Molecular Human Reproduction, Vol. 5, No. 11, 1011-1016,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Regulation of ovarian function |
The involvement of nitric oxide in corpus luteum regression in the rat: feedback mechanism between prostaglandin F2
and nitric oxide
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Serrano 669, (1414) Buenos Aires, Argentina
Abstract
In the corpus luteum (CL), prostaglandin F2
(PGF2) is a physiological agent with luteolytic actions. Nitric oxide (NO) is a messenger molecule capable of modulating diverse pathophysiological processes. The aim of the present study was to investigate the role of ovarian NO in PGE (a luteotrophic prostanoid) and PGF2 (a luteolytic prostanoid) production and in progesterone synthesis during CL regression in the rat. To obtain a longer functional CL, we used a pseudopregnant (PSP) rat model. By means of intrabursa ovarian sac treatment of two competitive nitric oxide synthase (NOS) inhibitors, NG-monomethyl-l-arginine (l-NMMA, 1 mg/kg) and NW-nitro-l-arginine methyl ester (l-NAME; 3 mg/kg), and sodium nitroprusside (SNP, 0.05 mg/kg) as a NO generator, we found that NO, produced by the ovarian tissue during the last 2 days of CL development (days 8 and 9), increased PGF2 production in the ovary and diminished serum progesterone concentrations leading to CL involution. We also proposed a positive feedback mechanism between PGF2 and NO, to ensure luteal regression. Thus, we injected intraperitoneally a luteolytic dose (3 µg/kg) of a synthetic PGF2 during the mid and late phase of CL development. Ovarian NOS activity was evaluated. The results confirmed our hypothesis; we did not see any effect in the mid-stage of CL development, but increased ovarian NOS activity was found in PGF2-injected late pseudopregnant rats.
corpus luteum/luteolysis/nitric oxide/prostaglandins/rat
Introduction
The ovary is a complex endocrine organ which undergoes profound structural and functional changes during the reproductive cycle. Nitric oxide (NO) has emerged as an important intracellular and intercellular messenger controlling many physiological processes (Palmer et al., 1987
; Nathan, 1992; Moncada and Higgs, 1993). NO is derived from L-arginine by the action of nitric oxide synthase (NOS) and multiple isoforms of this enzyme have been reported (Fosterman et al., 1991). Some effects of NO are mediated via activation of soluble guanylate cyclase and subsequent production of cGMP (Jackson and Busse, 1991). However, direct activation of haem-containing enzymes, such as cyclooxygenase 1 and 2, has been reported (Rettori et al., 1992; Salvemini et al., 1993). Recently, NOS mRNA was found in rat ovary (Zackrisson et al., 1996) and has been postulated to play a role in both ovulation and atresia (Ellman et al., 1993; Ben-Shlomo et al., 1994; Shukovski and Tsafiri, 1994). It is important to point out that cytokines modulate NO production. In human pre-ovulatory follicles interleukin (IL)-1ß increases nitrate generation compared with controls (Tao et al., 1997). In addition, NOS mRNA and protein have also been detected in cultured human granulosa–luteal cells (Van Voorhis et al., 1994) playing an antisteroidogenic role.
The fact that NO is involved in the physiology, biology and pathophysiology of the reproductive system may have clinical implications in developing therapeutic strategies to prevent NO-related reproductive disorders (Roselli et al., 1998). In a previous study of the mechanism of corpus luteum (CL) regression, we reported that oxytocin increased ovarian prostaglandin (PG) F2 production at the end of the CL development in pseudopregnant (PSP) rats (Motta et al., 1996). This action was mediated by enhancing ovarian NOS activity (Motta et al., 1997). We also found that endogenous NO increased the PGF2 synthesis only during the late phase of the CL development in PSP rats (Motta et al., 1997).
The aim of our study was to examine the involvement of the ovarian NO/NOS system and its relationship to ovarian PGF2 production in rats during CL regression. For this purpose, we injected two competitive inhibitors of NOS: NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg) or NW-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg) in the periovarian sac. These were the minimal doses (of each inhibitor) to cause the maximal effect in the inhibition of NOS activity and in the increase of PG production (Motta et al., 1997).
On the other hand, sodium nitroprusside (SNP; 0.05 mg/kg) was used as a NO generator. After these treatments, we measured PGE and PGF2 synthesis in ovarian tissue and serum progesterone concentrations. Finally, we evaluated the existence of a feedback mechanism between PGF2 and NO. Rats in mid (day 5) and late (day 9 of PSP) phase of CL development were injected with an intraperitoneal luteolytic dose of PGF2 (3 µg/kg), then ovarian NOS acitivity was evaluated.
