Reproductive Pharmacology Past Paper 2025 (RCSI)

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Reproductive Pharmacology Class Year 2 Medicine Module Endocrine & Breast Title Reproductive Pharmacology including contraception Lecturer Prof. Maria Morgan ([email protected]) Prof. Will Ford (...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Reproductive Pharmacology Class Year 2 Medicine Module Endocrine & Breast Title Reproductive Pharmacology including contraception Lecturer Prof. Maria Morgan ([email protected]) Prof. Will Ford ([email protected])  2 Learning Outcomes 1. Describe the mechanism of action, clinical uses, common adverse effects and contraindications of synthetic oestrogens and progestins commonly used in contraception 2. Describe the mechanism of action and clinical use of anti- oestrogens and anti-progestogens using specific examples 3. Differentiate between the combined and progesterone only contraceptives, in terms of their clinical applications and pharmacology  3 HORMONE CONTROL OF FEMALE REPRODUCTIVE SYSTEM (HYPOTHALAMIC- PITUITARY-GONADO AXIS) Abbreviations: GnRH: Gonadotrophin-releasing hormone, FSH: follicle-stimulating hormone LH: luteinizing hormone, GF: graafian follicle, CL: corpus luteum Recap from earlier 4 Oestrogens: Actions Fertility control - ovum maturation/ development of the ovum/follicular unit. Timing of follicular phase is controlled by E2 Preparation of uterus for implantation – proliferation/vascularisation of endometrial cells – induction of progesterone receptors to allow progesterone response during luteal phase Inhibit FSH release, negative feedback on AP Metabolic action – Mineralocorticoid-like - retention of Na+ and water Lipids – Increase [HDL] in plasma – Decrease [LDL], [cholesterol] Increase coagulability of blood – Increases a number of clotting factors Maintains bone density and elasticity of skin & blood vessels  5 Mechanism of Action Receptors: ER and ER Intracellular – Gene transcription: induction/repression Recently -some rapid oestrogen effects mediated via membrane receptors – implicating a non-genomic mechanism of signaling, e.g. acute vasodilation  6 Therapeutic Oestrogen Natural Preparations – Oestradiol – Oral – Oestriol – Transdermal – Rapidly metabolised in – Intramuscular liver – Implantable – Topical Synthetic – Mestranol Administered – Stilbestrol – Almost always with a – Ethinylestradiol progestogen – Degraded less rapidly  7 Oestrogen Clinical Uses: – (dependent on sex and sexual maturity) Contraception – given cyclically Replacement therapy – Primary ovarian failure (e.g. Turner’s syndrome) – Secondary ovarian failure (menopause), HRT  8 Side Effects - Oestrogen Nausea, vomiting Retention of salt and water - oedema -  BP  risk thromboembolism  risk for uterine (endometrial), ovarian and breast cancer In males - feminisation  9 Contraindications - Oestrogen Oestrogen dependent tumours – e.g. carcinoma of the endometrium, or high risk of breast cancer Undiagnosed genital bleeding Liver disease History of thromboembolic disorder Best avoided by heavy smokers  10 Anti-oestrogens Compete with natural oestrogens for receptors in target organs Tamoxifen Clomifene – Oestrogen antagonist (SERM) – Oestrogen antagonist (SERM) – To treat oestrogen +ve breast cancer – Induce ovulation - infertility treatment – Mild oestrogen-like side effects - partial agonist on – Inhibits oestrogen binding plasma lipids, endometrium & in anterior pituitary bone preventing normal negative feedback – Reduction in osteoporotic fractures – Causing FSH, LH – Stimulation of ovaries Recap from earlier 11 Progestogens: Actions Hormonal effects – maturation of the endometrium – supports gestation and embryogenesis Other effects – Increase basal insulin & insulin response to glucose – Increases body temperature – Depressant  12 Progestogen Preparations 1. a.) Naturally occurring hormone virtually inactive orally (metabolized by liver) b.) Derivatives e.g. Hydroxyprogesterone, administered i.m. 2. Testosterone derivatives – Can be given orally – E.g. Norgestrel (has androgenic activity) – Newer progestogens: e.g. Desogestrel – used in contraception, less adverse effects but higher risk of thromboembolism  13 Progestogens Clinical Uses – Contraception – Hormone replacement therapy – Endometriosis (growth of tissue like endometrium, beyond or outside the uterus) – Endometrial cancer  14 Anti-progestogen Mifepristone (RU486) In the presence of progesterone acts as a competitive receptor antagonist at the progesterone receptor [Also in the absence of progesterone acts as a partial agonist at progesterone receptors] Use Medical termination of intrauterine pregnancies Used alone or in combination with prostaglandin E1 analogue [gemeprost or misoprostol] (induce uterine contractions)  15 CONTRACEPTION Techniques and methods used to prevent human fertilization. Includes: – Barrier methods, e.g. condoms/diaphragm – Intrauterine system/device – Hormonal methods Approx. life of egg after ovulation is ~12-24 hours Fertilization can take place for about 12-24 hours after ovulation Possible for sperm to live in female reproductive tract for up to ~3-5 days therefore sexual intercourse 5 days before ovulation can result in fertilization  16 Hormonal Contraceptives Oral Contraceptives Combined pill Progestogen-only pill Long acting progestogen-only Emergency (post-coital) contraception  17 Oral Contraceptives I