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Endocrinology Vol. 139, No. 12 4962-4966
Copyright © 1998 by The Endocrine Society

ARTICLES

Troglitazone Inhibits Progesterone Production in Porcine Granulosa Cells1

Slavisa Gasic, Yvonne Bodenburg, Manubi Nagamani, Allan Green and Randall J. Urban

Division of Endocrinology (S.G., Y.B., A.G., R.J.U.), Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060; and Division of Reproductive Endocrinology (M.N.), Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-0587

Address all correspondence and requests for reprints to: Randall J. Urban, M.D., 8.138 Medical Research Building, 1060, Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas 77555-1060. E-mail: rurban{at}utmb.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Troglitazone (a thiazolidinedione that improves insulin resistance) lowers elevated androgen concentrations in women with polycystic ovarian syndrome. In this study, we assessed the direct effects of troglitazone on steroidogenesis in porcine granulosa cells. Troglitazone inhibited progesterone production in a dose- and time-dependent manner (earliest effects at 4 h, maximum at 24 h) without affecting cell viability. Progesterone production was also inhibited by troglitazone in the presence of 25-hydroxycholesterol, indicating that the drug does not affect intracellular cholesterol transport. Troglitazone also inhibited FSH- and forskolin-stimulated progesterone secretion. The reduced progesterone production was accompanied by marked elevations of pregnenolone concentrations, suggesting inhibition of 3ß-hydroxysteroid dehydrogenase (3ß-HSD). The activity of 3ß-HSD in troglitazone-treated granulosa cells was decreased by more than 60%, compared with controls after 24 h. Troglitazone did not affect aromatase activity in porcine granulosa cells. In summary, troglitazone has direct effects on porcine granulosa cell steroidogenesis. The drug specifically inhibits 3ß-HSD activity, resulting in impaired progesterone production. The clinical relevance of this direct in vitro effect on steroidogenesis needs further investigation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THIAZOLIDINEDIONES represent a new class of drugs that have been demonstrated to significantly improve the treatment of type 2 diabetes mellitus (1, 2). Thiazolidinediones act primarily at adipose and muscle tissue, where they increase insulin sensitivity at the postreceptor level (3). This improvement in insulin resistance is the basis for their use in diabetes. Thiazolidinediones are high-affinity ligands for the peroxisome-proliferator activated receptor {gamma} (4). Thiazolidinediones bind to and activate peroxisome-proliferator activated receptor {gamma} that forms a heterodimer with retinoic acid receptor and binds to an orphan nuclear receptor-binding motif [direct repeat one (DR-1)] in gene promoters (5). By acting at the transcriptional level, thiazolidinediones selectively increase the expression of genes that regulate glucose homeostasis (6), and they decrease the expression of genes that oppose insulin action (7). These agents also stimulate adipocyte differentiation from preadipocyte fibroblasts (8) and counteract negative effects of some cytokines on glucose and lipid metabolism (9).

Because thiazolidinediones improve peripheral insulin resistance and decrease hyperinsulinemia, they may also be used for the treatment of several disorders other than type 2 diabetes. One such disease is polycystic ovarian disease (PCO), where insulin resistance in peripheral tissues and resulting hyperinsulinemia are associated with increased androgen concentrations and oligomenorrhea (10). The thiazolidinedione troglitazone, when used for the treatment of PCO, improved insulin resistance and lowered androgen concentrations (11, 12). This beneficial effect of troglitazone was attributed to its lowering of serum insulin concentrations that are proposed to hyperstimulate the ovary (11, 12).

Another possibility is that troglitazone affects ovarian function by direct effects on steroidogenesis. In this study, we used porcine granulosa cells in primary culture to investigate the in vitro effects of troglitazone on progesterone production. We found that troglitazone inhibits progesterone production in granulosa cells by inhibiting the activity of 3ß-hydroxysteroid dehydrogenase (3ß-HSD).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
Pig ovaries were purchased from Brookshire Packing (Brookshire, TX). Troglitazone was obtained from Sankyo Pharmaceuticals. Restriction enzymes and MTS (a tetrazolium salt) Cell Viability Assay kit were obtained from Promega Corp. (Madison, WI). The human placental complementary DNA clone for 3ß-HSD was a generous gift from Dr. Ian Mason (University of Edinburgh, Edinburgh, Scotland, United Kingdom). Northern blot membrane was Magna Nylon from MSI (Westboro, MA). For Northern probe labeling, [{gamma}-32P]-(deoxycycidine triphosphate) and a random prime kit were obtained from Amersham Corp. (Arlington Heights, IL). For 3ß-HSD activity and aromatase assay, [3,7-3H]-pregnenolone and [1ß-3H]-androstenedione were purchased from Amersham. Silica gel-coated TLC plates (HL250 plates with preadsorbant layer) were from Analtech (Newark, DE). Pregnenolone concentrations were determined with an RIA kit from ICN Biomedicals, Inc. (Costa Mesa, CA). Cell culture media and FBS were purchased from Gibco BRL (Gaithersburg, MD). 25-hydroxy (25-OH) cholesterol was obtained from Fluka (Ronkonkoma, NY). All other chemicals and materials were from Sigma Chemical Co. (St. Louis, MO).

