Unit 4 week 1 Flashcards
1
Q
Integrative Health
A
Healing-oriented practice that incorporates the relationship between the provider and whole person (mind, body, spirit)
Emphasizes evidence and makes use of all appropriate therapeutic approaches to achieve optimal health and healing
2
Q
Dietary Supplement and Health Education Act (DSHEA) 1994
A
evaluates vitamins, herbals, amino acids, and other botanicals
Regulates herbal supplements more like food rather than medication
3
Q
DSHEA:
manufacturer vs. FDA responsibilities
A
Manufacturers:
- Does NOT require manufacturers to register or get FDA approval
- Require they ensure product is safe and label information is truthful
FDA: only takes action if product is unsafe once on the market
-MedWatch Reporting System is how providers and patients can report adverse events
4
Q
Higher Quality Supplement Requirements (4)
A
1) Label contains the REQUIRED DISCLAIMER - “not evaluated by FDA, not intended to diagnose, treat, cure, or prevent disease”
2) Label may include a structure-function claim - what to use it for
3) Manufacturer follows Good Manufacture Practices - verify quality of raw materials, FDA inspections, record keeping
4) Label may contain a Supplemental Seal of Approval - Good Manufacturer Practices (GMPs), Consumer Labs (CL), United States Pharmacopoeia (USP), National Sanitation Foundation (NSF)
5
Q
Supplements used for dyslipidemia treatment (4)
A
1) Fish oil / Omega-3 Fatty Acids
2) Fibers
3) Niacin
4) Plant Sterols and Stanols
6
Q
Fish oil/Omega-3 Fatty Acid
Mechanism of action
A
decrease hepatic secretion of VLDL, increase VLDL clearance, reduces TG transport
O-3 can compete with arachidonic acid in COX and lipoxygenase pathways
7
Q
Fish oil/Omega-3 Fatty Acid
Effects
A
20-50% decrease in TGs, can be combined with statins
Not effective for lowering TC or LDL-C
Can be used for primary/secondary prevention of CVD
8
Q
Fish oil/Omega-3 Fatty Acid
Adverse reactions
A
generally recognized as safe (GRAS)
Fish taste - can decrease by putting in freezer
GI upset, heartburn, belching
9
Q
Fish oil/Omega-3 Fatty Acid
Drug interactions
A
anti HTN, anticoag, contraceptives, orlistat
10
Q
Fish oil/Omega-3 Fatty Acid
Herb interactions
A
Garlic, ginger, ginkgo, ginseng → increase risk for bleeding
11
Q
Fibers
A
whole wheat, whole oats, barley, corn
“Reduces risk of heart disease” - claim allowed
12
Q
Niacin
Effects
A
Decreases LDL, and TGs, and increases HDL
Decrease risk of secondary MI, but no significant decrease in all cause mortality
13
Q
Niacin
Side Effects
A
HA, GI, flushing, increase blood glucose, and uric acid - must monitor LFTs for potential hepatotoxicity
14
Q
Mechanism and actions of Sterols
A
inhibit intestinal absorption of 50% of cholesterol
→ decreases TC, LDL, no effect on HDL
15
Q
Adverse reactions of Sterols
A
nausea, indigestion, diarrhea, constipation, gas
16
Q
Mechanism of action and effects of Stanols
A
inhibits dietary and biliary cholesterol
→ Decrease LDL, combine with statin for decreased TC and LDL
17
Q
Adverse reactions with Stanols
A
diarrhea, steatorrhea
18
Q
Stanols and Sterols:
clinical pearls
A
Takes 2-3 weeks to be effective
When discontinued, cholesterol levels rise back to baseline
Sterols and stanols appear to be equally effective
19
Q
Supplements/OTC used as weight loss supplements
A
1) Ephedra
2) Bitter orange
3) Calcium
4) Alli (Orlistat)
20
Q
Ephedra
Mechanism
A
non-selective alpha and beta receptor agonists (stimulants)
Only moderate weight loss benefits
21
Q
Ephedra
Adverse effects
A
dizziness, anxiety, insomnia, HA, dry mouth, N/V, heartburn, tachycardia, palpitations, increased BP, seizures, cardiomyopathy, MI, arrhythmias, sudden death
Product banned from market
HIGH RISK - low gain
22
Q
Bitter Orange
A
contains caffeine, generally safe (GRAS)
No evidence this supplement is safer than ephedra**
Due to FDA ban on ephedra, manufacturers switched to bitter orange
23
Q
Calcium
A
Used for weight loss
supplement alone does not equal low fat dietary intake of Ca2+
24
Q
Alli (Orlistat)
Mechanism
Effects?
A
FDA approved for long term weight loss
Mechanism: reversible inhibitor of pancreatic and gastric lipase
Patients with BMI > 27 have seen benefits
25
Alli (Orlistat)
Side effects?
HA, oily spotting, abdominal discomfort, gas steatorrhea, and liver related events**
26
Supplements used to treat diabetes (2)
1) Chromium
| 2) Vanadium
27
Chromium
no reliable data on effectiveness
Caution in hepatic and renal dysfunction
Used to treat type 2 diabetes
28
Vanadium
Mechanism
activates insulin receptor proteins, stimulates glucose oxidation and transport
Liver: stimulates glycogen synthesis
Adipose: inhibits lipolysis
Skeletal muscle: promotes glucose uptake
29
Vanadium
Side effects
Potential kidney toxicity, GI effects, tongue discoloration, lethargy, fatigue
Risk of bleeding when combined with other RX, OTC, supplements
30
Vanadium
Effects
effective in T2D*, improves insulin sensitivity and possible reduces blood glucose levels
31
Supplements used to treat HTN (2)
1) Garlic
| 2) Coenxyme Q10
32
Garlic Supplement
used to treat HTN
Generally safe (GRAS)
Must be chopped and sit for 10 minutes prior to use for best results
Discontinue 2-3 weeks prior to surgery
33
Coenzyme Q-10
Indications
congestive heart failure, preventing statin-induced myopathy
34
Coenzyme Q-10
Mechanism
antioxidant properties, cofactor in metabolic pathways
35
Coenzyme Q-10
Efficacy
no evidence as monotherapy, possible useful with prescription tx for HF, no evidence of benefit for myopathy or statin tolerability
36
Coenzyme Q10 interactions
Increase risk of bleeding, interact with anticoagulants
Increase T4/T8 labs in normalized patients
37
Anterior pituitary
aka __________
derived embryologically from __________
made up of pars _________, _________, and ___________
aka adenohypophysis
derived embryologically from Rathke’s pouch (oral ectoderm)
pars distalis
pars tuberalis
pars intermedia (not developed in humans)
38
Pars distalis
-part of anterior pituitary
- contains cells that synthesize, store, and release:
1) growth hormone (GH)
2) prolactin (PRL)
3) adrenocorticotropin (ACTH)
4) thyroid stimulating hormone (TSH)
5) follicle stimulating hormones (FSH)
6) Luteinizing hormone (LH)
- Contains extensive vasculature
- Hormone-secreting cells arranged in rows around capillary endothelial cells (fenestrated for rapid passage of hormones into hypophyseal portal system
39
5 types of hormone secreting cells in pars distalis of anterior pituitary
1) Somatotrophs (GH) - make up 50 % of secretory cells.
