Cortisol

Are hormone ratios useful in explaining health? Behavior? Neurobiology? Anything?

gettingwell4 2-3 stars Required further work, Cortisol, Neurochemicals, Stress, Testosterone

This 2015 Zurich human review addressed:

“A remarkable lack of discussion on the meaning and interpretation of frequently used hormone ratios.

The interpretation of hormone ratios is complicated and in many cases not sufficiently supported from a theoretical point of view.

Based on the assumption that the balance between two interdependent hormones determines their eventual effects on brain and other tissues, this index has been commonly interpreted as an indicator of the balance between two endocrine systems.

The ratio is typically calculated by simply dividing the raw value of one hormone by the raw value of a second hormone. However, endocrine parameters may fluctuate considerably within individuals across short periods of time on the basis of circadian rhythms or contextual factors. Nevertheless, the ratio method has so far only rarely been applied in the context of repeated endocrine assessments.”

The researchers made a non-exhaustive list of three dozen studies that used hormone ratios among cortisol, dehydroepiandrosterone sulfate (DHEA-S), estradiol, progesterone, testosterone, triiodothyronine (T3), thyroxine (T4), etc., to explain various outcome measures such as:

  • “Health status
  • Aggressive behavior
  • Psychopathy
  • Marital violence
  • fMRI response to angry and happy faces
  • Early life adversity
  • Depression
  • Chronic stress
  • Alexithymia”

Their 2015 study on “endocrine correlates of pro-environmental behavior” was used as an illustrative example. It had 229 male subjects between ages 19 and 77. Salivary cortisol (C) and testosterone (T) was sampled with these results:

“T/C and C/T ratios produce different means, standard deviations and distributional properties which significantly deviate from normality.

Height is not significantly associated with either T/C or C/T. In fact, looking at the original variables, C correlates positively with height while T shows no association.

When we include age as a covariate (assuming that it is associated with both height and hormone status) the partial correlation between T/C and height then is significant while the association between C/T and height is non-significant, even though both ratios are based on the exact same data.

Looking at the negative association between age and T/C the observed age-related ratio decline is mainly due to the fact that the T value in the numerator decreases with age while the C value in the denominator remains relatively constant. In this case, the analysis of the individual variables therefore offers more information and a more accurate picture of the underlying relationships.

A few previous studies have standardized the two underlying hormone distributions before calculating the ratio in order to account for the fact that two hormones often exhibit very different means and standard deviations. Standardization leads to values that express each subject’s hormone concentration relative to the sample mean.

A ratio calculated on the basis of such standardized hormones takes on a different meaning. In particular, the ratio no longer merely represents the proportion of the two hormones within the individual but also incorporates how high the two hormone concentrations are with respect to the sample distributions.”

Practices to improve the use and interpretation of hormone measurements included:

“Regression techniques employed on the original variables constitute a better suited alternative devoid of the problems associated with the ratio method. Moderation analysis, in particular, is a useful approach, which often provides more detailed insight into the relationships of interest.

Ratios should either be analyzed with non-parametric techniques, or be log-transformed before parametric statistical methods are applied.”

Set points and variations in an individual’s hormone balances are usually effects of underlying causes. Researchers will hopefully pay more attention to effectively dealing with ultimate causes as the preferred methods of managing an individual’s health, behavioral, and neurobiological effects.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015009531 “How to use and interpret hormone ratios” (not freely available)

Stress consequences on gut bacteria, behavior, immune system, and neurologic function

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress , ,

This 2015 Canadian rodent study found:

“Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community.

The degree of deficits in social, but not exploratory behavior, was correlated with group differences between the microbial community profile.

Defeated mice also exhibited reduced abundance of pathways involved in biosynthesis and metabolism of tyrosine and tryptophan: molecules that serve as precursors for synthesis of dopamine, norepinephrine, serotonin, and melatonin, respectively.

This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses.”

These researchers had an extensive Discussion section where they placed study findings in contexts with other rodent and human studies. For example:

“Our analyses also predicted reduced frequency of fatty acid biosynthesis and metabolism pathways, including that of propanoate and butanoate – byproducts of dietary carbohydrate fermentation by intestinal microorganisms.

