Human Reproduction, Vol. 16, No. 2, 221-225,
February 2001
© 2001 European Society of Human Reproduction and Embryology
The impact of ovarian stimulation on implantation and fetal development in mice
Department of Obstetrics and Gynecology, The National Hospital, University of Oslo, 0027 Oslo, Norway
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Abstract |
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The objective of this study was to evaluate, using an embryo donation model, whether impaired oocyte/embryo developmental competence and/or changes in uterine milieu are responsible for the previously observed adverse effects of superovulation with gonadotrophins on implantation and fetal development in mice. Embryos from superovulated and non-stimulated females were transferred to separate uterine horns within the same superovulated or non-stimulated pseudopregnant recipient mice. Embryo development was impaired as a significantly higher proportion of normal embryos from control donors (61%) were blastocysts on transfer day compared with superovulated donors (41%; P = 0.001). The implantation rate in control recipients was significantly reduced after transfer of embryos from superovulated donors (12%) compared with control donors (25%; P = 0.001). Uterine receptivity was impaired in superovulated recipients. The implantation rate of control embryos was significantly higher in control (25%) than in superovulated recipients (7%; P = 0.001). Transfer of embryos recovered from superovulated donors resulted in significantly higher post-implantation fetal mortality in superovulated recipients (69%) than in control recipients (36%; P = 0.01), and the mean weight of live fetuses was significantly lower for fetuses obtained from superovulated recipients (0.51 g) compared with that of fetuses obtained from control recipients (0.72 g; P = 0.006). Hence, ovarian stimulation appears to impair oocyte/embryo quality as well as uterine milieu.
Key words: embryo developmental competence/fetal development/implantation/mice/ovarian stimulation
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Gonadotrophins are commonly used for superovulation in animals and in humans, for example to increase the number of oocytes that can be retrieved for IVF, thus improving the overall chance for successful fertilization and pregnancy. Despite considerable progress in assisted reproduction technology in recent years, the pregnancy rate remains low as high numbers of transferred embryos fail to implant. Furthermore, increased incidence of gestational complications such as hypertension, bleeding, placenta praevia and low birth weight, have also been reported (Tanbo et al., 1995
; Maman et al., 1998). Exogenous administration of gonadotrophins results in higher concentrations of circulating steroids which may affect oocyte and/or embryo quality, oviductal and/or uterine environment as well as the synchrony that normally exists between the embryo and the endometrium at the time of implantation. Hence, a relationship may exist between ovarian stimulation with gonadotrophins and the low implantation rate and the gestational complications observed. For obvious ethical reasons, only minimal, directly derived scientific information exists on the impact of ovarian stimulation on embryo development, implantation and gestation in humans. Therefore, for the majority of such studies, rodents are the preferable model. Although in general it is not possible to extrapolate from animal models to humans, considerable similarities exist among many mammalian species in the early stages of development with respect to morphology and metabolism. This suggests that information obtained from peri-implantation embryos of laboratory animals might be applicable to those of the human (Brinster, 1975).
We have reported previously that treatment with gonadotrophins impairs pre- and post-implantation development in mice. Increased pre- and post-implantation mortality, low fetal weight and fetal growth retardation were observed in superovulated mice and in animals treated with ovulation induction alone (Ertzeid and Storeng, 1992). Furthermore, delayed implantation and presumably impaired implantation did occur (Ertzeid et al., 1993). The objective of this study was to evaluate whether impaired embryo quality and/or changes in uterine milieu are responsible for the previously observed adverse effects of superovulation with gonadotrophins on implantation and fetal development in mice. Taking advantage of the fact that the uterus in mice has two horns, an embryo donation model was used (Storeng and Jonsen, 1984), in which in-vitro-cultured embryos from superovulated and non-stimulated females were transferred to separate uterine horns within the same superovulated or non-stimulated pseudopregnant recipient.
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Materials and methods |
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Animals
Female C57Bl/6J mice (aged 2–3 months) and male fertile or vasectomized B6CBA/F1 mice (aged 3–12 months) were obtained from Bomholtgaard, Denmark for use in these experiments. The animals were housed under a 12 h light:12 h dark regimen (light on at 7:00), with a temperature of 23°C and relative humidity of 44%. The mice were fed a standard pellet diet ad libitum, and had free access to drinking water.
Gonadotrophin treatment of donor and recipient females
Pregnant mare's serum gonadotrophin (PMSG) (Folligon; Intervet Norge, Oslo, Norway) and human chorionic gonadotrophin (HCG) (Profasi; Serono, Geneva, Switzerland) were used. Donor and recipient females for the experiments were chosen without regard to their oestrous cycle, and were superovulated with an i.p. injection of 10 IU PMSG in 0.1 ml 0.145 mol/l NaCl at 12:00, followed 48 h later by an i.p. injection of 10 IU HCG in 0.1 ml 0.145 mol/l NaCl to induce ovulation. Controls were injected with the vehicle at the appropriate times. Donor females were mated with fertile males, and recipients were rendered pseudopregnant by mating with vasectomized males. The presence of a vaginal plug on the following day indicated successful mating, and this was designated day 1 of gestation. Since the presence of a coagulation plug does not necessarily indicate a pregnancy, it was assumed in this study that vaginal plug-positive mice may fail to become pregnant after transfer, due not only to the quality of the embryos and/or endometrium but also to failure to become pseudopregnant.
Embryo recovery and in-vitro culture
Pregnant donor mice were killed by cervical dislocation on gestational day 2. The oviducts were excised and flushed with M2 medium (Sigma Aldrich Norway AS, Oslo, Norway). Morphologically normal day 2 embryos (2- to 4-cell) were pooled after collection, washed twice in M2 medium and transferred to a 0.05 ml droplet of M16 Medium (Sigma), overlaid with paraffin oil, and incubated at 37°C in a humidified atmosphere of 5% CO2 in air for 48 h. At day 4, normal embryos were pooled and their number and stage of development (compacted morulae, early to fully expanded blastocysts) were recorded.
Embryo transfer
At day 4, normal embryos from control and superovulated mice were divided randomly and transferred to separate uterine horns within the same control or superovulated recipient (see Figure 1). Available normal embryos (two to six embryos) were transferred to the uterine horns of females on day 3 of pseudopregnancy. Briefly, the animals were anaesthetized with an i.p. injection of 0.2 ml Dormicum:Hypnorm (midazolam/fentanyl/fluanison; National Hospital Pharmacy, Oslo, Norway). A paralumbar incision was made on the recipient female and each uterine horn was consecutively pulled through the excision. The uterus was punctured with a needle, and through this hole embryos were transferred to the lumen, using a finely drawn glass pipette. Thereafter, the uterus was replaced in the abdominal cavity and the skin incision closed by clips. One recipient received control embryos in the right uterine horn, while embryos from superovulated donors were transferred in the left uterine horn. The next recipient received embryos derived from superovulated donors in the right uterine horn and control embryos in the left uterine horn. This pattern was followed throughout the experiments in order to alleviate any technically induced influence in the outcome of the embryo transfer. Seventeen replicate experiments with a total of 182 embryo transfers to 91 pseudopregnant recipient mice were performed. A total of 820 embryos was transferred as follows: 116 control embryos and 340 embryos from superovulated mice to control recipients; 134 control embryos and 230 embryos from superovulated mice to superovulated recipients.
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Assessment of implantation and post-implantation development
The recipients were killed on day 18 of gestation and the uterine contents examined. The number of live fetuses, stillborns and early and late resorptions in each uterine horn was recorded. Each fetus was examined for macroscopic malformations, and weighed. The implantation rate was calculated as: (total number of liveborns, stillborns and resorptions/number of embryos transferred). The post-implantation mortality was calculated as: (number of resorptions and stillborns/number of implantations).
Statistical analysis
The data were analysed using Student's t-test for continuous data and 
2 for categorical data. Differences were considered significant at P < 0.05.
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Results |
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This embryo donation model used to evaluate the impact of ovarian stimulation on embryo quality and/or uterine receptivity, yielded four groups of offspring from: (i) control embryos to control recipients; (ii) embryos from superovulated donors to control recipients; (iii) control embryos to superovulated recipients; and (iv) embryos from superovulated donors to superovulated recipients.
Impact of ovarian stimulation on embryo developmental competence
Morphological examination of normal embryos transferred on day 4 revealed that a significantly higher proportion of embryos from control donors had reached the blastocyst stage (61%) than had those from superovulated donors (41%; P < 0.001; Table I).
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Caesarean section on control recipients on gestational day 18 revealed a significantly reduced implantation rate (12%) after transfer of embryos from superovulated donors than from controls (25%; P = 0.001; Table II
). There was no difference in post-implantation mortality in control recipients after transfer of embryos from control or from superovulated donors (34 versus 36%; Table III). No difference in mortality was observed in superovulated recipients after transfer of embryos from control or from superovulated donors (89 versus 69%; Table III). The mean weight of live fetuses obtained from control recipients was similar both for fetuses obtained after transfer of embryos from superovulated donors (0.72 g) and for control embryos (0.89 g; P = 0.05; Table IV).
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Impact of ovarian stimulation on uterine milieu
The implantation rate of control embryos was significantly higher in control recipients (25%) than in superovulated recipients (7%; P = 0.0001; Table II
). Transfer of control embryos to superovulated recipients resulted in significantly higher post-implantation mortality (89%) than in control recipients (34%; P = 0.01; Table III). Furthermore, after transfer of embryos recovered from superovulated donors to superovulated recipients, post-implantation mortality was increased (69%) compared with that in control recipients (36%; P = 0.01; Table III).
The mean weight of live fetuses which developed after transfer of embryos derived from superovulated donors was significantly lower for those obtained from superovulated recipients (0.51 g) than from control recipients (0.72 g; P = 0.006; Table IV).
There were no macroscopic malformations observed in either group of offspring.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The objective of this study was to evaluate whether impaired embryo developmental capacity and/or changes in uterine milieu are responsible for the previously observed adverse effects of superovulation with gonadotrophins on implantation and fetal development in mice.
A negative effect of ovarian stimulation on oocyte/embryo developmental competence was observed as transfer of embryos from superovulated donors resulted in a significantly lower implantation rate in control recipients compared with that of embryos from control donors. No difference in post-implantation mortality was observed, indicating an early loss of non-viable embryos recovered from superovulated donors. The reduced weight of live fetuses after transfer to control recipients of embryos from superovulated donors was not statistically significant, but may suggest some negative effect of superovulation even on viable embryos.
In previous studies, increased pre-implantation mortality after superovulation has been reported in mice (Beaumont and Smith, 1975; Ertzeid and Storeng, 1992) and rats (Miller and Armstrong, 1981). Furthermore, in hamsters, embryos produced by superovulated females have been observed to be less viable upon transfer than embryos recovered from controls (McKiernan and Bavister, 1998).
The causes of the loss of developmental competence of embryos from superovulated donors remain unknown. Chromosomal abnormalities may account for reduced viability of embryos from superovulated females because superovulation has been found to increase the proportion of chromosomal abnormalities in murine embryos (Elbling and Colot, 1985, 1987; Luckett and Mukherjee, 1986) as well as in oocytes in rats (Tain et al., 2000). As ovarian stimulation produces a cascade of hormonal and physiological events, oocytes mature in an environment different from that of naturally matured oocytes (Foote and Ellington, 1988), and variation in the timing of ovulation may also occur (Allen and McLaren, 1971). New evidence from molecular biology studies of mammalian oogenesis has implicated a role for gonadotrophins in the control of meiosis in mammalian oocytes (Picton et al., 1998). In mice as well as in humans, there is evidence for steroids being regulators of gene expression, and that embryo morphology and rate of development—both of which reflect embryo quality—have a genetic basis (Warner et al., 1998). In the present study, within the group of normal day 4 embryos from superovulated donors, the proportion of morulae was higher than from control donors, indicating developmental retardation which may reflect reduced embryo quality.
