Reproductive Pharmacology Lecture Notes PDF

Thomas A. Kocarek, PhD Reproductive Pharmacology 1 [email protected] 2126 Integrative Biosciences Center LECTURE TITLE: REPRODUCTIVE PHARMACOLOGY SESSION LEARNING OBJECTIVES 1. Name the classes of gonadal steroids and examples of each class and descri...

Thomas A. Kocarek, PhD Reproductive Pharmacology 1 [email protected] 2126 Integrative Biosciences Center LECTURE TITLE: REPRODUCTIVE PHARMACOLOGY SESSION LEARNING OBJECTIVES 1. Name the classes of gonadal steroids and examples of each class and describe their biological effects and mechanisms of action. 2. Describe the clinical uses of gonadal steroids including such considerations as need for combination treatment, route of administration, adverse effects, and contraindications. 3. Describe the classes of drugs that are used to modulate gonadal steroid action. 4. Describe the clinical use of oxytocin. SESSION OUTLINE I. Overview of pharmacological classes II. Gonadal steroids: Brief review and introduction to the compounds A. Estrogens B. Progestins C. Androgens III. Clinical uses of gonadal steroids A. Female hormone replacement therapy Primary hypogonadism Postmenopausal hormonal therapy B. Contraception Combination estrogen-progestin contraceptives o Adverse effects, possible benefits, contraindications, cautions Progestin-only contraception Emergency Contraception C. Use of androgens and anabolic steroids Replacement therapy in hypogonadism Other reported uses Adverse effects, contraindications IV. Modulators of gonadal steroid action A. Gonadotropin releasing hormone agonists B. Gonadotropin releasing hormone receptor antagonists C. Gonadotropins D. Aromatase inhibitors E. Selective estrogen receptor modulators (SERMs) F. 5α-reductase inhibitors G. Androgen receptor antagonists H. Progesterone receptor antagonists V. Oxytocin Uses Adverse effects, contraindications Thomas A. Kocarek, PhD Reproducttive Pharma cology 2 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter I. Overviiew of pharmmacologica al classes: This T lecture covers the ffollowing classes of pharmaccological ageents that are used in reproductive phharmacologyy. These age ents include both endogenous molecules (e.g., ste eroid hormon nes, peptidee hormones) and synthettic drugs tha at mimic, anntagonize, or o modify thee production of the endog genous molecules. Agents th hat are used d during normmal physioloogical conditiions are presented in so ome detail. Agents th hat are used d mainly to trreat disease es are mentiooned but desscribed in le ess detail. Gonadal G stero oids and syn nthetic mimeetics o Estrog gens o Proge estins o Andro ogens Modulators M of gonadal steroid action o Gonad easing hormone agonistts and antag dotropin rele gonists o Gonad dotropins o Aroma atase inhibittors o Selective estrogen receptor modulators m (SSERMs) o 5α-Re eductase inhhibitors o Andro ogen recepto or antagonists o Proge esterone rece eptor antago onists Oxytocin O Figure 1 shows the pharmacolog p gical classess that are disscussed in tthis lecture, e except for oxytocin,, which is pro oduced by th and. The bassic system under he posterior pituitary gla consideraation is the hypothalami h c-pituitary-re eproduction (HPR) axis.. Figure 1 Thomas A. Kocarek, PhD Reproductive Pharmacology 3 [email protected] 2126 Integrative Biosciences Center II. Gonadal Steroids: Brief review and introduction to the compounds Synthesis of gonadal steroids: Figure 2 shows a simplified pathway for biosynthesis of the gonadal steroids. Steroid hormone biosynthesis begins with cholesterol. The long side chain of cholesterol is cleaved by a cytochrome P450 enzyme, CYP11A1 (aka P450scc [side-chain cleavage]) to form pregnenolone. Pregnenolone can be directly converted to the major endogenous progestin, progesterone. Progesterone is produced in the ovaries, placenta, and adrenal gland. Pregnenolone can be metabolized by two reactions that are catalyzed by the same enzyme, CYP17A1. The first catalyzes 17-hydroxylation and the second catalyzes cleavage of the short side chain from the 17-position (17,20-lyase). The product of these reactions, dehydroepiandrosterone (DHEA), and the related steroid androstenedione are the “adrenal androgens,” because they can be produced in the adrenal gland as well as the testis. The