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Shi-Hong Zhang ( 张世红 ) Email: shzhang713@zju

Pharmacology of reproductive system 生殖系统药理学. Shi-Hong Zhang ( 张世红 ) Email: shzhang713@zju.edu.cn. Content. Part 1. Oxytocics and Tocolytic drugs 子宫平滑肌兴奋药和抑制药 Part 2. Sex hormones and contraceptives 性激素类药和避孕药. Pharmacology of reproductive system.

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Shi-Hong Zhang ( 张世红 ) Email: shzhang713@zju

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  1. Pharmacology of reproductive system 生殖系统药理学 Shi-Hong Zhang (张世红) Email: shzhang713@zju.edu.cn

  2. Content Part 1. Oxytocics and Tocolytic drugs 子宫平滑肌兴奋药和抑制药 Part 2.Sex hormones and contraceptives 性激素类药和避孕药

  3. Pharmacology of reproductive system Oxytocics and Tocolytic drug子宫平滑肌兴奋药和抑制药 Part 1

  4. A. Oxytocics • Oxytocin (催产素，缩宫素) • Pituitrin (垂体后叶素) • Ergot alkaloids (麦角生物碱) • Prostaglandins (PGs, 前列腺素)

  5. Oxytocin (OXT, 催产素) A. Oxytocics 1. Pharmacological effects: (1) Uterus: Dose-dependently stimulates both the frequency and force of uterine contractions, highly dependent on the level of estrogen and condition of uterus. (2) Breast: milk ejection.

  6. Oxytocin (OXT, 催产素) A. Oxytocics 2. Clinical uses: (1) to expedite delivery and induced labor; (2) to reduce the incidence and extent of postpartum hemorrhage (产后出血).

  7. Oxytocin (OXT, 催产素) A. Oxytocics 3. Adverse effects: (1) Overdose: intrauterine asphyxia胎儿窘迫 or uterine rupture子宫破裂 (2) Allergy 4. Contraindications: --hypertonic dysfunction of uterus -- abnormality of birth canal -- abnormal fetal position, etc.

  8. A. Oxytocics Pituitrin(垂体后叶素) Containing: oxytocin 催产素 vasopressin 加压素，抗利尿激素

  9. A. Oxytocics Ergot alkaloids(麦角生物碱)Ergometrine(麦角新碱),Ergotamine(麦角胺), Ergotoxine(麦角毒) 1. Pharmacological effects: (1) Uterus (麦角新碱): stimulate uterine smooth muscle. (2) Blood vessel (麦角胺): contract peripheral and cerebral blood vessels. (3) block  receptor (麦角毒):

  10. A. Oxytocics Ergot alkaloids(麦角生物碱) 2. Clinical uses: (1) Endometrorrhagia (子宫出血), and puerperal replacement of uterus (产后子宫复位) : ergometrine; (2) Migraine (偏头痛) : ergotamine; (3) Hibernation therapy (冬眠疗法) : dihydroergotoxine (氢化麦角毒).

  11. A. Oxytocics Ergot alkaloids(麦角生物碱) 3. Adverse effects: -- nausea, vomiting, BP ; -- allergic reaction; -- not used in expediting delivery and induced labor.

  12. A. Oxytocics Prostaglandins(PGs, 前列腺素) Dinoprostone (地诺前列酮, PGE2) Dinoprost (地诺前列素,PGF2) Sulprostone (硫前列酮) 1. Pharmacological effect: stimulate uterine smooth muscle in early to late phase of pregnancy.

  13. A. Oxytocics Prostaglandins(PGs, 前列腺素) Dinoprostone (地诺前列酮, PGE2) Dinoprost (地诺前列素,PGF2) Sulprostone (硫前列酮) 2. Clinical uses: to terminate early pregnancy (PGE2) or induce labor (PGF2) and to treat endometrorrhagia 3. Adverse effects: GI reaction, asthma (PGF2), glaucoma (PGE2).

  14. B. Tocolytic drugs 2 adrenoceptor agonists Ritodrine (利托君)Terbutaline (特布他林)Salbutamol (沙丁胺醇) Other tocolytic drugs Magnesium sulfate (硫酸镁) Nifedipine (硝苯地平) Indomethacin (吲哚美辛)

  15. Pharmacology of reproductive system Sex hormones and contraceptives Part 2

  16. A B C D Basic structure of steroid hormones

  17. SHBG Signal transduction of steroids

  18. Part 2.Sex hormones and contraceptives Female hormones(女性激素类): Estrogens (雌激素) Antiestrogens (抗雌激素) Progestogens (孕激素) Antiprogestogens (抗孕激素) Male hormones (男性激素类): Androgens (雄激素) and Anabolic steroids(同化激素) Antiandrogens (抗雄激素) Contraceptives(避孕药): Female contraceptives (女性用避孕药) Male contraceptives (男性用避孕药)