Materials and methods
Animals
The animal model as well as the experimental procedures used were as described previously (Lahav et al., 1989). Briefly, immature (28–30 days) female rats of the Wistar strain were given 15 IU/rat of pregnant mare's serum gonadotrophin (PMSG; Sigma Chemical Co., MO, USA) to induce the formation of corpora lutea (CL) that remained functional for 9 ± 1 days. We considered day 0 of PSP at 48 h post-injection. Rats were housed under controlled temperature (22°C) and illumination (14 h light:10 h dark; lights on at 0500) and allowed free access to Purina rat chow and water ad libitum.
Experimental protocol
Experiment 1
We determined the time relationship between pseudopregnancy development, serum progesterone and PGF2 synthesis in ovarian tissue. Rats were killed by decapitation on different days of PSP; blood and ovaries were collected for hormonal analysis and PGF2 determination, respectively. By means of serum progesterone values, we classified ovarian tissue as early, mid and late (luteolysis) of CL development.
Experiment 2. Intrabursa treatment
Two different NOS inhibitors (L-NMMA, 1 mg/kg, or L-NAME, 3 mg/kg) were administered into the intrabursa sac. L-NMMA and L-NAME, are competitive inhibitors of NOS and act over both isoforms (constitutive and inducible). Two groups of 10 rats on days 8 and 9 of PSP were injected into the periovarian sac (intrabursal) unilaterally (the indicated concentration of each inhibitor in a volume of 50 µl/bursa). Rats were operated on under ether anaesthesia via a bilateral dorso-lumbar approach. The control group was given saline injections with the same volume. Animals were killed 2 h and 4 h after treatments.
We also injected sodium nitroprusside (SNP, 0.05 mg/kg) into the intrabursa sac as a NO generator. Ten PSP rats on days 8 and 9 of PSP were intrabursally treated. Ovarian tissue and blood were obtained 2 h and 4 h post SNP injection.
Experiment 3. PGF2-induced luteolysis
We also investigated a possible feedback mechanism between PGF2 and NO during luteolysis. To define the conditions for PGF2 inducing luteolysis, two groups of 10 rats (on day 5; early and day 9 of PSP; late phase) were injected intraperitoneally with a luteolytic dose: 3 µg PGF2/kg (synthetic derived: ILIREN, Hoechst, Roussel Vet, Argentina). Animals were killed at different times after treatment (0–2.5 h post PGF2), and luteolysis was evaluated by serum progesterone concentrations.
Nitric oxide synthase activity
NOS activity in ovarian homogenates was determined by monitoring the formation of L-[14C]citrulline from L-[14C]arginine as described (Salter et al., 1991). Briefly, the frozen tissue was homogenized (with a Tissuemizer Tekmar, Thomas Scientific, NJ, USA) at 0°C in 3 volumes of 50 mmol/l HEPES, 1 mmol/l L-dithiothreitol, 1 mmol/l NADPH (pH 7.5) and L-valine (50 mmol/l) to minimize any interference from arginase. Samples were incubated at 37°C with 10 µmol/l [14C]arginine (0.3 µCi; 1 Ci = 37 GBq). After 15 min of incubation, samples were centrifuged for 10 min at 100 g and then applied to 1 ml DOWEX AG50W-X8 (Na+ form) resin. The radioactivity was measured by liquid scintillation counting. Intra- and inter-assay variations were each <8.0%.
Determination of progesterone
Blood for hormone analysis was collected by decapitation of animals. The blood was allowed to clot and the serum removed and frozen until used. Serum was extracted with diethyl ether and progesterone concentrations were determined by radioimmunoassay. The progesterone antiserum, provided by Dr G.D.Niswender (Colorado State University, Fort Collins, CO, USA) was produced in rabbits against progesterone conjugated to bovine serum albumin at the 11 position. The antiserum was highly specific for progesterone with low cross-reactivities, <2.0% for 20 -dihydro-progesterone and deoxycorticosterone and 1.0% for other steroids normally in the serum. The sensitivity was 5–10 pg/tube so that 2–5 µl of serum was routinely assayed.
