BMS2047_03_Hormone Modulators_2022_Y.pdf
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BMS2047: Hormone Modulators; Female Sex hormones Lecture Bite 1 LEARNING OUTCOMES Describe mechanisms of action of contraceptive drugs and explain how these link to side effects. Explain mechanisms regulating hormones with relation to cancer therapy, hormone replacement and infertility Why do we...
BMS2047: Hormone Modulators; Female Sex hormones Lecture Bite 1 LEARNING OUTCOMES Describe mechanisms of action of contraceptive drugs and explain how these link to side effects. Explain mechanisms regulating hormones with relation to cancer therapy, hormone replacement and infertility Why do we care about manipulating reproductive hormones? In Females: ABOVE: Figure 28.26b Tortora & Derrickson Principles of Anatomy and Physiology (2017) 15th Edition RIGHT: Figure 35.1 Rang & Dales Pharmacology (2016) 8th Edition Female Contraceptives Combined pill: Oestrogen combined with progestogen e.g. ethinylestradiol & levonorgestrel Oral administration for 21 days, 7 days pill free Ovarian and Breast cancer risk is reduced SIDE EFFECTS: weight gain, nausea, flushing, dizziness and depression, increased blood pressure Rang & Dales Pharmacology (2016) 8th Edition Female Contraceptives Progesterone only (mini pill): Single progestogen: Testosterone derivatives e.g. norgestrel and ethynodiol Progesterone derivatives e.g. hydroxyprogesterone, medroxyprogesterone Oral administration for 28 days Newer progestogens e.g. desogestrel and gestodene may have fewer adverse effects SIDE EFFECTS: achne, depression, breakthrough bleeding, venous thromboembolic disease Rang & Dales Pharmacology (2016) 8th Edition Female Contraceptives Progesterone only: (Implant): Single progestogen: Nexplanon Lasts for 3 years SIDE EFFECTS: amenorrhoea, depression, breakthrough bleeding, venous thromboembolic disease Not compatible with: medicines for HIV, epilepsy and tuberculosis, St John's Wort, antibiotics including rifabutin or rifampicin (See drug:drug interactions ADME lectures) Rang & Dales Pharmacology (2016) 8th Edition Emergency contraception Selective Progesterone Receptor Modulators (SPRMs) Mifepristone combined with prostaglandin (e.g. gemeprost) to induce termination of pregnancy Mifepristone is a partial agonists of progesterone receptors (PR) PR in uterus sensitise the endometrium to prostaglandins Oral administration T1/2 of 21hrs in plasma Hormone Replacement Therapy (HRT) Low doses of one or more oestrogens, with or without a progestogen. Short-term HRT has some clear-cut benefits: Less symptoms of menopause e.g. hot flushes & vaginal dryness Preserve bone density Can be used in treatment of Turner Syndrome SIDE EFFECTS: cyclical withdrawal bleeding, increased risk of endometrial cancer, increased risk of breast cancer, increased risk of venous thromboembolism Oestrogen Ablation therapy Used during and after ER positive breast cancer e.g tamoxifen SERMs e.g. Raloxifene used in osteoporosis: Reduced proliferation in breast and uterus Stimulate ERs in bone → bone deposition After menopause the main source of Oestrgen is adipose tissue where Androstenedione is converted to Oestrone or Oestradiol E.g. Anastroxole inhibits aromatase enzyme that enables Oestrogen production Oestrogen Receptor activation drives proliferation through expression of cell cycle targets e.g. cyclin D1 Figure 35.3 Rang & Dales Pharmacology (2016) 8th Edition Why do we care about manipulating reproductive hormones? Male Reproductive therapies Lecture Bite 2 In Males: LH Leydig cells Figure 35.4 Rang & Dales Pharmacology (2016) 8th Edition Male Contraceptives New drug being tested: dimethandrolone undecanoate (DMAU) Combination of hormones; androgen and a progestin e.g. testosterone & a progestin SIDE EFFECTS: Weight gain, decreased HDL. Previous problems: Available forms of testosterone → liver inflammation Short T1/2 Effects of peripheral testosterone depletion https://www.theguardian.com/science/2019/mar/25/hopes-rise-male-contraceptivepill-breakthrough-side-effects Male Contraceptives New drug being tested: dimethandrolone undecanoate (DMAU) Combination of hormones; androgen and a progestin e.g. testosterone & a progestin SIDE EFFECTS: Weight gain, decreased HDL. Previous problems: Available forms of testosterone → liver inflammation Short T1/2 Effects of peripheral testosterone depletion Gava (2019) Ther Adv Endocrinol Metab.14;10:2042018819834846 Androgen Replacement therapy Used in either pituitary or testicular disease Synthetic androgens e.g. mesterolone Orally administered SIDE EFFECTS: In women and pre-pubescent children causes masculineisation, decrease in LH & FSH. testosterone mesterolone Androgen Ablation therapy Testosterone is converted to dihydrotestosterone (DHT) in peripheral organs Finasteride used to reduce benign prostate hyperplasia Figure 35.4 Rang & Dales Pharmacology (2016) 8th Edition Androgen Ablation therapy Testosterone is converted to dihydrotestosterone (DHT) in peripheral organs Finasteride used to reduce benign prostate hyperplasia E.g. enzalutamide used in prostate cancer therapy Androgen Receptor activation drives proliferation through gene expression Figure 35.4 Rang & Dales Pharmacology (2016) 8th Edition Drugs used in infertility Gonadotrophin-Releasing Hormone: Agonists (Females) E.g. Clomiphene Oestrogen antagonist Stimulates release of GnRH by inhibiting negative feedback of endogenous oestrogen by inhibiting oestrogen binding in the anterior pituitary Stimulates and enlarges the ovaries, increases oestrogen secretion and induces ovulation. Used in treatment of infertility when there is a lack of ovulation. Twins are common, but multiple pregnancy is unusual. SIDE EFFECTS: abdominal or pelvic pain, tenderness, Rang & Dales Pharmacology (2016) 8th Edition pressure, or swelling; flushing, nausea, vomiting, or diarrhoea, blurred vision, headache; abnormal uterine bleeding. Drugs used in infertility Phosphodiesterase inhibitors (Male) Used in treatment of erectile dysfunction to enhance the erectile response to sexual stimulation E.g. Sildenafil (Viagra) NO induced vasodilation in penis → increased blood flow Oral administration causes effects after ~30-120 minutes Metabolised by CYP3A4, which is induced by some other drugs and inhibited by some antibiotics, antifungals and antiviral drugs. References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. Recapping Physiology: Gerard J. Tortora & Bryan H. Derrickson. Principles of Anatomy and Physiology, 15th Edition (2017). (most figures from here). Access via Kortext to 15th Edition, 14th Edition available in the library – perfectly fine to use. Silverthorn Human Physiology: An Integrated Approach; 7th Ed; 2016; Pearson Education Ltd. Available as e-book through library website when you log on, also copies of 7th Edn in library. Or come and talk to me References IN MORE DETAIL: Thyroid Kogai, T., Taki, K., & Brent G.A. (2006) Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocrine-Related Cancer 13: 797–826. (TSH signalling) IN MORE DETAIL: Sex hormones Male pill: https://clinicaltrials.gov/ct2/show/NCT01382069 & https://www.endocrine.org/newsroom/2018/dimethandrolone-undecanoate-shows-promise-as-a-male-birth-control-pill Hoffman-Censits, J & Kelly, W,K. (2013) Enzalutamide: A Novel Antiandrogen for Patients with Castrate-Resistant Prostate Cancer. Clin Cancer Res19:1335-1339 https://www.bbc.co.uk/news/health-47691567 Anawalt BD, Roth MY, Ceponis J, Surampudi V, Amory JK, et al. (2019) Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men. Andrology. April 2019 [Epub ahead of print] Gava G1, Meriggiola MC2 (2019) Update on male hormonal contraception. Ther Adv Endocrinol Metab. 10:2042018819834846. Or come and talk to me
