1
Q
Neurosecretion of Hormones:
A
- Hypothalamic neurons secrete hormones
- Typical neurons secrete neurotransmitters
- The biochemical mechanism for secretion is the same for both
- Voltage gated K+ channels…out of cell (repolarize membrane)
- Voltage gated Na+ channel…into cell (depolarize membrane)
- Voltage gated Ca++ channel (influx triggers exocytosis release of hormone)
- Secretory vesicles containing hormone
- Exocytosis release of hormones
2
Q
Feedback Control in the HP axis
A
- Sensory input from environment
- Central nervous system
- Hypothalamus→hypothalamic releasing hormones
- Anterior pituitary→anterior pituitary hormones released into blood
- Target gland→ultimate hormones released
- Can feedback regulate at anterior pituitary, hypothalamus, or central nervous system
- Ultimate hormonal response
3
Q
Anterior Pituitary Hormones
A
- Growth Hormone (GH, Somatotropin)
- Thyroid Stimulating Hormone (TSH)
- Adrenocorticotropic Hormone (ACTH)
- Follicle Stimulating Hormones (FSH)
- Luteinizing Hormone (LH)
- Prolactin
4
Q
Growth Hormone
A
- Stimulates secretion of IGF-1 and IGF-2
- Regulates body growth and metabolism
5
Q
Thyroid Stimualting Hormone
A
Stimulation secretion of thyroid hormones and growth of thyroid gland
6
Q
ACTH
A
Stimulates cortisol secretion by the adrenal cortex and promotes growth of adrenal cortex
7
Q
FSH
A
- Stimulates growth and development of ovarian follicles
- Promotes secretion of estrogen by ovaries
- Required for sperm production
8
Q
LH
A
- Responsible for ovulation, corpus luteum formation, and ovarian secretion of female sex hormones
- Stimulates cells in the testes to secrete testosterone
9
Q
Prolactin
A
- Stimulates breast development and milk production
- Involved in testicular formation
10
Q
GH Has Direct Effects on Muscle, Adipose, and Liver
A
- Muscle
- Increase amino acid uptake
- Increase protein synthesis
- Decrease glucose uptake
- Increased Muscle Mass
- Liver
- Increase protein synthesis
- Increase RNA synthesis
- Increase gluconeogenesis
- Increase somatomedin production
- Adipose
- Increase lipolysis
- Decrease glucose uptake
- Decreased adiposity
- Somatomedins (IGF-1 and IGF-2)
- Bone Chondrocytes
- Increase collagen synthesis
- Increase protein synthesis
- Increase cell proliferation
- Increased linear growth
- Many Organs and Tissues
- Increase protein synthesis
- Increase RNA synthesis
- Increase DNA synthesis
- Increase cell number and size
- Increase tissue growth and organ size
- Bone Chondrocytes
- Overall effect of GH is to promote skeletal growth and the accumulation of lean body mass
11
Q
Feedback Control in the HPL axis
A
- IGF-1 and IGF-2 negative feedback control on GH
- Increase Somatostatin (GHIH)
12
Q
Cytokine Signaling Mechanism
A
- Cytokines interact with the membrane receptors of the cytokine receptor super family
- JAK tyrosine kinases and lead to phosphorylation of STAT transcription factors
- Phosphorylated STAT dimerize and translocate to nucleus
13
Q
Disorders of GH Release and Action
A
- Hypothalamus
- Dysplasia, trauma, surgery, hypothalamic tumors, genetic defects in GHIH or GHRH gene
- Pituitary Gland
- Dysplasia, trauma, surgery, pituitary tumors, genetic defects in GH gene
- Sites if IGF production
- GH receptor defect
- Full: Laron’s dwarfism=high [GH], but low [IGF]
- Partial: Pygmies=normal [GH], but low [IGF-1]
- Cartilage
- Resistance to IGF-1
14
Q
Idiopathic GH problems
A
- Precious Puberty
- Due to hypothalamic tumor
- Really tall
- GH deficiency
- Plasma GH values didn’t rise after provocative testing (give insulin or arginine)
- Really short
- Typical symptoms of GH deficiency are:
- Short statures
- Cherubic appearance
- Obesity
- Delayed skeletal age
- Provocative testing
- Intravenous administration of insulin or arginine
- Used to see if patient produces expected levels of GH
15
Q
Laron Syndrome: Rare Genetic Mutation in GH Receptor
A
- Patients have short statures
- Suffer from
- Hypoglycemia
- Poor muscle development
- Obesity
- Osteoporosis
- Long lived and resistant to diabetes or cancer
- Can be treated with IGF-1 to correct growth and certain metabolic changes
16
Q
Treatment for GH deficiency
A
- Main goal is to monitor serum IGF-1 levels
- Use until epiphyses are fused (puberty) or into adulthood
- Metabolic effects: acceleration of puberty, pancreatitis, intercranial hypertension, may increase risk of leukemia, stroke