adrenal androgens can then be converted to the major gonadal androgen, testosterone. Not shown is that testosterone is converted to dihydrotestosterone in androgen-target cells by 5α-reductase, which is an important pharmacological target. Androgens are converted to estrogens in ovary and some other tissues (e.g., adipose) by aromatization of the “A ring.” This reaction is catalyzed by CYP19 (aka aromatase). Cholesterol CYP11A1 – P450scc 3β-HSD CYP17A1 17α-Hydroxylase Pregnenolone Progesterone CYP17A1 Progestins 17α-Hydroxylase 17-Hydroxypregnenolone CYP17A1 17-Hydroxyprogesterone 17,20-Lyase 3β-HSD 17β-HSD Androgens Dehydroepiandrosterone Androstenedione Testosterone CYP19 (Aromatase) CYP19 Estrogens Estrone 17β-Estradiol Figure 30-1 (modified) from Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, Golan et al. 4th Ed. (Figure 30-1 [modified]) Figure 2 Thomas A. Kocarek, PhD Reproducttive Pharma cology 4 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter A. Estrogens Substances S that share coommon feminizing activi ty o 17β-e estradiol (E2)) – most potent naturallyy occurring eestrogen o Estron ne (E1) and estriol (E3) less potent All A estrogens are derived from aroma atization of p precursor an ndrogens, caatalyzed by CYP19 C (arom matase) Ovary O and pla acenta – hig ghest expres ssion of CYP P19 Certain C non-rreproductive tissues can n also aroma atize androge ens to estrog gen – e.g., adipose tissue, hypothala amic neurons, muscle o After menopause, m , majority of circulating e estrogen derrived from ad dipose tissue – also main m source of circulating estrogens in men Most M effects mediated m thrrough the nuuclear estroggen receptorrs Two T subtypes s of nuclear estrogen receptor – ER Rα (aka ESR R1, NR3A1) a and ERβ (ES SR2, NR3A2). N The e basic molec cular mecha anism of acti on of the nu uclear ERs (ii.e., ligand- activated tran nscription facctor) is show wn in Figure 3. Some S “non-genomic” effe ects of estrogens are me ediated throu ugh ER at ceell membran ne or by a non-nuclear estroge en receptor, GPER G (GPR R30) Citation: Estrogens, Progestin ns, and the Female Rep productive Tract, Bruntton LL, Hilal-Dandan R, R Knollmann BC. Gooddman & Gilman's: The Pharmacological Basiis of Therapeutics, 13e; 2017. Ava ailable at: https://access smedicine.mhmedical.c com/content.aspx?boo okid=2189&sectionid=1 172482097 Accessed: November 12, 2018 Copyrigght © 2018 McGraw -Hiill Education. All rights reserved r Figu ure 3 Thomas A. Kocarek, PhD Reproducttive Pharma cology 5 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter Several types of chemicals hav ve estrogennic activity. These include: Steroidal S estrrogens (e.g.,, 17β-estradiol) Synthetic S nonn-steroidal estrogens (e..g., diethylst ilbestrol [DE ES]) Plant P estroge ens (phytoes strogens, e.g g., genistein)) Anthropogen A ic estrogenic c chemicals (e.g., organnochlorine pe esticides, ce ertain polychlorinateed biphenylss, bisphenolss) Some S selectivve estrogen receptor mo odulators (i.e e., “SERMs””) Several examples e ounds are s hown in Figure 4. off these estrogenic compo Citation: The Gonadal Hormones & Inhibitors, Katzun ng BG. Basic & Clinica al Pharmacology, 14e; 2017. 2 Available at: accessmedicine.mhmed https://a dical.com/content.aspx x?bookid=2249&sectio onid=175222055 Acces ssed: November 12, 2018 Copyrigh ht © 2018 McGraw -Hill Education. All rights re eserved Figu ure 4 In additio on, a commo only used esstrogenic pre eparation is dderived from horsse urine. The Premarin” is an acronym of e product “P pregnantt mare’s urinne. These esstrogens are conjugated (3- sulfonatees), which increases their stability re elative to E2,, making them suittable for ora al use. The sulfonate con njugates aree inactive, however, and hydroly ysis is neces ssary to formm the active estrogens. The majo or conjugateed estrogenss found in Prremarin are sshown in Figure 5. 5 Fiigure 5 Thomas A. Kocarek, PhD Reproducttive Pharma cology 6 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter estins B. Proge Natural N proge estin – proge esterone o Requiired for main ntenance of pregnancy Synthetic S derrivatives of progesterone p e or testoste erone o Not un niform group p of compounds  Many have e other horm monal effectss: e.g., estro ogenic, anti-e estrogenic, androgenic, anti-andro ogenic, anabbolic effects  Progestero one derivativ ves: most cloosely relatedd to progesterone, chemicallyy and pharmmacologicallyy (e.g., hydrooxyprogesterone, medroxyprogesterone e)  17-Ethinyl testosterone derivativess (e.g., dime ethisterone)  19-Nortesttosterone de erivatives (e.g., norethin ndrone) thirrd-generatioon “19-nor, 1 3-ethyl” commpounds (e.g g., desogesttrel) cla aimed to havve lower and rogenic activity than oldder syntheticc pro ogestins Some pro ogestins are e shown in Figure F 6. Citation: The Gonadal Hormoones & Inhibitors, Katz ung BG. Basic & Clini cal Pharmacology, 14e e; 2017. Available at: https:///accessmedicine.mhm medical.com/content.as px?bookid=2249&secttionid=175222055 Acc essed: November 12, 2018 2 Copyr ight © 2018 McGraw -HHill Education. All rights s reserved Figure 6 Thomas A. Kocarek, PhD Reproducttive Pharma cology 7 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter ogens C. Andro Substances S required r for conversion c to t male phen notype durin ng developm ment and for male se exual matura ation DHEA, D androostenedione – adrenal an ndrogens (p pro-androgen ns) Testosterone T e and dihydro otestosteronne (DHT) o Testosterone – the classic circula ating androg gen o DHT – the classic c intracellular androogen Testosterone T e is essentially a prohorm mone o Modest affinity forr androgen receptor o Conve erted in targeet tissues to o DHT – bind ds androgen receptor witth 10- fold higher affinity y o DHT formation f ca atalyzed by 5α- 5 reductase (Figure e 7)  at least tw wo subtypes – differential expressionn provides some s pharmacologic specificity for 5α-reducta ase inhibitorrs  Inherited deficiencies d of 5α- Figuure 30-2 from Prrinciples of Pharm macology: The reductase – males Pat hophysiologic Baasis of Drug The erapy, Golan et a al. 4th Ed. phenotypic cally female SHBBG, sex hormone e-binding globuliin Fig gure 7: Intrace ellular converrsion of testos sterone to dihydrotestos sterone III. Clinic cal uses of gonadal g ste eroids The two main clinical uses of esttrogens and progestins aare for repla acement therrapy and forr contraception. The main m use of androgens a is s for replace ement therap py. Conditio ons of decreeased estro ogen or androgen secre etion Hypoogonadism Results R x hormone production is impaired be if sex efore adolescence Patients P do not undergo sexual s matuuration Meno opause Normal N physiologic respo onse to exhaaustion of ovvarian follicle es Androstenedi A ione continuues to be con nverted to esstrone by CY YP19 (aroma atase) in peripheral (m mainly adipos se) tissues – estrone lesss potent tha an estradiol Because B of re elative lack of o estrogen activity a afterr menopause e, many wom men experie ence hot flashes, sleep s disturb bances, vaginal dryness,, and decrea ased libido – postmenopau usal women also at risk for f osteoporrosis Men M do not experience e sudden decre ease in sex h hormones but androgen n secretion d does decline gradu ually with age Thomas A. Kocarek, PhD Reproductive Pharmacology 8 [email protected] 2126 Integrative Biosciences Center A. Female hormone replacement therapy Primary hypogonadism o Treatment attempts to mimic physiology of puberty o Usually begun at 11–13 years of age to stimulate development of secondary sex characteristics and menses, to stimulate optimal growth, to prevent osteoporosis, and to avoid psychological consequences of delayed puberty and estrogen deficiency Postmenopausal hormonal therapy o Deleterious effects of estrogen loss at menopause led to development of hormone replacement therapy o For women with uterus, estrogen therapy must be combined with progestin therapy to prevent induction of endometrial cancer o Current recommendation for postmenopausal women is to use hormone therapy only to treat bothersome symptoms, such as vasomotor symptoms or vaginal dryness, and to use the lowest possible dose for the shortest time Treatment Regimen Daily estrogen + progestin OR estrogen first 25 days of month with progestin added during last 10-14 days Various preparations available – oral, sublingual, intranasal, transdermal, vaginal, injectable, implantable Oral o Micronized estradiol and progesterone can be given orally o Common combination is conjugated equine estrogens or ethinyl estradiol and medroxyprogesterone Vaginal or transdermal estrogen o For patients with mild atrophic vaginitis who are at low risk of developing osteoporosis o Efficiently absorbed o Bypasses liver, thereby avoiding undesirable hepatic effects (e.g., increased synthesis of clotting factors and plasma renin substrate) Adverse Effects Uterine bleeding Cancer - subject of active investigation o Increased risk of endometrial carcinoma - concomitant use of a progestin prevents increased risk; might reduce the incidence to less than that in the general population o No adverse effect of short-term estrogen therapy on breast cancer incidence, but possible small increase with prolonged therapy – impact might be great since breast cancer is common – addition of a progestin does not have protective effect Nausea, breast tenderness, hyperpigmentation Increased frequency of migraine headaches, cholestasis, gallbladder disease, hypertension Thomas A. Kocarek, PhD Reproductive Pharmacology 9 [email protected] 2126 Integrative Biosciences Center Contraindications Patients with estrogen-dependent neoplasms Patients with undiagnosed genital bleeding, liver disease, or history of thromboembolic disorder Estrogens should be avoided by heavy smokers B. Contraception Two classes of widely used oral contraceptives: Estrogen-progestin combinations o Monophasic: Constant dose of estrogen + progestin during cycle o Bi-, tri-, or 4-phasic: Dose of one or both components changed during cycle Progestin-only contraceptives Combination estrogen-progestin contraceptives Estrogen used is either ethinyl estradiol or mestranol Use of unopposed estrogen promotes endometrial growth and increases risk of endometrial cancer – for a woman with a uterus, estrogen is always co-administered with a progestin to limit the extent of uterine growth Numerous progestins used Suppress GnRH, LH, and FSH secretion and follicular development, thereby inhibiting ovulation Also produce changes in cervical mucus, in uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease likelihood of conception and implantation Adverse effects: Moderate: o Breakthrough bleeding – more common with progestin-only drugs o Weight gain: more common with combination agents containing androgen-like progestins o Increased skin pigmentation o Acne may be exacerbated by agents containing androgen-like progestins o Hirsutism may be aggravated by the androgen-like progestins o Ureteral dilation → bacteriuria o Vaginal infections o Amenorrhea in some patients – following cessation of administration of oral contraceptives, 95% of patients with normal menstrual histories resume normal periods Severe: o Vascular disorders  Venous thromboembolic disease: Overall incidence of superficial or deep thromboembolic disease ~ 3-fold higher Thomas A. Kocarek, PhD Reproductive Pharmacology 10 [email protected] 2126 Integrative Biosciences Center  Myocardial infarction: Risk much higher in women who smoke  Cerebrovascular disease: Increased risk of stroke in current users of oral contraceptives over age 35 o Gallbladder disease o Depression: Depression sufficient to require cessation of therapy occurs in ~6% of patients Possible benefits Reduced risk of endometrial cancer: Constant administration of a progestin inhibits endometrial growth Reduced risk of ovarian cancer: Probably due to lowered circulating levels of gonadotropins Contraindications Patients with thrombophlebitis, thromboembolic phenomena, and cardiovascular and cerebrovascular disorders or history of these conditions Should not be used to treat vaginal bleeding when cause is unknown Patients with estrogen-dependent neoplasms Adolescents in whom epiphyseal closure has not yet been completed Cautions Avoid or use with caution in patients with liver disease, asthma, eczema, migraine, diabetes, hypertension, optic neuritis, retrobulbar neuritis, or convulsive disorders Since can cause edema, use with caution in patients in heart failure or other conditions where edema is undesirable or dangerous Since may increase the rate of growth of fibroids, for women with these tumors, agents with the smallest amounts of estrogen and the most androgenic progestins should be selected Be aware that co-administration of strong inducers of hepatic drug-metabolizing enzymes may increase liver catabolism of estrogens or progestins