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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2507-2512
Copyright © 1999 by The Endocrine Society

Original Studies

Paracrine Regulation of Insulin-Like Growth Factor I (IGF-I) and IGF-II on Prostaglandins F2{alpha} and E2 Synthesis by Human Corpus Luteum in Vitro: A Possible Balance of Luteotropic and Luteolytic Effects

Rosanna Apa, Fiorella Miceli, Emilia Pierro, Francesca Minici, Pierluigi Navarra, Alessandro Caruso, Maddalena Napolitano, Salvatore Mancuso and Antonio Lanzone

Departments of Obstetrics and Gynecology (A.P., M.F., P.E., M.F., C.A., M.S.) and Pharmacology (N.P.), Universitè Cattolica del Sacro Cuore, 00168 Rome; the Department of Experimental Medicine and Pathology, Universitè La Sapienza (N.M.), Rome; and OASI Institute for Research (L.A.), Troina, Italy

Address all correspondence and requests for reprints to: Apa Rosanna, M.D., Department of Obstetrics and Gynecology, Universitè Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The existence of a complete intraovarian insulin-like growth factor (IGF) system replete with ligands, receptors, and binding proteins has been demonstrated as well as the ability of IGF-I to positively affect steroidogenesis in human granulosa cells. Furthermore, we recently showed that IGF-I and IGF-II stimulate progesterone secretion by human luteal cells. As the PGs, PGE2 and PGF2{alpha}, are classically known to have luteotropic and luteolytic effects, we wanted to determine whether the IGFs could affect the human luteal phase by influencing the PG system. For this reason, human luteal cells were cultured for different times (12, 24, and 48 h) with IGF-I, IGF-II (10–100 ng/mL), and GH (100 ng/mL), and both PGs were assayed in the medium culture. We found that both IGF-I and IGF-II were able to stimulate PGE2 synthesis in a time- and dose-dependent way, whereas they both inhibited PGF2{alpha} production. GH, too, significantly reduced PGF2{alpha} synthesis; this effect was IGF-I mediated because it was reverted by increasing dilutions of an anti-IGF-I antibody. On the contrary, no GH effect was observed on PGE2 production. In conclusion, based on these data and on our previous results, we speculate that IGFs could influence luteal steroidogenesis through PG system.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PROGESTERONE (P) secreted by the human corpus luteum (CL) of the menstrual cycle is essential for an adequate length of the luteal phase, implantation, and maintenance of early embryo development (1). Its different secretion during the three different phases of the luteal period is the result of complex interactions between stimulatory (luteotropic) and inhibitory (luteolytic) factors still not completely known. In recent years evidence has been accumulated to favor a role for PGs in several functional processes in the ovary, mainly in the CL physiology. PGF2{alpha} seems to be essential for luteolysis in certain animal species (2), and many recent findings suggest a key role for it also in human CL regression (3, 4, 5). In fact, a negative correlation between the concentrations of P and PGF2{alpha} throughout the menstrual cycle has been demonstrated (6), and in vitro the intraluteal injection of PGF2{alpha} caused both an immediate fall in serum P and a shortening of the luteal phase (7). Conversely, there are several reports suggesting a luteotropic action for PGE2. In animals this PG stimulates luteal P secretion (8); in sheep, experiments using chronic intrauterine injections of PGE2 prevented mechanically induced luteolysis created by insertion of an intrauterine device (9). In humans, a positive correlation between P and PGE2 has been demonstrated throughout the entire menstrual cycle (10); in vitro, PGE2 was able to stimulate cAMP (4, 11) and P (11, 12) synthesis in isolated human CL.

Among the several factors regulating the complex luteal physiology, the pivotal roles of LH and gonadal steroids have been well documented (13). However, new substances have recently provoked interest in this regard. Of these, the insulin-like growth factor (IGF) system has received considerable attention. An increasing body of information is compatible with the existence of a complete intraovarian IGF system replete with ligands, receptors, and binding proteins (14), and a direct steroidogenic action of IGF-I has been shown, as it is able to positively affect steroidogenesis in human granulosa (15) and rabbit and rat luteal cells. Furthermore, in addition to these results, we recently demonstrated that IGF-I as well as IGF-II stimulate P secretion when cultured with human luteal cells (16).

