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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1281-1286
Copyright © 2001 by The Endocrine Society

Original Studies

The Role of Human Chorionic Gonadotropin on Decidualization of Endometrial Stromal Cells in Vitro1

Kyoko Kasahara, Kenji Takakura, Koichi Takebayashi, Fuminori Kimura, Keiko Nakanishi and Yoichi Noda

Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu 520-2192, Japan

Address all correspondence and requests for reprints to: Kenji Takakura, M.D., Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa Cho, Otsu, 520-2192, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although decidualization of endometrial stromal cells (ESC) is crucial for blastocyst implantation and maintenance of pregnancy, its complex mechanism still remains largely unknown. It has long been believed that hCG can directly induce in vitro decidualization of ESC via cAMP signaling. Recently, however, it has been reported that the LH/CG receptor is not present in human endometrium, and the direct effect of hCG on decidualization has become controversial. To reevaluate the exact effect of hCG on decidualization, human ESC were isolated and cultured with hCG and/or ovarian steroids.

ESC treated with 17ß-estradiol plus progesterone (E2/P) transformed morphologically and produced significant PRL, whereas ESC treated with hCG alone showed no significant increase in PRL in culture medium and exhibited no morphological changes. Moreover, hCG did not promote E2/P-induced PRL production or intracellular cAMP accumulation, and protein kinase A inhibitor failed to block E2/P-induced PRL production.

These results suggest that hCG does not directly affect in vitro decidualization of human ESC and that the process of E2/P-induced in vitro decidualization might consist of several pathways, including the intracellular cAMP signaling cascade.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A SATISFACTORY reproductive outcome requires synchronous growth and maturation of the endometrium throughout the menstrual cycle. The decidualization of human endometrial stromal cells (ESC), which develops in the late secretory stage of the menstrual cycle, is characterized by morphological and functional differentiation. ESC around the blood vessels begin to differentiate into a larger and rounder decidual phenotype on the 23rd day in women with a regular 28-day menstrual cycle (1). The secretion of various peptide hormones, cytokines, and extracellular matrix (2, 3, 4) is thought to be associated with the autocrine and paracrine functions of predecidual cells to prepare for blastocyst implantation. Although timely decidual transformation of ESC is undoubtedly important for successful implantation to occur in humans, little is known about the differentiation process.

A variety of substances, e.g. progesterone (5), cAMP (6), relaxin (7), gonadotropins (8), glycoprotein hormone {alpha}- subunit (9), and PGE2 (10), have been reported to induce or promote in vitro decidualization of ESC. Irwin et al. (5) reported that in isolated and cultured human ESC, 17ß-estradiol plus progesterone (E2/P) significantly induced the secretion of PRL, one of the major markers for decidualization in humans, whereas Telgmann et al. (11) insisted that E2/P has a low potency to differentiate ESC.

On the other hand, Tang et al. (6) showed that cAMP derivatives could induce PRL expression in human ESC and that hCG alone could increase intracellular cAMP accumulation throughout decidualization in vitro, resulting in hCG alone being able to induce in vitro decidualization via intracellular cAMP accumulation (8). In addition, Han et al. (12) showed that hCG did promote E2/P-induced in vitro decidualization. To date, hCG has often been described as a key substance that can both induce and promote in vitro decidualization of ESC. However, Stewart et al. (13) recently reported that the LH/CG receptor is not present in human endometrium. This means that further research is still needed to understand better the mechanism of gonadotropin action on decidualization. Therefore, in this study we reevaluated the role of hCG in in vitro decidualization of human ESC and investigated the mechanism of decidualization.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Collection of tissues

Human endometrium was obtained at hysterectomy from 68 normally cycling premenopausal women, aged 35–48 yr, who had received no hormonal treatment and who underwent surgery for nonendometrial abnormalities. This study was approved by the institutional review board at Shiga University of Medical Science. Informed consent was obtained from every patient. A portion of each endometrial tissue was examined histologically and dated according to the criteria of Noyes et al. (1).

