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

Estriol

Ryan Shelton, ND

Estrogens

Estrone

Estradiol

Estriol

Estetrol

E3 synthesis

16alpha-OH-estroneE3 conversion may be increased with iodine/iodide supplementation or inhibited by DIM supplementation Iodoral 2 tabs bid or SSKI 2 ggt bidSynthesized from estrone, estradiol, 16-alpha-hydroxyandrostenedione17-hydroxysteroid dehydrogenase16-alpha-hydroxylase

May be inhibited by DHEA, pregnenalone, androstenediol, estrone

Estrogen ReceptorsIntracellular nuclear hormone family which acts as DNA-binding transcription factor that regulates gene expression

Found in cytoplasmForms dimersMigrates to nucleusPresence of regional coactivators/corepressors can affect action of ligand

AlphaEndometrium, breast, ovaries, hypothalamus, leukocytes

BetaKidney, brain, bone, heart, lungs, intestines, endothelium, skin

E2 binds equally well to bothE1 binds mostly to alphaE3 binds mostly to beta (3:1 ratio)

ER-alpha knockout lacks vaginal response to estrogens while ER-beta knockout has normal response to estrogensEpigenetics (coactivators) likely involved

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 12.5-50% ‘less potent’ than E2

E3 short acting full agonist when given alone; antagonist when given with E2Differences in response may be attributable to retention of the estrogens at target tissues

Placental Estriol

Fetal adrenal gland converts maternal pregnenolone to DHEAs; Fetal liver converts DHEAs to 16-OH-DHEAsPlacenta converts 16-OH-DHEAs into estriolRole in pregnancy

Anti-inflammatory, anti-oxidant, immunologic privilege, downregulate Th1, ensure quiescent uterus, protect fetal neural structures?

Metabolized by maternal liver into 4 conjugatesestriol-3-sulfate, estriol-16-glucosiduronate, estriol-3-glucosiduronate, and estriol-3-sulfate-16-glucosiduronate

E3 levels

Bind SHBG weakly, most likely freeE3 administration does not seem to effect SHBG levels

24 hour urine is best testDay-today variation can be as much as 30%Circulating levels

50 & 150pg/ml follicular and luteal respectively; 6pg/ml post-menopausal; 15000 pg/ml at 38 wk of pregnancy24hr urine

Follicular 0-14mcg; Luteal 8-60mcg; 3rd Trimester 5000-50,000mcg

Production rates14 & 23mcg/d follicular and luteal respectively; 11mcg/d post-menopausal

Dermatology

Topical application increases density of collagen fibrils, elastin, and dermal connective tissueImprovement in wrinkle depth and pore sizes and skin water contentAt 0.3% topical E3 shows no systemic hormone changesSignificant facilitation of tissue expansion for reconstructive surgeriesDecreases comedomes in premenstrual acneIontophoresis of E3 dramatic improvement in acne scarring

Better than tretinoinE3 0.3% better than E2 0.1% in onset and extentMostly ER-beta expressed in epidermis and dermisSoftening of skin and positive histiological changes in scleroderma patientsFemale and male

Male mouse skin responsiveEstrogens improve wound healing, testosterone deleterious

Oral E3

Blood levels peak at 45-60min, at baseline in 3-4hrs; extensively conjugated3mg not better than placebo for urinary symptoms2mg decreases LH&FSH and decreases Menopausal Index

Japanese studiesIncreases salivary & IgA outputPositive effects on lipids and bone without increasing TG2mg E3 showed similar effects as 0.625 CE on BMDPotential negative effects

May increase hepatotoxicityMay diminish absorption of E1&E22mg increase breast density on mammogram by 6%2-12mg daily dosing did NOT proliferate endometrium, but BID dosing did

Vaginal E30.5-1mg vaginal=10mg oral achieve similar serum levels

Oral has 2nd peak pcOral 6&12mg resulted 125&320pg/ml at 45min, 33&50pg/ml at 4hrsVaginal 0.5mg resulted 110pg/ml at 60 min, 92.6pg/ml at 2hrs

Negligible after 15hrs– Recommended E2 levels for preventing bone loss 50-100pg/ml

Very helpful for lower UT and genital symtomsVaginal atrophy, pH, dryness, lactobacillus, UTI, incontinenceDosages range from 0.5-3.5mg applied vaginally

Decreases LH&FSH without changing serum E2 levelsE3 must be unconjugated to have this effect

Increases E&P receptors in vagina3.5mg decreases Menopausal Index, but no risk reduction in hip fracture

E3 & cardiovascular health

ERs found in vascular endothelium, vascular smooth muscleER stimulation results in vasodilation and vascular anti-inflammationER-beta stimulation by E3 increases cardiac perfusion and density of cardiac interstitiumOral E3 improvement of cholesterol not accompanied with increase in triglycerides Increased membrane fluidity and microviscosity of erythrocyte membraneSuggested that estrogens may be protective, not curative, and early treatment better

Later initial treatment may increase risk

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

Safety of E3

Continuous oral & and vaginal can stimulate uterine proliferation, especially in high divided doses Some studies do show no risk of hyperplasiaUse with progBreast cancer risk

Estrogen QuotientE3/E1+E2>1

Stimulatory effect on human breast cancer cellsDid not change normal breast tissue with mammographyMay act as antagonist in the presence of E2More pregnancies, less BRCAAsian women have higher E3 and less BRCA

E3 & Alzheimer’s

Two in vitro studies have shown E3 to be strongest estrogen to inhibit amyloid beta protein oligomer formation

E3 & MS

E3 8mg/d decreased lesions and resulted in symptomatic improvement in females and malesMany auto-immune diseases improve during pregnancyDecreases dendritic cell release of pro-inflammatory cytokines, increases output of immuno-tolerant cytokinesDecreases MMP-9 in CNS

Vaginal E3 alternative

Intravaginal DHEAImproves vaginal atrophy, decreases dyspareunia, decreases pH at 0.25%, 0.5%, 1.0%, and 1.8%Increases libido

Desire, arousal, orgasm, comfortEpithelium, lamina propria, muscularis

No increase in serum estrogens, testosterone, or 11 metabolitesUterine epithelium remains atrophic even at higher doses

Encourages cervical ripeningIncreases in BMDIntracrinology

Local synthesis of androgens & estrogens in the peripheryReleased from target cells after being>/=75% of estrogens in females