Based on this information we wanted to continue our investigation about the influence of IGFs on luteal physiology and determine whether these factors could also affect PGs luteal synthesis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Luteal cell culture preparation

CL were obtained at the time of hysterectomy performed for nonendocrine gynecological diseases (leiomyomatosis) in the midluteal phase of the menstrual cycle (days 5–6 from ovulation). Patients were between 30–43 yr of age. All of them had a history of regular menstrual cycles. A total of eight experiments were performed. Informed consent was obtained from each patient, and the study obtained approval from the internal review board. The age of the CL was determined as follows. All patients were monitored until ovulation by daily measurement of basal body temperature and ultrasound examination of follicular growth. When the maximal follicular diameter had reached 18 mm, daily determination of plasma P values was made. The time of ovulation (day 0) was detected by the biphasic pattern of basal body temperature, the typical ultrasound disappearance of the dominant follicle or the echographic detection of CL, and the rise of plasma P concentrations. At the time of surgery, plasma samples were collected immediately before anesthesia to determinate plasma P concentrations. The removed luteal tissue was immediately freed from blood vessels and ovarian stroma under a dissecting microscope, dissected, and minced. Human CL cultures were established as previously described (16). The luteal tissue was placed in Ham’s F-12 medium containing 10 mmol/L HEPES buffer and 5 mg/mL collagenase type IV, then incubated at 37 C in a shaking water bath for 2 h. The cell suspension was filtered through 40-µm pore size nylon mesh, centrifuged, and resuspended in fresh medium several times to obtain highly purified luteal cells. Cells were counted, and viability was determined by the trypan blue test. The cells were diluted to a final concentration of 80,000–100,000 live cells/mL medium supplemented with 2 mmol/L L-glutamine, 100 IU penicillin, and 100 mg/mL streptomycin with and without 10% FCS and were cultured in multiwell plates for 24 h in 5% CO2 and 95% air at 37 C. After this time the cells attached to the wells; the medium was then removed, and fresh serum-free medium supplemented with 5 ng/mL insulin, 5 mg/mL transferrin, and 40 ng/mL hydrocortisone was added to the cultures. At this point the cells were incubated with IGF-I or IGF-II (1–100 ng/mL) or with GH (4 µg/mL) alone or in association with an anti-IGF-I antibody at different dilutions (from 1:1000 to 1:8000). At the end of culture, the cells were stained for lipids with oil red O14 and counted. More than 90% of the luteal cells stained positive for lipids. The remainder of the cells did not stain for lipids, and there were occasional vascular cells, including erythrocytes and leukocytes. The medium was harvested after 12, 24, and 48 h of culture and was stored at -20 C until assay for PGs.

PG assays

The RIAs for PGE2 and PGF2{alpha} were first characterized for measurement of the prostanoids in human urine (17) and later were used successfully to measure PGs produced and released by several cell types in vitro, including cells from human ovaries (18). Briefly, for each assay, incubation mixtures of 1.5 mL were prepared in disposable plastic tubes in which 100 or 20 µL (for PGE2 or PGF2{alpha}, respectively) incubation medium were diluted to 250 µL with 0.025 mol/L phosphate buffer (pH 7.5). Tritiated PGE2 or PGF2{alpha} (2500–3500 cpm) and appropriately diluted antisera were added together to a final volume of 1.25 mL. The antisera, provided by Prof. G. Ciabattoni, were employed at a final dilution of 1:100,000 or 1:150,000 (for PGE2 or PGF2{alpha}, respectively). The standard curves ranged from 2–100 pg/tube. A duplicate standard curve was run for each assay. All tubes were incubated for 12–18 h at 4 C. Separation of antibody-bound prostanoids was obtained with 3 mg charcoal (Norit-A), which absorbs 95–98% of free PGs; charcoal suspension (3 mg/100 µL) in 0.025 mol/L phosphate buffer, pH 7.5, was added to each tube after the addition of 100 µL 5% BSA. The tubes were briefly shaken and then centrifuged for 10 min at 4 C. Supernatants were decanted into 10 mL scintillation liquid. Radioactivity was measured by liquid scintillation counting. The detection limit of the assay was 2 pg/tube in all cases. The inter- and intraassay variability coefficients were 2.7 and 2.9 for PGE2 and 3.2 and 2.8 for PGF2{alpha}, respectively. Pure human IGF-I and IGF-II were obtained from Boehringer Mannheim (Mannheim, Germany). Human GH was obtained from Serono (Rome, Italy), and the IGF-I antibody (monoclonal antibody against human somatomedin C/IGF-I) was obtained from the National Hormone and Pituitary Program, NIH. [3H]PGE2 and [3H]PGF2{alpha} were purchased from DuPont-New England Nuclear (Milan, Italy).

