Adrenal Hormones Biochemistry Flashcards
Steroid hormone overview
3 parts:
1) adrenal cortex (corticosteroids)
- secretes aldosterone: stimulates renal reabsorption of Na+ and excretion fo K+
- secretes cortisol: increases gluconeogenesis, anti-inflammatory action and protein catabolism
2) ovaries (sex hormone)
- secretes estrogen: controls menstrual cycle, promotes development of secondary female sex characteristics
- secretes progesterone: secretory phase of the uterus and mammary glands. Also promotes implantation and maturation of the fertilized ovum
3) testies (sex hormone)
- secretes testosterone: stimulates spermatogenesis, promotes development of secondary male sex characteristics, promotes anabolism in muscles
Two primary layers of the adrenal gland and what is secreted
Adrenal cortex:
- cortisol (glucocorticoid) and aldosterone (Mineralcorticoid)
- several androgenic steroids
Adrenal medulla:
- Epinephrine and Norepinephrine
What is the primary substrate used in making steroid hormones in the adrenal gland
Cholesterol
Comes from either de novo synthesis or LDL binding to LDL receptors
What are the 4 steps of cortisol production
1) cholesterol -> pregnenolone conversion
- this done inside the mitochondrial matrix
2) pregnenolone -> progesterone conversion
3) progesterone -> 11-deoxycortisol
4) 11-deoxycortisol -> cortisol
- conducted in mitochondria
Steps 2-3 are done in the endoplasmic reticulum
What are the two main ways steroid hormones act on their receptor targets
1) “Classical”
- steroids bind to cytoplasmic intracellular receptors which form a steroid hormone-receptor complex
- this complex then binds to HRE enhancer regions on DNA which causes easier binding of DNA poly to DNA segments causing transcription of whatever the steroid hormone is suppose to upregulate
2) “Nonclassical”
- steroid hormone receptors after binding to the steroid molecule, regulates cellular functions outside of their actions as transcription factors. This occurs via interacting with proteins at cell membranes and changes the scaffolded protein arrangement to influence signaling networks
- makes it easier to bind to certain things vs other things depending on the cell
- also upregulates certain accessory proteins dependent on the steroid
Nonclassical steroid hormone accessory protein
Testosterone/androgens
- ERK1/2 protiens and Src surface
17B-Estradiol/estrogens
- cAMP and AC
Cortisol/glucocorticoids
- eNOS, PI3 kinase, and NMDA receptor
Progesterone/progestins
- PKC and NMDA receptor
Aldosterone/Mineralcorticoids
- NA/H+ exchangers
What differs a steroid vs a sterol?
Sterols are a subgroup of steroid.with a hydroxyl group at position 3 on the A-ring
What is the “steroid nucleus”
The ABCD ring system that all steroids have
- excludes the hydrocarbon tail
What is the rate limiting step for all steroid hormone synthesis
The production of pregnenolone from cholesterol via CYP2A proteins
- this is the parental compound for all steroid hormones and is produced in all tissues that make steroid compounds
(Adrenal cortex/testes/ovaries/placenta)
3 general structures of all hormones
1) modified amino acids
- readily cross plasma membrane and can either signal at plasma membrane or intracellularly via receptor binding
- includes TH, adrenaline and NE
2) peptides/protiens/glycoproteins
- cant enter the cell and only signal via receptor binding
- includes GH, insulin and TSH
3) steroids
- signal only via intracellular receptors after passive diffusion across the plasma membrane
- includes cortisol, aldosterone, testosterone, estradiol
What cells inside the adrenal medulla generates catecholamines?
Chromaffin cells
What enzymes degrade catecholamines?
Monoamine oxidase enzymes (MAOs)
- breaks down epinephrine/NE into dihydroxymandelic acid
- can also break down metanephirne and normetanephrine into vanillylmandelic acid (which is urinated out)
COMT
- breaks down epinephrine and NE to metanephrine or normetanephrine respectively
- also breaks down dihydroxymandelic acid to vanillylmandelic acid (which is urinated out)
What is the enzyme that converts norepinephrine -> epinephrine?
