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 - Schuler’s hypothesis  Estrogen antagonists - clomiphene and tamoxifen  Synthetic progestins  Progesterone antagonists

Female Sex Hormonal Steroids Estradiol Estrone Estriol Intramuscular (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 Progesterone (Pregn-4-ene-3,20-dione) Natural Progestin (?????)

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

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

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

Biosynthesis and Metabolism of Estradiol and Progesterone cholesterol pregnenolone testosterone estradiol estriol Conjugation to glucuronides, sulfates, etc…. 6a-hydroxy metabolite 20  /  -hydroxy metabolite 5  -metabolite estrone progesterone

Synthetic Estrogenic Estradiol look-alikes ….. agonists

Synthetic Estrogenic Ethinyl-estradiol R = H Diethylstilbestrol Mestranol R = CH 3 Chlorotrianisene Dienestrol Diethyl-Stilbestrols (DES)

Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens

Synthetic Estrogenic

Estrogen Antagonists Chlorotrianisene (estrogenic ) Triphenylethylene Derivatives – Inverse Agonists

Selective Estrogen Receptor Modulators (SERM) – Tissue specific activity …. Estrogenic for bone growth; anti- estrogenic for uterine endometrial growth – Single Receptor  Single Response …. May not be valid!

Derivatize ring D Typical Progesterone Agonists 17  -hydroxy progesterone caproate Medroxyprogesterone acetate Megestrol acetate Chlormadinone acetate Progesterone Derivatize rings A & D

Testosterone Derivatives Unusual Progesterone Agonists Ethisterone Dimethisterone Norethisterone Norethindrone Norgestimate Norgestrel 19-Nor-testosterone Derivatives

Progesterone Antagonist Mifepristone (RU-486) (not the ‘morning-after pill’) Onapristone