Female Gonadal Hormone Analogs, Antagonists & Inhibitors PDF

ENDOCRINE PHARMACOLOGY: FEMALE GONADAL HORMONE ANALOGS, ANTAGONISTS & INHIBITORS Chapter 40: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 745-771) Chapter 24: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 912-941) Ch 44: Goodman & Gilman’s The Pharmacological Basis of...

ENDOCRINE PHARMACOLOGY: FEMALE GONADAL HORMONE ANALOGS, ANTAGONISTS & INHIBITORS Chapter 40: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 745-771) Chapter 24: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 912-941) Ch 44: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed.  LECTURE OBJECTIVES - 1 1. Explain female gonadal hormone function with respect to a. Stimulation by hypothalamic and pituitary hormones b. Biosynthesis of estrogens c. Mechanism and effects of conditions with altered hormone levels d. Biological targets for drug therapy 2. Explain significant aspects of estrogen/progesterone drugs a. Structure and relationship to function b. Mechanism of action and pharmacokinetics c. Indications, contraindications, and adverse effects 3. Explain significant aspects of anti-estrogen/progesterone drugs a. Structure and relationship to function  PHARMACOLOGICAL AGENTS COVERED IN THIS LECTURE 1 of 2 Estrogen analogs (ER agonists) Selective ER agonist  estradiol /antagonist  ethinyl estradiol  tamoxifen  conjugated estrogens  toremifene  esterified estrogens  Bazedoxifene ER Partial Agonists Estrogen Synthesis  clomiphene Inhibitors ER Antagonists Beco m  exemestane (Aromasin) es a  fulvestrantn ta g o ni s  anastrozole (Arimidex) t in p rese n ce o f fuletrozole l l ag o ni s (Femara) t  PHARMACOLOGICAL AGENTS COVERED IN THIS LECTURE 2 of 2 Progestin analogs (PR agonists)  progesterone  medroxyprogesterone PR Partial  levonorgestrel Agonists  megestrol  danazol  norethindrone PR Antagonists  drospirenone  mifepristone  HYPOTHALAMUS- PITUITARY - ENDOCRINE AXES 1. Hypothalamus produces (releasing) hormones / biomolecules to stimulate (+) or inhibits (-) the pituitary 2. Pituitary responds  synthesizes and releases specific hormones that enter the circulation 3. Circulating hormones act on specific endocrine glands/ tissues that respond by producing a biological effect HPG: hypothalamus – pituitary – Gonads (F) Harrison’s Principles of Internal Medicine, 18 th ed. Fig 44-2: Goodman & Gilman; 13th ed. Fig 40-5: Katzung; 14th ed.  GONADAL HORMONES estrogen testosterone progesterone ethinyl estradiol oxandrolone  PRODUCTION OF FEMALE STEROID HORMONES Estrogens Mature, premenopausal women (ovaries) Postmenopausal women and men (adipose tissue) Pregnancy (placenta) Progestins Ovaries, testis, and adrenals  TARGETS AND PHARMACOLOGICAL AGENTS Aromatase: enzymatic aromatization of steroid ring A  Converts androgens to estrogens  Inhibitor: anastrozole Estrogen receptors: endogenous agonist – estradiol/ estrone/ estriol  involved in female maturation, bone density and pregnancy  Agonist: ethinyl estradiol Partial agonist: clomiphene  Selective Ag/ Antag: tamoxifen Antagonist: fulvestrant Progesterone receptor: endogenous agonist - progesterone  NATURAL ESTROGENS  Estradiol (17β-estradiol; E2)  Major secretory estrogen of the ovary  Estrone (E1)  Produced in the liver from estradiol or androstenedione  Estriol (E3)  Produced in the liver from estradiol or  RELATIONSHIP BETWEEN ESTRADIOL AND ESTROGEN ANALOGS OH O OH H H H Na O H H O H H H H S HO O O HO Ethinyl estradiol Conjugated estrogens Estradiol OH N O OH H H HO F F Fulvestrant F S HO O F F Diethylstilbestrol Tamoxifen Diethylstilbestrol Fulvestrant ESTROGENIC COMPOUNDS  CELLULAR RESPONSE TO ESTROGEN