Reproductive system. CASE STUDY A 25-year-old woman with menarche at 13 years and normal menstrual...

Reproductive system

CASE STUDY

A 25-year-old woman with menarche at 13 years and normal menstrual periods until about 1 year ago complains of hot flushes, skin andvaginal dryness, weakness, poor sleep, and scanty and infrequent menstrual periods.

She visits her gynecologist who obtains plasma levelsof follicle-stimulating hormone and luteinizing hormone, both of which are moderately elevated.

She is diagnosed with premature ovarian failure and recommended estrogen and progesterone replacement therapy. She is advised to start taking daily transdermal estradiol therapy (100 mg/d) along with oral natural progesterone (200 mg/d) for the last 12 days of each 28-day cycle. She is also advised to get adequate exercise and increase her calcium and vitamin D intake.

On this regimen, her symptoms disappear and she has normal monthly uterine bleeding.

Drugs affecting reproductive system

Basic & Clinical Pharmacology

FemaleFemale

systemic systemic effectseffects

MaleMale

spermspermsystemic systemic effectseffects

1.1. Female hormones Female hormones EstrogensEstrogens AntiestrogensAntiestrogens Progesterone and progestogensProgesterone and progestogens AntiprogestogensAntiprogestogens Female contraception drugsFemale contraception drugs

2.2. Male hormonesMale hormones AndrogensAndrogens AntiandrogensAntiandrogens Anabolic steroidsAnabolic steroids Male contraception drugsMale contraception drugs

Sex hormones and related drugsSex hormones and related drugs

A. Estrogens and antiestrogensA. Estrogens and antiestrogens

C. Contraceptive drugsC. Contraceptive drugs

D. Drugs acting on uterus smooth muscleD. Drugs acting on uterus smooth muscle

B. Progestogens and antiprogestogensB. Progestogens and antiprogestogens

3 major naturally occurring oestrogens in women are estrone (E1), estradiol (E2), and estriol (E3).

•E2 the predominant form in nonpregnant females•E1 produced during menopause•E3 the primary oestrogen of pregnancy.


雌二醇雌二醇

H5C2

H5C2

NCH2CH2O C

Cl

C

H3C OH

HO

OH

HO

Estradiol Estradiol 雌二醇雌二醇 Diethylstibestrol Diethylstibestrol 己烯雌酚己烯雌酚

Clomiphene Clomiphene 氯米酚氯米酚


1. Pharmacological effects1. Pharmacological effects

(1) Development of the female genital tract and of the female secon(1) Development of the female genital tract and of the female secondary sex characeteristics.dary sex characeteristics.

(2) Maintenance of both proliferative and secretory phases of the ute(2) Maintenance of both proliferative and secretory phases of the uterine endometriumrine endometrium

(3) Ovulation: (3) Ovulation: (small doses) or (small doses) or (larger doses) (larger doses) (4) Development of the breast and lactescence(4) Development of the breast and lactescence (small doses) or (small doses) or (larger doses) (larger doses)

EstrogensEstrogens


(5) Other actions:(5) Other actions: decreasing postmenopausal disturbances in sleepdecreasing postmenopausal disturbances in sleep inhibiting the reabsorption of bone inhibiting the reabsorption of bone increasing aldosterone and causing water and Na+ retentionincreasing aldosterone and causing water and Na+ retention decreasing LDL and increasing HDL levels in plasmadecreasing LDL and increasing HDL levels in plasma increasing factor II, VII, IX, X and coagulationincreasing factor II, VII, IX, X and coagulation


Pharmacological effects of estrogensPharmacological effects of estrogens


2. Clinical uses2. Clinical uses

(1) (1) Postmenopausal syndromePostmenopausal syndrome （绝经期综合征）（绝经期综合征） :: Postmenpausal hormone replacement therapy (HRT):Postmenpausal hormone replacement therapy (HRT): prevention of osteoporosis; prevention of osteoporosis; - Fractures of the spine, wrist, and hips decrease by 50-70% and spinal - Fractures of the spine, wrist, and hips decrease by 50-70% and spinal

bone density increases by ~5% in women treated with estrogen withibone density increases by ~5% in women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter.n 3 years of the onset of menopause and for 5–10 years thereafter.