2) Lactotrophs (PRL)- make up 20%
3) Gonadotrophs (FSH, LH) about 5-10%
4) Corticotrophs (ACTH), about 15-20%
5) Thyrotrophs (TSH), about 5-10%
40
Pars tuberalis
cells around infundibular stalk, contain blood vessels from capillaries of median hypothalamic eminence to small vessels/capillaries of pars distalis
41
Blood flow into anterior pituitary
enters median eminence from superior hypophyseal arteries → larger vessels in tuberalis → deliver regulatory peptides (TSH-RH, GNRH, CRH, GHRH) secreted by hypothalamic neurons to cells in anterior pituitary
42
Posterior pituitary
aka ________
derived embryologically from __________
releases _______ and _______
made up of _________ and __________
aka pars nervosa
derived from neural ectoderm (extension of hypothalamus)
releases ADH and oxytocin
Infundibular stem/stalk + Median eminance
43
Posterior pituitary
Releases ADH (vasopressin) and oxytocin from axons of neurons with cell bodies in hypothalamus (unmyelinated)
Hormones produced in hypothalamus as prohormones (vasopressin-neurophysin and oxytocin-neurophysin and cleaved during vesicular transport down axons
44
Herring's bodies
bulbous structures innervated by hypothalamic neurons that contain neurosecretory vesicles, innervated by neurons from hypothalamus
45
Thyroid gland structure
multi-lobed gland comprised of a series of follicles
-Follicles have single epithelial layer surrounding a central colloid
-Extensive vascularization around follicles
Large storage capability of potential hormone in colloid
46
What does the extensive vascularization around thyroid follicles allow?
→ iodide (I-) pumped from blood → converted to iodine (I2) by epithelial cells
Secrete thyroglobulin into interior of follicle → takes up/digests thyroglobulin → generate thyroid hormones (T3, T4)
47
Calcitonin “C” Cells”
contain secretory granules with calcitonin that decreases release of calcium from bones (downregulate osteoclasts) and causes increase in blood calcium levels
present in thyroid gland
48
Blood supply to thyroid gland:
___________ artery branches of ___________
and _____________ artery branches off ___________
Thyroid is drained by ___________ and ________ into ________ and _______ respectively
Thyrocervical trunk → inferior thyroid artery
External carotid artery → superior thyroid artery
Drainage from:
inferior thyroid vein → subclavian vein
superior thyroid vein → jugular vein
49
Parathyroid Glands
3 cell types present
closely associated with thyroid gland
1) Chief cells
2) Oxyphil cells: contain many mitochondria
3) Adipose cells
50
Chief cells of parathyroid gland
produce PTH
| → increase osteoclast release of Ca2+ from bone, increase Ca2+ uptake from GI tract and kidney → increase Ca2+ levels
51
Adrenal gland is made up of the _________ and __________
cortex and medulla
52
Adrenal cortex
3 regions
secretes mineralocorticoids (aldosterone → Na+ balance), glucocorticoids, and sex steroids (e.g. DHEA-S) = salt, sugar, sex
1) Zona glomerulosa (outer)
2) Zona fasciculata
3) Zona reticularis (inner)
53
Zona glomerulosa
outer layer of adrenal cortex
secretes mineralocorticoids (aldosterone)
Lacks 17a-hydroxylase → cannot make GCs or sex steroids
Regulated through angiotensin system
54
Zona fasciculata
secretes glucocorticoids (cortisol)
Controlled by ACTH
High activity of 11B-hydroxylase for cortisol synthesis
55
Zona reticularis
inner layer of adrenal cortex
secretes androgens
Controlled by ACTH
56
Adrenal Medulla
derived from neural crest (neuroectodermal cells)
Made up of adrenal chromaffin cells that are stimulated by cholinergic (ACh) preganglionic fibers of SNS
→ Catecholamine release (epinephrine, NE) from secretory granules of chromaffin cells (Ca2+ dependent exocytosis)
Cells arranged in clusters around venous channels/sinusoids that drain toward central medullary vein
Under sympathetic and parasympathetic control
57
Blood supply to adrenal gland
superior, middle, and inferior suprarenal arteries → branch and enter through capsule via short cortical arteries → outer subcapsular arterial plexus → medullary region capillaries
Central medullary vein → suprarenal vein
58
Thyroid gland embryology
Thyroid follicle epithelial cells are derived from ___________ in the __________
Thyroid follicle epithelial cells → endoderm
Thyroid diverticulum between first and second pharyngeal pouches
59
Thyroid gland embryology
Ectodermal, Calcitonin-Secreting Cells are derived from _________ cells
neural crest
60
Ultimobranchial body
cells derived from neural crest (ectodermal) that give rise to calcitonin-secreting or parafollicular cells of the thyroid
61
Parathyroid gland embryology
Glandular cells → endoderm
- Inferior parathyroids → cells in clefts between 3rd and 4th pouches
- Superior parathyroids → cleft after 4th pouch
Vasculature → mesoderm
62
Adrenal Gland Embryology:
Cortex originates from _________
reticularis comes from ________ while the fasciculata and glomerulosa come from _________________
Cortex → originates from mesoderm
Originates from coelomic epithelium (mesothelium) in a cleft between gut and urogenital ridge
Reticularis comes from first wave of cells migrating in
Fasciculata and glomerulosa come from second group of cells that layer outside reticularis
63
Adrenal Gland Embryology:
Medulla originates from ________
Sympathogonia are...
Chromaffin cells are...
Medulla → originates from ectoderm
Sympathogonia: neural crest cells that migrate to a region to become sympathetic ganglia
Chromaffin cells: progenitors of epinephrine and NE producing cells of medulla
64
Peptides and Proteins:
synthesis and secretion
synthesized as pre-prohormone on ribosomes from mRNA → hormone targeted to RER → cleaved → prohormone transported to golgi → processed and packaged into secretory vesicles → secreted in Ca2+ dependent manner
*Transported in blood as free hormone but cleaved by proteases in blood, half-life limited
65
Peptides and proteins and tyrosine derived hormones:
signaling mechanism:
bind specific receptor on plasma membrane of target cell
66
3 types of receptors peptides/proteins/tyrosine derived hormones can bind
1) G-protein coupled (cAMP, DAG, IP3)
EX = Hypothalamic hormones
2) Cytokine Family → JAK/STAT receptors coupled to tyrosine kinases → phosphorylation of signal transducer proteins and activators of transcription (STATs)
EX = GH, PRL
3) EGF Receptor Family → Autophosphorylating receptors
EX = Insulin, IGF
67
Steroids
synthesis and secretion
from cholesterol precursor
not stored in cell - synthesized and immediately released into bloodstream
Carried by carrier proteins in bloodstream (some in free form) → freeform is the biologically active, bound form is reservoir
→ Longer half lives (hours to days)
Exists in equilibrium: Hormone + Hormone-Binding Protein ← →[H-HBP]
68
Steroids:
Signaling Mechanism
enter target cell and bind to INTRACELLULAR receptors in cytosol or nucleus → receptor-hormone complex → bind specific hormone responsive elements (HRE) → activate transcription of specific genes
69
Hormones that are tyrosine derivatives (3)
Epinephrine, NE, Thyroid hormone
70
Measurement of Hormone Levels via which 3 techniques?
1) Bioassays
2) Radioimmunoassays (RIA)
3) ELISA
71
Radioimmunoassays (RIA)
measure ab binding to specific region of hormone → not useful if abnormal form of hormone being secreted by pt
Most commonly used method
EX) Radiolabel Insulin + Ab → radiolabel-Insulin-Ab
Then add serum with insulin to this mixture → Insulin-Ab and radiolabel-Insulin-Ab
72
Regulation of Hormone Secretion
2 general ways...