Genomic effects will be dominant  Various non-genomic effects (granulosa cell Ca2+ uptake) Type I nuclear receptor predominantly found in nucleus Two ER isoforms; both found in many tissues, but ratios vary  ER-a: female reproductive tract and mammary glands  ER-b: bone, vascular endothelial cells, prostate  Estradiol binds both isoforms with equal affinity  CELLULAR RESPONSE TO ESTROGEN Ligand binds activation function-2 domain (AF2: ligand)  Conformational change and co-repressor (HSP) release  Receptors dimerize, bind estrogen response element (ERE)  Recruit necessary co-activators  Transcription of target genes Antagonists bind similarly  Can also induce dimerization  Conformation is different  Recruits co-repressors E Estradiol T Tamoxifen Tissue specific effects  ERa / ERb isoform distribution  CELLULAR RESPONSE TO PROGESTERONE Progesterone nuclear receptors  Two isoforms with identical ligand binding domains  Nuclear receptor: has DNA binding and N-terminal domains  Unlike estrogen receptors, PRs require a D4-A ring (3- ketone)  Agonist binding results in similar cellular events as ER  Conformational change, co-repressor release, receptor phosphorylation, dimerization, DNA binding to PRE, histone acetylation, gene transcription (different genes from ER)  Antagonists also induce dimerization and DNA binding  Altered conformation from agonist bound PR (like ER)  Recruit co-repressors and histone deacetylases  Enhanced DNA interactions with nucleosomes Inhibit stimulation of receptor  CONDITIONS BENEFITED FROM THERAPY  Agonists of ER and/or PR  Hormone-deficiency  hormone replacement  Primary hypogonadism  Post-menopause  Excessive ovarian androgen secretion  Hirsutism, amenorrhea  Hormonal contraceptives  Typically ER / PR agonist combination  Goal is to simulate pregnancy level hormones  CONDITIONS BENEFITED FROM THERAPY  Antagonists / Inhibitors of ER / PR  Breast cancer  ER partial agonists and antagonists,  Aromatase inhibitors  Hormonal contraception (ER partial agonist)  Infertility and ovulation (ER partial agonist)  Pregnancy termination (PR antagonist)  Precocious puberty (aromatase inhibitor)  ESTROGEN & PROGESTERONE RECEPTOR AGONISTS ESTROGEN ANALOGS Estrogen receptor agonists  Conjugated estrogens (Premarin)  Esterified estrogens (Cenestin, Enjuvia, Menest)  Estradiol (Estrace, others)  Estradiol transdermal (Estraderm, others)  Estrone (Menest)  Estropipate (Ogen)  RX HORMONAL CONTRACEPTIVES All are indicated to prevent pregnancy  Primary mechanism is by preventing ovulation  Additional effects that reduce the probability of implantation  Changes to cervical mucus, uterine endometrium, uterine tubes Some contraceptives have additional indications  Premenstrual dysphoric disorder  Yaz (EE/drospirenone)  Acne  Estrostep (EE/norethindrone), Ortho tri-Cyclen  HORMONAL CONTRACEPTIVES: ADVERSE EFFECTS Estrogen levels  Very low dose to low dose (most common, reduce EE ADEs)  High dose (break through bleeding, DDIs reducing efficacy) Mild ADEs associated with hormone levels  Estrogen too low  Breakthrough bleeding (early), light menses, vaginal dryness  Estrogen too high  Bloating, breast tenderness, nausea, weight gain, fibroid growth  Progestin too low  Breakthrough bleeding (late), heavy menses, no withdrawal bleeding  Progestin too high  Decreased libido, depression, low energy, noncyclical weight gain  Androgenic - acne, hirsutism, cholestatic jaundice, increased libido  ER AGONISTS: MOA & SAR Mechanism of action OH  activate estrogen receptors H  Activity in reproductive (ER-a) and H H  Activity in bone/vascular (ER-b) tissues HO  Esters and conjugated estrogens: slow release and Estradiol