Physiology-ACTH & Glucocorticoids Flashcards
Blood supply to the adrenal glands
Aorta, phrenic and renal arteries
Embryonic origins of the layers of the adrenal gland?
Cortex: mesenchyme. Medulla: neural crest.
Why is the fetal adrenal gland so big?
A lot hormones (estrogen and progesterone) are circulating in a pregnant woman. These are made in the placenta and modified in the adrenal and medulla of the fetus before they go back into the placenta and into the general circulation.
What are the three layers of the adrenal cortex and how can you identify them?
Zone glomerulosa (clusters of cells with descending arterioles between clusters), zona fasiculata (organized cords with fat vacuoles, “frothy”), zona reticularis (next to medulla)
What is the function of each layer of the adrenal cortex?
Zona glomerulosa: makes aldosterone, Zona fasiculata: contains cholesterol for steroidogenesis and synthesizes glucocorticoids, Zona reticularis: makes androgen. “Salt, sugar, sex”
Why does adrenal blood flow enter through the capsule and descend into the medulla into the suprarenal vein?
The adrenal medulla needs cortisol to activate PNMT so it can do the final conversion of NE to EPI
Abundance of what organelles would you expect to find in these cells of the adrenal cortex?
This is the zona fasiculata, not the foamy appearance of the cells. These cells synthesize glucocorticoids so they have a lot of substrate for this (lipid droplets) and machinery sER and mitochondria with tubular cristae.
Where does the rate limiting step of steroid synthesis occur?
Cholesterol -> Pregnenolone in the mitochondria of the cells in the zona glomerulosa (ATII (ACTH is minor) stimulation on to form mineralocorticoids), fasiculata (ACTH stimulation on to form glucocorticoids) and reticularis (ACTH stimulation on to form androgens).
Hypothalamic pituitary adrenal axis
Note that vasopressin and epinephrine sensitize the pituitary corticotroph to the effects of CRH from the hypothalamus. Note that cortisol has negative feedback to both the pituitary to suppress ACTH and to the hypothalamus to suppress CRH.
Pituitary hormone not stimulated by hypothalamus
Prolactin (it is inhibited by hypothalamus)
4 mechanisms for secretory control of ACTH
Negative feedback, episodic (pulsatile) secretion, diurnal rhythm and stress
What is the physiologic basis behind these fluctuations in cortisol during sleep and throughout the day?
Episodic (pulsatile) secretions of CRH from the hypothalamus and ACTH from the pituitary allow for maximum sensitization of the ACTH receptors on cells in the adrenal cortex to produce cortisol. If secretions were constant, then the receptor would be internalized and cells would become refractory to ACTH stimulation. The diurnal rhythm shows that the sensitivity of feedback inhibition by cortisol at nighttime is decreased and you get increased ACTH secretions and blood cortisol levels at night.
What psychologic diseases can be assessed by looking at the diurnal rhythm?
Depression and PTSD.
Where does cortisol go once it is secreted?
It binds to cortisol binding globulin with progesterone because it is lipophylic.
At what point can people become hypercortisolemic (Cushing’s syndrome)?
When the level of blood cortisol exceeds the binding and carrying capacity of cortisol binding globulin (CGB) because cortisol is active in the free form.
What do you need to do to excrete cortisol in the urine?
Conjugate it to glucuronide so it becomes lipophylic.
What does cortisol do for us metabolically?
It allows us to go for long periods of time without eating. It turns on liver gluconeogenic enzymes. It turns off insulin receptors in muscle and increased fatty oxidation and ketone body usage to conserve glucose for the CNS. It also promotes the breakdown of muscle protein for gluconeogenesis.
Why do you get osteoporosis with long-term glucocorticoid therapy?
Protein synthesis is turned off by glucocorticoids and proteins are degraded. The calcium transported proteins needed for bone growth are not made.
Why do people with Cushing’s have centripetal obesity (over face, shoulders and abdomen with skinny arms and legs)?
They have high cortisol levels and are still consuming calories. Fat will still be deposited in selected sites and blood glucose levels will still be high because gluconeogenesis is still turned on. They also have skinny limbs because muscle degradation is also turned on.
Why were glucocorticoids used for immunosuppression for a very long time?
Stabilization of lysosomes, decreased capillary permeability, decreased white cell proliferation & phagocytosis, inhibits accumulation of white cells, reduces fibroblast proliferation, prevents mast cell degranulation and inhibits cytokine production & signaling.
What does the cardiovascular system need cortisol for? CNS? Fetus?
Cardiovascular needs it for vascular tone (turns on PNMT for NE -> EPI), CNS needs it for euphoria and fetus needs it for lung surfactant.
5 cause of cortisol excess
1) Primary Cushing’s: coming from adrenal 2) Secondary Cushing’s: pituitary 3) Tertiary Cushing’s: hypothalamus 4) Ectopic ACTH 5) Iatrogenic
Cushing’s syndrome vs. Cushing’s disease
Disease = negative feedback set point is too high. Syndrome = all other forms of Cushing’s without set point regulation
What is the differential diagnosis for Cushing’s syndrome?
Start w/urine free cortisol level analysis w/low-dose dexamethasone suppression. If normal, then Cushing’s is excluded. If abnormal check plasma ACTH w/high-dose dexamethasone suppression. If ACTH is undetectable there is no suppression and there is an adrenal tumor. If ACTH is elevated there is no suppression and ectopic ACTH syndrome. If ACTH is normal to elevated with dexamethasone suppression < 50% baseline then they have Cushing’s disease.
What is the normal response to the dexamethasone suppression test?
Strong dex inhibits secretion of CRH and ACTH and cortisol levels will plummet to 0.
Is a urine of blood cortisol test better?
Urine, there is no spike or pulsatile secretions that will change throughout the day in urine.
How does the HPA axis work with Cushing’s disease? Cushing’s syndrome from adrenal neoplasm? Cushing’s syndrome from ectopic ACTH? CRH excess from depression, anorexia or EtOH Cushing’s?
Cushing’s disease: levels of ACTH and cortisol are equal but higher due to higher set point. Adrenal neoplasm: ACTH is low and cortisol is high due to HP suppression by cortisol. Ectopic ACTH: ACTH is high and cortisol is high. CRH excess: ACTH and Cortisol are high.
Why does skin bronzing occur in people without an adrenal gland?
The brain secretes high levels of ACTH due to lack of cortisol feedback. ACTH stimulates biosynthesis of alpha and beta-melanotropin (also comes from ACTH) and stimulates synthesis of melanin (it is a melanotropin)
3 types of hypocortisolism
Primary (Addison’s disease): adrenal destruction. Secondary failure of pituitary to produce ACTH and Tertiary: failure of hypothalamus to produce CRH
A 55 year old woman presents with reduced pigmentation, fatigue, hypotension, hypolipidemia, hypoglycemia and insulin sensitivity. Her labs are shown below. What is causing her condition?
1) Her ACTH and cortisol levels are initially low. 2) After CRH cortisol and ACTH levels both correct. She’s got tertiary hypocortisolism.
