What are the steps in female steroid release?
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)
What are the Naturally Occuring Estrogens?
Estrone (E2 > estrone > E3). 17 B-Estradiol (highest activity). Estriol (An antagonist). Estrone and 17 B-Estradiol rapidly convert back and forth
What are the main therapeutic uses of Estrogens?
Contraceptives (suppress FSH). More recent considerations have focused on preventative effects against several aging-related diseases in women
What are the therapeutic goals of using Estrogens?
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
What are the general persepctives on Orally-Active Agents?
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"
What are the SARs of Estrogens?
1) C3 has an -OH side chain. 2) C17 has a Beta -OH side chain. 3) "A" ring is fully double-bonded (planar)
What are done to synthetic estrogens to block catabolism and incraese active lifetime?
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
What are the reasons for Estrogens for Post-Menopause; Hormone Replacement Therapy?
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)
What are the to drugs used as Estrogens in hormone replacement therapy?
Premarin and Prempro use "conjugated estrogens"
What are Xenoestrogens?
Environmental compounds, many naturally-occuring plant products, some derived from man-made pesticides or industrial-derived "pollutants", that weakly activate the ER
What are Anti-Estrogens?
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
What do Impeded Estrogens do?
Compete for binding; bind weakly; do not activate (estriol)
What do Triphenylethylenes do?
Bind strongly but do not activate
What do Aromatase Inhibitors do?
Block the conversion of androgen precursors into estrogens
What is Aromasin?
Aromatase inhibitor. Salient features: Prodrug, irreversible suicide inhibitor, metabolized by CYP3A4 in liver
What is Arimidex or Anastrozole?
Triazole Aromatase Inhibitor. Salient features: for treatment of advanced breast cancer, postmenopausal women, tamoxifen-resistant, as good as tamoxifen in monotherapy (but not better)
What are Selective Estrogen Receptor Modulators (SERMs)?
Compounds that affect nuclear receptor function only/differently in select tissues (can act as agonists in one tissue, and antagonists in other tissues)
What are some examples of SERMs?
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)
How does the activation of steroid receptors occur?
"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
What is Estrogen Receptor alpha?
Primary form in female sex-specific tissue
What is Estrogen Receptor beta?
Primary form in endothelial cells, bone, male tissue. Both alpha and beta receptors have similar affinities for estradiol
What are the important component domains of estrogen receptors?
Transcription activation domains (AF). DNA binding domain. Ligand (steroid) binding domain (LBD)
What is the functional basis of steroid receptors?
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)
What happens when H12 is displaced?
Moves into the space where the co-activator GRIP would normally be found. This prevents GRIP from binding, antagonizing ability to activate transcription
How is there selective binding to Estrogen Receptors?
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
How are SERMS based on selective recruitment of Estrogen Receptor co-activators and co-repressors?
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