Endometrial tissues were obtained from 22 patients in the follicle stage of the menstrual cycle, from 6 patients in the periovulatory stage, from 12 patients in the early luteal stage, and from 28 patients in the mid to late secretory stage. The data shown in Fig. 1Go (A and B) are representative results obtained by using materials from the follicle and the mid to late secretory stages, and the data shown in Figs. 2–7GoGoGoGoGoGo are representative results of the mid to late secretory stage. In all experiments, similar results were also obtained by using materials from other stages of the menstrual cycle (data not shown).



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  		Figure 1. Effects of ovarian steroids on PRL production on day 14 of culture. P was added to the cultured cells at the different concentrations in the presence of a fixed dose of E2 (A). Similarly, E2 was added to the cells at various concentrations in the presence of a fixed dose of P (B). Dose-response effects were determined in each experiment, although untreated cells produced very little PRL. PRL production is expressed as a percentage with respect to control cultures performed with 10-7 mol/L P plus 10-8 mol/L E2. Each value represents the mean ± SD of four separate cultures.

 


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  		Figure 2. Morphological appearance of ESC on day 6 of culture under a phase contrast microscope. Although the untreated cells showed a fibroblast-like spindle-shaped appearance (A), the cells treated with E2/P were transformed into large polygonal cells, resembling decidual cells in vivo (B). The cells treated with 104 mIU/mL hCG alone showed no morphological changes (C). The cells treated with E2/P plus 104 mIU/mL hCG transformed into large polygonal cells like those treated with E2/P (D). Magnification, x200.

 


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  		Figure 3. Effect of hCG on PRL production and cell number on day 22 of culture. PRL levels in media were under the detection limit regardless of the concentration of hCG on day 22 of culture, although E2/P induced massive PRL production from the identical specimens. Values represent the mean ± SD of triplicate determinations from a representative experiments. *, P < 0.01 vs. untreated cells.

 


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  		Figure 4. Effect of hCG on E2/P-induced PRL production and cell number on day 22 of culture. Values represent the mean ± SD of triplicate determinations from a representative experiment. *, P < 0.05; **, P < 0.001 (vs. cells treated with E2/P alone).

 


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  		Figure 5. Time course of PRL production from ESC. The cells were exposed to E2/P with or without hCG (103–105 mIU/mL) for up to 22 days. In the presence of E2/P, PRL was first detected in the culture medium after a lag of 6 days, and the level increased gradually thereafter. hCG at 103 mIU/mL never affected E2/P-induced PRL production, and the inhibitory effect of 104–105 mIU/mL hCG was observed through 22 day of culture. Values represent the mean ± SD of triplicate determinations from a representative experiment. *, P < 0.05; **, P < 0.01 (vs. cells treated with E2/P alone).

 


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  		Figure 6. Comparison of PRL levels in media and intracellular cAMP levels. ESC were cultured for 14 days in the presence or absence of E2/P and hCG. *, P < 0.01 vs. cells treated with E2/P. **, P < 0.001 vs. untreated cells. Values represent the mean ± SD of triplicate determinations from a representative experiment.

 


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  		Figure 7. Effect of 10 µg/mL PKI on E2/P-induced PRL secretion on day 22 of culture. PKI suppressed E2/P-induced PRL secretion and cell growth to a similar extent per well (A), failing to affect PRL secretion per cell (B). The effect of E2/P alone was assigned a potency of 100% (B). Values represent the mean ± SD of triplicate determinations from a representative experiment.