treat vasomotor & CNS symptomstreat vasomotor & CNS symptoms - hot flushes, vaginal dryness, urinary stress incontinence, chilly sensa- hot flushes, vaginal dryness, urinary stress incontinence, chilly sensa

tions, dizziness, fatigue, irritability, and sweating. tions, dizziness, fatigue, irritability, and sweating. prevention of cardiovascular diseaseprevention of cardiovascular disease -lowers LDL ,TG; raises HDL levels -lowers LDL ,TG; raises HDL levels -endothelial vasodilatation properties , anti-inflammatory-endothelial vasodilatation properties , anti-inflammatory


(2) Primary hypogonadism ((2) Primary hypogonadism (卵巢功能不全卵巢功能不全 ):): replacementreplacement vaginal atrophy, hypoestrogenism vaginal atrophy, hypoestrogenism (3) Menstrual disorders(3) Menstrual disorders amenorrhea , dysmenorrhea, and oligomenorrhea; amenorrhea , dysmenorrhea, and oligomenorrhea; severe dysfunctional uterine bleedingsevere dysfunctional uterine bleeding(4) Contraception(4) Contraception(5) Others:(5) Others: suppress lactation after child birthsuppress lactation after child birth advanced breast cancer (postmenopausal) and prostatic canceradvanced breast cancer (postmenopausal) and prostatic cancer -hormone-sensitive or hormone-receptor-positive cancers-hormone-sensitive or hormone-receptor-positive cancers -hormone therapy, or anti-estrogen therapy hormone therapy, or anti-estrogen therapy (not to be confused wit(not to be confused wit

h hormone replacement therapy)h hormone replacement therapy) acneacne neuroprotectionneuroprotection


3. Adverse effects3. Adverse effects

(1) (1) Oral administration: nausea,vomiting, diarrheaOral administration: nausea,vomiting, diarrhea(2) Cardiovascular effects:(2) Cardiovascular effects: risk of venous thromboembolisisrisk of venous thromboembolisis plasma triglycerides plasma triglycerides hypertension, edemahypertension, edema(3) Others: (3) Others: gallbladder diseasegallbladder disease risk of breast and endometrial carcinomarisk of breast and endometrial carcinoma


The estrogen-aloneThe estrogen-alone stroke and deep vein thrombosis (DVT) in postmenopausal womestroke and deep vein thrombosis (DVT) in postmenopausal wome

n>50yn>50y dementia in postmenopausal women>65y using 0.625 mg of Predementia in postmenopausal women>65y using 0.625 mg of Pre

marin conjugated equine estrogens (CEE). marin conjugated equine estrogens (CEE). The estrogen-plus-progestinThe estrogen-plus-progestin risk of myocardial infarction, stroke, invasive breast cancer, pulmrisk of myocardial infarction, stroke, invasive breast cancer, pulm

onary emboli and DVT in postmenopausal women >50yonary emboli and DVT in postmenopausal women >50y dementia in postmenopausal women>65y using 0.625 mg of CEE dementia in postmenopausal women>65y using 0.625 mg of CEE

with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).


(1) Effects:(1) Effects: Partial agonist/antagonist for estrogen receptor Partial agonist/antagonist for estrogen receptor

H5C2

H5C2

NCH2CH2O C

Cl

C


Clomifene Clomifene

氯米芬氯米芬 (( 克罗米酚克罗米酚 ))

AntiestrogensAntiestrogens

(2) Uses:(2) Uses: anovulatory infertility (anovulatory infertility ( 无排卵性不孕无排卵性不孕 )) menstrual disordersmenstrual disorders advance breast canceradvance breast cancer functional amenorrhea (functional amenorrhea ( 功能性闭经功能性闭经 ) ) amenorrhea galactorrhea syndrome (amenorrhea galactorrhea syndrome ( 闭经溢乳综合征闭经溢乳综合征 ) )

(3) Adverse effects: (3) Adverse effects: Multiple ovulation with multiple pregnancy (Multiple ovulation with multiple pregnancy ( 多胎多胎 )) ovary tumefaction (ovary tumefaction ( 卵巢肿大卵巢肿大 )) ovarian carcinoma following multiple exposure. ovarian carcinoma following multiple exposure.