17
Q
Other Indications for RnGH use
A
- Small for gestational age (SGA)
- Smaller than most other babies after the same number of weeks of pregnancy
- GH used if don’t catch up to growth by age 2
- Prader-Willi Syndrome (PWS)
- Short stature, polyphagia, obesity, hypogonadism, and mild mental retardation
- GH supports growth, increased muscle mass, lessens polyphagia and obesity
- Turner Syndrome (TS)
- Lots of symptoms, but short stature is the main GH defect
- GH supports growth
- Idiopathic Short Stature (ISS)
- 2 SD below normal growth, growing at a rate in which won’t reach normal adult height, growth plates haven’t yet fused
- GH supports growth
- Requires higher GH doses than GH deficient patients; genetic factors influence dose
18
Q
Other Treatment Options for low GH
A
- Recombinant human IGF-1
- Optimal dosing necessary
- For patients with GH receptor mutants (Laron dwarfs)
- Sermorelin (synthetic GHRH)
- Less effective than GH
- Won’t work if defect is in pituitary
19
Q
Hypersecretion of Growth Hormone
A
- Usually due to pituitary hormone
- Pre-puberty: gigantism
- Post-puberty: acromegaly
- Growth of some tissues
- Metabolic effects: Type 2 diabetes and cardiovascular risks
20
Q
Treatment of GH Excess
A
- Surgery
- Bromocriptine (dopamine agonist)
- Paradoxical since dopamine normally stimulates GH release
- Octreotide (somatostatin analog)
- Best, more specific at inhibiting GH than somatostatin
- Pegvisomant (GH receptor antagonist)
- A peptide that binds and prevent GH action
21
Q
Vasopressin Receptors in Body
A
- V1 Receptors
- G Coupled IP3 Receptor System
- Increase vascular smooth muscle contraction (BP)
- Increase liver glycogenolysis
- Increase ACTH release
- Increase prostaglandin synthesis
- V2 Receptors
- G Couple cAMP Receptor System
- Increase water resorption in the kidney by increasing the water permeability of aquaporin-2 water channels in renal luminal membranes
- V3 in pituitary with V1 like mechanism
22
Q
Vasopressin Function in Kidneys
A
- Binds receptors in distal or collecting tubules
- Resorption of water
- Tubules are impermeable to water without vasopressin
- Insertion of water channels
- Decrease plasma osmolarity
- Increase urine osmolarity
23
Q
Kidney Aquaporins
A
- Aquaporin-2
- Regulated by V2R stimulated by cAMP
- Is a target for cAMP mediated PKA phosphorylation
- Vesicles containing AQP2 fuse to the apical membrane when cell is stimulated by vasopressin
- Aquaporin-3
- Resides constitutively on the basolateral membrane
- Allow water to flow out of cell after entering through AQP2 channel
24
Q
Regulation of Vasopressin Secretion
A
- Hypothalamic osmoreceptors
- Dehydration: secretion increased
- Secretion increased when BP and volume drops
- Stretch receptors in heart and large arteries
- Not as sensitive as osmolarity changes
- Stimulus of vasopressin is nausea and vomiting
25
Diabetes Insipidus
* Vasopressin dysregulation
* Neurogenic diabetes insipidus
* Deficiency in secretion from posterior pituitary
* Caused from head trauma, infection, tumors involving hypothalamus, or genetic mutation in vasopressin gene
* Nephrogenic diabetes insipidus
* Kidney unable to respond to vasopressin
* Common cause is renal disease
* Less common are mutation in the vasopressin receptor gene or the AQP2 gene
26
Diabetes Insipidus
* Excessive urination
* Must differentiate from polydipsia
* Rarely life threatening if lots of water is available
27
Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
* Excessive release of vasopressin
* Hyponatremia, hypo-osmolality
* Causes:
* CNS injuries/malignancies
* Psychotropic drugs
28
Therapeutic Uses of Vasopressin
* Neurogenic diabetes insipidus (not use chronically)
* Acute bleeding from esophageal varices or colonic diverticula
* CPR, often a alternative to epi
* Vasodilatory shock
29
Therapeutic Use of Desmopressin
* Neurogenic diabetes insipidus
* Bedwetting
* Mild to moderate hemophilia
* Hemophilia A (boosts factor VIII)
* Von Willebrand Syndrome (I and IIa only)
* VWF bind to VIII and prevent degradation
* Recruit factor VIII to site of clot
30
Cautions and Contraindication for vasopressin/desmopressin use
* Caution with conditions aggravated by water retention
* Avoid in cardiac insufficiency or with diuretics
* Caution in CF
* Vascular disease due to vasoconstriction
* Renal impairment, less effective and excreted slower