Butyrate is a potent histone deacetylase (HDAC) inhibitor that exerts antidepressant-like effects by increasing histone acetylation in the frontal cortex and hippocampus, and consequentially, raising BDNF transcript levels.

Although it was previously unclear whether systemic levels of these metabolites achieved in vivo were sufficient to produce behavioral changes, progress has been made by discovering their presence in cerebrospinal fluid and the brain, and demonstrating that colon-derived SCFAs [short chain fatty acids] cross the blood–brain barrier and preferentially accumulate in the hypothalamus, where they can affect CNS activity.”

http://www.psyneuen-journal.com/article/S0306-4530%2815%2900934-8/fulltext “Structural & functional consequences of chronic psychosocial stress on the microbiome & host”

Epigenetic consequences of early-life trauma: What are we waiting for?

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress, Vasopressin , , , , ,

This 2015 UK human review discussed:

“The progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 [glucocorticoid receptor] (GR) gene.

Gene linkage studies for depression, as well as for other common complex disorders, have been perceived by some to be of only limited success; hence the focus on GWAS [genome-wide association studies]. However, even for simple traits, genetic variants identified by GWAS are rarely shown to account for more than 20% of the heritability.

Epigenetic changes are potentially reversible and therefore amenable to intervention, as has been seen in cancer, cardiovascular disease and neurological disorders.”

Five of the review’s references included FKBP5 (a gene that produces a protein that dampens glucocorticoid receptor sensitivity) in their titles, but it wasn’t mentioned in the review itself. A search on FKBP5 also showed human studies such as the 2014 Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort that found:

“Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function.

Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.”

The authors listed seven human studies conducted 2008-2015 “investigating interactions between methylation of NR3C1, depression and early adversity”:

“Newborn offspring exposed to maternal depression in utero had increased methylation at [a GR CpG site] as well as adverse neurobehavioural outcomes.

Unlike the majority of animal studies examining NR3C1 methylation, many types of potential stressors, sometimes at different developmental stages, have been used to represent early human adversity.

Substantial differences can be expected in the nature of stresses prenatally compared with postnatally, as well as their developmental consequences.”

Seven human studies over the past eight years was a very small number considering both the topic’s importance and the number of relevant animal studies during the period.

Is the topic too offensive for human studies? What makes people pretend that adverse prenatal and perinatal environments have no lasting consequences to the child?

“Many more studies will be needed before effects directly attributable to early life trauma can be separated from those relating to tissue type.

Although investigators have amassed a considerable amount of evidence for an association between differential methylation and HPA axis function in humans, a causal relationship still needs to be fully established.”

Factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

Are the multitude of agendas that have resources thrown at them more important than ensuring the well-being of a human before and after they are born?

https://www.researchgate.net/publication/282048312_Early_life_trauma_depression_and_the_glucocorticoid_receptor_gene_-_an_epigenetic_perspective “Early life trauma, depression and the glucocorticoid receptor gene–an epigenetic perspective”

Fat made rats fat with dysfunctional brains

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Cerebrum, Cortisol, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Stress, Testosterone , , ,

This 2015 New York rodent study found:

“Early stage [diet-induced] obesity, before the onset of diabetes or metabolic syndrome, produced deficits on cognitive tasks that require the prefrontal cortex.

These results strongly suggest that obesity must be considered as a contributing factor to brain dysfunction.”

The difference in the diets of the adult male subjects was that the control group ate 10% fat (20% protein, 70% carbohydrates) whereas the obese group ate 45% fat (20% protein, 35% carbohydrates). Significant changes in body weight were present after the first two weeks on the diets, but testing didn’t begin until after eight weeks.

I thought the study design prematurely terminated the experiments. The study didn’t justify the ultimate purpose of conducting rodent experiments, which is to find possible human applicability.

