Grishma Parikh1, Takako Araki1, Michael Goldman1,

1
Vitamin D Receptor (VDR) is Expressed in Human
Ovarian Cells, likely Mediating the Effects of
Vitamin D on Steroidogenesis

• Grishma Parikh1, Takako Araki1, Michael
  Goldman1,
• Noga Chlamtac2, Zev Rosenwaks3,
• Leonid Poretsky1, Donna Seto-Young1

1Division of Endocrinology Friedman Diabetes
Institute, Department of Medicine, Beth -- Israel
Medical Center Albert Einstein College of
Medicine, New York, NY 10003 2Department of
Medicine, New York University School of Medicine,
New York, NY, 10016 3Center for Reproductive
Medicine Infertility, Weill Medical College of
Cornell University, New York, NY 10021
2
Introduction

• 1, 25-(OH)2D3 is active metabolite of vitamin D.
  Its primary role is to regulate calcium and
  phosphorus homeostasis and bone metabolism
• Recently, many other actions of vitamin D have
  been identified. These include
• role in muscle physiology
• immuno-modulator
• anti-proliferative compound in a wide variety of
  cells including ovarian cancer cell lines

Holick MF 2007 N Engl J Med 357266-281, Ahonen
MH et al 2000 Int J Cancer 8640-6
3
Vitamin D metabolism
4
Introduction ( Cont.)

• Effects of vitamin D are mediated through vitamin
  D receptor (VDR) - a member of nuclear receptor
  superfamily of ligand-activated transcription
  factors
• VDR is expressed widely in human tissues
  including colon, muscle, brain, ovary, heart,
  lymphocytes, mono-nuclear cells
• VDR is expressed in animal ovarian cells and
  appears to be necessary for ovarian function in
  animals
• Vitamin D deficiency in female rats is associated
  with reduced fertility

Agic A 2007 Reproductive Sciences 14486-497,
Holick MF 2007 N Engl J Med 357266-281 Yoshizawa
T Nat Genet 1997 16391, Johnson JA Histochem
Cell Biol 1996 1057-15,
5
Introduction (Cont.)

• VDR-null mutant mice have gonadal insufficiency.
  These mice also exhibit impaired folliculogenesis
  and uterine hypoplasia in females reduced sperm
  motility and sperm count are observed in males
• Calcitriol stimulates estradiol and progesterone
  production in trophoblast cells cultured from
  human placenta
• Abnormalities of Vitamin D and calcium
  homeostasis as possible pathologic mechanism of
  PCOS

Dukoh S Endocrinology 1983 112200-6, Kinuta K
1999 Endocrinology 1411317-1324, Barrera D 2007
Journal of Steroid Biochemistry Molecular
Biology 103529532, Thys-Jacobs S Steroids 1999
64430435
6
Introduction (Cont.)

• VDR-null mutant mice have gonadal insufficiency.
  These mice also exhibit impaired folliculogenesis
  and uterine hypoplasia in females reduced sperm
  motility and sperm count are observed in males
• Calcitriol stimulates estradiol and progesterone
  production in trophoblast cells cultured from
  human placenta
• Abnormalities of Vitamin D and calcium
  homeostasis as possible pathologic mechanism of
  PCOS
• Role of vitamin D, if any, in human ovarian
  function and, in particular, in steroid hormone
  synthesis is not known

Dukoh S Endocrinology 1983 112200-6, Kinuta K
1999 Endocrinology 1411317-1324, Barrera D 2007
Journal of Steroid Biochemistry Molecular
Biology 103529532, Thys-Jacobs S Steroids 1999
64430435
7
Cell Cultures
8
Vitamin D Receptor mRNA expression in human
ovarian cells by RT-PCR
Granulosa cell culture
Mixed ovarian cell culture
203 bp of VDR mRNA was detected in both human
mixed ovarian cell culture and purified granulosa
cell culture confirming the presence of VDR in
human ovary
9
Effect of 1,25-(OH)2 Vitamin D3 on steroid
hormone production in mixed ovarian cell cultures
1, 25-(OH)2D3 stimulated progesterone production
in mixed ovarian cell culture by 15 (plt0.001)
compared to control and had no effect on
testosterone production
10
Effect of 1,25-(OH)2 vitamin D3 on steroid
hormone production in purified granulosa cells
1, 25-(OH)2D3 stimulated estradiol and estrone
production in granulosa cell culture by 6
(plt0.05) and 21 (plt0.002) respectively compared
to control
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Synergistic effect of 1,25-(OH)2 vitamin D3 with
insulin on estradiol production in purified
granulosa cell cultures
Insulin alone has no significant effect on
estradiol production in granulosa cell culture
but addition of 1,25-(OH)2 vitamin D3 augments
insulin induced estradiol production by up to 90
(plt0.006)
12
Conclusions

• This report confirms presence of VDR in human
  ovarian cells and suggests that Vitamin D may
  have a physiological role in the human ovary
• 1, 25-(OH)2D3 stimulated steroid hormone
  production including progesterone, estradiol and
  estrone. Its effect on testosterone production
  was not significant. It may play a role in
  regulation of human ovarian steroidogenesis
• Addition of 1, 25-(OH)2D3 enhances
  insulin-induced estradiol production, possible
  mechanism being increased insulin sensitivity in
  ovarian tissue

13
Significance

• These findings suggest role of vitamin D in
  ovarian regulation and importance of detecting
  and correcting Vitamin D deficiency, especially
  in reproductive age women

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Acknowledgements

• We are thankful for the support from
• Gerald J. and Dorothy R. Friedman Foundation
• Chinese American Medical Association Chinese
  American Independent Practice Association