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Estrogen Potentiates The Effects Of Chronic Stress

Discussion in 'Scientific Studies' started by haidut, Jan 15, 2016.

  1. haidut

    haidut Member

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    A very, very important study, confirming Peat's views on how estrogen participates in the stress response manifested by release of CRF/CRH, ACTH, cortisol and adrenaline. Unfortunately, the public press release is misleading and many will take away the message that both estrogen and progesterone are implicated in potentiating the stress response. The actual studies only talk about estrogen and not progesterone.
    Finally, oxytocin - another hormone darling of the popular press and pharma industry - was shown to be implicated in the stress response. Oxytocin also increased anxiety in females.

    http://www.nature.com/mp/journal/v15/n9/full/mp201066a.html
    "...Stress-related psychiatric disorders (for example, depression, post-traumatic stress disorder) are twice as prevalent in women compared to men.1, 2, 3 Although the neurobiological basis for this is unknown, differences in stress reactivity have been implicated in this disparity.4, 5, 6, 7 Because corticotropin-releasing factor (CRF), a primary mediator of the stress response, is dysregulated in stress-related psychiatric disorders, it is a likely substrate for sex differences in stress vulnerability.8, 9, 10, 11 Indeed, evidence for direct estrogenic regulation of CRF gene expression provides a compelling mechanism for sexual dimorphism of stress reactivity and prevalence of stress-related psychopathology in women."

    http://www.ncbi.nlm.nih.gov/pubmed/8408641?dopt=Abstract&holding=npg
    "...The level of estrogen-induced transactivation by the 0.9- and 2.4-kb segments was determined by chloramphenicol acetyltransferase analysis in CV-1 cells cotransfected with estrogen receptor (ER) cDNA expression plasmids, and found to be respectively approximately 10% and 20% of that of the strongly estrogen-responsive Xenopus vitellogenin A2 enhancer. Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. These findings may constitute the basis of sexual dimorphism in the expression of the CRH gene in the central nervous system and periphery, and might shed light in existing gender differences in stress response and immune regulation."

    https://www.sciencenews.org/article/his-stress-not-her-stress

    "...Scientists have long known that women are more likely than men to suffer depression, post-traumatic stress disorder and other anxiety disorders, all of which have been linked to chronic stress, says Temple University psychologist Debra Bangasser. But until recently, studies of people’s responses to such stress have focused primarily on men."

    "...Fluctuations in sex hormones over a lifetime may influence the body’s reaction to stress, for better or worse. To look at that issue, Bangasser’s group studies how estrogen, progesterone and testosterone interact with a neuropeptide called corticotropin-releasing factor, or CRF, to influence cell signaling in the brains of stressed-out rodents."

    "...CRF acts as both a hormone and a neurotransmitter. As a hormone, it orchestrates the body’s stress response. When rodents — or people, for that matter — feel threatened or experience intense emotion, the brain secretes CRF. CRF molecules then alert the body to a potential threat when they lock on to matching receptor molecules on target cells, initiating a message that travels through the nervous system: Time to pay attention and get all hands on deck."

    "...In 2010, while in the laboratory of neurologist Rita Valentino of the University of Pennsylvania, Bangasser and colleagues found sex differences between CRF receptors in the brains of male and female rodents. The study, published in Molecular Psychiatry, showed that after a stressful 15-minute swim, females had more CRF receptors on the surface of target cells, making them very responsive to the stress hormone later on. In male rats exposed to stress, some of the CRF receptors moved from the membrane to the internal part of the nerve cell, or neuron. With fewer CRF receptors on the surface, the male rodents could better cope with similar stress in the future."

    "...Recently, Bangasser’s group found that when administered in high doses, CRF increased anxiety-related grooming in both male and female rats. But female rats groomed longer and more often. Females with the highest levels of estrogen and progesterone groomed obsessively."

    "...Oxytocin, known as the warm, fuzzy hormone, has been shown to slow heart rate and promote feelings of well-being. Clinical trials are under way to test the effects of a nose spray containing oxytocin on a variety of conditions, including depression, drug dependence, migraines and pain. But studies in Trainor’s lab show that elevated brain levels of oxytocin may stir more anxiety in female mice than in males after stressful experiences. After being housed with an aggressive mouse for brief periods over three days, male and female mice alike exhibited elevated oxytocin levels in certain brain regions. And for days, both froze in fear when encountering an unfamiliar mouse. Two weeks after clashing with others, males resumed near-normal behavior around unfamiliar mice. But females remained fearful long after the event, avoiding interaction with strangers for 10 weeks. The findings were published online October 19 in Biological Psychiatry. Examinations of brain tissue 10 weeks out show that getting bullied by a stranger increases the total number of both oxytocin-producing neurons and overall oxytocin production in a brain area in females, but not males. This area, the medioventral bed nucleus of the stria terminalis, is a primitive region located near the hypothalamus. Involved in regulating anxiety-like behaviors, this brain area can induce aversion to places or situations linked to stress, Trainor says."
     
