22 Sex Steroids: Estrogen Duncan

Question 1

What are the steps in female steroid release?

Answer 1

Hypothalamus releases LHRF (aka GnRH) which acts on the Pituitary. This causes the Pituitary to release Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). LH and FSH act on the Ovary which causes Progesterone release (has negative feedback on hypothalamus) and Estrogen release (has negative feedback on Pituitary)

Question 2

What are the Naturally Occuring Estrogens?

Answer 2

Estrone (E2 > estrone > E3). 17 B-Estradiol (highest activity). Estriol (An antagonist). Estrone and 17 B-Estradiol rapidly convert back and forth

Question 3

What are the main therapeutic uses of Estrogens?

Answer 3

Contraceptives (suppress FSH). More recent considerations have focused on preventative effects against several aging-related diseases in women

Question 4

What are the therapeutic goals of using Estrogens?

Answer 4

1) Develop a very easily administered form for contraception (i.e. an orally-active form). 2) Develop a form that is atheroprotective, cognition and bone preserving, but DOESN’T promote cancer

Question 5

What are the general persepctives on Orally-Active Agents?

Answer 5

Orally-administered steroids are rapidly catabolized by the liver during first pass interaction, by cytochrome P450 enzymes. Modifications that block (or significantly slow) normal catabolic pathways and enzymes will prolong active lifetime, leading to “Oral Activity”

Question 6

What are the SARs of Estrogens?

Answer 6

1) C3 has an -OH side chain. 2) C17 has a Beta -OH side chain. 3) “A” ring is fully double-bonded (planar)

Question 7

What are done to synthetic estrogens to block catabolism and incraese active lifetime?

Answer 7

Block catabolism with C17 alpha ethinyl. Increase active lifetime by creating prodrugs in which either the C3 or C17 (or both) hydroxyls are derivatized. Derivatized forms are active orally

Question 8

What are the reasons for Estrogens for Post-Menopause; Hormone Replacement Therapy?

Answer 8

Reduction in Estrogens post menopause can be associated with physical discomfort (hot flashes), dryness, itching, burning sensations. In addition, physiological decrements in vascular function, cognitive function, bone strength, and others can occur. In sum, these factors have suggested the therapeutic benefit of hormone replacement therapy. However, evidence is mixed and potential ADRs ahve been noted (e.g. cancer)

Question 9

What are the to drugs used as Estrogens in hormone replacement therapy?

Answer 9

Premarin and Prempro use “conjugated estrogens”

Question 10

What are Xenoestrogens?

Answer 10

Environmental compounds, many naturally-occuring plant products, some derived from man-made pesticides or industrial-derived “pollutants”, that weakly activate the ER

Question 11

What are Anti-Estrogens?

Answer 11

There are three main types of anti-estrogens (They are valuable in instances such as estrogen-dependent breast cancers). The three are: Impeded Estrogens, Triphenylethylenes, Aromatase Inhibitors

Question 12

What do Impeded Estrogens do?

Answer 12

Compete for binding; bind weakly; do not activate (estriol)

Question 13

What do Triphenylethylenes do?

Answer 13

Bind strongly but do not activate

Question 14

What do Aromatase Inhibitors do?

Answer 14

Block the conversion of androgen precursors into estrogens

Question 15

What is Aromasin?

Answer 15

Aromatase inhibitor. Salient features: Prodrug, irreversible suicide inhibitor, metabolized by CYP3A4 in liver

Question 16

What is Arimidex or Anastrozole?

Answer 16

Triazole Aromatase Inhibitor. Salient features: for treatment of advanced breast cancer, postmenopausal women, tamoxifen-resistant, as good as tamoxifen in monotherapy (but not better)

Question 17

What are Selective Estrogen Receptor Modulators (SERMs)?

Answer 17

Compounds that affect nuclear receptor function only/differently in select tissues (can act as agonists in one tissue, and antagonists in other tissues)

Question 18

What are some examples of SERMs?

Answer 18

Tamoxifen is antagonist in breast (good), but weak agonist in uterine tissue (bad), potential potentiator of uterine cancers. Raloxifene is antagonist in breast, but very little to no activity in uterine tissue (good)

Question 19

How does the activation of steroid receptors occur?

Answer 19

“Inactive” steroid receptor undergoes priming activation by the molecular chaperone Hsp70 with assistance of Hsp40. Primed SR is “handed off” to Hsp90 for final folding, using the chaperone Hop as an intermediary. Hsp90 undergoes stage one conformational change to go from the relaxed state to the partially “tensed state”. The co-chaperone Hop is released from the complex to be replaced by other co-chaperones (such as Cyp40, P23)…. blah blah blah blah

Question 20

What is Estrogen Receptor alpha?

Answer 20

Primary form in female sex-specific tissue

Question 21

What is Estrogen Receptor beta?

Answer 21

Primary form in endothelial cells, bone, male tissue. Both alpha and beta receptors have similar affinities for estradiol

Question 22

What are the important component domains of estrogen receptors?

Answer 22

Transcription activation domains (AF). DNA binding domain. Ligand (steroid) binding domain (LBD)

Question 23

What is the functional basis of steroid receptors?

Answer 23

Binding of the ligand induces a conformational change. Steroid receptors function in the nucleus, to activate the transcription of target genes. DNA binding domain binds to specific segments of DNA, called steroid receptor elements. Activation fucntion domain (AF) recruits transcription machinery (RNA polymerase) to increase transcription. AF domains also recruit accessory proteins (called co-activators and co-repressors) that further modulate transcription (co-activators are required to achieve high level gene activation)

Question 24

What happens when H12 is displaced?

Answer 24

Moves into the space where the co-activator GRIP would normally be found. This prevents GRIP from binding, antagonizing ability to activate transcription

Question 25

How is there selective binding to Estrogen Receptors?

Answer 25

There are ER-a and ER-B forms. Small differences in the shape of the E2 binding pocket may allow development of isoform-specific agonists and antagonists

Question 26

How are SERMS based on selective recruitment of Estrogen Receptor co-activators and co-repressors?

Answer 26

The LBD interacts with several different co-activator and co-repressor proteins. The functional importance of each co-activator interaction may be different in different tissues, based on differences in co-activator/repressor expression. Each SERM may induce a different receptor conformation upon binding, promoting the selective and differential recruitment of co-activators and co-repressors