Primary culture of porcine granulosa cells
The porcine granulosa cells were isolated from 1- to 5-mm follicles of ovaries from immature swine (60–70 kg) obtained from a local slaughterhouse (13). The cells were plated in DMEM and 3% FCS, at a concentration of 20–30 million cells/60-mm dish, for 12–16 h to facilitate granulosa cell attachment to the plates. Monolayer cultures were maintained at 37 C in 5% CO2 throughout the experiments. After granulosa cell attachment, medium containing the FCS was discarded, and serum-free medium with various concentrations of troglitazone was added for 24 h. One ml of medium was collected for measurement of progesterone or pregnenolone.

Cell viability assay
Granulosa cell viability was tested using a colorimetric assay that is dependent on the oxidation of MTS to formazan dye by dehydrogenase enzymes found in metabolically active cells (14). After 24 h treatment of granulosa cells with troglitazone, media was removed, and a new media, containing MTS reagent, was added, according to manufacturers’ directions. The cells were incubated with MTS for 2 h, media was removed, and its absorbance was measured at 490 nm.

3ß-HSD assay
Porcine granulosa cells in primary cultures were treated in serum-free media and washed once with PBS. Whole granulosa cell homogenates were suspended in 0.1 M Bicine buffer, pH 9.0, with protease inhibitors and homogenized by shearing with polytron apparatus. The homogenates were incubated in 100 mM Bicine buffer, pH 9.0, 0.5 mM NAD with 25 µM unlabeled pregnenolone and a tracer amount of [3H]-pregnenolone in a total vol of 20 µl for 3 h at 37 C. Reactions were stopped by addition of 5 µl (4 µg/ml) unlabeled pregnenolone and progesterone in ethanol, and all 25-µl reactions were loaded on silica gel HL 250-µm TLC plates (Analtech). The TLC plates were run twice with benzene/acetone 4:1 mixture. After drying the plates, pregnenolone and progesterone spots were developed by spraying with water, scraped into scintillation vials, and counted (15).

Aromatase assay
Aromatase activity was measured by incubating live porcine granulosa cells with [1ß-3H]-androstenedione (Amersham), as described before (16). Briefly, medium from porcine granulosa cells, incubated for 6 h with labeled [1ß-3H]-androstenedione, was extracted with chloroform and centrifuged. Aqueous supernatant was incubated with 5% charcoal/0.5% dextran to separate 3H from labeled androstenedione. This mixture was centrifuged and an aliquot added to scintillation fluid and counted in a liquid scintillation counter.

RIAs
The RIA for progesterone, which has been described, uses the chromatographic separation of steroids to enhance specificity (17). The pregnenolone RIA was performed with a kit from ICN, that uses a [3H]-pregnenolone tracer and charcoal-dextran method for separation of bound and free tracer. The kit includes an antibody that is specific for pregnenolone and pregnenolone-sulfate, with no significant cross-reactivity with other steroids. Hormone concentrations were normalized to granulosa cell DNA, which were measured by fluorometric assay using DNA-binding dye Hoechst 33258 (17).

Northern blot hybridization
Northern blot hybridizations were performed as previously described (17), except that hybridization and washing was done at 37 C.

Statistical analysis
Differences between progesterone values for control and treated cells were determined by one-way ANOVA. Probability levels of less than 0.05 were considered statistically significant. All data-points are presented as a mean ± SE.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Troglitazone effects on steroidogenesis
To determine whether troglitazone affects steroidogenesis, porcine granulosa cells were incubated for 24 h with various concentrations of this thiazolidinedione (Fig. 1Go). Troglitazone was a potent inhibitor of progesterone release from the cells, causing almost complete inhibition at a concentration of 10 µg/ml, with an approximate EC50 of less then 1 µg/ml. Two related compounds, pioglitazone and BRL 49653, also inhibited progesterone release but were not as potent, especially at the 1-µg/ml dose that most closely approximates serum concentrations of troglitazone in humans.



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  		Figure 1. Dose-response of troglitazone inhibition of porcine granulosa progesterone production. Porcine granulosa cells were treated for 24 h with increasing concentrations of troglitazone, Pioglitazone, and BRL 49635. The data represent the mean from three experiments done in triplicate. Progesterone concentrations were corrected for DNA content in treated cells and are presented as a percentage of control progesterone production. For clarity, error bars are not shown in the graph, but the SEs were as follows: troglitazone, 2.4–7.2%; Pioglitazone, 8.8–13.3%; BRL 49653, 8.4–18.2%.