1) Hormone level is regulated variable = Negative Feedback Loop
EX) TRH-TSH-TH
2) Plasma concentration of metabolite or mineral is regulated variable
EX) [glucose] on B-cells and a-cells
73
Pituitary testing:
Hormone excess is assessed by _________ test (EX?)
Hormone deficiency is assessed by _______ test (EX?)
use known physiologic stimulators and suppressors of pituitary hormone release
Hormone Excess: asses by SUPPRESSION test
-e.g. oral glucose tolerance test for GH suppression to confirm acromegaly
Hormone Deficiency: assessed by STIMULATION test
-e.g. insulin tolerance test to evaluate pituitary ACTH/GH reserves
74
Normal secretion of GH sequence: _______ --> ______ (cell in pituitary) --> ________ --> __________(organ) --> ________
Somatostatin role in GH?
GHRH → Somatotroph cell in anterior pituitary → GH → Liver→ IGF-1
Somatostatin inhibits GH release
75
Regulation of GH release (2 factors)
GH inhibits pituitary and hypothalamus
IGF-1 inhibits pituitary and hypothalamus
76
Actions of growth hormone (4)
Increase bone and cartilage mass/growth
Increase protein synthesis / muscle mass
Increase fat breakdown and TGA levels
Increase salt and H2O retention
77
Gigantism
GH excess before puberty (before closure of growth plates)
78
Acromegaly
GH excess after puberty (linear growth complete)
79
Diagnosis of growth hormone excess (4)
1) Clinical features
2) Elevated IGF-1 level = BEST screening test
3) GH levels less reliable (fluctuate widely over 24hrs)
4) Pituitary MRI-macroadenomas detected in > 80% of acromegaly
80
Treatment of growth hormone excess?
surgery (first line)
medical therapies (somatostatin analogs, GH receptor antagonist)
radiation therapies
81
Manifestations of growth hormone deficiency (4)
1) Body composition: increased fat deposition, decreased muscle mass, strength, exercise capacity
2) Bone strength: increase bone loss and fracture risk
3) Metabolic and CV Effects: increased cholesterol, increased inflammatory/prothrombotic markers (CRP)
4) Psychological well-being: impaired energy and mood
82
Treatment of GH deficiency
GH supplement is frequently abused
GH therapy is still controversial in adults (only modest benefits)
83
Diagnosis of growth hormone deficiency (2)
1) Insulin induced hypoglycemia (gold standard)
| 2) Low IGF-1 Level (gender/age matched)
84
Normal secretion of prolactin:
______ (releasing hormone) --> __________ (cell in pituitary) --> ________ --> ________ (tissue in body) --> _____________
________ inhibits prolactin secretion
TRH → Lactotrope → Prolactin → breast → lactation
DA inhibits Prolactin secretion from lactotrophs
85
Hyperprolactinemia
causes:
physiological
pharmacological
pathological
1) Physiological: pregnancy, suckling, sleep, stress
2) Pharmacological: Estrogens (OCPs), antipsychotics, antidepressants (TCAs), antiemetics (reglan), opiates
3) Pathological:
- Pituitary stalk interruption
- Hypothyroidism
- Chronic Renal/Liver Failure
- Prolactinoma
86
Prolactinoma
clinical features (males vs. females)
Female:Male = 10:1
Most common functional pituitary adenoma
Female = *galactorrhea, menstrual irregularity, infertility, impairs GnRH pulse generator, microadenomas*
Male = galactorrhea (less common)*, visual field abnormalities, headache, impotence, EOM paralysis, ant. pit. malfunction, macroadenomas*
87
Diagnosis of prolactinoma (2)
Random PRL level - correlates with tumor size
| Pituitary MRI
88
Treatment of prolactinoma
pharmacological (surgery not usually done)
- Bromocriptine (DA agonist)
- Cabergoline
89
Prolactin deficiency can arise how?
Severe pituitary (lactotrope) destruction from any cause...
Pituitary tumor, infiltrative disease, infectious diseases, infarction, neurosurgery, radiation
90
Clinical presentation of prolactin deficiency
failed lactation in postpartum females
No known effect in males
DX with low basal PRL level
91
Normal secretion of FSH/LH:
_______ (releasing hormone)-->_________ (cell in pituitary) --> ________ --> _______ (organ) --> __________
GnRH → Gonadotroph (anterior pituitary cell) → FSH, LH → Gonads → sex steroids
92
High FSH/LH = hypergonadotropic
Causes?
```
Congenital Anorchia
Klinefelter’s Syndrome
Testicular injury
Autoimmune testicular disease
Glycoprotein tumor (rare)
```
93
Hypergonadotropic (gonadotrope adenoma)
clinical presentation?
**Majority are clinically silent
Typically middle-aged patients (males > females) with macroadenomas and related mass effects
→ headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies
94
Diagnosis of gonadotrope adenoma (hypergonadotropic)
- Blood tests: usually low FSH/LH, T/E2
- Pituitary MRI
- Immunohistochemical analysis (+FSH, LH, or ASU stain) of resected tumor
95
Causes of low FSH/LH (hypogonadotropic hypogonadism)
Hypothalamic/Pituitary diseases:
- Macroadenomas
- Prolactinomas
- Isolated GnRH deficiency
- Hemochromatosis
“Functional” Deficiency:
-Critical illness, OSA, starvation, Meds (opiates, glucocorticoids)
96
Clinical features of hypogonadotropic hypogonadism
Females?
anovolatory cycles (oligo/amenorrhea, infertility), vaginal dryness, dyspareunia, hot flashes, decreased libido, breast atrophy, reduced bone mineral density
97
Clinical features of hypogonadotropic hypogonadism
Males?
reduced libido, ED, oligospermia or azoospermia, infertility, decreased muscle mass, testicular atrophy and decreased bone mineral density, hot flashes
98
Normal secretion of ACTH
_______ (releasing hormone) --> _______ (cell in pituitary) --> _________ --> _________ (organ) --> _________
when is cortisol secretion at its highest?
CRF → Corticotrope → ACTH → Adrenals → cortisol and DHEA-S
Cortisol Rhythms: Major ACTH/cortisol burst in early morning (before awakening)
99
Cortisol
primary function? (3)
catabolic “stress” hormone essential for life
Primary functions:
1) Gluconeogenesis
2) Breakdown of fat and protein for glucose
3) Control inflammatory reactions
100
ACTH actions on adrenal cortex (3)
Zona fasciculata → stimulate glucocorticoid production
Zona glomerulosa → mineralocorticoids increased with very high ACTH
Zona reticulata → stimulate steroid hormone synthesis
101
Complications of hypercortisolism? (15)
1) Changes in carb, protein, and fat metabolism
2) Peripheral wasting of fat/muscle
3) Central obesity, fat pads
4) Moon facies
5) Wide (> 1 cm violaceous striae)
6) Osteoporosis
7) Diabetes
8) Hypertriglyceridemia
9) Changes in sex hormones
10) Amenorrhea/Infertility
11) Excess hair growth
12) Impotence
13) Salt and water retention → HTN and edema
14) Impaired immunity
15) Neurocognitive changes
102
ACTH dependent vs. ACTH independent
1) ACTH Dependent → 70-75% of cases
- Corticotrope Adenoma (Cushing’s Disease)
- Ectopic Cushing’s (ACTH/CRH tumors)
2) ACTH independent → 25-30% of cases (high cortisol, nml ACTH)
- Adrenal adenoma
- Adrenal carcinoma
- Nodular hyperplasia (micro or macro)
103
Pseudo-Cushing’s Disease
overactivation of HPA axis without tumorous cortisol hypersecretion
Occurs with: severe depression, anxiety, OCD, severe obesity, obstructive sleep apnea, alcoholism, poorly controlled DM, physical stress (acute illness, surgery, pain)
104
Causes of central adrenal insufficiency
Suppression of HPA axis due to...
