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Drugs Affecting Reproductive System
Ling Ding, Ph. D., Associate Professor
College of Pharmaceutical Sciences
Zhejiang University
China 310058
Email: [email protected]
Female
systemic
effects
Male
systemic
effects
sperm
Sex hormones and related drugs
• Estrogens and antiestrogens
• Progestogens and antiprogestogens
• Contraceptive drugs
• Drugs acting on uterus smooth muscle
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
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
Estrogens and antiestrogens
H3C OH
OH
HO
HO
Estradiol 雌二醇
Diethylstibestrol 己烯雌酚
Cl
H5C2
NCH2CH2O
H5C2
Clomiphene 氯米酚
C
C
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)
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
Estrogens
Pharmacological effects of estrogens
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
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
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
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).
Antiestrogens
Clomifene
氯米芬 (克罗米酚)
Cl
H5C2
NCH2CH2O
C
C
H5C2
(1) Effects: Partial agonist/antagonist for estrogen receptor
Antiestrogens
(1)
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.
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
Progestogens
CH3
C
CH3
OH
O
C
CH3
O
Progesterone 黄体酮（孕酮）
O
Norethisterone 炔诺酮
CH
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
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)
Progestogens
(2) Cancers megestrol acetate(甲地孕酮)
•endometrial & prostatic carcinoma,
•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.
Progestogens
3. Adverse effects
•
•
•
•
•
•
GI reactions
edema
virilization (男性化)
acne
hirsulism (多毛)
weight gain etc.
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
Antiprogestogens
Clinical uses
1.Medical termination of intrauterine pregnancies of up 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.
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.
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
Contraceptive Drugs
• 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.
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)
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
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
Female
systemic
effects
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
Contraceptive drugs
国内常用甾体避孕药成分
乙炔雌二醇
炔诺孕酮
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
contraceptive drugs
attenuate
the
effect
of
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
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.
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
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
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
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.
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
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
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
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
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
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
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）
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
Drugs acting on uterus smooth muscle
Relaxants of uterus
•
Ritodrine 利托君
•
Terbutaline 特布他林
•
Salbuterol 沙丁胺醇
•
Magnesiun sulfate 硫酸镁
Used in
• Dysmenorrhoea 痛经
• premature birth 早产