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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1869-1873
Copyright © 1997 by The Endocrine Society

Experimental Studies

Triiodothyronine and Follicle-Stimulating Hormone, Alone and Additively Together, Stimulate Production of the Tissue Inhibitor of Metalloproteinases-1 in Cultured Human Luteinized Granulosa Cells

S. Goldman, M. Dirnfeld, H. Abramovici and Z. Kraiem

Endocrine Research Unit (S.G., Z.K.) and Department of Obstetrics and Gynecology (M.D., H.A.), Carmel Medical Center; and the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology (H.A., Z.K.), Haifa, Israel

Address all correspondence and requests for reprints to: Z. Kraiem, Endocrine Research Unit, Carmel Medical Center, 7 Michal Street, Haifa 34362, Israel.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Thyroid disorders have been frequently associated with menstrual disturbances and impaired fertility. To characterize the nature of thyroid hormone action in the ovary, the direct effects of T3-gonadotropin interactions were investigated in vitro using a culture system of human luteinized granulosa cells in serum-free medium. Although FSH alone was devoid of any significant effect on cell proliferation, it inhibited T3-stimulated cell growth. The electrophoretic profiles of the radiolabeled proteins induced by the different hormonal treatments revealed similarity in overall protein patterns but differences in intensity of labeling. Human CG, alone or combined with T3, had no major influence on the total intensity of labeling compared with control, whereas T3 or FSH alone reduced total labeling intensity but a 30,000 Da protein band was increased. FSH combined with T3 augmented the total intensity of labeling, including the 30,000-Da protein band. Western blot analysis revealed the presence of the tissue inhibitor of metalloproteinases-1 (TIMP-1), mol wt 30,000, known to play a key role in ovarian function. TIMP-1 was dose dependently stimulated by T3 and FSH, and an additive effect was obtained when both hormones were combined.

This is the first report of TIMP-1 modulation by FSH in ovarian cells and of an effect by thyroid hormone on TIMP-1 levels. The study shows TIMP-1 induction in human ovarian cells not only by FSH, i.e. via a probable protein kinase A mechanism, but also demonstrates an additional mode of TIMP-1 hormonal induction: via thyroid hormone stimulation, acting by modulation of gene transcription. The present study provides novel data on TIMP-1 hormonal modulation and of direct T3 in vitro ovarian effects that may account for the in vivo indications of a thyroid-ovarian connection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THYROID disorders have been frequently associated with menstrual disturbances and impaired fertility (reviewed in 1 . Moreover, a number of in vitro studies have also shown a direct effect of T3 on ovarian cells (reviewed in Refs. 2 and 3). In a previous study in cultured human luteinized granulosa cells in serum-free medium (2), we demonstrated that such cells indeed contain thyroid hormone binding sites, and that they serve as target to T3 action, in particular T3 modulating human CG (hCG)-mediated ovarian cell proliferation and function (cAMP formation and progesterone secretion).

Ovarian proteins, such as metalloproteinases and their inhibitors, are believed to be involved in the ovarian processes of follicular rupture and luteolysis (reviewed in 4 . Using the same serum-free system of human luteinized granulosa cells cultured with the same agents at the same doses and culture period as in our previous study (2), we examined the profile of radiolabeled proteins synthesized by such cells when challenged by T3, FSH, or hCG, alone and in combination, as well as the effect of T3-FSH interactions on cell growth.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human luteinized granulosa cells were harvested from large (>17 mm diameter) dominant preovulatory follicles from women under the age of 40 yr with tubal infertility undergoing oocyte retrieval for in vitro fertilization. The protocol for ovarian stimulation and cell preparation was as commonly used (e.g. in Refs. 5 and 6) and was identical to that described in detail in our previous study (2). Cells were cultured in triplicate at a density of 200,000 cells/well in 0.5 ml Ham’s F-10 medium containing 0.1% heat-inactivated human serum plus antibiotics. After 24 h of culture for cell attachment, the medium was removed and serum-free Ham’s F-10 medium plus antibiotics with or without hormones (hCG (Chorigon, Teva, Israel) and/or FSH (Metrodin, Ikapharm, Israel) and/or T3 (Sigma Chemical Co., St. Louis, MO) was added to the monolayer culture. Viability of cells, as assessed by trypan blue, following treatment with hCG, FSH, T3, and combinations thereof, ranged from 86–91%. The protocol used by the in vitro fertilization unit of the Carmel Medical Center where the work was performed has been approved by the Israel Scientific Council and Israel Ministry of Health.

After culturing the cells for 4 days in the presence and absence of hormones, the cell DNA content was measured by fluorimetry as described previously (7), and incorporation of [3H]-thymidine (Amersham International, Amersham, Bucks, UK), added during the last 24 h of culture, was measured as described previously (8). To determine the protein electrophoretic profile at the end of the culture period (4 days), the monolayer was washed with methionine-free DMEM, and 0.5 mL of the same medium containing 10 µCi [35S]methionine (Amersham International) was added to each well. After 6 h incubation, the medium was removed and the cell monolayer washed with 100 µL Dulbecco’s PBS, which was then discarded. SDS sample buffer was added to each culture well to remove the cells, which were then frozen. Electrophoresis was performed on 5–15% polyacrylamide gradient slab gels with the use of the Laemmli SDS buffer system (9). All samples, except those undergoing Western blot analysis, were reduced with ß-mercaptoethanol before electrophoresis. Gels were autoradiographed and then quantitated by densitometry using the BioImaging gel documentation system (Dinco & Renium, Jerusalem, Israel) and the TINA software (Raytest, Staubenhardt, Germany).

For Western blot analysis, the proteins (50 µg/lane) following SDS-PAGE were blotted onto 0.45-µm nitrocellulose membranes (Schleicher & Schuell, Dassel, Germany). Nonspecific binding sites were blocked by incubating the nitrocellulose membranes overnight with 20% nonfat milk and Tris-buffered saline containing 0.01% Tween-20. The membranes were then washed twice with Tris-buffered saline containing 0.5% Tween-20, and incubated for 1 h with mouse antihuman tissue inhibitor of metalloproteinases-1 (TIMP-1) monoclonal antibody (Oncogene Science, Cambridge, MA) in 10% nonfat milk and Tris-buffered saline containing 0.01% Tween-20. The membranes were subsequently washed with Tris-buffered saline containing 0.5% Tween-20 and incubated for 1 h with horseradish peroxidase-conjugated antirabbit secondary antibody (Jackson ImmunoResearch, West Grove, PA) in 10% nonfat milk and Tris-buffered saline containing 0.01% Tween-20, then detected by enhanced chemiluminescence (Amersham International) and quantitated by densitometry as specified above.

Each experiment was repeated at least three times using cell preparations obtained from separate patients. Statistical analysis of the data was performed using Student’s t test when two treatments were compared and ANOVA test when more than two treatments were evaluated (e.g. dose-dependent responses). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Cell proliferation

T3 markedly increased DNA content, with maximum levels reached at a concentration of 10-9 M (Fig. 1Go). Whereas FSH alone had no significant effect on DNA content, addition of the gonadotropin to 10-9 M T3 inhibited the thyroid hormone-induced stimulation of DNA to levels below those reached by control (Fig. 1Go). These results on the effect of T3, FSH, and T3 combined with FSH, were corroborated by measurements of tritiated thymidine incorporation (mean ± SEM cpm/well: control, 8670 ± 430; FSH (20 ng/mL), 9020 ± 640; T3 (10-9 M), 19775 ± 890; T3 (10-9 M) + FSH (20 ng/mL), 3440 ± 290. T3 vs. control was P < 0.01; T3 + FSH vs. control was P < 0.01.



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  		Figure 1. DNA content measured following culture for 4 days of human luteinized granulosa cells in absence and presence of T3 (10-11–10-7 M) or FSH (20 ng/mL) alone, or T3 (10-11–10-7 M) combined with FSH (20 ng/mL). Each bar represents mean ± SEM of four experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.005 compared with control.

