HPA axis Flashcards
Neuro Week 11
Is the Pituitary part of the brain?
No, it’s a gland attached to the hypothalamus but not technically a part of the brain= main ways brain communicates to rest of body
HPA Axis- works through hormones to communicate in bloodstream to organs
how does the pituitary gland grow from childhood to adulthood
- ingrown oral epithelium known as Rathke pouch as an extension of the developing oral cavity
- eventually cut off from origin of growth by sphenoid bone and settles in sella turcica (saddle shaped, base of brain, bone depression)
- rapid growth in childhood and adult (20s) slower growth
Anterior pituitary/adenohypophysis is responsible for nerves that release hormones or hormone release?
hormone release (adrenal gland)
posterior pituitary gland/ Neurohypophysis controls nerves or hormone release?
nerve stimulation that direct hormone release (nerves)
Which pituitary is larger?
anterior- accounts for most of glands size and weight
helps children grow, plays a role in metabolism, bone and muscle health, fat distribution in adults
controls body proportion in extremities and jaw, controls bone growth and height
Growth hormone function
stimulates breast milk production, impacts sex drive and sperm count in men
prolactin
plays a different role whether you have testes or ovaries- sex development and reproduction
In females: stimulates the ovaries to produce eggs and follicles, and helps manage the menstrual cycle.
In males: stimulates the testes to produce sperm
follicle stimulating hormone (FSH)
plays a different role whether you have testes or ovaries
In women: triggers ovulation, the release of progesterone, and the production of steroid hormones in the ovaries.
A sharp increase in levels, known as an ___ surge, occurs around the time of ovulation.
In men: causes the testes to produce testosterone and the Leydig cells to grow.
Regulation: is regulated by gonadotropin-releasing hormone (GnRH), which is produced in the hypothalamus.
luteinizing hormone (LH)
controls production of cortisol; natural steroid needed to stimulate the adrenal gland to release other hormones that regulate blood pressure, blood sugar, and metabolism
Adrenocorticotropic hormone (ACTH)
prompts the thyroid gland to produce thyroid hormones controlling functions such as metabolism, heart rate and appetite
thyroid stimulating hormone
where do most pituitary adenomas develop?
adenohypophysis/ ant pituitary- usually benign and successfully treatable
how common are pituitary tumors in primary brain tumors?
pituitary tumors account for 12-19% of primary brain tumors (3rd most common primary brain tumors in adults). Inc risk with age mostly after 30s.
They are classified by if they secrete excessive amounts of pituitary hormones or not.
It may inc hormone production from the cell it arises from or may dec production of hormones from other cells
which type of radiological workup is the best imaging technique for detecting pituitary tumors CT or MRI?
MRI - 100% sensitive and 91% specific
CT- 17-22% sensitive
This HPA ds is prevalent in older individuals but in increasing in children. It parallels to obesity incidence and is highest in Americans.
Metabolic disorder
- abdominal obesity (inc in waist circumference)
- high blood pressure
- high blood sugar - can damage blood vessels and inc risk of blood clots
- high triglycerides- inc LDL (risk of atherosclerosis)
- low HDL cholesterol- low levels of HDL (good cholesterol) - make it harder for body to remove bad cholesterol
3/5 of these would be diagnosed with what disease?
Metabolic syndrome
what ds has these symptoms:
- polyuria- inc urine
- polydipsia- excessive thirst
- polyphagia- excessive eating
(present in DM- main component)
Metabolic syndrome
Mechanism of ds: insulin resistance and adipose dysfunction, chronic inflammation
(impaired insulin secretion- impaired glucose metabolism, fat deposition, cardiotoxicity and chronic inflammation)
Metabolic disorder
acromegaly symptoms
- enlarged hands and feet
- gradually changes in face shape - protruding lower jaw and brow bones
- enlarged nose
- thickened lips
- frequent headache
- excessive perspiration
- hypertension
- sleep apnea
etc
mechanism of acromegaly
chronic exposure to excess GH from somatotroph pituitary adenoma
- excessive GH and it targets IGF-1
- typically benign
- changes occur gradually leading o delayed diagnosis
central ___________ is most common which affects secretion of ADH from the posterior pituitary
diabetes insipidus
symptoms of DI
- polyuria/ nocturia
- polydipsia- thirsty
- nausea and vomiting
- dizziness, fatigue, light headiness
- dry mouth, dry lips
common in children- vision, delayed growth, weight loss, constipation, fever and vomiting
endocrine ds affecting posterior pituitary hormone ADH/vasopressin- body cannot regulate water balance, leading to excessive thirst and excreting large amounts of diluted urine, not related to blood glucose
Diabetes insipidus
__________ __________occurs when there is either a deficiency in ADH production or an impaired response to ADH in the kidneys. This leads to a lack of water reabsorption, resulting in the production of large volumes of dilute urine and dehydration.
Diabetes insipidus
4 types of DI:
- Central DI: NO ADH
This type is due to a deficiency of ADH, often from damage to the hypothalamus or pituitary gland caused by tumors, head trauma, infection, or surgery. Without adequate ADH, the kidneys cannot retain water. - Nephrogenic DI: Kidneys do not respond to ADH
This form occurs when the kidneys do not respond to ADH, even though it is present in sufficient amounts. Causes include genetic mutations, chronic kidney disease, or drugs (e.g., lithium). - Dipsogenic DI: lots of fluid supress ADH
Caused by a malfunction in the thirst mechanism within the hypothalamus, leading to excessive fluid intake that suppresses ADH release. - Gestational DI: Placenta enzyme breaks down ADH
A rare type occurring during pregnancy when an enzyme produced by the placenta breaks down ADH, leading to its deficiency.
Clinical Manifestations of DI
The lack of ADH effect in DI leads to the production of excessive, dilute urine. The body’s response to dehydration is increased thirst, aiming to replace lost water. If fluid intake does not match urine output, dehydration, and electrolyte imbalances can occur, leading to complications like low blood pressure, confusion, and kidney dysfunction.
Addison’s ds is more common in females or males?
females
Addison’s ds
primary adrenal insufficiency- the adrenal glands produce insufficient amounts of cortisol and aldosterone= affects adrenal cortex, which produces critical hormones controlling metabolism, blood pressure regulation, and the body’s response to stress
what is the most common cause of addisons ds?
**autoimmune destruction of the adrenal cortex - accounting for 70-90% of cases
addisons ds symptoms
insidious and gradual onset of nonspecific symptoms
Initial presenting features
1. Fatigue, generalized weakness, weight loss, nausea, vomiting, abdominal pain, dizziness, tachycardia, and hypotension
2.** Hyperpigmentation of skin and mucous membranes**
Commonly diagnosed after hospitalization of acute adrenal crisis
1. Hypotension, hyponatremia, hyperkalemia, and hypoglycemia
● Hypotension (low blood pressure)
● hyponatremia (low sodium)
● hyperkalemia (too much potassium- chemical that nerve and muscle cells (including those of the heart) need to function= muscle weakness, palpitations, numbness, chest pain, nausea, vomiting, and trouble breathing)
● hypoglycemia (low blood sugar) can occur together in adrenal crisis, a severe endocrine emergency
treatment addisons ds
acute- 100 mg of hydrocortisone should be administered intravenously or intramuscularly
chronic- lifelong hormonal replacement therapy
Addison’s Disease-Mechanism of Disease
- Leads to decreased adrenocortical hormones which include cortisol, aldosterone and androgens- control metabolisms, stress response and bp (aldosterone-affects fluid balance)
- Results in increased adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH) due to the loss of negative feedback inhibition
- Insidious course of action presents with a glucocorticoid deficiency followed by mineralocorticoid deficiency
most common cause of Addison’s disease is
autoimmune adrenalitis—an immune response in which the body’s immune system mistakenly attacks the adrenal cortex, damaging the cells responsible for producing cortisol and aldosterone.
Low cortisol levels= impair body’s ability to regulate blood glucose and manage the stress response. symptoms like fatigue, muscle weakness, low blood sugar, and poor stress tolerance.
lack of aldosterone disrupts sodium and potassium balance, causing the kidneys to excrete too much sodium while retaining potassium leading to low blood pressure, dehydration, and electrolyte imbalances, which contribute to symptoms like dizziness, salt cravings, and weakness
what is cushing’s ds?
Excessive ATCH leading to hypercortisolism
too much cortisol:
- Increased blood sugar: Cortisol raises blood glucose levels by stimulating the liver to release stored sugar, potentially leading to diabetes if chronically elevated.
- Fat redistribution: Excess cortisol can lead to fat accumulation in the abdomen and upper body, creating a “buffalo hump” between the shoulders while thinning the limbs.
- Muscle breakdown: Cortisol promotes muscle protein breakdown to provide energy during stressful situations, leading to muscle weakness when levels are persistently high.
can be from pituitary adenoma (80%) leading to excessive release of ATCH from ant pituitary
Patient Population cushing’s ds
3x more common in women
average age of onset is 40 years old
Pituitary ATCH dependent cushings disease causes ____ % to ____ % of cushings ds
60-70 %
what other comorbidities is Cushing’s ds associated with?
diabetes (blood sugar/energy), hypertension (bp), clotting disorders
Patient population: onset age of cushing’s ds and female vs male
3 times as common in women, 40 years old onset
what is Iatrogenic Cushing’s Syndrome
A result of taking medications containing glucocorticoids = inc cortisol
cushings ds symptoms in adults
weight gain
thin arms and legs
round face
inc fat around the neck
fatty lump b/w shoulders - buffalo hump
easily bruises
wide purple stretch marks mainly in abdomen, breasts, hips, armpits
weak muscles
cushings ds symptoms in children
- obesity
- grow slower than other children
cushings ds symptoms in females
- excess hair on face, neck, chest, abdomen and thighs
- menstrual periods irregular
- amenorrhea- absence of menstruation in a female of reproductive age
cushings ds symptoms in males
- dec fertility
- dec libido
- erectile dysfunction
Mechanism of disease #1. cushings ds:
a corticotrpoh adenoma (tumor on ant pit) or pituitary adenoma (pituitary tumor) causes what effects?
inc anterior pituitary activity- makes too much ACTH (80% of cushings ds)
inc cortisol= growth, reproduction, stress response, and metabolism (TSH, FSH, LH, GSH etc)
non cancerous growth
Mechanism of disease #2. cushings ds:
ectopic tumor= develop outside the pituitary gland
( in lungs, pancreas, thymus, thyroid) causes what effects?
inc ACTH production/release- inc cortisol
can be cancerous
Mechanism of disease #3. cushings ds:
adrenal gland tumor causes what effect?
increased adrenal cortex activity- inc cortisol
**makes too much cortisol itself **
mostly benign but can be cancerous
What is Cushing’s Disease Mechanism of Disease?
Adrenocorticotropic hormone (ACTH) which is created by the anterior pituitary tells the adrenal glands to make too much cortisol
what is the most common endocrine pathology in reproductive aged females ?
polycystic ovarian syndrome (PCOS)
affects 5-15% of females
PCOS symptoms
- hair loss
- hirsutism- excessive growth of coarse, dark hair in women in areas where men typically have hair (chest, back)
- pelvic pain
- infertility
- overweight
- irregular periods
- fatigue
- high testosterone levels
- acne
2/3 symptoms have to be present when there is PCOS (Must rule out similar pathologies such as thyroid disease, hyperprolactinemia, and adrenal hyperplasia)
- chronic anovulation: cycle length > 35 days (long pepriod)
2.** hyperandrogenisms**- hirsutism, alopecia (hair loss), acne
- **polycystic ovaries- **
≥ 12 follicles measuring 2-9mm
or
increased ovarian size >10ml
PCOS mechanism of disease
Hyperandrogenic state with oligo-anovulation
Androgens help people enter puberty and mature physically- a lot of male characteristics due to too much testosterone/ too much puberty hormones
Oligo-ovulation - ovulation doesn’t occur regularly, resulting in menstrual cycles that are longer than 35 days or fewer than 10 periods per year. It’s a common cause of infertility and can be difficult to identify without medical help
What are the most common causes for traumatic experiences (PTSD)?
MVA/car accidents and assault
__ to __ % of the adult population in the United States will at some point during their lifetime, meet the criteria for a diagnosis of PTSD
6-7 %
PTSD general symptoms:
- Excessive physical exhaustion
- Anger and irritability (angst)
- Depressed mood
What are the criteria to diagnose PTSD
- One intrusive symptom (distressing memories and/or dreams, dissociative reactions such as flashbacks, intense or prolonged psychological distress to triggers)
- **One avoidance symptom **(avoidance of memories, feelings, or thoughts of trauma)
- Two Negative Alterations to cognition or mood related to trauma (negative beliefs of self worth, negative emotional state, feelings of detachment from others, inability to experience positive emotions)
- Two symptoms of marked alterations in arousal and reactivity (irritability or anger outbursts, self-destructive behaviors, problems with concentration, sleep disturbance)
what are some Neurohormonal changes for PTSD that occur?
