Endocrinology

Question 1

summary of main points (endo)

Answer 1

• Hormones are chemical agents that provide slow & long-lasting behaviour effects
• Hormones affect growth & every physiological function (e.g. sex, sleep
• Hypothalamus is the master regulator & enables top-down control of hormones via connections with other brain regions
  Hormones have receptors in the brain & can affect behaviour in addition to their metabolic effects

Question 2

glucocorticoids: cortisol and corticosterone

Answer 2

• Hormones that help to cope with stress (e.g., trauma, infection, surgery, perceived stress)
• increase glucose level (for muscles)
• supports genesis of new glucose
• mobilises free fatty acids (energy)
• mobilises amino acids (proteins)
• increases proteins in liver & plasma
• decreases immune responses- immune system takes up too much energy so in immediate view of stressor you need to conserve energy for fight or flight
  decreases inflammation

Question 3

diurnal rhythm

Answer 3

• There is a diurnal profile in secretion of ACTH and cortisol. ACTH is secreted in response to hypothalamic CRH; in absence of CRH, the pituitary would secrete only little ACTH. Note how ACTH bursts precede those of cortisol.
  Glucocorticoids are regulated by hormone corticotropin or ACTH, secreted in anterior pituitary. ACTH stands for adrenocorticotropic hormone. Please note, in the left-hand panel, the daily profile of cortisol and ACTH secretion. Increases in secretion of cortisol lag behind the surges of the pituitary ACTH. Please note that the maximum level of cortisol is at 8AM and it is very low during the night.

Question 4

hypothalamic pituitary adrenal axis

Answer 4

hypothalamus –> (releasing factor)–> anterior pituitary –> (ACTH through blood) –>adrenal cortex –> cortisol

Question 5

hypothalamus

Answer 5

controls body functions e.g. sweating, bladder, rage, blood pressure, hunger etc

Question 6

hypothalamic releasing and inhibitory hormones

Answer 6

• Hypothalamus releases a number of different hormones- both releasing (communicate to other hormones to release) and inhibitory (communicates to other hormones to stop)
• Thyrotropin-releasing hormone = TRH
  
  • stimulates secretion of thyroid-stimulating hormone in anterior pituitary
• Gonadotropin-releasing hormone = GnRH
  
  • stimulates secretion of luteinising & follicle stimulating hormones in anterior pituitary
• Growth hormone-releasing hormone = GHRH
  
  • stimulates secretion of growth hormone in anterior pituitary
• Growth hormone-inhibitory hormone = somatostatin
  
  • inhibits secretion of growth hormone in anterior pituitary
• Prolactin-inhibiting hormone = PIH
  
  • inhibits secretion of prolactin in anterior pituitary
• Corticotropin-releasing hormone = CRH (from paraventricular nucleus)
  stimulates secretion of adrenocorticotropic hormone in anterior pituitary

Question 7

anterior pituitary hormones

Answer 7

• Growth hormone (somatotropin) – GH
  
  • stimulates body growth, cell multiplication & differentiation
• Thyroid stimulating hormone – TSH
  
  • stimulates secretion of thyroid hormones
• Follicle-stimulating hormone – FSH
  
  • stimulates development of ovarian follicles & spermatogenesis in testis
• Luteinizing hormone – LH
  
  • causes ovulation & stimulates the corpus luteum; stimulates secretion of estrogen & progesterone in ovaries; stimulates testosterone in testes
• Adrenocorticotropic hormone – ACTH
  stimulates secretion of glucocorticoids & androgens in adrenal cortex

Question 8

3 ways HPA axis activity is regulated

Answer 8

• Diurnal rhythm
  
  • HPA is functioning in accordance of when sleeping and waking- raising up before you sleep and it is going down during the day
• Negative feedback
  
  • body senses you have enough cortisol in the bloodstream in response to the stressor so feedbacks to the brain to tell it to stop
    Stress

Question 9

where does cortisol go?

