Neuroendocrinology Flashcards
Name the nuclei of the hypothalamus
Preoptic, paraventricular, ventromedial, arcuate, suprachiasmatic
Function of preoptic nucleus
Thermoregulation, contained GnRH neurons
Paraventricular nucleus secretes
Oxytocin, vasopressin/ADH, and TRH
Loss of vasopressin leads to
Diabetes insipidus and hypernatremia
Continuous vasopressin secression leads to
SIADH and hyponatremia
Function and product of ventromedial nucleus
Feeding, fear, thermoregulation, and sexual activitiy Secretes oxycotocin (inhibits appetite, stimulates sexual behavior)
Arcuate nucleus secretes
POMC, NPY, GHRH, kisspeptin, dopamine
Suprachiasmatic nucleus controls
Circadian rhythms
Suprachiasmatic nucleus location
Above optic chiasm
What are neurophysins at what do they do?
Carrier proteins which transport the hormones oxytocin (NP1) and vasopressin (NP2) to the posterior pituitary from the paraventricular and supraoptic nucleus of the hypothalamus
Location of genes for neurophysin 1/2
Chromosome 20
Location of GnRH and other factor release into portal system for delivery to anterior pituitary
Median eminence
Location of median eminence
Base of the third ventricle
Internal zone of median eminence contains:
Lined with tanycytes (ependymal cells), contains portal capillary loops and fibers of supraopticohypophysial tract
External zone of median eminence contains:
fibers from parvocellular neurons throughout forebrain
Long feedback loop
Effect of circulating levels of target gland hormones on the hypothalamus and pituitary
Short feedback loop
Negative feedback of pituitary hormones on their own secretion by inhibitory effects of hypothalamic releasing hormones [retrograde flow in portal system]
Ultrashort feedback loop
Inhibition by the releasing hormone on its own synthesis
AAs in GnRH
10
AAs in TRH
3
AAs in oxyctocin
9
Stimulatory feedback on GnRH
Norepi, NPY, Kisspeptins, Oxytocin (inhibits degradation enzymes), activin (stimulates GnRH-R)
Inhibitory feedback on GnRH
Dopamine, serotonin, opioids (beta-endorphin and dynorphin), CRH, melatonin, PRL, GABA
GnRH pulsatility in follicular and luteal phases
Follicular phase: High frequency, low amplitude -> LH
Luteal phase: Low frequency, high amplitude -> FSH
Kallman’s syndrome pathogenesis
Failure of olfactory and GnRH neuronal migration from olfactory placode
Kallman’s syndrom mutations (2)
• X-linked (most common): Anosmin 1
Encoded by KAL gene on X chromosome (short arm)
Part of fibronectin family, responsible for cell adhesion and protease inhibition
• Autosomal:
Fibroblast growth factor receptor (FGF-1 R) and prokinecticin
Both autosomal recessive and autosomal dominant forms
GnRH agonist substitution
Sub of Gly at position 6 or replacing C-termin glycine-amine which inhibits degradation
GnRH agonist response
Initially due to desensitization (uncoupling of receptor for effector system)
Sustained response 2/2 loss of receptors by downregulation and internalization
GnRH antagonist molecular change
Multiple amino acid subs
GnRH antagonist function
Bind to GnRH receptor and competitively inhibit endogenous GnRH
Pituitary somatotropes: % and product
50%, GH
Pituitary lactotropes: % and product
10-25%, PRL
PItuiitary corticotropes: % and product
10-20%, Pro-opiomelanocortin (POMC) –> cleaves to ACTH, beta-lipotropin, and MSH
Pituitary thyrotropes: % and product
10%, TSH
Pituitary gonadotropes: % and product
10%, FSH/LH
Most common deficiencies in hypopituitarism
PRL and GH
next MC: gonadotropins > ACTH > TSH
LH pulse freq throughout menstrual cycle
- Early follicular phase – q 90 minutes
- Late follicular phase – q 60-70 minutes (highest preparing for pre-ovulatory surge)
