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Endocrinology Vol. 138, No. 11 4806-4811
Copyright © 1997 by The Endocrine Society


ARTICLES

Corticotropin-Releasing Hormone (CRH) Inhibits Steroid Biosynthesis by Cultured Human Granulosa-Lutein Cells in a CRH and Interleukin-1 Receptor-Mediated Fashion1

Lucia Ghizzoni, George Mastorakos, Alessandra Vottero, Antonina Barreca, Mariangela Furlini, Arianna Cesarone, Bruno Ferrari, George P. Chrousos and Sergio Bernasconi

Department of Pediatrics (L.G., A.V., M.F.) and Department of Obstetrics and Gynecology (B.F.), University of Parma, 43100 Parma, Italy; Department of Endocrinology and Metabolism (A.B., A.C.), University of Genova, 16132 Genova, Italy; Evgenidion Hospital (G.M.), Athens University, Medical School, Endocrine Unit, 11528 Athens, Greece; National Institute of Child Health and Human Development (G.P.C.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Pediatrics (S.B.), University of Modena, 41100 Modena, Italy

Address all correspondence and requests for reprints to: Lucia Ghizzoni, M.D., Department of Pediatrics, University of Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: lughizzo{at}ipruniv.cce.unipr.it


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The presence of immunoreactive CRH was recently demonstrated in human ovaries. CRH immunoreactivity was localized by immunohistochemistry in the cytoplasm of thecal cells surrounding the ovarian follicles, in luteinized cells of the stroma, and in large granulosa-derived luteinized cells of developing corpora lutea. Also, CRH and its receptors were identified in Leydig cells of the testis where CRH was shown to inhibit testosterone biosynthesis. To examine the role of CRH in the ovary, we studied its effect on estradiol (E2) and progesterone (P4) release by human granulosa cells obtained from women undergoing in vitro fertilization for male factor infertility or uni- or bilateral tubal impatency. In all subjects, superovulation was induced by treatment with gonadotropins. The effects of graded doses of ovine CRH (10-11–10-6 mol/liter) were evaluated in the conditioned medium obtained after 24 h incubation of the cells. All CRH concentrations employed except for the lowest one (10-11 mol/liter) caused a significant decrease of media E2 and P4 levels. Maximal inhibition for both E2 and P4 production was obtained by 10-6 mol/liter CRH concentration, which decreased hormone production by 39% and 34%, respectively. The {alpha}-helical CRH9–41 antagonist at 10-6 and 10-7 mol/liter blocked the suppressive effect of 10-9 mol/liter CRH on both E2 and P4 secretion, while it had no effect when added to the culture media without CRH. Since interleukin (IL-1)-1 mediates certain actions of CRH on leukocytes, we examined whether the CRH effect on ovarian steroidogenesis was IL-1-mediated. Interleukin-1 receptor antagonist at 10-7 and 10-6 mol/liter blocked the inhibitory effects of CRH on E2 and P4 secretion, while it had no effect in the absence of CRH. In conclusion, CRH exerts a CRH- and IL-1 receptor-mediated inhibitory effect on ovarian steroidogenesis and might be actively involved in the still enigmatic processes of follicular atresia and luteolysis.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
CRH (1, 2), a 41-amino acid neuropeptide secreted by the paraventricular nucleus of the hypothalamus, is the principal regulator of ACTH secretion by the pituitary (3), and it exerts a major coordinatory role for the stress response, including activation of the arousal and sympathetic systems, central suppression of the immune system, and elicitation of stress-related behaviors (4, 5, 6). CRH immunoreactivity and/or messenger RNA (mRNA) were also detected outside the central nervous system, in subpopulations of human white blood cells and rat and human immune accessory cells (macrophages, tissue fibroblasts, and endothelial cells) in diverse inflammatory sites (7, 8, 9). In contrast to its systemic indirect immunosuppressive effects, CRH acts locally at inflammatory sites as an autocrine or paracrine proinflammatory mediator, possibly through stimulation of interleukin (IL)-1 secretion (10) and expression of IL-2 receptors by leukocytes (11).