Data analyses

Data were first analyzed by the Kolmorogov-Smirnov test to assess differences in the general shapes of distribution. Normally distributed data were then analyzed by one-way ANOVA with Bonferroni correction to perform pairwise comparisons between group means.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
First we investigated the effects of different doses of IGF-I and IGF-II (1–100 ng/mL) on PGF2{alpha} and PGE2 production by human luteal cells cultured for 24 h. As shown in Fig. 1aGo, both IGFs were able to progressively reduce PGF2{alpha} synthesis compared to the control value; this inhibitory effect was dose dependent and statistically significant at a dose of 100 ng/mL (IGF-I vs. control, P < 0.001; IGF-II vs. control, P < 0.05). Conversely, both factors significantly stimulated PGE2 synthesis by the same cells (Fig. 1bGo). Also in this case, the effect was dose dependent; the amount of PGE2 induced by IGF-I was statistically different from the control value at a dose of 10 ng/mL (P < 0.01), whereas for IGF-II, the effective significant dose was 100 ng/mL (P < 0.01). We next cultured luteal cells with a single dose of IGFs (100 ng/mL) for different times. Interestingly, the negative effect of IGF-I on PGF2{alpha} production was statistically present at 12 h (P < 0.05) and was still present after 48 h of culture (P < 0.05; Fig. 2aGo, left panel). On the contrary, the inhibitory action of IGF-II was present at 24 h (P < 0.05), whereas no effect was seen at either 12 or 48 h (Fig. 2aGo, right panel). A positive effect was observed on PGE2 production for IGF-I and IGF-II, as both of them were able to significantly stimulate, in a time-dependent way, PGE2 synthesis at 24 and 48 h (IGF-I, P < 0.001 at 24 h and P < 0.05 at 48 h; Fig. 2bGo, left panel; IGF-II, P < 0.01 at 24 h and P < 0.05 at 48 h; Fig. 2bGo, right panel).



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  		Figure 1. Dose-dependent effects of IGF-I and IGF-II on PGF2{alpha} (a) and PGE2 (b) production by human luteal cells. Luteal cells were cultured for 24 h with medium alone (CTR) or with increasing concentrations of IGF-I and IGF-II (1–100 ng/mL). Data represent the mean ± SEM of eight experiments. Significance vs. control: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 


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  		Figure 2. Time-dependent effects of IGF-I (left panel) and IGF-II (right panel) on PGF2{alpha} (a) and PGE2 (b) synthesis by human luteal cells. Luteal cells were cultured for 12, 24, or 48 h with medium alone (CTR) or with 100 ng/mL IGF-I or IGF-II. Data represent the mean ± SEM of eight experiments for the 24-h period and of six experiments for the 12- and 48-h periods. Significance vs. control: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 
It is well known that GH is able to induce intraovarian IGF-I production (19) and that many of its effects are mediated by IGF. To evaluate whether GH was able to affect PG production, human luteal cells were cultured for 24 h with 4 µg/mL GH. As shown in Fig. 3aGo, GH was able to significantly reduce PGF2{alpha} production (P < 0.01) in a manner similar to that of the two IGFs, whereas it did not show any effect on PGE2 synthesis (Fig. 3bGo). At this point, to determine whether the action of GH on PGF2{alpha} was direct or mediated by IGF-I, luteal cells were incubated with GH (4 µg/mL) alone or combined with increasing dilutions of an anti-IGF-I antibody (from 1:1000 to 1:8000). As shown in Fig. 4Go, the inhibitory GH effect was progressively blocked by coincubation with the antibody, which significantly reduced the GH effect at a dilution of 1:2000 (P < 0.05). When used at a dilution of 1:1000 the IGF-I antibody brought the GH-induced PGF2{alpha} level to values similar to those observed in untreated luteal cells, whereas when incubated alone, it had no effect on basal PGF2{alpha} production. Figure 5Go shows the specificity of the IGF-I antibody. Used in association with IGF-I (100 ng/mL), it induced a progressive reduction of the IGF-I inhibitory effect on PGF2{alpha} synthesis (Fig. 5aGo) and a progressive reduction of the IGF-I stimulatory action on PGE2 production (Fig. 5bGo); both effects disappeared at the highest dilution.



