sex hormones

Natural Estrogens: Rank E1, E2, E3 by potency.

Estradiol (E2) is most potent > Estrone (E1) is moderate > Estriol (E3) is very weak.

Estradiol (E2 = Di-namite): Potency & ROA issue?

Most potent natural estrogen; has very poor oral absorption.

Estrone (E1 = EstrONE): Structural feature?

Features a ketone at the C17 position.

Estriol (E3 = TRIVIAL): Structural feature & Potency?

Contains a 16-alpha, 17-beta-hydroxy group; it is the weakest natural estrogen.

Estrogen Toxicity Mnemonic (T-BEE): What are the 4 main toxicities?

Thromboembolism, Breast Cancer, Edema, Endometrial Carcinoma.

Estrogen Carcinogenic Pathway: How does E2 cause DNA damage?

E2 is metabolized to 4-Hydroxyestrogen -> 3,4-Estrogen quinone -> Depurinated DNA adducts.

Estrogen SAR (Essentials): What 3 features are required for estrogenic activity?

1) Aromatic A-ring, 2) C3-OH group, 3) Oxygen distance of 10.3 to 12.1 Angstroms.

Estrogen SAR (Oral Protection): What modification makes estradiol orally active?

Adding a 17-alpha-ethynyl group (creates Ethinyl Estradiol) to block first-pass metabolism.

Estrogen SAR (Inactivators): What modifications destroy estrogenic activity?

C1 substitution, C6/C7/C11 hydroxylation, D-ring enlargement, or B-ring unsaturation.

Diethylstilbestrol (DES): Which isomer is more active and why? (Exam Trap)

TRANS-DES is 10x more active than cis-DES because it perfectly mimics the 10.3-12.1 Angstrom distance of Estradiol.

Mestranol: Mechanism of activation? (Exam Trap)

Mestranol is an INACTIVE prodrug (3-methyl ether) that requires hepatic O-demethylation to become active Ethinyl Estradiol.

Premarin: Clinical indication? (Exam Trap)

Used for postmenopausal hormone replacement therapy (HRT). It is NOT an oral contraceptive.

Fosfestrol: Indication and activation mechanism?

Used for prostate cancer; it is a DES diphosphate prodrug activated locally by prostatic acid phosphatase.

Estramustine: Cleavage and mechanism? (Exam Trap)

It acts as an INTACT carbamate conjugate. The nitrogen mustard is NOT cleaved off; only the C17-phosphate is hydrolyzed in the GI tract for absorption.

Depot Estrogens: Name two IM prodrugs.

Estradiol Valerate and Estradiol Cypionate.

Steroid Frameworks: Match the carbon count to the class (C18, C19, C21).

C18 = Estrane (Estrogens, aromatic A-ring). C19 = Androstane (Androgens). C21 = Pregnane (Progestins, 4-ene, diketone).