Female Sex Hormonal Steroids

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Female 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
• - Schulers hypothesis
• Estrogen antagonists
• - clomiphene and tamoxifen
• Synthetic progestins
• Progesterone antagonists

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Female Sex Hormonal Steroids
Natural Estrogens
Estradiol
Estrone
Estriol Intramuscular (100)
intramuscular (33) oral (1.6)
(estr-1,3,5-triene-3,17b-diol)
(3-hydroxy-estr-1,3,5-triene-17-one)
(?????)
Natural Progestin
Progesterone
(Pregn-4-ene-3,20-dione)
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Female 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

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Female 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

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Female 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

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Biosynthesis and Metabolism of Estradiol and
Progesterone
cholesterol
pregnenolone testosterone
estradiol
progesterone
estrone
6a-hydroxy metabolite
20a/b-hydroxy metabolite
5b-metabolite
estriol
Conjugation to glucuronides, sulfates, etc.
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Synthetic Estrogenic
Estradiol look-alikes .. agonists
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Synthetic Estrogenic
Diethyl-Stilbestrols (DES)
Ethinyl-estradiol R H
Diethylstilbestrol Mestranol R CH3
Chlorotrianisene
Dienestrol
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Synthetic Estrogenic
Schulers Hypothesis for Synthetic Estrogens
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Synthetic Estrogenic
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Estrogen Antagonists
Triphenylethylene Derivatives Inverse Agonists
Chlorotrianisene (estrogenic)
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Selective Estrogen Receptor Modulators (SERM)
Single Receptor ?? Single Response . May not
be valid!
Tissue specific activity . Estrogenic for bone
growth anti-estrogenic for uterine endometrial
growth
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Typical Progesterone Agonists
Derivatize ring D
Derivatize rings A D
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Unusual Progesterone Agonists
Testosterone Derivatives
Ethisterone
Dimethisterone
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Progesterone Antagonist
Mifepristone (RU-486) (not the morning-after
pill)
Onapristone