 
Isolation and culture of ESC

Human ESC were isolated and cultured as previously described (14). Briefly, tissue samples were washed with Dulbecco’s PBS (Nissui Pharmaceutical Co., Tokyo, Japan) and minced into small pieces of less than 1 mm3. These tissue pieces were then incubated for 1 h at 37 C in a humidified atmosphere of 5% CO2 in air in DMEM (phenol red-free, Life Technologies, Inc., Grand Island, NY) containing 0.2% collagenase (from Clostridium histolyticum, Wako Pure Chemical Co., Osaka, Japan) and 0.005% deoxyribonuclease I (type IV: from bovine pancreas, Sigma, St. Louis, MO), with gentle pipetting every 15 min. After digestion, the cell suspension was left in an upright position for 5 min. Then the supernatant, the stromal cell-rich fraction, was transferred onto 40-µm nylon mesh (Becton Dickinson, Franklin Lakes, NJ) and centrifuged for 10 min. The purity of stromal cells obtained by this method was usually greater than 90%, as determined by immunohistochemical staining against vimentin (stromal cell marker) and cytokeratin (epithelial cell marker). The purified stromal cells were washed three times, and the number of viable cells was counted by trypan blue dye exclusion. One million viable cells were inoculated into each well of six-well plates (Becton Dickinson). Cells were cultured at 37 C in a humidified atmosphere of 5% CO2 in air with 4 mL DMEM supplemented with 10% charcoal-stripped FBS (Life Technologies, Inc.), 100 IU/mL penicillin, 100 µg/mL streptomycin (Sigma), and some other materials, such as E2 (Sigma), P (4-pregnene-3,20-dione; Sigma), and hCG (Teikokuzouki Pharmaceutical Co. Ltd., Tokyo, Japan). The bioactivity of hCG used in this study was confirmed by ovulation induction in mice. The culture medium was changed every 2 days, and morphological assessment was performed under a phase contrast microscope (IM-T2, Olympus Corp., Tokyo, Japan).

All experiments described in this study were also performed under the condition of 2% FBS in culture medium, which has often been proposed by other investigators as a suitable condition for inducing in vitro decidualization (6, 8, 15). The same results were obtained even in this low serum condition (data not shown).

PRL measurement

At the completion of each culture, cell number was counted by the citric acid-crystal violet method (16). PRL in culture medium was measured by RIA (Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan). The detection limit of this assay was 0.3 ng/mL, and the intra- and interassay coefficients of variation were 1.9–7.1% and 1.6–3.6%, respectively.

cAMP measurement

Intracellular cAMP of ESC was measured at the completion of culture. After retrieval of culture media for the PRL assay, each cell pellet was homogenized in ice-cold 0.1 N HCl and centrifuged. The supernatant was pooled and stored at -20 C until measurement. The cAMP concentration was determined by RIA (Yamasa assay kit, Tokyo, Japan). The protein concentration in each sample was determined using a Non- Interfering Protein Assay kit (Geno Technology, Inc., St. Louis, MO).

Protein kinase A inhibitor experiment

ESC was cultured in the presence of 10-8 mol/L E2 plus 10-7 mol/L P (E2/P) with or without 10 µg/mL protein kinase inhibitor (PKI; a synthetic 20-amino acid peptide, rabbit sequence; Sigma) (17), according to the method of Aronica et al. (18). At the completion of each culture, PRL was measured as described above.

Replication of experiments and statistical analysis

Each experiment was performed at least in triplicate and repeated at least three times on different specimens. Statistical differences between sample means were calculated by ANOVA, followed by Fisher’s protected least significant differences test. The results are expressed as the mean ± SD. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Optimal concentration of E2 and P for in vitro decidualization

To determine the optimal concentrations of E2 and P for PRL secretion from ESC, P was added to cells obtained in various stages of the cycle at concentrations of 10-11–10-5 mol/L for 14 days in the presence of 10-8 mol/L E2 (Fig. 1AGo). P stimulated PRL release in a dose-dependent manner, reaching a maximum level at 10-7 mol/L, although cells treated without P produced a very low level of PRL. Then, in the presence of 10-7 mol/L P, E2 was added to the cells at concentrations of 10-12–10-6 mol/L for 14 days (Fig. 1BGo). Dose-related effects were also observed, and 10-8 mol/L E2 showed the maximum effect on PRL production. Therefore, the optimal concentrations of E2 and P for in vitro decidualization were determined to be 10-8 and 10-7 mol/L, respectively. These are within the physiological limits of blood serum concentrations during normal pregnancy, and most investigators (5, 12, 14, 15) have also used the same or similar concentrations for in vitro decidualization experiments. In the presence of 10-8 mol/L E2 plus 10-7 mol/L P (E2/P), PRL was first detected in culture medium after a lag of 6–8 days, and its level increased gradually thereafter. Similar results were obtained by using materials in other stages of the cycle, although specimens obtained in follicle and secretory stages secreted the maximal PRL level in media on days 36–40 and 16–20, respectively (data not shown).

