Endocrinology, lecture on Adrenal Axis
XV. Adrenal Axis
A. Control of CRH (corticotropin releasing hormone, also CRF) secretion
1. -Negative Feedback of F/B on hypothalamus and hippocampus
a. hippocampus has highest density of G-R
i. amygdala and septum with high G-R density also
2. tracts from the hippocampus inhibit CRH release
a. increased [G-R] increases feedback
b. ñ -feedback ® ñ depolarization of hippocampal neurons
c. [CRH] ¯ in plasma
i. cutting tracts or ablating hippocampus leads to
a hypersecretion of CRH, ACTH, and B/F
ii. hippocampal inhibition indirect via septal
+ bed stria terminalis nuclei
(1) GABA directly ¯ PVN CRH release
3. other parts of the brain are connected to the hippocampus
a. axons from the locus coeruleus terminate
in the hippocampus and secrete NE
i. NE increases hippocampal depolarizations
b. Amygdala reciprocally communicates with hippocampus
4. Amygdalar tracts stimulate CRH release from PVN
a. indirect via bed nucleus of the stria terminalis
i. GABA on GABA disinhibtion
b. directly stimulates PVN
i. Glu excitation
1) blocked by B/F negative feedback activating endocannabinoids
5. Several Neurotransmitters have been shown to affect CRH secretion
a. increase CRH secretion: 5-HT, Epi, ACh, even NE
b. decrease CRH secretion: NE, GABA, and 5-HT
c. NO (nitric oxide is a gaseous transmitter) stimulates
transcription of CRH and CRH-R1 mRNA
i. NO effective in PVN, CeA, hippocampus
6. CRH is made in the PVN
a. but also in the SON, amygdala (CeA),
bed nucleus of the stria terminalis,
locus ceruleus, olfactory bulbs
i. acts as a neurotransmitter
ii. also found in the adrenal, lung, placenta,
pancreas, and gastrointestinal tract
b. CRH is 41 aa long from a 196 aa preprohormone molecule
i. very similar to sauvagine from frog skin
ii. very similar to the urotensins
(1) secreted from the urophysis
(a caudal neurosecretory ganglion) of fish
iii. similar to urocortins in the brain
7. high affinity membrane receptors (KD~ 1nM) in the anterior
pituitary and discrete sites of the brain
a. 2 types: CRH-R1, CRH-R2
i. CRH-R1 for hormonal effects on pituitary (ACTH release)
ii. CRH-R1 + CRH-R2a on neurons,
CRH-R2b on choroid plexus and central blood vessels
b. 2nd messenger is cAMP
8. Functions of CRH
a. stimulation of ACTH secretion
i. increases POMC mRNA transcription
b. inhibits the release of GnRH & LH
i. inhibits sexual receptivity and behavior
ii. acts centrally on many behaviors
c. inhibits GH by ¯ GHRH and ñ somatostatin
B. Control of POMC (pro-opiomelanocortin) production and ACTH
(corticotropin or adrenocorticotropic hormone) secretion
1. CRH, AVP, OT, NE, Epi, VIP, histidine-isoleucinamide, and angiotensin II
all stimulate pituitary secretion of POMC-derived peptides
a. POMC is cleaved into ACTH (39aa), b-endorphin,
b-lipotropin, g-lipotropin, and a-MSH
i. all peptides secreted from the preprohormone POMC
concommitantly
(1) different peptides are secreted
by cleaving POMC in different spots
(a) a-MSH in the intermediate lobe
(b) requires different enzymes
in the secretory vesicles
b. extrapituitray POMC is found in the central nervous system
i. ACTH, bEnd and a-MSH are neurotransmitters
ii. also found in the placenta, female reproductive tract,
ovary, testes, GI tract, lung,
and immune cells (platelets and lymphocytes)
2. CRH is by far the most potent stimulator of ACTH release
a. not a very potent releaser of a-MSH
i. Epi/NE stimulate a-MSH release
ii. DA inhibits a-MSH
3. Potentiation of CRH
a. other ACTH secretogogues, especially AVP,
synergistically enhance the effect of CRH
i. AVP neuron terminals in the median eminence
(1) colocalized with CRH
4. Mechanism of ACTH action
a. pulsatile secretion
b. high affinity membrane receptors = MC2, MC3 (negative feedback)
c. 2nd messenger for MC2: Gs ® AC ® cAMP
d. ñ cAMP ® ñ transport of free cholesterol
to a mitochondrial P450scc
i. ñ RNA, protein synthesis,
phosphorylation and dephosphorylation
e. Ca++ dependent
5. 1o function of ACTH is the production and release of glucocorticoids
a. lipolysis
i. as are other POMC fragments
b. central effects of ACTH
i. homeostasis
(1) blood pressure and thermoregulation
ii.¯ pituitary LH secretion
iii. behavior associated with stress
(1) a-MSH and b-End (+ CRH) also have
behavioral effects associated with stress
(2) b-End has analgesic properities
c. ACTH enhances catecholamine production
C. Corticosteroid function (organismal)
1. Stress
a. all of the cellular functions of F/B serve the function of
increased ability to cope with stressful situations
b. ¯ cellular uptake of nutrients
i. ñ blood glucose, available for the brain
ii. ¯ gluconeogenesis/glycogenogenesis,
ñ mobilization of cellular energy stores
(1) quick enenergy
(2) enhanced by catecholamines
also secreted during stress
c. ¯ & redirects immune function
i. limits swelling, congestion, fever
(all actions of the immune cells and biochemicals)
(1) adrenal axis hormones may be involved in
normal supression of lymphocyte activity
- lymphocytes produce ACTH
ii. ñ immune cell activity in peripheral tissues
d. ¯ reproductive function and behavior
i. also ¯ by CRH and ACTH
ii. ¯ energy output and offspring production
during environmentally inopportune times
(1) drought, famine
iii. ¯ inappropriate behavior and
possibility of predation or loss of foraging time
e. stimulation of catecholamine production
i. activation of sympathetic nervous system
ii. ¯ digestion
iii.ñ awareness
f. stress oriented behavior
i. all stimulated by CRH, ACTH, and F/B
ii. aggression/submission
iii. decreased feeding
iv. obsessive-compulsive disorders,
anorexia-nervosa, alcoholism / addiction
v. depression
vi. changed activity level
vii. hypertension
viii. ¯ sexual behavior
2. General Adaptation Syndrome (GAS) - Hans Selye 1936
a. Alarm Phase
i. Acute
(1) activation of sympathetic NS,
ñ plasma NE, Epi from adrenal
(a) very fast
(b) eyespot
ii. Acute + (possibly) Chronic
ñ CRH ® ñ ACTH ® ñ F/B
b. Phase of Resistance
c. exhaustion
i. leads to death
d. ubiquitous among vertebrates
i. why are individual responses variable?
(1) magnitude and timing
(2) control of feedback
a) B/F bind membrane receptors
i) GP ® ñ IP3 ® ñ DG
ii) DG ® ñ 2-AG (2 arachidonylglycerol)
iii) 2-AG retrograde signal to Amygdala Glu terminal
iv) 2-AG binds Cb1 receptor
v) Cb1 ® ñ Gi ® ¯ AC ® ¯ Glu release
vi) ® ¯ CRF release
b) glucocorticoids down regulate G-R
c) kill hippocampal cells
(3) alteration of biological rhythms
3. Biological Rhythms
a. Ultradian (Pulsatility), Circadian,
Circalunar, Circannual
i. CRH, ACTH and B all pulsatile
b. adrenal axis hormones oscillate rhythmically
in all vertebrates tested
i. the neural oscillator = suprachiasmatic nucleus
secretes AVP (effects CRH?)
ii. stress may phase delay rhythms
(1) 5-HT (stimulates CRH release) also delays rhythms
iii. most species have ñ circannual levels
during the reproductive season
iv. Humans peak just before awakening
(1) ñ blood sugar and catecholamines
