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RESEARCH |
1 Department of Physiology, 2 Monash Immunology and Stem Cell Laboratories, 3 Prince Henry’s Institute of Medical research, Monash Medical Centre, Clayton, Australia 3168 and 4 Department of Anatomy and Cell Biology, Monash University, Clayton, Australia 3800
Correspondence should be addressed to H Y Yang; Email: Hsiao.yang{at}med.monash.edu.au
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Abstract |
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Introduction |
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Research on animals has shown that live young can be obtained from oocytes of ovaries grafted to either orthotopic (returned to normal position) or heterotopic (alternative positions) sites, but there have not been any studies directly comparing oocyte quality or yield between the different graft sites. Orthotopic grafts permit natural conception and circumvent the need for in vitro maturation (IVM) and/or in vitro fertilization (IVF) that is required for heterotopic grafts (Jones & Krohn 1960, Gosden et al. 1994, Cox et al. 1996, Petroianu et al. 2002, Almodin et al. 2004a, b, Donnez et al. 2004). However, most clinical studies to date have placed ovarian grafts under the skin to permit easy monitoring of follicle growth and provide ready access to the graft for oocyte collection (Oktay & Yih 2002, Oktay et al. 2003, 2004).
Heterotopic ovarian grafts placed under the kidney capsule of mice yield viable oocytes that can develop after fertilization to term when placed in gestational surrogates (Carroll et al. 1990, Waterhouse et al. 2004). The only report of a live young derived from a subcutaneously located graft occurred in a monkey when the resulting embryos were transferred to a gestational surrogate (Lee et al. 2004). Oocytes collected from human ovarian tissue grafted under the skin of the forearm have proved difficult to successfully fertilize and establish a pregnancy (Oktay et al. 2003). A four-cell embryo was produced from one woman by intracytoplasmic sperm injection from oocytes harvested from ovarian tissue grafted subcutaneously to the abdominal wall. However, this four-cell embryo failed to implant following transfer into the patient’s uterus (Oktay et al. 2004).
In experimental animal models, the pregnancy rates of recipients of fresh or frozen ovarian orthotopic grafts tend to be lower than for non-grafted controls (Cox et al. 1996, Candy et al. 2000, Shaw et al. 2000, Wang et al. 2002a, Almodin et al. 2004a) and has been attributed to reduced follicle numbers and adhesions rather than reduced oocyte quality. However, studies on sheep indicate that oocyte quality may be compromised generally in ovarian grafts (Gosden et al. 1994, Aubard et al. 1999,, Salle et al. 2002, 2003). If proven to be correct, this could be a concern for clinical application of grafting cryopreserved ovarian tissue. Sheep oocytes usually develop well in vitro, but oocytes collected from subcutaneous grafts appear to have compromised developmental potential as none developed beyond the four-cell stage (Aubard et al. 1999). Another study found a very high death rate (50%) among male lambs born following spontaneous conception to sheep with ovarian orthotopic grafts (Salle et al. 2002, 2003). However it has not yet been established whether these deaths could be attributed to ovarian grafting or to other unrelated factors such as the choice of ram used.
If oocytes are to be collected from ovarian grafts for IVF, it will be important to maximize the graft yield of normal, mature oocytes. The number that can be collected will depend not only on how long the grafts remain functional but also on whether follicle growth and oocyte maturation can be stimulated with exogenous gonadotrophins. Ovarian grafts in mice can function for one year (Candy et al. 2000, Shaw et al. 2000) and grafts in sheep have been reported to function for up to two years (Baird et al. 1999). Ovarian grafts in humans may cease to function after a single menstrual cycle (Radford et al. 2001) or remain functional for a year or more (Oktay et al. 2001, Oktay & Yih 2002, Donnez et al. 2004, Meirow et al. 2005, Siegel-Itzkovich 2005). In mice with ovarian grafts under the kidney capsule, administration of gonadotrophins does not significantly increase the oocyte yield (Carroll et al. 1990, Waterhouse et al. 2004). The effect of gonadotropins on subcutaneous grafts in mice is not known. Stimulation with exogenous gonadotrophins has been used for patients with ovarian grafts to in an attempt to enhance the likelihood of obtaining mature oocytes (Oktay & Yih 2002), but whether this influences oocyte yield or quality is not known.
The present study investigates the ability of mouse oocytes collected from orthotopic and heterotopic sites to produce embryos, fetuses and live young with and without gonadotrophin stimulation.