S/p tumor resection for Cushing’s
Supraphysiologic exogenous glucocorticoid use
Drugs (opioids, megace)
105
Clinical presentation of adrenal insufficiency (6)
1) Fatigue
2) Anorexia, nausea, vomiting, weight loss
3) Generalized malaise/aches
4) Scant axillary/pubic hair
5) Hyponatremia
6) hypoglycemia
106
Diagnosis of adrenal insufficiency (2)
Basal testing: random a.m. cortisol level
Stimulation tests:
-Insulin-induced hypoglycemia (gold standard)
107
Normal secretion of TSH:
________ (releasing hormone) --> _________ (pituitary cell) --> _______ --> _________ (organ/tissue) --> ________
______ inhibits TSH secretion
TRH → Thyrotrope → TSH → Thyroid → T4, T3
SRIF (somatostatin) inhibits thyrotrope secretion of TSH
108
Clinical presentation of Thyrotropin (TSH) elevation
goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses, mass effect symptoms from macroadenoma (headaches, vision loss, loss of pituitary gland function)
109
Diagnosis of Thyrotropin (TSH) elevation (2)
elevated free T4 and non-suppressed TSH**
Pituitary MRI (> 80% macroadenomas)
110
Central TSH deficiency:
clinical presentation
fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses, possible mass effect
111
Central TSH deficiency:
Diagnosis (1)
low free T4 levels in setting of low/normal TSH**
112
Hypopituitarism
deficiency of 1 or more pituitary hormone
Panhypopituitarism = loss of all pituitary hormones
Typically progresses from GH (LH/FSH) → TSH (ACTH) → PRL loss = Predictable pattern of loss of ant. Pit hormones
113
Causes of hypopituitarism
1) Congenital-Genetic Diseases
2) Acquired pituitary lesions and/or their treatments = 75%
- Macroadenomas/Pituitary surgery/Radiation
- Infiltrative, infectious, granulomatous disease
- TBI, subarachnoid hemorrhage
- Apoplexy
114
Apoplexy
clinical syndrome of headache, vision changes, ophthalmoplegia, AMS caused by sudden hemorrhage or infarction of pituitary gland
Occurs in 10-15% of pituitary adenomas
Dx: pituitary MRI or CT
Tx: emergent surgery
115
Management of hypopituitarism
Treat hormone deficiency with end hormone replacement
Thyroid → multiple L-thyroxine formulations available
Adrenal → hydrocortisone, prednisone
Gonadal → oral/transdermal E2, transdermal/IM testosterone, or GnRH therapy
Growth Hormone: SQ shots (not orally active)
116
ADH
Mechanism of action at its 2 receptors (V1 vs. V2)
V1: vascular vasoconstriction, platelet aggregation
V2: antidiuretic effects in kidney
AC activation → movement of aquaporin water channels to cell membrane → water reabsorption
117
SIADH
syndrome of inappropriate ADH release/action in absence of physiologic osmotic or hypovolemic stimulus
Hallmark = excretion of inappropriately concentrated urine in setting of hypoosmolality and hyponatremia
MOST frequent cause of hyponatremia
118
Causes of SIADH
Malignant disease - carcinoma, lymphoma, sarcoma
Pulmonary disorders - infections, asthma, CF, positive pressure ventilation
CNS disorders - infection tumors, trauma, bleeds
Drugs - stimulate/potentiate ADH release/actions
Narcotics, nicotine, antipsychotics, carbamazepine, vincristine
Other - nausea, stress, and pain
119
Presentation of SIADH:
Na+ = 130-135 → ?
Na+ = 125-130 → ?
Na+ = 115-125 → ?
Na+ < 115 → ?
depends on severity of hyponatremia and rapidity of development (acute is < 48hrs)
-Manifests with neuro symptoms from osmotic fluid shifts and brain edema
Na+ = 130-135 → asymptomatic
Na+ = 125-130 → anorexia, N/V, headaches, irritable
Na+ = 115-125 → altered sensorium, gait disturbance
Na+ < 115 → Seizure, coma, death
120
Diagnosis of SIADH
4 main criteria
1) Hyponatremia (Na < 135 mmol/L) + hypotonic plasma (osmolality < 275 mOsm/kg)
2) Inappropriate urine concentration (urine Osm > 100 mOsm/kg) with NORMAL renal function
3) Euvolemic status (no orthostatic hypotension)
4) Exclusion of other potential causes of euvolemic hypo osmolality = hypothyroidism, hypocortisolism
121
Treatment of hyponatremia
depends on severity of hyponatremia
Identify and reverse underlying disorder
Mild-Moderate = Na+ 120-134
Water restriction
--> V2 receptor antagonists
--> Salt tablets, lasix, urea
Severe = Na+ <120
--> Hypertonic saline (if pt symptomatic)
*Correct slowly to prevent complications
122
Diabetes Insipidus
syndrome of hypotonic polyuria as a result of either inadequate ADH secretion or inadequate renal response to ADH
Hallmark = Voluminous dilute urine
123
Main causes of Diabetes insipidus (4)
Central DI: neoplasms, idiopathic, congenital defects, inflammatory/infectious/granuloma/pit. Disease, trauma/vascular event
Nephrogenic DI:
Congenital, drugs, electrolyte abnormalities, infiltrative kidney diseases, vascular disease
Pregnancy
Psychogenic Polydipsia
124
Diagnosis of diabetes insipidus (4)
1) Confirm polyuria with 24 hr urine volume collection
2) Exclude hyperglycemia, renal insufficiency, and electrolyte disturbances
3) Assess urine and plasma osmolality
4) Water deprivation test: fluid restricted to limit ADH release → measure Uosm, Posm, serum Na+, and urine output
125
Pituitary Adenoma
85% of sellar region masses, typically grade I (DO NOT invade blood vessels)
Can invade bone and dura
Treated with surgical resection
Can be an incidental finding on autopsy
Typically SPORADIC, syndromic is rare but possible (EX - MEN1)
Pediatric/young adults may have syndromic constellation of sx
Functional or nonfunctional
Micro (<1cm) / Macro (>1cm) adenoma
126
Functional vs. Non-functional pituitary adenomas
- Can be hyperfunctioning → produce physiologically unregulated excess of endocrine hormones
- Can be non-functioning and produce mass effect due to compression of nearby structures
--> Visual disturbances, headache, CN palsies (ptosis, diplopia), pituitary hormone deficits (panhypopituitarism), seizures, stroke, CSF leak
127
List pituitary masses in order of frequency
1) Pituitary adenoma (85% of cases)
2) Craniopharyngioma
3) Hypophysitis
4) Pituicytoma
5) Spindle cell oncocytoma
128
Pituitary blastoma
rare infantile pituitary masses
DICER1 mutation
ACTH IHC (+)
129
Craniopharyngioma
Predominantly kids (5-15 yrs) and middle-aged adults (45-60 yrs)
2nd most common sellar region mass
130
ACTH (corticotroph) secreting adenomas
positive for what transcription factor?
main features?
