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The effect of oocyte dysmorphism on further embryo development is controversial. It is generally accepted that serious oocyte abnormalities can have a negative effect on further fertilization and development. A couple reported to the clinic following 2 years of infertility and underwent five IVF/intracytoplasmic sperm injection treatments due to severe male factor infertility. A total of 42 oocytes were collected. The majority of the oocytes showed at least one large, fluid-filled and centrally located cytoplasmic vacuole and unusually thin zona pellucida. Only seven oocytes showed normal fertilization. The first four IVF treatments did not result in pregnancy. In the fifth IVF treatment, three poor-quality vacuolized embryos were transferred. A singleton pregnancy was detected. A baby girl was born at term who required surgery because of a double left kidney and ureter. This case report demonstrates that serious oocyte abnormalities can be a recurrent phenomenon in the same patient. However, the presence of a large vacuole does not completely block the fertilization process and this abnormal cohort of oocytes can still result in normal embryo development and a viable offspring. Rigorous prenatal care and follow-up should be carried out following the transfer of embryos developed from dysmorphic oocytes.
Oocyte morphology strongly influences the viability and developmental competence of human preimplantation embryos in assisted reproductive treatments. Oocyte dysmorphisms can be divided into cytoplasmic anomalies, such as increased granularity, presence of vacuoles, refractile bodies, and extracytoplasmic anomalies, such as irregular shape or thickness of zona pellucida, enlarged perivitelline space or abnormal morphology of the first polar body (
Intracytoplasmic sperm injection: correlation of oocyte grade based on polar body, perivitelline space and cytoplasmic inclusions with fertilization rate and embryo quality.
One of the most common oocyte dysmorphisms is cytoplasmic vacuolization. Vacuoles are membrane-bound cytoplasmic inclusions filled with fluid that is virtually identical with perivitelline fluid. They vary in size as well as in number and can be observed in 5–12% of oocytes (
El Shafie, M., Suosa, M., Windt, M.L., Kruger, T.F. 2000. An atlas of the ultrastructure of human oocytes. A guide for assisted reproduction. New York, London, Parthenon Publishing, pp. 151–171.
Occurrence and developmental consequences of aberrant cellular organization in meiotically mature human oocytes after exogenous ovarian hyperstimulation.
). It has also been reported that serious oocyte dysmorphisms, such as clusters and vacuoles in the cytoplasm, can be a recurrent phenomenon in consecutive IVF treatments for the same patient (
Vacuolated oocytes: fertilization and embryonic arrest following intra-cytoplasmic sperm injection in a patient exhibiting persistent oocyte macro vacuolization – case report.
). In these cases, it is often difficult to counsel patients as to how to proceed.
This case report describes the successful treatment of an infertile couple where a recurrent serious vacuolization was observed over five consecutive IVF/intracytoplasmic sperm injection (ICSI) treatments.
Case report
A couple visited our clinic after 2 years of infertility. The female partner was 36 years old and had secondary infertility. A pregnancy from a previous partner was terminated artificially. The anatomy of the uterus was normal but the left tube was blocked. Baseline hormonal assessment showed normal values. The male partner, aged 46 years, presented with severe oligoasthenoteratozoospermia.
The couple underwent five consecutive IVF/ICSI cycles within 2.5 years. Standard long-protocol stimulation was performed using gonadotrophin-releasing hormone agonist triptorelin (Decapeptyl; Ferring, Kiel, Germany) for down-regulation followed by urinary gonadotrophins or recombinant FSH ovarian stimulation in all five cycles (Fostimon, IBSA, Lugano, Switzerland; Gonal-F, EMD Serono, Geneva, Switzerland; Menogon, Ferring; Menopur, IBSA). The type of gonadotrophin used for ovarian stimulation was always the same in one stimulation cycle. Oocyte collection, ICSI treatment, embryo culture and embryo transfer were performed using standard procedures.