  2. ecstatichamster

    ecstatichamster Member

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    oxytocin isn't all fuzzy and warm. It enhances imprinting behavior.

    There's this study too, which says brain feminization is an ONGOING process that uses DNA methylation. Presumably brain masculinization might be reversed or imperfect in some men, and feminization in some women. This may tie to the methylation craze that seems to be sweeping the health blogosphere

    http://www.nature.com/neuro/journal/v18/n5/full/nn.3988.html

    The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.
     
  3. OP
    haidut

    haidut Member

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    Thanks. It has also been shown to enhance violent behavior towards strangers in humans - i.e it radicalizes group behavior. I have yet to see a pituitary hormone with beneficial effects.
     
  4. ecstatichamster

    ecstatichamster Member

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    Really? I'm a huge fan of oxytocin. It really is the happiness hormone. I'm sure it has its downside, but naturally producing it feels great. Of course the drug companies want to find something that acts like it, or something to sell that resembles it. But it doesn't work to supplement with it. You have to produce it naturally. It's awesome!
     
  5. OP
    haidut

    haidut Member

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    It is a "bonding" hormone and it's release is correlated with stress. It can make people very group-centric and even attack outsiders for no reason other than to feel that "bond" with someone. Of course, everything in the body has physiological purpose but increasing oxytocin levels pharmacologically is definitely something I would not recommend. It is used to make the uterus contract to stop bleeding after birth. Hospitals give as an injection of IV. Naturally, is makes other muscles contract as well and prevents relaxation. The heart muscle is a good example. I think oxytocin is negatively lusitropic - i.e. blocks muscle relaxation.
     
  6. aguilaroja

    aguilaroja Member

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    Haidut and others raised many interesting points about oxytocin. Maybe there should be a separate thread-I leave that to the moderators and haidut. There have been interesting findings about oxytocin, but understanding of context may be incomplete.

    The hype about oxytocin as "the love molecule" is so frenzied that "sophisticated" biomedical people may bash curious readers who are cautious or want better understanding of how oxytocin relates to metabolic framework. Describing oxytocin as the hormone of womb contraction, or chronically reduced social behavior is less romantic.

    It is reminiscent of the "enthusiasm" nitric oxide action when its action was beginning to be studied. Adherents that boosting nitric oxide was exclusively beneficial. Sadly, the momentum of hype can skew "scientific" understanding for decades.

    One thing of note is that oxytocin is chemically similar to vasopressin. Dr. Peat had a newsletter in 2015, where he discussed the beneficial metabolic action of vasopressin antagonism, discussed by haidut in this thread:
    https://www.raypeatforum.com/forums/threads/rays-latest-newsletter-vasopressin-adh-antagonists.7807/
    --
    http://www.ncbi.nlm.nih.gov/pubmed/23481917
    Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior.
    Rault JL1, Carter CS, Garner JP, Marchant-Forde JN, Richert BT, Lay DC Jr.
    Physiol Behav. 2013 Mar 15;112-113:40-8. doi: 10.1016/j.physbeh.2013.02.007. Epub 2013 Feb 26.
    "Contrary to our predictions, when socially mixed after weaning at 17 days of age, neonatally OT[Oxytocin]-administered pigs received more aggressive interactions and performed more aggressive interactions in return, showed greater locomotion, spent less time in social contact, and had greater cortisol concentrations than control pigs. When this social mixing was repeated at 8 weeks of age, OT pigs still performed more aggressive interactions and had greater adrenocorticotropic hormone concentrations than control pigs."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688331/
    Is Oxytocin Application for Autism Spectrum Disorder Evidence-Based?
    Seung Yup Lee,1 Ah Rah Lee,2 Ram Hwangbo,3 Juhee Han,3 Minha Hong,4 and Geon Ho Bahn5
    Exp Neurobiol. 2015 Dec; 24(4): 312–324. doi: 10.5607/en.2015.24.4.312 PMCID: PMC4688331
    "Safety of oxytocin treatment
    There is some evidence that very young animals may show long-lasting negative consequences in social behavior following direct intraperitoneal injection of large doses of oxytocin [89]. Chronic or repeated intranasal oxytocin treatment in humans might also result in undesired counter-regulatory consequences [90]. A 55-year old patient with obsessive compulsive disorder showed clear improvement in symptoms following intranasal oxytocin treatment for 4 weeks, but concurrently developed severe memory impairments [91]. This case lends support for the amnestic properties of the peptide. When administrating intravenous oxytocin for labor induction or abortion, adverse effects such as reflex tachycardia, seizures, headache, memory impairment, hyponatremia, a syndrome of inappropriate antidiuretic hormone secretion, and anaphylaxis have been reported [92]. Large cohort studies have suggested a very small but significant risk for the future development of autism later in life following augmented childbirth with oxytocin [93]."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957104/
    Chronic and acute intranasal oxytocin produce divergent social effects in mice.
    Huang H1, Michetti C2, Busnelli M3, Managò F1, Sannino S1, Scheggia D1, Giancardo L4, Sona D4, Murino V4, Chini B5, Scattoni ML6, Papaleo F7.
    Neuropsychopharmacology. 2014 Apr;39(5):1102-14. doi: 10.1038/npp.2013.310. Epub 2013 Nov 4.
    "C57BL/6J male mice chronically treated with intranasal OXT [Oxytocin] decreased social interaction behaviors towards opposite-sex novel-stimulus female mice as well as towards same-sex familiar cagemates. Concomitantly, chronic intranasal OXT treatment... consistently reduced both social behaviors and communication."

