Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells

Velen L. Nelson-DeGrave, Jessica K. Wickenheisser, Jennifer E. Cockrell, Jennifer R. Wood, Richard S. Legro, Jerome F. Strauss, Jan M. McAllister

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 μM), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17α-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 μM) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 μM) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 μM, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17α-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 μM) treatment was observed to increase histone H3 acetylation and P450 17α-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 μM) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 μM), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.

Original languageEnglish (US)
Pages (from-to)799-808
Number of pages10
JournalEndocrinology
Volume145
Issue number2
DOIs
StatePublished - Feb 1 2004

Fingerprint

Theca Cells
Valproic Acid
Androgens
Acetylation
Dehydroepiandrosterone
Colforsin
Histones
Histone Deacetylase Inhibitors
Polycystic Ovary Syndrome
Mixed Function Oxygenases
Therapeutics
Progesterone
Epilepsy
Histone Code
17-alpha-Hydroxyprogesterone
Aptitude
Histone Deacetylases
Butyric Acid
Androstenedione
Hyperinsulinism

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Nelson-DeGrave, V. L., Wickenheisser, J. K., Cockrell, J. E., Wood, J. R., Legro, R. S., Strauss, J. F., & McAllister, J. M. (2004). Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells. Endocrinology, 145(2), 799-808. https://doi.org/10.1210/en.2003-0940
Nelson-DeGrave, Velen L. ; Wickenheisser, Jessica K. ; Cockrell, Jennifer E. ; Wood, Jennifer R. ; Legro, Richard S. ; Strauss, Jerome F. ; McAllister, Jan M. / Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells. In: Endocrinology. 2004 ; Vol. 145, No. 2. pp. 799-808.
@article{3c60320b165046f1b3b95a07b0074901,
title = "Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells",
abstract = "In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 μM), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17α-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 μM) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 μM) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 μM, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17α-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 μM) treatment was observed to increase histone H3 acetylation and P450 17α-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 μM) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 μM), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.",
author = "Nelson-DeGrave, {Velen L.} and Wickenheisser, {Jessica K.} and Cockrell, {Jennifer E.} and Wood, {Jennifer R.} and Legro, {Richard S.} and Strauss, {Jerome F.} and McAllister, {Jan M.}",
year = "2004",
month = "2",
day = "1",
doi = "10.1210/en.2003-0940",
language = "English (US)",
volume = "145",
pages = "799--808",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "2",

}

Nelson-DeGrave, VL, Wickenheisser, JK, Cockrell, JE, Wood, JR, Legro, RS, Strauss, JF & McAllister, JM 2004, 'Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells', Endocrinology, vol. 145, no. 2, pp. 799-808. https://doi.org/10.1210/en.2003-0940

Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells. / Nelson-DeGrave, Velen L.; Wickenheisser, Jessica K.; Cockrell, Jennifer E.; Wood, Jennifer R.; Legro, Richard S.; Strauss, Jerome F.; McAllister, Jan M.

In: Endocrinology, Vol. 145, No. 2, 01.02.2004, p. 799-808.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells

AU - Nelson-DeGrave, Velen L.

AU - Wickenheisser, Jessica K.

AU - Cockrell, Jennifer E.

AU - Wood, Jennifer R.

AU - Legro, Richard S.

AU - Strauss, Jerome F.

AU - McAllister, Jan M.

PY - 2004/2/1

Y1 - 2004/2/1

N2 - In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 μM), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17α-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 μM) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 μM) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 μM, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17α-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 μM) treatment was observed to increase histone H3 acetylation and P450 17α-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 μM) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 μM), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.

AB - In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 μM), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17α-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 μM) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 μM) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 μM, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17α-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 μM) treatment was observed to increase histone H3 acetylation and P450 17α-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 μM) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 μM), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.

UR - http://www.scopus.com/inward/record.url?scp=0842334582&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0842334582&partnerID=8YFLogxK

U2 - 10.1210/en.2003-0940

DO - 10.1210/en.2003-0940

M3 - Article

C2 - 14576182

AN - SCOPUS:0842334582

VL - 145

SP - 799

EP - 808

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 2

ER -

Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, Wood JR, Legro RS, Strauss JF et al. Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells. Endocrinology. 2004 Feb 1;145(2):799-808. https://doi.org/10.1210/en.2003-0940