Discussion of corticotropin-releasing hormone and MPB

This study below suggests that early childhood may influence the release of CRH, and therefore, possibly predispose one towards more aggressive hair loss than another.

Abstract:

Stress exposure during early development causes long-lasting alterations in behavior
and hypothalamic pituitary adrenal (HPA) axis activity, including increased expression of
corticotropin releasing hormone (CRH). The aim of this study was to test the hypothesis that
early life stress causes epigenetic changes in the CRH promoter leading to increased CRH
transcription. Groups of 8-week old female and male rats, which had been subjected to maternal
deprivation (MD) between days 2 and 10 post-birth, were killed in basal conditions or following
30 or 60 min restraint stress for evaluation of plasma ACTH and corticosterone, and CRH
hnRNA (as an index of CRH transcription) responses to stress. Additional groups of control and
MD were used for methylation analysis of the CRH promoter in the hypothalamic
paraventricular nucleus (PVN) and the central nucleus of the amygdala (CeA). The results show
that adrenal weight, basal levels of plasma corticosterone and hypothalamic CRH hnRNA were
higher in MD females but not in males. However, plasma corticosterone and CRH hnRNA
responses to acute restraint stress were higher in MD of both sexes. DNA methylation analysis of
the CRH promoter in the PVN revealed a lower percent of methylation specifically in two CpG
sites located immediately preceding (#1) and inside (#2) the cAMP-responsive element (CRE) at
-230bp in the CRH promoter, in both sexes. In contrast to the PVN, the percentage of
methylation of CpGs #1 and #2 in the CeA were identical in control and MD rats. These findings
demonstrate that HPA axis hypersensitivity caused by neonatal stress induces long-lasting
enhanced CRH transcriptional activity in the PVN of both sexes. Hypomethylation of the CRH
promoter CRE, a region critical for CRH transcriptional activation, is likely to serve as a
mechanism for the increased transcriptional responses to stress observed in MD rats.


Pharmacol Biochem Behav. 2002 Aug;73(1):147-58.
Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress.
Makino S, Hashimoto K, Gold PW.

Second Department of Internal Medicine, Kochi Medical School, Okoh-cho, Nankoku, Japan. fwjf6671@mb.infoweb.ne.jp
Abstract
Stress-associated disorders such as melancholic depression are characterized by persistent hypothalamic-pituitary-adrenocortical (HPA) axis activation and intensive anxiety. Corticotropin-releasing hormone (CRH) appears to play an essential role in pathophysiology of such disorders. In an attempt to elucidate possible mechanisms underlying persistent activation of CRH in the central nervous system (CNS), we examined responses of hypothalamic and extrahypothalamic CRH systems to the stressors (immobilization stress or psychological stress) and interactions between these CRH systems and glucocorticoids in rats. We propose multiple feedback loops activating central CRH system: (1) attenuation of glucocorticoid-induced negative feedback on the activity of the hypothalamic and brainstem nuclei during chronic stress, (2) autoregulation of CRH biosynthesis in the hypothalamic paraventricular nucleus (PVN) through up-regulation of Type-1 CRH receptor (CRHR-1), and (3) glucocorticoid-mediated positive effects on the amygdaloid CRH system. Stress initially activates the hypothalamic CRH system, resulting in the hypersecretion of glucocorticoids from the adrenal gland. In addition, the psychological component of the stressor stimulates the amygdaloid CRH system. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the locus coeruleus (LC) fails to restrain hyperfunction of the HPA axis, and persistent activation of the HPA axis further up-regulates the amygdaloid CRH system. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during chronic stress, which is responsible for the clinical manifestations of stress-associated disorders.

PLoS One. 2011 Jan 27;6(1):e16447.
Induction of the wnt antagonist dickkopf-1 is involved in stress-induced hippocampal damage.
Matrisciano F, Busceti CL, Bucci D, Orlando R, Caruso A, Molinaro G, Cappuccio I, Riozzi B, Gradini R, Motolese M, Caraci F, Copani A, Scaccianoce S, Melchiorri D, Bruno V, Battaglia G, Nicoletti F.