 
The time course for the effect of troglitazone on progesterone production by granulosa cells was investigated over a 24-h time period (Fig. 2Go). Granulosa cells were treated with either of two concentrations of troglitazone (1 or 10 µg/ml). Progesterone production showed an inhibition as early as 4 h after addition of the drug. The amount of inhibition increased over time, with the greatest effect occurring at 24 h (Fig. 2Go).



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  		Figure 2. Time course of troglitazone inhibition of progesterone production by porcine granulosa cells. Cultures of porcine granulosa cells were treated with troglitazone (1 and 10 µg/ml) at 2, 4, 6, 12, and 24 h. Progesterone production (corrected for DNA content) was measured as shown above. The data represent the mean ± SE from three experiments done in triplicate.

 
With such a pronounced effect of troglitazone on progesterone secretion, it was necessary to determine whether troglitazone has a nonspecific, toxic effect on granulosa cells. This was investigated by treating granulosa cells for 24 h with troglitazone. The metabolic activity of the cells was determined with a tetrazolium (MTS)-based dye-reduction assay. Porcine granulosa cell viability was not affected, even after treatment with 10 µg/ml troglitazone (data not shown).

One of the limiting factors in steroid hormone biosynthesis is the delivery of cholesterol, which is poorly soluble, from its intracellular stores to the mitochondria. The first step in steroidogenesis, cleavage of the cholesterol side-chain, is accomplished by P-450 cholesterol side-chain cleavage (P450scc), which is located on the inner mitochondria membrane (18). To determine whether troglitazone interferes with intramitochondrial cholesterol transport, we tested its effect on granulosa cell progesterone production in the presence of 25-OH cholesterol, a water-soluble cholesterol analog that is not dependent on intramitochondrial transport. Troglitazone inhibited progesterone production, even in the presence of 25-OH cholesterol (Fig. 3Go), demonstrating that inhibition of progesterone release by troglitazone is not caused by inhibition of intramitochondrial cholesterol transport.



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  		Figure 3. Effects of 25-OH cholesterol on troglitazone suppression of porcine granulosa cell progesterone production. Porcine granulosa cells were cultured for 24 h in serum-free medium (circle) or in the presence of 30 µg/ml of 25-OH cholesterol (triangle). Under both conditions, porcine granulosa cells were treated with troglitazone, at a 1 and 10 µg/ml concentration, for 24 h. Data represent mean ± SEM from two experiments done in triplicate.

 
Two enzymes, P450scc and 3ß-HSD, mediate progesterone production by granulosa cells. Using standard Northern methodology, we found that troglitazone (24-h treatment, 5 µg/ml) did not affect messenger RNA concentrations of P450scc and 3-ßHSD (data not shown). However, measurement of pregnenolone (a precursor of progesterone and the substrate of 3ß-HSD) in media from granulosa cells treated with troglitazone showed that pregnenolone release from the cells was markedly increased, whereas that of progesterone was decreased (Fig. 4Go). This finding indicates that troglitazone decreases the activity of 3ß-HSD enzyme.



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  		Figure 4. Effects of troglitazone on pregnenolone secretion in porcine granulosa cells. Porcine granulosa cells were treated for 24 h with increasing concentrations of troglitazone and progesterone, and pregnenolone concentrations were measured simultaneously in treated cells. Pregnenolone concentrations (right axis) were significantly increased during troglitazone treatment as all progesterone concentrations were decreased by troglitazone.

 
The effect of troglitazone on FSH- and forskolin-stimulated progesterone production
The release of progesterone from granulosa cells is strongly stimulated by an increase in intracellular cAMP. We used FSH, which stimulates cAMP production through a G-protein-coupled receptor, and forskolin as direct stimulators of adenylyl cyclase. The granulosa cells were treated in primary culture for 24 h with maximally effective concentrations of FSH and forskolin, with or without troglitazone (Fig. 5Go). Troglitazone inhibited both FSH- and forskolin-stimulated progesterone release, demonstrating that it acts downstream from the cAMP-mediated signaling mechanism for progesterone release.



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  		Figure 5. Effect of troglitazone on progesterone secretion stimulated by FSH and Forskolin. Porcine granulosa cells were treated with maximally active doses of FSH (200 ng/ml, upper panel) and Forskolin (10 µM, lower panel), together with or without troglitazone (Trog), at 5 µg/ml, for 24 h. Progesterone concentrations in the media were measured with RIA and normalized to basal secretion (mean ± SE, n = 3).

