Steroid Hormones

Estrogen & Progesterone

The Female Body

Estrogen– Development of

secondary sex characteristics

– Growth of uterus during puberty

– Initial growth of endometrium during menstrual cycle

Progesterone– Development of

breasts during puberty

– Growth of endometrium during menstrual cycle

– Inhibition of uterine contractions during pregnancy

The Ovarian Cycle

Follicular Stage

-GnRH induces release of LH & FSH

-Follicular growth & secretion of estradiol

Ovulation Stage

-Follicle bursts releasing mature ovum

-Broken follicle develops into corpus luteum

The Ovarian Cycle

Luteal Stage-Corpus luteum secretes estrogen and progesterone-Estrogen & progesterone decrease GnRH, LH & FSH levels inhibiting further ovulation-No fertilization in 25 days leads to the endometrial deterioration

Fertilization-Zygote produces an LH-like hormone so the corpus luteum can secrete estrogen & progestrone causing the endometrium to stay in place

Endogenous Estrogens

Biosynthesis of Estrogen and Progesterone

Aromatase Inhibitors

Aromatase

- Cytochrome P-450 complex that catalyzes the conversion of androstenedione to estrone and testtosterone to estradiol

Steroidal Aromatase Inhibitors

- Irreversible

- Act as natural substrate of aromatose

Aromatase Inhibitors

Non-Steroidal Aromatase Inhibitors

- Reversible

- Enough estrogen displaces these

- Anastrozole (Shown)

Estrogen Receptor Types

ER-α

- Found in uterus, vagina, breasts, and kidneys

- 595 amino acid residues

ER-β

- Found in ovaries, lungs, and bladder

- 485 amino acid residues

Estrogen Receptor Domains

A/B Domain

- Contains AF-1

C Domain

- DNA binding domain

- Contains 2 Zinc fingers

D Domain

- Translocates complex into nucleus

E Domain

- Hormone / Ligand binding region

- Contains AF-2

- Where ER-α and ER-β differ

Estrogen Receptor Action

Agonists

- Cause helix 12 to sit snuggly over domain D

- AF-2 is capable of achieving transcription

Antagonists

- Rearrange formation of helix 12

- AF-2 is incapable of transcription

Estrogen Antagonists

- Help treat and prevent estrogen dependent breast cancer

- Characteristics of a good antagonist - Substitution at 7-α with long alkyl chain - Substitution at 11-β with long, non polar substituents

- Characteristics of a bad antagonist

- Substitution at 7-α with bulky chains, alcohol, carboxylic acid, aryl, or ester groups

-Substitution at 11-β with polar groups

Fulvestrant

Selective Estrogen Receptor Modulators

Tamoxifen

- Antagonist to breast tissue

- Agonist to endometrium, liver, and bone tissue

Raloxifen

- Antagonist to breast and endometrial tissue

- Agonist to bone tissue

Progestins

Natural Progesterone

Synthetic Progestins- Deletion of methyl group at carbon-13- Addition of double bond between carbon 6 and 7- Added substituent at carbon-12

Oral Contraceptive Agents

- Believed to suppress the production of LH and FSH so that ovulation does not occur

- Monophasic combinations such as Yasmin, contain the same amount of drug in each tablet ( 3 mg of drosperinone and 30 mg of ethinyl estradiol )

Oral Contraceptive Agents

- Biphasic and triphasic combinations mimic the variation of estrogen and progesterone levels naturally created by the body- Ortho-Tri-Cyclen

- Tablet of 0.18 mg of norgestimate and 35 mg of ethinyl estradiol for 7 days

- Tablet of 0.215 mg of norgestrimate and 35 mg of ethinyl estradiol for 7 days

- Tablet of 0.25 mg of norgestrimate and 35 mg of ethinyl estradiol for 7 days

Abortifacient : Mifepristone

- Progesterone receptor antagonist of the uterus- Promotes shedding of endometrium, softening of

the cervix, and uterine contractions leading to spontaneous abortion

- Often used in conjunction with misoprostol prostoglandin

Conclusion

- The natural steroid hormones estrogen and progesterone are produced in large quantities by our bodies.

- Synthesized versions are important to the medical community because they provide hope for breast cancer patients, allow for contraception, and can be used for abortion.