Department of Physiology and Pharmacology, University "Sapienza", Roma, Italy.

The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.

CS,

This is pretty grim stuff... What is to be taken from this other than apparently children can be "scarred for life".

Related note: coffee consumption. Has to be a bad thing for hair right?

Related note 2: I tried (carelessly) a drug that suppressed corticosteroids back in 1999 called Cytadren, after a report from someone online claiming regrowth. I only took it for a few a week maybe because I was scared of what it could do and I had some understanding of how dangerous it could be. Anyways... The first time I took it, I noticed a calm, content feeling come over me like everything was alright for the first time. My lifelong anxiety of 19 years at the time was wiped out. The next few times I took it, I didn't get that same effect as much. Shortly thereafter I was the only time I have ever seen regrowth at the hairline. This darker than vellus hair only lasted a few days and then disappeared, but I was only a NW1 at the time and this hair was in FRONT of my hairline. It was basically my childhood hairline that started to grow a little.

I have other questions about these studies and AF, but I'll save them for now.

Forgot there's no edit option

Wanted to mention after reading the study about maternal separation that it happened to me as a newborn. I was taken away from my Mom for some reason for hours right after I was born. There was no medical reason as far as I remember. I'm going to ask her again. She was distraught over it though. Then she lost my baby pictures when she left the hospital after setting them on top of the car and driving off. Lol... poor lady.

Paradox - Very interesting. I know relatively little about this, but from several sources I have been told that very important processes occur, and the impact of touch and the presence of the mother have many physiological effects. I'm sure that many of these processes will be elucidated in the future (maybe they are already known).

I wonder what regular doses of GABA (750 mg) would do for this.

I should add that if GABA doesn't work, would suggest taking a few Inositol capsules per day

http://tinyurl.com/4nx2jso

Usually hair loss supplements (multi's) contain this nutrient, but not at proper dosage levels. Anxiety ridden people usually need at least a few grams of it.

Not sure how long after I was born, I think immediately I was taken to an incubator for around 5-7 days I think because I had problems. Had fits, was blue, the doctors told my parents I would never walk, however I'm not disabled in any way, not had a fit since.

Has that had any impact on how I am now?

CausticSymmetry wrote:Paradox - Very interesting. I know relatively little about this, but from several sources I have been told that very important processes occur, and the impact of touch and the presence of the mother have many physiological effects. I'm sure that many of these processes will be elucidated in the future (maybe they are already known).

I wonder what regular doses of GABA (750 mg) would do for this.

So far GABA seems like a dead end based on my experience thus far. While I am enjoying deeper sleep, it hasn't done much for hair, but I am quite sure that I fall into the androgenic loss category

CausticSymmetry wrote:I should add that if GABA doesn't work, would suggest taking a few Inositol capsules per day

http://tinyurl.com/4nx2jso

Usually hair loss supplements (multi's) contain this nutrient, but not at proper dosage levels. Anxiety ridden people usually need at least a few grams of it.

CS,

In ortho psych there are 2 conditions relating to high/low histamine levels. I don't know if I buy into it really, but supposedly if you have low histamine you should stay away from inositol because it can make things worse, but it works "great" if you have high histamine (OCD). Basically it works differently on different people. It's more beneficial for low serotonin conditions I guess. Histamine is used as a marker for methylation, and there's a negative relationship.

Gaba is all but useless IME/O. I would hands down recommend niacinamide, ashwagandha, along with the staples: Mg, C, Zinc. Niacinamide acts similarly to a benzodiazepine. They actually admitted inventing valium by trying to copy b3.

Paradox - Yes, the bottom line is when it comes to anxiety, stress, etc, people respond differently to various agents. Trial and error is essential here. I've seen many people respond quickly to GABA, and also many who haven't.

Might as well add niacinamide to that list of possibilities too.

I really like niacinamide, seems to help me a lot.