One study design possibility would have been to continue through old age to find how the conditions progressed. Another possibility would have been to reverse the high-fat diet to find whether the conditions reversed.

http://www.pnas.org/content/112/51/15731.full “Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function”

It is known: Are a study’s agendas more important than its evidence?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2015 Swiss human study’s Abstract began:

“It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling.”

The study had several statements that were unconvincingly supported by the study’s findings. One such statement in the Conclusions section was:

“This study supports the view that early-life adversity may induce long-lasting epigenetic changes in stress-related genes, thus offering clues as to how intergenerational transmission of anxiety and trauma could occur.”

However, the study’s evidence for “intergenerational transmission of anxiety and trauma” as summarized in the Limitations section was:

“This study did not directly associate child behavior or biology to maternal behavior and biology.”

In another example, the Discussion section began with:

“The severity of maternal anxiety was significantly correlated with mean overall methylation of 4 CpG sites located in exon IV of the BDNF promoter region as measured from DNA extracted from mothers’ saliva.

In addition, methylation at CpG3 was also significantly associated with maternal exposure to domestic violence during childhood, suggesting that BDNF gene methylation levels are modulated by early adverse experiences.”

The researchers assessed five DNA methylation values (four individual sites and the overall average). The CpG3 site was “significantly associated with maternal exposure to domestic violence during childhood” and the three other CpG sites’ methylation values were not.

IAW, the researchers found only one of four sites’ methylation values significantly associated to only one of many studied early adverse experiences. This finding didn’t provide sufficient evidence to support the overarching statement:

“BDNF gene methylation levels are modulated by early adverse experiences.”

To make such a generally applicable statement – more than one BDNF gene’s methylation levels could be directly altered by more than one early adverse experience – the researchers would, AT A MINIMUM, need to provide evidence that:

  1. The one category of significantly associated early adverse experience directly altered the one significantly associated CpG site’s DNA methylation level
  2. Other categories of early adverse experiences were fairly represented by the one significantly associated experience category
  3. Other categories of early adverse experiences could directly alter other BDNF genes’ DNA methylation levels
  4. The significantly associated DNA methylation level of only one out of four CpG sites was fairly represented by the overall average of the four sites
  5. Other BDNF gene’s methylation levels were fairly represented by the overall average of the four sites

If researchers and sponsors must have agendas, a worthwhile, evidence-supported one would be to investigate prenatal and perinatal epigenetic causes for later-life adverse effects.

As Grokking an Adverse Childhood Experiences (ACE) score pointed out, environmental factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

What’s the downside of conducting studies that may “directly associate child behavior or biology to maternal behavior and biology” during time periods when a child’s environment has the greatest impact on their development?

When prenatal and perinatal periods aren’t addressed, researchers and sponsors neglect the times during which many harmful epigenetic consequences may be prevented. It is known.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143427 “BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample”

Brain-region-specific energy metabolism affected the social competitiveness of highly-anxious rats

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Cerebrum, Cortisol, Dopamine, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , ,

This 2015 Swiss rodent study found:

“Mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats.

Treatment with nicotinamide, an amide form of vitamin B3 that boosts mitochondrial respiration, into the NAc [nucleus accumbens] of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration, abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals.

Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.”

The researchers handled individual differences of the outbred subjects by separating them into high-, intermediate-, and low-anxiety categories according to their responses on two tests. The high- and low-anxiety subjects were matched by weight, age, and social experience.

Here are a few examples of the researchers thoroughly ruling out confounding factors:

“Differences in social competitiveness are not related to overall differences in social motivation or sociability.

Although social competition did significantly increase corticosterone compared with baseline levels, there were no significant differences between anxiety groups at either time point.

Microinfusion of either ROT, MA, or 3NP [mitochondrial respiration inhibitors] reduced the success of treated animals to win the social contest.

Importantly, these treatments did not induce side effects on social investigation or auto-grooming during social competition, or alter locomotor activity, anxiety, or sociability in additional experiments.

Furthermore, these inhibitor treatments did not produce neurotoxic effects, as the drugs were infused at low doses and we confirmed the absence of lesion and neuronal death.