Tpit + (Transcription factor)
85% are microadenomas
Can present with Cushing’s disease
131
Gonadotroph adenoma
positive for what transcription factor?
main features?
most common type of clinically nonfunctioning adenoma
most common adenoma type to come to surgery
SF-1 + (steroidogenic factor)
132
prolactinomas
positive for what transcription factor?
main features?
Most prolactinomas in premenopausal women are microadenomas
Symptoms: amenorrhea, galactorrhea, impotence (men)
NOT related to birth control pill use
Pit-1 + (pituitary TF)
133
Growth hormone adenoma
positive for what transcription factor?
main features?
stained so you can treat GH effects
Pit-1 + (pituitary TF)
134
Blood enters median eminence via __________ arteries and forms capillary plexus
Superior hypophyseal
135
Nerve terminals of hypothalamic neurons located in capillary plexus in median eminence →
release neurohormones into capillary plexus
136
Neurohormones in capillary plexus --->
transported via hypothalamo-hypophyseal portal system to second capillary plexus in anterior lobe of pituitary
137
Adenohypohysis
Anterior pituitary
138
Anterior pituitary is derived from?
Rathke's pouch
139
Structure of anterior pituitary
pars tuberalis, pars intermedia, pars distalis (anterior lobe)
Anterior lobe secretes hormones
140
Anterior lobe (pars distalis)
secretes hormones under control of hypothalamic hormones secreted into hypothalamo-hypophyseal portal system
141
All hypothalamic hormones are _______ and act via _________ receptors
peptides
G-protein coupled
142
Gs →
AC, cAMP = CRH, GHRH
143
Gi →
decrease AC, cAMP = Somatostatin, DA
144
Gq →
PIP2 → IP3/Ca2+ and DAG/PKC
145
Thyrotropin releasing hormone (TRH)
Thyrotrophs → TSH, PRL
PRL = polypeptide
146
Gonadotropin releasing hormone (GNRH)→
Gonadotrophs →LH/FSH
LH, FSH, TSH = glycoproteins
147
Corticotropin releasing hormone (CRH) →
Corticotrophs → POMC, ACTH (ACTH is a derivative of POMC)
148
Growth hormone releasing factor (GHRH) →
Somatotrophs → GH
GH = polypeptide
149
Somatostatin (GH inhibiting hormone, GIH) →
Somatotrophs → decrease GH and TSH
150
Prolactin inhibiting factor (PIH) (aka Dopamine)→
Lactotrophs → decrease PRL
151
Pulsatile Secretion and Circadian Secretion
Release of hormones from ant. pituitary not constant over time (pulses)
Circadian = ACTH highest during early morning hours, GH secretion elevated sPosterior pituitary dervidehortly after sleep onset
Circadian and pulsatile secretion patterns are superimposed
152
Neurohypophysis
Posterior pituitary
153
Posterior pituitary derived from?
Derived from neural tissue arising from embryological evagination of diencephalon
154
Posterior pituitary directly connected to
hypothalamus and brain
155
_____ and _____ synthesized in cell bodies of large hypothalamic neurons (_______ neurons) → prohormone packaged into secretory vesicles → cleaved into _____ + ______→ vesicles travel down axon of neuron into posterior pituitary → released when AP reaches terminal and ______ channels open
ADH and oxytocin synthesized in cell bodies of large hypothalamic neurons (magnocellular neurons) → prohormone packaged into secretory vesicles → cleaved into hormone + neurophysin → vesicles travel down axon of neuron into posterior pituitary → released when AP reaches terminal and Ca2+ channels open
156
ADH secreted in response to? (2)
secreted in response to an increase in plasma osmolarity or a decrease in blood pressure
157
ADH actions
Acts on cells of renal tubule and collecting ducts to alter water permeability and conserve water
158
Two types of ADH receptors
V1 → Gq → PLC pathway → mediate vasopressive action of ADH
V2 → Gs → cAMP → regulate effect of ADH on glomerular filtration rate in kidney
159
Oxytocin secreted during (3)
1) Passage of infant through cervix at childbirth
2) During sexual intercourse
3) Response to suckling by infant during breastfeeding
160
Actions of oxytocin
Acts to cause contraction of myometrium (during childbirth), contraction of myoepithelial cells (milk ejection)
161
Structure of posterior pituitary
median eminence, infundibular stem, infundibular process (pars nervosa)
162
Paraventricular nucleus and supraoptic nucleus:
part of hypothalamus that synthesize and secrete hormones into posterior pituitary
163
Two cell types of paraventriclar and supraoptic nucleus
2. Magnocellular neurons
| 2. Parvocellular neurons
164
Magnocellular neurons
processes extend into post. Pituitary and end in pars nervosa
165
Parvocellular neurons
end at median eminence close to endings of hypothalamic neurons that produces ant. Pit regulating hormones
→ ADH can increase ACTH production, and cortisol (regulated by ADH) can inhibit ADH in kidneys and hypothalamus
166
General Principles of Hormone Release from Hypothalamic Neurons:
Hormones released from hypothalamic neurons when appropriate stimulus generates an AP → Ca2+ entry at nerve terminal via Ca2+ voltage dependent channels → hormone release from secretory vesicles
167
Receptors and Signal Transduction Mechanisms for Hypothalamic Hormones:
1. CRH and GHRH
2. Somatostatin
3. DA
Hypothalamic hormones interact with specific receptors on their appropriate target cells in the anterior pituitary
1. CRH and GHRH → Gs → increase cAMP in corticotrophs and somatotrophs
2. Somatostatin → Gi → decrease cAMP
3. DA → Gi → decrease cAMP in lactotrophs
168
Growth hormone secreted by?
secreted by somatotrophs from anterior pituitary
169
Secretion and synthesis of growth hormone
GH synthesized as part of prohormone → signal peptide cleaved → GH stored in secretory granules of somatotrophs of adenohypophysis
170
GH secretion is under control of?
GHRH and Somatostatin
GHRH → increase cAMP in pituitary somatotrophs
Somatostatin → decrease cAMP in pituitary somatotrophs
171
Negative feedback control of GH
GH inhibits GHRH secretion and activates somatostatin secretion
172
Effect of GH on organs and systems (4)
stimulate somatic growth, regulate metabolism
1) Adipose tissue: increased lipolysis (hormone sensitive lipase), increased plasma free fatty acids (FFAs) → loss of subcutaneous fat
2) Muscle: increase AA transport into muscle and protein synthesis
3) Liver: increase RNA, protein, and gluconeogenesis
Counter-regulatory hormone to insulin = “Anti-Insulin” actions
Excess GH = Diabetogenic
Protein is spared
4) IGF-1 secreted → mediate indirect growth effects
173
Extrinsic factors that stimulate GH (6)
1) Hypoglycemia
2) Increased AAs (arginine)
3) Low FFAs
4) a-adrenergic agonists (clonidine)
5) B-adrenergic antagonists (propranolol)
6) Estrogens
174
Extrinsic factors that inhibit GH (6)
hyperglycemia, FFAs, obesity, a-adrenergic antagonists, B-adrenergic agonists, corticosteroids
175
GH mechanism of action
Binds cytokine receptor family → JAK/STAT pathway activated
176
Hyper-GH (4)
1. High levels of serum glucose → diabetogenic
2. High levels of insulin (because of high glucose)→ excess IGF production → gigantism
3. Cardiac hypertrophy
4. Acromegaly (high GH post puberty)
177
Hypo-Growth Hormone (2)
Dwarfism
1. Laron Dwarfism - due to GH receptor problem
2. African Pygmies - due to low IGF response
178
Production of IGF-1 reqires
Production of IGF requires BOTH insulin and GH
179
Regulation of IGF-1 secretion (2)
1. High glucose, high AA → insulin and GH present → IGF secreted
2. Low glucose, low AA → low insulin, low GH → IGF NOT secreted
180
Function of IGF-1
powerful mitogen and growth-promoting agent
1. IGF-1 levels increase slowly from birth until puberty
2. Bone/Cartilage: promote long bone growth via proliferation of epiphyseal cartilage
After puberty, epiphyses seal, and IGF-1 no longer works here
3. Muscle: stimulate proliferation, differentiation, and protein synthesis
4. Adipose tissue: stimulate uptake of glucose and inhibit lipolysis (antagonizes GH)
181
IGF-1 mechanism of action
IGF-1 receptors (EGF family receptors) have inherent tyrosine kinase activity upon ligand binding
Insulin receptor associated proteins bind IGF receptors → autophosphorylation of receptor and IRS protein → MAP kinase pathway or PI-3 kinase transduction
182
Prolactin secreted by?
