Endocrinology, lecture on Steroids
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 61-80 for this lecture
acronyms    end
XIV. Steroids 			

	A. Cyclopentanoperhydrophenanthrene

		1. number from left top counterclockwise around 2 bottom rings, 
		   then clockwise around the top hexane, ccw around pentane

			a. 18 & 19 following 17 between rings

				i. 20... following 17 on extensions


		2. addition of the  18th C = estrane
		                         19th = androstane
		                         21 = pregnane


		3. lipoidal compounds built from cholesterol

			a. androgens, estrogens, progestogens, corticoids,
			   calcitriol (vitamin D)


	B. Biosynthesis

			several steps/enzymes
		1. Acetyl CoA ---------------® cholesterol = C27 steroid

			a. cytochrome P450 involved in many steps of steroid biosynthesis


			b. P450scc

				i. scc = side chain cleaving ® yields C21

				ii. P450scc and P450C11  in mitochondria

					(1) chemiosmotic phosphorylation
					    cytochrome P450 enzymes
					    are also in mitochondria


		2. next critical junction: pregnenolone = C21

			a. all steroid hormones begin here


		3. first direction: progesterone made from pregnenolone


			a. enzyme necessary =
			   D5,3 b-hydroxysteroid dehydrogenase  (3b-HSD)


				i. sER


		4. 2nd alternative: 17 a-hydroxypregnenalone converted to T   or

			 17 a-hydroxyprogesterone (from P)  to Testosterone

			a. T ® 5a-reductase ® 5a-DHT


		5. Estrogens made from T


		6. 3 paths from P to Cortisol or Corticosterone

			a. 11 b-hydroxylase necessary = P450C11


		7. Corticosterone to Aldosterone


	C. Progestogens

		1. Pregnenolone is the precursor to all steroid hormones


		2. P is the 1o plasma progestogen


		3. P produced in the Corpus Luteum

			a. Luteinized (LH) ovarian follicle

				i. follicle previously (before luteinization + ovulation)
				   makes E2


		4. P produced by the placenta


		5. Neuroactive progestogens made in the brain

			a. either de novo or by metabolism


			b. P ® allopregnanolone (THP or 3a-OH-DHP)


				i. catalysed by 5a-reductase
				    + 3a-hydroxysteroid oxidorecuctase


			c. THP binds to a special site on the GABAA-R

				i. allosterically increases Cl- influx


		6. Receptors are nuclear


			a. also membrane receptors + GABAA

				i. amphibian eggs   brain


		7. Functions of  P


			a. uterus


				i. stimulates secretory uterine glands in endometrium
				                        (uteroglobin)

					(1) preparatory to implantation

					(2) maintains gestation (pro gest erone)


				ii. relaxes myometrium


			b. mammary development

				i. inhibits lactogenesis


		8. Neuroactive THP and THDOC are anxiolytic,
		   sedative and anticonvulsant

			a. DHEAS has the opposite effect


		9. Catabolized in the liver and kidney

			a. as are other steroids


	D. Androgens

		1. Produced in the interstitial or Leydig cells of the testes


			a. and by the follicle cells of the ovary

			b. and by the adrenal cortex


			c. and by glial cells in the brain


			d. stimulated by LH


		2. Testicular (Strong) Androgens = T

			a. T is most often a prohormone
			   converted to to dihydrotestosterone at the
			   tissues by 5a-reductase

			b. T may act as a hormone
			   (when DHT conversion is small; as in muscle)

			c. Androgen Receptor affinity is greatest for DHT

				i. A-R is up-regulated by androgens


			d. in fatty tissues, such as the brain, T is 
			   converted to an estrogen and then binds to E-R


		3. Weak (Adrenal) Androgens = dehydroepiandrosterone (DHEA),
		   DHEA-S, Androstenedione

			a. major type of androgen found in females


		4. Neuroactive DHEA and DHEAS

			a. catalyzed from pregnenolone by P450C17a

			
			b. inhibit GABAA  Cl-, stimulate NMDA(Glu)  Ca++ channels


		5. Functions of androgens

			a. stimulate male secondary sex characteristics
			   - prostate, seminal vesicles, facial hair

			b. stimulate spermatogenesis

				i. acts here as a paracrine

				
			c. stimulate development

				i. of masculine genitalia (DHT)

				ii. Wolffian duct ® Vas Deferens

				iii. functional (masculinizing) differentiation of the brain
						via/with E2

			d. sexual behavior

				i. males and females

				ii. peripheral androgens need not be present
				    at the time in humans

					
			e. stimulatory effect on erythropoiesis

			
			f. anabolic effect on bone and muscle


		6. carried in the blood by sex hormone binding proteins (SBP)
		   along with estrogens (TEBG)

			a. also to albumin and CBG


	E. Estrogens

		1. Produced by the follicle cells of the ovary
		   (before luteinization) = E2 stimulated by LH

			a. P450aro = aromatase converts T

			b. and by brain and adipose tissue


		2. Made by the feto-placental unit during pregnancy

			a. P is made in the placenta

			
				i. transferred to the fetal zone of the adrenal cortex
				   and converted to DHEA
	   