recirculation  Ethinyl derivatives: prevent oxidation of C17 hydroxyl to estrone Structure activity relationship  Aromatic A ring and C3-OH are essential for activity  Distance between C3-OH and C17-OH is important  C17-OH (versus ketone) is important for activity  Four ring structure not required to activate receptors  ER AGONIST ANALOGS Ethinyl estradiol OH  17a-alkyl groups increase stability R2 H  Prevents oxidation to estrone H H R1O Estradiol R1, R2 = H Conjugated estrogens Ethinyl estradiol R1 = H; R2 = CCH Mestranol R1 = CH3; R2 = CCH  Prodrugs that require hydrolysis of 3-sulfate  Charged sulfate increases water solubility and half- life (EHR) O  Requires hydrolysis in GI by bacteria (DDI w/ H antibiotics) Na O O H H S O O Conjugated estrogens  ER AGONISTS & SIDE/ADVERSE EFFECTS  Increased risk for estrogen dependent cancer  Contraindicated w/ existing risk factors for developing ED cancer  Uterine bleeding in postmenopausal women  Higher doses increase the risk of endometrial cancer  5- to 15-fold increased risk; combining progestin reduces this risk  Risk for gallbladder disease  Increased cholesterol content in bile, reduced bile acid production  Stroke and venous thromboembolic disease  Progestins  Levonorgestrel (Norplant)  Medroxyprogesterone acetate (Provera)  Megestrol acetate (Megace)  Norethindrone acetate (Aygestin)  Progesterone (generic)  PROGESTERONE AGONISTS / ANALOGS O Mechanism of action  Activates PR  suppress release of LH H  Prevents follicle development and ovulationH H O Structure activity relationship Progesterone  Require 4-ring scaffold; D4 and 3-ketone in AOH ring H H  Removal of C19 methyl increases activity H (19-H O nor) L-Norgestrel  17-a substituents increase oral bioavailability Side/ adverse effects  Increased blood pressure & Na+ elimination (via antag at MR)  SELECTIVITY OF PR AGONISTS O O OH O H O H H H H H H H H H O O O Progesterone L-Norgestrel Medroxyprogesterone acetate  SELECTIVE AGONISTS & ANTAGONISTS Progesterone & Estrogen Receptor  ER SELECTIVE / PARTIAL AGONISTS AND ANTAGONISTS ER selective agonists/antagonists  Tamoxifen (Nolvadex)  Toremifene (Fareston)  Raloxifene (Evista)  Bazedoxifene (Duavee*) O N Tamoxifen ER partial agonists  Clomiphene (Clomid, Serophene, Milophene) ER antagonists  Fulvestrant (Faslodex)  ER ANTAGONISTS: MOA & SAR Mechanism of action  Blocks normal estrogenic activity  Compete for ER and have weak estrogenic activity  Anti-estrogens  High ER affinity allows binding and dimerization  Altered receptor conformation prevents co-activator binding  May block receptor translocation or productive DNA interactions Structure activity relationship  Antagonists are structurally similar to substrates  Drug binds but prevents activation (diethylstilbestrol vs. tamoxifen)  PARTIAL AGONISTS OR ANTAGONIST AT E- ESTROGEN RECEPTOR (trans) Clomiphene (partial agonist)  Two isomers: (E-potent antagonist; Z-clomiphene: agonist)  Main effect: block pituitary gonadotrope ER receptors Z-(cis)  Stimulates ovulation OH Pharmacokinetics: Half-life (t1/2) of 5 days H H HO Fulvestrant (antagonist) F F F S O  Effective in tamoxifen-resistant breast F F cancer Fulvestrant  Inhibits both AF2 / AF1 domains of transcription  AGONIST/ANTAGONIST AT ESTROGEN RECEPTORS Mechanism of Action  Different actions in different tissues  Agonist at ERβ in bone ( bone density)  Antagonist at ERα in breast (inhibits breast cancer growth)  Differing effects from these drugs is due to binding w/ ER isoforms  recruitment of co-activators vs. co-repressors SAR: Aminoethyl ether is essential Agents in this class include:  Tamoxifen   Bazedoxifene  Toremifene  Raloxifene ( osteoporosis)  