(1) A nonsteroid competitive estrogen antago(1) A nonsteroid competitive estrogen antagonistnist

(2) Used for treatment of estrogen dependent (2) Used for treatment of estrogen dependent breast cancer breast cancer


Tamoxifen Tamoxifen

三苯氧胺（他莫昔三苯氧胺（他莫昔芬）芬）

ProgesteroneProgesterone黄体酮黄体酮 (( 孕酮孕酮 ))

CH3

CH3

O

OC

CH3

OH

O

CHC

Progesterone Progesterone 黄体酮（孕酮）黄体酮（孕酮） Norethisterone Norethisterone 炔诺酮炔诺酮



ProgestogensProgestogens


(1) Converting the uterine epithelium from the proliferative to the sec(1) Converting the uterine epithelium from the proliferative to the secretory phaseretory phase

(2) Inhibiting LH secretion and ovulation(2) Inhibiting LH secretion and ovulation(3) Development of galactophore (3) Development of galactophore （乳管）（乳管）(4) Thermoregulation: increasing body temperature(4) Thermoregulation: increasing body temperature(5) Metabolism: antagonizing aldosterone, inducing hepatic drug-me(5) Metabolism: antagonizing aldosterone, inducing hepatic drug-me

tabolizing enzymetabolizing enzyme


(1)Menstrual disorders(1)Menstrual disorders secondary amenorrhage, exacerbated uterine bleeding, dysecondary amenorrhage, exacerbated uterine bleeding, dy

smenorrhea (smenorrhea ( 痛经痛经 ) and premenstrual syndrome, etc.) and premenstrual syndrome, etc. artificially induce progestogen withdrawal bleeding. artificially induce progestogen withdrawal bleeding. - Norethindrone acetate - Norethindrone acetate -medroxyprogesterone acetate -medroxyprogesterone acetate



(2) Cancers (2) Cancers megestrol acetatemegestrol acetate•solid malignancy, especially gastric and pancreatic cancer, solid malignancy, especially gastric and pancreatic cancer, • improve appetite and reduce wasting. improve appetite and reduce wasting. • used in combination with dexamethasone.used in combination with dexamethasone.• effects take several weeks to become apparent, but are relatively long-effects take several weeks to become apparent, but are relatively long-lived compared to those of corticosteroids.lived compared to those of corticosteroids.• the only drugs to increase lean body mass. the only drugs to increase lean body mass.

(3) Others(3) Others•endometriosis (endometriosis ( 子宫内膜异位症子宫内膜异位症 ), hormone replacement therapy (HRT), ), hormone replacement therapy (HRT), premature pregnancy (premature pregnancy ( 流产流产 ), etc.), etc.

3. Adverse effects3. Adverse effects

GI reactionsGI reactions edemaedema virilization (virilization ( 男性化男性化 )) acneacne hirsulism (hirsulism ( 多毛多毛 )) weight gain etc.weight gain etc.


AntiprogestogensAntiprogestogens


• A synthetic steroid compound used as a pharmaceutical. A synthetic steroid compound used as a pharmaceutical.

•It is a progesterone receptor antagonist used as an abortifacient in tIt is a progesterone receptor antagonist used as an abortifacient in the first two months of pregnancy, and in smaller doses as an emergehe first two months of pregnancy, and in smaller doses as an emergency contraceptivency contraceptive

Mifepristone Mifepristone 米米非司酮非司酮

Clinical usesClinical 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.



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

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.


Other uses Other uses

Phase II clinical trials include :•Oral contraceptive regular long-term use

•Uterine fibroids, endometriosis, major depression with psychotic features, glaucoma, meningiomas, 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 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.

A contraceptive drug should:A contraceptive drug should:

(1) extremely safe as well as highly effective(1) extremely safe as well as highly effective(2) its action must be quick in onset and quickly and complete(2) its action must be quick in onset and quickly and complete

ly reversible, even after years of continuous usely reversible, even after years of continuous use(3) it must not affect libido ((3) it must not affect libido ( 性欲性欲 ))


For female:For female:(1) Inhibition of ovulation(1) Inhibition of ovulation(2) Prevention of fertilization(2) Prevention of fertilization(3) Inhibition of implantation (3) Inhibition of implantation (4) Use of spermicides in the vagina(4) Use of spermicides in the vagina

For male:For male: (1) Direct inhibition of spermatomatogenesis(1) Direct inhibition of spermatomatogenesis(2) Indirect inhibition of spermatomatogenesis(2) Indirect inhibition of spermatomatogenesis



(1) Inhibition of ovulation(1) Inhibition of ovulation(2) Inhibition of implantation (2) Inhibition of implantation (3) Increase in viscidity of cervical mucus(3) Increase in viscidity of cervical mucus （宫颈黏液）（宫颈黏液） (4) Others: interfering uterus or oviducal motility(4) Others: interfering uterus or oviducal motility