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Materials and Methods |
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Ovarian transplantation procedure
Each female mouse acted as both ovarian tissue donor and graft recipient in order to minimize animal usage. Ovarian grafting was performed using standard procedures (Cox et al. 1996, Shaw et al. 2000, Cleary et al. 2003). Briefly, pairs of female mice were simultaneously anaesthetised by administering each with 0.2 ml i.p. injection containing 1 mg/ml xylazine hydrochloride (Ilium Xylazil-20; Troy Laboratories, Smithtown, Australia) and 5 mg/ml ketamine hydrochloride (Ketamine; Parnell Laboratories, Alexandria, Australia). Once anaesthetized, the dorsal skin of both mice was swabbed with 70% (v/v) alcohol, a 1 cm dorsal incision was made through the skin and bilateral ovariectomy was performed on each mouse. The excised ovaries were placed in Dulbecco’s phosphate-buffered saline (PBS; Gibco BRL, Gaithersburg, USA) and were cut in half before being grafted. Recipients received either two hemi-ovarian grafts under each kidney capsule, or four hemi-ovarian grafts placed subcutaneously onto the back of the mouse, or one hemi-ovarian graft into each bursal cavity. To facilitate identification of the subcutaneous grafts, the graft sites were marked with 1-0 silk suture. The skin was closed with 9 mm Michel clips (Clay Adams, Sparks, USA).
Gonadotrophin stimulation protocol
In the third week after grafting, the graft recipients in the hormone treatment group were all treated with 5 IU pregnant mare serum gonadotrophin (PMSG; Folligon; Intervet, Castle Hill, Australia) and 5 IU hCG (Chorulon, Intervet, Castle Hill, Australia) 48 h later and were killed on day 21, 10 h after the hCG injection. Age matched intact female controls were superovulated with the same dose of PMSG and hCG.
In vitro culture
The graft recipients were killed three weeks after grafting because in mice primordial follicles take three weeks to reach the preovulatory stage (Cox et al. 2000). Mice that were stimulated with gonadotrophins were killed 10 h after the hCG injection to avoid ovulation of oocytes from the graft. The mice were killed by cervical dislocation and the grafts were collected into equilibrated (5% CO2 at 37 °C) minimum essential medium alpha (MEM
; Sigma), supplemented with 10% fetal calf serum (FCS, Gibco) under mineral oil (Sigma). The number of grafts retrieved was noted. The oocytes were released by puncturing large antral follicles with a 26G needle and the oocytes collected. Oocytes were then moved into fresh equilibrated MEM maturation media supplemented with 10% v/v FCS, 1 IU/ml PMSG, 1 IU/ml hCG and 1 ng/ml EGF (Sigma). The maturity and number of oocytes collected per graft was noted. Oocytes with compact cumulus cells and germinal vesicles (GV) were cultured at 37 °C with 5% CO2 for 16–18 h before being fertilized in vitro. Oocytes with an expanded cumulus were fertilized in vitro approximately 2 h after oocyte collection. IVF was performed in equilibrated mT6 medium using sperm capacitated in mT6 for 1 h. Oocytes were left with sperm in the fertilization medium for 2 h and were washed before being moved to equilibrated KSOMaa embryo culture medium (Ho et al. 1995) at 37 °C with 5% CO2 for 24 h. The number of two-cell embryos produced was scored at this time.
GV oocytes collected from intact F1 females the same age as the recipients served as an IVM control. The GV oocytes were collected from the non-stimulated female controls and then matured and fertilized in vitro under the same conditions as oocytes retrieved from grafts (see above). In vivo matured oocytes collected from oviducts of intact superovulated F1 females were used as a second control group. In these controls the ovulated oocytes were collected 14 h after the hCG injection to allow insemination at the same time as the oocytes from the ovarian grafts. All culture and handling procedures were identical to those described for the grafted group.
Embryo transfer
Adult female F1 hybrid mice were placed with vasectomised males of the same strain. Females were examined for evidence of a vaginal plug. On the day of finding a vaginal plug, the two-cell embryos were transferred to the oviducts. Recipients were anaesthetised as described above. Each oviduct was located and exteriorised and the embryos (up to 6 per uterine horn) were inserted into the opening of the oviduct using a thin glass pipette. The reproductive tract was returned to its original position and the skin was closed with Michel clips. Females that were to be allowed to progress to term had embryos belonging to a single treatment group transferred to both oviducts. Females which were to be examined on day 15 of gestation had a different treatment group transferred to the two oviducts to control for between female variations.