AGONIST/ANTAGONIST AT ESTROGEN RECEPTORS Tamoxifen  Pure Z-isomer; parent t1/2 = 7 days  N-dealkylation (via CYP3A4); metabolite (≈ activity); t ½ 14 days  Can  proliferation of endometrial tissue; cataracts Toremifene  Chloro-ethyl substituent replaces ethyl  PK: metabolized via CYP3A4 ; t½ ≈ 5 days  ADE: diaphoresis, hot flashes, nausea  Warn/contra: dose-depend QT-prolongation Bazedoxifene (combined with estrogens : Duavee®)  Rigid core, similar to tamoxifen  Duavee® reduces proliferation of endometrial tissue  PROGESTERONE RECEPTOR PARTIAL AGONIST DANAZOL Clinical Uses: endometriosis Structure / SAR:  Contains required 4-ring steroid structure  Lacks true ketone at C-3 position MOA: weak, partial PR agonist; androgen receptor (AR) agonist  Suppresses HPO axis and LH/FSH secretion; halts E2 synthesis O HO Side effects: Hirsutism, weight gain, acne, hair loss H H (androgenic) H H N H H O Contraindicated in Pregnancy O Progesterone Danazol Drug-drug interactions (DDIs):  RU-486) PROGESTERONE RECEPTOR ANTAGONIST Use: Emergency contraceptive Structure activity relationship  Antagonist core steroid structure / D4 / and C3- ketone  Modifications including bulky 11b p-aniline (mifepristone) Mechanism of action  Antagonist at PR receptors produces  inactive conformation  Prevent binding of endogenous progestins  Antagonist at GR (hypothalamus/pituitary  affects cortisol level) Pharmacokinetics: AROMATASE INHIBITORS Exemestane Anastrozole Letrozole  SE INHIBITOR S Irreversible aromatase inhibitors  Exemestane (Aromasin) Dose: 25 mg PO 1x daily Reversible aromatase inhibitors  Anastrozole (Arimidex) Dose: 1 mg PO 1x daily anastrozole  Letrozole (Femara) Dose: 2.5 mg PO 1x daily Structure Activity Relationship (SAR)  Exemestane is structurally similar to androstenedione  Triazole aromatase inhibitors (anastrozole /  AROMATASE INHIBITORS: MOA Aromatase (i.e., estrogen synthetase; CYP19A1): Enzyme converts androgens into estrogens  Androstenedione into estrone;  Testosterone into estradiol Inhibitors prevent the final step in biosynthesis to estrogens  Androstenedione analogs: irreversible inhibitors - exemestane  Triazoles: N4 binds heme:Fe in enzyme; reversible inhibitors  prevent testosterone conversion to estradiol  Drugs: anastrozole (metabolized by CYP1A2, 2C8/9, 3A4) letrozole (metabolized by CYP2A6 & 3A4) Used in postmenopausal tamoxifen-resistant breast cancer  INHIBITORS: SIDE EFFECTS & DDIS Adverse effects  Edema, nausea and dizziness, sweating and hot flashes  Increased cholesterol levels (monitor; possible medication)  Higher rates of fractures and myalgia compared to tamoxifen  Long-term use can result in osteoporosis  Lower risk of endometrial cancer & thromboembolic events Drug-drug Interactions  Letrozole strong inhibitor of CYP2A6 (few DDIs)  Exemestane is extensively metabolized by  ENDOCRINE PHARMACOLOGY: MALE GONADAL HORMONE ANALOGS, ANTAGONISTS & INHIBITORS Chapter 40: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 745-771) Chapter 24: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 941-964) Ch 44: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed.  LECTURE OBJECTIVES 1. Explain male gonadal hormone function with respect to a. Stimulation by hypothalamic and pituitary hormones b. Biosynthesis of testosterone c. Mechanism and effects of conditions with altered hormone levels d. Biological targets for drug therapy 2. Explain significant aspects of androgenic drugs a. Structure and relationship to function b. Mechanism of action and pharmacokinetics c. Indications, contraindications, and adverse effects 3. Explain significant aspects of anti- androgenic drugs a. Structure and relationship to function b. Mechanism of action and pharmacokinetics  HIGHLIGHTS FOR THIS SECTION Androgen SAR and analogs  Testosterone structure, analogs  Metabolism; modifications to enhance stability  Agonists: methyltestosterone, testosterone  Anabolic agonists: fluoxymesterone, nandrolone decanoate, oxandrolone Androgen synthesis inhibitor – abiraterone Androgen receptor  Natural role: male maturation, muscle growth  Androgenic activity / anabolic activity  Antagonists: flutamide, nilutamide, biclutamide, apalutamide*  Other antagonists: spironolactone 5a-reductase  Natural role: converts testosterone to dihydrotestosterone (DHT)  Inhibitors: finasteride, dutasteride  PHARMACOLOGICAL AGENTS COVERED IN THIS LECTURE Testosterone Analogs  testosterone AR Agonists  methyl testosterone fluoxymesterone   nandrolone decanoate AR Antagonists  oxandrolone  spironolactone  apalutamide* Androgen Synthesis  biclutamide Inhibitors  flutamide  finasteride (Proscar)  nilutamide  dutasteride (Avodart)  abiraterone (Zytiga)  GONADAL HORMONES estrogen testosterone progesterone ethinyl estradiol oxandrolone norethindrone  IMPORTANT ANDROGENIC MOLECULES Testosterone (19 carbons)  Pulsatile production peaks at 8 AM  3 to 5 mg produced daily in normal males Testosterone   activity in muscle, brain, bone, bone marrow  Only 2% free; remainder (98%) protein bound (SHBG & albumin)  SHBG synthesis  by TSH & estrogen;  by GH & androgens Dihydrotestosterone (DHT)  Active metabolite of testosterone via 5a-reductase   activity in genitalia, prostate, skin, hair follicles Dihydrotestosterone  REPRESENTATIVE DRUGS  GnRH receptor (GnRH)  Superagonist: leuprolide  Antagonist: ganirelix  Androgen receptor (testosterone)  Agonist: testosterone / analogs  Antagonist: flutamide  5a-reductase (testosterone)  Inhibitor: finasteride  17a-hydroxylase (pregnenolone) C17,20 lyase (17a- hydroxypregnenolone)  Reversible inhibitor: spironolactone  Irreversible inhibitor: abiraterone  AND PHARMACOLOGICAL AGENTS 5α-reductase: enzyme reduction C5-C4 bond; ring A  Converts testosterone to dihydroxytestosterone (DHT)  Inhibitor: finasteride and dutasteride Testosterone Biosynthesis inhibitor: CYP17,21-lyase  ↓ DHEA production  Inhibitor: abiraterone (irreversible) spironolactone (reversible) Androgen receptors: endogenous agonist – testosterone Dihydrotestosteron  involved in male maturation e  Agonist: methyltestosterone, nandrolone,  Antagonist: flutamide, bicalutamide, nilutamide, apalutamide  CONDITIONS REQUIRING THERAPY Male Hormone Deficiency  Condition: Low endogenous levels of testosterone (Low-T)  Goal: Restore normal testosterone and DHT levels  Drugs: Androgen receptor (AR) agonists (testosterone analogs) Benign Prostatic Hypertrophy (BPH)  Condition: Hyperplasia of inner prostate tissue (not hypertrophy)  Goal: Reduce tissue growth to restore urinary function  Drugs: 5α-reductase inhibitors (Specific inhibitors of DHT synth.)  RESPONSE FROM ANDROGEN VS. ANABOLIC ACTIVITY  Androgenic activity  Inhibit LH and GnRH production Develop / maintain male 2nd sex characteristics  Body hair; vocal chords thicken;  sebaceous secretions (acne)  aggressive /competitiveness play; sexual behavior & interest rises Maintain spermatogenesis  Anabolic activity  Decrease protein breakdown; increase growth- promoting effects Review of earlier  Electrolyte / water retention and kidney growth slide  Androgenic and anabolic activity  GENERAL STRUCTURE ACTIVITY RELATIONSHIPS  Androgenic activity  Steroid core structure is required D  Oxygen at C3 and C17 are not required A  Anabolic activity  Oxygens in A ring  anabolic activity  4-OH (oxymesterone)  2-CHO (oxymetholone); 2-oxa (oxandrolone)  b-Fluoro group at C4 or C9 increases activity  19-nor analogs increase anabolic activity  Androgenic and anabolic activity  17b-OH substituent is optimal, 17a-OH has no effect  17a-alkyls prevent metabolism, bulkier groups  Figure 41-6; Goodman & Gilman; 13th ed ANDROGEN STRUCTURES (TESTOSTERONE ANALOGS)  ANDROGEN RECEPTOR AGONISTS Oral / parenteral Androgens  Methyltestosterone (10 – 50 mg PO, 1X daily)  Testosterone cypionate (generic, Depo- testosterone)  Testosterone enanthate (generic, Delatestryl) Transdermal testosterone Nandrolon e  Patch (Androderm) decanoate Oxandrolone  Gel (AndroGel) Oxymetholone Oral / parenteral Anabolics  Fluoxymesterone (2.5 – 20 mg PO, 1X daily)  Nandrolone decanoate (generic)  TESTOSTERONE AND ESTERS  Testosterone  Free alcohol used in buccal and transdermal  Insufficient oral bioavailability (t ~ 30 mins) ½ Testosterone Cypionate  Testosterone C17 esters  Various lipophilic esters formulations for IM administration  Avoids first pass; slow hydrolysis releases testosterone  Extends duration of action  17a-methyl analogs 17-methyltestosterone  Small 17a-alky groups prevent metabolism  Increased oral bioavailability  9a-fluoro increases activity Fluoxymesterone  SYNTHETIC ANABOLIC AGENTS Further modifications  selectivity for anabolic effects  Most changes affect the 3-D structure of the A-ring (more planar)  Testosterone 1 : 1 (androgenic : anabolic)  Nandrolone 1 : 2.5 to 1 : 4  Oxandrolone 1 : 3 to 1 : 13 Removal of C10 methyl (C19-nortestosterone analogs) Further unsaturation of the A-ring, heteroatom replacement  All changes will prevent aromatase activity Most retain the 17a-methyl to increase oral Nandrolon stability e decanoate 17-methanddrostenolone Oxandrolone  ANDROGEN RECEPTOR Apalutamide ANTAGONISTS Non-steroidal AR antagonists  Apalutamide (Erleada) Bicalutamide  Bicalutamide (Casodex)  Flutamide (Eulexin) Nilutamide  Nilutamide (Nilandron) Flutamide Steroidal androgen receptor (AR) antagonists  Spironolactone (Aldactone)  FLUTAMIDE (EULEXIN®)  Combined w/ GnRH agonist for prostate cancer  Dose: 250 mg PO, 3x/day Mechansim of action: Non-steroidal antagonist at AR  Competes with testosterone and DHT; inactive complex Pharmacokinetics:  Metabolized by CYP1A; Parent t½ = 5 hrs  Metabolite more potent; also has weak AR agonist activity* Side Effects:  Common: hot flashes,  libido, diarrhea,  APALUTAMIDE, BICALUTAMIDE AND NILUTAMIDE Indications: Prostate Cancer SAR/PK distinctions:  A: 3rd generation non-steroidal AR antagonist  t½ ~ 3 days; metabolized via CYP2C8/3A4 to active metabolite  B: R-enantiomer greater activity  t½ ~ 6 days;  in patients w/liver impairment  N: 2nd generation non-steroidal AR antagonist  t½ 45 hours; extended DOA is (due to t1/2 metabolites) Adverse effects: hot flashes, less GI upset < flutamide  A: hypertension, skin rash, edema, anemia, dyslipidemia  B: headache pain, edema, constipation  N: nocturnal amblyopia (delay recovering vision after bright light)  NE: MINOR AR ANTAGONIST Spironolactone Indications:  Anti-MR activity: Edema, HTN, hypokalemia, etc.  Anti-AR activity: Hirsutism, polycystic ovary disease MOA: Steroidal competitive antagonist at AR and MR  Spironolactone also inhibits 17a-hydroxylase activity Pharmacokinetics:  Metab.  canerone (active metabolite); t1/2 = 1-3 hrs (parent) Side / adverse effects:  STEROID BIOSYNTHESIS INHIBITORS 5a-reductase inhibitorsType 1 - in reproductive tissue  dutasteride (Avodart) Type 2 - in skin & liver  finasteride (Propecia, Proscar) Finasteride What is the impact??? Steroid synthesis inhibitors  abiraterone (Zytiga) Dutasteride What is the impact???  