Thiazolidinediones Inhibit Aromatase Activity in Human Granulosa Cells by Interfering with Androgen Binding to
Aromatase
Takako Araki M.D. Dimiter Avtanski PhD Grishma Parikh M.D. Michael Goldman M.D. Zev Rosenwaks M.D.
Leonid Poretsky M.D. Donna Seto-Young PhD.
Department of MedicineDivision of Endocrinology & Metabolism
Beth Israel Medical CenterAlbert Einstein College of Medicine
New York, NY
• Insulin plays a role in human ovarian function
• Among other effects, insulin regulates steroidogenesis,
upregulates insulin-like growth factor 1 receptors,
and inhibits insulin-like growth factor binding protein 1
production in human ovary
Role of Insulin in Human Ovary
Hyperinsulinemia stimulates ovarian growth and cyst formation, probably contributing to the pathogenesis of polycystic ovary syndrome (PCOS)
Treatment of PCOS Weight loss: lifestyle modifications via diet
and exercise
Regulation of menstrual cycles: oral contraceptives
Anti-androgens: spironolactone
Insulin-sensitizing agents: metformin, thiazolidinediones (TZDs)
• TZDs are a group of medications used as insulin sensitizers in treatment of diabetes • TZDs, acting as PPAR- agonists, enhance insulin sensitivity of tissues and improve glucose tolerance in patients with insulin resistant states
• TZDs reduce hyperandrogenemia and restore ovulation in PCOS
Thiazolidinediones (TZDs)
AromataseAromataseCytochrome P-450 superfamilyCytochrome P-450 superfamilyProduct of the CYP19 geneProduct of the CYP19 geneHeme structure is responsible for binding Heme structure is responsible for binding androgenic steroidandrogenic steroidHighly expressed in placenta and granulosa Highly expressed in placenta and granulosa cellscellsKey enzyme that regulates estrogen Key enzyme that regulates estrogen synthesis in ovarysynthesis in ovaryPresent in subcutaneous fat (adipose Present in subcutaneous fat (adipose tissue), fetal liver, muscle, brain, bone, tissue), fetal liver, muscle, brain, bone, breast, and testisbreast, and testis
Cholesterol
Estradiol
Estrone
Pregnenolone 17-hydroxypregnelone DHEA
17-hydroxyprogesterone
Aromatase
Aromatase
3 Beta HSD 3 Beta HSD 3 Beta HSD
17 Alpha
17 Alpha
17-20 lyase
17-20 lyase
17 Beta HSD
17 Beta HSD
StAR/SCC
Progesterone
Testosterone
Androstenedione
17-hydroxysteroid dehydrogenase:17-HSD
Aromatase InhibitorAromatase InhibitorType 1 Inhibitors: Steroidal Inhibitors
Type 2 Inhibitors: Non-steroidal Inhibitors
Androstenedione Estrone
TZDs inhibit estrone productionTZDs effect was abolished when aromatase activity was inhibited
Testosterone Estradiol
TZDs inhibit estradiol productionTZDs effect was abolished when aromatase activity was inhibited
Aromatase mRNA ExpressionAromatase mRNA Expression
Aromatase mRNA expression was not changed by TZDs
Aromatase Enzyme ExpressionAromatase Enzyme Expression
Aromatase enzyme expression was not changed by TZDs
TZD Effect on Substrate bindingto Aromatase
TZDs inhibit aromatase activity by interfering with substrate binding
1/V
1/S0
Competitive Inhibitor
Competitive Inhibitor
No Inhibitor
1/Km
Vmax
1/S
1/V
0
Non-competitive Inhibitor
Non-competitive Inhibitor
No Inhibitor
1/Km
Vmax
1/V
1/S0
Uncompetitive Inhibitor
Uncompetitive Inhibitor
No Inhibitor
1/Km
Vmax
Kinetic Study - Estradiol -
Km 6.4Km 11.3Km 7.3Km 10.6Km 9.8
SummarySummary~~in Human Granulosa Cells~in Human Granulosa Cells~
TZDs inhibit estrogen productionTZDs inhibit estrogen production
TZDs do not change aromatase mRNA or TZDs do not change aromatase mRNA or enzyme protein expressionenzyme protein expression
TZDs inhibit aromatase activity by interfering TZDs inhibit aromatase activity by interfering with androgen binding to aromatase, acting with androgen binding to aromatase, acting as uncompetitive inhibitorsas uncompetitive inhibitors
TZDs as Aromatase Inhibitors TZDs as Aromatase Inhibitors ~ ~ Future Directions and Future Directions and
Possible Clinical Implications Possible Clinical Implications ~~
Potential use in estrogen – dependent Potential use in estrogen – dependent diseases:diseases:Breast cancerBreast cancerEndometriosisEndometriosis
Our findings may explain in partOur findings may explain in part
the relationship between TZDs and the relationship between TZDs and osteoporosisosteoporosis
Thank youWe are thankful for the support fromWe are thankful for the support from
Gerald J. and Dorothy R. Friedman Gerald J. and Dorothy R. Friedman FoundationFoundation