Estrogens + progestogensEstrogens + progestogens

Steroid contraceptives for femaleSteroid contraceptives for female


(1) Oral: (1) Oral: short-acting contraceptives short-acting contraceptives long-acting contraceptives long-acting contraceptives postcoital (postcoital ( 事后，探亲事后，探亲 ) contraceptives) contraceptives(2) long-acting injections (2) long-acting injections (3) Slow-releasing preparations (3) Slow-releasing preparations (4) Multiphasic preparations(4) Multiphasic preparations


3. Adverse effects3. Adverse effects(1) GI reactions(1) GI reactions(2) Menstrual disorders: breakthrough bleeding, amenorrhea(2) Menstrual disorders: breakthrough bleeding, amenorrhea(3) Increased coagulation: venous thromboembolism(3) Increased coagulation: venous thromboembolism(4) Others: edema, depression, weight gain, acne, hirsutism, etc.(4) Others: edema, depression, weight gain, acne, hirsutism, etc.

Drug interactions:Drug interactions: Hepatic enzyme inducers attenuate the effect of contraceptive drugHepatic enzyme inducers attenuate the effect of contraceptive drug

ss


Other contraceptives for female Other contraceptives for female

For termination of early pregnancy For termination of early pregnancy Mifepristone Mifepristone 米非司酮米非司酮 bleeding (treated by prostagladins)bleeding (treated by prostagladins)

spermicides in the vaginaspermicides in the vagina nonoxinol, menfenol, alkyl polyethoxy phenoxyethanol nonoxinol, menfenol, alkyl polyethoxy phenoxyethanol


This compound destroys elements of the seminiferous epitheThis compound destroys elements of the seminiferous epithelium (lium ( 生精上皮生精上皮 ) but does not alter the endocrine function of ) but does not alter the endocrine function of the testis.the testis.

GI and hepatic reactions, hypopotassaemia, etc.GI and hepatic reactions, hypopotassaemia, etc.


Gossypol Gossypol 棉酚棉酚Contraceptives for maleContraceptives for male


Other contraceptives for maleOther contraceptives for male

Cyproterone acetate(1,2-Cyproterone acetate(1,2- 环次甲基氯地孕酮环次甲基氯地孕酮 ))AndrogenAndrogenProgestrone-androgen compoundProgestrone-androgen compoundGnRH analog-androgen compoundGnRH analog-androgen compound


Stimulatants of uterusStimulatants of uterus Oxytocin Oxytocin 缩宫素（催产素）缩宫素（催产素） Pituitrin Pituitrin 垂体后叶素垂体后叶素 Ergot alkaloid Ergot alkaloid 麦角生物碱麦角生物碱 Prostaglandins Prostaglandins 前列腺素类前列腺素类

Relaxants of uterusRelaxants of uterus Ritodrine Ritodrine 利托君利托君 Terbutaline Terbutaline 特布他林特布他林 Salbuterol Salbuterol 沙丁胺醇沙丁胺醇 Magnesiun sulfate Magnesiun sulfate 硫酸镁硫酸镁

A peptide hormone (a nonapeptide),synthesized in hypothalamusA peptide hormone (a nonapeptide),synthesized in hypothalamus released in large amounts released in large amounts 1) after distension of the cervix and uterus during labor1) after distension of the cervix and uterus during labor2) after stimulation of the nipples2) after stimulation of the nipples→→facilitating birth and breastfeeding. facilitating birth and breastfeeding. role in various behaviors, including orgasm, social recognition, pair bonding,role in various behaviors, including orgasm, social recognition, pair bonding,

anxiety, and maternal behaviors anxiety, and maternal behaviors→→love hormonelove hormone


Oxytocin Oxytocin 缩宫素（催产素）缩宫素（催产素）Stimulatants of uterusStimulatants of uterus


Pharmacological effectsPharmacological 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.

Clinical usesClinical uses

Small doses (2-5 U): rhythmic contraction; induction of laborSmall doses (2-5 U): rhythmic contraction; induction of laborLarge doses (5-10 U): tonic contraction; postpartum hemorrhageLarge doses (5-10 U): tonic contraction; postpartum hemorrhage

relatively safe when used at recommended doses, and side effects are relatively safe when used at recommended doses, and side effects are uncommonuncommon

Cautions in induction of laborCautions in induction of labor


Adverse effectsAdverse effects

Recommended dosesRecommended doses relatively safe when used at, and side effects relatively safe when used at, and side effects are uncommonare uncommon

Excessive dosage or long term administrationExcessive dosage or long term administration (over a period of 24 (over a period of 24 hours or longer) hours or longer)

- tetanic uterine contractions, uterine rupture, postpartum hemorr- tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.hage, and water intoxication, sometimes fatal.