    http://www.ncbi.nlm.nih.gov/pubmed/23872596
    Fear-enhancing effects of septal oxytocin receptors.
    Guzmán YF1, Tronson NC, Jovasevic V, Sato K, Guedea AL, Mizukami H, Nishimori K, Radulovic J.
    Nat Neurosci. 2013 Sep;16(9):1185-7. doi: 10.1038/nn.3465. Epub 2013 Jul 21.
    "...evidence for anxiogenic actions of oxytocin in humans has recently emerged. Using region-specific manipulations of the mouse oxytocin receptor (Oxtr) gene (Oxtr), we identified the lateral septum as the brain region mediating fear-enhancing effects of Oxtr. These effects emerge after social defeat and require Oxtr specifically coupled to the extracellular signal-regulated protein kinase pathway."

    https://en.wikipedia.org/wiki/Oxytocin
    "The structure of oxytocin is very similar to that of vasopressin (cys – tyr – phe – gln – asn – cys – pro – arg – gly – NH2), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by two amino acids."
     
  7. aguilaroja

    aguilaroja Member

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    As haidut mentioned, oxytocin's stimulation of uterine contraction may be a clue that non-physiologic oxytocin interferes with smooth muscle function elsewhere, when acting in events unrelated to childbirth.
    --
    http://www.ncbi.nlm.nih.gov/pubmed/25152590
    Oxytocin decreases colonic motility of cold water stressed rats via oxytocin receptors.
    Yang X1, Xi TF1, Li YX1, Wang HH1, Qin Y1, Zhang JP1, Cai WT1, Huang MT1, Shen JQ1, Fan XM1, Shi XZ1, Xie DP1.
    World J Gastroenterol. 2014 Aug 21;20(31):10886-94. doi: 10.3748/wjg.v20.i31.10886.
    "Cold water intake inhibits colonic motility partially through oxytocin-oxytocin receptor signaling in the myenteric nervous system pathway, which is estrogen dependent."

    http://www.ncbi.nlm.nih.gov/pubmed/24139438
    Oxytocin: an unexpected risk for cardiologic and broncho-obstructive effects, and allergic reactions in susceptible delivering women.
    Liccardi G, Bilò M, Mauro C, Salzillo A, Piccolo A, D'Amato M, Liccardi A, D'Amato G.
    Multidiscip Respir Med. 2013 Oct 20;8(1):67. doi: 10.1186/2049-6958-8-67.
    "Some oxytocin cardiovascular activities such as lowering blood pressure, negative cardiac inotropy and chronotropy, parasympathetic neuromodulation, vasodilatation etc. can induce significant side effects mimicking cardiac anaphylaxis, and constitute an additional differential diagnostic problem in delivering women with suspected or real allergic background. Finally, some ex vivo models have shown that oxytocin, under pro-inflammatory cytokines stimulation, such as those occurring in asthma, may induce contraction of smooth muscle and airway narrowing."

    http://www.ncbi.nlm.nih.gov/pubmed/25702249
    Single-cell mechanics and calcium signaling in organotypic slices of human myometrium.
    Loftus FC1, Richardson MJ2, Shmygol A3.
    J Biomech. 2015 Jun 25;48(9):1620-4. doi: 10.1016/j.jbiomech.2015.01.046. Epub 2015 Feb 8.
    "...oxytocin induces asynchronous [Ca(2+)]i oscillations in individual myocytes within intact myometrium which are similar to those observed in cultured cells. The oscillations occur between synchronous action potential-driven [Ca(2+)]i transients but appear to be unrelated to contractions."
     
