an Endocrine Hypothesis

The Introduction includes a sporadically updated blog on where I'm currently focusing most of my attention.   Historical Background & Free Book  tells where I began.  Internal links are in green.  
My other websites:  Children of the Amphioxus    Subcortical Brain     

These websites are an ongoing effort and will gradually change as I continue to research the relevant topics.  Please send questions and/or comments to: 
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    I've spent 15 years as a very part-time substitute teacher in the public school system of a moderately large American city.  It's been my observation that, using very broad averages, the educational effort is defeated by about 10% of the students whose constant disruptions prevent the other 90% of the students from receiving the quality education which they really want.  After I had befriended the disruptors, they explained their situation to me. 

    "We don't have fathers." 

    Once I had been given this key, I was able to confirm it over and over.  If a young man was misbehaving, and the disruptors are almost always male, I would ask him:

    "How would your father feel if he saw you behaving like this?"  Their answer was always, always, always the same. 

    "I don't have a father." 

    And it was always said with great sadness.  They know something important is missing from their lives.   

    Some time later, I took a class on teaching children who have disabilities.  We had to write a term paper, and the instructor was broad-minded enough to allow me to write mine on the disability of not having a father.  The result was the first version of "Boys without Fathers, an Endocrine Hypothesis". 


    Boys who are forced to try to grow up without a father face many difficulties above and beyond the problems they have and present in school.  See:  Family Structure   .  This paper offers an endocrine hypothesis as to why a boy who grows up without a father might end up with the difficulties that seem to come with father-absence. 

    Research into the influence that the endocrine system has on behavior employs two different but mutually reinforcing methodologies.  The first methodology is to gather data on the endocrine systems and behavior of a large number of individuals of the same species, either human or non human, and then examine the data for statistically significant correlations between behavior and the levels of the bioactive compounds of interest.  The second methodology is to artificially change the levels of the bioactive compounds of interest and then look for changes in behavior.  Ethical considerations generally limit this second methodology to experiments with non humans. 

    Both of these methods face practical constraints on the number of parameters that can be measured simultaneously.  Because of the enormous complexity of the Human Endocrine System it's never possible to measure all relevant parameters at the same time.  So researchers have no choice but to measure some parameters and ignore others, and the decision as to which parameters to measure and which to ignore varies from researcher to researcher.  What's more, the various bioactive compounds often have effects on one another, and many of these effects are as yet unresearched.  Therefore, we have no choice but to compile the incomplete data that is available and then try to fit it all together into some sort of coherent whole.   

The Criminal Neuro-Endocrine System:  

     As summarized in  Criminal Hormones , socially deviant adults often show abnormalities in their neuro-endocrine systems.  The most commonly found abnormalities are: 

    1.  decreased turnover of the Neurotransmitter   Serotonin    
    2.  decreased circulating levels of the Hormone   Cortisol
    3.  increased circulating levels of the Hormone   Testosterone  , and when serotonin, cortisol and testosterone are all measured at the same time, these abnormalities are found together. 
     See:  Cortisol & Testosterone & Serotonin  . 

    Statistical analysis of the variations within these abnormalities shows that the increased Testosterone is responsible for the Aggression common to the syndrome, while the reduced   Serotonin is responsible for the Impulsivity
     See:   Criminal Testosterone & Serotonin and  Serotonin References

    Notice that the above abnormalities concern three very different physiological realms: the reproductive hormonal system, the stress response hormonal system and that portion of the nervous system that uses  Serotonin as a neurotransmitter.    In spite of the great difference between these three systems, all of the abnormalities described above can be traced back to the body's response to  Stress  .  