- Decreased heart rate , arrhythmia, brain damage, seizures, death - Decreased heart rate , arrhythmia, brain damage, seizures, death in the fetus/neonate, due to increased uterine motility in the fetus/neonate, due to increased uterine motility

Cautions in induction of laborCautions in induction of labor


Pharmacological effectsPharmacological effects Contracting vasculaturesContracting vasculatures

Clinical usesClinical uses Used in controlling bleedingsUsed in controlling bleedings

Adverse effectsAdverse effects Pale face; BP elevation; palpitation; abdominal painPale face; BP elevation; palpitation; abdominal pain


Pituitrin Pituitrin 垂体后叶素垂体后叶素

Ergot alkaloid Ergot alkaloid 麦角生物碱麦角生物碱

胺麦角碱胺麦角碱肽麦角碱肽麦角碱

Ergometrine Ergometrine 麦角新碱麦角新碱Methylergometrine Methylergometrine 甲基麦甲基麦

角新碱角新碱Selectively contracting uterus Selectively contracting uterus

smooth musclesmooth muscle

Ergotamine Ergotamine 麦角胺麦角胺Contracting arteries and veinsContracting arteries and veins



Pharmacological effectsPharmacological effects

1.Uterine smooth muscle stimulation1.Uterine smooth muscle stimulationSelectively and determined by the functional state of the uterusSelectively and determined by the functional state of the uterus

2.Vessel-contracting effect2.Vessel-contracting effectDirectly contract artery and venous vesselsDirectly contract artery and venous vesselsDamage vascular endothelial cells at high doseDamage vascular endothelial cells at high doseLead to dry gangrene of the extremities after long term useLead to dry gangrene of the extremities after long term use

3.3.αα-receptor blocking effect-receptor blocking effectReverse the BP-elevating effect of NAReverse the BP-elevating effect of NA

Used in Used in uterus bleeding uterus bleeding postpartum hemorrhagepostpartum hemorrhage （产后出血）（产后出血） migrainemigraine （偏头痛）（偏头痛）

Adverse effectsAdverse effects GI disturbances: diarrhea, nausea, and vomiting prolonged vasosGI disturbances: diarrhea, nausea, and vomiting prolonged vasos

pasmpasm

ContraindicationsContraindications obstructive vascular; pregnancyobstructive vascular; pregnancy


Prostaglandins Prostaglandins 前列腺素类前列腺素类 dinoprostonedinoprostone （地诺前列酮，（地诺前列酮， PGE2PGE2 ）） dinoprostdinoprost （地诺前列素，（地诺前列素， PGF2PGF2 ）） sulprostonesulprostone （硫前列酮）（硫前列酮） carboprost carboprost （卡前列素）（卡前列素）


Used inUsed in AbortionAbortion （流产）（流产） : combined with mifepristone: combined with mifepristone Facilitation of laborFacilitation of labor

Adverse effectsAdverse effects GI disturbances: nausea, vomiting and abdominal painGI disturbances: nausea, vomiting and abdominal pain

Contraindications Contraindications bronchial asthma; glaucoma bronchial asthma; glaucoma


Relaxants of uterusRelaxants of uterus Ritodrine Ritodrine 利托君利托君 Terbutaline Terbutaline 特布他林特布他林 Salbuterol Salbuterol 沙丁胺醇沙丁胺醇 Magnesiun sulfate Magnesiun sulfate 硫酸镁硫酸镁

Used inUsed in Dysmenorrhoea Dysmenorrhoea 痛经痛经 premature birth premature birth 早产早产


Further readingFurther reading

Bertram G. Katzung, Susan B. Masters, Anthony J. TrevorBertram G. Katzung, Susan B. Masters, Anthony J. TrevorChapter 16. Histamine, Serotonin, & the Ergot AlkaloidsChapter 16. Histamine, Serotonin, & the Ergot AlkaloidsChapter 40. The Gonadal Hormones & InhibitorsChapter 40. The Gonadal Hormones & InhibitorsBasic and Clinical Pharmacology, 11e.Basic and Clinical Pharmacology, 11e. 2010 The McGraw-Hill Co 2010 The McGraw-Hill Companies.mpanies.

Reproductive system. CASE STUDY A 25-year-old woman with menarche at 13 years and normal menstrual...

Documents

Transcript of Reproductive system. CASE STUDY A 25-year-old woman with menarche at 13 years and normal menstrual...