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  		Figure 3. Effects of GH on PGF2{alpha} (a) and PGE2 (b) synthesis by human luteal cells. Luteal cells were cultured for 24 h with medium alone (CTR), IGF-I (100 ng/mL), IGF-II (100 ng/mL), or GH (4 µg/mL). Data represent the mean ± SEM of eight experiments. Significance vs. control: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 


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  		Figure 4. Dose-dependent reversal of the GH inhibition of PGF2{alpha} synthesis by an anti-IGF-I antibody. Human luteal cells were incubated for 24 h with medium alone (CTR) or GH (4 µg/mL) alone or combined with increasing dilutions of the antibody (from 1:1000 to 1:8000). The antibody was also used alone at the highest concentration (1:1000). Data represent the mean ± SEM of six experiments. Significance vs. control: ***, P < 0.001. Significance vs. GH: {bigcirc}, P < 0.05; {bigcirc}{bigcirc}, P < 0.01.

 


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  		Figure 5. Dose-dependent reversal of an anti-IGF-I antibody on the IGF-I effects on PGF2{alpha} (a) and PGE2 (b) synthesis by human luteal cells. Luteal cells were cultured with medium alone (CTR) or with IGF-I (100 ng/mL) alone or combined with increasing dilutions of the antibody (from 1:1000 to 1:8000). The antibody was also used alone at the highest concentration (1:1000). Values represent the mean ± SEM of six experiments. Significance vs. control: ***, P < 0.001. Significance vs. IGF: {bigcirc}, P < 0.05; {bigcirc}{bigcirc}, P < 0.01; {bigcirc}{bigcirc}{bigcirc}, P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cyclic ovarian follicular development is dependent on gonadotropins and growth factors that act synergistically with or as mediators of gonadotropin action (20). In fact, intraovarian regulatory systems have been postulated to be involved in gonadal regulation, as classic endocrine theories for gonadotropins cannot fully explain the development of the dominant follicle, the simultaneous demise of the remaining cohort, and the CL activity. The IGF- system, comprised of IGF-I and IGF-II peptides, IGF-binding proteins (IGFBP), IGFBP proteases, and IGF receptors (21), is one of the several growth factor systems that probably serves this adjunctive role in ovarian activities (22). The presence and the influence of IGF-I and IGF-II in the human follicular phase has been abundantly demonstrated, whereas little was known about their role in the luteal phase. IGF-II gene expression was the first to be detected in human luteal cells as well as type I and II IGF receptor messenger ribonucleic acids (14). Successive studies also demonstrated the presence of IGF-I messenger ribonucleic acid in the human CL (23). Furthermore, in vivo, there were marked differences in IGF-I concentration between human ovarian veins; IGF-I levels were significantly higher in the ovarian vein bearing the CL (24). Therefore, the human CL can be considered as a site of secretion, action, and reception of IGFs. We were the first to demonstrate that both IGFs were able to positively affect human CL steroidogenesis either by acting directly on luteal cells or by amplifying the classic stimulatory effect of hCG (16). A similar positive role was demonstrated for GH (25), which, however, required the intermediacy of IGF-I to accomplish its effect (16). The aim of the present study was to continue our research about IGFs and CL to clarify another possible mechanism(s) through which they can affect luteal physiology.