Prostaglandin radioimmunoassays
The tissues (each ovary) were weighed and incubated in Krebs–Ringer–bicarbonate (KRB) with glucose (11.0 mmol/l) as external substrate (pH 7.0), for 1 h in a Dubnoff metabolic shaker, under an atmosphere of 5% CO2 in 95% O2 at 37°C. At the end of the incubation period, the tissue was removed, and the solution was acidified to pH 3.0 with 1 mol/l HCl and extracted for prostaglandin determination three times with 1 volume of ethyl acetate. Pooled ethyl acetate extracts were dried under an atmosphere of N2 and stored at –20°C until prostaglandin radioimmunoassay. Prostaglandins were quantified by radioimmunoassay using rabbit antiserum from Sigma Chemical Co. (St Louis, MO, USA). Sensitivies of these assays were 10 pg/tube for both PGE and PGF2. The cross-reactivity of PGE2 was 100% with PGE1 and <0.1% with other prostaglandins.
Statistical analysis
The statistical significance of differences between means was assessed by analysis of variance (ANOVA). P < 0.05 was considered significant.
Results
In order to examine the stages of CL development, we determined the time relationship in: (i) the serum progesterone concentrations from day 1 to day 14 of PSP, at 10 rats/day; (ii) the ovarian PGF2 concentration for the same period, at 10 rats/day.
On day 2 of PSP the progesterone concentration was significantly higher (P < 0.001) than on day 1 of PSP but was even greater on day 5 of PSP. From then on, hormonal concentrations diminished until day 9 of PSP. On day 10, it did not show any significant difference from day 1 of PSP. PGF2 released into the incubation medium from ovaries during the PSP significantly increased with time and peaked on day 9 of PSP (P < 0.05). In relation to the above data, Table I shows serum progesterone and ovarian PGF2 production during the different stages of CL development: early CL development (days 1 and 2), mid (day 5) and late CL development (days 8 and 9 of PSP).
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In order to determine the role of ovarian NO during the CL regression mechanism, rats in the late phase of CL development, days 8 and 9 of PSP, were injected intrabursally with two different inhibitors of NOS (L-NMMA and L-NAME). Animals were killed 2 and 4 h after treatment. On days 8 and 9 of PSP, we found that only in rats killed 4 h post bursa injection was ovarian NOS activity significantly diminished (P < 0.001; Table II
). In spite of these results, we also used rats killed 2 h post treatment (not shown in Figures) to ensure that ovarian NO was the agent responsible for producing any change in progesterone and PG concentrations.
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On day 8 of PSP, L-NMMA and L-NAME had no effect on PGF2
production 2 h post-injection, but ovarian tissue obtained from rats killed 4 h after treatment showed a significant (P < 0.05) decrease in the PGF2 synthesis (Figure 1). Each of the inhibitors had no effect on PGE synthesis in ovarian tissue obtained from rats killed 2 h or 4 h (Figure 1) post injection. Moreover, the serum progesterone concentrations were significantly (P < 0.05) increased after the intrabursal injection of L-NMMA or L-NAME, in tissue obtained 4 h but not 2 h after treatment (Figure 1).
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Similar data were obtained when we evaluated the effect of ovarian NOS inhibitors in rats on day 9 of PSP: no effect on PGF2
production was seen 2 h post-treatment, yet the PGF2 synthesis in ovarian tissue obtained from rats killed 4 h after treatments diminished significantly (P < 0.05) (Figure 2). The intrabursal treatments had no effect on PGE production. Similary, the animals showed an increase in the serum progesterone concentrations only 4 h post treatment (Figure 2).
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To confirm that NO was responsible for the above results, we administrated a NO generator (SNP, 0.05 mg/kg) in the bursa sac of rats on day 8 and 9 of PSP. On days 8 and 9 of PSP, SNP produced a significant (P < 0.05) increase in the PGF2
synthesis and a significant (P < 0.05) decrease on serum progesterone concentrations (Figure 3).
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We also proposed a possible feedback mechanism between PGF2
and NO at the end of the PSP.
Rats in the early phase of PSP did not modify serum progesterone concentrations after treatment, but rats in the late phase of the CL development showed injection mean serum progesterone concentrations of 46 ± 3 ng/ml at the time of PGF2. Progesterone concentrations then decreased significantly (P < 0.05) by 1 h, to 40% of the concentration at time 0, and continued to decrease. The greatest decline in progesterone concentrations was observed at 2 h post- PGF2 injection, when concentrations fell to <5 ng/ml, remaining constant after this time. In the view of this result, we killed rats after 2 h post-PGF2 injection.