Recently, we demonstrated that rat (12) and human ovaries (13) contain immunoreactive (Ir) CRH in theca cells surrounding follicles, as well as in stroma cells, mature oocytes within antral follicles, and ovarian resident macrophages. In developing corpora lutea, we detected IrCRH in the cytoplasm of both small theca-derived and large granulosa-derived luteinized cells, indicating that with luteinization, CRH persists in theca-derived and appears de novo in granulosa-derived luteinized cells. In addition, we localized CRH receptors autoradiographically in stroma and theca cells around follicles, as well as in cells of the cumulus oophorus. We found CRH receptors sparsely distributed within corpora lutea but not in the granulosa layer of follicles. By specific in situ hybridization, Nappi and Rivest (14) confirmed these findings in rat ovaries and characterized the ovarian CRH receptors as type I. Ovulation, luteolysis, and, perhaps, follicular atresia, three key ovarian functions, have characteristics of an aseptic immune/inflammatory reaction (15). Resident macrophages constitute a major cellular component of the ovary (16, 17), and inflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor-{alpha}, participate in the regulation of these functions, as well as of follicular and luteal steroidogenesis (18, 19).

Earlier, CRH and its receptors were identified in Leydig cells of the testis, where CRH was shown to exert autocrine inhibitory actions on testosterone biosynthesis (20, 21). Since the ovarian theca cell is considered the embryological and functional equivalent of the testicular Leydig cell (22), it is reasonable to hypothesize that CRH plays a similar role in the estrogen and progesterone (P4) biosynthesis of the ovary. We examined this hypothesis by measuring estradiol (E2) and P4 concentrations in the culture media of human granulosa-lutein cells incubated with ovine (o) CRH in the absence or presence of a specific CRH antagonist. In addition, to examine whether the presumed effect of CRH on ovarian steroidogenesis was IL-1 mediated, we also measured E2 and P4 concentrations in the culture media of human granulosa-lutein cells incubated with IL-1 receptor antagonist (ra) in the presence and absence of oCRH.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Patients
Twenty-one women, ages 22–36 yr, with spontaneous ovulatory cycles and infertility due to uni- or bilateral tubal impatency or male factor, were studied. Informed consent was obtained from all subjects, and follicular fluids were coded and studied in a blinded fashion. All patients received a GnRH analog (Decapeptyl; Ipsen, Paris, France; 3.75 mg im), one month before FSH therapy was started. Subsequently, superovulation for in vitro fertilization/embryo transfer was induced with purified urinary FSH (Metrodin, Serono, Rome, Italy; 75 IU FSH/ampoule; two ampoules/day from day 1–3 and individualized thereafter, depending on daily plasma E2 levels and measurements of follicular growth by transvaginal ultrasound examination). When at least one follicle reached 16 mm in diameter and plasma E2 levels were greater than 200 pg/mL, hCG (Profasi, Serono, Rome, Italy; 10,000 IU) was administered. Follicular aspiration for oocyte retrieval was performed by laparoscopy under general anesthesia 34–38 h after hCG administration.

Materials
Synthetic rat/human (r/h) CRH-(1–41) and {alpha}-helical CRH9–41 antagonist were purchased from Peninsula Laboratories (Belmont, CA); ovine (o) CRH was obtained from UCB (Braine-l’Alleud, Belgium); interleukin (IL)-1 receptor antagonist (ra) (23, 24) was provided by AMGEN (Boulder, CO); HPLC-purified [125I]r/hCRH was obtained from New England Nuclear Corp. (Boston, MA). Multiwell dishes were purchased from Falcon Plastics (Los Angeles, CA); medium 199 with Earle’s salt, L-glutamine, penicillin, and streptomycin sulfate were obtained from ICN Biomedicals (Costa Mesa, CA).