Answer 9

• Almost every cell in the body has cortisol receptors
• Up to 95% of secreted cortisol is bound to large proteins (e.g. globulin & albumin) & carried in the body through the blood
• Unbound cortisol can freely enter all tissues, passing through parotid gland into saliva & through kidney into the urine
  Unbound cortisol can cross the blood-brain barrier

Question 10

amygdala

Answer 10

• Has glucocorticoid receptors
• Acute (1 day) & chronic (10 days) administration of corticosterone caused prolongation of dendrites in basolateral nucleus of amygdala in rodents (Mitra & Sapolsky, 2008)
  Similarly, acute (1 day) or chronic (10 day) immobilisation stress in rats caused increase in the number of dendritic spines in basolateral amygdala after 10 days in rodents (Mitra et al., 2005)

Question 11

hippocampus

Answer 11

• Has glucocorticoid receptors
• Glucocorticoids affect hippocampus in neurotoxic ways (Lupien & McEwen, 1997, McEwen, 1999):
  
  • Decreased neuronal firing
  • Further decreases in neuronal excitability later
  • Impaired neurogenesis in the dentate gyrus of hippocampus, which projects to amygdala
    Loss of neurons, shrinkage of neuronal bodies & retraction of dendrites in CA1-3 regions

Question 12

stress causes adrenal gland enlargement and hippocampus degeneration in monkeys

Answer 12

• Uno et al., 1989
• This study illustrates further the degenerative changes in hippocampus due to chronic stress. The study analysed the structure and number of neurons in hippocampus in 8 monkeys living in captivity for years and were either in dominant or subdominant roles. A subdominant status was recognised by seeing many healed wounds from bites etc., basically a subordinate monkey was bullied by dominant monkeys.
  The degenerative changes in subdominant monkeys were much more abundant compared to dominant monkeys. Degeneration was mostly seen in cornu ammonis (CA) regions 1-4 and it was evidenced in the reduced number of pyramidal neurons and reduced volume of hippocampal subregions. There were no similar reductions outside hippocampus and subdominant monkeys also showed other changes signifying presence of stress, such as stomach ulcers and enlarged adrenal glands.

Question 13

prefrontal cortex

Answer 13

• Has an abundance of glucocorticoid receptors
• Activity in ventral medial PFC decreased during acute stress in healthy people, correlating with cortisol increases (Sinha et al., 2016)
  Daily injections of corticosterone for 3 weeks or 10 min/day stress caused shortening of dendrites in PFC neurons in rodents (Brown et al., 2005)

Question 14

how does cortisol modify behaviour?

Answer 14

• Emotion regulation impaired- amygdala becoming more sensitive
• Complex effects on memory, disrupting memory formation but sharpening memory consolidation & retrieval
• Cognitive deficits in learning & decision making, & slow extinction of fearful memories
  Observed in rodents & people after long-term exposure to corticosterone/cortisol or stress, suggesting evolutionarily-based functions during stress

Question 15

5 ways to assess cortisol

Answer 15

• Single Sample
  
  • Overnight cortisol
• Multiple Samples
  
  • Total cortisol concentration over the day (area under the curve, or AUC)
  • Diurnal cortisol rhythm
  • Cortisol awakening response (CAR)
    Cortisol reactivity & recovery

Question 16

cortisol sample collection

Answer 16

• blood and saliva (activity in past 10-60 min)
• urine (activity in the past 24 hours
• hair (activity in the past months)

Question 17

overnight cortisol

Answer 17

• Researcher interested in non stimulated cortisol levels (not in response to a stressor)
• Urine sample
• Provides measure of non-stimulated level of cortisol activity
• Greater overnight cortisol associated w/ increased mortality risk & declines in cognitive & physical function (Seeman et al., 2001)

Question 18

total cortisol concentration over the day (area under the curve)

Answer 18

• Saliva or blood samples, ≥ 2 per day, ≥ 3 days
• Provides daily measure of cortisol activity w/ more precision than overnight cortisol
• Differentiates from overnight cortisol- more precision through multiple measures and fluctuating concentrations

Question 19

diurnal cortisol rhythm

Answer 19

• Saliva or blood samples, ≥ 2 per day, ≥ 3 days
• Provides a measure of changes in cortisol activity throughout the day
  Specifically choose periods that allow us to look at the rhythm throughout the day
• Slope (change in cortisol throughout the day)
• Researchers interested looking at changes in the diurnal rhythm- everyone should have peak level in the morning
• Difference between fatigue ppts and non fatigued- cortisol has a role in fatigue
  Cortisol slope and high depression vs low depression- difference earlier in the day- starting higher and going lower but the high depression group does not have much of an awakening response so slope is flatter