secreted by lactotrophs in anterior pituitary
183
Charles Ventriglia
An alright guy
184
Secretion of prolactin (3)
1. Hypothalamus tonically inhibits secretion of PRL via DA
DA → Gi → reduce synthesis of PRL, inhibit lactotroph cell division / DNA synthesis, increase destruction of PRL secretory granules
- Dopamine is primary controller of PRL release
2. TRH increases prolactin secretion
3. Estrogen and progesterone activate mammogenesis and inhibit lactogenesis and galactopoiesis
185
Chilliam Tran
A great guy
186
Actions of prolactin
1) Breast (mammary gland) = principal target → stimulates...
- Mammogenesis
- Lactogenesis
- Galactopoiesis
2) Inhibits reproduction due to inhibition of GnRH production
PRL has a short half life
187
Prolactin mechanism of action
prolactin binds to GH/cytokine receptor on target cell → JAK/STAT (signal transducers and activators of transcription) pathway activation
188
Hyperprolactinemia (4)
Galactorrhea, amenorrhea, loss of libido, overgrowth of mammary gland
189
Hypoprolactinemia
rare, usually due to panhypopituitarism
190
Sheehan's syndrome
during childbirth, hemorrhagic destruction of pituitary gland
191
Treatment Goals for Pituitary Tumors: (6)
```
Control tumor growth/mass effects
Preserve pituitary function
Prevent recurrence
Relieve symptoms
Control hormone hypersecretion
Improve mortality rates
```
192
Types of pituitary tumors that most often require surgical treatment
Surgery is first line treatment for all pituitary tumors EXCEPT for tumors that secrete prolactin
IF they secrete prolactin AND growth hormone → surgery
193
Complications from surgery on the pituitary gland (7)
1) Postoperative spinal fluid leakage
- -> Requires placement of spinal drain and increased hospital stay
2) Diabetes insipidus: inability to concentrate urine
- -> Due to injury to posterior pituitary gland
- -> Requires tx with DDAVP
- -> Usually transient
3) Injury to optic nerves
4) Injury to carotid artery (stroke)
5) Injury to normal pituitary gland
6) Chronic sinusitis
7) Meningitis
194
Cholesterol molecule
-molecules synthesized from cholesterol? (3, how many carbons do they have)
27-carbon steroid molecule
All 27 carbons derived from acetyl CoA
Molecules synthesized from cholesterol:
1) Glucocorticoids: cortisol (C-21)
2) Mineralocorticoids: aldosterone (C-21)
3) Sex steroids
195
Sex steroids (3), how many carbons do they have?
all sex steroids are derived from _________ (__-C) via __________ (enzyme) located in the mitochondrial membrane
progestins (C-21), androgens (C-19), estrogens (C-18)
All sex steroids derived from pregnenolone (21-C)
Cholesterol → pregnenolone via 20, 22 desmolase (rate limiting step) located in mitochondrial membrane
196
Biosynthesis of sex steroids
occurs where? (6)
Involves a progressive reduction in number of carbon atoms
Location: primarily in gonads
Extra-gonadal tissue:
- Placenta, adrenal cortex → source of sex steroids
- Liver, skin, adipose tissue → convert metabolites to sex steroids
197
Transport of sex steroids (3)
Hydrophobic, so predominantly in bloodstream bound to plasma proteins
1) Albumin
2) Sex hormone binding globulin (SHBG):
- Produced in liver
- Oral exogenous estrogens stimulate hepatic synthesis of SHBG
3) Corticosteroid binding globulin (CBG)
198
Progestins have _____ carbons
3 types of progestins
21-C
1) Pregnenolone, 17-alpha-hydroxypregnenolone
2) Progesterone
3) 17-alpha-hydroxyprogesterone (17-OH-P)
199
Progesterone
type of progestin (21-C)
- Major circulating progestin
- Present in higher concentrations in females
- Levels fluctuate during normal menstrual cycle
Function: growth/development of tissues and organs related to ovulation, menses, pregnancy, and lactation
Key feedback inhibitor of hypothalamus and pituitary
200
17-alpha-hydroxyprogesterone (17-OH-P)
used as a marker for what?
type of progestin (21-C)
Major circulating progestin
Used as marker for late onset congenital adrenal hyperplasia
201
General function of progestins:
progestins are precursors for production of ________ and _______ by _________
Progestins act on _______, _______, and __________
Precursors for production of aldosterone and cortisol by adrenal gland
Affect uterus, ovaries, and breasts
202
Androgens have _____ carbons
Types of androgens (4)
19 carbons
1) Testosterone
2) Dehydroepiandrosterone (DHEA)
3) Dihydrotestosterone (DHT)
4) Androstenedione
203
Testosterone
Type of androgen (19C)
95% produced in testes
Major feedback inhibitor of hypothalamus and pituitary
204
Function of testosterone - 2 major categories of effects
Androgenic effects: growth/development of internal and external genitalia, development/ maintenance of secondary sex characteristics, spermatogenesis, libido, sebum production
Anabolic effects: growth-promoting effects on somatic tissues (bone, muscle)
205
Dehydroepiandrosterone (DHEA)
- produced where?
- marker of what?
Type of androgen (19C)
Majority produced in adrenal cortex
Excellent marker of adrenal androgen activity
206
Dihydrotestosterone (DHT)
_______ converts ______ to DHT in target cells, however DHT CANNOT be converted to _________
DHT vs. testosterone
Type of androgen (19C)
5-alpha-reductase converts testosterone → DHT in target cells
DHT CANNOT be converted to estrogens
DHT is 30-50x more active than testosterone
207
Androstenedione
Produced by _______ cells in _______
Precursor for ovarian _________ production by _______ cells and precursor for extraglandular _______ formation in ______ and ______ tissues
Type of androgen (19C)
Produced by THECA cells in ovary
Precursor for ovarian ESTRADIOL production by GRANULOSA cells and precursor for extraglandular ESTROGEN formation in LIVER and ADIPOSE tissues
208
Estrogens (18-C)
what is the sequence of estrogen production starting from cholesterol?
```
what main enzyme is involved and at what step?
what tissues (4) is this enzyme present in?