 
Time course of troglitazone effect on 3ß-HSD activity
Granulosa cells were cultured over a time course with or without troglitazone (5 µg/ml). After cell homogenization, the maximal activity of 3ß-HSD enzyme was determined with a saturating substrate concentration (25 µM pregnenolone; published Km for this enzyme in porcine ovary is approximately 1.3 µM). The enzyme activities of both control and treated cells were similar for the first 12 h (data not shown). At 24 h, troglitazone significantly inhibited 3ß-HSD activity, when compared with control cells (Table 1Go).


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  		Table 1. 3ß-HSD enzyme activity in porcine granulosa cell homogenates after 24 h treatment with 5 µg/ml troglitazone

 
Troglitazone effects on estradiol secretion
Direct measurement of aromatase activity, with a tritiated water-release assay, by using [1ß-3H]-androstenedione as a substrate, was also performed. Aromatase activity, measured in porcine granulosa cells in the presence of troglitazone, was not significantly changed by troglitazone treatment, when compared with control granulosa cells (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we determined that troglitazone markedly inhibits progesterone production in primary cultures of porcine granulosa cells. In a dose range of 1–5 µg/ml, which is a pharmacologically relevant therapeutic range for humans, troglitazone almost completely blocked progesterone production. Furthermore, we have established that troglitazone decreases progesterone secretion by decreasing the activity of 3ß-HSD. Consistent with this mechanism, the decrease in 3ß-HSD activity is accompanied by an increase in release of the substrate of this enzyme, pregnenolone. This inhibition occurs, even when granulosa cell cAMP pathway is stimulated by FSH or forskolin, and is specific for 3ß-HSD, because troglitazone does not affect aromatase activity.

Recent clinical studies show that troglitazone effectively treated many of the metabolic abnormalities associated with PCO. The mechanism for the effectiveness of troglitazone was hypothesized to result from the decrease in insulin resistance caused by the drug (11, 12). However, the findings from our in vitro study indicate that troglitazone has direct effects on granulosa cell steroidogenesis. This may not only be a possible explanation for the effectiveness of troglitazone in PCO, but it also implies that troglitazone has additional clinical applications in the female reproductive system.

In comparison with the other two thiazolidinediones tested in the study, troglitazone was the most proficient at suppressing progesterone production. However, troglitazone is not the most potent thiazolidinedione in reducing insulin resistance, ranking in the middle of potency in this class of drugs (19). Troglitazone is a unique thiazolidinedione because of an {alpha}-tocopherol (vitamin E) substitution attached to its thiazolidine core. Vitamin E has effects on reproductive function, and reproductive organs actively transport it inside cells (20, 21). Therefore, the enhanced effects of troglitazone, as compared with other thiazolidinediones, could be related to its tocopherol substitution.

The observed decrease in 3ß-HSD activity, after troglitazone treatment, happened without a concomitant decrease in messenger RNA concentrations. This decreased activity of 3ß-HSD could be the result of either a decrease in the amount of enzyme (translation or degradation) or an effect of troglitazone on a cofactor involved in the activity of 3ß-HSD. Moreover, the early suppression of progesterone production in granulosa cells, before a decrease in 3ß-HSD activity, indicates that troglitazone itself may have direct inhibitory effects on 3ß-HSD activity. The marked elevation of pregnenolone concentrations in our experiments is caused by the lack of activity of 17{alpha}-hydroxylase in granulosa cells (22).

In summary, we have shown that troglitazone suppresses progesterone production in porcine granulosa cells, specifically by inhibiting the activity of 3ß-HSD. These direct effects of troglitazone on ovarian steroidogenesis could be clinically relevant in its use for the treatment of PCO and other ovarian syndromes.


   Acknowledgments
 
We wish to thank Dr. Charles Blomquist (Ramsey Clinic and St. Paul-Ramsey Medical Center, St. Paul, MN) for his helpful comments regarding the 3ß-HSD activity assay.


   Footnotes
 
1 This work was supported by a grant from the Sankyo Corporation (to R.J.U. and A.G.) and NIH Grant RO1-CA45181 (to M.N.). Back

Received May 26, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  7. De Vos PA, Lefebvre M, Miller SG, Guerre-Millo M, Wong K, Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J 1996 Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator- activated receptor gamma. J Clin Invest 98:1004–1009[Medline]
  8. Kletzien RF, Clarke SD, Ulrich RG 1992 Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol Pharmacol 41:393–498[Abstract]
  9. Szalkowski D, White-Carrington S, Berger J, Zhang B 1995 Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3–L1 cells. Endocrinology 136:1474–1481[Abstract]
  10. Udoff L, Adashi EY 1995 Polycystic ovarian disease: a new look at an old subject. Curr Opin Obstet Gynecol 7:340–343[Medline]
  11. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996 The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299–3306[Abstract]
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