Granulosa-lutein cell cultures
After oocyte recovery, granulosa cells were obtained from follicular fluid by centrifugation at 800 rpm for 15 min; cells were resuspended with a 1:1 mixture of medium 199 and Hanks’ salt solution, and pools were prepared from each individual patient. The suspension (10 ml) was layered in 10 ml of lymphocyte separation medium (Ficoll, ICN Biomedicals) and centrifuged at 1800 rpm at room temperature for 30 min to separate the red cells. Granulosa cells were recovered from the Ficoll interface, washed three times with HBSS, and resuspended with 3 ml medium 199. Aliquots of the cell suspension were counted with a hemocytometer to determine the number of cells and plated (5 x 105 cells per well) in multiwell dishes in 1 ml medium 199 with Earle’s salt supplemented with 2% L-glutamine, 1% nonessential amino acids, 1% penicillin-streptomycin, 1% tylosin, 10% FBS. Cultures were maintained in humidified 95% air-5% CO2 at 37 C. After 24 h, culture medium was replaced with 1 mL serum-free medium, and cells were cultured for 24 h with the following treatments: medium alone (control), and medium containing oCRH and/or CRH9–41 antagonist and/or IL-1 receptor antagonist (IL-1ra), depending on the protocol. The serum-free medium contained 10-7 mol/liter androstenedione as substrate for E2 production when E2 production was to be studied. Culture media were removed after 24 h, and stored at -20 C until tested for E2 and P4 content.

Protocol
CRH effect on E2 and P4 production by granulosa cell cultures.
The in vitro effect of CRH was tested by adding increasing doses of oCRH (10-11 to 10-6 mol/liter) to the culture media of the granulosa cells, which stimulates the CRH receptor as efficiently as hCRH (25). We did not test the CRH effect with doses lower than 10-11 since such concentrations would not have provided physiologically relevant information. Furthermore, we examined whether the CRH effect on E2 and P4 production could be abolished by incubating granulosa-lutein cell cultures with 10-9 mol/liter of oCRH in the presence and absence of 10-6 and 10-7 mol/liter of the {alpha}-helical CRH9–41 antagonist, whose affinity for the ligand is about 5 x 10-9 M. To test the effect of the CRH antagonist on CRH activity, we have arbitrarily chosen the 10-9 mol/liter CRH concentration as the most physiological. IL-1ß concentrations in the culture media were also measured at baseline and after the addition of 10-9 mol/liter CRH.

IL-1ra effect on CRH suppression of estrogen and P4 production by granulosa cell cultures.
We examined whether the CRH-inhibitory effect on E2 and P4 production could be abolished by incubating granulosa-lutein cell cultures with increasing concentrations of a highly specific and selective IL-1ra (10-7 to 10-6 mol/liter) (26, 27) with and without 10-9 mol/liter CRH.

Each treatment was examined in at least six different experiments. Each experiment was carried out in triplicate. E2 and P4 content were measured in the media of at least six wells with granulosa cells, and these levels served as controls (basal levels) for the corresponding experiment.

Hormone assays
E2 and P4 were assayed using commercially available RIA kits (DPC, Los Angeles, CA). The mean intra- and interassay coefficients of variation were 5.34% and 6.4%, respectively, for E2, and 5.39% and 6.78%, respectively, for P4. IL-1ß was measured by the enzyme-linked immunosorbent assay method (R&D Systems, Minneapolis, MN). The mean intra- and interassay coefficients of variation were 2.9 and 4.9%, respectively.

Baseline concentrations of CRH in the follicular aspirates and media of granulosa-lutein cell cultures were measured by RIA as previously described (13). The CRH antiserum (TS-2) employed has been characterized in detail previously (28). [125I]r/hCRH was used as the tracer, and synthetic r/hCRH was used as the standard. The within-assay coefficient of variation and sensitivity were 4% and 1 pmol/liter, respectively. Recovery in the CRH RIA was 82 ± 3.5%.