```
Cholesterol → Pregnenolone → Progestins → Androgens → Estrogens
Androgen → Estrogens via AROMATASE
Aromatase present in gonads, adipose, liver, CNS
209
Types of estrogens (3)
Estrone (E1) - one hydroxyl group
Estradiol (E2) - two hydroxyl groups
Estriol (E3) - three hydroxyl groups
210
Estrone (E1)
derived from __________ in ________
Derived from androstenedione in adipose tissue
211
Estradiol (E2
Most potent estrogen
Major circulating estrogen
Produced by granulosa cells of ovary and sertoli cells of testes
Function: growth/development of tissues and organs related to ovulation, menses, pregnancy, and lactation
Levels fluctuate during normal menstrual cycle
Key feedback inhibitor of hypothalamus and pituitary
212
Estriol (E3)
Least potent estrogen
| Important placental product
213
Hypothalamic-Pituitary-Gonadal Axis:
1) Hypothalamus secretes _________ from ________ and _________ in a _______ pattern
2) Anterior pituitary secretes _____ and _____ from ________ in response to GnRH from
3) FSH and LH stimulate production of ________ and ______ which each act to negatively feedback on what?
1) Hypothalamus secretes GNRH from ARCUATE NUCLEUS and PREOPTIC AREA in a PULSATILE pattern
- constant GnRH administration actually SUPPRESSES pituitary response
2) Anterior pituitary secretes FSH and LH in response to GnRH from GONADOTROPHS
3) FSH and LH stimulate production of SEX STEROIDS and INHIBIN
→ negative feedback control on reproductive axis
Inhibin = negative feedback on pituitary only
214
Hypothalamic-Pituitary-Gonadal Axis:
Men
GnRH pulses 8-14x every 24 hrs
| FSH/LH also important for male gonadal function
215
Hypothalamic-Pituitary-Gonadal Axis:
Women
GnRH pulses and FSH and LH secretion vary throughout menstrual cycle
FSH/LH in ovulatory women vary throughout menstrual cycle
-Peak shortly before ovulation
Estradiol and progesterone produced in response to FSH/LH
-Estradiol mid cycle in ovulatory women exert POSITIVE feedback on pituitary gland → surge in FSH/LH
216
Men have ______ and ______ cells in their testes
Women have _______ and ______ cells in their ovaries
Men: in testes, Leydig and Sertoli Cells
Women: in ovary, Theca and Granulosa Cells
217
Leydig Cells
Located in interstitial layer surrounding seminiferous tubules
In response to LH → produce 95% of testosterone in males
Testosterone then acts on Sertoli cells to support spermatogenesis
Negative feedback onto hypothalamus/pit
218
In Leydig cells, LH stimulates rate limiting conversion of cholesterol into pregnenolone by: (2)
1) Increasing amount of desmolase
| 2) Enhancing affinity of desmolase for cholesterol
219
Sertoli Cells
Located in direct contact with developing spermatozoa
Support/nurse cells of developing spermatozoa
Organized into tubular epithelium = seminiferous tubule
Tight gap junctions between cells
220
Spermatogenesis requires...
Spermatogenesis requires LH, FSH, Leydig cells, Sertoli cells, and testosterone
221
FSH acts on sertoli cells to... (3)
1) Produce androgen binding protein
2) Enhance conversion of testosterone from Leydig cells → estradiol
3) Production of inhibin
222
Theca Cells
Located in ovarian stroma surrounding follicles
LH acts on theca cells to produce progesterone and androgens
223
Granulosa cells
In direct contact with oogonia
Gametes + surrounding granulosa cells = primordial follicles
One follicle matures each month in women of reproductive age
224
Oogensis and ovulation requires...
Oogenesis and ovulation requires LH, FSH, granulosa cells, theca cells, estradiol, and testosterone
225
Granulosa cells lack enzyme to convert _______ --> ________
Thus ______ from granulosa cells must diffuse to Theca cells to be converted into _________ and diffuse back into granulosa cells for conversion to ________
Lack enzyme to convert progesterone → androgens
Progesterone
Andrsostenedione
Estradiol
226
Leydig (male) and Theca (female) Cells
4 shared characteristics
Interstitial cells
Contain LH receptors
Make androgens
Cannot make estrogens due to absence of aromatase
227
Sertoli (male) and Granulosa (female) Cells
4 shared characteristics
Adjacent to developing gametes
Contain FSH receptors
Make inhibin
Convert androgens → estrogen in presence of aromatase
228
Treatment of GH Hyposecretion (2)
1) Sermolin (GHRH analog)
| 2) Somatropin (GH analog)
229
Sermorelin
mechanism of action
activates anterior pituitary release of growth hormone
GHRH analog: stimulate GH synthesis and secretion via binding to GPCR (Gs) on somatotrophs
230
Sermorelin
Uses (2)
potential use in GH-deficiency children
diagnostic eval of patients with GH deficiency
231
Somatropin (GH analog)
uses (4)
1) Replacement therapy in children with GH deficiency (can be very expensive)
- Daily bedtime SC injection
- If GH insensitive, can treat with recombinant IGF-1
2) Poor growth due to Turner Syndrome, Prader-Willi, or chronic renal insufficiency
3) Adults with GH deficiency
4) Illicit use (athletes, “anti-aging”)
232
Somatropin (GH analog)
Side effects (5)
1) Generally safe in children
2) Insulin resistance, glucose intolerance
3) Increased risk for idiopathic intracranial hypertension
4) Rarely pancreatitis, Gynecomastia, Nevus growth
5) Misuse in athletes → acromegaly, arthropathy, visceromegaly, extremity enlargement
233
Treatment of GH and Prolactin Hypersecretion (3)
1) Octreotide (Somatostatin)
2) Bromocriptine (DA agonist, D2/D1)
3) Cabergoline (DA agonist, D2)
234
Octreotide (Somatostatin)
mechanism (3 main actions)
1) Inhibit GH release via Gi → decrease cAMP, activate K+ channels
2) Decrease GI motility, decrease gastric enzyme secretion
3) Decrease insulin/glucagon release
235
Octreotide (Somatostatin)
uses (2)
1) Pituitary excess of growth hormone (Acromegaly, gigantism)
2) Control bleeding from esophageal varices and GI hemorrhage
**More effective than DA to treat GH excess
236
Octreotide (Somatostatin)
Side effects (3)
1) Hyperglycemia
2) Abdominal cramps, loose stools
3) Cardiac effects (sinus bradycardia, conduction disturbances)
237
Bromocriptine
Mechanism
inhibits anterior pituitary secretion of growth hormone
Mechanism: dopamine agonist
- Not as effective as SST analog for GH suppression
- DA inhibits prolactin secretion via D2 receptors, but works on D1 receptors also
238
Bromocriptine
Uses
Hyperprolactinemia (pituitary adenoma) → DA decreases secretion of PRL and reduces tumor size
239
Bromocriptine
Side effects
nausea, vomiting, headache, postural hypotension, psychosis, insomnia
Mostly due to D1 actions also
240
Cabergoline
mechanism and use
preferred agent for hyperprolactinemia
Dopamine agonist, more selective for D2 receptors
241
Cabergoline
side effects
better tolerated than Bromocriptine, may cause hypotension and dizziness
242
Desmopressin
use and mechanism?