    In none of the articles discussing people with the above endocrine profile was there any mention of the  Family Structure in which the individuals having the profile had grown up.  In particular, there was no way of telling whether or not they had grown up without a father. 
    However, "(R)esults from longitudinal event-history analysis showed that, although a sizable portion of the risk that appeared to be due to father absence could actually be attributed to other factors, such as teen motherhood, low parent education, racial inequalities, and poverty, adolescents in father-absent households still faced elevated incarceration risks."
    See:  Family Structure
    So there is probably considerable overlap between individuals having the above endocrine profile and men who have grown up without a father.  This paper presents an hypothesis as to why a boy who grows up without a father might end up with the above endocrine profile and all of the difficulties that seem to come with it. 

Endocrine Data:  
    In particular, we will be discussing how the presence or absence of a father affects the levels and actions of eight bioactive compounds within his son.  Four of these are all members of the Corticotropin-releasing factor family (CRF) .  The eight bioactive compounds we will be discussing are, in decreasing order of importance:

    1.   Serotonin ,   which is sometimes called the "happiness hormone"
          but which is actually both a Neurotransmitter and a Neuromodulator .
    The four members of the  Corticotropin-releasing factor family (CRF) ,
    2.  Corticotropin-releasing hormone (CRH)   and   
    3.  The three Urocortins
           -  urocortin I  (also written urocortin 1 or Ucn1)     
    4.    -  urocortin II   (also written urocortin 2 or Ucn2)   
    5.    -  urocortin III   (also written urocortin 3 or Ucn3) ,
        all of which seem to be Neuromodulators ,    
    6.  the two  Steroid   Hormones
          Cortisol   and
    7.   Testosterone and
    8.   the  Posterior Pituitary   Hormone   Arginine Vasopressin (AVP).   

    Because of the importance of Serotonin to this hypothesis, I've compiled a list of the pages on this site which discuss Serotonin
    See:  Serotonin References

Three Different Pathways:       

    The Corticotropin-releasing factor family (CRF) seems to  be the key.  It has direct influence on the levels of both  Serotonin  and  Cortisol , and indirect influence on the levels of both  Arginine Vasopressin (AVP) and  Testosterone.     
    Unfortunately, there's a complication here.  See  Abbreviations .  

    If I understand correctly, members of the Corticotropin-releasing factor family (CRF) influence Serotonin and Cortisol through three different pathways.  The three pathways are:

   the Direct Serotonin Pathway ,

   the Direct Cortisol Pathway .  and

   the Indirect Serotonin Pathway

   Although, the boys who cause problems in the classroom seem more Impulsive than violent, the endocrinology of Impulsivity is more complex and less well understood than the endocrinology of  Aggression .  So I originally intended to begin this paper by focusing on  Aggression .  However, I've changed my mind. 

    As discussed in  Amphioxus Stress Hormones , the Amphioxus does not have many of the elements of the Direct Cortisol Pathway and therefore has very little Cortisol . In humans, low Cortisol is associated with  Aggression .   

    In contrast, as discussed in  Amphioxus Serotonin System , the amphioxus does have many elements of the  Direct Serotonin Pathway .  
    This provides strong evidence that the more complex  Direct Serotonin Pathway evolved before the less complex  Direct Cortisol Pathway   In humans low Serotonin is associated with   Impulsivity

    I was thinking that I would deal with the  Direct Cortisol Pathway   first, because of its greater simplicity.  But, whenever possible, I prefer to take things in their evolutionary order.  So I'll consider the  Direct Serotonin Pathway first, followed by the Direct Cortisol Pathway and finally by the Indirect Serotonin Pathway.   Since the Indirect Serotonin Pathway is initiated by Cortisol , it seems safe to assume that the Indirect Serotonin Pathway evolved after the Direct Cortisol Pathway

    For more details see:  Direct vs. Indirect 5-HT .       

    This will not be an easy task.  The   Human Endocrine System   is extremely complex, and, even when we limit our inquiry to just the eight bioactive compounds listed above, we will find that there is still much that is not yet fully understood. 

