Drugs Affecting Reproductive System

1. Drugs Affecting Reproductive System Ling Ding, Ph. D., Associate Professor College of Pharmaceutical Sciences Zhejiang UniversityChina 310058Email: ld362@zju.edu.cn

2. Female systemic effects

3. Male systemic effects sperm

4. Sex hormones and related drugs • Estrogens and antiestrogens • Progestogens and antiprogestogens • Contraceptive drugs • Drugs acting on uterus smooth muscle

5. Estrogens and antiestrogens • Three major naturally occurring oestrogens in women • Estradiol (E2)the predominant form in nonpregnant • females • Estrone (E1) produced during menopause • Estriol (E3) the primary oestrogen of pregnancy

6. 雌二醇 戊酸雌二醇 雌二醇环戊丙酸脂 乙炔雌二醇 氢甲睾丸素 炔雌醚 雌酮 马烯雌酮

7. Estrogens and antiestrogens Estradiol 雌二醇Diethylstibestrol 己烯雌酚 Clomiphene 氯米酚

8. Estrogens Pharmacological effects • Development of the female genital tract and of the female secondary sex characeteristics. • Maintenance of both proliferative and secretory phases of the uterine endometrium • Ovulation:  (small doses) or  (larger doses) • Development of the breast and lactescence •  (small doses) or  (larger doses)

9. Estrogens Pharmacological effects Other actions: • decreasing postmenopausal disturbances in sleep • inhibiting the reabsorption of bone • increasing aldosterone and causing water and Na+ retention • decreasing LDL and increasing HDL levels in plasma • increasing factor II, VII, IX, X and coagulation

10. Estrogens Pharmacological effects of estrogens

11. Estrogens Clinical uses (1) Postmenopausal syndrome- tibolone Postmenpausal hormone replacement therapy (HRT): • prevention of osteoporosis; - Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter. • treat vasomotor & CNS symptoms - hot flushes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. • prevention of cardiovascular disease -lowers LDL ,TG; raises HDL levels -endothelial vasodilatation properties , anti-inflammatory

12. Estrogens (2) Primary hypogonadism (卵巢功能不全): replacement • vaginal atrophy, hypoestrogenism (3) Menstrual disorders • amenorrhea , dysmenorrhea, and oligomenorrhea; • severe dysfunctional uterine bleeding (4) Contraception (5) Others: • suppress lactation after child birth • advanced breast cancer (postmenopausal) and prostatic cancer -hormone-sensitive or hormone-receptor-positive cancers -hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy) • acne • neuroprotection

13. Estrogens 3. Adverse effects (1) Oral administration: nausea,vomiting, diarrhea (2) Cardiovascular effects: • risk of venous thromboembolisis • plasma triglycerides  • hypertension, edema (3) Others: • gallbladder disease • risk of breast and endometrial carcinoma

14. Estrogens The estrogen-alone •  stroke and deep vein thrombosis (DVT) in postmenopausal women>50y •  dementia in postmenopausal women>65y using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin •  risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women >50y •  dementia in postmenopausal women>65y using 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).

15. Antiestrogens Clomifene 氯米芬 (克罗米酚) (1) Effects: Partial agonist/antagonist for estrogen receptor

16. Antiestrogens • Effects: Partial agonist/antagonist for estrogen receptor (2) Uses: • anovulatory infertility (无排卵性不孕) • menstrual disorders • advanced breast cancer • functional amenorrhea (功能性闭经) • amenorrhea galactorrhea syndrome (闭经溢乳综合征) (3) Adverse effects: • Multiple ovulation with multiple pregnancy (多胎) • ovary tumefaction (卵巢肿大) • ovarian carcinoma following multiple exposure.