and decrease efficacy of oral contraceptives Progestin-Only Contraception When estrogen use contraindicated, use of continuous low-dose oral progestins may be warranted Progestin-only oral contraception prevents ovulation 70-80% of time but 96-98% effective, suggesting secondary mechanisms such as alterations in cervical mucus, endometrial receptivity, and tubal peristalsis Administered orally, by IM injection, by implantation under skin, or by intrauterine devices o Two progestin-only oral “minipills” available in US – norgestrel and norethindrone o Medroxyprogesterone acetate injected IM every 3 months  ovulation inhibited at least 14 weeks  not desirable for women planning a pregnancy soon after cessation of therapy Thomas A. Kocarek, PhD Reproductive Pharmacology 11 [email protected] 2126 Integrative Biosciences Center o Subcutaneous implantation of capsules containing etonogestrel  very effective and lasts 2–4 years  disadvantages include the need for surgical insertion and removal of capsules o Levonorgestrel-releasing IUDs Emergency (Morning-After) Contraception Administration of medications to prevent pregnancy after failure of a barrier contraceptive or recent unprotected intercourse Ulipristal o Selective progesterone receptor modulator o Effective up to 120 hours after unprotected intercourse o Requires prescription Levonorgestrel 1.5 mg tablet (Plan B and similar products) o Can be taken within 72 hours after unprotected sex o Available over the counter C. Use of androgens and anabolic steroids Hypogonadism Oral testosterone ineffective because of high hepatic first-pass metabolism Two esters, testosterone enanthate and testosterone cypionate, can be injected IM every 2-4 weeks Other preparations – transdermal patch, topical gel, buccal tablet Other Reported Uses Treatment of certain gynecological disorders Protein anabolic agents – questionable efficacy Treatment of refractory anemias – largely replaced by erythropoietin Treatment of osteoporosis – largely replaced by bisphosphonates Stimulation of growth in boys with delayed puberty – extreme caution required - somatotropin usually more appropriate Abuse in sports o Increase muscle mass and fat-free mass o Suppress HPR axis → suppression of testicular function, decreased sperm production, and impaired fertility o Because many androgens can be converted to estrogens, pharmacologic doses can also cause increase in plasma estrogen → gynecomastia o High levels of androgens associated with erythrocytosis, severe acne, and derangements in lipid metabolism (increased LDL and decreased HDL) Adverse Effects Largely due to masculinizing actions - most noticeable in women and prepubertal children - hirsutism, acne, amenorrhea, clitoral enlargement, deepening of the voice Thomas A. Kocarek, PhD Reproducttive Pharma cology 12 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter ndications – should not use in: Contrain Pregnant P wommen or wom men who may y become prregnant during the coursse of therapyy Male M patients s with carcinoma of the prostate p or b breast Innfants and yooung childre en IV. Moduulators of goonadal sterroid action Refer to Figure 1 forr classes of agent a and sites of action n One of th he major use es of these agents a is to treat t pathop physiological conditions w where there is inapprop priate growth of hormonee-dependentt tissues. Exa hese conditio amples of th ons are: Endometriosi E s – growth of o endometriial tissue outtside uterus o Foci ofo endometriosis respond d to estroge n stimulation n Breast B canceer o Many breast canc cers expresss ER and the eir growth is often stimullated by endoggenous levells of estroge en and inhibiited by anti-e estrogens Prostate P grow wth: benign prostatic p hyp pertrophy an nd prostate ccancer o Andro ogen-depend dent – requirres local con estosterone to DHT by 5 nversion of te 5α- reductase Gonadottropin relea asing hormo one (GnRH)) agonists a and antagon nists GnRH G – decaapeptide found in all mammmals Under U physio ologic conditiions, hypoth halamus releeases GnRH H in pulsatile fashion – sttimulates pittuitary gonad s to synthesiize and secrrete gonadottropins: dotroph cells lu uteinizing ho ormone (LH) and follicle--stimulating hhormone (FS SH) Continuous C administratio a n of GnRH suppresses s rather than sstimulates