Endocrinology, lecture on Adrenal Axis
USD Department of Biology
Endocrinology
Summers
Hormones
Endocrine Glands
Receptors
Homeostasis
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Steroids
Adrenal Axis
Adrenal Medulla
Osmotic-Pressure Balance
Reproductive Endocrinology
Prolactin
Somatic Axis
Growth Factors
Immune Factors
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Neurosteroids
Neuropeptides
Endocrine Evolution
Figures for Endocrionology
text:Vertebrate Endocrinology5th Edition - David O. Norris:
Read pages 261-273, 280-284, 291-299 for this lecture
acronyms    end
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.  -feedback ®  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  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.  cAMP ®  transport of free cholesterol
				 to a mitochondrial P450scc	


				i.  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.  blood glucose, available for the brain


				ii. ¯ gluconeogenesis/glycogenogenesis,
				     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.  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. 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,
					     plasma NE, Epi from adrenal

						(a) very fast

						(b) eyespot

				ii. Acute + (possibly) Chronic

				 CRH ®  ACTH ®  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 ®  IP3 ®  DG

							ii) DG ®  2-AG (2 arachidonylglycerol)

							iii) 2-AG retrograde signal to Amygdala Glu terminal

							iv) 2-AG binds Cb1 receptor

							v) Cb1 ®  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  circannual levels
				     during the reproductive season


				iv. Humans peak just before awakening

					(1)  blood sugar and catecholamines

XVI. Adrenal Medulla