The effects of complex I or complex II inhibition on social competition were specific for the NAc, as infusions of the same inhibitors into the BLA [basolateral amygdala] had no effect on social dominance and did not affect general locomotor activity.

We further showed that, unlike infusion of muscimol [a GABA receptor agonist] in the BLA that interferes with BLA-dependent auditory fear conditioning, 3NP did not affect conditioning in this task, discarding that neuronal inactivation could be a general mechanism whereby impairing mitochondrial function would affect putative functions from the affected brain region.

The impact of mitochondrial function in social competition described here is not mediated by oxidative stress.”

http://www.pnas.org/content/112/50/15486.full “Mitochondrial function in the brain links anxiety with social subordination”

A study of stress factors and neuroplasticity during infancy/early childhood

gettingwell4 2-3 stars Required further work, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress , , , , ,

This 2015 French rodent study found:

“The coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.

Genetic strategies that disrupted GR [glucocorticoid receptor] phosphorylation or TrkB [the BDNF receptor] signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine.

We demonstrate that fluoxetine prevented the neuroplasticity of chronic stress by priming GR phosphorylation at BDNF-sensitive sites.”

It wasn’t too difficult to see how many of the stressors had human equivalents during infancy/early childhood:

“To determine the plasticity of GR phosphorylation upon changes in the endogenous levels of BDNF and glucocorticoids, mice were exposed to a chronic unpredictable stress that included one daily random stressor for 10 consecutive days from P21 [immediately after weaning] to 1 mo of age.

Chronic unpredictable stress includes one of the following daily random stressors (wet bedding, no bedding, food deprivation, crowded cage, 2 h or 6 h restraining, forced swim, tail suspension).”

But who would give fluoxetine – Prozac – to a human infant or young child to prevent “the neuroplasticity of chronic stress” from having adverse effects?

http://www.pnas.org/content/112/51/15737.full “Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment”

Mitochondria interface genetic/epigenetic responses to psychological stress

gettingwell4 2-3 stars Required further work, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress , , ,

This 2015 Pennsylvania rodent study found:

“Mitochondria can regulate complex whole-body physiological responses, impacting stress perception at the cellular and organismal levels.

Mitochondrial dysfunctions altered the

  1. hypothalamic–pituitary–adrenal [HPA] axis, sympathetic adrenal–medullary activation and catecholamine levels,
  2. the inflammatory cytokine IL-6,
  3. circulating metabolites, and
  4. hippocampal gene expression

responses to stress.

Stress-induced

  1. neuroendocrine,
  2. inflammatory,
  3. metabolic, and
  4. transcriptional responses

coalesced into unique signatures that distinguish groups based on their mitochondrial genotype.”

The study’s design was comprehensive for the subject of mitochondrial function and stress response categories. It interrelated elements that had a common cause of stress, such as:

  • Hyperglycemia
  • Increased lipids
  • Corticosterone sensitivity
  • Epigenetic changes within the brain

The study’s Figure 6E was a hierarchical “heat map” of the correlations among the 77 stress-induced changes that were measured. Figure 6G presented these variables per the five mitochondrial genotypes (a control wild-type and four genetic dysfunctions). Many of the lines forming the hierarchy needed careful reading of the study’s interpretations.

I downgraded the study’s rating because the authors inappropriately forced the “allostatic load” buzzword into the Significance statement and otherwise informative Discussion section. The term refers to a hypothetical long-term situation, but the study’s experiments lasted 2 hours at most before the subjects were killed.

www.pnas.org/content/112/48/E6614.full “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress”

Familiar stress opens up an epigenetic window of neural plasticity

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Glutamate, Hippocampus, Limbic system, Neurochemicals, Stress , , ,

This 2015 Italian rodent study found:

“There is a window of plasticity that allows familiar and novel experiences to alter anxiety– and depressive-like behaviors, reflected also in electrophysiological changes in the dentate gyrus (DG).

