126493
     
  7. miki14

    miki14 Member

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    I used nicotine gum with 2 & 4mg every other day and had really good results. Then I discovered cigarettes...:arghh:
     
  8. Captain_Coconut

    Captain_Coconut Member

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    To answer my own question. From reviewing the study haidut posted on baboons. It appears the hed to reduce estrogen in the amygdala by ~39% would be around 1 to 1.5 mg nicotine every 90 minutes. However the paper also mentions cotinine having an effect, I know cotinine has a much longer half life... so I think a longer term study would be more revealing. Also this was on female baboons only.
     
  9. Captain_Coconut

    Captain_Coconut Member

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  10. OP
    haidut

    haidut Member

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    Cotinine is indeed a much more powerful AI than nicotine, and longer-lasting too. Similar to caffeine where Peat said "coffee is more than caffeine", I'd say "smoking is more than nicotine". One thing is for sure - smokers do have much higher androgen and lower estrogen levels than non-smokers. Most of the harms from smoking is from the tobacco treatment (ammonia) and other toxins they add such as flame retardants, anti-mold, etc. Pure tobacco, smoked through an activated charcoal filter is probably not nearly as bad and may even be...healthy?? Here is one long and fascinating thread on Longecity that for those interested in seeing authoritarianism and group-think in action.
    Smoking is good for you! - Lifestyle - LONGECITY

    Look for the comments by user @nightlight in that thread.
     
  11. OP
    haidut

    haidut Member

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    Absolutely. And if big companies had not ruined the quality of tobacco products by adding all sorts of toxic and carcinogenic chemicals I'd dare to say that occasional smoking may be even good for us. See my comment directly above this. A fascinating (and bitter) discussion on smoking risks/benefits.
     
  12. Wagner83

    Wagner83 Member

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    Travis suggested using some gamma tocopherols to reduce the risks even further, some brilliant or at least long lived people have smoked their entire life (cuban cigars?..). I'm curious what would be the differences between quality cigars and cigarettes, I never looked into it. From what I remember Ray didn't like some of the effects. You mentioned great mood and digestive boost from it, it was also one of the few supplements tyw had reported good success with when used as needed. It seems that some problems may arise from chronic use (e.g. hard time quitting).
    Nicotine [Through A Peat Prism?]
     
  13. OP
    haidut

    haidut Member

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    I think the main difference is the manufacturing methods and the additional processing that cigarettes undergo. Kind of like the difference between a steak and a burger. With steak, you mostly know what you are getting, but just about anything can be ground and put into a "burger". Many cigars are hand made and all they have in them is tobacco. I think in cigarettes, up to 30% is something other than tobacco and (similar to food labeling) if a certain ingredient does not cross a specific threshold amount it does not even have to be reported. Tobacco by itself has been shown to be non-carcinogenic to rodents, even as smoke, while cigarettes have. So, something in those cigarettes is giving cancer. The food and pharma industry conveniently exclude countries like Cuba and Dominican Republic from their longevity studies because otherwise they'd have to explain how come heavy cigar-smoking and rum-drinking populations live for so long.
     
  14. Regina

    Regina Member

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    Haha. I smoked from age 12 - 20. (mostly rolled my own. Yes, I was that kind of 12 year old).
     
  15. Ron J

    Ron J Member

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    @haidut
    What about eating tobacco? Is it problematic for the gut? If it isn't, would it have the same effects as smoking it?
     
  16. tankasnowgod

    tankasnowgod Member

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    Fascinating. Nightlight makes some really good points in that thread. I have never been much of a smoker but never brought fully into the anti-smoking propaganda, either. About 10-15 years ago, I experimented with smoking casually about 2-3 days a week. Mostly, I was interested in the "expensive" cigarettes. Even basically being a novice smoker, I could tell a world of difference between a Nat Sherman Cigarette, and the major brands. The Nat Sherman was pleasant. Other brands? Not so much. I don't even think the Nat Sherman's impacted me by the next day. Any major brand suuuuure did.

    I also remember seeing a book on Amazon by some doctor who recommended using chewing tobacco to quit smoking, even over nicotine patches. His main point was that chewing tobacco was less harmful than smoking, and even just regularly using that was a big improvement to health (and he had a whole section on special oral care), and that some people may eventually step down to not using tobacco at all. I can not find that book anywhere anymore.

    Also, in Broda Barnes "Hypothyroidism" book, I remember him taking about how cigarettes and alcohol were positively associated with heart attacks, exercise was inversely associated, but he was still cautious to jump to the conclusion that any of the behaviors were causal.
     
  17. OP
    haidut

    haidut Member

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    Nightlight addresses many of these correlations in the thread above. It seems that unhealthy people tend to drink/smoke more and when they have a CVD event it is blamed on the tobacco/alcohol. We already know that alcohol abuse is a form of self-medication to blunt cortisol, so I don't see why smoking would also not be a similar self-medication, possibly for low dopamine.
    Here is another contrarian view to keep you confused and searching for truth :): A medical student cured his IBD by smoking 3-4 cigarretes a day. Much bigger studies have repeatedly confirmed the link between smoking and remission or cure of IBD in the past. Doctors just never advertise those news but the article talks about them. I think what the medicla student achieve could also be done by chewing tobacco and possibly nicotine gum/patch.
    'Doctors don't always know best:' Student claims he cured debilitating bowel disease by taking up smoking | Daily Mail Online
     
  18. OP
    haidut

    haidut Member

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    I don't know about eating, but chewing and spitting it is probably a lot less harmful than smoking it.
     
  19. tankasnowgod

    tankasnowgod Member

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    Excellent article. One thing that strikes me very clear in this, that both you and Nightlight point out.... if a big enough entity starts a campaign against something, labeling that substance as "dangerous," they can effectively make this a self fulfilling prophecy. In this case, just make cigarettes so filled with toxins that it can't be disputed that they are very harmful to your health, even if pure tobacco is much more benign, or even a net positive for health. Similar techniques have been used in the campaigns against saturated fat and sugar.

    This also reminds me of this article by Kurt Harris, where he describes how encouraging the adding of toxins to both drugs and alcohol have been used in both prohibition and the war on drugs- https://www.psychologytoday.com/us/blog/archevore/201103/tylenol-and-the-war-drugs
     
  20. schultz

    schultz Member

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    Haha, yah but some people don't seem to understand this, especially since tobacco has been demonized so much.

    Tea is generally considered healthy by the mainstream, but that doesn't mean smoking it is going to be so great.

    Another example would be something like kale. You would expect it to be unhealthy to smoke the stuff lol.

    It's possible that both of these examples could be worse than tobacco, who the heck knows. Nobody is smoking 2 packs of kale a day for 50 years.
     
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