In the complex regulation of CL physiology, PGs seem to play an important role. It is well known that human CL produces both PGE2 and PGF2{alpha} (26, 27), and in a large number of species, including the human, PGF2{alpha} seems to be of importance for luteolysis (2, 3, 4, 5), whereas there is accumulating evidence that the effect of PGE2 on luteal function is luteotropic. In the present study we demonstrate the ability of IGF-I and IGF-II to stimulate PGE2 and to inhibit PGF2{alpha} production by human luteal cells in a dose- and time-dependent manner. The stimulatory effect of both IGFs on PGE2 production was stronger than their inhibition of PGF2{alpha} synthesis, and it was reached at lower doses. It is unlikely that this effect can be explained by a possible mitogenic action of IGF-I and IGF-II, because luteal cells are highly differentiated cells, and mitosis was not observed during the culture period (28). Based on these results it is tempting to speculate that IGFs could influence luteal steroidogenesis through PGs. We know that the PGE2 to PGF2{alpha} ratio in the human CL varies during the menstrual cycle, being higher in the early and midluteal phases than in the late luteal phase (10, 26). Among the factors influencing this balance, which, in turn, influences the different luteal phases, IGFs can play an interesting role. It has been demonstrated that dominant follicles contain significantly higher concentrations of IGF-I than their cohorts, and that after the LH surge a further significant increase in dominant follicular fluid IGF-I occurs (29). Similarly, follicular fluid IGF-II levels are higher in the dominant follicles and they are positively correlated with the amount of estradiol (30). Based on these and our data, a possible mechanism(s) of IGF action could be the following. Around and immediately after ovulation, high intraovarian IGF-I and IGF-II levels could stimulate PGE2 production while inhibiting PGF2{alpha} synthesis, resulting in high P levels. Conversely, a progressive reduction in IGF levels occurring in the late luteal phase could be at least in part responsible for the change in the PGE2/PGF2{alpha} ratio, resulting in a fall in P levels. In addition, the fact that intrafollicular IGFBP-1 production increases predominantly in the largest follicles around luteinization, with a possible consequent modulation of IGFs and therefore PG levels (30) indirectly confirms this hypothesis. Furthermore, the recently demonstrated ability of PGF2{alpha} to stimulate the release of IGFBP-3 from human granulosa-luteal cells (31) with a corresponding reduction in IGF levels suggests another mechanism relating the two systems by which they can modulate each other.

Much information has been accumulated indicating the ovary as a site of GH action and reception. The potential interest in the GH effect in gonadal function arises from clinical and experimental studies. In human in vivo studies, GH was found to vary in fertile women, with an increase in the late follicular phase (32), whereas anovulatory women appear to be mildly GH insufficient compared to ovulatory women (33). Furthermore, GH significantly increased the ovarian response to gonadotropin stimulation (34). In animal in vitro studies, GH augmented FSH-stimulated LH receptor formation and P biosynthesis (35) and stimulated plasminogen activator synthesis (36) and oocyte maturation (37, 38). In humans, GH stimulates estradiol production by granulosa cells (39) and P synthesis by luteal cells (25); this latter effect was obtained through the intermediacy of IGF-I (16). In fact, it seems that GH can accomplish its effects either directly or by stimulating ovarian production of IGF-I, which, in turn, mediates GH effects. In our study we found that GH is able to inhibit PGF2{alpha} synthesis. This effect could be one of the mechanisms by which GH influences luteal steroidogenesis; furthermore, the disappearance of the GH effect we observed in the presence of antibodies raised against IGF-I clearly indicates that at least in this case GH inhibition was obtained through the IGF-I intermediacy. Recently, in the human CL, a GH receptor bearing no similarity to PRL or placental lactogen receptors has been identified (40). Therefore, given the presence of pure GH receptors, it is reasonable to believe that lactogenic receptors are not involved in GH action. Finally, no GH effect on PGE2 synthesis was observed. At the moment we do not have any explanation for this dualistic GH action on PGs. It can simply be that GH is not necessarily involved in all of the effects of IGFs; however, a better knowledge of the intraovarian PG and IGF systems through molecular biology will allow us in the future to answer questions such as this.

In conclusion, this work has probably added another small piece to the complex mosaic regarding CL physiology. To our knowledge, this is the first study correlating IGFs and PGs, even though it is clear that much work remains to further elucidate the mechanism(s) of action of both IGFs and PGs and their relationships. In this regard, experiments are currently in progress in our laboratory.

Received December 14, 1998.

Revised March 19, 1999.

Accepted April 8, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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