INHIBITORS: MECHANISM-BASED INHIBITOR OH OH OH OH OH OH steroid 5a-reductase O steroid 5a-reductase HO O H H O H H O NADP HO O H 5a-Dihydrotestosterone NH2 H H H O NADP Testosterone Testosterone N NH2 5a-Dihydrotestosterone Testosterone R (R = phospho adenosine diphosphate) DHT R N R NADPH2 RN R NR (R = phospho adenosine diphosphate) N NADPH2 N H2N H2N H2N O H H finasteride H2N O R NH2 N O H H O H R NH2 NADPH 2 O N 5-reductase H O NADPH2 O N 5-reductase H O N O N H H H H H H NADP O N H O N O N adduct NADP-finasteride H H H H H H Finasteride NADP NADP-finasteride adduct Finasteride (R = phospho adenosine diphosphate)  FINASTERIDE (PROSCAR®) Finasteride Clinical Uses: BPH and male pattern baldness Dose: 5 mg PO, once daily (also avail. combined w/ doxazosin) Mechanism of action: Selective type-2: 5a-reductase inhibitor  Prevents testosterone metabolism  [DHT]  by 65% (~24 hrs)  No activity at AR, PR, or ER  DHT levels suppressed by 65% in ~ 24 hours Pharmacokinetics:  Extensive CYP3A4 metabolism (CO H on tbutyl); t 5 – 6 2 ½ hours Side effects:  Erectile dysfunction, gynecomastia,  libido Contraindicated in Pregnancy  No major clinical DDIs  DUTASTERIDE (AVODART®) Dutasteride Greater, more consistent DHT suppression (>95%) Dose: 0.5 mg PO, once daily (also combined w/ tamsulosin) MOA: Inhibitor of both type-1 & -2 isoforms of 5a- reductase Pharmacokinetics:  Extensive CYP3A4 metabolism  t = 5 weeks (much longer than fin); detected for 6 ½ months Side effects:  Erectile dysfunction, gynecomastia,  libido Contraindicated in Pregnancy No major clinical DDIs (for either drug)  ANDROGEN SYNTHESIS Abiraterone INHIBITORS: ABIRATERONE & OTHERS Abiraterone (Zytiga®)  Metastatic castration-resistant prostate cancer  MOA: Inhibits CYP17 (17a-hydroxylation and C17,20 lyase)  Reduces cortisol and DHEA steroid biosynthesis  Significant ADEs: prevents GC synthesis but not aldosterone  May result in both adrenocortical insufficiency and MC Take on excess empty  Hypertension, hypokalemia, and fluid retention stomac  Contraindicated in pregnancy; inhibitor of CYP2D6 h Spironolactone  MOA: inhibits 17a-hydroxylase activity (see earlier slide)  ADE: K+ sparing diuretic; may cause hyperkalemia  Top 300 Drugs Androgens testosterone  testosterone gel (HRT for Low-T)  Testosterone cypionate Anti-androgens  None Dutasteride 5a-reductase inhibitors  dutasteride (Avodart) for BPH  finasteride (Proscar) for Finasteride BPH  CLASSIFYING DRUGS Androgen receptor agonists (natural & synthetic androgens)  Testosterone (and esters), methyltestosterone, nandrolone, fluoxymesterone, oxymetholone, oxandrolone Gonadal suppressors (GnRH analogs)  Goserelin, nafarelin, leuprolide Androgen biosynthesis inhibitors  Ketoconazole (general), abiraterone (precursor conversion)  Finasteride, dutasteride (testosterone to DHT conversion)  PEARLS: MALE GONADAL ENDOCRINE SYSTEM 1. Regardless of the specific drug(s), hormone replacement therapy should use the minimum dose and duration for the desired therapeutic end point. 2. Testosterone delivery systems are designed to avoid hepatic catabolism that occurs when testosterone is ingested orally. 3. Androgen receptor antagonists such as flutamide are used to treat metastatic prostate cancer. 4. Finasteride, a 5α-reductase inhibitor, is used to treat benign prostatic hypertrophy. 5. The 17α-alkylated androgens are the only androgens that cause hepatotoxicity.  MALE ENDOCRINE CASES A 46-year-old man is diagnosed with hypogonadism and low serum testosterone Q1: What options are available for his testosterone replacement therapy? Q2: What are the risks and untoward effects of testosterone therapy that should be discussed with this patient?  