    First I'll discuss the direct pathway by which members of the  Corticotropin-releasing factor family (CRF) influence Serotonin
    Second I'll discuss the direct pathway by which members of the  Corticotropin-releasing factor family (CRF) influence Cortisol
    Third I'll consider the indirect pathway by which members of the  Corticotropin-releasing factor family (CRF) influence Testosterone
    Fourth I'll consider the indirect pathway by which members of the  Corticotropin-releasing factor family (CRF)   influence Serotonin  , and  
    Fifth I'll consider the indirect pathway by which members of the  Corticotropin-releasing factor family (CRF) influence Arginine Vasopressin

    After analyzing the papers which consider  members of the  Corticotropin-releasing factor family (CRF)   and only one other parameter, I'll look at the papers which measured multiple parameters. 

    Direct Serotonin Pathway

    I've summarized all the references which deal with serotonin here:  

    The  Dorsal Raphe Nucleus (DRN) is a major source of Serotonin transmission to the rest of the brain.  Members of the  Corticotropin-releasing factor family influence the level of  Serotonin in the brain by modulating the activity of serotonergic neurons in the caudal portion of the DRN .   

     CRF & Serotonin  gives a meta analysis of some of the references on the relationship between  Corticotropin-releasing factor family (CRF)  and Serotonin .  

    CRF Receptors  discusses the difference between the two receptors: CRF1R and CRF2R.   Although this area is still an active field of research and many questions are still unanswered, much has been learned.    

    In particular, even though CRF1R and CRF2R are both stimulatory, they have opposite affects on the transmission of  Serotonin to other parts of the nervous system.  Activation of CRF1R reduces the transmission of serotonin while activation of CRF2R increases the transmission.   

    At the moment, the most likely explanation for this seems to be that the CRF1R are located on and activate GABA-ergic interneurons which inhibit the serotonergic neurons with which they Synapse while the CRF2R are located directly on serotonergic neurons, which they stimulate. 

    For reasons which are still unclear, CRF1R activation and subsequent inhibition of serotonergic neurons occurs at low levels of 
Corticotropin-releasing factor family (CRF)  while CRF2R activation and subsequent excitation of serotonergic neurons occurs at high levels of CRF.  Therefore, at low levels of CRF, the transmission of serotonin is reduced, and at high levels of CRF, the transmission of serotonin is increased. 

    Urocortins   provides at least two suggestions as to how members of the   Corticotropin-releasing factor family (CRF)  regulate the the transmission of Serotonin from the Dorsal Raphe Nucleus to the Nucleus Accumbens Septi .  At the moment, the hypothesis that I find the most appealing is that the CRF1R receptor is activated by  Corticotropin-releasing hormone (CRH) and the CRF2R receptor is activated by Ucn2.  However, this is still very much a matter of continuing research, and there is only a very tentative suggestion that initial and/or mild stress produces CRH which activates the CRF1R receptor while prolonged and/or sustained or repeated stress produces Ucn2 which activates CRF2R receptor.    
    The origin of the CRH-type ligand which modulates the serotonergic neurons in the DRN is uncertain.  Early research suggested that it is extrahypothalmic.  That is that it does not come from the  Paraventricular nucleus (PVN) of the Hypothalamus .  Rather it seemed more likely to originate in the Amygdala  and/or Bed Nucleus of the Stria Terminalis and/or Hippocampus and/or 
Edinger-Westphal nucleus and/or Locus Ceruleus (LC) .  Now, more recent research opens the possibility that it may originate in the PVN   after all.
    As discussed in: 

        Serotonin & Impulsivity ,         
        Criminal Serotonin,          

decreased whole-brain serotonergic activity, as measured by low concentrations of the Serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the Cerebrospinal Fluid (CSF) seems to be the chief endocrine correlate of impulsivity. 

    However, extensive research has not yet determined how Serotonin modulates the level of Dopamine  at the Dopamine Receptors  in the Nucleus Accumbens Septi (NAC), which seems to be the critical factor determining the level of  Impulsivity.  

