Flashcards in Hormones Deck (56):
drug that binds to a receptor and mimics the normal ligand action (e.g. isoproterenol acts like adrenaline at beta adrenoreceptors - treat bradycardia, slow heart rate)
prevents the action of a hormone
Clinical uses of hormones
Insulin to treat diabetics
Anticancer therapies (block testosterone action for prostate cancer with flutamide (prostate cancer is testosterone responsive))(block estrogen action for breast cancer with FASLODEX (fulvestrant) an estrogen receptor antagonist (competes for binding site))
Types of hormones
endocrine - made in one tissue and travel to target organ, paracrine - made in a cell and travel short distance, autocrine - made and functions in same cell (or nearby)
Peptide - includes growth factors, amino-acid derived hormones, usually water soluble, bind cell surface receptors
Steroid - membrane permeable, bind intracellular receptors
insulin is an example
made in one tissue
travel to target organ through blood
Tend to be stable, larger amounts, longer half-life
Acetylcholine is an example
Made in a cell
Travels a short distance
Bind receptors on neighboring cells
Smaller amounts, shorter half life
Nitric oxide is an example
Made and functions in same cell or near by
small amount, short half life
Includes growth factors, amino-acid derived hormones
Usually water soluble, bind cell surface receptors
Insulin, glucagon, adrenocorticotropin hormone (ACTH) are examples
Membrane permeable (lipid soluble)
Bind intracellular receptors
Adrenal hormones: Cortisol (glucocorticoid), aldosterone (mineralcorticoid)
Sex and Progestational hormones: 17 beta estradiol (estrogen), testosterone (androgen), and progesterone (progestin) are examples
Derived from cholesterol
Things to remember about hormones that bind to cell surface receptors
The binding is tight
It is swift and reversible
Receptor specificity and affinity for hormone is high
Examples of basic signal transduction mechanisms include:
1. Receptor coupled to adenylate cyclase (cAMP)
2. Receptor kinase activity (phosphorylation)
3. Receptor coupled to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2)
Endogenous production of insulin can be detected by:
presence of C-peptide
Human insulin analogs
Lispro and Aspart (short-acting and rapidly absorbed), Glargine (long-acting, peakless, low rates of hyperglycemia)
Tyrosine kinase receptor
phosphorylates itself and IRS
allows binding of proteins with SH2 domains (Grb2 and PLCgamma)
activates PI3 kinase
Activates protein kinase B (also called Akt)
Epinephrine binds alpha-adrenergic receptors and beta-adrenergic receptor
In the liver, epinephrine acts through G proteins and PIP2 signaling (IP3 causes release of calcium)
In muscle, epinephrine acts through cAMP signaling
Phosholipase C is involved, as well as Protein kinase C. Calmodulin-dependent protein kinase and phosphorylase kinase are activated, which inactivate glycogen synthase and activate glycogen phosphorylase
acts through cAMP
Glucagon leads to inhibition of glycogen synthase
uses G protein, cAMP, Active protein kinase A
Examples of second messengers are Calcium, cAMP, diacylglycerol, and inositol triphosphate
(Epinephrine and glucagon work in similar ways)
Transport of steroids
Plasma albumin is a nonspecific carrier
Transcortin (aka cortico-steroid binding globulin) transports cortisol and corticosterone
Sex-hormone binding globulin carries testosterone and 17-beta estradiol
All steroid hormones are synthesized from __.
Hormone synthesizing enzymes are activated by __.
FSH, ACTH, and LH
ACTH, FSH, and LH activate ___.
hormone synthesizing enzymes
A cholesterol esterase to produce rapid supply of cholesterol
Synthesis of LDL receptors
ACTH activates ____.
Cortisol synthesis is activated by ___.
LH activates ___.
Testosterone synthesis is activated by ___.
Lutenizing hormone (LH)
FSH activates ___.
Estrogen synthesis is activated by ___.
FSH (follicle stimulating hormone)
____ are key in steroid hormone synthesis.
Hydroxylation reactions of cholesterol use ___.
"mixed function oxygenases" that all have a similar mechanism with multi-enzyme complexes that use molecular oxygen and NADPH
Regulation of steroid hormone synthesis
The primary regulatory enzyme is 20,22-lyase (CYP11A)
activated by phosphorylation
the primary regulatory enzyme of steroid hormone synthesis
Activated by phosphorylation
aka 20,22-desmolase or cholesterol desmolase
enzyme that catalyzes the cleavage of C-C bond in a subtration with formation of 2 products by a process other than hydrolysis
Biosynthesis of steroid hormones overview
cholesterol desmolase (CYP11A) converts cholesterol to pregnenolone. This is converted to progesterone and androstendione. Progesterone is converted to deoxycorticosterone, which is converted to aldosterone (zona glomerulosa, using CYP11B2) or cortisol (zona faciculata using CYP21A2). Androstendione is converted to estron (using aromatase/CYP19) or testosterone (using 17 beta-hydroxysteroid dehydrogenase). Estron or testosterone can be converted to estrogen using aromatase CYP19 (testosterone) or 17beta-hydoxysteroid dehydrogenase (estron).