Phenylethanolamine N-methyltransferase (PNMT)
- catalyzes the transfer of a methyl group for SAM -> NE to generate epinephrine
what are high yield hydroxylase and dehydrogenase in the generation of aldosterone and cortisol
Hydroxylase:
- CYP21A2
Dehydrogenase:
- HSD17B/B1
Aldosterone signaling
Binds to globulin carrier glycoproteins in the blood and then binds to Mineralcorticoid receptors
Two target cell pathways
1) nuclear receptor translocation (genomic)
2) Kinase activation (non-genomic)
both pathways effect gene expression and ion concentration
Aldosterone production regulation
Requires angiotensin 2 to bind to its receptors on adrenal-cortical cells and upregulates intracellular calcium
Intracellular calcium increases turns on cyp11B2 to induce aldosterone production
- in no Ang2 presence or high levels of aldosterone in blood/ high VP/high sodium, hyperpolarizes adrenal-cortical cells and this prevents Cyp11B2 protein production which turns off aldosterone
- MicroRNAs are responsible for this also
Cortisol signaling
Binds to a glucocorticoid receptor (GR) which generates genomic and non-genomic actions
- genomic: upregulations trans activation of DNA and proteins
- nongenomic: very broad and integrative. Are much faster and have extensive cellular effects
Cortisol regulation
Expression is induced via stressors
- stress directly causes CRH release in the hypothalamus. This results in ACTH release in the anterior pituitary which then results in cortisol production.
Circadian rhythm occurs with this hormone also
- AM = high
- PM = low
negative feedback with cortisol levels in blood
What is the first step in producing sex hormones (and is technically the rate limiting steps for sex hormones)
Conversion of pregnenolone -> DHEA via CYP17 enzymes
This step locks pregnenolone into becoming a sex hormone
What are the three carrier proteins for steroids? Also where are steroids degredated the most?
Carriers:
- Sex hormone-binding globulin (SHBG)
- Corticosteroid-binding globulin (CBG)
- albumin
Most is degraded in the liver
Pheochromocytoma
A rare form of hypertension caused by a neoplasm in the adrenal medulla that secretes excess Catecholamines
Symptoms (all acute, severe and come and go)
- increased BP
- heart palpitations
- throbbing headache
- diaphoresis
leads to impaired glucose tolerance and causes diabetes mellitus
Addison disease
Under-active adrenal glands And underproduction of adrenal hormones
Causes: autoimmune reactions, cancer, infections or removal of too much adrenal glands
Symptoms:
- fatigue
- orthostatic hypotension
- hyperpigmentation
- hyponatremia and Hyperkalemia
Treatment = give corticosteroid administration
Cushing disease
Hyperaldosteronism and cortisol caused usually by tumors in either the adrenal gland, pituitary gland or hypothalamus or excessive ACTH hormone
- if in pituitary ACTH will be high, if in adrenal gland ACTH is low
- if the tumor is in the adrenal gland itself = conn syndrome
Symptoms:
- fatigue
- strain on abdomen and moon facies
- buffalo hump
- excessive bruising
- atrophied limb muscles
- poor DTRs
- flushing of skin
- high BP and hypokalemia
- periods of paralysis
Treatment = tumor removal
Congenital adrenal hyperplasia (CAH)
Group of autosomal recessive disorders that result in impaired cortisol biosynthesis
- most common = 21-hydroxylase defects**
Symptoms:
- infertility
- perturbed sexual development
- HTN
- chronic infections
Treatment = provide synthetic deficient enzyme or hormone product
3-B-hydroxysteroid dehydrogenase deficiency
A subset of CAH
Results in virtually no glucocorticoids, mineralcorticoids, active androgens and estrogens
- this is because no 3-B-hydroxysteroid dehydrogenase results in to conversion of pregnenolone -> progesterone AND no pregnenolone -> DHEA
*Unique symptom = excessive sodium in urine and fluid loss and males present with female-like genitalia
17-a-hydroxylase deficiency
Results in no conversion of pregneleone -> DEHA and Progesterone -> 17-hydroxyprogesterone
Results in no sex hormones at all and cortisol
- HOWEVER aldosterone is still produced at very excessive levels in the blood (since progesterone builds up and has no other pathway to go down
*Unique = shows HTN and fluid retention on top of female-like genitalia
21-a hydroxylase Deficency
MOST common form of CAH (90%)
Results in no production of cortisol and aldosterone since progesterone cant be converted into aldosterone and instead all is converted to 17-a-hydroxyprogesterone
- however, 17-a-hydroxyprogesterone cant be converted to 11-deoxycortisol and instead is shuttled to androstenedione
This results in massive amounts of estrone, estradiol, testosterone.
Unique: salt wasting with overproduction of masculinization of genitalia or virilization in males
11-B1 hydroxylase deficiency
Prevents cortisol and aldosterone from being developed however it does develop a lot of deoxycorticosterone intermediate
Results in similar to 21-a-hydroxylase deficiency except the excess deocycorticosterone leads to suppression of the RAAS system and no aldosterone.
- However 11-Deoxycorticosterone is still produced in large amounts and acts as 80% aldosterone
- this results in unique hypertension with low renin**
Also shows overproduction of androgens which causes masculinization and virilization of the external genitalia
3-B-hydroxysteroid dehydrogenase enzyme
Results in no cortisol or aldosterone