Assessment of day 15 fetuses and live-born pups
Recipients which were killed on day 15 of gestation, had the implantation sites counted and the health of the fetuses assessed. The weight of each fetus and its placenta was recorded. Those fetuses that were allowed to develop to term had their health monitored until the time of weaning. The surrogate mothers were killed by cervical dislocation at the time of weaning, their uteri were dissected out and the number of implantation sites were counted and compared with the number of pups to determine how many embryos were lost during the pregnancy. Live born pups were either killed by cervical dislocation at four weeks of age or were kept and then mated with their siblings from the same litter for fertility testing.
Statistical analyses
In each treatment group, data were pooled and chi-square tests were used to statistically analyse graft recovery, number of two-cell embryos, implantation sites and fetuses between groups. The number of oocytes collected was expressed as the mean±S.E.M. per ovary (equivalent of two hemi-ovarian grafts). The fetal and placental weights were expressed as mean±S.E.M. One way ANOVA was used for statistical analysis of the number of oocytes and fetal and placental weights between the treatment groups. Results were considered significant when P = 0.05. All statistical analysis was carried out using the computer statistical package SPSS11.0 (SPSS Inc., Chicago, USA).
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). When the graft was not clearly visible, the graft site was searched carefully under high power magnification for any evidence of ovarian remnants.
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). Graft recipients that received no gonadotrophin, had similar oocyte yields for the bursal cavity and kidney capsule (10.1 ± 1.2 and 11.9 ± 1.7, respectively). Subcutaneously placed ovaries had a significantly lower oocyte yield (2.0 ± 0.2 oocytes per ovary) than those placed under the kidney capsule or in the bursal cavity. All collected oocytes, regardless of graft site, were at the GV stage of development.
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The number of oocytes recovered did not increase significantly after treatment with exogenous gonadotrophins. Both the bursal cavity and subcutaneous graft sites had similar numbers of oocytes at collection regardless of whether they were exposed to gonadotrophins. Grafts from under the kidney capsule, however, had significantly fewer oocytes collected from the gonadotrophin stimulated group compared with the groups that were not treated with exogenous gonadotrophins (Fig. 1
).
Two-cell cleavage rate
The two-cell cleavage rate of in vitro matured GV oocytes collected from non-stimulated grafts was significantly higher for the orthotopic group (bursal cavity, 36%) than for both of the heterotopic graft sites. The cleavage rate for the two heterotopic sites was not significantly different (kidney capsule, 19% and subcutaneous, 16%; Fig. 2).
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). There was no significant difference in the cleavage rates of MII eggs between the three grafts sites (bursal cavity 55%, kidney capsule 42%, subcutaneous 49%). There was no significant difference in the cleavage rate between GV and MII eggs from the bursal cavity and kidney capsule graft sites. At the subcutaneous graft site, however, there was a significantly lower cleavage rate for GV oocytes compared with MII eggs retrieved from the same grafts site.
The recipients in the gonadotrophin-treated group of the bursal cavity and kidney capsule graft sites had significantly higher cleavage to two-cells when compared with the non-treated group. At the subcutaneous graft site however, only the MII eggs of the gonadotrophin-treated group had a significantly better cleavage rate when compared with the non-treated group, GV oocytes had comparable cleavage rates. Oocytes in grafts at all graft sites in both the stimulated and non-stimulated treatment groups had significantly lower development to two-cells than both the in vitro and in vivo matured oocytes from the control ovaries (78% and 86% cleavage, P < 0.05; Fig. 2).
Fetuses and live born pups
The fetuses collected 15 days after the transfer of two-cell embryos were phenotypically normal in the non-stimulated group for all graft sites. There was no significant difference in the proportion of two-cell embryos that implanted or formed fetuses for the three different graft sites (Table 2). There was no significant difference in the implantation rate between the grafted groups and the controls but fewer embryos from grafts formed fetuses.
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Overall, irrespective of the graft site or hormone treatment, the fetal and placental weights of the fetuses did not differ significantly from the control group, with the exception of the subcutaneous fetuses from the non-stimulated treatment group, which had a significantly lower fetal weight (P < 0.05; Table 3).
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Discussion |
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Oocytes collected from ovarian grafts appear to have a reduced developmental potential in comparison to the oocytes produced in situ. The grafting process causes ischemic-reperfusion injury that occurs as the graft establishes a new blood supply. This period of poor vascular support may adversely affect the oocyte and growing follicles. Damage to the perivascular and endothelial cells has been shown to have an influence on the integrity of ovarian follicles and oocytes in ovarian grafts (Israely et al. 2003). Ovarian grafting also disrupts innervation of the ovary. The ovary is innervated by extrinsic and intrinsic nerves that are believed to control blood flow, as well as follicle and oocyte development (Dissen et al. 1995, D’Albora et al. 2000, 2002, Anesetti et al. 2001, Aguado 2002). Normal follicle development and the production of viable oocytes is a complicated process that involves coordination of numerous molecules including hormones, growth factors and receptors, in various signalling pathways that act in autocrine, paracrine and endocrine manners (Yamashita et al. 2000, Josefsberg & Dekel 2002, Matzuk & Lamb 2002, Drummond et al. 2003). Although grafted ovaries do become re-vascularized and re-innervated, the grafting process may perturb the systems that are essential for normal follicle growth and oocyte development and thus result in a reduced number of developmentally competent oocytes.
In addition, embryos produced from oocytes collected from grafts have significantly lower capacity to develop to fetuses when compared with intact ovaries, even though the implantation rates are comparable. This was due to the higher reabsorption rates from embryos of graft origin. The lower quality of oocytes produced from ovarian grafts may account for the high embryonic reabsorption rate as the quality of the oocyte is a primary determinant of embryo quality (Gosden 2002). Despite this, the fertilized oocytes that completed development formed phenotypically normal fetuses and pups which developed into normally fertile adults. This shows that at least some oocytes retrieved from ovarian grafts are developmentally viable.
The position of the graft influenced graft recovery and the number of oocytes retrieved. The bursal cavity and kidney capsule yielded more grafts and oocytes than the subcutaneous graft site. This is comparable to previous reports (Cleary et al. 2003, Hernandez-Fonseca et al. 2004, Waterhouse et al. 2004). The bursal cavity and kidney capsule graft site have a relatively good blood supply that facilitates the revascularization process which is essential for graft establishment and the support of follicular growth. The main cause for graft and follicle loss in the process of ovarian transplantation is believed to be post-transplant ischaemia. In mice, transplantation accounts for approximately 42% of the loss in follicle population while cryopreservation reduces the loss of follicles by a further 9% (Liu et al. 2002). This substantial loss of follicles is also observed in larger animal models (Baird et al. 1999). The duration of the ischaemia prior to revascularization of transplanted ovarian tissue depends on several factors, such as the size of the tissue, the graft site and the presence of angiogenic factors. Rodent ovaries are relatively small and re-vascularize within 24–48 h of grafting (Dissen et al. 1994). Israely et al.(2003) reported that subcutaneous grafts have a poor blood supply and altered vascular integrity. Loss and damage of perivascular and endothelial cells was closely correlated with loss of follicular and oocyte integrity. Thus in this present study, an altered vascular supply may not have provided sufficient support (e.g. hormonal) for the ovarian grafts and follicles at the subcutaneous site. This could be why so many of the subcutaneous grafts failed to become established.
Although it is not clear from this study why orthotopic grafts produce better oocytes than heterotopic grafts, a plausible reason is that oocytes from grafts in heterotopic groups are deprived of local factors from the uterus or orthotopic site that are required for normal follicle and oocyte development. Furthermore, transplantation of ovarian tissue to other sites within the body may disrupt some ovarian processes and/or expose the ovary to a different environment. The renin–angiotensin system in the kidney regulates systemic blood pressure and fluid homeostasis. There are data supporting the idea that the renin–angiotensin system also exerts an influence in the ovary playing a role in follicular development, steroidogenesis, oocyte maturation, ovulation and follicle atresia (Yoshimura 1997, Li et al. 2004), and that this system is regulated by gonadotrophins (Kuji et al. 1996). It is, therefore, possible that the renal renin–angiotensin system affects follicle development and oocyte maturation in ovarian grafts placed on the kidney.
Alternatively, physical changes may interrupt follicle/oocyte competence in ovarian grafts. Donnez et al.(2004) suggested that because subcutaneous ovarian grafts, are placed close to the body surface, they may experience changes in temperature and pressure that could damage oocytes. Decreasing or increasing the temperature of oocytes results in damage to the cytoskeleton and meiotic spindle (Liu et al. 2003, Payton et al. 2004, Sun et al. 2004a,b).
Hormonal feedback between the pituitary and ovary regulates oocyte development and may be disturbed by grafting and in particular grafting to heterotopic sites. Although endocrine function was not monitored in this study, ovarian grafting in sheep results in perturbations in hormone levels. The secretion of inhibin A in ovarian grafts is decreased which in turn causes a rise in FSH concentrations and may result from the reduced number of preantral follicles in ovarian grafts. LH concentrations are also elevated in sheep with ovarian grafts, however progesterone and oestrogen levels are normal throughout the cycle (Baird et al. 2004). Whereas in rats, oestrogen and cyclic activity are altered in heterotopic ovarian grafts (Petroianu et al. 2005). Abnormalities in hormonal concentrations may alter follicle development. There is evidence that in the grafts in mice and sheep, both the rate of recruitment and the rate of follicle development are accelerated following grafting (Cox et al. 2000, Baird et al. 2004). This indicates that abnormalities in ovarian function within ovarian grafts may be due to an altered endocrine environment within ovarian graft recipients. This may account for the poor follicle response and reduced developmental competence of oocytes within ovarian grafts observed in this study.
Treatment of the graft recipients with the standard mouse superovulation protocol did not significantly increase the number of oocytes at any of the three graft sites. Previous studies where exogenous PMSG was administered to stimulate ovarian tissue grafted under the kidney capsule also failed to increase the yield of oocytes from ovarian grafts (Snow et al. 2002, Waterhouse et al. 2004). Collectively, data from this study and previous studies indicate that developing follicles in ovarian grafts, irrespective of the graft site, do not respond to exogenous gonadotrophins in the same manner as intact ovaries. The reason for this is not known, but it may be possible that the vascular remodelling that occurs in the ovarian graft does not allow adequate delivery of the gonadotrophin to the grafts. It may also be possible that the altered response may be due to low numbers of follicles in the ovarian grafts, as studies have shown that women with small ovarian reserves have a lower response rate to ovarian stimulation with gonadotrophins (El-Toukhy et al. 2002, Younis et al. 2005).
Mature MII eggs were retrieved from the ovaries of gonadotrophin-treated recipients at all three graft sites. The cumulus cells surrounding the oocytes were expanded and had the same morphology as the ovulated eggs from the control group. The mucification process is known to occur before ovulation and is triggered by gonadotrophins, which induce the production and secretion of hyaluronic acid from the cumulus cells (Eppig 1979). The MII oocytes had extruded the first polar body (data not shown) and could be fertilized without IVM. Waterhouse et al.(2004) and Carroll et al.(1990) collected oocytes from ovarian grafts on the kidney 12 h after hCG injection, but the majority of the oocytes retrieved from their studies were GV oocytes and required IVM before fertilization. In the mouse, it is believed that the extrusion of the first polar body occurs in vivo from 10 h onwards after hCG injection (Nagy et al. 2003). The ability of the oocytes in the grafts to undergo mucification and first polar body extrusion indicates that some exogenous hormones reached the follicles and produced an effect on the ovarian grafts.
Gonadotrophin treatment of graft recipients improved the embryo development of fertilized oocytes. Both GV oocytes and MII oocytes collected from ovarian grafts stimulated with exogenous hormones had a higher cleavage rate than the unstimulated group. This was previously reported by Waterhouse et al.(2004) who also observed a significantly higher rate of two-cell embryos after PMSG and hCG treatment of graft recipients when compared with unstimulated graft recipients. However these rates of development were still lower than the in vitro and in vivo controls as observed in the present study.
Embryos that arose from gonadotrophin-treated grafts (irrespective of graft site) had comparable rates of implantation and fetal development when compared with the control group. However, only a small number of embryos were transferred. Some embryos that were transferred did not implant and some surrogate mothers did not become pregnant (data not shown). It is not known whether it is because the quality of the embryos was reduced or whether the surrogate mothers were unable to sustain the pregnancy. The weights of the fetus and placenta are comparable across all groups, the only exception was the subcutaneous group, where the fetal weight was significantly lower (the placental weight was normal). However, only two fetuses developed in this group and definitive conclusions are not possible with the small sample size.
This study demonstrated that viable oocytes, capable of developing into normal fetuses and live young, can be collected from orthotopic and heterotopic ovarian grafts. However, significantly more developmentally competent oocytes are produced from orthotopic grafts than heterotopic grafts. Thus, graft site is an important consideration for the production of developmentally competent oocytes from ovarian grafts. Stimulation of ovarian grafts with exogenous gonadotrophin induces meiotic maturation in oocytes within ovarian grafts but it does not increase oocyte yield.
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Footnotes |
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References |
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