- Hypo-responsive hypothalamic- pituitary axis
- Hyper-responsive catecholamine system (stress hormones)
—–Elevated blood norepinephrine levels
—–Lower glucocorticoid levels (regulate metabolism and have anti-inflammatory, anti-allergic, and immunosuppressive effects) - Mitochondrial dysfunction (energy issues)
- Neurohormonal abnormalities influence the structural brain changes in amygdala (emotional processing) and hippocampus (stress response)
Mechanism of ds for PTSD
severe anxiety disorder that develops after exposure to an event with actual, threatened, or perceived death or serious injury or a threat to others or oneself
In addition to a severe stressful event what are multiple other factors that can affect PSTD?
- Genetic susceptibility
- Past experiences
- Cultural, spiritual, and personal beliefs
- Bullying and harassment
- Lack of support at workplace, social, and home environment
supraoptic nucleus (SO) and dorsomedial nucleus control (DMN)
**thirst and water balance **
lead to Diabetes insipidus and hypernatremia
anterior and posterior hypothalamus controls
temperature (hyper and hypothermia)
ventral medial nucleus (VMN)
and
lateral hypothalamus (LH) control
**satiety and hunger **
and manifest into
hyperphagia (too much eating), obesity
and
anorexia (hypophagia)
suprachiasmatic nucleus (SCN)
circadian rythym- sleep
arcuate nucleus (ACN)
paraventricular nucleus (PVN) are both sympathetic or _______________
autonomic:
energy imbalance
sympathetic mediated hypertension, hypotension
what does the mammalian body hypothalamic nucleus function as
memory= leads to short term memory loss if there is an issue
function of brown fat (BAT)
energy expenditure: inc mitochondrial
inc thermogenesis (gives up heat)- produces HEAT when cold
balance/ inc energy expenditure
function of white adipose tissue WAT
energy storage and endocrine signaling
low [ ]
___ is abundant in newborns because they cannot shiver properly but in adults it is in the neck, upper chest and around kidneys
improves insulin sensitivity, lowers blood sugar levels, protects against metabolic disorders
BAT
_____ contains large, single lipid droplets with fewer mitochondria. It is less vascularized and innervated compared to BAT
Energy Function- store energy in form of triglycerides (can be released as free fatty acids and glycerol when the body need energy)
Endocrine Function- secrete cytokines such as leptin which regulate metabolism, insulin sensitivity, appetite and inflammation
WAT
____ is distributed throughout the body, with significant deposits in subcutaneous under the skin and visceral (around internal organs)*
WAT
The ventromedial hypothalamic Nucleus (VMH) signals fullness or emptiness of stomach?
VMH signals fullness - satiety center= stops eating bc you are full **(VERY MUCH HUNGRY)
**
adipose tissue releases leptin combined with high glucose levels- tell VMH body is full
medial side of hypothalamus
Hyperphagia (excessive eating) is damage to the LH or VMH ?
VMH lesion - stops feeling of fullness from happening, so you keep eating
stimulation of VMH- reduce food intake- promote healthy body weight
The Lateral Nucleus (LH) signals fullness or emptiness of stomach?
LH says your stomach is empty (LESS HUNGRY)- so you are hungry- motivates you to eat
“Hunger center”- makes you hungry- stimulates eating
Lateral region of hypothalamus
responds to ghrelin (when stomach is empty) and low glucose levels (indicates body needs more energy)
Hypophagia is damage to LH or VMH?
Hypophagia= dec in food intake caused by lesions in the lateral hypothalamus (LH- less hungry- eat more= but there is damage it so it does not make you eat), leading to reduced appetite and metabolic rate
Arcuate nucleus has 2 different neuron types:
ARH integrates signals about hunger and satiety to regulate energy intake and expenditure
- POMC
- AgRP
- POMC- Satiety/fullness neurons- No food
stimulated by leptin after feeding
release EXCITATORY NT onto satiety neurons (PVN) =
to inc feeling of satiety ( or feeling full) –> dec food intake
______________________________________
2. AgRP- Want Food
Activated by Ghrelin hormones (+)
Inc feeding by release more GABA (inhibitory neurons into the PVN- stops the satiety from feeling full) = eat more food
inc food intake
Describe the negative feedback loop of food intake?
eat food- GI tract stimulated by food intake - mechanoreceptors stretch when we ingest food- inc satiety signals (leptin)- promote fullness- DEC FOOD REWARD
Hunger neurons
AgRP neurons- “I am hunGRy”
satiety signal
POMC neurons (proopiomelanocortin)- “I aM full”
What happens to leptin in obesity?