A consistent biomarker of mood-related behaviors in DG is reduced type 2 metabotropic glutamate (mGlu2), which regulates the release of glutamate. Within this window, familiar stress rapidly and epigenetically up-regulates mGlu2..and improves mood behaviors.

These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.”

The current study included two of the authors of A common dietary supplement that has rapid and lasting antidepressant effects.

The supplementary material showed the:

“Light–dark test as a screening method allowed identification of clusters of animals with a different baseline anxiety profile”

for the BDNF Val66Met subjects. This research methodology better handled the individual differences that often confound studies.

The study’s press release provided further details such as:

“Here again, in experiments relevant to humans, we saw the same window of plasticity, with the same up-then-down fluctuations in mGlu2 and P300 in the hippocampus, Nasca says. This result suggests we can take advantage of these windows of plasticity through treatments, including the next generation of drugs, such as acetyl-L-carnitine, that target mGlu2—not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I disagree with the authoring researchers’ extrapolation of these rodent findings to humans, which seemed to favor chemical intervention. Causes of human stress should be removed or otherwise addressed.

I hope that the study’s “familiar stress” findings won’t be use to attempt to justify potentially harmful practices such as Critical Incident Stress Debriefing, which mandatorily guides people to process recent trauma. Instead, An interview with Dr. Rachel Yehuda on biological and conscious responses to stress made a point about “windows of plasticity” that’s relevant to who we are as feeling human beings:

“What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.”

http://www.pnas.org/content/112/48/14960.full “Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity”

A review of genetic and epigenetic approaches to autism

gettingwell4 0-1 star Wasted resources, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres, Thalamus , , , , , , , ,

This 2015 Chicago review noted:

“Recent developments in the research of ASD [autistic spectrum disorder] with a focus on epigenetic pathways as a complement to current genetic screening.

Not all children with a predisposing genotype develop ASD. This suggests that additional environmental factors likely interact with the genome in producing ASD.

Increased risk of ASD is associated with mutations in genes that overlap with chromatin remodeling proteins, transcriptional regulators and synapse-associated proteins. Interestingly, these genes are also targets of environmentally induced changes in gene expression.”

Evidence was discussed for both broad and specific epigenetic ASD causes originating in the prenatal environment:

  • Maternal stress:

    “Prenatal stress exerts a profound epigenetic influence on GABAergic interneurons by altering the levels of proteins such as DNMT1 and Tet1 and decreasing the expression of various targets such as BDNF.

    Ultimately, this results in reducing the numbers of fully functional GABAergic neurons postnatally and a concomitant increased susceptibility toward hyperexcitability. The delayed migration of GABAergic interneuron progenitors results in reduced gene expression postnatally which is likely the consequence of increased amounts of DNA methylation.

    The net effect of stress during early development is to disrupt the balance of excitatory/inhibitory neuronal firing due to the loss of function associated with disrupted neuronal migration and maturation.”

  • Prenatal nutrition:

    “Exposure to a wide range of environmental toxins that impact neurodevelopment also result in global DNA hypomethylation. This model was extended to connect pathways between dietary nutrition and environmental exposures in the context of DNA hypomethylation. More recently, this hypothesis was expanded to show how dietary nutrients, environmental toxins, genome instability and neuroinflammation interact to produce changes to the DNA methylome.”

  • Maternal infections:

    “Inflammation, autoimmunity and maternal immune activation have long been suspected in the context of aberrant neurodevelopment and ASD risk.”

  • Exposure to pollutants, medications, alcohol

This was a current review with many 2015 and 2014 references. However, one word in the reviewers’ vernacular that’s leftover from previous centuries was “idiopathic,” as in:

“Idiopathic (nonsyndromic) ASD, for which an underlying cause has not been identified, represent the majority of cases.”

It wasn’t sufficiently explanatory to use categorization terminology from thousands of years ago.

Science has progressed enough with measured evidence from the referenced studies that the reviewers could have discarded the “idiopathic” category and expressed probabilistic understanding of causes. They could have generalized conditional origins of a disease, and not reverted to “an underlying cause has not been identified.”

