Molecular Human Reproduction, Vol. 5, No. 5, 391-395,
May 1999
© 1999 European Society of Human Reproduction and Embryology
Functional evidence for divergent receptor activation mechanisms of luteotrophic and luteolytic events in the human corpus luteum
1 Department of Obstetrics and Gynecology, Umeå University Hospital, S-901 85 Umeå, and 2 Department of Physiology, Umeå University, S-901 87 Umeå, Sweden
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Abstract |
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Using a dispersed human luteal cell culture model, progesterone synthesis following treatment by incremental doses of human chorionic gonadotrophin (HCG) and the stable prostaglandin F2
(PGF2) analogue cloprostenol, alone or in combination, was related to corpora lutea (CL) mRNA transcript abundance coding for the luteinizing hormone (LH)/HCG receptor (LH-R) and PGF2-receptor (FP) by semi-quantitative reverse transcription–polymerase chain reaction (RT–PCR) in 33 otherwise healthy women, scheduled for surgery due to benign conditions. CL were grouped according to age, based on the occurrence of a preovulatory LH surge where post-LH days 2–5 were designated as early luteal phase; days 6–10 as mid-luteal phase and days 11–14 as late luteal phase. When exposed to HCG, maximal progesterone output was raised 2.2-fold (P = 0.08, n = 5) compared with untreated controls in the early CL, while it increased 5.7- and 4.6-fold in the mid- and late groups respectively (P < 0.05, n = 4 mid-luteal phase, n = 3 late luteal phase). This stimulation pattern was found to be concordant with the value of mRNA coding for LH-R in all groups (n = 6 early luteal phase, n = 5 mid-luteal phase, n = 6 late luteal phase). The integrated response to HCG and cloprostenol showed a dose-dependent 60% inhibition of progesterone production, but only in late luteal phase luteal cells (P < 0.01, n = 3). FP mRNA values were lowest in early luteal phase, and increased with the age of the CL. Interestingly, lowest CL tissue concentrations of the natural FP agonist PGF2, were found during mid-luteal phase while it increased again 1.6-fold during late luteal phase (P < 0.05, n = 8 versus mid-luteal phase, n = 6). Collectively, these data demonstrate that (i) the extrinsic functional control (or rescue of CL in the event of pregnancy) occurs when the sensitivity towards LH/HCG is maximal; and (ii) the demise of CL function is mediated via an acquisition of sensitivity towards the intrinsic luteolytic signal, PGF2, in the ageing CL.
corpus luteum/HCG/LH receptor/PGF2 receptor (FP)/progesterone
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Introduction |
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Luteinizing hormone receptor (LH-R) stimulation has been reported to induce hyperaemic and cellular trophic responses, resulting in increased steroidogenesis by the ovary (Eberson and Silverberg, 1931
; Armstrong et al., 1964). In horses, monkeys and women, this mechanism is physiologically exploited by the trophoblastic synthesis of a chorionic gonadotrophin, which in turn binds to and activates the LH-R, resulting in continuously elevated systemic progesterone concentrations. These events serve to prolong the life span of the corpus luteum (CL) and prevent the menstrual shedding of the embryo (Braunstein, 1996; Roberts et al., 1996). Hence, in the event of a non-fertile cycle, functional demise of the CL follows. Although the detailed mechanisms of luteolysis are largely unknown, prostaglandin (PG) F2 has been postulated to be intimately involved in the induction of luteolysis due to its antisteroidogenic action (Rothchild, 1981). Accordingly, data obtained from subprimate and monkey CL and in-vitro experiments using isolated pieces of CL tissue or luteal cells obtained from women, have indicated an antigonadotropic role for PGF2 (Olofsson and Leung, 1994). However, age-related characterization of progesterone production and its functional response to ligand-activation, as well as the regulation of gene expression encoding the prostaglandin (PG) F2 receptor (FP) and LH-R, have not been demonstrated in luteal tissue of regularly cycling women. Capitalizing on the recent identification of the human FP cDNA sequence (Abramovitz et al., 1994; Lake et al., 1994), the current study was undertaken to study changes in FP mRNA values during different phases of the human CL of the menstrual cycle. These findings were correlated with changes in luteal tissue concentrations of PGF2. In addition, functional studies of the integrated response to human chorionic gonadotrophin (HCG) and the stable PGF2 analogue, cloprostenol, were performed, employing an in-vitro culture model of human luteal cells. |
Materials and methods |
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Patients
Women (n = 33) were recruited in the study. All had given informed consent and the study was approved by the Ethical Committee of Umeå University Hospital. Ovarian tissue was obtained from women scheduled for laparotomy due to benign conditions (i.e. legal sterilization or uterine fibroma) at the Department of Obstetrics and Gynecology, Umeå University Hospital. The patients had not received any hormonal therapy during the preceding month and were otherwise healthy. The average age of the patients was 39.2 years (range 29–47). All women had proven fertility, and had a history of regular menstrual cycles of 24–30 days. The CL age was determined according to onset of last period of menstruation and detection of an ovulatory LH-surge in urine (Clearplan One Step, Unipath Ltd, Bedford, UK). Day 1 was defined as the first day after a positive LH test. According to these two parameters, the patients were scheduled for surgery in early (days 2–5) luteal phase, mid-luteal phase (days 6–10) or late (days 11–14) luteal phase. On the day of surgery a preoperative ultrasound was performed to localize the CL and blood samples were taken. During surgery the CL was extirpated and either immediately divided into pieces and placed in liquid nitrogen for further analysis or prepared for cell cultivation.
Luteal cell culture procedure
All cell culture reagents and drugs were purchased from Life Technologies/Gibco BRL (Gaithersburg, MD, USA) unless otherwise specified. Freshly obtained CL tissue was immediately transported to the laboratory in ice-chilled incubation medium where the tissue was carefully minced and enzymatically dissociated in sterile filtered M199, containing 1.0 mg/ml collagenase type V, 50 µg/ml DNAse 1, 1.5% bovine serum albumin (BSA) and 0.95 mmol/l CaCl2 (all from Sigma-Aldrich Corporation, St Louis, MO, USA). The cell suspension combined with an equal volume of sterile saline (0.154 mol/l) was layered onto 3.0 ml of a fixed Percoll gradient (density 1.117 g/ml) and centrifuged at 400 g for 40 min to remove blood cells and cellular debris. The enrichment of luteal cells was carefully collected from the interface, washed and resuspended in fresh M199 medium containing 26 mmol/l NaHCO3, 25 mmol/l HEPES, 50 IU/ml penicillin, 50 µg/ml streptomycin and 1% heat-inactivated fetal bovine serum. Cells were counted in a Bürker chamber under a light microscope and the viability was in all experiments estimated to be >90% by the Trypan Blue dye exclusion method. The volume of cell suspension was adjusted with M199 medium to give a concentration of 1.5x105 cells/ml medium and added to cell culture dishes (Nunclon; Nunc A/S Roskilde, Denmark) and pre-incubated at 37°C in humidified air/5% CO2 for 18–24 h in a Forma-Scientific CO2 incubator, model 3196 (Marietta, OH, USA). Following the change to fresh medium, adherent cells were treated by incremental doses of HCG (Profasi®; Ares-Serono S.A. Geneva, Switzerland) or the stable PGF2 analogue, cloprostenol (Sigma-Aldrich), in triplicate wells. The concentration used in the dose response for HCG was 0.0001–1.0 IU/ml and for cloprostenol from 10 nmol/l to 10 µmol/l. To study the integrated response to agonists used, a high dose of HCG (0.1 IU/ml) was chosen and added to all wells while increasing doses of cloprostenol (range 10 nmol/l to 10 µmol/l) was supplemented. Cultures were terminated after 24 h and the medium collected and stored at –20°C until assayed for progesterone concentration.
Semi-quantitative reverse transcription–polymerase chain reaction (RT–PCR)
Total cellular RNA was prepared from tissues following homogenization according to previously established protocols (Glisin et al., 1974; Chomczynski and Sacchi, 1987). Complementary DNA was synthesized from 5.0 µg total RNA, using a first strand cDNA synthesis kit (Pharmacia Ltd, Uppsala, Sweden) whereafter PCR was performed and repeated, similarly to methods earlier described in detail (Olofsson et al., 1995, 1996), with some modifications. PCR primers consisted of oligonucleotides specific to the human FP, LH-R and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) sequences (Table I). FP and G3PDH fluorescent PCR-primers (Cy5-labelled) were custom synthesized by Pharmacia for use with the ALFexpress sequencer (Pharmacia Ltd, Uppsala, Sweden). For FP mRNA quantification, PCR was performed with concurrent amplification of both FP and G3PDH (as an internal control) products in one tube, using HotStart 50 tubes according to the manufacturer's specifications (Molecular Bioproducts, San Diego, CA, USA). The upper layer, on top of the wax seal, consisted of 1 µl of cDNA and 24 µl of 1x reaction buffer and 1 IU Taq DNA polymerase (GibcoBRL). Tubes were then heated at 95°C for 45 s, thus mixing the upper and lower layers and bringing the final reaction composition to: 10 mmol/l Tris–Cl (pH 8.3), 50 mmol/l KCl, 2.0 mmol/l MgCl2, 0.4 mmol/l dNTPs, 5 µmol/l each primer, and 1 U Taq DNA polymerase in 50 µl. Samples were cycled through 27 cycles of 30 s at 95°C, 30 s at 55°C and 90 s at 72°C, and a final 15 min extension step at 72°C. A 3 µl aliquot of the PCR product with 2 µl of loading dye was loaded onto a 0.3 mm 6% polyacrylamide gel and electrophoresed on the ALFexpress automated sequencer according to the manufacturer's instructions. The area underneath each peak was quantified by the Fragment analyser software package (Pharmacia). The ratio of numbers obtained for FP and G3PDH PCR products was determined and statistical analyses performed. For LH-R analysis, a previously validated semi-quantitative RT–PCR assay, combined with Southern blotting for detection, was performed as described in detail (Olofsson et al., 1995, 1996), albeit using different PCR primers (Table I). A 410 bp monkey cDNA was utilized as an internal probe (Ottander et al., 1997) and labelled by a PCR fluorescence labelling mix (Boehringer Mannheim, Mannheim, Germany).
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PGF2
analysisCL tissue concentrations of PGF2
were determined according to a previously described method (Olofsson et al., 1990). Briefly, 50–100 mg pieces of human CL tissue were allowed to thaw and homogenized after adding 2.0 ml phosphate-buffered saline (10 mmol/l acidified to pH 4.0 with 1.0 mol/l HCl to prevent the de-novo synthesis of PGs) and samples were extracted by loading to a C18-LRC solid phase extraction cartridge (Bond-Elute; Analythichem Inc, Harbor City, CA, USA). Extracts were re-dissolved in Tris–HCl (10 mmol/l, pH 7.4, with 0.1% weight/volume gelatin added) and assayed by radioimmunoassay using a specific antibody (Advanced Magnetics Inc, Cambridge, MA, USA). All samples were measured in duplicate in a single assay where the coefficient of variation was <10%. Tissue prostaglandin concentrations (expressed as pmol per mg protein) were assayed using BSA as standard according to a previously described method (Lowry et al., 1951).
Hormonal assays
Concentrations of progesterone in medium were determined by a direct time-resolved fluorometric assay (DELFIA®; Wallac Ltd, Turkku, Finland) according to the manufacturer's protocol. All medium samples were assayed in triplets, and a mean value was calculated. All samples from one experiment (one patient) were analysed in the same assay.
Statistical analysis
Each cell culture experiment was repeated three to four times and the progesterone data presented are from triplicate experiments and are pooled from all patients, after normalization of control values to 100% and presented as mean ± SEM. In cases of combined treatment with HCG and cloprostenol, the value of HCG treatment alone was standardized to 100%. Differences between groups were tested by one-way analysis of variance and the Mann–Whitney U-test. P < 0.05 was considered to be statistically significant.