MALE ENDOCRINE CASES A 56-year-old man with metastatic prostate cancer is being treated with flutamide. Q1: What is flutamide and what are its mechanisms of action? Q2: What are the untoward effects of flutamide? What about other drugs in the same class? Top 200 Drugs Estrogens and progestins  Conjugated estrogens (HRT)  Conjugated estrogens w/ medroxyprogesterone acetate (HRT)  Estradiol (HRT)  Ethinyl estradiol and drospirenone (contraception)  Ethinyl estradiol and norethindrone (contraception)  Ethinyl estradiol and norgestimate (contraception)  Ethinyl estradiol and norgestimate triphasic (contraception) Top 200 Drugs  Estrogen receptor partial agonist  Tamoxifen (breast cancer)  Aromatase inhibitor  Anastrozole (breast cancer)  REFERENCES 1. Basic & Clinical Pharmacology, 15th ed. (2021) by BG Katzung and TW Vanderah. McGraw-Hill Medical (accessed via AccessPharmacy) 2. Foye’s Principles of Medicinal Chemistry, 8th ed. (2019) by Victoria F. Roche, S. William Zito, Thomas L. Lemke, and David A. Williams. Lippincott Williams & Wilkins 3. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. (2018) by L.L. Brunton, J.S. Lazo, and K.L. Parker. McGraw-Hill (accessed via AccessPharmacy)  PEARLS: FEMALE GONADAL ENDOCRINE SYSTEM 1. In postmenopausal woman, hormone replacement therapy is most commonly used to treat vasomotor disturbances (“hot flashes”). 2. In postmenopausal women with an intact uterus, a progestin is included in the hormone replacement therapy to prevent endometrial cancer. 3. Regardless of the specific drug(s), hormone replacement therapy should use the minimum dose and duration for the desired therapeutic end point. 4. Estrogens and progestins are widely used as combination contraceptives and are 99% effective in preventing ovulation. 5. Progestin-only contraceptives are available when estrogen-containing products are contraindicated.  PEARLS: FEMALE GONADAL ENDOCRINE SYSTEM 6. Tamoxifen is a selective estrogen receptor modulator widely used for the adjuvant treatment of breast cancer and for prophylaxis in high-risk women, but treatment should be limited to 5 years. 7. Fulvestrant, a pure estrogen antagonist, is used to treat breast cancer. 8. Clomiphene is an estrogen antagonist used to treat infertility. 9. A levonorgestrel-only product and ulipristal are available for emergency contraception within 72 hours or 120 hours of unprotected intercourse, respectively. 10.Mifepristone, administered with a prostaglandin, is used as an anti-progestin for medical abortion.  FEMALE ENDOCRINE CASES A 49-year-old woman has been 6 months without menstruation. She is now experiencing severe “hot flashes” that are impacting her daily life. She would like some therapy that would make her more comfortable. Q1: What hormone replacement therapy is available for her? Q2: She is being treated with a combination of estrogen/progesterone (ethinyl estradiol / norethindrone); why is the progesterone added onto the estrogen? Q3: What are the mechanisms of action for estrogen and progesterone? Q4: What are the risks of hormone replacement therapy that should be discussed with the patient?  FEMALE ENDOCRINE CASES A 53-year-old woman is diagnosed with breast cancer. The “lump” is removed and lymph nodes are negative for signs of cancer. She is started on tamoxifen, a selective estrogen receptor modulator (SERM). Q1: What are SERMs? Q2: What are the untoward effects of using tamoxifen? A 24-year-old woman with polycystic ovary syndrome is being treated with clomiphene for infertility. Q3: What kind of drug is clomiphene and what is its MOA? Q4: What are the untoward effects of clomiphene?