p pituitary gonadotroph activity Can C suppress s HPR axis by b continuou us administrration of a GnRH agonisst or administration n of a GnRHH receptor anntagonist H agonists A. GnRH Preparattions Currently C ava ailable GnRH H analogs arre peptides aand are administe ered by non--oral routes such s as in njection or na asal spray Gonadorelin G - acetate salt of synthetiic human GnRH G Substitution S of o amino acid ds at the 6 position p or re eplacement of C-termina al glycine-ammide producees syynthetic ago onists; e.g., goserelin g (Fiigure 8), le euprolide, naafarelin Figure e8 o Modifications mak ke compounds more pottent and loonger-lastingg than nativee GnRH and gonadorelin n Thomas A. Kocarek, PhD Reproductive Pharmacology 13 [email protected] 2126 Integrative Biosciences Center Administration Pulsatile intravenous administration of gonadorelin every 1-4 hours stimulates FSH and LH secretion Continuous administration of gonadorelin or its longer-acting analogs produces biphasic response o First 7–10 days of treatment – agonist effect results in increased gonadal hormones; initial phase referred to as flare o Continued treatment – inhibitory action due to GnRH receptor downregulation and changes in signaling pathways – decreased gonadotropins and gonadal steroids (hypogonadotropic hypogonadal state) Uses Occasionally used for stimulation of gonadotropin production. Mainly used for suppression of gonadotropin release Gonadal suppression in men with prostate cancer o Combined therapy with continuous GnRH agonist and androgen receptor antagonist as effective as surgical castration in reducing serum testosterone concentrations and effects Gonadal suppression in children with central precocious puberty o Onset of secondary sex characteristics before 7–8 years in girls or 9 years in boys Treatment of women with gynecologic problem that is benefited by ovarian suppression o Endometriosis, uterine leiomyomata (uterine fibroids) Management of advanced breast and ovarian cancer Treatment of women undergoing assisted reproductive technology procedures B. GnRH antagonists Synthetic decapeptides that function as competitive antagonists of GnRH receptors Advantages relative to GnRH agonists: o Avoid the flare o Produce more rapid decrease in gonadotropins Ganirelix and cetrorelix approved for preventing the LH surge during controlled ovarian stimulation procedures Degarelix and abarelix approved for the treatment of advanced prostate cancer C. Gonadotropins Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) o Produced by gonadotroph cells of anterior pituitary Human chorionic gonadotropin (hCG) o Produced by the human placenta FSH, LH, and hCG all act through G protein-coupled receptors Heterodimers that share nearly identical α subunit β subunits confer receptor specificity β subunits of hCG and LH nearly identical Thomas A. Kocarek, PhD Reproducttive Pharma cology 14 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter o β subunit of hCG contains 30 amino acidss at carboxyyl end not present in n LH o two ho ormones use ed interchan ngeably Figure 9 summarizes the effects s of LH and FSH F on test icular and ovarian cells. c In male es, LH binds ptor on Leydiig cells, whicch s to its recep stimulate es testosteroone synthesis. FSH binds to its recep ptor on Sertooli cells, which increasees the produc ction of andrrogen-bindinng protein (ABP), which w is nece essary for ma aintaining th he high conccentrations o of testosterrone that are e necessary for spermato ogenesis. Inn females, LHH binds to its receptor on o thecal ce ells, which sttimulates and drogen synthesiss. FSH binds s to its recep ptor on granulosa cells, w which increases s aromatasee activity, whhich converts s the androggen to estroggen. Preparattions and Administrati A on Menotropins M (human men nopausal go onadotropinss, hMG): firstt coommercial gonadotropin g n product containing both FSH and L LH Figure 330-4 from Principples of exxtracted fromm urine of po ostmenopau usal women Pharmacology: The FSH: Two rec combinant foorms of FSH and Pathoph H available: ffollitropin α a hysiologic Basis o th of Drug Therapyy, Golan et al. 4 Ed. ABP, fo ollitropin β androge en-binding protein n LH: Lutropin α, α first and only o recombinant form oof human LH, Figure 9 was w introduce ed in