Human Reproduction, Vol. 16, No. 1, 107-109,
January 2001
© 2001 European Society of Human Reproduction and Embryology
Achieving pregnancy against the odds: successful implantation of frozen–thawed embryos generated by ICSI using spermatozoa banked prior to chemo/radiotherapy for Hodgkin's disease and acute leukaemia: Case Report
1 Department of Reproductive Medicine, St Mary's Hospital, Manchester M13 0JH, 2 Directorate of Laboratory Medicine, Central Healthcare Trust, Manchester, 3 Department of Medical Oncology, Christie Hospital and Holt Radium Unit, Manchester, and 4 Department of Haematology, Manchester Royal Infirmary, Manchester, UK
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Abstract |
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Two cases are reported of successful pregnancies following long-term semen banking prior to chemotherapy and radiotherapy for malignancy. With the first case, the patient banked semen at the age of 20 years prior to chemotherapy for Hodgkin's disease; 11 years later the thawed semen was used for IVF with intracytoplasmic sperm injection (ICSI), resulting in twins being born following the transfer of frozen–thawed embryos. In the second case, the patient banked semen at the age of 17 years prior to chemotherapy and radiotherapy for acute myeloid leukaemia; 8 years later it was used for ICSI, resulting in triplets being born following the transfer of frozen–thawed embryos. These cases support long-term semen banking for men whose future fertility may be compromised by suppression of spermatogenesis secondary to administration of chemo/radiotherapy treatment. The advent of successful ICSI combined with embryo cryopreservation has increased the chance of thawed cryopreserved semen achieving fertilization. Banking of a single ejaculate prior to commencement of chemotherapy/radiotherapy treatment may preserve potential fertility without compromising the oncology treatment.
Key words: acute myeloid leukaemia/cryopreserved embryos/cryopreserved semen/Hodgkin's disease/ICSI
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Introduction |
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Hodgkin's disease and acute leukaemia are common malignancies occurring during a patient's reproductive lifetime (Agarwal and Newton, 1991
; Meirow and Schenker, 1995), affecting men twice as commonly as women (Glick, 1992; Meirow and Schenker, 1995). Post-treatment prognoses of these conditions have improved considerably over the last few years (Glick, 1992; Meirow and Schenker, 1995), a fact that has focused attention on the associated treatment-induced sterility (Tournaye et al., 1991; Bokemeyer et al., 1994; Meirow and Schenker, 1995). In men, semen cryopreservation before the start of treatment allows even small numbers of spermatozoa to be available for the subsequent application of assisted reproductive techniques. These have included vaginal or intrauterine insemination (IUI) (Scammell et al., 1985; Redmond et al., 1987; K.Fletcher, G.Horne, A.Atkinson, D.R.Brison, and B.A.Lieberman, unpublished data), gamete intra-Fallopian transfer (GIFT) (Al-Shawaf et al., 1991), IVF and embryo transfer (Tournaye et al., 1991) and intracytoplasmic sperm injection (ICSI) (Chen et al., 1996; Hallak et al., 1998). These techniques extend the role of sperm banking and provide affected couples with a potential reproductive future even in circumstances where the disease process itself has depressed spermatogenesis before the start of treatment (Sanger et al., 1980; Thachil et al., 1981; Whitehead et al., 1982; Hendry et al., 1983). |
Case 1 |
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A 20-year-old single male presented in 1987 with clinical stage IIIB Hodgkin's disease (in the lymph nodes of the left neck region) and was referred to this unit for semen banking prior to commencing chemotherapy, and radiotherapy. He banked four semen samples (over 7 days), with sperm concentrations ranging from 18–87x106/ml, progressive motility of 30–50%, and normal morphology of 20–40%. The semen was frozen in 13 ampoules, with a pre-freeze normal motile sperm concentration range of 4.3–16.3x106/ml (Read and Schnieden, 1975
). Following semen cryopreservation he received six cycles of MVPP (mustine, vinblastine, prednisolone, procarbazine) chemotherapy followed by radiation treatment to the neck and chest. He remained in remission until 1992 when he suffered a relapse, and was treated with six cycles of Ch1VPP/EVA (chlorambucil, vinblastine, prednisolone, procarbazine, etoposide, vincristine, doxorubicin) hybrid chemotherapy. A semen analysis was repeated in 1994 and showed complete azoospermia following high-speed centrifugation. In 1996, the couple had four cycles of IUI (using six ampoules of semen) (Horne, 1998). The total post-preparation sperm count was <0.1x106/motile spermatozoa per insemination, with <5% progressively motile spermatozoa. This treatment was unsuccessful, necessitating further treatment by ICSI, commencing in 1998.
