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Estriol Ryan Shelton, ND. Estrogens Estrone Estradiol Estriol Estetrol.

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Presentation on theme: "Estriol Ryan Shelton, ND. Estrogens Estrone Estradiol Estriol Estetrol."— Presentation transcript:

1 Estriol Ryan Shelton, ND

2 Estrogens Estrone Estradiol Estriol Estetrol

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4 E3 synthesis 16alpha-OH-estrone  E3 conversion may be increased with iodine/iodide supplementation or inhibited by DIM supplementation Iodoral 2 tabs bid or SSKI 2 ggt bid Synthesized from estrone, estradiol, 16- alpha-hydroxyandrostenedione 17-hydroxysteroid dehydrogenase 16-alpha-hydroxylase May be inhibited by DHEA, pregnenalone, androstenediol, estrone

5 Estrogen Receptors Intracellular nuclear hormone family which acts as DNA- binding transcription factor that regulates gene expression Found in cytoplasm  Forms dimers  Migrates to nucleus Presence of regional coactivators/corepressors can affect action of ligand Alpha Endometrium, breast, ovaries, hypothalamus, leukocytes Beta Kidney, brain, bone, heart, lungs, intestines, endothelium, skin E2 binds equally well to both E1 binds mostly to alpha E3 binds mostly to beta (3:1 ratio) ER-alpha knockout lacks vaginal response to estrogens while ER-beta knockout has normal response to estrogens Epigenetics (coactivators) likely involved

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7 E3 relative strength Claims range from 20-30% less potent to 80 times less potent than E2 80 times based on one study conducted by Dr Wright Administration of E3 half the potency of E2 which approached unity as interval of E3 administration decreases Likely range between % ‘less potent’ than E2 E3 short acting full agonist when given alone; antagonist when given with E2 Differences in response may be attributable to retention of the estrogens at target tissues

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13 Placental Estriol Fetal adrenal gland converts maternal pregnenolone to DHEAs; Fetal liver converts DHEAs to 16-OH-DHEAs Placenta converts 16-OH-DHEAs into estriol Role in pregnancy Anti-inflammatory, anti-oxidant, immunologic privilege, downregulate Th1, ensure quiescent uterus, protect fetal neural structures? Metabolized by maternal liver into 4 conjugates estriol-3-sulfate, estriol-16-glucosiduronate, estriol-3-glucosiduronate, and estriol-3-sulfate- 16-glucosiduronate

14 E3 levels Bind SHBG weakly, most likely free E3 administration does not seem to effect SHBG levels 24 hour urine is best test Day-today variation can be as much as 30% Circulating levels 50 & 150pg/ml follicular and luteal respectively; 6pg/ml post-menopausal; pg/ml at 38 wk of pregnancy 24hr urine Follicular 0-14mcg; Luteal 8-60mcg; 3 rd Trimester ,000mcg Production rates 14 & 23mcg/d follicular and luteal respectively; 11mcg/d post-menopausal

15 Dermatology Topical application increases density of collagen fibrils, elastin, and dermal connective tissue Improvement in wrinkle depth and pore sizes and skin water content At 0.3% topical E3 shows no systemic hormone changes Significant facilitation of tissue expansion for reconstructive surgeries Decreases comedomes in premenstrual acne Iontophoresis of E3 dramatic improvement in acne scarring Better than tretinoin E3 0.3% better than E2 0.1% in onset and extent Mostly ER-beta expressed in epidermis and dermis Softening of skin and positive histiological changes in scleroderma patients Female and male Male mouse skin responsive Estrogens improve wound healing, testosterone deleterious

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17 Oral E3 Blood levels peak at 45-60min, at baseline in 3-4hrs; extensively conjugated 3mg not better than placebo for urinary symptoms 2mg decreases LH&FSH and decreases Menopausal Index Japanese studies Increases salivary & IgA output Positive effects on lipids and bone without increasing TG 2mg E3 showed similar effects as CE on BMD Potential negative effects May increase hepatotoxicity May diminish absorption of E1&E2 2mg increase breast density on mammogram by 6% 2-12mg daily dosing did NOT proliferate endometrium, but BID dosing did

18 Vaginal E mg vaginal=10mg oral achieve similar serum levels Oral has 2 nd peak pc Oral 6&12mg resulted 125&320pg/ml at 45min, 33&50pg/ml at 4hrs Vaginal 0.5mg resulted 110pg/ml at 60 min, 92.6pg/ml at 2hrs Negligible after 15hrs –Recommended E2 levels for preventing bone loss pg/ml Very helpful for lower UT and genital symtoms Vaginal atrophy, pH, dryness, lactobacillus, UTI, incontinence Dosages range from mg applied vaginally Decreases LH&FSH without changing serum E2 levels E3 must be unconjugated to have this effect Increases E&P receptors in vagina 3.5mg decreases Menopausal Index, but no risk reduction in hip fracture

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20 E3 & cardiovascular health ERs found in vascular endothelium, vascular smooth muscle ER stimulation results in vasodilation and vascular anti-inflammation ER-beta stimulation by E3 increases cardiac perfusion and density of cardiac interstitium Oral E3 improvement of cholesterol not accompanied with increase in triglycerides Increased membrane fluidity and microviscosity of erythrocyte membrane Suggested that estrogens may be protective, not curative, and early treatment better Later initial treatment may increase risk

21 E3 & bone health In vitro osteoblastic proliferation with E3 In vitro Vit D3 receptor expression on osteoblasts Improvement in DEXA over 12 months with oral E3 Bone preserving effects of 2.0mg E3 oral similar to 0.625mg E2

22 Safety of E3 Continuous oral & and vaginal can stimulate uterine proliferation, especially in high divided doses Some studies do show no risk of hyperplasia Use with prog Breast cancer risk Estrogen Quotient E3/E1+E2>1 Stimulatory effect on human breast cancer cells Did not change normal breast tissue with mammography May act as antagonist in the presence of E2 More pregnancies, less BRCA Asian women have higher E3 and less BRCA

23 E3 & Alzheimer’s Two in vitro studies have shown E3 to be strongest estrogen to inhibit amyloid beta protein oligomer formation

24 E3 & MS E3 8mg/d decreased lesions and resulted in symptomatic improvement in females and males Many auto-immune diseases improve during pregnancy Decreases dendritic cell release of pro-inflammatory cytokines, increases output of immuno-tolerant cytokines Decreases MMP-9 in CNS

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26 Vaginal E3 alternative Intravaginal DHEA Improves vaginal atrophy, decreases dyspareunia, decreases pH at 0.25%, 0.5%, 1.0%, and 1.8% Increases libido Desire, arousal, orgasm, comfort Epithelium, lamina propria, muscularis No increase in serum estrogens, testosterone, or 11 metabolites Uterine epithelium remains atrophic even at higher doses Encourages cervical ripening Increases in BMD Intracrinology Local synthesis of androgens & estrogens in the periphery Released from target cells after being >/=75% of estrogens in females

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