| Title |
The Anti-Epileptic Drug Valproic Acid (VPA) Inhibits Steroidogenesis in Bovine Theca and Granulosa Cells In Vitro
|
|---|---|
| Published in |
PLOS ONE, November 2012
|
| DOI | 10.1371/journal.pone.0049553 |
| Pubmed ID | |
| Authors |
Claire Glister, Leanne Satchell, Anthony E. Michael, Andrew B. Bicknell, Philip G. Knight |
| Abstract |
Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC. |
X Demographics
The data shown below were collected from the profiles of 3 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Egypt | 1 | 33% |
| Unknown | 2 | 67% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 67% |
| Practitioners (doctors, other healthcare professionals) | 1 | 33% |
Mendeley readers
The data shown below were compiled from readership statistics for 29 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 29 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 6 | 21% |
| Student > Ph. D. Student | 5 | 17% |
| Researcher | 4 | 14% |
| Student > Master | 4 | 14% |
| Student > Doctoral Student | 3 | 10% |
| Other | 4 | 14% |
| Unknown | 3 | 10% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 7 | 24% |
| Medicine and Dentistry | 3 | 10% |
| Biochemistry, Genetics and Molecular Biology | 2 | 7% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 7% |
| Psychology | 2 | 7% |
| Other | 4 | 14% |
| Unknown | 9 | 31% |