Flashcards in L4 Adrenal Gland Deck (20):
What are the 3 layers of the adrenal cortex and what hormones do each secrete?
- Zona glomerulosa produces mineralocorticoid (aldosterone: regulates blood pressure and electrolyte balance)
- Zona fasciculata produces glucocorticoids (i.e. cortisol): regulates glycogen and lipid metabolism, immune system suppression
- Zona reticularis produces androgens (steroid hormones that become mature sex hormones in target organs)
- Adrenal cortex is derived from mesoderm and is essential for life
What is the adrenal medulla?
- Core of the adrenal gland
- Derived from neural crest
- epi, NE, dopa, DA
- Modified post-ganglionic sympathetic nerve cells
- Total loss is not life threatening
What is the rate limiting step in steroid hormone synthesis in the adrenal cortex?
The cholesterol to pregnenolone step - catalyzed by 20,22 desmolase (aka P450 side-chain cleavage enzyme)
What are the effects of aldosterone? Where is it synthesized?
- Increase NaCl reabsorption from distal nephron segments
- Increase potassium secretion by distal nephron segments
- Synthesized in the zona glomerulosa of the adrenal cortex. This layer lacks 17alpha-hydroxylase but has aldosterone synthase
How and where is cortisol synthesized?
- Synthesized in the zona fasciculata --> lacks aldosterone synthase but has 17alpha-hydroxylase (corticosterone to cortisol)
How and where are androgens synthesized?
- Synthesized in the zona reticularis --> has 17alpha-hydroxylase
- Androgens made from 17,20 desmolase are DHEA and androstenedione
- Androstenedione can be converted to testosterone in peripheral tissues
- DHEA is important for the maintenance of sex drive in women after menopause
What is cortisol's mechanism of action?
1. Hypothalamus secretes CRH --> stim anterior pituitary to release ACTH --> stim cortisol release
2. Free cortisol (3%) enters target cell by diffusion
3. Cortisol binds to cytoplasmic receptor (GR)
4. GR complex migrates to nucleus and binds GRE (glucocorticoid response element)
5. Modulates gene transcription
Feedback inhibition loop: cortisol inhibits expression of CRH receptor and ACTH in anterior pituitary, also inhibits transcription of POMC gene (makes the POMC peptide that ACTH is cleaved off)
What are the metabolic effects of cortisol?
- Stimulates gluconeogenesis in liver
- Enhances protein breakdown in muscle cells
- Stimulates lipolysis in adipose tissue
- Decreases osteoblastic activity in bone and interferes with Ca absorption from gut
What are the anti-inflammatory effects of cortisol?
- Inhibits production of cytokines
- Inhibits production of chemo-attractant molecules
- Stabilize lysosome enzymes
- Contributes to vasoconstriction and decreased capillary permiability
What are the immunosuppressive effects of cortisol?
- Decreases lymphocyte proliferation
- Inhibits hypersensitivity reactions
* Going out in the cold can "make" you sick because cortisol is released in response to stress (cold), which leads to immunosuppression
CRH and the CRH receptor
CRH (made in paraventricular of hypothalamus) is released --> binds GPCR on corticotroph cells --> second messengers lead to increased intracellular calcium --> exocytosis of ACTH
- Prolonged CRH receptor activation also leads to increased gene transcription and synthesis of ACTH precursor
How is cortisol secretion controlled?
CRH from hypothalamus --> ACTH rom anterior pituitary --> stimulates synthesis of cortisol in adrenal gland
- Circulating cortisol negatively feedbacks to inhibit release of ACTH and CRH
- ACTH and cortisol production undergoes diurnal variation (highest in morning, lower at night)
- Physical, psychological, and biochemical stresses enhance CRH secretion (ex. cold weather, hypoglycemia)
ACTH and the ACTH receptor
- ACTH is secreted by corticotroph cells in anterior pituitary
- Produced by post-translational processing of POMC peptide
- GPCR called melanocortin-2 receptor
- ACTH binding GPCR results in increase cAMP, which activates PKA to phosphorylate proteins
- Rapid effect of ACTH is to stimulate the rate-limiting step in cortisol formation (cholesterol --> pregenolone)
21-alpha Hydroxylase Deficiency
- Most common form of congenital adrenal hyperplasia
- Genetic mutation causes decreased production of cortisol and aldosterone
- Without negative feedback ACTH production increases
- Adrenal hyperplasia (increased size of gland)
- Increased androgen production
- Ambiguous genitalia in females
DX: elevated 17-hydroxprogesterone
TX: Hormone replacement therapy (prednisone and dexamethasone decrease ACTH levels)
What are the consequences of 21-alpha Hydroxylase Deficiency?
- Decreased aldosterone synthesis --> loss of salt, hypotension, dehydration
- Decreased cortisol synthesis --> hypoglycemia, increased size of adrenal gland (hyperplasia)
- Increased androgen synthesis --> virilizing effect in males, ambiguous genitalia in females
17-alpha Hydroxylase Deficiency
- Reduced cortisol and androgen synthesis
- Increased cortiserone and aldosterone
- Reduced estrogen synthesis
Clinical symptoms: hypertension, hypokalemia, sexual infantilism in genetic females, pseudohermaphroditism and sexual infantilism in males
TX: hormone replacement therapy (glucos for hypertension, estrogen/testosterone)
What are the consequences of 17-alpha Hydroxylase Deficiency?
- Increased aldosterone synthesis --> hypertension, hypokalemia
- Decreased cortisol synthesis (but increased corticosterone) --> increased size of adrenal gland (hyperplasia)
- Decreased androgen synthesis --> sexual infantilism in females, pseudohermaphroditism in males
- Hyperadrenal function leading to hypercortisolism
- Refers to excess cortisol of any etiology (different than the disease)
- Causes: prolonged use of immunosuppression drugs, adrenal tumors, tumors that increase ACTH
- Symptoms: moon face, upper body obesity, increased fat around neck, thinning of arms and legs, increased frequency of infections, muscle wasting/weakness, hypokalemia and hypertension, skin ulcers (impaired wound healing)
How is Cushing's Disease diagnosed?
- Disease refers only to hypercortisolism secondary to exposure of excess ACTH from pituitary gland adenoma
- Dx by dexamethasone suppression test (acts as cortisol, provides negative feedback to suppress secretion of ACTH)
- Take dexamethasone at night, if serum cortisol high in morning --> positive test result for Cushing's disease