  8. aguilaroja

    aguilaroja Member

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    One more thing about oxytocin. Oxytocin has association with other factors of stress and impaired metabolism. Oxytocin appears to stimulate multidrug resistance-associated protein 4, which is increased in certain cancers. It activates NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), which has a role in inflammation and cancer.

    Tumor Necrosis Factor alpha and Interleukin-13 regulate the expression of oxytocin in the smooth muscle of the airway. Melatonin sensitizes the uterine muscle to oxytocin, which may explain the common early morning timing of delivery. How is melatonin sensitizing tissues to oxytocin elsewhere?

    Many frontiers remain in oxytocin research. But as with, say, melatonin and growth hormone, the narrow usefulness in a particular event is not a good clue to overall effects.
    --
    The multidrug resistance-associated protein 4 (MRP4) appears as a functional carrier of prostaglandins regulated by oxytocin in the bovine endometrium.
    Lacroix-Pépin N1, Danyod G, Krishnaswamy N, Mondal S, Rong PM, Chapdelaine P, Fortier MA.
    Endocrinology. 2011 Dec;152(12):4993-5004. doi: 10.1210/en.2011-1406. Epub 2011 Oct 11.

    "Oxytocin (OT) stimulated PGF2α production and MRP4 mRNA and protein in a time- and dose-dependent manner...."

    http://www.ncbi.nlm.nih.gov/pubmed/26148856
    The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4.
    Wen J1, Luo J1, Huang W1, Tang J1, Zhou H1, Zhang W2.
    J Pharmacol Exp Ther. 2015 Sep;354(3):358-75. doi: 10.1124/jpet.115.225656. Epub 2015 Jul 6.
    "In the context of several cancers in which MRP4 is overexpressed, MRP4 inhibition shows striking effects against cancer progression and drug resistance."

    http://www.ncbi.nlm.nih.gov/pubmed/25451977
    Oxytocin activates NF-κB-mediated inflammatory pathways in human gestational tissues.
    Kim SH1, MacIntyre DA1, Firmino Da Silva M1, Blanks AM2, Lee YS1, Thornton S3, Bennett PR1, Terzidou V4
    Mol Cell Endocrinol. 2015 Mar 5;403:64-77. doi: 10.1016/j.mce.2014.11.008. Epub 2014 Nov 14.

    http://en.wikipedia.org/wiki/NF-κB#Inflammation
    "...elevation of some NF-κB activators, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.[58][59] Elevated NF-κB has also been associated with schizophrenia.[60] Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and sarcopenia.[61]"

    http://en.wikipedia.org/wiki/NF-κB#Cancers
    "Aberrant activation of NF-κB is frequently observed in many cancers. Moreover, suppression of NF-κB limits the proliferation of cancer cells. In addition, NF-κB is a key player in the inflammatory response. Hence methods of inhibiting NF-κB signaling has potential therapeutic application in cancer and inflammatory diseases.[80][81]"

    http://www.ncbi.nlm.nih.gov/pubmed/20670427
    Respir Res. 2010 Jul 29;11:104. doi: 10.1186/1465-9921-11-104.
    Expression and activation of the oxytocin receptor in airway smooth muscle cells: Regulation by TNFalpha and IL-13.
    Amrani Y1, Syed F, Huang C, Li K, Liu V, Jain D, Keslacy S, Sims MW, Baidouri H, Cooper PR, Zhao H, Siddiqui S, Brightling CE, Griswold D, Li L, Panettieri RA Jr.
    "...cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a potential role for inflammation-induced changes in oxytocin receptor signaling in the regulation of airway hyper-responsiveness in asthma."

    J Clin Endocrinol Metab. 2010 Jun;95(6):2902-8. doi: 10.1210/jc.2009-2137. Epub 2010 Apr 9.
    Melatonin sensitizes human myometrial cells to oxytocin in a protein kinase C alpha/extracellular-signal regulated kinase-dependent manner.
    Sharkey JT1, Cable C, Olcese J.
     
  9. DaveFoster

    DaveFoster Member

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    Maybe oxytocin's role as a stress hormone underscores the negative aspects of intense pair bonding, which can lead to individual depression and suicide in the event of separation from a partner.
     
  10. Peat Tong

    Peat Tong Member

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    what are some non-prescription oxytocin antagonists?
     
  11. OP
    haidut

    haidut Member

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  12. ecstatichamster

    ecstatichamster Member

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    Seems the studies of oxytocin have been done with intranasal dosages that are massively non physiologic.
     
  13. Momado965

    Momado965 Member

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  14. Momado965

    Momado965 Member

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    Can this mean actively seeking to methylate will feminise men's brain even in adulthood?
     
  15. OP
    haidut

    haidut Member

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    Anything with activity on the PR should have this effect.
     
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