17. Antiestrogens Tamoxifen 三苯氧胺（他莫昔芬） (1) A nonsteroid competitive estrogen antagonist (2) Used for treatment of estrogen dependent breast cancer

18. Progestogens Norethisterone 炔诺酮 Progesterone 黄体酮（孕酮）

19. Progestogens 1. Pharmacological effects (1) Converting the uterine epithelium from the proliferative to the secretory phase (2) Inhibiting LH secretion and ovulation (3) Development of galactophore （乳管） (4) Thermoregulation: increasing body temperature (5) Metabolism: antagonizing aldosterone, inducing hepatic drug-metabolizing enzyme

20. Progestogens 2. Clinical uses (1)Menstrual disorders • secondary amenorrhage, exacerbated uterine bleeding, dysmenorrhea (痛经) and premenstrual syndrome, etc. • artificially induce progestogen withdrawal bleeding. - Norethindrone acetate(炔诺酮) -medroxyprogesterone acetate(甲羟孕酮)

21. Progestogens • (2) Cancers megestrol acetate(甲地孕酮) • endometrial & prostaticcarcinoma, • solid malignancy, especially gastric and pancreatic cancer, • improve appetite and reduce wasting. • used in combination with dexamethasone. • effects take several weeks to become apparent, but are relatively long-lived compared to those of corticosteroids. • the only drugs to increase lean body mass. • (3) Others • endometriosis (子宫内膜异位症), hormone replacement therapy (HRT), premature pregnancy (流产), etc.

22. Progestogens 3. Adverse effects • GI reactions • edema • virilization (男性化) • acne • hirsulism (多毛) • weight gain etc.

23. Antiprogestogens Mifepristone 米非司酮 • A synthetic steroid compound used as a pharmaceutical. • It is a progesterone receptor antagonist used as an abortifacient in the first two months of pregnancy, and in smaller doses as an emergency contraceptive

24. Antiprogestogens Clinical uses • 1.Medical termination of intrauterine pregnancies ofup to 49 days gestation (up to 63 days gestation in Britain and Sweden) • 600 mg + misoprostol 400 µg (2 days later) →terminated 96 to 99% of pregnancies of up to 49 days gestation. • If expulsion of fetal tissue does not occur during the observation period, surgical abortion is offered.

25. Antiprogestogens • 3. termination of pregnancies between 13 and 24 weeks gestation • softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination • in combination with gemeprost(前列甲酯) • 4.Labor induction in fetal death in utero. • 5.emergency contraceptive • used in smaller doses (10 mg) • taken after sex but before ovulation→prevent ovulation and so prevent pregnancy.

26. Antiprogestogens • Other uses • Phase II clinical trials include : • Oral contraceptive regular long-term use • Uterine fibroids(子宫平滑肌瘤), endometriosis, major depression with psychotic features, glaucoma, meningiomas(脑膜瘤), breast cancer, ovarian cancer, and prostate cancer. • Cushing's syndrome with treatment durations being as long as 10 years without noticeable adverse effect. • psychotic major depression limited by small study group and limited treatment duration

27. Contraceptive Drugs

28. Contraceptive drugs have been identified that inhibit fertility by a number of different mechanisms,for example, preventing ovulation, impairing gametogenesis or gamete maturation, or interfering with gestation.

29. Contraceptive drugs A contraceptive drug should: (1) extremely safe as well as highly effective (2) its action must be quick in onset and quickly and completely reversible, even after years of continuous use (3) it must not affect libido (性欲)

30. Contraceptive drugs For female: (1) Inhibition of ovulation (2) Prevention of fertilization (3) Inhibition of implantation (4) Use of spermicides in the vagina For male: (1) Direct inhibition of spermatomatogenesis (2) Indirect inhibition of spermatomatogenesis

31. Contraceptive drugs Estrogens + progestogens 1. Pharmacological effects (1) Inhibition of ovulation (2) Inhibition of implantation (3) Increase in viscidity of cervical mucus（宫颈黏液） (4) Others: interfering uterus or oviducal motility

32. Female systemic effects

33. Contraceptive drugs 2. Clinical uses (1) Oral: • short-acting contraceptives • long-acting contraceptives • postcoital (事后，探亲) contraceptives (2) long-acting injections (3) Slow-releasing preparations (4) Multiphasic preparations

34. Contraceptive drugs 国内常用甾体避孕药成分

35. 乙炔雌二醇 炔诺孕酮

36. Contraceptive drugs 3. Adverse effects (1) GI reactions (2) Menstrual disorders: breakthrough bleeding, amenorrhea (3) Increased coagulation: venous thromboembolism (4) Others: edema, depression, weight gain, acne, hirsutism, etc. 4. Drug interactions: • Hepatic enzyme inducers attenuate the effect of contraceptive drugs

37. Contraceptive drugs Other contraceptives for female For termination of early pregnancy • Mifepristone 米非司酮 • bleeding (treated by prostagladins) spermicides in the vagina • nonoxinol壬苯聚醇, menfenol, alkyl polyethoxy phenoxyethanol苯氧乙醇

38. Contraceptive drugs--male Gossypol 棉酚 • This compound destroys elements of the seminiferous epithelium (生精上皮) but does not alter the endocrine function of the testis. • GI and hepatic reactions, hypopotassaemia, etc.