A negative effect of ovarian stimulation on uterine receptivity was also observed. The implantation rate was significantly reduced and the mortality greatly increased in superovulated recipients compared with controls. The mean weight of live fetuses in stimulated recipients was reduced, indicating impaired implantation and gestation.
Successful implantation depends on embryo quality, uterine receptivity and synchronization of embryo development and endometrial maturation. The relative contribution of the endometrium to the success rate is not known, and there are no accepted criteria for evaluating endometrial receptivity. However, preparation of the endometrium is primarily under the control of ovarian steroid hormones, and increasing evidence suggests that their effects are mediated by locally produced cytokines which then exert their action in an autocrine or paracrine manner (Klentzeris, 1997; Stewart and Cullinan, 1997; Beier and Beier-Hellwig, 1998; Simón et al., 1998a; Giudice, 1999). In the present study, exogenous administration of gonadotrophins, affecting the concentrations of circulating ovarian steroids (Ertzeid and Storeng, 1992), may have changed the local expression of cytokines in the endometrium in superovulated recipients, and hence its receptivity. Female mice were chosen without regard to their oestrous cycle. However, the adverse effects of gonadotrophins presumably cannot be attributed to asynchrony, as an earlier study has shown that superovulation after synchronization also increased embryonic loss (Beaumont and Smith, 1975).
Previous studies in immature rats, superovulated with PMSG, but without HCG as ovulation induction, reported pregnancy failure due to changes in the uterine milieu (Walton et al., 1982; Walton and Armstrong, 1983). In agreement with the results presented here, a higher implantation rate on gestational day 5 was observed when embryos from superovulated donor mice were transferred to non-stimulated than to stimulated recipient mice (Fossum et al., 1989). Compared with this study, the implantation rate in the current study in superovulated as well as control recipients was lower, possibly due to a period of embryonic in-vitro culture in this study, as well as the difference in the strain of mice used. Furthermore, a stimulated oviductal environment has also been shown to have a negative influence on the implantation capacity of mouse embryos (Van der Auwera et al., 1999). In humans, synthetic oestrogen has been used as an effective emergency contraceptive agent to prevent implantation (Haspels, 1976). In IVF, ovarian stimulation with high oestradiol concentrations has been reported to be detrimental to implantation and pregnancy rates (Pellicer et al., 1996; Simón et al., 1998b; Valbueña et al., 1999; Ng et al., 2000). While high serum oestradiol concentrations in fresh IVF cycles significantly reduced the implantation rate, the implantation and pregnancy rates in frozen–thawed cycles for surplus embryos were similar. Hence, the impairment in implantation was attributed to hostile environment in the endometrium (Ng et al., 2000).
In conclusion, ovarian stimulation impairs implantation and fetal development in mice. These experiments, using the mouse embryo donation model, indicate that reduced embryo quality or developmental competence as well as changes in the uterine milieu are responsible for the adverse effects observed.
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Notes |
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1 To whom correspondence should be addressed. E-mail: gudvor.ertzeid{at}rikshopitalet.no
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Submitted on September 1, 2000; accepted on November 2, 2000.
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R.M. Sibug, F.M. Helmerhorst, A.M.I. Tijssen, E.R. de Kloet, and J. de Koning Gonadotrophin stimulation reduces VEGF120 expression in the mouse uterus during the peri-implantation period Hum. Reprod., June 1, 2002; 17(6): 1643 - 1648. [Abstract] [Full Text] [PDF]
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A.K. Omland, P. Fedorcsak, R. Storeng, P.O. Dale, T. Abyholm, and T. Tanbo Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility Hum. Reprod., December 1, 2001; 16(12): 2587 - 2592. [Abstract] [Full Text] [PDF]
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I. Van der Auwera and T. D'Hooghe Superovulation of female mice delays embryonic and fetal development Hum. Reprod., June 1, 2001; 16(6): 1237 - 1243. [Abstract] [Full Text] [PDF]
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