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UIC PCOL 425 - LECTURE NOTES

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1 ORAL CONTRACEPTIVE THERAPY (OCT), SERMs Dorie Schwertz, Ph.D. (2002) UNIVERSITY OF ILLINOIS, College of Medicine, College of Nursing Hypothalamic Pituitary Gonadal Axis Development and maintenance of the female reproductive system is dependent on the balance between estrogen and progesterone. Estrogens are recognized as promoters of cell proliferation while progesterone is known to facilitate cellular differentiation. This is reflected, for instance, in the phases of uterine endometrium: 1) The proliferative or follicular phase (estrogen dominant) a growth phase, uterine glands grow and proliferate. 2) Secretory (luteal) phase (progesterone dominant) glands become tightly coiled and secrete. 3) Menses (without hormonal support) spiral arteries constrict and endometrium sloughed. ________________________________________ 1) FSH - (from ant. pit.) stimulates follicular growth maturation of ovum. 2) Follicle secretes increasing estradiol. 3) Exposure of hypothalamus to high levels of estradiol for an adequate period of time causes pulsatile release of GnRH - gonadotropin releasing hormone - positive feedback. 4) Pulsatile GnRH release causes surge of LH (and FSH) release from ant. pit. 5) LH surge causes ovulation and supports corpus luteum development.2 6) Corpus luteum - secretes progesterone. 7) Rising levels of estrogen and progesterone - negative feedback 8) Degeneration of corpus luteum - decreased levels of estrogen and progesterone. 17 beta-estradiol is the principal estrogen secreted by the ovary. Of endogenous estrogens, estradiol has highest affinity for estrogen receptor. Estrone is also produced by the ovary in small amounts. WHEN CONCEPTION OCCURS -Corpus luteum secretes progesterone - maintains uterine lining -After implantation, trophoblast (future placenta) secretes hCG -Human chorion gonadotropin maintains corpus luteum - progesterone continues to be secreted Progesterone supports pregnancy -supports endometrium -inhibits uterine sensitivity to contractile agents (PGs & oxytocin) -firms cervix and inhibits dilation -favors formation of mucus plug -progesterone blocks ovulation by negative feedback on LH release After 9 weeks placenta takes over the job of progesterone production. Placenta also secretes estrogen. Relationship between Estrogen and Progesterone 1) Estrogen is needed as "primer" to induce full progesterone sensitivity. 2) Estrogen also stimulates the expression of Estrogen receptors (positive feedback) 3) Progesterone has antiestrogenic properties. - The synthesis of progesterone receptors are dependent on estrogen. - Progesterone depletes the cytosol of estrogen receptors by: - Suppressing synthesis of estrogen receptors - Facilitating metabolism of estradiol to weaker metabolites - Acting as a partial antagonist at the estrogen receptor Without estrogenic stimulation there is a decrease in progesterone receptors. - Therefore progesterone antagonizes the synthesis of its own receptors. - These properties are exploited clinically. Mechanism of Action Receptor hormone complex acts as a transcription factor trabslocates to the nucleus - associates with regulatory domain of target gene - increases (or decreases the rate of transcription of the gene - usually alters rate of transcription of protein product3 ESTROGEN RECEPTOR SUBTYPES Recently (~1996) discovered that there are 2 (at least) estrogen receptor subtypes: α and β Not splice variants but separate genes 95% homology at DNA binding domain 60% homology at C terminal ligand binding domain 20% homology at N terminal region where other transcription factors bind 17β-estradiol binding affinity similar at the two receptors Binding affinity of synthetic estrogens (tamoxifen and raloxifene - SERMS - smart estrogen receptor modulators) is different for each receptor Hormone/receptor complex - DNA binding 1) At Estrogen Response Element (ERE) May form homodimers (ββ, αα) or heterodimers (αβ) Phosphorylation steps involved Binding to ERE can result in an increase or a decrease of gene transcription 2) AP1 Site A single ligand/receptor complex associates with fos/jun heterodimer The total complex binds to an AP1 regulatory site ER and ERβ will differentially regulate gene expression associated with the AP1 response site Possible implications: Evidence suggests that tissue-specific co-activators and co-repressors can alter the response to ER ligands in a given tissue The balance of subtype and level of estrogen receptors can change in a tissue over time If a breast cancer cell has ERβ - it is possible that an anti-estrogen drug (or SERM) could (paradoxically) cause activation of estrogen-dependent transcription See later - Discussion of SERMs4 Progesterone - two progesterone receptors - splice variants of one gene -Progesterone/receptor complex is not retained in the nucleus for long periods. Progesterone promotes protein synthesis but not cell growth. -Affects of progesterone are seen in tissues previously stimulated by estrogens (up regulation of progesterone receptor by estrogen -Evidence for cell surface membrane receptors (estrogen, progesterone and testosterone) giving the sex steroids capacity to elicit response within seconds to minutes. Rapid responses to progesterone detected in brain, sperm, liver, heart, and kidney. In brain Progesterone and progesterone metabolites bind to GABA receptor - enhancing inhibitory effects of GABA in brain. Rapid responses to estrogen - increased nitric oxide release Indications for the use of Estrogens 1) Replacement in estrogen deficiency Female hypogonadal or postmenopausal 2) Treatment of estrogen negative breast tumor (primarily in males) 3) Advanced prostatic cancer 4) Oral contraceptive therapy PHYSIOLOGIC EFFECTS OF ESTROGENS 1) Normal female maturation - secondary sex characteristics -stimulates stromal and ductal growth of the breast 2) Accelerated growth phase at puberty and closing of long bone epiphyseal plate 3) Antagonizes the effect of parathyroid hormone on bone resorption - increases bone density 4) Promotes growth of endometrium - prolonged unopposed exposure causes hyperplasia 5) Maintains skin and blood vessel integrity 6) Alters liver metabolism - primarily when given orally - increases production of plasma proteins Transport proteins: transcortin, thyroxin binding globulin, sex hormone binding globulin, transferrin Proteins related to hemostasis


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UIC PCOL 425 - LECTURE NOTES

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