Understanding Sex Steroids and Their Clinical Applications

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University of British Columbia**We aren't endorsed by this school

Course

CHEM 205

Subject

Biology

Date

Dec 12, 2024

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Uploaded by LieutenantHippopotamusMaster1071

REPRODUCTIVE PHARMACOLOGYPCTH 325Andrew Horne, PhDandrew.horne@ubc.caOffice: MEDC 309

NaturalSyntheticEstrogensestradiolestroneestriolethinyl estradioldiethylstilbestrolProgesteronesprogesterone(a.k.a. progestins)levonorgestrelnorethindrone…and many moreAndrogenstestosteronedihydrotestosteronemanySex Steroidsethinyl estradiollevonorgestrel

Feldman & Feldman 2001. Nat Rev Cancer 1Specificcytoplasmicreceptors,otherwise stabilized by heat shockproteinsAssociationwithspecificpromotorsequences (x-response elements)n.b.additionalindirecteffectsonmodulationofothermediators(autacoids, growth factors, cytokines)General Pharmacodynamics

■Replacement therapy–Hypogonadism–(estrogens) Symptomatic treatment in menopause■Growth stimulation–Induce puberty and/or sexual development–(androgens) Muscle wasting due to injury or disease■(androgens) Gynecological disorders■(progesterones) Tempering agent to estrogen therapy–Reduced risk of side effects (particularly endometrial cancer)Clinical Use of Sex Steroids

Endocrine Reproductive Function

Menstrual Cycle

CONTRACEPTION

■Hormonal■Synthetic estrogen + synthetic progesterone■Oral only■Synthetic progesterone alone■Oral■Injectable■Implantable■Non-hormonal■Copper intrauterine deviceContraceptives for Femalesa.k.a. progestins

■Primary indication (usually): prevention of pregnancy■Secondary indications:■Management of menstrual symptoms■Irregular periods and/or intermenstrual bleeding■Premenstrual syndrome/tension/dysphoric disorder■Intense cramping (dysmenorrhea)■Reduction of iron deficiency anemia■Endometriosis■Treatment/prevention of uterine fibroids and ovarian cysts■Acne(Hormonal) Contraceptives for Females

Combined oral contraceptives■Combinationofsyntheticestrogen(usuallyethinyl estradiol) and progestin (usually one oflevonorgestrel or norethindrone)■Primary pharmacological effect:–Stableplasmaconcentrationsofbothestrogenandprogesterone(or,moreaccurately, exogenous analogues)–Actualconcentrationsdependentonthespecific contraceptive, but as an illustrativeexample using mean data…■20µg Ethinyl Estradiol~10-77 pg/mL■100µg levonorgestrel~1.9-6 ng/mL

Combined oral contraceptives■Combinationofsyntheticestrogen(usuallyethinyl estradiol) and progestin (usually one oflevonorgestrel or norethindrone)■Mechanism of Action:–Suppression of FSH/LH release (estrogen-and progestin-mediated negative feedback)■Impaired follicular development■Inhibition of ovulation and/or implantation–Thickeningofuterinemucuslining(progestin)■Inhibition of sperm mobility–Alterationofendometriumstructuretodiscourage implantation

Combined oral contraceptives■Standard prescription–21 combination hormone tablets–7 placebo tablets■Withdrawal bleeding period–Repeat on a 4-week cycle for aslong as contraception is desired

Combined oral contraceptives■Monophasic formulations–Identical estrogen/progestin doses throughout■Biphasic/triphasic formulations–Two/Three different combination doses–Designed to more closely approximate natural hormone variationsAdapted from https://kinfertility.com.au/blog/what-is-a-triphasic-pill

Combined oral contraceptives■Extended-cycle formulations possible–e.g. Seasonale®■84 combination hormone tablets■7 placebo tablets–e.g. Lybrel®/AmethystTM■Only combination hormone tablets (no placebo interval)–Useful for females with significant perimenstrual side effects and/or anemian.b. Both Seasonale®and Lybrel®use the same synthetic hormones (levonorgestrel and ethinyl estradiol), but at different doses

Progestin-Only Contraceptives■a.k.a. the “minipill”■Typically a lower dose than in combined oral contraceptive–Reduced probability of negative feedback on pituitary gland■MOA:–Decreased sperm motility through thickening of cervical and uterine mucus lining–May suppress ovulation in some cases

Progestin-Only Contraceptives■Useful where estrogen is inadvisable–Estrogen-responsive cancers■Daily administration; no placebo period–Withdrawal bleeding may or may not occur■Requirement of more consistent dosing–Take at same time every day Sources of potential anxiety that limit patient acceptance

