Steroid Hormones

1
Steroid Hormones

• Estrogen Progesterone

2
The Female Body

• Progesterone
• Development of breasts during puberty
• Growth of endometrium during menstrual cycle
• Inhibition of uterine contractions during
  pregnancy

• Estrogen
• Development of secondary sex characteristics
• Growth of uterus during puberty
• Initial growth of endometrium during menstrual
  cycle

3
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

4
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

5
Endogenous Estrogens
6
Biosynthesis of Estrogen and Progesterone
7
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

8
Aromatase Inhibitors

• Non-Steroidal Aromatase Inhibitors
• - Reversible
• - Enough estrogen displaces these
• - Anastrozole (Shown)

9
Estrogen Receptor Types

• ER-a
• - Found in uterus, vagina, breasts, and kidneys
• - 595 amino acid residues
• ER-ß
• - Found in ovaries, lungs, and bladder
• - 485 amino acid residues

10
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-a and ER-ß differ

11
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
12
Estrogen Antagonists

• - Help treat and prevent estrogen dependent
  breast cancer

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

Fulvestrant

• Characteristics of a bad antagonist
• Substitution at 7-a with bulky chains, alcohol,
  carboxylic acid, aryl, or ester groups
• Substitution at 11-ß with polar groups

13
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
14
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

15
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 )

16
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

17
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

18
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.