Vitamin D might influence CRH, maybe in a positive way.

Exp Dermatol. 2006 Mar;15(3):143-53.
The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease.
O'Kane M, Murphy EP, Kirby B.

Department of Dermatology, Adelaide and Meath Hospital, Dublin 24, Ireland. mokdoc@hotmail.com
Abstract
Corticotropin-releasing hormone (CRH) coordinates the systemic stress response via hypothalamic-pituitary-adrenal (HPA) axis activation with subsequent modulation of the inflammatory response. Stress is known to affect expression of immune-mediated inflammatory diseases, many of which are associated with HPA axis abnormalities. HPA axis components including CRH and its receptors (CRH-R) exist in the skin and exhibit differential expression according to cell type, physiological fluctuations and disease states. This confirms a local functioning cutaneous HPA-like system. Peripheral CRH may exhibit proinflammatory effects. Animal studies confirm that peripheral CRH is required for induction of the inflammatory response in vivo. CRH and CRH-R are upregulated in inflammatory arthritis synovium and psoriatic skin. CRH may influence mast cell activation, direct modulation of immune cells, angiogenesis and induction of the novel orphan nuclear receptor NURR1. This transcription factor is part of the steroid/thyroid superfamily of related nuclear receptors that includes receptors for steroids, retinoids and vitamin D; ligands of these receptors are effective in treating psoriasis. The roles of CRH and NURR1 in psoriasis and inflammatory skin diseases, especially those associated with stress, remain to be elucidated. This stress may be psychological or physical. CRH, produced locally or delivered by peripheral nerves, may mediate interactions between a cutaneous HPA axis-like system and the central HPA axis--the "brain-skin axis".

Excellent post CS! Very very interesting, especially regarding the Auto-immune link. Mind if I copy that into my thread?

act<react - Sure, by all means

And, one for you CS!

immune response to infection and autoimmunity

Abstract

Stress proteins are frequently the target of humoral and cell-mediated immune responses to infection. These proteins belong to highly conserved gene families and there is substantial sequence homology between antigens produced by pathogenic organisms and the corresponding proteins from mammalian cells. Human T cells from sites of infectious and autoimmune lesions proliferate in response to stress proteins, and mapping of antigenic determinants on a mycobacterial stress protein shows that both species specific and highly conserved, ‘self-like’, regions of the molecule can take part in immune recognition. It is proposed that the lymphocyte population induced in response to stress proteins of pathogens during infection includes cells capable of autolmmune recognition of the corresponding self protein. Local accumulation of self stress proteins—in response to viral infection, for example—may subsequently provide a stimulus for proliferation of such autoreactive lymphocytes, thereby triggering a cycle of events which may contribute to the pathological damage associated with autoimmune disease.

EMDR

Powerful stuff, much more so than GABA, IMHO

Vibrate to health...

M

What do you guys think of other forms of GABA such as PharmaGaba?

Pharmacol Biochem Behav. 2005 Dec;82(4):686-94. Epub 2005 Dec 27.
Antidepressant-like effect of icariin and its possible mechanism in mice.
Pan Y, Kong L, Xia X, Zhang W, Xia Z, Jiang F.

State Key Laboratory of Pharmaceutical Biotechnology, Immunobiological Laboratory, Institute of Functional Biomolecule, Nanjing University, PR China.

The behavioral, neurochemical and neuroendocrine effects of icariin isolated from Epimedium brevicornum were investigated in behavioral despair models of KunMing strain of male mice. Icariin was found to significantly shorten immobility time in the forced swimming test (FST) after orally administration for 21 consecutive days. Icarrin also produced a marked reduction in immobility time in the tail suspension test (TST) when administered for at least 7 consecutive days. The preferable antidepressant action by icariin was obtained at 17.5 and 35 mg/kg in the present study. Moreover, it was observed that the stress of FST exposure induced increases in brain monoamine oxidase (MAO) A and B activities, serum corticotropin-releasing factor (CRF) levels, as well as decreases in brain monoamine neurotransmitter levels. Treatment of icariin for 21 consecutive days mainly reversed the above effects in the mouse FST. These results suggested that icarrin possessed potent antidepressant-like properties that were mediated via neurochemical and neuroendocrine systems.