We become leptin resistant- leptin does not stop us from eating more bc we do not feel full (leptin usually means we are full)
Obese people may feel enhanced food reward after eating, so they eat more= even with leptin bc they are resistant
when **GLP-1R (glucagon like peptide-1) agonists **are administered, they….
act on the brain centers to **reduce appetite and inc satiety **helping people feel full- dec caloric intake= weight loss
How do GLP-1 medications help dec weight?
makes your body produce more insulin- dec sugar, slow down digestion, and reduces the amount of sugar your liver makes (inhibits glucagon release)
GLP-1 effect on insulin and glucose
Stimulates insulin secretion (lowers the high glucose levels- moves glucose from the blood into cells, where it can be used for energy) and reduces glucagon release in response to food (regulate blood glucose levels) and prevent hunger strikes
GLP-1 agonists work by:
Reducing appetite, Slowing digestion, Increasing metabolism, and Triggering insulin release from the pancreas.
GLP-1 agonists can also help lower blood pressure, improve lipid disorders, and reduce the risk of heart disease and kidney disease.
if POMC is inactivated what happens to body weight?
**POMC is satiety (fullness) in arcuate nucleus, if it is inactivated - body weight increases because you eat more
what happens if there is a leptin deficiency?
no leptin= Obesity
When leptin levels are low, it can lead to a constant feeling of hunger, excessive eating (hyperphagia), rapid weight gain, and potential development of obesity due to the body not receiving the signal to stop eating when it has sufficient energy store
leptin is released after feeding but neurons have dec sensitivity- no activation of MCR4 neurons- decreased satiety (fullness)- want to eat more
a loss of MC4R (melanocortin 4) which receives POMC neurons (satiety neuron) leads to
Hyperphagia- extreme unsatisfied drive to consume food
in humans is the most single genetic cause of obesity
POMC (fullness)= relates to MCR4= neither of those- obesity
how does dopamine play a role in hunger behaviors?
controls motivation to eat, **stimulates AGRP (hunger neurons)- promotes eating **
______________________________________
dopamine inc- release inhibitory NTM GABA- inhibit MCRP neurons to decrease satiety (fullness)- so you want to eat more
______________________________________
MC4R (Melanocortin 4 Receptor) plays a key role in regulating hunger by acting as a satiety signal in the brain, where its activation by the hormone α-melanocyte stimulating hormone (α-MSH) leads to decreased food intake and increased energy expenditure, essentially signaling that the body is full and should stop eating; disruption of this pathway through MC4R mutations can result in hyperphagia (excessive eating) and obesity
______________________________________
α-MSH is produced by pro-opiomelanocortin (POMC) neurons in the hypothalamus, which release this hormone upon activation by leptin (a satiety hormone)
MCR4 hunger mechanism of action
MORE HUNGRY= Low leptin (starved state):
When leptin levels are low, POMC neurons are less active, leading to decreased α-MSH production and reduced MC4R activation, which results in **increased hunger. **
LESS HUNGRY= High leptin (fed state):
When leptin levels are high, POMC neurons are stimulated, increasing α-MSH release and activating MC4R, signaling satiety and reducing food intake.
what happens if you have decreased dopamine?
dec dopamine- dec eating
inc dopamine- inc eating
How does ghrelin relate to dopamine?
Ghrelin signals hunger= increases dopamine in brains reward centers= Enhances eating
**inc ghrelin, inc dopamine, inc eating **
How does leptin relate to dopamine?
leptin- signals satiety (fullness) = **leptin decreases dopamine (usually dopamine causes you to eat)
if it is decreased- helps you to stop eating **
disruption in leptin or dopamine- causes overeating
more leptin- less dopamine- less eating
Agrp promotes eating or stops eating?
**Promotes eating **
MCR4 activation limit eating and counteract AgRP
POMC, MCR4 pathway
- POMC neurons in arcuate nucleus of hypothalamus respond to leptin and insulin (indicate energy sufficiency)
- POMC activation= release α-melanocyte-STIMULATING hormone (α-MSH) which travels to PVN (paraventricular nucleus) and binds to Melanocortin-4-RECEPTORS (MCR4).
- when MSH binds to MC4R, it suppresses hunger, so you feel full
describe role of AgRP Neurons as Opponents to POMC Neurons
When energy levels are low, AgRP neurons inhibit MC4R, reducing satiety (makes you hungrier) and encouraging feeding behaviors.
When energy is sufficient, POMC neurons are activated, promoting MC4R activation and inc satiety (making you less hungry).