				ii. DHEA to DHEA-S in the liver

			b. DHEAS to Estriol (E3) in the placenta

				i. to maternal blood stream

				ii. serves as estrogen supply during pregnancy

		3. estrone (E1) is the primary estrogen during menopause

		
		4. Carried by SBP and albumin
		
		
		5.  Nuclear receptors E-Ra and E-Rb

		
			a. E-Ra in uterine endometrium
			   hypothalamus, mammary tissue


			b. E-Rb in brain, bone, heart
			   lungs, intestine, and prostate

			   
			c. E-R up-regulated by E ; down-regulated by P or T
	
			
			d. also neural membrane-bound E-R


		6. Functions of Estrogens

			a. an estrogen is defined as
			   any hormone which will stimulate growth of the uterus

				i. endometrium during each menstrual/estrous cycle

				ii. other 2o sex organs


			b. prepare mammary gland for lactogenesis


			c. E2 modulates positive feedback for LH surge at ovulation


			d. modify sexual behavior

				i. stimulate lordosis

				ii. converted from T masculinizes brain


					(1) necessary for male sexual behavior


			e. angiogenic


			f. anabolic:  osteoblast activity
			   (prevents osteoporosis)


	F. Corticosteroids


		1. Two types: Glucocorticoids (B or F) and Mineralocorticoids (Aldo)

			a. both C21 steroids

			
		2. Protein carriers

			a. CBG = corticosteroid binding globulin = transcortin

				i. binds glucorticoids and progestogens with high 
				   affinity, Aldosterone only very weakly


		3. Receptors - Nuclear and Membrane

			a. Nuclear

				i. MR or Type I - binds Aldosterone, B, &
				   F with high affinity

					(1) site dependent specificity

					   (a) kidney - aldosterone binds because of
					      high concentrations of CBG and 11b-HSD =
					      P450C11b protecting it from glucocorticoids
					      (by breaking them down)

					   (b) limbic area of the brain
					      (incl. hippocampus, amygdala, striatum)
					      lack CBG and P450C11b;
					      B binds and aldosterone antagonizes


				ii. GR or Type II bind glucocorticoids,
				    10X lower affinity than Type I

					(1) only significantly occupied during stress
					    and at the circadian peak


			b. Membrane receptors

				i. found in an amphibian & bird brain

					(1) rapid behavioral responses to B

						(a) other species have rapid behavioral
						    responses to glucorticoids

				ii. THDOC binds to GABAA-R
				
				
		4. Mineralocorticosteroids = Aldosterone (Aldo)

			a. produced in the zona glomerulosa from B

				i. outer layer of the adrenal cortex

					(1) 18-hydroxylase  necessary


			b. Aldo secretion stimulated by Angiotensin II, [K+], & ACTH

				i. Aldo does not feedback on ACTH

				
			c. carried only weakly by CBG and albumin, mostly free
			
			
			d. binds to M-R (Type I) only  	(not to G-R or Type II)


			e. Functions of Aldo

				i. conserve Na+ and excrete K+ from renal tubules


		5. Glucocorticosteroids = corticosterone (B),
		    cortisol (F, hydrocortisone), deoxycorticosterone (DOC),
		     tetrahydro-DOC (THDOC), 11-deoxycortisol (S), cortisone


			a. made in the zona fasciculata (middle layer) of the 
			   adrenal cortex stimulated by ACTH


				i. P450C11b necessary for B;    P450C17 for F

					(1) presence of C11b or C17 
					    determines which is secreted

						(a) rats, lizards don't have much F,
						    humans & salmon do


				ii. zona reticularis, closest to adrenal medulla, 
				    makes adrenal androgens (some in fasciculata)


				iii. 3 cortical zones are 1 fetal zone during
				     gestation producing DHEA from placental P
					 to make E3 (in the placenta)


			b. THDOC made in the brain from DOC

				i. 5a-reductase + 3a-hydroxysteroid oxidorecuctase

				ii. stimulates GABAA Cl-


			c. Functions of glucocorticoids


				i. Parturition - conversion of the fetal adrenal is the last
				   developmental change in the embryo before labor begins


					(1) ACTH or F stimulate labor (sheep, not humans)

						(a) by up-regulating OT receptors?


				ii. Development - liver & lung (surfactant)


				iii. lacatation - synergizes with PrL influence on fat metabolism


				iv. Sugar Protein and Fat Metabolism


					(1) blocked uptake (70%) by non-neural cells

						(a) may lead to cell death


					(2) blood glucose

						(a) available to the brain

						(b) liver glycogenogenesis


				v. immune inhibition (redirection)

					(1) redirection of immune cells to periphery
			
					
					(2) reduction in lymphoid tissue and immune cells

					(3) antiphlogistic - topical creams


				vi. inhibition of reproductive systems

					(1) inhibits hormones of the gonadal axis
					   (especially LH) and gonads


				vii. stimulation of catecholamine production (DA, NE, Epi)

					(1) along with ACTH


				viii. increased gastric HCl ® ulcers


					(1) GI tract inhibited by catecholamines


				ix. Stress Hormone

					(1) major component of the endocrine stress response


						(a) inhibited by neural THDOC


					(2) all above functions are important
					    during a stressful situation

XV. Adrenal Axis