Another word the reviewers used was “pharmacotherapeutic,” as in:

“The goal for the foreseeable future is to provide a better understanding of how specific genes function to disrupt specific biological pathways and whether these pathways are amenable to pharmacotherapeutic interventions.”

Taking “idiopathic” and “pharmacotherapeutic” together – causes for the disease weren’t specifically identified, but the goal of research should be to find specific drug treatments?

Of course reviewers from the Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago are biased to believe that “the design of better pharmacotherapeutic treatments” will fulfill peoples’ needs.

Are their beliefs supported by evidence? Without using drugs, are humans largely incapable of therapeutic actions such as:

  • Preventing epigenetic diseases from beginning in the prenatal environment?
  • Treating epigenetic causes for and alleviating symptoms of their own disease?

http://www.futuremedicine.com/doi/full/10.2217/epi.15.92 “Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder”

An interview with Dr. Rachel Yehuda on biological and conscious responses to stress

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Memory, Neurochemicals, Stress , , , ,

How Trauma and Resilience Cross Generations

“The purpose of epigenetic changes, I think, is simply to increase the repertoire of possible responses.

So let’s say, for some reason, your parents transmitted to you biologic changes that are very appropriate to starvation, but you don’t live in a culture where food is not plentiful.

You’re just not optimized, but I think that if we develop an awareness of what the biologic changes from stress and trauma are meant to do, then I think we can develop a better way of explaining to ourselves what our true capabilities and potentials are.

What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.

Feel it instead of running to someone to give you a sleeping pill.”

Transcript: http://www.onbeing.org/program/rachel-yehuda-how-trauma-and-resilience-cross-generations/transcript/7791

Telomere dynamics, stress, and aging across generations

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres , , ,

This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

 

http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

Psychological therapy and DNA methylation

gettingwell4 0-1 star Wasted resources, Amygdala, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress ,

This 2015 worldwide human study was:

“The largest study to date investigating the role of HPA [hypothalamic–pituitary–adrenal] axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.

In this study, we tested the association between polymorphisms of FKBP5 [a gene that produces a protein that dampens glucocorticoid receptor sensitivity primarily in areas of the limbic system such as the hippocampus and amygdala] and GR [glucocorticoid receptor gene] and response to CBT [cognitive behavior therapy] in children with anxiety disorders (N = 1,152), and examined change in DNA methylation at specific regions of these genes during the course of CBT in a subset of the sample (n = 98).

No significant association was found between GR methylation and response. Allele-specific change in FKBP5 methylation was associated with treatment response.”

Regarding “treatment response:”

“Subjects aged 5–18 (mean: 9.8 years) met DSM-IV criteria for primary diagnosis of an anxiety disorder.

Clinical severity ratings (CSRs) were usually based on composite parent and child reports, and were assigned on a scale of 0–8. [36] [linked below]

Treatment response was defined as the change in primary anxiety disorder severity from pretreatment to follow-up. A diagnosis was made when the child met diagnostic criteria and received a CSR of 4 or more. Remission was regarded as the absence of the primary anxiety according to diagnostic criteria, as determined by the clinicians at the follow-up interview.”

Scenarios where nine-year-olds and their parents may have benefited from skewing their “composite parent and child reports” either way:

  1. Parents benefited from an anxious-child report (financial support provided, social services provided, avoided undesirable activities like going to work, continued psychological dependence, provided victim celebrity, enabled their own problems)
  2. Parents benefited from a well-child report (freed up time to pursue desirable activities, financial relief, relief from court-ordered or social-services-required activities, covered up their own contributions to the child’s problems)
  3. Nine-year-olds benefited from an anxious report (relief from undesirable activities like school attendance, continued psychological dependence, provided victim celebrity, activities structured around their condition, enabled the parents’ problems)
  4. Nine-year-olds benefited from a well report (symptom reduction, met parental expectations, freed up time to pursue desirable activities, covered up the parents’ contributions to the child’s problems).