Figure 4 shows the effect of intraperitoneal injection of a luteolytic dose (3 µg/kg) of PGF2 on ovarian NOS activity 2 h before death. During the mid phase of CL development, the PGF2 treatment had no effect on the NOS activity. Meanwhile, on day 9 of PSP, ovarian tissue obtained from PGF2-injected animals showed a significant (P < 0.05) increase in the enzymatic activity (Figure 4).
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Discussion
There is now compelling evidence that NO is one of many intraovarian mediators with effects on the ovulatory process and regulation of corpus luteum function (Van Voorhis et al., 1994; Powers et al., 1995; Bonello et al., 1996; Zackrisson et al., 1996; Tao et al., 1997). Another kind of messenger molecule is prostaglandin, which is a product of arachidonic acid metabolism. One important action of PG in the mammalian reproductive system is its participation in CL regression, where PGF2 is considered a luteolytic agent in several species (Rothchild, 1981). However, the exact mechanism (s) involved in PGF2-induced luteolysis is unclear. One action of PGF2 in rat luteal cells appears to involve increased generation of reactive oxygen species (Sawada and Carlson, 1991), an event that has been linked to a loss of progesterone biosynthesis (Musicki et al., 1994).
In previous works, we demonstrated that NO was involved in CL regression in the rat, as an intracellular messenger of the oxytocin action (Motta et al., 1997) and that in spite of NOS activity diminishing with age of CL (Motta et al., 1997), endogenous NO produced by ovaries increases PGF2 production during luteolysis. It could be due to the fact that oxidative status of the ovarian tissue is increased during luteolysis leading to an increase of lipidic peroxides, enhancing PGF2 production (unpublished data).
In the present study we investigated the role of NO during the CL involution and the possible correlation with PG and progesterone production. The PSP animals were injected in vivo with two NOS blockers at the end of the CL development. Ovarian PGF2 production decreased while serum progesterone concentrations increased after 4 h post-intrabursa treatment with both competitive NOS inhibitors (L-NMMA and L-NAME). The NO generator (SNP) produced the inverse effects, i.e. increased ovarian PGF2 synthesis and diminished serum progesterone concentrations. These data demonstrated that the NO/NOS system, produced locally by ovaries is responsible for these actions.
Since PGF2 injection reduces progesterone concentrations by means of a decrease in 3ß-hydroxysteroid dehydrogenase protein and mRNA levels (Tian, 1994; McLean, 1995), we can infer that serum progesterone concentrations rise because the NOS blockers reduce PGF2 synthesis. We do not ignore the fact that a direct inhibitory action of NO on progesterone synthesis was found in granulosa human cells (Van Voorhis et al., 1994).
Neither L-NMMA nor L-NAME had any effect on the PGH2/PGE pathway, suggesting that NO could act selectively in the pathway that leads to PGF2 formation, but these speculations need further confirmation. Before NOS inhibition took place, 2 h post treatment, no effect on ovarian PGF2 synthesis or serum progesterone concentrations was found, this led us to suppose that NO could be mediating both effects.
The present study is the first demonstration of an enhanced feedback mechanism between PGF2 and NO during CL regression. This is an important means ensuring cellular regression. These results are in agreement with a recent report (Perez-Martinez et al., 1998) which found that exogenous PGF2 modulated the Ca2+-independent NOS activity in rat oviduct controlling contractility.
The fact that we did not observe this increase during mid CL development could be due to a `refractory' CL at this time. However, little is known about the mechanisms responsible for this insensitivity of the early CL to the luteolytic action of PGF2. Following the cloning of mouse cDNA for PGF2 receptor (Sugimoto et al., 1994) an abundant expression of the receptor mRNA was demonstrated in the regressing CL of pregnant (Sugimoto et al., 1994) and pseudopregnant mice (Hasumoto et al., 1997).
Early studies on PGF2-mediated luteolysis in the rat demonstrated an inhibition of luteinizing hormone stimulated adenylate cyclase activity, and this inhibition increased with luteal age (Khan et al., 1979).
We may also consider that exposure of the CL to PGF2 results in an influx of immune cells that play an important role in the luteolytic process through their release of cytokines and/or their phagocytic properties (Bagavandoss et al., 1990; Wang et al., 1992). It is also possible that macrophages represent an important source of NO production and could be responsible for the increase in PGF2 synthesis by means of cyclooxygenase activation. We are currently investigating the relationship between oxidative free radical damage and prostaglandins in the induction of luteolysis.