 
Electrophoretic profiles of [35S]methionine-labeled proteins

The electrophoretic profiles of the radiolabeled proteins (Fig. 2Go) revealed a large number of protein bands with no major apparent difference in overall pattern between the different treatments (i.e. control, T3, hCG, FSH, and combinations thereof). Densitometric analysis confirmed the similarity in protein patterns but revealed differences in intensity of labeling (Fig. 3Go). T3 reduced the total intensity of labeling of the sum of all the protein bands (total optical absorbance of the sum total of all the protein bands compared with control: 76%). hCG, alone or combined with T3, did not induce any marked change in the total intensity of labeling of the sum of all the protein bands. FSH diminished the total intensity of labeling of the sum of all the protein bands (74% of total optical absorbance compared with control). T3 combined with FSH enhanced the total intensity of labeling of the sum of all the protein bands (141% of total optical absorbance compared with control). Despite the reduction of total intensity of labeling by T3 or FSH, the intensity of labeling of a 30,000-Da protein band, expressed as percent of sum total of labeling intensity of all the bands in the same lane (i.e. treatment), was higher than the intensity of labeling of this band (30,000 Da protein) expressed as percent of labeling intensity of all the bands in the control lane (i.e. treatment): 38% and 45% higher than control for T3 and FSH, respectively. When T3 and FSH were combined, the 30,000-Da protein band was enhanced even more: 3.4-fold higher than control.



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  		Figure 2. Autoradiograph representative of four experiments of electrophoretic profiles of [35S]methionine-labeled proteins (50 µg protein/lane) in human luteinized granulosa cells following 4 days culture in absence (control, lane 1) and presence of hCG (1 IU/mL, lane 2), FSH (20 ng/mL, lane 3), T3 (10-9 M, lane 4), T3 (10-9 M) + hCG 1 IU/mL, lane 5), and T3 (10-9 M) + FSH 20 ng/mL, lane 6).

 


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  		Figure 3. Densitometric scans of autoradiograph of human luteinized granulosa cell proteins shown in Fig. 2Go. Lanes were scanned vertically so that intensity of labeling of each band is relative to that of other bands in same lane, i.e. treatment.

 
Western blot analysis

Western blot analysis revealed that the TIMP-1 antibody recognized a 30,000-Da protein (Fig. 4Go), thus providing evidence that the radiolabeled protein band at 30,000 Da described earlier was composed, at least in part, of this protein. As shown in Fig. 4Go, hCG slightly stimulated TIMP-1, whereas T3 and FSH markedly augmented levels of the protein; T3 in combination with FSH had an additive effect on TIMP-1. Figures 5Go, 6Go, and 7Go show the dose-dependent stimulation of TIMP-1 by T3, FSH, and hCG, respectively.



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  		Figure 4. Western blot analysis following culture of human luteinized granulosa cells for 4 days in absence (control) and presence of hCG (1 IU/mL), T3 (10-9 M), FSH (20 ng/mL), hCG (1 IU/mL) + T3 (10-9 M), FSH (20 ng/ml) + T3 (10-9 M). Std. on autoradiograph represents TIMP-1 standard (kindly donated by Dr. H. Nagase). Histograms represent densitometric values (mean ± SEM) of three experiments. The autoradiograph shown is that of a representative experiment. *, P < 0.05; **, P < 0.01; ***, P < 0.005 compared with control.

 


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  		Figure 5. Western blot analysis following culture of human luteinized granulosa cells for 4 days in absence and presence of various concentrations of T3. Densitometric values are mean ± SEM of three experiments. The autoradiograph shown is that of a representative experiment. *, P < 0.05; **, P < 0.01; ***, P < 0.005 compared with control. ANOVA of T3 stimulation of TIMP-1 was P < 0.05.

 


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  		Figure 6. Western blot analysis following culture of human luteinized granulosa cells for 4 days in absence and presence of various concentrations of FSH. Densitometric values are mean ± SEM of three experiments. The autoradiograph shown is that of a representative experiment. *, P < 0.05; **, P < 0.01 compared with control. ANOVA of FSH stimulation of TIMP-1 was P < 0.05.

 


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  		Figure 7. Western blot analysis following culture of human luteinized granulosa cells for 4 days in absence and presence of various concentrations of hCG. Densitometric values are mean ± SEM of three experiments. The autoradiograph shown is that of a representative experiment. *, P < 0.05; **, P < 0.01 compared with control. ANOVA of hCG stimulation of TIMP-1 was P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In cultured human luteinized granulosa cells, the salient findings of the present study are as follows. 1) Although FSH alone was devoid of any significant effect on cell proliferation, it inhibited, similar to what was observed regarding hCG in our previous study (2), T3-stimulated cell growth. 2) The electrophoretic profiles of the radiolabeled proteins induced by the different hormonal treatments revealed similarity in overall protein patterns but differences in intensity of labeling because hCG, alone or combined with T3, had no major influence on the total intensity of labeling compared with control, whereas T3 or FSH alone reduced total labeling intensity, but a 30,000-Da protein band was increased. More-over, FSH combined with T3 augmented the intensity of total labeling, including the 30,000-Da protein band. 3) Western blotting revealed the presence of TIMP-1, mol wt 30,000, which was increased in the presence of T3 and FSH, alone and additively, when both hormones were combined. It should be kept in mind that the response of differentiated luteinized granulosa cells to treatment in vitro may not represent the response of follicular phase granulosa cells in vivo.