Question 20

cortisol awakening response (CAR)

Answer 20

• Saliva or blood samples, ≥ 2 on day, 1 immediately after waking (before getting out of bed), 1 30-45 min post-waking
• Unbound cortisol levels increase by 50-75% within the first 30 min post-waking
  “Blunted” or “exaggerated” rise may be associated with psychopathology
• Left- control group has natural diurnal rhythm but ptsd has blunted awakening response
  Right- both groups see a peak and decline but the depression group have a hyper-responsive cortisol awakening response

Question 21

cortisol reactivity and recovery

Answer 21

• Saliva or blood samples, ≥ 3 on day, 1 pre-stress, 1 20 min post-stress (peak), ≥ 1 15-20 min after peak
  
  • Best to conduct studies in late afternoon to minimize diurnal rhythm influence/have lower baseline
• Cortisol increases in response to certain types of stress (Lecture 6)

Question 22

pain

Answer 22

An unpleasant sensory & emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the Study of Pain, 1994)

Question 23

stress induced analgesia

Answer 23

• Based on observation of Col. Henry Beecher (1946) on soldiers sustaining major injuries in combat zones of WW2
  
  • 73% of wounded soldiers did not require any morphine
    “Stress-induced analgesia is a built-in mammalian pain suppression response that occurs during or following exposure to a stressful or fearful stimulus” (Butler & Finn, 2009)

Question 24

summary of main points

Answer 24

• HPA axis components & communication = Hypothalamus releases CRH from paraventricular nucleus à anterior Pituitary secretes ACTH à Adrenal cortex releases cortisol
• Amygdala, hippocampus, & prefrontal cortex have glucocorticoid receptors, so cortisol modifies emotion regulation, memory, & cognitive functions
• Cortisol is in blood, saliva, urine, & hair, & there are 5 ways to assess it: (1) overnight, (2) area under the curve, (3) diurnal rhythm, (4) awakening response, & (5) reactivity & recovery
  Cortisol is involved in stress-induced analgesia whilst also being elevated in chronic pain patients

Question 25

what are the symptoms of psychopathology?

Answer 25

• Depression: depressed mood, loss of interest/pleasure, weight loss or gain, insomnia or hypersomnia, psychomotor restlessness or slowness, fatigue, feeling worthless or excessive guilt, decreased concentration, thoughts of death/suicide
  ○ DSM V symptoms for depression
  ○ Cortisol may cause: decreased concentration
  Schizophrenia/psychosis: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behaviour, negative symptoms (i.e., affective flattening)

Question 26

cortisol elevated in adults with depression (Murri et al., 2014)

Answer 26

• Meta analysis of cortisol elevation in depression
  
  • Right of red dotted line shows impact of depression- further away is a greater effect
  • Pretty large association between cortisol and depression which suggests cortisol could have a causal role in depression
    ○ Stronger case for causality but it is not a causal design (cannot manipulate levels of cortisol in a person and see if they get depression-unethical)
    Evening levels of cortisol is highest but effect size between morning cortisol and depression is large

Question 27

cortisol elevated in adults with schizophrenia

Answer 27

• Girshkin et al., 2014)
• • 44 studies were analysed. Each individual study analysed morning increase in cortisol level in patients with SZ and healthy controls. There was a significantly larger morning increase in cortisol level in SZ compared to controls (d=0.39, P < 0.001) suggesting a disruption of daily secretion of cortisol.
  • Centre value- anything to the right is positive, anything to left is negative
  • Effect size across all studies is .39- pretty small effect size
    Cortisol could be linked to some symptoms but not finding a large evidence base to suggest cortisol is directly linked to schizophrenia

Question 28

cortisol elevated in adults having first episode of psychosis

Answer 28

• Hubbard & Miller, 2019
  
  • People at the time of their first episode of a psychotic disease have a mildly increased cortisol level (d=0.37, P<0.001).
    Not the strongest evidence- on average the effect size is .37 (small effect size)

Question 29

is cortisol a correlate or cause of psychopathology?

Answer 29

“Although the evidence favours cortisol’s participation in the pathophysiology of psychosis, the exact cause–effect sequence and the intertwining of cortisol with psychopathology are still unclear.” (Karanikas et al., 2014, p. 268)