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: [email protected]

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

ContentContent

Oxytocics and Tocolytic drug

子宫平滑肌兴奋药和抑制药


Part 1

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 )

A. Oxytocics

Oxytocin (OXT, 催产素 )

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.

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 ).


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.


A. Oxytocics

Pituitrin( 垂体后叶素 )

Containing:

oxytocin 催产素 vasopressin 加压素，抗利尿激素

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 ):

A. Oxytocics

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 ).


A. Oxytocics

3. Adverse effects: -- nausea, vomiting, BP ; -- allergic reaction;

-- not used in expediting delivery and induced labor.


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.

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).

A. Oxytocics

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 )

B. Tocolytic drugs

Sex hormones and contraceeptives


Part 2

Basic structure of steroid hormones

AB

CD

Signal transductionof steroids

SHBG

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 )

雌二醇

戊酸雌二醇

炔雌醇

环丙戊酸雌二醇

雌酮

甲炔雌醇

炔雌醚

硫酸雌酮

马烯雌酮

雌激素类药物的基本结构 :

A. Estrogens & antiestrogens

Diethystibestol ( 己烯雌酚 , 乙菧酚 )


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)

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.

Estrogens


2. Clinical uses:

(1) Postmenopausal syndrome 更年期综合症 :

Hormone replacement therapy (HRT)

Osteoporoosis ( 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 ).

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

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.

Estrogens


AntiestrogensClomifene ( 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.


AntiestrogensClomifene( 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.


Tamoxifen ( 他莫昔芬 , 三苯氧胺 )


A non-steroid competitive antagonist to ER in breasts.

2. Clinical uses: Estrogen dependent breast cancer and

postmenopausal osteoporoosis. 3. Adverse effects Increases the risk of endometrial carcinoma.


Antiestrogens

术后 5 年他莫昔芬获益

EBCTCG, Lancet 2011

10y

14.2%

15y

13.2%

10y

7.2%

15y

9.2%

Recurrence Breast Cancer Mortality

5y

Δ 12.3%

5y

Δ 3.3%

Raloxifene ( 雷洛昔芬 )


Selectively stimulates ER in the bone.

2. Clinical uses: Postmenopausal osteoporoosis.


Antiestrogens

Anatrozole ( 阿那曲唑 )


Aromatase inhibitor ( 芳香化酶抑制剂 ).

2. Clinical uses: Estrogen-dependent breast cancer.


Antiestrogens

雌激素

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

芳香化酶抑制剂AI

X

绝经后患者

卵巢功能抑制GnRH 抑制剂

或卵巢切除

绝经前患者

肿瘤细胞

ER ER

外生性雌激素• 来自外周环境• 药物源性

雌激素受体拮抗剂TAM

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

黄体酮 ( 孕酮 ) ( 乙酸 ) 甲羟孕酮（安宫黄体酮）

( 乙酸 ) 甲地孕酮

炔诺酮乙醋炔诺酮19- 去甲睾酮

炔诺孕酮肟炔诺酯甲烯炔诺酮

B. Progestogens & antiprogestogens


Progestogens


(1) Convert the uterine epithelium from the proliferative to the

secretory phase;

(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


Progestogens2. 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.

3. Adverse effects:

Gastrointestinal reactions;

Virilization in female fetus ( 女性胎儿男性化 ); Acne ( 痤疮 ); Hirsulism ( 多毛 )


Progestogens

Antiprogestogens ( 抗孕激素药 )

Mifepristone ( 米非司酮 )

- a derivation of synthetic progestogens norethindrone ( 炔诺酮 ).

- antagonizes the receptors of progestogen.

- used for emergency contraception and termination of early pregnancy.


Androgens ( 雄激素 )

Testosterone( 睾酮 , 睾丸酮 )

Testosterone undecanoate ( 十一酸睾酮 ) 。。。。。。

Natural androgens:

Synthetic androgens:

Methyltestosterone ( 甲睾酮 )Testosterone propionate ( 丙酸睾酮 )

Testosterone phenylacetate ( 苯乙酸睾酮 )

C. Androgens & antiandrogens


1. Pharmacological effects:(1) Development of the male sexual organs and

secondary sex characteristics;

(2) Necessary for normal spermatogenesis;

(3) Promote growth of blood cells in bone marrow (by

increasing EPO)

(4) Increase protein anabolism (anabolic effect).


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.



3. Adverse effects: (1) Female: Virilescence in female ( 女性男性化 ) (2) Male: Sexual disturbance (hyperesthesis and

hypoesthesis).

(3) Hepatic toxicity.



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.


Antiandrogens ( 抗雄激素药 )

Cyproterone ( 环丙孕酮 )

1. Pharmacological effects: Inhibits hypothalamus-pituitary axis LH , FSH

testosterone ; Antagonizing androgen2. 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.


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.

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 )

D. Contraceptives

Combination contraceptives

Estrogens + Progestogens


(1) Inhibition of ovulation;

(2) Prevention of fertilization;

(3) Inhibition of implantation.

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.

D. Contraceptives

Estrogens + Progestogens

Emergency contraceptive pills(ECPs)

Levonorgestrel ( 左炔诺酮 , 毓婷 )

Similar effects with norethindrone ( 炔诺酮 );

High progestogen-like activity;

High androgen-like activity;

Anti-estrogen activity;

Anti-ovulation activity;

Anti-implantation

D. Contraceptives

Mifepristone ( 米非司酮，弗乃尔 )

Gossypol ( 棉酚 )

1. Pharmacological effects: Inhibition of spermatogenesis

2. Adverse reactions: (1) GI reaction, palpitation, hepatic injury; (2) Hypokalemia; (3) Irreversible spermatogenic disturbance

Male Contraceptives ( 男性避孕药 )

D. Contraceptives

Documents

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