During the five cycles, 42 oocytes (range 5–13, average 8.4/cycle) were collected. Maturity and morphology of the oocytes was assessed and recorded before sperm injection. Pictures of the oocytes were also recorded and measurements were taken using Octax Eyewere Imaging software (MTG, Bruckberg, Germany). Summarizing the characteristics of all oocytes collected in the five cycles, 76.2% of the oocytes (range 5–9, average 6.4/cycle) were mature (metaphase II) at the time of sperm injection, 9.5% were immature and 14.3% were degenerated. The rate of oocyte immaturity was similar but the rate of degenerated oocytes was much higher than normal rates observed at the study centre over the same period (14.3% versus 2%; P< 0.001). Most of the mature oocytes (81.3%) contained at least one large, centrally located, fluid-filled cytoplasmic vacuole (Figure 1A–C), 29.2–61.0 μm in diameter (52.2 μm average). Also, 75% of the oocytes had a fragmented or enlarged first polar body. The zona pellucida was also extraordinarily thin in most of the oocytes, the average thickness was 9.7 μm which is significantly different from the average zona thickness of normal oocytes (18.2 μm; P< 0.001) collected in the department.
Figure 1Fertilization and cleavage of oocytes showing one (A and B) or multiple (C) large vacuoles and extremely thin zona pellucida. Oocytes 1 and 2 had normal (2PN) fertilization (D and E) while oocyte 3 resulted in 1PN fertilization (F). Embryos with two (G and H) or four (I) blastomeres were transferred and resulted in singleton pregnancies. mv = multiple vacuoles; v = vacuole; 1PN = one pronucleus; 2PN = two pronuclei.
All 32 mature oocytes were injected. Seven zygotes showed normal fertilization (22%) and one zygote showed one pronuclear fertilization and 24 oocytes (75%) did not show any sign of fertilization. Most of the embryos had poor morphology before the embryo transfer, but there was at least one embryo available for transfer in each cycle (1, 1, 2, 1 and 3 embryos, respectively). The first four IVF cycles did not result in a pregnancy. In the fifth IVF cycle two oocytes were fertilized normally (Figure 1D and E) and one oocyte showed one pronuclear fertilization (Figure 1F). These zygotes reached the 2–4-cell stage on day 2 and all of them still contained large vacuoles (Figure 1G–I). These embryos were transferred according to the centre’s transfer policy and resulted in a singleton pregnancy with fetal heart activity. During prenatal care, the fetus was found to have a double left kidney and ureter but was otherwise healthy. No prenatal nor postnatal karyotyping was performed on the child according to the parents’ decision. A baby girl of weight 3200 g and height 55 cm was delivered by Cesarean section in week 39 of pregnancy. Her kidney disorder was treated by surgery at 1 year of age without requiring any other interventions or medications and up to now she is healthy.
Discussion
As far as is known this is the first case in the literature reporting a pregnancy and viable offspring following IVF treatments of a woman who had large vacuoles in most of the oocytes collected in consecutive ICSI cycles. The most remarkable phenomenon in these oocytes was the large, fluid-filled and centrally located vacuole. This serious dysmorphism was associated with irregularly thin zona pellucida and fragmented or enlarged first polar bodies in most of the oocytes. The first polar body can fragment or degenerate during post-ovulatory aging of oocytes (
Recurrent failure in polar body formation and premature chromosome condensation in oocytes from a human patient: indicators of asynchrony in nuclear and cytoplasmic maturation.
Oogenesis and oocyte maturation may be affected by ovarian stimulation. There are, however, very few and conflicting studies examining the effects of different gonadotrophin preparation on oocyte morphology and quality.
reported that cytoplasmic appearance of oocytes is influenced by the gonadotrophin preparation used for ovarian stimulation. However, other studies did not confirm this finding when analysing the effect of hormonal stimulation on the oocyte morphology (
Impact of highly purified versus recombinant follicle stimulating hormone on oocyte quality and embryo development in intracytoplasmic sperm injection cycles.
The multiple anomalies and the high number of degenerated oocytes indicates that these oocytes endured serious intrinsic adverse effects during oogenesis and maturation. The present report confirms previous findings (
Vacuolated oocytes: fertilization and embryonic arrest following intra-cytoplasmic sperm injection in a patient exhibiting persistent oocyte macro vacuolization – case report.