Combined pill: Oestrogen + a Progestogen – E.g. >20g Ethinylestradiol + >100g Norethisterone (or levonorgestrel) – Taken for 21 consecutive days, 7 hormone-free days MOA: Oestrogen: inhibits FSH release & development of ovarian follicle Progestogen: inhibits LH release & prevents ovulation, Makes cervical mucus inhospitable to sperm 99.5% successful if compliant Can be mono-, bi- or tri-phasic Progestogen withdrawal after 21 days precipitates menstruation Side effects – Weight gain, nausea, mood changes, skin pigmentation – S/E mostly limited to first few cycles – Hypertension, breast cancer, thromboembolism: rare  18 Oral Contraceptives II Progestogen-only pill (Mini-pill) – E.g. 350 g norethisterone (Noriday) – or 75 g desogestrel (Cerazette) less common – Taken daily, no interruption MOA: makes cervical mucus inhospitable to sperm/hinders implantations, inhibits LH release & prevents ovulation 99% reliable if compliant Irregular menstruation or amenorrhoea Ovarian cysts a risk Uses: where oestrogen contraindicated, women with e.g.  BP with oestrogen History of venous thromboembolism (VTE) Smokers over 35 yrs Can be used by nursing mothers  19 Drug Interactions with Oral Contraceptive Pill (OCP) Minimum effective dose hormone used, any ↓ in absorption or ↑ in its clearance  contraceptive failure. Vomiting & severe diarrhoea may interfere with absorption. OCP’s metabolized by hepatic cytochrome P450 enzymes. Medications which interfere with OCP and require additional contraceptive precautions include: CYP enzyme-inducing antibiotics: rifampicin and rifabutin If an antibiotic causes vomiting or diarrhoea - advise to follow “seven day rule”; use other methods of contraception during period of illness and until seven active pills have been taken. Seizure Medication: Phenytoin (enhances CYP450 activity) St John's wort (enhances CYP450 activity)  20 Contraceptives III Long acting progestogen-only 1. Progestogen-only injectables Medroxyprogesterone acetate 150 mg (DepoProvera) Slowly released into the systemic circulation following intramuscular injection Every 3 months, effective, but menstrual irregularities common Reduction in bone mineral density and rarely, osteoporosis – not suitable for long term use (>2yrs) Suppress ovulation and cervical mucus is thickened, preventing sperm penetration 2. Progestogen-only subdermal implant Etonogestrel 68mg implanted subcutaneously non-biodegradable capsules (Implanon NXT/Nexplanon) Release over 3yrs, removed no later than end of 3rd year Irregular bleeding/headaches Suppress ovulation and cervical mucus is thickened, preventing sperm penetration  21 Contraceptives IV Emergency (post-coital) contraception after unprotected intercourse or contraceptive failure Emergency contraceptive pills are not 100% effective Mechanism of action: delay/inhibition of ovulation, also modifies cervical mucus – First half of cycle: prevents ovulation – Second half of cycle if ovulation has already occurred - delays movement of egg in fallopian tube and thickens cervical mucus Emergency contraceptive pills cannot interrupt an established pregnancy 1. Progestin-only: Levonorgestrel (1.5 mg tablet) – must be taken within 72 hours, efficacy decreases with time – nausea and vomiting common – weight will affect efficacy – e.g.: Levonelle or NorLevo (Ireland- 2011 prescription no longer required) Plan B (US) 2. Ulipristal acetate (ellaOne) – used to prevent pregnancy up to 120 hours (5 days) – a progesterone receptor modulator  22 FURTHER READING Pharmacology, (Authors: Rang, Dale, Ritter, Moore) Section 3, Chapter 29 Reproductive System Overview of the use of oestrogen-progestin contraceptives: http://www.uptodate.com/contents/overview-of-the-use-of-estrogen- progestin-contraceptives?source=see_link&anchor=H27#H27 The Science of 'Plan B' - Emergency Contraception: http://www.youtube.com/watch?v=7Vozr9vHeMo&feature=endscreen&NR=1 Postmenopausal hormone therapy: http://www.uptodate.com/contents/postmenopausal-hormone-therapy-benefits-and- risks?source=search_result&search=menopause+treatment&selectedTitle=4%7E150 Email comments/questions to: [email protected] SUMMARY 1 Anti-oestrogens – Compete with natural oestrogens for receptors in target organs – Tamoxifen – Clomifene Anti-progestogen – Mifepristone (RU486) - In the presence of progesterone acts as a competitive receptor antagonist at the progesterone receptor – Used alone or in combination with prostaglandin E1 analogue [gemeprost or misoprostol] (induce uterine contractions) HORMONAL CONTRACEPTION SUMMARY 2 Oral Contraceptives 1. Combined pill - Oestrogen + a Progestogen. E.g. Ethinylestradiol + Norethisterone (or levonorgestrel) 2. Progestogen-only pill - E.g. Norethisterone or desogestrel Long acting progestogen-only 1. Progestogen-only injectables - Medroxyprogesterone acetate (DepoProvera) 2. Progestogen-only subdermal implant - Etonogestrel implanted subcutaneously non-biodegradable capsules (Implanon NXT/Nexplanon) Emergency contraception 1. Progestin-only method: Levonorgestrel (1.5 mg tablet) 2. Ulipristal acetate (ellaOne) effective up to 120 hours (5 days)  25 Appendix – for reference only 26  STUDENT REQUIRING ASSISTANCE? RCSI CoMPPAS Student Assistance Programme (24 hrs/365 days) – a confidential and independent counselling and specialist information service available to all RCSI students located anywhere at anytime. 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