  19. A. Estrogens & antiestrogens 雌激素类药物的基本结构: 雌二醇 戊酸雌二醇 环丙戊酸雌二醇 炔雌醇 甲炔雌醇 炔雌醚 雌酮 硫酸雌酮 马烯雌酮

  20. A. Estrogens & antiestrogens Diethystibestol (己烯雌酚, 乙菧酚)

  21. A. Estrogens & antiestrogens Estrogens 1.Pharmacological effects: (1) Development of female sexual organs and female secondary sex characteristics; (2) Maintenance of both proliferation and thickening of endometrium 子宫内膜; (3) Ovulation:  (small doses), or  (large doses) (4) Development of breast and lactation:  (small doses), or  (large doses)

  22. A. Estrogens & antiestrogens Estrogens (5) Other actions:  aldosterone excretion, H2O and Na+ retention; LDL and  triglycerides,  HDL levels;  calcium deposit of bone; activity of factor Ⅱ, Ⅶ, Ⅸ, Ⅹ,  coagulation; postmenopausal sleep disturbances; Against androgen.

  23. A. Estrogens & antiestrogens Estrogens 2.Clinical uses: (1) Postmenopausal syndrome更年期综合症: Hormone replacement therapy (HRT) Osteoporosis (骨质疏松症); vasomotor symptoms; Prevention of cardiovascular diseases (2) Menstrual disorders月经紊乱: Hypoovaria (卵巢功能不全) & amenorrhea (闭经); Dysfunctional uterine bleeding (功能性子宫出血).

  24. A. Estrogens & antiestrogens Estrogens 2.Clinical uses: (3) Contraception: combined with progestogens (4)Others: Androgen-dependent carcinoma: postmenopausal breast cancer; prostatic cancer; Acne (痤疮); Delactation (回奶) at large doses

  25. A. Estrogens & antiestrogens Estrogens 3. Adverse effects: (1) General adverse effects: nausea, vomiting, diarrhea, etc. (2) Cardiovascular effects:  risk of venous thromboembolisis;  plasma triglycerides; hypertension, edema. (3) Others:  risk of breast and endometrial carcinoma.

  26. A. Estrogens & antiestrogens Antiestrogens Clomifene (氯米芬, 克罗米酚) 1. Pharmacological effects: Partial agonist for estrogen receptor (analog of diethystibestol, 己烯雌酚) . 2. Clinical uses: (1) Functional (anovulatory) infertility; (2) Menstrual disorders; (3) Advanced breast cancer.

  27. A. Estrogens & antiestrogens Antiestrogens Clomifene(氯米芬, 克罗米酚) 3.Adverse effects: (1) Multiple ovulation with multiple pregnancy; (2) Visual disturbance (2) Ovarian hypertrophy following long time and large dose use.

  28. A. Estrogens & antiestrogens Antiestrogens Tamoxifen (他莫昔芬, 三苯氧胺) 1. Pharmacological effects: A non-steroid competitive antagonist to ER in breasts. 2. Clinical uses: Estrogen dependent breast cancer and postmenopausal osteoporosis. 3. Adverse effects Increases the risk of endometrial carcinoma.

  29. 术后5年他莫昔芬获益 Recurrence BreastCancerMortality 5y Δ12.3% 10y 14.2% 15y 13.2% 5y Δ3.3% 10y 7.2% 15y 9.2% EBCTCG,Lancet2011

  30. A. Estrogens & antiestrogens Antiestrogens Raloxifene (雷洛昔芬) 1. Pharmacological effects: Selectively stimulates ER in the bone. 2. Clinical uses: Postmenopausal osteoporosis.

  31. A. Estrogens & antiestrogens Antiestrogens Anatrozole (阿那曲唑) 1. Pharmacological effects: Aromatase inhibitor (芳香化酶抑制剂). 2. Clinical uses: Estrogen-dependent breast cancer.

  32. AI与TAM的作用机理不同 为绝经后ER阳性乳癌患者提供了新的选择 ER ER 绝经后患者 绝经前患者 来自卵巢 来自外周 脂肪组织: 包括乳房脂肪组织 纤维原细胞: 存在于原发灶及转移灶周围 卵巢功能抑制GnRH 抑制剂 或卵巢切除 芳香化酶抑制剂AI 雌激素 雌激素受体拮抗剂TAM • 外生性雌激素 • 来自外周环境 • 药物源性 X 肿瘤 细胞

  33. B. Progestogens & antiprogestogens 黄体酮(孕酮) (乙酸)甲地孕酮 (乙酸)甲羟孕酮 （安宫黄体酮） 19-去甲睾酮 炔诺酮 乙醋炔诺酮 甲烯炔诺酮 肟炔诺酯 炔诺孕酮

  34. B. Progestogens & antiprogestogens Progestogens 1. Pharmacological effects: (1) Converttheuterineepitheliumfrom theproliferativetothesecretoryphase; (2) Inhibit LH secretion and ovulation (contraceptive effect); (3) Inhibit uterine contraction (4) Mammary acinus (乳腺腺泡) development; (5) Affect thermoregulation, promote protein catabolism

  35. B. Progestogens & antiprogestogens Progestogens 2. Clinical uses: (1) Menstrual disorders: dysfunctional uterine bleeding; dysmenorrhea (痛经); endometriosis(子宫内膜异位症); postmenopausal syndrome, etc. (2) Endometrial cancer (子宫内膜癌); (3) Prostatic hypertrophy 前列腺肥大 and cancer; (4) Abortion: threatened abortion(先兆流产), and habitual abortion(习惯性流产), etc. (5) Contraception combining with estrogens.

  36. B. Progestogens & antiprogestogens Progestogens 3.Adverse effects: Gastrointestinal reactions; Virilization in female fetus (女性胎儿男性化); Acne (痤疮); Hirsulism (多毛)

  37. B. Progestogens & antiprogestogens Antiprogestogens (抗孕激素药) Mifepristone (米非司酮) - a derivationofsyntheticprogestogens norethindrone (炔诺酮). - antagonizes the receptors of progestogen. - usedfor emergency contraception and terminationofearlypregnancy.

  38. C. Androgens & antiandrogens Androgens (雄激素) Natural androgens: Testosterone(睾酮, 睾丸酮) Synthetic androgens: Methyltestosterone (甲睾酮) Testosterone propionate (丙酸睾酮) Testosterone phenylacetate (苯乙酸睾酮) Testosterone undecanoate (十一酸睾酮) 。。。。。。

  39. C. Androgens & antiandrogens Androgens (雄激素) 1. Pharmacological effects: (1) Developmentofthemalesexualorgans and secondary sex characteristics; (2) Necessaryfornormalspermatogenesis; (3) Promotegrowthofbloodcellsinbone marrow (by increasing EPO) (4) Increase protein anabolism (anabolic effect).

  40. C. Androgens & antiandrogens Androgens (雄激素) 2. Clinical uses: (1) Replacement therapy: male hypogonadism (男性性腺发育不全) (2) Dysfunctional uterine bleeding (3) Advanced breast and ovarian cancers (4) Postmenopausal syndrome (5) Anemia: aplastic anemia (再生障碍性贫血). (6) Others: infirmity (体质虚弱), prevention of benign prostatic hypertrophy, etc.

  41. C. Androgens & antiandrogens Androgens (雄激素) 3.Adverse effects: (1) Female:Virilescence in female (女性男性化) (2) Male: Sexual disturbance (hyperesthesis and hypoesthesis). (3) Hepatic toxicity.

  42. C. Androgens & antiandrogens Anabolic hormones (同化激素类药) Nandrolonpheypropionate (苯丙酸诺龙) Metandienone (美雄酮, 去氢甲基睾丸素, 大力补) Stanozolol (司坦唑醇, 康力龙) -- Promote synthesis of protein; inhibiting protein catabolism. -- Used for serious malnutrition; cachexia (恶病质); serious burn; senile osteoporosis; etc. -- Adverse effects: H2O and Na+ retention, virilescence in female, etc.

  43. C. Androgens & antiandrogens Antiandrogens (抗雄激素药) Cyproterone (环丙孕酮) 1. Pharmacological effects: Inhibits hypothalamus-pituitary axis  LH , FSH  testosterone ; Antagonizing androgen 2. Clinical uses:Prostatic cancer, severe acne and hirsutism (多毛症), contraception for males. 3. Adverse effects:Suppresses development of sex organs and function, affects hepatic function, etc.

  44. D. Contraceptives 1. Features of good contraceptives: (1) Extremely safe as well as highly effective; (2) The effects must be quick in onset, quickly and completely reversible, even after years of continuous use; (3) Unable to affect libido.

  45. D. Contraceptives 2. The types of female contraceptives: (1) Oral preparations: - Short-effect contraceptives - Long-effect contraceptives - Temporary contraceptives (2) Long-effect injectable contraceptives (3) Delay-releasing preparations of contraceptives (4) Heterogeneous preparations of contraceptives (5) External contraceptives (spermicides, 杀精剂)

  46. D. Contraceptives Combination contraceptives Estrogens + Progestogens 1. Pharmacological effects: (1) Inhibition of ovulation; (2) Prevention of fertilization; (3) Inhibition of implantation.

  47. D. Contraceptives Estrogens + Progestogens 2. Adverse effects: (1) Gastrointestinal reactions; (2) Menstrual disorders; (3) Increased coagulation; (4) Contraindication: acute hepatitis, acute nephritis, and mastoplastia (乳房组织增生), etc.

  48. D. Contraceptives Emergency contraceptive pills (ECPs) Levonorgestrel (左炔诺酮, 毓婷) Similar effects withnorethindrone (炔诺酮); High progestogen-like activity; High androgen-like activity; Anti-estrogen activity; Anti-ovulation activity; Anti-implantation Mifepristone (米非司酮，弗乃尔)

  49. D. Contraceptives Male Contraceptives (男性避孕药) Gossypol (棉酚) 1. Pharmacological effects: Inhibition of spermatogenesis 2. Adverse reactions: (1) GI reaction, palpitation, hepatic injury; (2) Hypokalemia; (3) Irreversiblespermatogenic disturbance

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