Finally, the positive feedback mechanism between PGF2 and NO could ensure high concentrations of this prostanoid at the end of the PSP, leading to the structural and functional luteolysis. The interaction between NO and PG is mediated by a direct activation of cyclooxygenase 1 or 2 by NO (Rettori et al., 1992; Salvemini et al., 1993). We are now investigating the relationship between PGF2 production and NO, and speculate that it could be due to the mobilization of intracellular Ca2+.
In summary, we present compelling evidence to suggest that the NO/NOS system could participate in the mechanism of corpus luteum involution by enhancing ovarian PGF2 synthesis and inhibiting luteal steroidogenesis.
Acknowledgments
The authors thank Consejo de Investigaciones Científicas y Técnicas (CONICET, PIP 4076, PEI 0045/97) and Programa Latinoamericano de Capacitación e Investigación en Reproducción Humana (PLACIRH, Re-Entry Grant PRE-020/98) for financial support and María Inés Casella and Ramona Morales for their technical support.
Notes
1 To whom correspondence should be addressed 
References
Bagavandoss, P., Wiggins, R.C., Kunkel, SL. et al. (1990) Tumor necrosis factor production and accumulation of inflammatory cells in the corpus luteum of pseudopregnancy and pregnancy rabbits. Biol. Reprod., 42, 367–376.[Abstract]
Ben-Shlomo, I, Kokia, E., Jackson, M. et al. (1994) Interleukin-1b stimulates nitrite production in the rat ovary: evidence for heterologous cell–cell interaction and for insulin-mediated regulation of the inducible isoform of nitric oxide synthase. Biol. Reprod., 51, 310–318.[Abstract]
Bonello, N., McKie, K., Jasper, M. et al. (1996) Inhibition of nitric oxide: effects on IL-1b-enhanced ovulation rate, steroid hormones, and ovarian leukocyte distribution at ovulation in the rat. Biol. Reprod., 54, 436–445.[Abstract]
Ellman, C., Corbett, J.A., Misko, T.P. et al. (1993) Nitric oxide mediates interleukin-1ß induced cellular cytotoxicity. A potential role for nitric oxide in the ovulatory process. J. Clin. Invest, 92, 3053–3056.
Fosterman, U., Schmidt, H.H.W., Pollock, J.S. et al. (1991) Isoform of nitric oxide synthase: characterization and purification from different cell types. Biochem. Pharmacol., 42, 1849–1857.[Web of Science][Medline]
Hasumoto, K., Sugimoto, Y., Yamasaki, T. et al. (1997) Association of expression of mRNA encoding the PGF2 receptor with luteal cell apoptosis in ovaries of pseudopregnant mice. J. Reprod. Fertil., 109, 45–51
Jackson, W.F. and Busse,R. (1991) Elevated guanosine 3'-5'-cyclic monophosphate mediates the depression of nitrovasodilator reactivity in endothelium-intact blood vesels. Arch. Pharmacol., 344, 345–350.
Khan, M.I., Rosberg, S., Lahav, M. et al. (1979) Studies on the mechanism of action of the inhibitory effect of prostaglandin F2 on cyclic AMP accumulation in rat corpora lutea of various ages. Biol. Reprod., 21, 1175–1183.[Abstract]
Lahav, M., Davis, J.S. and Rennert, H. (1979) Mechanism of the luteolytic action of prostaglandin F2 in the rat. J. Reprod. Fertil., 37 (Suppl.), 233–240.
McLean, M.P., Billheimer, J.T., Warden, K.J. and Irby, R.B. (1995) Prostaglandin 2 mediates ovarian sterol carrier protein-2 expression during luteolysis. Endocrinology, 136, 4963–4972.[Abstract]
Moncada, S.R. and Higgs, A. (1993) The L-arginine–nitric oxide pathway. N. Engl. J. Med., 329, 2002–2012.
Motta, A.B. and Gimeno, M.A.F. (1997) Nitric oxide participates in the corpus luteum regression in ovaries isolated from pseudopregnant rats. Can. J. Physiol. Pharmacol., 75, 1335–1339.[Web of Science][Medline]
Motta, A.B., Franchi, A., Faletti, A. and Gimeno, M.A.F. (1996) Effect of an oxytocin receptor antagonist on ovarian and uterine synthesis and release of prostaglandin F2 in pseudopregnant rats. Prost. Leukotr. Essent. Fatty Acids, 52, 95–100.