ADH analog, more stable to degradation
Use: central DI
243
Desmopressin
Side effects
nasal irritation (intranasal application), GI sx, asthenia, mild liver enzyme elevations, headache, nausea, abdominal cramps, allergic reaction, water intoxication
244
Vasopressin (ADH) is released from _________ of the hypothalamus
Its main stimulus for release is ___________, but can also be released in response to __________
ADH release is inhibited by _________
Released from supraoptic nuclei of hypothalamus
Main stimulus is rising blood OSMOLALITY
Also released in response to decrease in circulating blood volume
Release inhibited by alcohol
245
Vasopressin actions at V2 receptor
```
Renal actions (Gs)
-Increase rate of insertion of aquaporins into luminal membrane of collecting duct → increase water permeability → antidiuretic effect
```
NON-RENAL actions = release of coagulation factor 8 and vWF
246
Vasopressin actions at V1 receptor
V1 Receptors: (Gq) → vasoconstriction of vascular smooth muscle
247
Central DI
what is it?
what causes it?
inadequate ADH secretion from posterior pituitary
Due to head injury, pituitary tumors, cerebral aneurysm, ischemia
248
Best 2 drugs used to treat central DI
Desmopressin, Chlorpropamide
249
Nephrogenic DI
what is it?
what causes it (2 drugs + 1 other)
inadequate ADH actions
Causes:
1) Congenital - receptor/aquaporin mutations
2) Drug induced - Lithium (V2 stimulation of AC), Demeclocycline (tetracycline abx)
250
Treatment of Nephrogenic DI (3)
Low salt, low protein diet
Thiazide diuretics
NSAIDs
251
SIADH
what is it?
what drugs can cause it? (4)
incomplete suppression of ADH secretion under hypoosmolar conditions
Drug causes:
1) Psychotropic agents (SSRIs, haloperidol, TCAs)
2) Sulfonylureas (Chlorpropamide)
3) Vinca alkaloids (chemo)
4) MDMA
252
SIADH treatment (3)
1) Water restriction
2) Demeclocycline: inhibit ADH effect on distal tubule
3) V2 receptor antagonist: Tolvaptan, Conivaptan
253
Tolvaptan
V2 receptor antagonist
oral, can cause hepatotoxicity
254
Conivaptan
V2 receptor antagonist
IV, given in hospital
255
Steroid hormone biosynthesis:
How is cholesterol made available for steroid synthesis?
Cholesterol --> __________
via what enzyme?
occurs where in the adrenal gland? where in the cell?
1) Cholesterol released from lipid droplets by removal of esters
LDL endocytosed into cell → esterified and stored in lipid droplets
-Cholesterol can also be synthesized from acetyl CoA
2) In MITOCHONDRIA or ER → rate limiting step
Cytochrome P450 enzymes or 20, 22 desmolase → Pregnenolone
Occurs throughout the cortex
256
21-hydroxylase:
converts ________ and __________ to ________ and __________
converts 17-hydroxyprogesterone and progesterone → precursors of cortisol/aldosterone (11-deoxycortisol, 11-deoxycorticosterone)
257
21-hydroxylase deficiency
aldo, cortisol, sex steroid levels?
decreased aldosterone
decreased cortisol
increased sex steroids
258
11-hydroxylase
converts ________ and _______ to ________ and ___________
11-Deoxycortison and 11-deoxycortisol to corticosterone and cortisol respectively
259
11-hydroxylase deficiency
aldo, cortisol, sex steroid levels?
some aldosterone still made --> decrease Na+ wasting --> HTN
Decreased cortisol
Increased sex steroids
260
17-hydroxylase
converts ________ and _______ to ________ and ___________
converts prenenolone and progesterone to 17-OH pregnenolone and 17-OH progesterone respectively
261
Transport of Glucocorticoids (cortisol) in Plasma
10% circulates in free form (regulated form)
90% bound to proteins → 75% bound to cortisol binding globulin (CBG), 15% bound to albumin
262
Benefits of cortisol being bound to proteins in blood (CBG and albumin)
```
Increases plasma concentration of hormone
Prevents excretion by kidney
Prolongs half-life
Reservoir of extra hormone
NOT biologically active
```
263
Free cortisol actions
regulated form
Binds cortisol receptor in cytosol
HSP-90 (heat shock protein) holds cortisol receptor in cytosol, and dissociates from receptor after cortisol binds receptor
Allows cortisol-receptor complex to travel into nucleus
264
Actions of cortisol (11)
1) Stimulate gluconeogenesis in liver 2) Increase proteolysis in muscle
3) Muscle weakness
4) Thinning of skin, increased capillary fragility (easy bruising)
5) Interfere with Ca2+absorption/bone formation → osteoporosis, bone fx
6) Adipose tissue deposition on trunk, abdomen, and face, and fat mobilization from extremities
7) Increase water excretion (inhibit ADH function)
8) Increase gastric acid secretion
9) Paracrine effect on adrenal medulla → stimulate synthesis and activity of phenyl-N-methyl transferase (PNMT) → increase epi/NE production
10) Anti-inflammatory and immunosuppressant effects
11) Cushing’s disease
265
Regulation of ACTH production and release
3 levels of control
1) Hypothalamus, CRH → anterior pituitary, ACTH
- Ca2+-dependent ACTH release via AC activation
- POMC (proopiomelanocortin) gene transcription activated
2) ACTH → zona fasciculata and reticularis, cortisol
3) Cortisol → feedback onto hypothalamus and pituitary to inhibit CRH and ACTH
266
Actions of ACTH
ACTH increases cAMP levels in adrenal cortex
→ increase rate of synthesis of pregnenolone, LDL uptake, and transport of cholesterol into mitochondria
267
Mineralocorticoids (aldosterone)
Secretion regulated by RAAS - angiotensin II = major stimulus for aldo secretion
Aldo secretion increased in response to high plasma K+
Actions: stimulate Na+ absorption, K+/H+ excretion to maintain or increase blood volume
268
Catecholamine synthesis:
occurs in ________ cells of adrenal __________
chromaffin cells
| adrenal medulla
269
Catecholamine synthesis
1) ________ converts tyrosine --> __________
2) DA --> taken up into secretory granules via _______ --> DA converted into ________ in vesicle by __________
3) NE transported out of vesicle and converted into _________ by ____________
4) Epinephrine pumped back into vesicle
1) Tyrosine hydroxylase converts tyrosine → L-DOPA
2) Dopamine → taken up into secretory granules via VMAT1 (vesicular monoamine transporter) → DA converted to NE in vesicle by dopamine B-hydroxylase
3) NE transported out of vesicle and converted into epinephrine by PNMT (phenylethanolamine N-methyltransferase)
4) epinephrine pumped back into vesicle
270
Mechanism of epinephrine release
Final common pathway of activation is greater splanchnic nerve ACh release onto chromaffin cells
1) ACh binds nicotinic ACh receptors (nAChRs) on chromaffin cells → depolarization → Ca2+ increase in cell
2) ACh binds muscarinic ACh-R → Gq → IP3 → Ca2+ release
- Takes longer, lasts longer
271
Body’s Integrated Response to Stress
2 regions of activated - each have what effects?
1) Stressor activate CRH, ADH, NE neurons in HYPOTHALAMUS
- CRH → activate ACTH-cortisol axis
- Stimulation of splanchnic nerve → release epinephrine from adrenal medulla
2) LOCUS COERULEUS → releases NE
→ arousal
272
Adrenergic recptors: a1 and a2
mechanism
preferentially activated by what?
activated preferentially by NE**
A2 → G1 → inhibit cAMP production
A1 → Gq → PLC → increase Ca2+ and PKC
273
B-adrenergic receptors: B1 and B2, B3
mechanism
preferentially activated by what?
B1, B2, B3 → Gs → AC → cAMP
| Activated preferentially by epinephrine