    As recorded in: 

        Accumbal 5-HT Receptors         
        Serotonin & Dopamine            
        Book: 5-HT DA Interaction:   Chap 1: CNS     

there are as many as ten Serotonin Receptors (5-HTRs) in the NAC, and, as far as I can tell, we have not yet determined the specific neurons on which any of them are located.  So this may be as far as I can go in that direction at this moment.

    Direct Cortisol Pathway     

    The first function of Corticotropin-releasing hormone (CRH) to be discovered was its role in releasing ACTH (originally known as 'corticotropin') from the anterior portion of the   Pituitary Gland .   

    From the anterior portion of the pituitary, the corticotropin (latin for 'that which goes to the cortex') is carried by the blood to the  Adrenal Cortex .  The adrenal cortex responds to the ACTH  by releasing  Cortisol  back into the blood stream.  This is known as the  HPA Axis .  
    It's important to recognize that this pathway by which members of the  Corticotropin-releasing factor family influence the level of  Cortisol  in the blood stream is separate from the pathway by which members of the  Corticotropin-releasing factor family influence  the amount of Serotonin supplied by the Dorsal Raphe Nucleus (DRN) to other parts of the nervous system, particularly the brain, as described in the previous section.   
    For more detailed discussion, see:    

        Cortisol & Behavior
        Cortisol & Dominance     
        Criminal Cortisol 

    Indirect Testosterone Pathway       

        As is the case for Arginine Vasopressin (see below),  Corticotropin-releasing hormone (CRH) influences Testosterone only through the HPA Axis  (the Direct Cortisol Pathway) .  I found no evidence that CRH or the Urocortins influence Testosterone through the Dorsal Raphe Nucleus (the Direct Serotonin Pathway).  

        Cortisol  directly inhibits testicular Luteinizing Hormone (LH) receptor function without decreasing the level of circulating LH.  Therefore, increased levels of circulating cortisol cause decreased levels of circulating testosterone.   Since increased levels of CRH cause increased levels of cortisol via the  Direct Cortisol Pathway , increased levels of CRH cause decreased levels of testosterone.     
    See also : 

        CRH & Testosterone     
        Criminal Testosterone

    Indirect Serotonin Pathway        

The Older, Second Half of the Indirect Serotonin Pathway

The summary of  Rodent Testosterone 5-HT Interaction says:
    "These references specify three serotonin receptors that seem to be down regulated by testosterone.  The three are: 5-HT1AR, 5-HT2AR and 5-HT3R.".

The Newer, First Half of the Indirect Serotonin Pathway

     Cortisol & Testosterone   provides an explanation for the first part of the sequence, in which Cortisol reduces the sensitivity of Testosterone   Receptors .

The final summary of the fourteen references says: 

   " ACTH treatment ... elevated Cortisol ... reduced Testosterone ... independent of the Luteinizing Hormone (LH) ... cortisol directly interacts with the Leydig cells" 
    " Stress -mediated elevations in circulating Glucocorticoid levels lead to corresponding rapid declines in Testosterone"

    Indirect Arginine Vassopressin Pathway       

        According to the articles reported in the sections below, Corticotropin-releasing hormone (CRH) influences Arginine Vasopressin (AVP) only through the HPA Axis (the Direct Cortisol Pathway).  I found no evidence that CRH or the  Urocortins influence AVP through the  Dorsal Raphe Nucleus  (the Direct Serotonin Pathway).  


        Arginine Vasopressin         
        Criminal Vasopressin    
        CRH & Vasopressin   

    Simultaneous Pairwise Data       

    As mentioned, above, researchers have no choice but to measure some parameters and ignore others, and the decision as to which parameters to measure and which to ignore varies from researcher to researcher.  This poses a dilemma for those of us who try to index their results. 