Statistical analysis
Data are expressed as mean ± SEM. The data were analyzed by ANOVA followed by Scheffe’s test (29). Statistical significance was set at P < 0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Presence of IrCRH in human ovarian follicular fluid and in granulosa-lutein cell culture media
IrCRH concentrations were measured in the follicular fluids from hormonally stimulated human ovaries. The levels varied between 22.6 and 80.9 pmol/liter (mean ± SEM 47.6 ± 9.7 pmol/liter). Mean IrCRH concentrations in the media of the control granulosa-lutein cell cultures were 13.17 ± 2.9 pmol/liter, 48 h after plating. IrCRH levels in follicular fluids did not correlate with those in the media from the corresponding granulosa-lutein cell cultures 48 h after plating.

CRH inhibits E2 production by granulosa-lutein cells (Fig. 1Go)
Baseline E2 production by granulosa-lutein cells was 53.52 ± 10.88 nmol/liter (mean ± SEM). Exposure of granulosa-lutein cells to increasing concentrations of CRH caused a reduction of E2 concentrations in the media. E2 production was inhibited by all CRH concentrations employed between 10-10 and 10-6 mol/liter, except for the lowest one (10-11 mol/liter). Maximal effect was obtained at the concentration of 10-6 mol/liter, which caused a 39% decrease in E2 production. The concentrations of 10-6 or 10-7 mol/liter of the {alpha}-helical CRH9–41 antagonist blocked the suppressive effect of 10-9 mol/liter of CRH on E2 secretion by cultured granulosa-lutein cells but had no effect when added alone to the culture media.



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Figure 1. Ovine CRH effect on E2 production by granulosa-lutein cells. Upper panel, Effects of increasing concentrations of oCRH (10-11 to 10-6 mol/liter) on E2 production. Data are expressed as the percent of control values ± SEM for a total of 16 experiments (n = 16) performed in triplicate. The asterisk indicates statistically significant difference vs. control hormone levels (ANOVA, P < 0.05). Lower panel, Effects of 10-7 and 10-6 mol/liter {alpha}-helical CRH9–41 (CRHant) on 10-9 mol/liter CRH-inhibited E2 production. Data are expressed as the percent of control values ± SEM for a total of six experiments (n = 6) performed in triplicate. The asterisk indicates statistically significant difference vs. all other treatment groups (ANOVA, P < 0.05). Control hormone levels were measured in granulosa-lutein cells media cultured with serum-free medium alone.

 
CRH inhibits P4 production by granulosa-lutein cells (Fig. 2Go)
Baseline P4 production by granulosa-lutein cells was 1026.75 ± 343.4 nmol/liter (mean ± SEM). Exposure of granulosa-lutein cells to increasing concentrations of CRH also produced a decrease of P4 concentrations in the media. P4 production was inhibited by all CRH concentrations between 10-10 and 10-6 mol/liter, except for the lowest one (10-11 mol/liter). Maximal effect was achieved by the concentration of 10-6 mol/liter, which suppressed P4 production by 34%. The concentrations of 10-6 or 10-7 mol/liter of the {alpha}-helical CRH9–41 antagonist blocked the suppressive effect of 10-9 mol/liter of CRH on P4 secretion by cultured granulosa-lutein cells but had no effect when added alone to the culture media.



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Figure 2. Ovine CRH effect on P4 production by granulosa-lutein cells. Upper panel, Effects of increasing concentrations of oCRH (10-11 to 10-6 mol/liter) on P4 production. Data are expressed as the percent of control values ± SEM for a total of six experiments (n = 6) performed in triplicate. The asterisk indicates statistically significant difference vs. control hormone levels (ANOVA, P < 0.05). Lower panel, Effects of 10-7 and 10-6 mol/liter {alpha}-helical CRH9–41 (CRHant) on 10-9 mol/liter CRH-inhibited P4 production. Data are expressed as the percent of control values ± SEM for a total of six experiments (n = 6) performed in triplicate. The asterisk indicates statistically significant difference vs. all other treatment groups (ANOVA, P < 0.05). Control hormone levels were measured in granulosa-lutein cell media cultured with serum-free medium alone.

