female sex hormonal steroids overall organization of the topic structure and nomenclature -...
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Female Sex Hormonal SteroidsFemale Sex Hormonal Steroids
Overall Organization of the Topic
Structure and nomenclature
- Estradiol, estrone, estriol, and progesterone Biosynthesis and metabolism of estradiol and
progesterone Synthetic estrogens
- Schuler’s hypothesis Estrogen antagonists
- clomiphene and tamoxifen Synthetic progestins Progesterone antagonists
Female Sex Hormonal SteroidsFemale Sex Hormonal Steroids
CH3OH
OH
CH3
OH
O CH3
OH
OH
OH
Estradiol Estrone EstriolIntramuscular (100%) intramuscular (33%) oral (1.6%)
(estr-1,3,5-triene-3,17-diol)
(3-hydroxy-estr-1,3,5-triene-17-one)
Natural Estrogens
CH3
CH3CH3
O
O
Progesterone(Pregn-4-ene-3,20-dione)
Natural Progestin
(?????)
Female Sex SteroidsFemale Sex Steroids
Physiological Activity of Natural Estrogens• Reproduction and development of female sex organs• Growth of secondary sex characteristics (male + female)• Role in ovulation and pregnancy• Role in bone density modulation (male + female)• Role in mineral, carbohydrate, protein and lipid metabolism
Physiological Activity of Progesterone• Maintenance of Pregnancy• Inhibition of follicular maturation and ovulation• Prevention of spontaneous uterine contractions
Female Sex SteroidsFemale Sex Steroids
Concerns about carcinogenic actions of Estrogens/Progestins• Early studies … tumors of breast, uterus, testis, bone, kidney …• ‘Unopposed’ estrogen … especially higher risk• Estrogen – progestin combination … standard practice now• In a WHI study … increased total risk of breast cancer by 24%• Carcinogenic actions due to trophic effects (cell proliferation effects)• Alternate theory … conversion to quinones ROS DNA damage
Female Sex SteroidsFemale Sex Steroids
Therapeutic Uses
• Combination oral contraceptives(block ovulation)
• Menopausal Hormone Therapy (MHT)(secondary effects of decreased hormones … hot flashes, bone loss …)
• Estrogen/Progestin – dependent cancers(antagonism of ER and PR)
• Abortifacients(induction of uterine contractions)
• Other uses
Biosynthesis and Metabolism of Estradiol and ProgesteroneBiosynthesis and Metabolism of Estradiol and Progesterone
OH
CH3
CH3
CH3CH3
CH3
OH
CH3
CH3
CH3 O
CH3
CH3OH
O
CH3OH
OH
OH
CH3
OH
O
CH3
OH
OH
cholesterol pregnenolone testosterone estradiol
estriol
Conjugation to glucuronides, sulfates, etc….
CH3
O
CH3
CH3
O
OH6a-hydroxymetabolite
CH3
O
CH3
CH3
OH
20/-hydroxy metabolite
CH3
OH
CH3
CH3
OH
H
5-metabolite
estrone
CH3
O
CH3
CH3
O
progesterone
OHCH3
OH
OHCH3
OH
OHOHCH3
OH
OHOHCH3
OH
OHCH3
OH
CH3
OH
OH
CH3
OH
O
Synthetic EstrogenicSynthetic Estrogenic
Estradiol look-alikes ….. agonists
Synthetic EstrogenicSynthetic Estrogenic
CH3OH
RO
CHC CH2
CH2OH CH3
CH3 OH
CH
CHOH
OH
CH3
CH3OMe
MeO
Cl
OMe
Ethinyl-estradiol R = H DiethylstilbestrolMestranol R = CH3
Chlorotrianisene Dienestrol
Diethyl-Stilbestrols (DES)
Synthetic EstrogenicSynthetic Estrogenic
Schuler’s Hypothesis for Synthetic Estrogens
Synthetic EstrogenicSynthetic Estrogenic
Estrogen AntagonistsEstrogen Antagonists
OMe
MeO
Cl
OMe
Cl
OCH2CH2N(CH2CH3)2
ClOCH2CH2N(CH2CH3)2
OCH2CH2N(CH2CH3)2
CH3
R
Enclomiphene Zuclomiphene Tamoxiphen R = H4-Hydroxy tamoxiphen R = OH
Chlorotrianisene(estrogenic)
Triphenylethylene Derivatives – Inverse Agonists
Selective Estrogen Receptor Modulators (SERM)Selective Estrogen Receptor Modulators (SERM)
– Tissue specific activity …. Estrogenic for bone growth; anti-estrogenic for uterine endometrial growth
N
SOH
O
O
OH
OH
NO
NO
Cl
CH3
CH3
Raloxifene Nafoxidine Toremifene
– Single Receptor Single Response …. May not be valid!
Derivatize ring DDerivatize ring D
Typical Progesterone AgonistsTypical Progesterone Agonists
CH3
CH3
CH3
O
O
OCO(CH2)4CH3
17-hydroxy progesteronecaproate
CH3
CH3
CH3
O
O
OCOCH3
CH3
Medroxyprogesterone acetate
CH3
CH3
CH3
O
O
OCOCH3
CH3Megestrolacetate
CH3
CH3
CH3
O
O
OCOCH3
ClChlormadinoneacetate
CH3
O
CH3
CH3
O
Progesterone
Derivatize rings A & DDerivatize rings A & D
Testosterone DerivativesTestosterone Derivatives
Unusual Progesterone AgonistsUnusual Progesterone Agonists
CH3
CH3OH
O
CH
Ethisterone
CH3
CH3OH
O
CCH3
CH3
Dimethisterone
CH3OH
O
CH
H
Norethisterone
CH3OH
O
CH
H
Norethindrone
OCOCH3
N
CH
CH3
OH
H
Norgestimate
OH
O
CH
CH3
H
Norgestrel
19-Nor-testosterone Derivatives19-Nor-testosterone Derivatives
Progesterone AntagonistProgesterone Antagonist
CH3
O
OH
CCH3
N
CH3
CH3 CH3
O
OH
CH2CH2CH2OH
N
CH3
CH3
Mifepristone(RU-486)
(not the ‘morning-after pill’)
Onapristone