Motta, A.B., Franchi, A.M. and Gimeno, M.A.F. (1997) Role of nitric oxide on uterine and ovarian prostaglandin synthesis during luteolysis in the rat. Prost. Leukotr. Essent. Fatty Acids, 56, 265–269.
Musicki, B., Aten, R.F. and Behrman, H.R. (1994) Inhibition of protein synthesis and hormone-sensitive steroidogenesis in response to hydrogen peroxide in rat luteal cells. Endocrinology, 134, 588–595.
Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells. FEBS J., 6, 3051–3064.
Palmer, M.G., Ferridge, A.G. and Moncada, S.R. (1987) Nitric oxide release accounts for the biological activity of endothelial-derived relaxing factor. Nature (Lond.), 327, 524–526.[Medline]
Perez-Martinez, S., Franchi, A.M., Viggiano, J.M. et al. (1998) Effect of prostaglandin F2 (PGF2) on oviductal nitric oxide synthase (NOS) activity: possible role of endogenous NO on PGF2-induced contractions in rat oviduct. Prost and other Lipid Mediat., 56, 155–166.
Powers, R.W., Chen, L., Russel, P.T. et al. (1995) Gonadotropin-stimulated regulation of blood- follicle barrier is mediated by nitric oxide. Am. J. Physiol., 269, E290–E298.
Rettori, V., Gimeno, M.A.F., Lyson, K. and McCann, S.M. (1992) Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from hypothalamus. Proc. Natl. Acad. Sci. USA., 89, 11543–11546.
Rosselli, M., Keller, P.J. and Dubey, R.K. (1998) Role of nitric oxide in biology, physiology and pathophysiology of reproduction. Hum. Reprod. Update, 4, 3–24.
Rothchild, I. (1981) The regulation of the mammalian corpus luteum. Recent Prog. Horm. Res., 37, 183–298.
Salter, M., Knowles, R.G. and Moncada, S. (1991) Widespread tissue distribution, species distribution and changes in activity of Ca2+-dependent and Ca2+-independent nitric oxide synthases. FEBS Lett., 291, 145–149[Web of Science][Medline]
Salvemini, D., Misko, T.P., Masferrer, J.L. et al. (1993) Nitric oxide activates cyclooxygenase enzymes. Proc. Natl. Acad. Sci. USA, 90, 7240–7244.
Sawada, M. and Carlson, J. C. (1991) Rapid plasma membrane changes in superoxide radical formation, fluidity and phospholipase A2: activity in the corpus luteum of the rat during induction of luteolysis. Endocrinology, 128, 2992–2998.
Shukovski, L. and Tsafiri, A. (1994) The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology, 135, 2287–2290.[Abstract]
Sugimoto, Y., Hasamoto, K., Namba, T. et al. (1994) Cloning and expression of cDNA for mouse prostaglandin F receptor. J. Biol. Chem., 269, 1356–1360
Tian, X.C., Berndtson, A.K. and Fortune, J.E. (1994) Changes in levels of messenger ribonucleic acid for cytochrome P 450 side-chain cleavage and 3ß-hydroxysteroid dehydrogenase during prostaglandin F2-induced luteolysis in cattle. Biol. Reprod., 50, 349–356.[Abstract]
Tao, M., Kodama, H., Kagabu, S. et al. (1997) Possible contribution of follicular interleukin-1 beta to nitric oxide generation in human pre-ovulatory follicles. Hum. Reprod., 12, 2220–2225.
Van Voorhis, B.J., Dunn, M.S., Snyder, G.D. and Weiner, C P. (1994) Nitric oxide: an autocrine regulator of human granulosa–luteal cell steroidogenesis. Endocrinology, 135, 1799–1806.[Abstract]
Wang, I.J., Pascoe, V., Petrucco, O.M. et al. (1992) Distribution of leukocyte subpopulations in the human corpus luteum. Hum. Reprod., 7, 197–202.
Zackrisson, U., Mikuni, M., Wallin, A. et al. (1996) Cell-specific localization of nitric oxide synthases (NOS) in the rat ovary during follicular development, ovulation and luteal formation. Hum. Reprod., 12, 2667–2673.
Submitted on December 18, 1998; accepted on August 17, 1999.
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