 
IL-1ra reverses CRH inhibition of E2 and P4 production by granulosa-lutein cells (Fig. 3Go).
When cultured granulosa-lutein cells were incubated with 10-6 or 10-7 mol/liter IL-1ra and 10-9 mol/liter CRH, the suppressive effect of CRH on E2 secretion was reversed. IL-1ra addition to the culture media alone caused no effect on basal E2 secretion. Furthermore, 10-6 or 10-7 mol/liter IL-1ra added to the cultured granulosa-lutein cells together with 10-9 mol/liter CRH reversed the suppressive effect of CRH on P4 in a similar way, whereas addition of IL-1ra to the culture media alone caused no effect on basal P4 secretion.



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Figure 3. Effects of 10-7 (A and D) and 10-6 (B and E) mol/liter IL-1ra on E2 (upper panel) and P4 (lower panel) production by granulosa-lutein cells in the presence (C, D, and E) and absence (A and B) of 10-9 mol/liter oCRH. Data are expressed as the percent of control values ± SEM for a total of six experiments (n = 6) performed in triplicate. The asterisk indicates statistically significant difference vs. all other treatment groups (ANOVA, P < 0.05). Control hormone levels were measured in granulosa-lutein cell media cultured with serum-free medium alone.

 
IL-1 concentrations were measured in the culture media at baseline and after the addition of CRH 10-9 mol/liter. Baseline IL-1 levels varied between 6.6 and 15.6 pg/ml (mean ± SEM 7.7 ± 0.7 pg/ml) and were significantly increased (P < 0.005) after the addition of CRH (10.2 ± 0.9 pg/ml). The IL-1 increase induced by CRH (31.5 ± 2.3%) paralleled the decrease in E2 and P4 caused by the same concentration of the neuropeptide.


    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Small amounts of IrCRH were measured within the media of granulosa-lutein cell cultures. It is likely that most of this CRH is produced by these cells, given that large granulosa-derived luteinized cells within developing human corpora lutea contain IrCRH in situ (13). Some IrCRH might also be produced by resident macrophages of the ovary present in the cultures, since no cell fractionation was attempted during isolation of granulosa-lutein cells. Indeed, CRH mRNA and peptide have been shown in peripheral blood mononuclear cells and in macrophages in diverse human and rat inflammatory sites (7, 8, 9), whereas the presence of a large number of extravascular macrophages has been well established in the ovarian stroma and corpora lutea (16, 17). Definitely, the endogenously produced CRH levels are 10-fold lower than the lowest concentration of CRH added in the culture media able to modify steroid concentrations and should have no bearing on the results.

We found that exposure of granulosa-lutein cells to increasing concentrations of CRH caused a moderate but consistent reduction of both E2 and P4 concentrations in the media, which was not dose-dependent, most probably because the system was maximally inhibited at the lower concentration employed. This is not surprising, since no other effect of CRH has ever been described at levels lower than 10-11 M. For example, the EC50 for the CRH-induced ACTH release is approximately 10-9 M. The proinflammatory effect of CRH in uveitis (30) or caraggeenin-induced inflammation (31) starts at levels higher than 10-11 M, as well as its inhibitory effect on testicular steroid biosynthesis (20). The reduction of both E2 and P4 concentrations in the media was completely abolished by the addition of excess {alpha}-helical CRH9–41 antagonist, indicating that it is CRH receptor-mediated. Indeed, sparse CRH-binding sites were found by autoradiography in rat corpora lutea (12), and CRH receptors were shown in human ovaries by in situ hybridization techniques (32). While this study was being conducted, Calogero et al. (33) reported a CRH-mediated inhibition of estrogen biosynthesis by FSH from rat granulosa and human granulosa-lutein cells, which seems to be linked to inhibition of aromatase activity. The results of the present study are compatible with those of Calogero et al. and further expand on the mechanisms underlying the inhibitory effect of CRH on ovarian steroidogenesis.

In analogy to its autoregulatory action on testosterone biosynthesis in the testis (20, 21), ovarian CRH may participate in the local regulation of steroid biosynthesis in the ovaries. The inhibitory effect of CRH on E2 secretion indicates the presence of a direct and/or indirect effect of the former on the aromatase and/or 17-ketoreductase activities of the granulosa-lutein cells. The IL-1-mediated action of CRH at peripheral inflammatory sites (10) made IL-1 a possible candidate for the indirect effect of CRH in the ovary. Indeed, when granulosa-lutein cells were incubated simultaneously with CRH and IL-1ra, the CRH-induced suppression of E2 secretion was completely abolished, whereas the addition of IL-1ra alone to the cultured cells had no effect on basal E2 secretion. Furthermore, IL-1 concentrations in the culture media were significantly increased by addition of CRH, with an increment that paralleled the decrease in E2 and P4 levels induced by the same CRH concentration. These data indicate that ovarian IL-1 mediates the CRH suppressive effect on E2 secretion. IL-1 receptor is present on human granulosa cells (34), and the IL-1 gene is expressed in the gonadotropin-pretreated human ovary (35). Moreover, the IL-1ß gene is induced by forskolin (35), a potent activator of adenylate cyclase in human granulosa cells, while CRH increases intracellular cAMP in several tissues (36). Thus, ovarian CRH might activate IL-1ß production by human granulosa cells through an intracellular increase of cAMP. Alternatively, CRH might stimulate IL-1 of macrophage origin to attenuate granulosa cell aromatase activity, as previously proposed in the rat ovary (37).

The inhibitory effect of CRH on P4 secretion might also be exerted directly and/or indirectly on different enzymatic activities. When we incubated granulosa-lutein cells simultaneously with CRH and IL-1ra, the CRH-induced suppression of P4 secretion was completely abolished, whereas the addition of IL-1ra alone to the cultured cells had no effect on basal P4 secretion. These data indicate that the CRH suppressive effect on P4 secretion from granulosa-lutein cells is also IL-1-mediated. IL-1 has been shown to inhibit P4 secretion in cultures of porcine and rat granulosa cells (38), as well as androsterone production by rat theca-interstitial cells and whole ovarian dispersates (39). The inhibitory effect of IL-1 on gonadotropin-stimulated granulosa cell steroidogenesis is accompanied by the arrested transcription of the mitochondrial cholesterol side chain cleavage enzyme (P450scc) and 3,ß-hydroxysteroid dehydrogenase/{delta}-5,4-isomerase (40), both of which are involved in P4 biosynthesis. This IL-1 effect might be due to IL-1-mediated inhibition of steroidogenic acute regulatory protein mRNA levels (41). Steroidogenic acute regulatory protein is a mitochondrial nonenzymatic phosphoprotein that transports cholesterol into the inner mitochondrial membrane, a function indispensable for the acute biosynthesis of steroids (42). Alternatively, CRH might exert a deleterious effect on the growth of granulosa-lutein cells through its yet unexplored proinflammatory properties, which might explain the reduction of steroid biosynthesis via stimulation of prostanoids and other inflammatory mediators. An association of ovarian CRH with the aseptic inflammatory phenomena of luteolysis was suggested previously (13).

The CRH effect on ovarian steroid biosynthesis might be associated with the elevated ovarian androgen production in women with the polycystic ovary syndrome who have decreased ovarian CRH levels (13). Conversely, ovarian CRH hypersecretion might be involved in various abnormalities of the menstrual cycle, particularly those observed during the luteal phase. Such abnormalities have been associated with anxiety and/or stress-related phenomena, which are known to be accompanied by high portal CRH levels (4). In this regard, although immunohistochemically detected ovarian CRH in corpora lutea is not grossly decreased in the rat ovary after a 2-h immobilization stress (43), CRH receptors are markedly increased (14), probably resulting in an enhanced overall biological effect of this peptide. Interestingly, in the CRH gene knock-out mouse, no major abnormality of the reproductive process was observed (44). This is not surprising, since, in this animal, other systems might have compensated for the defect, as it happened with the activity of the hypothalamic-pituitary-adrenal axis, which was not altered in a major fashion, probably because arginine vasopressin compensated for the CRH defect.


    Footnotes
 
1 This work was presented, in part, at the 10th International Congress of Endocrinology, San Francisco, California, 1996 (Abstract P3–481). Back

Received March 10, 1997.


    References
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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