Infertility Clinic, The Family Federation of Finland, Kalevankatu 16, FIN-00100 Helsinki Finland
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: endometrium/miscarriage/oocyte donation/pregnancy/Turner's syndrome
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Oocyte donation is now an option in the treatment of childlessness in Turner's syndrome. Subjects with Turner's syndrome have been included in oocyte donation programmes since the early days of this treatment (Abdalla et al., 1990; Sauer and Paulson, 1990
; Press et al., 1995
; Khastgir et al., 1997
). Pregnancy rates of Turner's syndrome subjects have been similar to those among other women in oocyte donation programmes (Press et al., 1995
; Khastgir et al., 1997
) or lower (Yaron et al., 1996
), but relatively small numbers of these cases have been described. Impaired receptivity of endometrium in these patients has been suspected (Rogers et al., 1992
; Yaron et al., 1996
).
We have treated 18 women with Turner's syndrome in our oocyte donation programme, and report here the pregnancy results.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
One of the subjects had had coarctation of the aorta, which had been operated upon in childhood. She also had epilepsy, which was well controlled with sodium valproate medication. One had had aplasia of the vagina, which had been treated operatively. Thyroid antibodies had been detected in two women. Two had unexplained hepatopathies with slightly to moderately elevated enzyme concentrations. Two had hypertension, which was treated by metoprolol tartrate medication in one case, and followed-up in the other. No women were excluded from the programme because of illnesses.
One subject had had spontaneous menarche with one spontaneous period. Her karyotype was 46X, i(Xq).
The oocytes were obtained from healthy voluntary donors, recruited through the media. They were younger than 35 years of age, and they did not receive any financial reward. For ovarian stimulation, they were down-regulated using a long-acting gonadotrophin-releasing hormone (GnRH) agonist, goserelin (Zoladex; Zeneca Pharma, Helsinki, Finland), giving a single injection (3.6 mg) at the mid-luteal phase of the previous cycle. Human menopausal gonadotrophin (Pergonal; Serono, Aubonne, Switzerland) or follicle stimulating hormone (Fertinorm-HP; Serono) was used for stimulation. Human chorionic gonadotrophin (HCG) (Profasi; Serono), 5000 IU, was given when the largest one to three follicles were at least 18 mm in diameter. Transvaginal ultrasound-guided follicle aspiration was carried out 3436 h later.
The collected oocytes were pre-incubated in 5% CO2 in air at 37°C for 24 h before insemination with spermatozoa (100450x103) from the recipient's partner. Percoll density gradient centrifugation was used for preparation of semen.
The women with Turner's syndrome usually continued their pre-existing hormonal replacement therapy (HRT) until they were known to be due to receive donated oocytes within a few months. The replacement therapy was then changed to oral oestradiol valerate (Progynova; Schering, Turku, Finland) and micronized vaginally administered progesterone (Lugesteron; Leiras, Turku, Finland), 600 mg, daily. Oestradiol was used as a fixed dose, 4 mg at first, but it was increased to 6 or 8 mg if the endometrium was thinner than 67 mm in an ultrasound scan carried out during a test cycle before the first treatment cycle. The echo pattern of the endometrium was also recorded. The actual embryo transfer cycles were also monitored by an ultrasound scan before transfer.
The HRT was timed so that the subjects started receiving oestradiol 45 days before the donor's ovarian stimulation commenced. Progesterone was started 1 day before or on the day of the donor's oocyte retrieval. One or two embryos were usually transferred to the recipient's uterine cavity on the second day after oocyte retrieval. Excess embryos were frozen using propanediol as a cryoprotectant. Frozen embryos were similarly transferred during later HRT cycles.
The serum HCG concentration was measured 1417 days after embryo transfer. If it reflected a positive result, similar HRT was continued for up to 12 weeks. The pregnancies were carefully followed-up in collaboration with the antenatal units of the obstetric hospitals concerned.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Treatment with fresh embryos
Thirteen clinical and one biochemical pregnancies were achieved among 17 recipients in 28 transfers of a mean of 1.8 fresh embryos (Table I). The clinical pregnancy rate per embryo transfer was 46%, and the implantation rate 30%. There was one twin pregnancy which ended in intrauterine death of one twin and termination of the pregnancy because the second twin had encephalocele. Six other pregnancies ended in spontaneous abortion, the miscarriage rate being 54%.
|
|
Twelve healthy infants were born in 11 deliveries. One pregnancy is still ongoing.
All 11 deliveries were by Caesarean section. The indications were small pelvis and lack of spontaneous contractions, partial placenta praevia in one, and intrauterine growth retardation of the fetus of one pre-eclamptic mother.
The mean (range) birth weight of the singletons was 2852 (15003370) g. One infant was small for gestational age: 1500 g at 36 weeks. The mother had pre-eclampsia. The mean gestational age was 38 (range 3639) weeks. The birth weights of the twins were 2130 and 2810 g. They were born at 36 weeks of gestation, and the mother had severe bleeding (5000 ml) as a result of placenta accreta during delivery. Supravaginal amputation of the uterus was needed to stop the bleeding. She has recovered well.
There was a total of eight miscarriages (40% of all clinical pregnancies).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The pregnancy and implantation rates in our survey were also higher than those in Turner's syndrome subjects treated by Khastgir et al. (1997). In that survey, the HRT was different. Oestradiol was given stepwise in many patients, and the dose of progesterone was only half of that used in our survey. In oocyte donation programmes, in which occasional Turner's syndrome subjects have been treated, the dosage of oestradiol has been stepwise (Davies et al., 1990; Sauer et al., 1991
; Pados et al., 1992
), and completetely different progesterone preparations have been used. Also IVF patients as donors (Davies et al., 1990
; Pados et al., 1992
; Michalas et al., 1996
) may have contributed to the lower pregnancy and implantation rates.
Pregnancies among Turner's syndrome women are not without risk. Cardiovascular abnormalities are common in women with Turner's syndrome (Lippe, 1991). Coarctation of the aorta is seen in about 10%, and a bicuspid aortic valve is found in about one-third of the women without coarctation (Lippe, 1991
). Arterial hypertension is frequently seen. Aortic dissection is potentially the most serious complication among subjects with Turner's syndrome. Two fatal cases of aortic dissection have been reported in Turner's syndrome patients during pregnancies which resulted from oocyte donation (Nagel and Tesch, 1997
). This underlines the importance of careful assessment of these women before treatment, as suggested also by Birdsall and Kennedy (1996). Cardiological investigation with ultrasonography scan or magnetic resonance imaging is necessary before treatment and during the first trimester of pregnancy.
Among our subjects, two had pre-existing hypertension, two had transient hypertension during pregnancy, and two others developed pre-eclampsia. One of them had a growth retarded infant, who was otherwise healthy. The incidence of hypertension among these women was similar to that which we have observed in our oocyte recipients in general (Söderström-Anttila et al., 1998). In Turner's syndrome, there is also a high risk of disturbance of carbohydrate metabolism (Lippe, 1991; Holl et al., 1994
), but there was no case of impaired glucose tolerance among our subjects.
One severe bleeding complication occurred after twin delivery in one of our subjects. We are now transferring only one embryo at a time to women with Turner's syndrome. We can at least avoid the additional risks resulting from twin pregnancy. Because the implantation rate is high in these women, transfer of one embryo is acceptable, and can be highly recommended.
Because of their short stature, all women with Turner's syndrome have a small pelvis, which predisposes them to fetopelvic disproportion. This was the main reason why all our subjects delivered by Caesarean section. In some more favourable cases spontaneous labour and delivery may be possible.
Spontaneous pregnancies among women with Turner's syndrome are associated with a high risk of miscarriage and an increased risk of trisomy 21 in the offspring (King et al., 1978; Nielsen et al., 1979
; Swapp et al., 1989
). Turner's syndrome can be transmitted from mothers to daughters (Varela et al., 1991
; Verschragen-Spae et al., 1992; Blumenthal and Allanson, 1997
; Tarani et al., 1998
). Although the main causes of miscarriage in Turner's syndrome have been thought to be of genetic origin, there may also be other causes. The miscarriage rate among our subjects was 40%. Three of six pregnancies of Turner's syndrome subjects ended in abortion in a survey reported by Press et al. (1995), and two of five in a study reported by Yaron et al. (1996). In the survey reported by Khastgir et al. (1997), the miscarriage rate was as high as 50%. Low blood flow in a hypoplastic uterus might be one explanation.
The mechanism behind early oocyte loss in Turner's syndrome (Singh and Carr, 1966; Weiss, 1971
) is not known. It would be interesting to know if there is a factor in the second X chromosome which prevents follicular atresia. Because some girls with Turner's syndrome still have follicles in their ovaries during postnatal life, one treatment option in the future might be cryopreservation of ovarian tissue at a young age (Hovatta et al., 1996
; Newton et al., 1996
), and later replantation or maturation of ovarian follicles in vitro.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Baudier, M.M., Chihal, H.J. and Dickey, R.P. (1985) Pregnancy and reproductive function in a patient with a non-mosaic Turner syndrome. Obstet. Gynecol., 65, 6064.[Abstract]
Birdsall, M. and Kennedy, S. (1996) The risk of aortic dissection in women with Turner syndrome. Hum. Reprod., 11, 1587.
Blumenthal, A.L. and Allanson, J.E. (1997) Turner syndrome in a mother and daughter: r(X) and fertility. Clin. Genet., 52, 187191.[ISI][Medline]
Davies, M.C., Anderson, M.C., Mason, Jacobs, H.S. (1990) Oocyte donation: the role of endometrial receptivity. Hum. Reprod., 5, 862869.[Abstract]
Holl, R.W., Kunze, D., Etzrodt, H. et al. (1994) Turner syndrome: final height, glucose tolerance, bone density and psychological status in 25 adult patients. Eur. J. Pediatr., 153, 1116.[ISI][Medline]
Hovatta, O., Silye, R., Krausz, T. et al. (1996) Cryopreservation of human ovarian tissue using dimethylsulphoxide and propanediol-sucrose as cryoprotectants. Hum. Reprod., 11, 12681272.[Abstract]
King, C.R., Magenis, E. and Bennett, S. (1978) Pregnancy in Turner syndrome. Obstet. Gynecol., 52, 617624.[Abstract]
Khastgir, G., Abdalla, H., Thomas, A. et al. (1997) Oocyte donation in Turner's syndrome: an analysis of the factors affecting the outcome. Hum. Reprod., 12, 279285.[Abstract]
Kohler, C., Steinbach, C. and Müller, R. (1985) Fertilität und Turner-Syndrom. Zentralbl.-Gynakol., 107, 904907.
Lindsten, J. (1963) The Nature and Origin of X Chromosome Aberrations in Turner's Syndrome: a Cytogenetical and Clinical Study of 57 Patients. Thesis from Uppsala University, published by Almquist and Wiksell, Uppsala, Sweden.
Lippe, B. (1991) Turner syndrome. Endocrin. Metab. Clin. N. Am., 20, 121152.[ISI][Medline]
Magee, A.C., Nevin, N.C., Armstrong, M.J. et al. (1998) UllrichTurner syndrome: seven pregnancies in an apparent 45,X woman. Am. J. Med. Genet., 32, 13.
Michalas, S., Loutradis, D., Drakakis, P. et al. (1996) A flexible protocol for the induction of recipient endometrial cycles in an oocyte donation programme. Hum. Reprod., 11, 10631066.[Abstract]
Meyer, L., Birkhauser, M., Bühler, E. and Bavic, N. (1989) Fertilität und Turner-Mosaik-Syndrom. Geburtshilfe.-Frauenheilkd., 49, 825829.
Nagel, T.C. and Tesch, L.G. (1997) ART and high risk pregnancies. Fertil. Steril., 68, 748749.[ISI][Medline]
Newton, H. Aubard, Y,. Rutherford, A. et al. (1996) Low temperature storage and grafting of human ovarian tissue. Hum. Reprod., 11, 14871491.
Nielsen, J., Sillesen, I. and Hansen, K.B. (1979) Fertility in Turner's syndrome. Case report and review of literature. Br. J. Obstet. Gynaecol., 86, 833829.[ISI][Medline]
Pados, G., Camus, M., Van Waesbergeh, L. et al. (1992) Oocyte and embryo donation: evaluation of 412 consecutive trials. Hum. Reprod., 7, 11111117.[Abstract]
Philip, J. and Sele, V. (1976) 45, XO Turner's syndrome without evidence of mosaicism in a patient with two pregnancies. Acta Obstet. Gynecol. Scand., 55, 283286.[ISI][Medline]
Press, F., Shapiro, H.M., Cowell, C.A. and Oliver, G.D. (1995) Outcome of ovum donation in Turner's syndrome patients. Fertil. Steril., 64, 995998.[ISI][Medline]
Rogers, P.A.W., Murphy, C.R., Leeton, J. et al. (1992) Turner's syndrome patients lack tight junctions between uterine epithelial cells. Hum. Reprod., 7, 883885.[Abstract]
Sauer, M.V. and Paulson, R.J. (1990) Human oocyte and preembryo donation: an evolving method for the treatment of infertility. Am. J. Obstet. Gynecol., 163, 14211424.[ISI][Medline]
Sauer, M.V., Paulson, R.J., Macaso, T.M. et al. (1991) Oocyte and pre-embryo donation to women with ovarian failure: an extended clinical trial. Fertil. Steril., 55, 3943.[ISI][Medline]
Singh, R.P. and Carr, D.H. (1966) The anatomy and histology of XO human embryos and fetuses. Anat. Rec., 155, 369375.[ISI][Medline]
Singh, G.H., Hara, S., Foster, H.W. and Grimes, E.M. (1980) Reproductive performance in women with sex chromosome mosaicism. Obstet. Gynecol., 55, 608611.[Abstract]
Söderström-Anttila, V. (1998a) Oocyte Donation in the Treatment of Infertility. Tummavuoren kirjapaino Oy, Vantaa, Finland.
Söderström-Anttila, V., Tiitinen, A., Foudila, T. and Hovatta, O. (1998b) Obstetric and perinatal outcome after oocyte donation: comparison with in-vitro fertilization pregnancies. Hum. Reprod., 13, 483490.[ISI][Medline]
Swapp, G.H., Johnston, A.W., Watt, J.L. et al. (1989) A fertile woman with non-mosaic Turner's syndrome. Case report and review of literature. Br. J. Obstet. Gynaecol., 96, 876880.[ISI][Medline]
Tarani, L., Lampariello, G., Raguso, F. et al. (1998) Pregnancy in patients with Turner's syndrome: six new cases and review of literature. Gynecol. Endocrinol., 12, 8387.[ISI][Medline]
Varela, M., Shapira, E. and Hyman D.B. (1991) Ullrich-Turner syndrome in mother and daughter: Prenatal diagnosis of a 46,X,del(X) (p21) offspring from a 45,X mother with low-level mosaicism for the del(X) (p21) in one ovary. Am. J. Med. Genet., 39, 411412.[ISI][Medline]
Verschraegen-Spae, M.-R., Depypere, H., Speleman, H. et al. (1992) Familial Turner syndrome. Clin. Genet., 41, 218220.[ISI][Medline]
Weiss, L. (1971) Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J. Med. Genet., 8, 540544.[ISI][Medline]
Wray, H.L., Freeman, M.V.R. and Ming, P.-M.L. (1981) Pregnancy in the Turner syndrome with only 45,X chromosomal constitution. Fertil. Steril., 35, 509514.[ISI][Medline]
Yaron, Y., Ochshorn, Y., Amit, A. et al. (1996) Patients with Turner's syndrome may have an inherent endometrial abnormality affecting receptivity in oocyte donation. Fertil. Steril., 65, 12491252.[ISI][Medline]
Submitted on June 22, 1998; accepted on October 28, 1998.