    If a researcher measures more than one parameter, under which parameter do we file their research?  In the list of pairwise data below, I've placed papers concerning serotonin at the top of the list, followed by those concerning cortisol and finally by those concerning testosterone and vasopressin.       

    Cortisol & Serotonin        

    So far, I've found only one paper which measured both cortisol and serotonin and nothing else.  I didn't find its interpretation of its results convincing.  I had originally intended to eliminate, or at least trim back, the meta analysis I made of the article, but I ended up leaving it in place.        

    Criminal Vasopressin & Serotonin
    Criminal Testosterone & Serotonin   

    Cortisol & Testosterone  
    Criminal Cortisol & Testosterone      
    Testosterone & AVP
    Criminal Testosterone & Vasopressin       

    Simultaneous Three-way Data   

  Cortisol & Testosterone & Serotonin    
  Cortisol, Testosterone & Dominance      
  Criminal Testosterone, Serotonin & ACTH

    Although I haven't yet provided comments on the sets of pairwise and three-way data listed above, I'm going to go on and attempt a first statement of an endocrine hypothesis which emphasizes Serotonin.  I'll come back and add comments on the list of data sets, above, after I've made a first statement of the endocrine hypothesis. 

The Male Dominance Hierarchy:        
     There is a phenomenon, usually referred to as the "  Male Dominance Hierarchy " , which seems to be universal among all vertebrates, including humans.   This paper will offer an endocrine explanation for the male dominance hierarchy and then suggest how its disruption might help to explain the many difficulties faced by boys who try to grow up without a father.   
    See:  Family Structure

    In particular, fathers train their sons' endocrine systems as the boys grow into manhood.  The endocrine systems of boys who grow up without the influence of an older, dominant male, such as a father, never receive this training, and their untrained endocrine systems prevent them from ever fitting comfortably into society.   

The Endocrine Hypothesis

    As explained in the Direct Serotonin Pathway, the  Dorsal Raphe Nucleus (DRN) may be, if not the only, at least one of the sites at which Serotonin turnover is modulated.  Low levels of Corticotropin-releasing hormone (CRH) and/or the Urocortins inhibit the serotonergic neurons and reduce transmission of  Serotonin to other parts of the brain.   Higher levels of CRH stimulate the serotonergic neurons and increase transmission of serotonin to other parts of the brain.  Increased serotonin increases self-control by decreasing Impulsivity .  Very high levels of serotonin result in  Learned Helplessness .  
    A dominant father controls his son's  Serotonin level through  Stress .   He uses stress to adjust the amount of serotonin transmitted from the  Dorsal Raphe Nucleus (DRN) to the remainder of his son's brain.  He adjusts the amount of serotonin transmitted from his son's DRN so that his son's Impulsivity remains within acceptable limits without lapsing into Learned Helplessness .   
    As a son matures into manhood, his father will allow his son's serotonin to decline during approved activities such as competition in sports, academics or business, but will maintain his son's elevated serotonin level relative to unapproved activities such as disrupting class in school, selling drugs or other forms of crime.   

    When a boy doesn't have a father to keep his serotonin level up, he experiences  an inappropriate decrease in serotonin leading to poor impulse control.    

    As explained in Direct Cortisol Pathway, the stress imposed by a father on his son also controls the his son's level of circulating Cortisol , and this in turn controls the level of his son's circulating Testosterone which, in turn, controls his son's Aggression.    

    When a boy doesn't have a father to keep his Serotonin level up and his Testosterone level down, he experiences an inappropriate decrease in serotonin leading to poor impulse control ( Impulsivity), and an inappropriate increase in testosterone, leading to Aggression .   

    From the point of view of the Male Dominance Hierarchy, a boy without a father is making a premature attempt to assert himself as dominant.  All boys struggle to ascend the male dominance hierarchy, but we live in a complex world.  Males who achieve endocrine dominance before mastering civilization's complexity can do society more harm than good.     


    All references now have at least some links, whether included in the original copy or provided by me.    

