Thiazolidinediones Inhibit Aromatase Activity in Human Granulosa Cells by Interfering with Androgen Binding to Aromatase

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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 Medicine
• Division of Endocrinology Metabolism
• Beth Israel Medical Center
• Albert Einstein College of Medicine
• New York, NY

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Role of Insulin in Human Ovary

• 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

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• 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)

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Thiazolidinediones (TZDs)

• TZDs are a group of medications used as
  insulin sensitizers in treatment of diabetes
• TZDs, acting as PPAR-g agonists, enhance
  insulin sensitivity of tissues and improve
  glucose tolerance in patients with
• insulin resistant states
• TZDs reduce hyperandrogenemia
• and restore ovulation in PCOS

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Aromatase

• Cytochrome P-450 superfamily
• Product of the CYP19 gene
• Heme structure is responsible for binding
  androgenic steroid
• Highly expressed in placenta and granulosa cells
• Key enzyme that regulates estrogen synthesis in
  ovary
• Present in subcutaneous fat (adipose tissue),
  fetal liver, muscle, brain, bone, breast, and
  testis

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Cholesterol
StAR/SCC
17 Alpha
17-20 lyase
3 Beta HSD
3 Beta HSD
3 Beta HSD
17 Alpha
17-20 lyase
Progesterone
17-hydroxyprogesterone
Androstenedione
17 Beta HSD
Aromatase
Testosterone
Estrone
Aromatase
17 Beta HSD
Estradiol
17b-hydroxysteroid dehydrogenase17b-HSD
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Aromatase Inhibitor
Type 1 Inhibitors Steroidal Inhibitors
Type 2 Inhibitors Non-steroidal Inhibitors
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TZDs inhibit estrone production TZDs effect was
abolished when aromatase activity was inhibited
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Estradiol
Testosterone
TZDs inhibit estradiol production TZDs effect was
abolished when aromatase activity was inhibited
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Aromatase mRNA Expression
Aromatase mRNA expression was not changed by TZDs
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Aromatase Enzyme Expression
Aromatase enzyme expression was not changed by
TZDs
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TZD Effect on Substrate binding to Aromatase
TZDs inhibit aromatase activity by interfering
with substrate binding
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Kinetic Study - Estradiol -
Km 6.4 Km 11.3 Km 7.3 Km 10.6 Km 9.8
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Summaryin Human Granulosa Cells

• TZDs inhibit estrogen production
• TZDs do not change aromatase mRNA or enzyme
  protein expression
• TZDs inhibit aromatase activity by interfering
  with androgen binding to aromatase, acting as
  uncompetitive inhibitors

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TZDs as Aromatase Inhibitors Future Directions
and Possible Clinical Implications

• Potential use in estrogen dependent diseases
• Breast cancer
• Endometriosis
• Our findings may explain in part
• the relationship between TZDs and osteoporosis

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• Thank you
• We are thankful for the support from
• Gerald J. and Dorothy R. Friedman Foundation