Vacuolated oocytes: fertilization and embryonic arrest following intra-cytoplasmic sperm injection in a patient exhibiting persistent oocyte macro vacuolization – case report.
) which was confirmed by the extremely low (22%) fertilization rate in the present case. Single or multiple large vacuoles may displace the meiotic spindle from its polar position or disturb the cytoskeleton resulting in fertilization failure (
Occurrence and developmental consequences of aberrant cellular organization in meiotically mature human oocytes after exogenous ovarian hyperstimulation.
In spite of this, some of the oocytes fertilized and underwent further cleavage cycles in the present case. However, vacuoles were observed in cells throughout development. The effect of serious oocyte anomalies on further embryo development and implantation is rather controversial in the literature. It has been reported that oocytes with granular cytoplasm or irregular thickness and shape of zona pellucida resulted in normal fertilization, implantation and a viable offspring (
published a case where oocytes with serious multiple abnormalities (granular and dark cytoplasm, dark and thick zona pellucida) were able to fertilize, cleave and develop to a viable offspring. Oocytes containing large smooth endoplasmic reticulum aggregations also resulted in clinical pregnancies, but chromosomal abnormality and multiple fetal anomalies were described in these cases (
). The present report clearly demonstrates that oocytes showing large, centrally located, fluid-filled vacuoles, abnormal first polar bodies and zona pellucida can be normally fertilized, resulting in viable offspring. Rigorous prenatal care and follow-up should be carried out following the transfer of embryos developed from dysmorphic oocytes.
References
Akarsu C.
Çağlar G.
Vicdan K.
Sözen E.
Biberoğlu K.
Smooth endoplasmic reticulum aggregations in all retrieved oocytes causing recurrent multiple anomalies: case report.
Recurrent failure in polar body formation and premature chromosome condensation in oocytes from a human patient: indicators of asynchrony in nuclear and cytoplasmic maturation.
El Shafie, M., Suosa, M., Windt, M.L., Kruger, T.F. 2000. An atlas of the ultrastructure of human oocytes. A guide for assisted reproduction. New York, London, Parthenon Publishing, pp. 151–171.
Impact of highly purified versus recombinant follicle stimulating hormone on oocyte quality and embryo development in intracytoplasmic sperm injection cycles.
Occurrence and developmental consequences of aberrant cellular organization in meiotically mature human oocytes after exogenous ovarian hyperstimulation.
Vacuolated oocytes: fertilization and embryonic arrest following intra-cytoplasmic sperm injection in a patient exhibiting persistent oocyte macro vacuolization – case report.
Intracytoplasmic sperm injection: correlation of oocyte grade based on polar body, perivitelline space and cytoplasmic inclusions with fertilization rate and embryo quality.
Declaration: The author reports no financial or commercial conflicts of interest.
Footnotes
Peter Fancsovits obtained his MSc in reproductive biology from Gödöllő University of Agricultural Sciences in 1993. Since 1998 he has been the head of the Embryology Laboratory at the Division of Assisted Reproduction, Semmelweis University School of Medicine. He obtained his PhD in 2006 and his certification as senior clinical embryologist in 2008. His special interests are oocyte and embryo morphology and the effect of morphological parameters on IVF outcome. In 2008, he became a member of Executive Committee of ALPHA and was elected to the Committee of National Representatives of European Society of Human Reproduction and Embryology.
Peter Fancsovits obtained his MSc in reproductive biology from Gödöllő University of Agricultural Sciences in 1993. Since 1998 he has been the head of the Embryology Laboratory at the Division of Assisted Reproduction, Semmelweis University School of Medicine. He obtained his PhD in 2006 and his certification as senior clinical embryologist in 2008. His special interests are oocyte and embryo morphology and the effect of morphological parameters on IVF outcome. In 2008, he became a member of Executive Committee of ALPHA and was elected to the Committee of National Representatives of European Society of Human Reproduction and Embryology.
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