Pituitary desensitization was achieved using buserelin acetate 0.5 mg i.m. daily, and ovarian stimulation commenced with 300 IU i.m. per day of FSH (Fostimon; Denfleet International Ltd, London, UK). With a serum oestradiol concentration of 4417 pg/ml and three follicles with a diameter of 
20 mm, 10 000 IU of human chorionic gonadotrophin (HCG, Pregnyl; Organon, Laboratories Ltd, Cambridge, UK) was administered and oocytes recovered 35 h later. Five oocytes were retrieved and four metaphase-II stage oocytes subjected to ICSI (Van Steirteghem et al., 1993). Two ampoules of semen were thawed and prepared using standard laboratory procedures (Horne et al., 1997) and three oocytes fertilized normally. All three embryos were cryopreserved at the pronuclear stage (Horne et al; 1997), based upon the high serum oestradiol concentration, to diminish the risk of developing ovarian hyperstimulation syndrome (OHSS) (Wada et al., 1992). Embryos were replaced in a natural cycle; the LH surge was detected on cycle day 12 and two thawed embryos replaced on day 15. One of the three embryos thawed was degenerate and discarded.
Pregnancy was confirmed using a qualitative serum pregnancy test and an ultrasound scan at 7 weeks confirmed two gestational sacs and fetal poles containing two fetal hearts. Following an uneventful pregnancy, twin girls (weighing 3000 and 2400 g) were born following a Caesarean section at 38 weeks gestation.
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Case 2 |
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A 17-year-old single male was referred to this unit in 1991 prior to commencing chemotherapy and radiotherapy for acute myeloid leukaemia. He banked one semen sample, with a sperm count of 110x106/ml, progressive motility of 90%, and normal morphology of 70%. The semen was frozen in three ampoules (Read and Schnieden, 1975
), each with a pre-freeze motile sperm concentration of 89.5x106/ml. His oncological treatment consisted of induction chemotherapy with DAT (Daunorubicin, Ara-C and Thioguanine), followed by two further consolidation courses. He subsequently received an allogenic bone marrow transplant from a histocompatible sibling; pre-bone marrow transplant conditioning comprised high dose cyclophosphamide and total body irradiation, 1000 cGy in two fractions. Following a successful bone marrow transplant, he remained in complete remission of his leukaemia. In 1994, the patient and his partner attended the unit for fertility treatment. A repeat semen analysis revealed complete azoospermia following high-speed centrifugation. The couple underwent two unsuccessful attempts at ICSI in the private sector and were then offered a cycle in the National Health Service sector with the single semen ampoule remaining.