I wonder what “treatment response” criteria were available other than self-serving reports and “diagnostic criteria, as determined by the clinicians.” Every day medical personnel hear patients self-report conditions where biological measurements may confirm or indicate something different. Did the “diagnostic criteria, as determined by the clinicians” include comparisons to relevant biological measurements?

The related study linked below points out:

“Although CBT has been established as an efficacious treatment, roughly 40% of children retain their disorder after treatment.”

Its focus was also on predictors (other than genetic) of CBT outcomes.

Neither study provided evidence of attempts to find originating causes for the children’s conditions. Were the international CBT approaches only interested in treating symptoms?

http://onlinelibrary.wiley.com/doi/10.1002/da.22430/full “HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS”

Related 2015 study: http://www.jaacap.com/article/S0890-8567%2815%2900191-4/pdf “Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study”

Fetal exposure to sex hormones and female anxiety

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress, Testosterone

This 2015 Swedish rodent study found:

“Women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring.

Although clinical data are inconsistent, there are indications that androgens play a crucial role in behavior and mood regulation in females.

Studies on the link between testosterone and anxiety behavior in males have generated inconsistent results.

Higher circulating testosterone has previously been reported in female rat PNA [prenatal androgen] offspring. This discrepancy may be a result of the higher doses of maternal testosterone (5 mg) used in the previous study compared with the present study (0.5 mg).

Although the anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens, the reduced AR [androgen receptor] expression in the amygdala suggests a compensatory response to the high prenatal testosterone exposure, a result implicating the amygdala as the CNS site underlying the changes in anxiety in the PNA offspring. This idea is further strengthened by our experiment showing that subchronic testosterone exposure into amygdala is sufficient to produce anxiety-like behavior in adult females.

Maternal testosterone exposure causes anxiety-like behavior in female, and to a lesser extent male offspring, an effect that seems to occur during fetal life and to be mediated via AR in the amygdala, together with changes in ER [estrogen receptor] and in the serotonergic and GABAergic pathways in the amygdala and hippocampus of female PNA rats.”

The news coverage – too much testosterone caused anxiety-like symptoms in females whether they are adults or fetuses – was NOT what the study found. The headlines disregarded its caveat:

“The anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens.”

I look forward to research on floor levels of testosterone, below which there are also adverse effects on females. There is such evidence, but would it play well with popular memes?

See Sex hormone exposure to the developing female fetus causes infertility in adulthood for another study that used the PCOS phenotype.

http://www.pnas.org/content/112/46/14348.full “Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring”

Transgenerational epigenetic programming with stress and microRNA

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Stress , , , ,

This 2015 Pennsylvania rodent study found:

“Sperm miRs [microRNAs, a small non-coding RNA that has a role in gene expression] function to reduce maternal mRNA [messenger RNA, a large RNA that carries codes for protein production] stores in early zygotes, ultimately reprogramming gene expression in the offspring hypothalamus and recapitulating the offspring stress dysregulation phenotype.”

These researchers caused stress-induced changes at an early stage of embryonic development with microRNA injections. Resultant adverse effects weren’t observed until subjects were adults!

Most news coverage focused on it being a male’s stress, not a female’s, that affected a developing embryo. Either or both sexes can epigenetically disadvantage a fetus – okay.

Demonstrating how a damaging influence can begin immediately after conception, but symptoms didn’t present until adulthood made this study newsworthy.

Although the term “transgenerational” was used in the study’s title, abstract, and elsewhere, studied epigenetic effects were intergenerational rather than transgenerational. Per A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply, researchers need to provide evidence in at least the next 2 male or non-gestating female generations and/or 3 gestating female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

From a press release, a study coauthor who also coauthored How to make a child less capable even before they are born: stress the pregnant mother-to-be stated:

“Bale suspects that when a male experiences stress it may trigger the release of miRs contained in exosomes from epithelial cells that line the epididymis, the storage and maturation site for sperm between the testes and the vas deferens. These miRs may be incorporated into maturing sperm and influence development at fertilization.”

Not all stress-related gene expression in pituitary and adrenal glands differed.

http://www.pnas.org/content/112/44/13699.full “Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress”