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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 with cervical dilation, highly dependent on the level of estrogen and condition of uterus. (2) Breast: milk ejection（泌乳反射）.

  6. Oxytocin (OXT, 催产素) A. Oxytocics 2. Clinical uses: (1) to expedite delivery (催产) and to induce labor (引产); (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, -- scar uterus, 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) 1. Pharmacological effects: (1) Uterus（麦角新碱）: stimulate uterine smooth muscle, more effective on pregnant uterus, strong and long lasting effect, without distension of the cervix. (2) Blood vessel（麦角胺） contract peripheral and cerebral blood vessels.

  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

  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 at both early and late phase of pregnancy.

  13. A. Oxytocics Prostaglandins(PGs, 前列腺素) 2. Clinical uses: to terminate early pregnancy (PGE2) or induce labor (PGF2) and to treat endometrorrhagia (子宫出血) 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 替勃龙 tibolone 雌激素类药物的基本结构: 乙烯雌酚 Diethystibestol 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 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)

  21. 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.

  22. 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 (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).

  23. 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) （large doses ）

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

  25. 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) , stimulates FSH and LH secretion. 2. Clinical uses: (1) Functional (anovulatory) infertility; (2) Menstrual disorders; (3) Advanced breast cancer.

  26. 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 term and large dose use.

  27. 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, but an agonist in the bone and endometrium. 2. Clinical uses: Estrogen dependent breast cancer and postmenopausal osteoporosis. 3. Adverse effects Increases the risk of endometrial carcinoma.

  28. 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

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

  30. 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.

  31. 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

  32. 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

  33. 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

  34. B. Progestogens & antiprogestogens Progestogens 2. Clinical uses: (1) Menstrual disorders: dysfunctional uterine bleeding; dysmenorrhea (痛经); endometriosis(子宫内膜异位症). (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.

  35. 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)

  36. B. Progestogens & antiprogestogens Antiprogestogens (抗孕激素药) Mifepristone (米非司酮) - a derivation of synthetic progestogens norethindrone (炔诺酮). - antagonizes progestogen receptors. - used for emergency contraception and termination of early pregnancy.

  37. 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) 。。。。。。

  38. 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).

  39. 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,especially with postmenopausal syndrome (3) Advanced breast and ovarian cancers (4) Anemia: aplastic anemia (再生障碍性贫血). (5) Others: infirmity (体质虚弱), prevention of benign prostatic hypertrophy, etc.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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)

  45. D. Contraceptives 1. Pharmacological effects: (1) Inhibition of ovulation; (2) Prevention of fertilization; (3) Inhibition of implantation.

  46. D. Contraceptives 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.

  47. 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)

  48. 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) Irreversible spermatogenic disturbance

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