Children of the Amphioxus  
Subcortical Brain  
Brain of the Tiger Salamander   

  Family Structure       

  Human Endocrine System     
      Criminal Hormones   
       Corticotropin-releasing factor family (CRF)
           CRF Receptors  
                  CRH Receptor    
      Corticotropin-releasing hormone (CRH)        
           Criminal Corticotropin-Releasing Hormone  
        Pro-opiomelanocortin (POMC)  
            Criminal Cortisol 
            Cortisol-Testosterone Loop     
         Glucocorticoid Receptor      
            Criminal Testosterone       
       Gonadotropin-Releasing Hormone (GnRH)        
         Luteinizing Hormone    
            Luteinizing Hormone Receptor    
        Arginine Vasopressin    
            Criminal Vasopressin        

            Multiple Synapses   
        Serotonin Detection  
        Serotonin References   
        Criminal Serotonin
         Serotonin Receptors
       Biogenic Amines           
           Dopamine Receptors   
          Tyrosine Hydroxylase      
          Dopaminergic Cell Groups   
          Dopamine Hypothesis     
          Neuromodulator Receptors       

  Dorsal Raphe Nucleus       
   Edinger-Westphal nucleus   
  Paraventricular nucleus (PVN)      
  Bed Nucleus of the Stria Terminalis     
  Basal Ganglia          
  Globus Pallidus     
  Nucleus Accumbens Septi      
       Accumbal 5-HT Receptors    
  Ventral Tegmental Area    
  Substantia Nigra
  Limbic System
  Hypophyseal Portal System       
  Pituitary Gland      
      Anterior Pituitary      
      Posterior Pituitary
  Adrenal Gland
      Adrenal Cortex
      Adrenal Medulla
  HPA Axis
   Reticular Activating System          
   Cerebral Cortex    
         Cortical Development   
   Prefrontal Cortex
   Periaquiductal Gray
  Cingulate Cortex
  Ventricular System
  Cerebrospinal Fluid
  Locus Ceruleus (LC)
   Medulla Oblongata      
   Central Nervous System (CNS)        
  Autonomic Nervous System      
  Sympathetic Nervous System      
  Parasympathetic Nervous System      
      CRH Receptors
        G-Protein Coupled Receptors              
      Stress Evolution       
   Agonistic Behavior   
  Learned Helplessness

  CRF & Serotonin
      CRH & Serotonin      
  Serotonin & Impulsivity      

   Serotonin & Dominance        
   Serotonin & Dopamine    
   Book: 5-HT DA Interaction    
       Chap 1: CNS    

Criminal Corticotropin-Releasing Hormone        
Testosterone Serotonin Interaction

Cortisol & Behavior           
  Cortisol & Dominance

  CRH & Vasopressin      
  Criminal CRH & Vasopressin     
  CRH & Testosterone       

  Cortisol & Serotonin
  Cortisol & Testosterone
  Testosterone & AVP
   Criminal Testosterone & Serotonin
Criminal Vasopressin & Serotonin
Criminal Cortisol & Testosterone
Criminal Testosterone & Vasopressin         

Cortisol, Testosterone & Dominance          
Cortisol & Testosterone & Serotonin   
Criminal Testosterone, Serotonin & ACTH

Direct Cortisol Pathway
Direct Serotonin Pathway    
    Indirect Serotonin Pathway    
    Direct vs. Indirect 5-HT   

Male Dominance Hierarchy

Lamprey Dominance Hierarchies         
Shark Dominence Hierarchies
Teleost Dominance Hierarchies
Lungfish Dominance Hierarchies
Salamander Dominance Hierarchies
Monotreme Dominance Hierarchies
Marsupial Dominance Hierarchies
Rodent Dominance Hierarchies   
Primate Dominance Hierarchies   
Human Dominance Hierarchies  

Endocrinology of Dominance

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Fig Stor 2    

Evolution of Boys without Fathers    

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