39. Contraceptive drugs--male Other contraceptives for male • Cyproterone acetate(1,2-环次甲基氯地孕酮) • Androgen • Progestrone-androgen compound • GnRH analog-androgen compound

40. Drugs acting on uterus smooth muscle Stimulatants of uterus • Oxytocin 缩宫素（催产素） • Pituitrin 垂体后叶素 • Ergot alkaloid 麦角生物碱 • Prostaglandins 前列腺素类 Relaxants of uterus • Ritodrine 利托君 • Terbutaline 特布他林 • Salbuterol 沙丁胺醇 • Magnesiun sulfate 硫酸镁

41. Drugs acting on uterus smooth muscle Oxytocin 缩宫素（催产素） • A peptide hormone (a nonapeptide),synthesized in hypothalamus • released in large amounts 1) after distension of the cervix and uterus during labor 2) after stimulation of the nipples→facilitating birth and breastfeeding. • role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors→love hormone

42. Drugs acting on uterus smooth muscle Pharmacological effects • Uterine contraction • important for cervical dilation before birth and causes contractions during the second and third stages of labor. • assist the uterus in clotting the placental attachment point postpartum- during the first few weeks of lactation. • However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition are normal.

43. Drugs acting on uterus smooth muscle Clinical uses • Small doses (2-5 U): rhythmic contraction; induction of labor • Large doses (5-10 U): tonic contraction; postpartum hemorrhage • relatively safe when used at recommended doses, and side effects are uncommon • Cautions in induction of labor

44. Drugs acting on uterus smooth muscle Adverse effects • Recommended doses relatively safe when used at, and side effects are uncommon • Excessive dosage or long term administration (over a period of 24 hours or longer) - tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal. - Decreased heart rate , arrhythmia, brain damage, seizures, death in the fetus/neonate, due to increased uterine motility Cautions in induction of labor

45. Drugs acting on uterus smooth muscle Pituitrin 垂体后叶素 Pharmacological effects • Contracting vasculatures Clinical uses • Used in controlling bleedings Adverse effects • Pale face; BP elevation; palpitation; abdominal pain

46. Drugs acting on uterus smooth muscle Ergot alkaloid 麦角生物碱 胺麦角碱 肽麦角碱 Ergometrine 麦角新碱 Methylergometrine 甲基麦角新碱 Selectively contracting uterus smooth muscle Ergotamine 麦角胺 Contracting arteries and veins

47. Drugs acting on uterus smooth muscle Pharmacological effects 1.Uterine smooth muscle stimulation • Selectively and determined by the functional state of the uterus 2.Vessel-contracting effect • Directly contract artery and venous vessels • Damage vascular endothelial cells at high dose • Lead to dry gangrene of the extremities after long term use 3.α-receptor blocking effect • Reverse the BP-elevating effect of NA

48. Drugs acting on uterus smooth muscle Used in • uterus bleeding • postpartum hemorrhage（产后出血） • migraine（偏头痛） Adverse effects • GI disturbances: diarrhea, nausea, and vomiting prolonged vasospasm Contraindications • obstructive vascular; pregnancy

49. Drugs acting on uterus smooth muscle Prostaglandins 前列腺素类 • dinoprostone（地诺前列酮，PGE2） • dinoprost（地诺前列素，PGF2） • sulprostone（硫前列酮） • carboprost （卡前列素）

50. Drugs acting on uterus smooth muscle Used in • Abortion（流产）: combined with mifepristone • Facilitation of labor Adverse effects • GI disturbances: nausea, vomiting and abdominal pain Contraindications bronchial asthma; glaucoma