- Early luteal phase – q 100 minutes
- Late luteal phase – q200 minutes (slowest preparing for luteal rise in FSH)
Male LH deficiency dx and tx
dx: measure testosterone
tx: testosterone replacement if secondary hypogonadism and not interested in fertility
Female LH deficiency dx and tx
dx: measure FSH/LH/E2, progesterone withdrawal
tx: E2/P4 replacement if not interested in fertility
ACTH deficiency test/results
AM serum cortisol
• ≤ 3 mcg/dL, confirms low ACTH
• ≥ 18 mcg/dL, ACTH secretion is adequate
• In between, do ACTH reserve test
ACTH reserve tests (3)
Metyrapone test, insulin-induced hypoglycemia test, cosyntropin stim test
Metyrapone test
Blocks 11β-hydroxylase (CYP11B1) which converts 11-deoxycortisol to cortisol, should cause increase in ACTH and increase in steroidogenesis
- Normal: Decline in AM serum cortisol < 5mcg/dL (demonstrates metyrapone adequately blocking) and 8AM 11-deoxycortisol concentration 7-22 mcg/dL - Abnormal: 11-deoxycortisol < 7 mcg/dL + suppressed cortisol
Insulin-induced hypoglycemia test
Hypoglycemia induced by insulin is sufficient stress to stimulate ACTH and therefore cortisol
Normal: Cortisol ≥ 18 mcg/dL and glucose < 50 mg/dL after 120 min
Cosyntropin stim test
Adrenal glands atrophy when not stimulated in prolonged period so do not secrete cortisol in response to ACTH
Normal: serum cortisol ≥ 18 mcg/dL after 60 minutes
Tx ACTH deficiency
hydrocortisone rx (cortisol replacement) –> note: may unmask diaBetes insipidus
Prolactin forms (3) and size
o Monomeric (23 kDa) – most biologically active (80-90%)
o Dimers/trimers (50-60 kDa) – less biologically active (big prolactin)
o Large polymers (>100kDa) – less biologically active
PRL feedback regulator
Pit-1 (regulated by PROP-1) - most likely cause of hypo/hypo
Stimulatory feedback to PRL
- TRH, VIP, EGF, GnRH, GHRH, Serotonin
- Estrogen and opioids act via inhibition of dopamine
- Demonstrated in vitro: growth factors, Angiotensin II, vasopressin
- Medications: phenothiazines, amphetamines, reserpine, opiates, alpha methyl dopa, butyrophenones, TCAs, metoclopramide (dopamine antagonist); NOT diazepams at normal doses
Inhibitory feedback to PRL (3)
- Dopamine (via receptor that inhibits G-protein/cAMP activity)
- GABA
- NPY (via inhibition of dopamine)
Etiologies of hyperprolactinemia
• Physiologic – exercise, lactation, pregnancy, sleep, stress
• Pharmacologic – see above
• Pathologic:
• Hypothalamic-pituitary stalk damage (i.e. radiation, trauma, tumors)
• Pituitary (i.e. prolactinoma, GH-secreting tumor, macroadenoma)
~10% of adenomas that secrete prolactin also secrete GH, leading some to recommend measuring the serum IGF-1 concentrations, even in women with microadenomas
25-40% of GH-secreting tumors secrete PRL
• Systemic disorders (i.e. cirrhosis, renal failure, Cushing’s)
Mechanism of hyper-PRL induced amenorrhea
Hyperprolactinemia inhibits pulsatile hypothalamic GnRH secretion, resulting in decreased levels of pituitary FSH and LH secretion (no galactorrhea bc low estrogen due to low gonadotropins)
Tx hyperprolactinemia induced amenorrhea
- Desires fertility: Bromocriptine vs cabergoline
* Not trying to conceive: OCPs
Sequelae of PRL deficiency
Inability to lactate
GH deficiency testing
o Test: Measure IGF-1 and/or do provocative test (insulin-induced hypoglycemia or arginine/GHRH)
o For insurance coverage, must have:
• low IGF-1 concentration or poor GH response to two standard stimuli, and
• hypopituitarism due to pituitary or hypothalamic damage
GH deficiency effects in adult
unfavorable serum lipid profiles, increased body fat, decreased muscle mass, decreased BMD, diminished sense of well-being