* Oxytoxic effect in 3rd trimester of pregnancy
31
Antagonists or enhancers of vasopressin action
* APAP or indomethacin: block prostaglandin synthesis in kidney and increase response to vasopressin
* Lithium: polyuria and antagonize vasopressin effects
* Demeclocycline: antagonize vasopressin action on kidney downstream of V2R
32
Vasopressin Receptor Antagonists
* Useful for hyponatermia associated with:
* SIADH
* CHF edema
* Cirrhosis edema
* V1a/V2R antagonist
* Conivaptan
* V2R specific antagonist
* Tolvaptan
* Lixivaptan
33
Oxytocin: Contraction of mammary alveoli
* Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns
34
Oxytocin: Maternal bonding
* Increased in cerebrospinal fluid during birth
* Continued suckling of an infant stimulates release of oxytocin during feeding
* Oxytocin released from pituitary can’t re-enter brain because of BBB
* Effects of oxytocin are due to release from centrally projecting hypothalamic neurons
35
Oxytocin Receptors in the Body
* Oxytocin acts through oxytocin receptors
* IP3 mechanism
* Mobilization of calcium
* Increase uterine and mammary smooth muscle contraction
36
Other factors that regulate oxytocin
* Sensitive to acute stress (inhibited)
* Production of oxytocin and response to oxytocin are modulated by circulating levels of sex steroids
* Increase uterine oxytocin receptors late in gestation results from increased circulating estrogen
* Burst of oxytocin at birth is triggered by cervical and vaginal stimulation by fetus and abruptly declining progesterone
* A number of enzymes in a variety of tissues degrade oxytocin
* Oxytocinase appears in maternal plasma during pregnancy
* Produced in placenta
* Through to protect the fetal brain from being squished by reducing excitability
37
Oxytoxic Drugs
* Synthetic Oxytocin Analogs
* Carboteocin, demoxytocin
* Destroyed in GI tract
* IM or IV administration does not enter brain, excluded by BBB
* Used to induce labor and support labor in case of non-progression of birth
* Ergometrine: preparation of ergot
* Chemically similar to LSD
* Used to facilitate delivery of the placenta and to prevent bleeding after childbirth
* Causes smooth muscle in blood vessels to narrow, reducing blood flow
* Usually combined with oxytocin as syntometrine
* Misoprostol: prostaglandin E1 analog
* Commonly used to induce labor
* Causes uterine contractions and the ripening of the cervix
* More effective in starting labor than other drugs used for labor induction
* Oxytocin analogs don’t work well when the cervix is not yet ripe
* Can be used with oxytocin
* Often used for nonsurgical abortions
* In many countries, commonly used with mifepristone (RU486)
38
Oxytocin: Advantages and Disadvantages
* Advantages
* Causes uterus to contracts
* Acts within 2.5 minutes when given IM
* Generally does not cause side effects
* Disadvantages
* More expensive than ergometrine
* IM or IV preparations only
* Not heat stable
39
Ergometrine: Advantages and Disadvantages
* Advantages
* Low price
* Effects lasts 2-4 hours
* Disadvantages
* Takes 6-7 minutes to become effective when given IM
* Oral form insufficiently effective
* Causes tonic uterine contraction
* Increased risk of hypertension, vomiting, headache
* Contraindicated in women with hypertension or heart disease
* Not heat stable
40
Synometrine: Advantages and Disadvantages
* Advantages
* Combined effect of rapid action of oxytocin and sustained action of ergometrine
* Disadvantage
* Increased risk of hypertension, nausea and vomiting
* Not heat stable
41
Misoprostol: Advantages and Disadvantages
* Advantages
* Shorter time from induction to birth
* Low cost
* Oral, vaginal, rectal administration
* Heat stable
* Disadvantages
* Possible torn uterus when used for labor and delivery
* More common in women who have had previous uterine surgery, a previous C-section, or several previous births
* Rare amniotic fluid embolism
42
Steroid Biosynthesis: Cortisol as an example
* ACTH binds to ACTH receptor
* G-alpha activates adenylyl cyclase and increases cAMP
* cAMP activates protein kinases
* Protein kinases activate cholesterol esterases to release free cholesterol
* Protein-mediates transport of cholesterol into mitochondrion
* The cholesterol is converted to pregnenolone
* Pregnenolone→progesterone→17-hydroxyprogesterone→11-deoxycortisol→cortisol
43
Transfer of cholesterol into mitochondrion