the United States in 2004 but w withdrawn in n 2016 hCG o Extrac cted and purrified from urrine o Recom mbinant: Choriogonadottropin alpha (rhCG) All A preparatio ons administe ered by subcutaneous o or intramusccular injectionn, usually on na daily basis Uses Ovulation O Ind duction o Induce e follicle dev velopment and ovulation n in women w with anovula ation seconddary to hyp pogonadotro opic hypogon nadism, polyycystic ovaryy syndrome, and other cause es o Becau use of high cost c and neeed for close monitoring d during admin nistration, generrally reserved d for women n who fail to respond to o other less co omplicated fforms of trea atment (e.g.,, clomiphene e, discussed d later underr SERMs) o Contro olled ovarian n stimulationn in assisted d reproductivve technolog gy procedure es (e.g., in vitro fertilization) Male M Infertility y o Most signss and syymptoms of hypogonadi sm in maless adequatelyy treated with h exoge enous androgen o Treatm ment of inferrtility in hypo ogonadal me en requires LLH and FSH H Thomas A. Kocarek, PhD Reproducttive Pharma cology 15 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter e Effects Adverse Two T most serrious complications in women: w o ovaria an hyperstim mulation synd drome o multipple pregnanccies D. Aromatase Inhib bitors Used U bit growth of estrogen-de to inhib ependent tum mors such ass ER-positivve breast can ncer Several S highly selective aromatase a in nhibitors havve been devveloped (anaastrozole, le etrozole, exeemestane) All A currently used u for trea atment of me etastatic breaast cancer a and for preve ention of re ecurrences of o cancers trreated by surgery and ra adiation Aromatase A in nhibitors prodduce profounnd suppresssion of estroggen action, a and estroge en is major m regulattor of bone density d – women taking a aromatase inhibitors have increasedd risk off osteoporottic fractures E. Selective Estroge en Recepto or Modulators Certain C agentts are neithe er pure agon nists nor puree antagonistts, but rather produce distinct, tissue e-specific biological effe ects o Tamoxifen – ER antagonist a inn breast; parrtial agonist in bone and endometriu um o Ralox xifene – ER antagonist a in n breast andd endometriu um; agonist iin bone Evidence E that different SE ERMs induc ce distinct coonformationa al changes inn the ER – rresult in n different intteractions with w co-activa ating or co-re epressing prroteins, thuss leading to diverse biolog gical effects Figure 10 shows ribbon structures for the ERα ligand-binding domain bound b to eith her the naturral ligand, E2 2 or to the SERM, e. Binding of raloxifene E2, which fits neatly within the e ligand- binding pocket, p caus ses a differen nt conforma ational chang ge in the rec ceptor than does bind ding of raloxifene e, which extends outside o of th he a indicated by pocket, as the position of helix 12 1 Figure 100 (H12). Thhe conforma ation induced d by E2 can recruit coa activators that lead to full transcriptio onal activation. The con nformation induced by raloxifene e cannot rec cruit the samme set of core egulators. T The conforma ations induced Thomas A. Kocarek, PhD Reproductive Pharmacology 16 [email protected] 2126 Integrative Biosciences Center by other SERMs would be somewhat different from that induced by raloxifene and would result in the recruitment of somewhat different sets of coregulators. Three SERMs in current clinical use: Tamoxifen Only SERM currently approved for use in treatment and prevention of breast cancer ER antagonist in breast but partial agonist in bone and endometrium – inhibition of estrogen-dependent growth of breast cancer but stimulation of endometrial growth Because of latter effect, use associated with 4-6-fold increase in incidence of endometrial cancer – to minimize risk of iatrogenic endometrial cancer, typically administered no more than 5 years Raloxifene ER agonist in bone but antagonist in both breast and endometrium Does not appear to increase incidence of endometrial cancer Agonist activity in bone decreases bone resorption Approved for use in prevention of breast cancer and prevention and treatment of osteoporosis Clomiphene Used to induce ovulation ER antagonist in hypothalamus and anterior pituitary; partial agonist in ovary Antagonist activity in hypothalamus and anterior pituitary