■Similar rates of effectiveness (Combination and Progestin-only)–Approximately 3 unplanned pregnancies per 1000 women years (99.7%)…■…When used PERFECTLY–Typical use ~80-90 unplanned pregnancies/1000 woman years (91-92%)Effectiveness of Hormonal ContraceptionWhy the discrepancy between perfect and typical use?•Missed doses/improper dose timing (“off” by a few hours)•Drug interactions•CYP450 Induction•Phenytoin, St. John’s Wort

Long term Contraceptives■Injectable treatments–e.g. Depo-provera®(medroxyprogesterone acetate)■Intramuscularly every 3 months–MOA: identical to that of oral POCs■Implantable devices–Subcutaneous implantations–Intrauterine devices (IUD)■Progestin-releasing IUD 3-5 years of contraception–MOA: identical to that of oral POCs*■Copper IUDs ~10 years of contraception–MOA: sperm toxicity (movement and inhibition of fertilization)**A localized inflammatory response can occur, and may in fact contribute to contraception by creating a more inhospitable environment for implantation

Adverse Effects – Mild/Moderate■Breast pain (mastalgia)■Breakthrough (mid-cycle) bleeding■Lack of withdrawal bleeding■Weight gain, acne and hirsutism–Generally most prevalent with more androgenic progestins■(i.e. increased testosterone-like properties) ■Many effects will respond to a change in pill formulation–Different synthetic hormone and/or change in dosen.b.contraceptiveformulationswithnon-androgenicprogestinsmay actually reduce acne

Adverse effects - Severe■Depression■Thromboembolic disease–3-fold increase (1 to 3 events per 1000 women years)■Cardiovascular event/Stroke–Increased risk over age 35

Contraceptives and TED■General mechanism attributed to estrogen-induced increase in expression of several pro-coagulant clotting factors–Relative risk proportional to dose(L) https://www.ebmconsult.com/articles/oral-contraceptive-clotting-factors-thrombosis-dvt-pe(R) http://www.contraceptivetechnology.org/wp-content/uploads/2015/06/Blood-clot-risk.jpg (accessed March 2020)

■High-dose progestins(96.9-99.4%)–>> prophylactic contraception doses–Aim to inhibit ovulation■Selective Progestin Receptor Modulators (SPRMs)–Ulipristal(97.9-99.1%)■Partial agonist of progesterone receptor–RU-486 (mifepristone)■Antagonist of progesterone receptors■Approved in Canada (2015) as one half of mifegysimo (w/ misoprostol) (96.8-98.3%)–Also seem to work by inhibiting ovulation■Copper IUD (~99.9%)–Toxicity to sperm and ova, local inflammatory response–Most effective method, with pro/con of ongoing contraceptionEmergency ContraceptionSo… full agonists, partial agonists andantagonists of progesterone receptorsallworkasemergencycontraceptives???Efficacy data from Cleland et al. 2014. Clin Obstet Gynecol 57(4) and Fjerstad et al. 2009. Contraception 80(3)

Male Hormonal Contraception■Same strategy as in female hormonal contraception■Major challenge is inhibiting the scale of sperm cell production■Testosterone alone requires very high doses–Mosttherapylooksatcombination with progestins,or derivative agentsThirumalai and Page 2020. Annu. Rev. Med. 71

■Other, non-testosterone methods are being developed■2019 Study (Yuen et al. 2019. Presentation Abstract, ENDO 2019)–Synthetic testosterone derivative with progestational and androgenic activities■11β-MNT (given as 11β-MNTDC, an orally available prodrug)–Phase I Clinical trial results (40 men)■Concerned with safety over effectiveness–30 men, over 28 days, had reduced LH/FSH levels–No dropouts–Some side effects, but nothing classified as serious or significant■Fatigue (4), headache (6), acne (5), decreased libido (5), mild ED (2)■No change in depression scoresMale Hormonal Contraception

REPRODUCTIVE ASSISTANCE

■Inability to produce or maintain an erection sufficient for intercourse■Organic (physiogenic)–Altered function of the major systems involved in penile erection■Vascular■Neurologic■Endocrine–Possible causes: certain chronic diseases, medication use, lifestyle factors, aging■Non-organic (psychogenic)–No clear physiological cause–Harder to treat pharmacologicallyErectile Dysfunction

Physiology of an Erection1.Basal sympathetic tone is reduced, andincreased parasympathetic activity dilatescavernosal arterysmooth muscle–Nitric oxide and prostaglandin-mediated–Complex testosterone role2.Increased blood flow increases volume ofcorporal spaces3.Compressionofvenuleshelpsretainblood locallyOpenStax College. Anatomy and Physiology II. Available online at http://www.ubooks.pub/Books/ON/B0/E28R8369/TOC.html

Pharmacological Treatment■Phosphodiesterase Type 5 (PDE-5) Inhibitors–The “-afil” drugs■sildenafil (Viagra®), tadalafil (Cialis®), and vardenafil (Levitra®)■Alprostadil–Prostaglandin E1analogue■Testosterone–Only effective if basal endogenous hormone levels are low, but in such cases should be first line treatment

Pharmacodynamic Mechanisms■Cyclic GMP (cGMP) and cyclic AMP (cAMP) can both lead to decreased smooth muscle calcium concentrations and, consequently, smooth muscle relaxation■PDE-5 metabolizes cGMP; its inhibition by sildenafil et al. will preserve cGMP-mediated vasodilation, but there has to be an initial stimulus that produces the messenger molecule (i.e. as a class, these drugs are erection facilitators, not initiators)■PGE1-mediated stimulation of adenylyl cyclase is sufficient to initiate an erection without prior stimulus (in up to 90% of men)

Phosphodiesterase-5 inhibitors■First-line therapies–Convenient oral dosing■Sildenafil and vardenafil3-4 hour half-lives–Tadalafil18 hour half-life■Adverse effects via non-specific vasodilation…–…or interaction with other PDEs■e.g. altered color perception (PDE6 in retina)■Contraindicated with nitrate therapy■Cautioned if usingα-adrenoreceptor antagonistsMurthy and Mangot 2015. Indian J Pharmacology 47(6)

Alprostadil■Second-line therapy–Requires direct injection into corpus cavernosumor via transurethral suppository■Training required■Fear of needles–Lack of spontaneity■Inject 5-20 minutes before intercourse■Short half-life; erection lasts < 1 hour■Adverse effects–Pain, bleeding and/or bruising at injection site–Priaprism (painful, persistent erection)

Clomiphene■Partial agonist at estrogen receptors■Competes with estrogen for binding,but does not produce the same degreeof gonadotropin reduction–i.e. reduced negative feedback■Increased FSH/LH/estrogen secretion■10% multiple pregnancy rate

■Where anovulation is secondary to hypogonadic secretions■Expensive, complex try clomiphene first■Can also use to harvest oocytes for in vitro fertilization■Example protocol:1.FSH alone, or FSH + LH2.Monitor and adjust dose based on serum estrogens, follicular growth (ultrasound)3.Stop gonadotropin(s) and GnRH agonist/antagonist (if using) and give hCG to induce maturation and ovulation1.(optional) to prevent endogenous LH surges4.Inseminate, or retrieve oocytes5.Necessary due to decreased endogenous LH to support luteal phaseGonadotropin-mediated Ovulation

Drug Summary■Contraception–Hormonal■Combined oral contraceptives–Standard/Extended Cycle■Progestin-only contraceptives–Oral/Injectable/Implantable–Non-hormonal■Copper intrauterine device (IUD)–Emergency■High-dose progestins■Ulipristal■Mifepristone■Copper IUD■Reproductive Assistance–Erectile Dysfunction■Phosphodiesterase-5 Inhibitors–The “-afils”■Alprostadil–Clomiphene–Gonadotropin-mediated ovulation

Learning objectives1. For the sex steroids:a. Identifythemajorsubclass,themajorhormoneswithineach,andanydifferentiatingcharacteristics between themb. Describe some of the major clinical uses2. Explain how negative feedback occurs within the reproductive endocrine system, and how this isrelevant in terms of therapeutic and adverse effects of exogenous sex hormones3. Describe the primary mechanisms through which hormonal contraceptives may prevent fertilization4. Compareandcontrastcombinedoralcontraceptiveswithprogestin-onlycontraceptivesandimplantable devices in terms of the basic features (including alternative options within each class),mechanism(s) of action, indications and contraindications5. Describe the major factors that can lead to oral contraceptive failure6. Summarize the potential side effects associated with oral contraceptive use7. Explain the options (and mechanisms of action) for emergency (postcoital) contraception8. Describe the two major types of drugs useful in treating erectile dysfunction, their mechanisms ofaction, conditions of use, and their potential side effects and contraindications9. Describe how clomiphene may be useful in facilitating reproduction, including its mechanism of action10.Explain the general strategy through which GnRH agonists and antagonists can be used in assistedreproduction