Biol Pharm Bull. 2006 Dec;29(12):2399-403.
Effects of icariin on hypothalamic-pituitary-adrenal axis action and cytokine levels in stressed Sprague-Dawley rats.
Pan Y, Zhang WY, Xia X, Kong LD.

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.

Icariin is one of the major active flavonoids constituents of Epimedium brevicornum MAXIM (Berberidaceae). Icariin and E. brevicornum have a wide range of pharmacological activities. Abnormality in the hypothalamic-pituitary-adrenal (HPA) axis is considered to be a key neurobilogical factor in major depression, and cytokines have a close relationship with the activation of the HPA axis. In the present study, the aim was to determine whether icariin possesses an antidepressant-like activity, and to explore the effects of icariin on the HPA axis and cytokine levels in chronic mild stress (CMS) model of depression in Sprague-Dawley rats. Icariin significantly increased the sucrose intake of CMS-treated rats from week 3. It not only attenuated the CMS-induced increases in serum corticotropin-releasing factor (CRF) and cortisol levels, but also reversed the abnormal levels of serum interleukin-6 (IL-6) and tumor-necrosis-factor alpha (TNF-alpha) to the normal in the stressed rats. These results suggested that icariin possessed an antidepressant-like property that was at least in part mediated by neuroendocrine and immune systems.

Pharmacol Biochem Behav. 2007 May;87(1):130-40. Epub 2007 Apr 19.
Icariin from Epimedium brevicornum attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats.
Pan Y, Kong LD, Li YC, Xia X, Kung HF, Jiang FX.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.

Chronic mild stress (CMS) is suggested to produce abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamus-pituitary-thyroid (HPT) axis. Therefore, compound that attenuates the neuroendocrinological alterations may have potential as antidepressant. The behavioral and neuroendocrinological effects of icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, were investigated in the CMS model of depression in male Wistar rats. CMS procedure caused an anhedonic state in rats resulted in increased corticotropin-releasing factor (CRF) concentrations in dissected brain regions and serum, decreased total triiodothyronine (tT3) in serum with no significant changes in serum adrenocorticotrophic hormone (ACTH) and thyroxine (tT4). Administration of icariin reversed CMS-induced sucrose intake reduction and CRF elevation. These results suggested that icariin possessed potent antidepressant-like activities which were at least in part mediated by improving the abnormalities in the HPA axis functions. However, we did not find a clear correlation between the HPT axis and icariin treatment in the CMS-treated rats.

Psychoneuroendocrinology. 2010 Feb;35(2):272-83. Epub 2009 Jul 23.
Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats.
Pan Y, Wang FM, Qiang LQ, Zhang DM, Kong LD.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.

Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.

I always shed when I'm more stressed out. I tend to worry about stupid stuff too. So I'm sure this is a part of my hair loss.

CS- My mothers father was dying of cancer, while my mom was pregnant with me. I'm sure naturally this was a stressful time in her life. Do you think that could make me more susceptible to stress and its effects now?

MilBA - It's possible. Here is just one of many articles on this:

Researchers led by Professor Vivette Glover at Imperial College London and Dr Pampa Sarkar of Wexham Park Hospital, Berkshire, studied 267 women, taking a blood sample from the mother and a sample from the amniotic fluid surrounding the baby.

They measured levels of a stress hormone called cortisol in both samples, says a report published in the journal Clinical Endocrinology.

At the age of 17 weeks and older, they found the higher the level of cortisol in the mother's blood, the greater the level of cortisol in the amniotic fluid.

Amniotic fluid is predominantly produced by the unborn baby by fetus and reflects the exposure of the fetus to various substances including hormones.