Direct effect of hCG on morphological changes in ESC

The cultured cells, which were spindle-shaped when they were plated, reached confluence on the third to sixth culture day, representing some morphological features. The untreated cells retained a fibroblast-like appearance (Fig. 2AGo). In the presence of E2/P, the cells were transformed into large polygonal cells with enlarged nuclei and an increased amount of cytoplasm, resembling decidual cells in vivo (Fig. 2BGo). As the cells proceeded to differentiation, their borders became less distinct because of the extracellular matrix formation. With further differentiation, cells began to form aggregates and increased in size and number.

The cells treated with hCG alone showed no morphological change, resembling the appearance of untreated cells (Fig. 2CGo). Morphological transformation induced by E2/P was not affected by the addition of hCG (Fig. 2DGo). These morphological features remained throughout the culture period (data not shown).

Direct effect of hCG on PRL secretion from ESC

To reevaluate whether hCG by itself can induce in vitro decidualization, hCG was added to culture media at concentrations of 10–105 mIU/mL for 22 days, and PRL levels in media and cell number per well were measured. On day 22, hCG at any concentration had failed to release a significant level of PRL from ESC, whereas E2/P had significantly induced PRL secretion. ESC treated with hCG showed no significant differences in number, whereas ESC treated with E2/P significantly increased in number (Fig. 3Go). Moreover, hCG failed to induce PRL secretion from ESC, not only on day 22, but throughout the culture period (data not shown). Similar results were obtained in 11 separate experiments using endometrium of different cycle stages.

Direct effect of hCG on E2/P-induced PRL secretion

To investigate the promotive effect of hCG on E2/P- induced in vitro decidualization, 10–105 mIU/mL hCG was added to culture media in the presence of E2/P. hCG did not show any promotive effect on E2/P-induced PRL production and cell number on day 22 of culture (Fig. 4Go). In addition, ESC cultured with 104 or 105 mIU/mL hCG in the presence of E2/P produced significantly lower amounts of PRL compared with those cultured with E2/P alone. Cell proliferation was not suppressed at any concentration of hCG, and hCG did not promote E2/P-induced PRL production throughout the culture period (Fig. 5Go). Similar results were obtained in nine separate experiments using endometrium of different cycle stages, although in three separate experiments ESC cultured with 104 mIU/mL hCG did not produce significantly lower amounts of PRL throughout the culture period (data not shown). Even in these cases, ESC cultured with 105 mIU/mL hCG in the presence of E2/P produced significantly lower amounts of PRL than those cultured with E2/P alone throughout the culture period.

hCG and intracellular cAMP in ESC

To investigate the effect of hCG on intracellular cAMP accumulation, 103–105 mIU/mL hCG was added to culture media in the presence and absence of E2/P. The intracellular cAMP level was elevated significantly by E2/P, but not by hCG. Moreover, hCG did not show any promotive effect on intracellular cAMP accumulation in ESC (Fig. 6Go). hCG at 105 mIU/mL, rather, suppressed intracellular cAMP accumulation induced by E2/P. The protein concentrations among all samples were not significantly different (data not shown). Similar results were obtained in 12 separate experiments using endometrium of different cycle stages.

