BMS2047 Hormone Modulators Lecture Notes PDF

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