FSH in bovine (10) and hCG in rat (11) cultured granulosa cells has been reported to increase the synthesis of a number of specific radiolabeled proteins, unlike the lack of effect with hCG or inhibitory effect with FSH we observed in human luteinized granulosa cells. Also unlike our observations, a 220,000-Da protein, identified as fibronectin, has been reported to be induced in rat (12), bovine (13), and human (14) cultured granulosa cells. The explanation for the discrepancy in data could be because of species differences. It could also be because the latter study (14), the only other report to the best of our knowledge that examined the electrophoretic profiles of radiolabeled proteins from granulosa cells of human origin, used cells from before the LH surge, compared with our study, which used cells obtained from hCG-treated patients.

Of particular interest is the presence of TIMP-1 that we detected and its modulation by T3 and FSH. Metalloproteinases, such as collagenase and stromelysin, are metal-dependent enzymes that degrade protein components of the extracellular matrix. These enzymes, together with their inhibitors, the TIMPs, are believed to play key roles in extracellular matrix remodeling, and therefore have been implicated in tissue resorption and degradation in a range of normal and abnormal processes (reviewed in Refs. 15 and 16). Although the role of TIMP-1 in ovarian function is not yet completely understood, it has been postulated to regulate proteolytic activity, and therefore to be crucial to the ovulatory process, luteal development, and regression, as well as trophoblast invasion (15, 17, 18, 19, 20, 21). As we have observed, T3 and FSH modulate TIMP-1 levels, therefore any change in the level of these hormones, such as may occur in certain disease states, could influence TIMP-1 levels and consequently affect ovarian processes and eventually lead to disturbed reproductive function.

TIMP-1, or TIMP-1 messenger RNA (mRNA), has been identified in rat, ovine, and porcine granulosa and luteal cells (17, 18, 19, 20, 22, 23, 24, 25) and bovine luteal cells (18), as well as during pseudopregnancy in the rat (21). Moreover, the presence of TIMP-1 has been reported in human granulosa cells (26) and follicular fluid (27) and TIMP-1 mRNA has been reported in human granulosa cells (28). LH/hCG treatment increased TIMP-1 mRNA in rat ovarian (17), granulosa (22, 24), and thecal (29) cells, and in porcine granulosa cells (20). FSH stimulated TIMP-1 expression in rat Sertoli cells (30). Our study is the first report, however, of TIMP-1 modulation by FSH in ovarian cells and of an effect by thyroid hormone on TIMP-1 levels, with the results showing a dose-dependent stimulation of TIMP-1 by FSH and T3 in cultured human luteinized granulosa cells in serum-free medium. It is relevant to note in this context that T3 has been shown previously to increase the expression of matrix metalloproteinases in a mammary cell line (31).

Our findings that the combination of FSH and T3 stimulated TIMP-1 more than either alone at maximal doses indicates a different mechanism of action by the two hormones, as would be expected of hormones belonging to different classes. TIMP-1 has been shown to be induced in rat granulosa cells by two separate pathways: an LH-cAMP-dependent protein kinase A pathway and a cAMP-independent protein kinase C pathway (17). The present study shows TIMP-1 induction in human ovarian cells not only by FSH, i.e. via a probable protein kinase A mechanism, but it is also the first to demonstrate an additional mode of TIMP-1 hormonal induction: via thyroid hormone stimulation acting by modulation of gene transcription (32). It is noteworthy that steroid hormones, which as thyroid hormones are members of the steroid-thyroid hormone superfamily with similar mechanisms of action, have also been reported to stimulate TIMP-1 (reviewed in 15 .

In conclusion, the present study provides novel data on TIMP-1 hormonal modulation and of direct T3 in vitro ovarian effects, which may account for the in vivo indications of a thyroid-ovarian connection.

Received August 22, 1996.

Revised January 30, 1997.

Accepted February 25, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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