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Results |
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Regulatory studies of human CL FP and LH-R mRNA and tissue concentrations of PGF2
Due to the limited amount of human tissue available, methods to measure steady-state values of mRNA transcripts for both the human FP and LH-R using semi-quantitative RT–PCR, were established. Both PCR products were also cloned and sequenced and their sequence was found to be identical to sequences deposited in GenBank (Table I
). Initially in this study, validation experiments were performed and linear relationships between the amount of RNA used for reverse transcription and PCR products formed were found (data not shown). Moreover, in all experiments negative controls were included (without reverse transcriptase in the RT reaction or without cDNA in the PCR reactions, data not shown), ruling out cross-contamination between samples. PCR amplification of G3PDH as an internal control from the same target cDNA yielded products of similar size, but no statistically different changes were noted between the different age groups of CL tissue tested (Figure 1). Notably, a three-fold increase in the transcript value of LH-R mRNA was noted in the mid-luteal age-groups, when compared with younger CL (P < 0.05), followed by a decrease of almost 30% in the slightly older age-group, albeit this change was not statistically significant (P = 0.23) (Figure 1). FP transcripts were measured by a non-radioactive technique not employing Southern detection but instead the direct quantification of target gene specific fluorescence signal using the ALFexpress system. As can be seen in Figure 2, a significant increase of FP transcript values, relative to those of G3PDH could be seen, with a 2.5-fold higher FP/G3PDH mRNA ratio in the late luteal age-group compared to the early luteal phase CL and 1.6-fold compared with mid-luteal phase CL respectively (P < 0.05). Likewise in this assay, G3PDH mRNA values did not show any significant baseline alterations (10043 ± 503, 9580 ± 526, 9383 ± 714 arbitrary units, for early, mid- and late luteal phase groups respectively, n = 5–6, P > 0.05). Interestingly, this increase in FP mRNA, was not correlated to tissue concentrations of PGF2, which exhibited 40% lower concentrations during the mid-luteal phase, compared with those of the early and late luteal phase groups respectively (Figure 2).
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Sensitivity to HCG and cloprostenol in cultured human luteal cells
In an effort to isolate the effects of receptor agonists, an in-vitro culture system of enriched luteal cells obtained from freshly excised human corpora lutea was established. Under the conditions used herein, the cell viability as routinely assessed by exclusion of Trypan Blue is >90% in plated and washed cells. No difference in rate of cell death was found between the different luteal phases (in all cases of <10%, data not shown). As expected, these cells responded to treatment with HCG with up to 5.7-fold increases in progesterone output in mid-luteal phase luteal cells (Figure 3
). This response was specific to LH-R activation since human recombinant follicle stimulating hormone (FSH) did not alter progesterone synthesis (data not shown). Under the circumstances used herein, no clear and repeatable response by cloprostenol treatment alone in luteal cell progesterone synthesis was noted (data not shown). However, the hypothesis that more mature luteal cells do express functional FP was further corroborated by the finding that a low dose of cloprostenol (10 nmol/l) when added in conjunction with HCG, markedly reduced the response in progesterone synthesis, albeit in the late CL age-group only (Figure 4). Furthermore, this antigonadotrophic effect was dose-dependent, with maximum effects seen at 10 µmol/l cloprostenol. Interestingly, the response pattern seen after cloprostenol treatment did not resemble the corresponding FP mRNA expression level of the different CL-age groups as closely. HCG-stimulation and LH-R mRNA produced similar results. Hence, while FP mRNA values were increased in the mid-luteal age groups, no statistically significant response was seen following a cloprostenol challenge when added together with HCG.
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Discussion |
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FP receptor transcripts have recently been identified in cultured ovarian follicular cells, obtained from women undergoing IVF controlled ovarian hyperstimulation regimens (Carrasco et al., 1997
; Ristimäki et al., 1997; Väänänen et al., 1997). However, the present report constitutes the premier attempt to analyse the relative abundance of FP mRNA and their relation to CL cellular progesterone production in addition to sensitivity to cloprostenol during different functional stages of the human CL of the menstrual cycle. These findings add further support to the hypothesis of an important role for PGF2 in the human ovary, as a locally produced factor intimately involved in luteolysis.
While important for the interpretation of data, it should be emphasized that the material herein contains only tissue and cells obtained from healthy, fertile women, with no prior exogenous hormonal stimulation. Uncharacterized differences in pharmacological controlled ovarian hyperstimulation regimens may possibly account for discrepancies in results obtained from recent studies of HCG-regulation of FP mRNA in granulosa–luteal cells (Ristimäki et al., 1997; Väänänen et al., 1997). The method used to isolate and culture human luteal cells described does not employ any protease pre-treatment and yields consistent results with regard to steroidogenic sensitivity to HCG which, in turn, was largely correlated with amounts of LH-R gene transcripts. Such an age-related LH-R expression pattern in the human CL is in agreement with findings in other recent studies, conducted both at the protein and mRNA level (Nishimori et al., 1995; Bukovsky et al., 1997; Minegishi et al., 1997; Tako et al., 1997). Importantly, in terms of progesterone output, the PGF2 analogue, cloprostenol was demonstrated to strongly inhibit the response to chorionic gonadotrophin treatment during the period of functional regression. Thus, although not specifically addressed in this study, the assumption that the low amounts of FP mRNA detected by semi-quantitative RT–PCR are indeed translated into functional receptors, seems highly likely. Furthermore, lowest concentrations of PGF2 were seen during the mid-luteal phase, a finding closely resembling the situation seen in the rat CL, where PGF2 concentrations are inversely correlated with progesterone output (Olofsson et al., 1990) and moreover, both HCG binding sites and LH-R mRNA are down-regulated by PGF2 or cloprostenol (Grinwich et al., 1976; Bjurulf and Selstam, 1997). The seemingly inconsistent finding that, despite increased FP receptor gene expression in mid-luteal CLs, cloprostenol treatment did not influence HCG-stimulated progesterone synthesis, needs further attention in future studies. However, a similarly intriguing situation is known to occur in early stage bovine CL where, despite clear FP-mediated responses, this does not seem to confer luteal regression, possibly accounted for by the lack of intercellular communication by immunoregulatory activators such as monocyte chemoattractant protein-1 (MCP-1) (Tsai et al., 1998).
As LH or HCG generally promote CL function and PGF2 antagonizes many gonadotrophin actions, it has been suggested that PGF2 may act as a luteolytic factor. This notion has recently been further substantiated by the finding that PGF2 in experimental models of sub-primate mammalian species (Murdoch, 1995; Bjurulf and Selstam, 1997; Hasumoto et al., 1997) and also in monkeys (Young et al., 1997) has been closely associated with apoptotic cell death in the ovary and inhibits steroidogenesis. This effect has recently been attributed to involve an inhibitory control of the steroidogenic acute regulatory protein (StAR) in bovine as well as human corpora lutea (Pescador et al., 1996; Chung et al., 1998). Moreover, in transgenic FP-deficient mice, the decrease in ovarian steroidogenesis which normally precedes parturition was not seen, indicative of `blocked' luteolysis (Sugimoto et al., 1997). Therefore, it is interesting to note that FP gene expression is highest during the luteolytic period of the human CL, coinciding in time with a clear dose-dependent reduction of steroidogenesis following cloprostenol challenge, albeit only when added in conjunction with HCG. Thus, when incorporating our finding that PGF2 CL tissue concentrations are elevated during the late luteal stage in a conceptual model of luteal regression, we postulate that an auto-regulatory feed-back loop exists, possibly driven by prostaglandin synthesis stimulatory agents such as interleukin-1ß (Dawood et al., 1997; Hurwitz et al., 1997; Narko et al., 1997) which ultimately leads to CL regression.
In summary, our findings have demonstrated that the value of FP transcripts is positively influenced by the age of the human CL of the menstrual cycle, while a simultaneous increased sensitivity to a FP agonist in the functionally regressing CL was observed. A functional divergence in luteotropic and luteolytic receptor mediated events, such as translation, coupling mechanisms or intracellular activity is suggested by the findings that (i) the increased amount of FP transcripts did not confer increased sensitivity to cloprostenol during the mid-luteal phase, but (in the older CLs) further increases in FP mRNA values were associated with a diminished HCG-mediated progesterone production, while (ii) such alterations in LH-R mRNA values were in agreement with the progesterone response pattern following HCG stimulation during all stages.
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Acknowledgments |
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Supported by grants from The Swedish Medical Research Council #11832 and 13144, the Swedish Society of Medicine and The Swedish Society for Medical Research and Umeå University. The skilful technical assistance of Monica Isaksson and Jennifer Ross was warmly appreciated.
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3 To whom correspondence should be addressed
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References |
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Submitted on October 23, 1998; accepted on February 9, 1999.
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F.M. Young, F.E. Rodger, P.J. Illingworth, and H.M. Fraser Cell proliferation and vascular morphology in the marmoset corpus luteum Hum. Reprod., March 1, 2000; 15(3): 557 - 566. [Abstract] [Full Text] [PDF]
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U. Ottander, K. Hosokawa, K. Liu, A. Bergh, T. Ny, and J. I. Olofsson A Putative Stimulatory Role of Progesterone Acting via Progesterone Receptors in the Steroidogenic Cells of the Human Corpus Luteum Biol Reprod, March 1, 2000; 62(3): 655 - 663. [Abstract] [Full Text]
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