Steroid hormone diseases
Congenital adrenal hyperplasia or aldosterone synthase deficiency
congenital adrenal hyperplasia
95% due to steroid 21-hydroxylase deficiency (CYP21A2)
Symptoms include vomiting and dehydration for severe deficiency, to infertility in mild deficiency)
Reduces aldosterone and cortisol production
Diagnosis based on elevated 17 hydroxyprogesterone
Aldosterone synthase deficiency
aldosterone stimulates sodium reuptake. Hydroxylation of deoxycorticosterone at C11b and C18 required to form aldosterone. CYP11B2 required for all reactions. Enzyme deficiency causes electrolyte imbalance, vomiting, dehydration in infancy
Mechanisms of Steroid Hormone action
pass through the cell membrane (hydrophobic)
bind specific intracellular receptor (cytoplasmic or nuclear receptor) (hormone dependent transcription factor)
Hormone/receptor complexes go to nucleus (bind regulatory DNA sequences)(Hormone-responsive elements, HRE, or SRE (steroid RE))
Turn transcription of specific genes on or off
Steroid hormone effects:
can last for relatively long periods (hours to days)
Influence growth and differentiation of specific tissues
Steroid hormone receptors are ___ factors.
transcription (most are activated by dimerization. Large family of receptors that bind to hormone response elements in DNA)
DNA binding domain
two zinc fingers, side by side
Each has a peptide loop with a zinc atom at the core
one binds DNA (major groove)
other lets receptors dimerize
allows receptor to sit on the surface of the DNA double helix
How production of cortisol is activated and controlled
Body stress stimulated hypothalamus to produce CRH (Corticotropin-releasing hormone)
Activates anterior pituitary to produce ACTH (adrenocorticotropin hormone)
Activates adrenal cortex to produce cortisol
acts on fibroblasts and hepatocytes (etc.)
Cortisol inactivates production of CRH and ACTH
Functions of cortisol
1. metabolism: increased degradation of muscle to provide amino acids for gluconeogenesis; increased lipolysis in adipose tissue
How do glucocorticoids related to patients in critical care?
Critical care patients often have elevated glucocorticoid levels due to stress or treatment with methylprednisone or dexamethasone to reduce inflammation (they inhibit phospholipase A). These increase blood glucose levels by increasing gluconeogenesis at the same time as tube or IV feedings. ICU patients have frequent blood glucose monitoring.
Due to over administration of excess amounts of glucocorticoids (prednisolone, dexamethasone)
Most cases are caused by ACTH-secreting pituitary adenoma
"moon face", truncal obesity, dorsocervical fat pads (buffalo hump)
ACTH stimulation of cortisol synthesis
1. G protein coupled receptor
2. cAMP production by adenylate cyclase
3. Protein kinase A activation
4. Cholesterol released into mitochondria
Thyroid hormone pathway
Hypothalamus produces TRH (thyroid releasing hormone), which activates the Anterior pituitary to produce TSH, which activates the thyroid to make T3 and T4
660kDa protein that has 115 Tyr residues that can be modified by iodide (oxidized iodine) to form monoiodotyrostine (MIT) or diiodotyrosine (DIT). These are coupled to form T4 or T3
Low levels of T3 and T4 activate ___.
Synthesis of TSH
Thyroid hormone release
Iodine is pumped into thyroid follicular cell
Tyrosine residues iodinated by thyroid peroxidase in colloid of thyroid
TSH stimulates endocytosis, degradation of thyroglobulin by proteases and release of T4, T3
Most plasma T3 and T4 are bound by thyroxin-binding globulin
Thyroid hormone act through nuclear receptors to modulate gene transcription
What protein iodinates tyrosine residues?
Most plasma T3 and T4 are bound by ___.
Thyroid hormones act through nuclear receptors to modulate ___.
Possible cause of hypothyroidism
How is thyroid hormone related to thermoregulation?
Through release of norepinephrine stimulating uncoupling protein (thermogenin) in brown fat and permeability of muscle to sodium. Increases sodium, potassium ATPase and ATP turnover. Longer term increases enzymes of fuel oxidation.
Hyperthyroidism is associated with ___.
Insulin resistance (as well as increased hepatic gluconeogenesis and rapid gastrointestinal glucose absorption)
Elevated TSH with no symptoms
True or False: Higher cholesterol values can be caused by hyperthyroidism.
False, Hypothyroidism can cause higher cholesterol values, though whether hyeprthyroidism causes it I am actually not sure.