Dr Pampa Sarkar said 'We are all a product of our developmental history.
'One of the times when we are most susceptible to the influences of our surrounding environment is when we are developing as a fetus in our mother's womb.

'Our research shows that the fetus is exposed to cortisol in the maternal blood, and we also demonstrated that at and above 17 weeks, the cortisol in amniotic fluid had a strong positive relationship with cortisol in maternal blood.
'We found that the strength of this correlation became stronger with increasing gestational age.'
She said stress hormones were a reaction to anxiety and useful in the short term because they helped the body deal with stressful situations.

But if the stress goes on for a long time, the hormones can affect people's health leading to tiredness, depression and illness, she added.

Dr Sarkar said 'We now need to carry out further work to unravel the mechanisms by which maternal stress affects the fetus, both during fetal life and through into childhood.
'We do not wish to unduly worry pregnant women.
'It should be remembered that one of the best ways for people to avoid general stress is to lead a healthy, balanced lifestyle.'

Previous research found babies exposed to the highest levels of cortisol while in the womb had lower IQs at 18 months, compared with the infants of mothers who were less stressed.

Studies show the children of highly stressed and anxious pregnant women were at double the risk of hyperactivity and ADHD (Attention Deficit Hyperactivity Disorder) at the age of four.

Anxiety in pregnancy seems to have greater effects than antenatal depression, according to study findings.
Prof Glover, professor of perinatal psychobiology at Imperial College School of Medicine, London, found children in the top five per cent band for behavioural problems were more likely to have a mother under stress in pregnancy.
She says women should be screened in pregnancy so interventions can be used, including counselling for those under most severe stress.

Prof Glover added 'The most important thing women can do for themselves is to talk through any worries they have during pregnancy with their partners or family. We know that helps relieve anxiety and depression - don't suffer in silence but seek help.'

Claire Friars, midwife at the charity Tommy's, said 'This is an important study as for the first time, there's solid evidence to show that an unborn child may be exposed to maternal stress as early as 17 weeks in development.
'A crucial next step would be to uncover to what extent different levels of maternal stress can potentially affect an unborn child.

'For now - based on previous research - one thing is clear: high levels of stress in pregnancy can, in some cases, be detrimental to the health of the baby.

'To remain as stress-free as possible is certainly important during pregnancy.
'Of course, this is easier said than done as pregnancy itself can incite all sorts of feelings - from feeling overwhelmed, happy and nervous.

'Pregnancy can signify major emotional changes in mums-to-be, from mood swings to feeling incredibly anxious, which may well elevate women's stress levels.
'It is vital that pregnant women are given adequate support and reassurance from their family, friends and employers, to ensure they have a happy and healthy pregnancy.'

Cs, I can relate a massive amount to that study you just posted, what would you recommend for helping this? Just the usual niacinamide, ashwaghanda, magnesium, vit c, zinc, vit d? Anything else?

Very interesting CS, thank you. I can't say I ever suffered from ADHD, depression or some of the other problems noted in the article. But, I do certainly let minor things stress me out, and it takes a toll on my hair and skin.

I saw you recommended Inositol, GABA, and perhaps that calcium supplement for stress related hair loss. Any other recommendations--supplement wise or even strategies for dealing with stress. Meditation...etc?

Would it be safe to say that horny goat weed ( icariin ) as a topical would be a bad idea? Enhances T but also has phyto estros in it, nitric oxide boost, but builds osteroblasts - maybe bad, right?

Maybe you have to take it 2 hours before you want your hair to look good.

Please no "wrong head" jokes thx

It's hard to know what is the most universally effective. GABA, Inositol for instance do not work for everyone. Niacinamide helps some.

Then there are some others to look at. I have a good feeling about Azadirachta indica (neem leaf), because this has been shown to offer potent anti-anxiety effects. No idea what it does for CRF. Icarrin is excellent for kidney health and whether it will work topically or not (no idea). Icarrin is worth a try.

There's absolutely nothing wrong with Icarrin (HWG/Epimedium) increasing osteoblasts. That's a good thing (regenerative).