GLOMERULOSA CAPSULE FASCICULATA ALDOSTERONE ADRENAL CORTEX MEDULLA RETICULARIS RETICULARIS CORTISOL MEDULLA MEDULLA ANDROGENS SECRETION OF INDIVIDUAL STEROID HORMONES IS RESTRICTED TO SPECIFIC REGIONS OF THE ADRENAL CORTEX NOREPINEPHRINE EPINEPHRINE

STEROID SYNTHESIS GONADS ADRENAL CORTEX ALL STEROIDOGENIC TISSUES CHOLESTEROL (C27) + 20-keto minus side chain GONADS - SIDE CHAIN PREGNENOLONE (C21) PREGNENOLONE (C21) DEHYDROEPIANDROSTERONE SULFATE (C19 :“DHEA-S”) + 3-keto + 17-OH desmolase sulfotransferase 17-OH PREGNENOLONE DEHYDROEPIANDROSTERONE” ’’DHEA” PROGESTERONE + 21-OH + 17-OH + 3-keto + 3-keto desmolase + 11-OH 17-OH PROGESTERONE ANDROSTENEDIONE (C19) 17-OH PREGNENOLONE CORTICOSTERONE + 21-OH TESTOSTERONE aromatase + 18-ALDEHYDE + 11-OH +3-keto ESTRONE ALDOSTERONE (C21) aromatase need to add drawing of follicle ( time for “round trip”) passive diffusion into colloid space CORTISOL (C21) ADRENAL CORTEX DIHYDROTESTOSTERONE (C19) ESTRADIOL (C19)

SYNTHESIS AND “SECRETION” OF STEROID HORMONES BY ADRENAL CORTEX 1 CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM INTRACELLULAR CHOLESTEROL ESTERS “STORED” IN LIPID DROPLETS UPTAKE OF CHOLESTEROL ESTER FROM LDL AND HDL IN PLASMA KIDNEY StAR facilitates transfer of cholesterol molecules between inner and outer membranes ALDOSTERONE 2 Cholesterol in Intracellular Lipid droplets DIFFUSION OF STEROIDS OUT OF CELL P450scc StAR CORTISOL 4 P450c11 11-HYDROXYLASE 11-DEOXYCORTISOL CO-0RDINATE COLORS p. 931/932 figS 51-2/ 51-3 SSBG AND CORTISOL-BINDING GLOBULIN “ADRENOXIN” ACTH STIMULATES WITHIN MINUTES due TO CHOLESTEROL ALREADY PRESENT IN MITOCHONDRIAL INNER MEMRANE KNOWN TO BE BLOCKED BY INHIBITOR OF PROTEIN SYNTHESIS TRANSLOCATION OF STAR TO THE INNER MEMBRANE IS NOT REQUIRED "STAR" IS NOT REMOVAL OF SIDE CHAIN ANDROGEN PRECURSORS 17-OH PROGESTERONE ENDOPLASMIC RETICULUM OXIDATION OF STEROID NUCLEUS BY SPECIFIC P-450 HYDROXYLASES 5 - PREGNENOLONE (C21) GONADS 3

 5-PREGNENOLONE CHOLESTEROL D C A B D C A B 17-OH PROGESTERONE D D C 18 12 11 19 2 20 21 3 7 8 5 9 A 10 14 15 16 17 1 13 CHOLESTEROL  5-PREGNENOLONE H 3 C C O 12 18 17 20,22-Desmolase P-450scc D 16 11 13 C 1 19 4 6 9 14 15 A 2 10 8 DEHYDROGENASE B D C 12 11 A 13 O H 3 3 7 H 3 C 5 4 6 17-OH PROGESTERONE C O 18 Need to emphasize that steroids can move across membranes 12 18 D OH 16 11 16 13 C 1 19 1 19 9 9 14 15 2 9 9 14 15 10 10 8 2 A 10 10 8 B B 17-HYDROXYLASE 7 7 5 5 O O 6 4 6 PROGESTERONE

Martin Low: delta 5 pathway is favored ANDROSTENEDIONE ESTRONE D D C C 12 18 17 12 18 D D OH 11 16 13 11 13 C C 1 19 1 19 14 15 17 2 9 14 15 A 10 8 2 9 A 17 10 8 B B Aromatase 7 7 5 O 5 HO 4 6 6 4 OH OH 12 18 17 12 18 D D 11 11 13 13 Aromatase inhibitors/ tamoxifen/SERMS C Martin Low: delta 5 pathway is favored C 1 19 1 19 14 15 14 15 2 9 A 2 9 A 10 8 10 8 B B 7 Aromatase 7 5 O HO 5 6 4 6 ESTRADIOL TESTOSTERONE DIHYDROTESTOSTERONE

“PRE-RECEPTOR REGULATION” OF STEROID HORMONE ACTION 11ß-HYDROXYSTEROID DEHYDROGENASE - (11ß-HSD) 11ß- HSD TYPE 1 (LIVER) 11ß- HSD TYPE 2 (KIDNEY) CORTISOL 40 ACTIVE CORTISONE INACTIVE OH CH20H C O C O 12 12 18 OH 18 O OH OH D D 16 11 11 11 13 13 16 C 1 19 1 19 15 9 14 15 2 9 9 14 2 9 A A 8 10 10 8 10 10 B B B 3 3 3 3 7 7 5 5 O O 6 4 6 4

FROM INAPPROPRIATE ACTIVATION LOCAL DEHYDROGENATION OF THE C11 HYDROXYL GROUP ON CORTISOL PROTECTS MINERALOCORTICOID RECEPTORS (MR) FROM INAPPROPRIATE ACTIVATION ALDOSTERONE:MR Kd~1nM CORTISOL or CORTISONE : MR Kd~1nM CORTISOL or CORTISONE : GR Kd~10nM IN SPITE OF THE HIGH AFFINITY OF CORTISOL / CORTISONE FOR THE MR IN VITRO, GLUCOCORTICOIDS DO NOT BIND TO MR IN TARGET TISSUES. THIS IS DUE TO THE “PRE-RECEPTOR INACTIVATION” OF CORTISOL BY 11ß-HSD2 CORTISOL CORTISOL LIVER ADIPOSE GONADS 11ß-HSD2 11ß-HSD1 OXIDATION OF C11 HYDROXYL CORTISOL CORTISONE GR MR KIDNEY,COLON SALIVARY GLAND, HEART RESPONSE nucleus NO RESPONSE nucleus

BINDING AFFINITIES OF STEROIDS TO PLASMA PROTEINS CORTISOL BINDING PROTEIN (CBP) SEX HORMONE BINDING GLOBULIN (SHBG) ALBUMIN HORMONE CORTISOL 76 1.6 0.003 CORTISONE 7.8 2.7 0.005 ESTRADIOL 0.06 680 0.06 PREGNENOLONE 0.18 14 0.06 PROGESTERONE 24 8.8 0.06 17α -OH-PROGESTERONE 55 9.9 0.4 TESTOSTERONE 5.3 1600 0.04