results in relief of negative feedback inhibition by endogenous estrogen → increased release of GnRH and gonadotropins → increased follicle growth → ovulation Main adverse effect is can cause multiple follicles to grow F. 5α-Reductase Inhibitors Prostate cells depend on androgen stimulation for survival Blocking local conversion of testosterone to DHT blocks local action of testosterone Finasteride – selective inhibitor of type II reductase, which is highly expressed in prostate Dutasteride – inhibitor of both type II and type I reductase (expressed in skin and prostate) Finasteride and dutasteride approved for treatment of symptoms resulting from benign prostatic hypertrophy, e.g., decreased urine flow and difficulty initiating urination Drugs are potential alternatives to transurethral resection of prostate Adverse effects include decreased libido and erectile dysfunction G. Androgen Receptor Antagonists Competitively inhibit binding of endogenous androgens to androgen receptor Block action of testosterone and DHT on target tissues Flutamide – approved only for treatment of metastatic prostate cancer – also used in treatment of benign prostatic hypertrophy Thomas A. Kocarek, PhD Reproducttive Pharma cology 17 t.kocarek [email protected] du 2126 Inte egrative Bios sciences Ce enter Spironolacton S ne – originally approved as mineraloocorticoid receptor antag gonist – also o has significant antagonist activity at andro or ogen recepto H. Proge esterone Re eceptor Antagonists Mifepristone M (RU-486) o Comp petitive antag gonist of pro ogesterone re eceptor o Used to induce ab p to 63 days of pregnanccy bortion at up Asoprisnil A o Does not cause abortion a but inhibits i grow wth of tissuess derived fro om endomettrium and myometrium m – may be efffective in tre eatment of eendometriosis and uterin ne leiomyyomata (fibrooids) V. Oxyto ocin 9-amino-acid peptide horrmone secre eted by posteerior pituitary (Figu ure 11) Stimulates S muscular conttractions in uterus u and myoepithelial m contractions in the breaast – involve ed in parturition and milk letdow wn Acts A through G protein-co oupled recepptor and phosphoinosiitide-calcium m second-me essenger sysstem to coontract uterine smooth muscle. m Also o stimulates release of prostaglandin ns and leuko otrienes that augment ute erine coontraction Administered A by injection n – not boundd to plasma proteins and rapidly eliminated by y the kidneys s and liver; h half-life of 5 minutes Citattion: Hypothalamic & Pituitary P Hormones, Katzung BG. Basic & Clinnical Pharmacology, 14 4e; 2017. Available at: httpss://accessmedicine.mhhmedical.com/content.a aspx?bookid=2249&se ectionid=175221494 Acccessed: November 12 2, 2018 Copy yright © 2018 McGraw w -Hill Education. All righ hts reserved Figu ure 11 Uses Administered A intravenous sly via infusion pump to induce labor for conditio ons requiring g ex xpedited vag ginal deliverry o e.g., uncontrolled u maternal diabetes, worssening preeclampsia, in ntrauterine infectiion, rupturedd membrane es after 34 geestational w weeks Augment A prottracted labor Administered A intramuscularly in the im mmediate po ostpartum period to stopp vaginal bleeding due to uterine atony Diagnostic D test o During g the antepa artum period d, oxytocin in nduces uterinne contractio ons that transieently reducee placental blood b flow to the fetus Thomas A. Kocarek, PhD Reproductive Pharmacology 18 [email protected] 2126 Integrative Biosciences Center o Oxytocin challenge test measures fetal heart rate response to standardized oxytocin infusion o Abnormal response indicates fetal hypoxia and may warrant immediate cesarean delivery Adverse Effects Rare; toxicity that does occur is due either to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors Contraindications fetal distress, fetal malpresentation, placental abruption, and other predispositions for uterine rupture Oxytocin Receptor Antagonist Atosiban – Approved outside United States as treatment for preterm labor. Not approved in US. Additional Reading: Basic & Clinical Pharmacology, 14th Edition by Katzung, Trevor & Masters, McGraw Hill, New York, 2018. https://accessmedicine.mhmedical.com/book.aspx?bookid=2249 Chapter 37: Hypothalamic & Pituitary Hormones (relevant portions) and Chapter 40: The Gonadal Hormones & Inhibitors