Effect of PKI on E2/P-induced in vitro decidualization

To examine whether PKI, which blocks the intracellular cAMP signaling cascade, has an adverse effect on E2/P-induced in vitro decidualization, 10 µg/mL PKI were added to each culture medium in the presence of E2/P. In each well, PKI lowered E2/P-induced PRL production and E2/P- induced cell proliferation to the same extent (mean, -19.5% and -21.5%; SD, 8.7% and 6.2%, respectively; n = 3; Fig. 7AGo). Therefore, PKI did not significantly affect E2/P-induced PRL secretion per cell (Fig. 7BGo). Moreover, PKI did not affect E2/P-induced morphological changes in ESC (data not shown). The same results were obtained in three independent experiments.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
For infertile women, hCG is frequently used for luteal support as well as ovulation induction. hCG binds to the LH/CG receptor expressed in the ovary and some cell lineages, allowing it to carry out its physiological function. The presence of the LH/CG receptor in human endometrium has been shown by immunohistochemistry and a molecular biological method (19, 20). However, Stewart et al. (13) pointed out that the technical limitations of previous studies raised questions about the strength of the data and concluded, from the results obtained using a RT-PCR method, that the traditional gonadal LH/CG receptor is not present in human endometrium. Hence, not only the presence of the hCG receptor but also the direct action of hCG on human endometrium have become controversial issues recently (21).

To reevaluate these problems, we first established an in vitro model of decidualization and reconfirmed that E2/P could induce PRL secretion of ESC in a dose-dependent manner and that the optimum concentrations of E2 and P for induction of in vitro decidualization were 10-8 and 10-7 mol/L, respectively. These observations were consistent with other previous reports (5).

The present study demonstrated that hCG never directly induces or promotes in vitro decidualization of human ESC in point of morphological changes, PRL secretion, and intracellular cAMP accumulation. Furthermore, a high dose of hCG significantly inhibits E2/P-induced PRL secretion and intracellular cAMP accumulation without suppressing cell proliferation. One of the explanations for this inhibitory effect of an extraphysiologically high concentration of hCG is that the contaminants in hCG provided commercially through purification from stocked urine may interfere with hCG action. Another possible explanation is that a high dose of hCG may interact with an unidentified low affinity LH/CG receptor and inhibit PRL secretion.

We also demonstrated that although E2/P-induced in vitro decidualization was accompanied by intracellular cAMP accumulation, PKI failed to suppress E2/P-induced PRL secretion per cell. Per well, PKI as well as another PKA inhibitor, 8-bromoadenosine-3',5'-cyclic monophosphorothioate (15), eventually reduced E2/P-induced PRL secretion to some extent. Concurrently, to the same extent, PKI suppressed E2/P-induced cell proliferation, which required activation of the intracellular cAMP signaling cascade. Taken together, the results indicated that inhibition of the cAMP signaling cascade does not suppress decidualization per cell.

Thus, our results indicated that the process of E2/P- induced in vitro decidualization might consist of several pathways, including the intracellular cAMP signaling cascade, and that hCG does not directly affect in vitro decidualization of human ESC. In other words, the decidualizing potency of E2/P is sufficiently large to overcome the suppression of cAMP signaling, and E2/P could be one of the most powerful decidualizing effectors of human ESC obtained from various stages of the menstrual cycle.

As other investigators (5, 9, 12) also observed variabilities among endometrial specimens, we performed the experiments repeatedly using materials from various stages of the cycle and several lots of hCG. However, we cannot clearly explain why our results differ from those obtained in other laboratories. One possible explanation for this discrepancy is the addition of insulin to culture medium in some laboratories (6, 8, 9, 12). Another possible explanation is the differences in lots of serum and hCG. Although highly purified hCG has been used in most studies to date, completely pure hCG (recombinant hCG) and serum-free medium will be better tools for the standard assay in future studies of decidualization.


   Footnotes
 
1 This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture (Grant 11770937). Back

Received July 18, 2000.

Revised October 9, 2000.

Revised November 15, 2000.

Accepted November 16, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  9. Moy E, Kimzey LM, Nelson LM, Blithe DL. 1996 Glycoprotein hormone {alpha}-subunit functions synergistically with progesterone to stimulate differentiation of cultured human endometrial stromal cells to decidualized cells: a novel role for free {alpha}-subunit in reproduction. Endocrinology. 137:1332–1339.[Abstract]
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals