Steroid-based DrugsAdrenocortical HormonesSlide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Sex SteroidsSlide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35BIMM118Steroid-based Drugs•Adrenocortical HormonesBIMM118Adrenocortical HormonesAdrenal gland:•Medulla:–produces Epinephrine(stimulated by sympathetic impulse)•Cortex:–Zona glomerulosa – produces Aldosterone(stimulated by Angiotensin II and ACTH)–Zona fasciculata – produces Glucocorticoids(stimulated by ACTH = Corticotropin)–Zona reticularis – produces Androgens(physiological role unclear)BIMM118Adrenocortical HormonesSteroid hormone synthesis:•Pregnenolone synthesis is rate-limiting step•C21 hydroxylase: –Prevents hydroxylation of C17 (-> c)=> Only mineralocorticoids•C17 hydroxylase: –Hydroxylation of C17 (-> f, g) can be followed by hydroxylation of C11 and C21 (-> h, j, k)=> Sex hormones and glucocorticoids •P450C17 hydroxylase: –Produces 17-Keto-steroids (-> l) => Sex hormonesBIMM118Adrenocortical HormonesSteroid hormone classification:•Progesterone: –C21–C 3: =O–C17: -OH or =O•Mineralocorticoids: –C21–C21: -OH–C3: =O•Glucocorticoids : –C21–C21, C17: -OH–C 3: =O–C11: -OH or =O•Estrogens : –C18–C17: -OH or =O–C 3: -OH•Androgens : –C19–C17: -OH –C 3: =OBIMM118Adrenocortical HormonesGlucocorticoids (GC):•Inhibit all phases of inflammatory reaction•Promote fetal development (lungs)•Inhibit NFB nuclear translocation => transcription of proinflammatory mediators is prevented•Upregulate lipocortin => inhibits PLA2 => no PG and LT synthesis•Undesirable effects of increased GC:–Immune suppression–Increased glucose release (=> “steroid diabetes”)–Glucose coverted to fat => adiposity–Increased protein catabolism => muscle atrophy–Salt and water retention (increased GC lead to reduction in ACTH => decreases levels of aldosterone) => hypertension–OsteoporosisBIMM118Adrenocortical HormonesGlucocorticoids (GC):•Adrenal cortex failure (= Addison’s disease)Lack of GC production:–Chronic fatigue and muscle weakness.–Loss of appetite, inability to digest food, and weight loss.–Low blood pressure (hypotension) –Blotchy, dark tanning and freckling of the skin (feedback missing => increased corticotropin)–Blood sugar abnormalities–Inability to cope with stress•Adrenal cortex tumors (= Cushing Syndrome)GC overproduction–Upper body obesity–“Buffalo hump”–Red, round face–Hypertension–Water retention–Thin skin and bruising–Poor wound healingBIMM118Adrenocortical HormonesGlucocorticoids (GC):Clinical uses:•Allergic Rhinitis•Rheumatoid Arthritis•Asthma•Multiple Sclerosis•Carpal Tunnel Syndrome•Dermatitis•COPD•Osteoarthritis•Gout•Psoriasis•Inflammatory Bowel Disease •Sinusitis•Lupus Erythematosus•Many conditions flare up if GC therapy is discontinued due to adreno-corticol atrophyBIMM118Adrenocortical HormonesGlucocorticoids (GC):•Hydrocortison (= Cortisol)–Main glucocortocoid in humans–Also binds mineralocorticoid receptor (Cortison does NOT)–Used for replacement therapy (Addison’s Disease)–Otherwise mostly topical application due tosodium-retaining effectsBIMM118Adrenocortical HormonesGlucocorticoids (GC):•Prednisone–Inactive until converted to •Prednisolone–Drug of choice for systemic application–Lower sodium-retaining effectsCH3CH3OOOHOHOHPrednisoloneCH3CH3OOOHOHOPrednisoneBIMM118Adrenocortical HormonesGlucocorticoids (GC):•Triamcinoline–Stronger anti-inflammatory (5x) than cortisol–No sodium-retaining effect Halogenated GC•Betamethasone•Dexamethasone–30x more potent than cortisol–No water and sodium retaining effectsCH3CH3OOOHOOHOCH3CH3OOOHOHOHFCH3CH3CH3OOOHOHOHFCH3BIMM118Adrenocortical HormonesGlucocorticoids (GC):•Administration–Oral–Nasal–Cutaneous–IV–InhalationBIMM118Steroid-based Drugs•Sex SteroidsBIMM118Sex Steroids•Female reproductive cycle–Gonadotropin Releasing Hormone(GnRH) = Gonadoliberinstimulates release of –Follicle stimulating hormone(FSH) = Follitropin and–Luteinising Hormone(LH) = Lutropinwhich trigger production of–Estrogens (E) and Gestagens (G)which in turn negatively regulate–Pituitary (E+G) and Hypothalamus (G)hormone productionBIMM118Sex Steroids•Female reproductive cycle–Cycle length varies from 21-35 days•Menstruation 3-6 days–First (= Proliferative) phase:•Variable (7-21 days)•FSH and LH promote follicle development•One follicle becomes the Graafian follicle(the rest degenerate)•Graaffian Follicle:–Consists of thecal and granulosa cellswhich surround the ovum•FSH-stimulated granulosa cells produce estrogens from androgen precursors generated by LH-stimulated thecal cells•Estrogens are responsible for the proliferative phase: increase in thickness and vascularity of endometrium; secretion of protein+ carbo-rich mucus•Constant low estrogen inhibits LH/FSH production BUT high estrogen cause surge of LH production => swellign and rupture of Graafian follicle = OvulationBIMM118Sex Steroids•Female reproductive cycle–Second (= Secretory) phase:•Secretory phase constant (~ 14 days)•LH-stimulated ruptured follicle developsinto Corpus luteum which secretsProgesterone •Progesterone (Pg) is responsible for the secretory phase: endometrium becomessuitable for implantation; mucus thickens•Thermogenic effects of Pg =>body temperature increase 0.5º C•Without implantation: Pg secretion stops=> menstuation is triggered•With implantation: continued Pg productionwhich (via inhibition of LH and FSH prod.) blocks further ovulation•Chorion (“precursor” of placenta) secreteshuman chorionic gonadotropin (HCG) whichmaintains endometrium lining throughoutpregnancy (HCG -> see pregnancy test)BIMM118Sex Steroids•Female reproductive cycleBIMM118Sex SteroidsEstrogensAll produced from androgen precursorsThree main endogenous estrogens:•Estradiol–Primary estrogen in humans–Breast development–Improving bone density–Growth of the uterus –Accelerating bone maturation and epiphyses closure–Development of the endometrium to support pregnancy–Promoting vaginal mucosal thickness and secretions–Increase HDL•Estrone•Estriol–only during pregnancy (made by fetus)BIMM118Sex SteroidsEstrogens–Estrogens induce
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