Pituitary desensitization was achieved using buserelin acetate 0.5 mg daily, and ovarian stimulation commenced with 150 IU per day of FSH. With a serum oestradiol concentration of 4237 pg/ml and three follicles with a diameter of 20 mm, 10000 IU of HCG (Pregnyl) was administered and oocyte recovery performed 35 h later. A total of 12 oocytes were retrieved and 10 metaphase II oocytes were subjected to ICSI. Five oocytes fertilized and were cryopreserved at the pronuclear stage, in order to reduce the risk of OHSS. One attempt at natural cycle frozen embryo replacement was abandoned when the two thawed embryos failed to divide (Horne et al, 1997). In a second cycle, the remaining three embryos were thawed, one failed to divide and was discarded and two 4-cell embryos were replaced on day 15 of the cycle (3 days after the LH surge). Pregnancy was confirmed using a qualitative serum pregnancy test and an ultrasound scan at 7 weeks confirmed the presence of three gestational sacs and fetal poles containing fetal hearts, with the appearance of a trichorionic triamniotic pregnancy. Following an uneventful pregnancy, a Caesarean section was performed at 35 weeks, resulting in the birth of one female (2300 g) and two male (both weighing 2100 g) babies.
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Discussion |
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TopAbstractIntroductionCase 1Case 2DiscussionReferences |
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Chemotherapy and/or radiotherapy disrupt spermatogenesis and cause deleterious effects on sperm quality, which can result in infertility (Ash, 1980
; Schilsky et al., 1980; Howard, 1991). There is variability in the effect on individual patients' fertility potential (Ash, 1980). The reduction, as well as recovery, of potential fertility, is related to the toxicity of the agents used and the dose, duration and intensity of exposure (Schilsky et al., 1980; Kinsella, 1989; Howard, 1991; Bokemeyer et al., 1994; Kulkarni et al., 1997). This has led to the suggestion that semen should be cryopreserved for later use under such circumstances (Khalifa et al., 1992; Koeppel, 1995; Naysmith et al., 1998).
Spermatozoa cryopreserved during the course of chemotherapy and/or radiotherapy and subsequently used for assisted conception have been reported as safe (Carson et al., 1991). However, fears of potential genetic risks to offspring from using such semen have prompted calls for semen cryopreservation to be carried out before the start of chemotherapy and/or radiotherapy (Meistrich, 1993; Rousseaux et al., 1993; Robbins et al., 1997) and this is now routine practice. Malignancies, as well as general body stresses, appear to adversely affect fertility potential even before treatment commences (Sanger et al., 1980; Thachil et al., 1981; Whitehead et al., 1982; Hendry et al., 1983; Agarwal and Newton, 1991). However, the results of these two cases suggest the quality of the stored spermatozoa was good: percentage fertilization rate 57% (8/14) and a very high embryo viability with 100% implantation rate.
Sperm cryopreservation and storage is the most effective and reliable way of circumventing treatment-induced infertility in men. Long-term sperm banking began in this unit in 1977 and, up to 1998, 1464 men have banked semen for future use. A total of 19 clinical pregnancies, resulting in 22 live births, have so far been achieved using artificial inseminations with the husbands spermatozoa (AIH), IUI and IVF with or without ICSI (K.Fletcher, G.Horne, A.Atkinson, D.R.Brison, and B.A.Lieberman, unpublished data). A previous paper has also reported a successful live birth following frozen–thawed embryos achieved by ICSI of cryopreserved testicular sperm cells extracted post-operatively after an orchidectomy for seminoma (Yavetz et al, 1997). The two cases reported here illustrate the successful use of two cryopreservation strategies—a programme of long-term sperm banking with subsequent assisted conception combined with embryo cryopreservation to diminish the risk of developing OHSS. With increased implantation rates of embryos following ICSI (zona-manipulated embryos in general), it is suggested that two instead of three embryos should be replaced electively to reduce the risk of multiple gestations (Staessen et al., 1995; Tasdemir et al., 1995; Slotnick and Ortega, 1996; Lieberman, 1998; Tarlatzis and Bili, 1998). As shown in these cases, it is difficult to completely avoid multiple pregnancies, despite adherence to this policy.
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Notes |
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5 To whom correspondence should be addressed. E-mail: Greg{at}smh1.cmht.nwest.nhs.uk
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Submitted on May 11, 2000; accepted on September 29, 2000.
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