* Cholesterol is transported from the cytoplasm by transporter proteins that dock to the outer mitochondrial membrane
* Cholesterol in then inserted into the outer membrane
* The **rate limiting step** lies with the steroidogenic acute regulatory protein (StAR), which facilitates cholesterol crossing the aqueous inner membrane space
* The mechanism of StAR is not known
* Once transferred to the inner membrane, conversion of cholesterol to pregnenolone occurs by the membrane-bound cytochrome P450scc
44
Enzymology of steroid synthesis:
* Cholesterol→prenenolone
* Enzymes:
* A=17 alpha hydroxylase
* B=3 beta dehydrogenase
* C=21 alpha hydroxylase
* D=11 beta hydroxylase
* Pregnenolone→17-hydroxy-pregnenolone (A)
* Pregnenolone→progesterone (B)
* Progesterone→17-hydroxy-progesterone (A)
* 17-hydroxy-pregnenolone→17-hydroxy-progesterone (B)
* Progesterone→deoxycorticosterone (C)
* 17-hydroxy-progesterone→11-deoxycortisol (C)
* deoxycorticosterone→coricosterone (D)
* 11-deoxycortisol→cortisol (D)
* 17-hydroxy-pregnenolone→dehydroepiandrosterone
* dehydroepiandrosterone→androstenedione (B)
* androstenedione→testosterone
* testosterone→estradiol (aromatase)
45
Key aspects of steroid metabolism
* Inactivated by glucuronide conjugation in the liver
* Converted to less active steroid
* Estradiol→estrone→estriol
* Altered to have increased affinity or altered specificity
* Testosterone→dihydrotestosterone
* Increases affinity for androgen receptor
* Catalyzed by 5-alpha-reductase
* Testosterone→Estradiol
* Altered receptor specificity
* Catalyzed by aromatase
46
Mechanism of Steroid Action
* Steroid hormones interact with intracellular receptors of the nuclear receptor super family
* Different than membrane receptors in that they are transcription factors
* Directly activate gene transcription without kinase cascade
* Dimerize and translocate to the nucleus after binding their ligands
47
Nuclear receptor agonism/antagonism
* Agonists
* Endogenous ligands normally upregulate gene expression
* Agonists induce a receptor conformation that favors coactivator binding
* Antagonists
* No effect on transcription in the absence of endogenous ligand
* Block endogenous ligand effects by competitive binding
* Antagonists induce a conformation of the receptor that prevents coactivator binding and promotes corepressor binding
48
Inverse agonists and selective modulators
* Inverse agonists
* Some receptors promote a low level of transcription without agonists
* Some synthetic ligands reduce the basal level of activity
* Selective receptor modulators (SRMs)
* Some synthetic ligands have an agonist response in some tissues and an antagonistic response in other tissues
* It is though that these work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism
* Where coactivators are more abundant, the SRM behaves as an agonist
* Where corepressors are more abundant, the SRM is an antagonist
49
Therapeutic Uses of Agonists/Antagonists
* Replacement therapy
* Adrenal steroids for Addison’s disease
* Estrogen and progesterone for menopause
* Pharmacologic (non-physiological) uses
* Glucocorticoids as anti-inflammatory agents
* Estrogen/progesterone for contraception
* Androgens for increased muscle mass
* Mifepristone (RU486) for pregnancy termination
* Cancer chemotherapy
* Tamoxifen for breast cancer
* Flutamide/bicalutamide for prostate cancer
50
‘Tripartite’ Pharmacology of Nuclear Receptor Action
* Ligands
* Natural, synthetic, environmental
* Receptor
* Subtypes, isoforms, splice variants
* Effectors
* DNA response elements, Co-regulators (activators, repressors), other TFs or Res
* Actions
* Transcription, other actions
51
Mechanisms of Nuclear Receptor Functions
* Classical
* NRE-independent
* Ligand independent
* Nongenomic
52
Genomic vs. Nongenomic
* Genomic
* Changes in gene expression
* Delayed (hrs-days)
* Required nuclear receptor
* Prevented by transcription and translation inhibitors
* Nongenomic
* Changes in existing enzyme activity and/or protein structure
* Rapid (sec-min)
* Unknown cytosolic mechanisms
* Not affected by transcription and translation inhibitors
53
The complexity of nuclear receptor activation
* The mechanism(s) by which nuclear recptors activate transcription will depend on:
* The receptor subtype
* The dimeric form
* The ligand (endogenous, environmental, synthetic)
* The cell or tissue type
Phcol 401
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