Human Reproduction, Vol. 17, No. 1, 124-127,
January 2002
© 2002 European Society of Human Reproduction and Embryology
Pregnancies after oocyte donation in women with ovarian failure caused by an inactivating mutation in the follicle stimulating hormone receptor
1 The Infertility Clinic of the Family Federation of Finland in Helsinki and 2 Oulu, 3 Department of Gynaecology and Obstetrics and 4 Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland and 5 Department of Obstetrics and Gynaecology, Karolinska Institutet, Huddinge University Hospital, Sweden
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Abstract |
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BACKGROUND: An inactivating point mutation (Ala189Val) in the FSH receptor (FSHR) causes primary ovarian failure. It has not been known if FSH action is necessary during pregnancy and childbirth. METHODS: In 1991–2001, donated oocytes were used to treat the infertility of 12 women with ovarian failure due to this mutation. RESULTS: When 30 fresh and 15 frozen-thawed embryo transfers were performed, 14 clinical and two biochemical pregnancies resulted. To date, 12 children have been born to eight women, while one pregnancy ended in miscarriage. Three women had twin pregnancies, and one woman has delivered twice. Additionally, there are three ongoing pregnancies, of which two are second pregnancies of women who previously had a normal delivery after similar treatment. In all, 10 out of the 12 women became pregnant. Two deliveries were by Caesarean section. The rate of complications was comparable with that in pregnancies resulting from oocyte donation in general. CONCLUSIONS: Achieving and undergoing a successful pregnancy is possible when FSH action is severely decreased. Oocyte donation is an effective infertility treatment for women with FSHR mutations.
Key words: FSH receptor/mutation/oocyte donation/ovary/pregnancy
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Introduction |
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A point mutation (C566T predicting an Ala189Val substitution) in the FSH receptor (FSHR) has been identified in Finnish women with hypergonadotrophic primary amenorrhoea (Aittomäki et al., 1995
). These women have low serum estradiol concentrations, high serum concentrations of FSH and LH, and deficient pubertal development. Unlike most patients with hypergonadotrophic ovarian failure, however, their ovaries contain primordial and primary follicles (Aittomäki et al., 1996). Although this recessively inherited condition seems to be rare in other countries, as only four other inactivating mutations have been identified in women with ovarian failure worldwide (Beau et al., 1998; Touraine et al.,1999), in some areas of Finland the carrier frequency of the mutation is as high as 1 in 85 (Jiang et al., 1998). As some of the women with FSHR mutations were relatively young, and there was an ongoing oocyte donation programme, this treatment was offered to the women in the two units of the Infertility Clinic of the Family Federation of Finland, in Helsinki and Oulu. In addition, our units also have ample experience of using this treatment in individuals with ovarian failure from other causes (Söderström-Anttila et al., 2001).
Oocyte recipients often differ from traditional IVF patients as regards the cause of infertility and endocrine background. Recipients with ovarian failure appear to have a higher incidence of complications, such as first trimester bleeding, intrauterine growth retardation and pre-eclampsia than women with functioning ovaries (Abdalla et al., 1990;Söderström-Anttila, 2001). Although previous studies have shown that oocyte donation treatment is successful in individuals with primary amenorrhoea, it was not known if the lack of FSH action would interfere with the outcome of pregnancy, and therefore it was important to analyse the obstetrical and perinatal outcome of these pregnancies.
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Materials and methods |
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Fourteen women who were homozygous for the Ala189Val point mutation and had been identified on the basis of hypergonadotrophic primary amenorrhoea and/or having a recognized case with the mutation among close relatives, were counselled regarding the possibility and risks of a pregnancy using donated oocytes. Two of the women had been treated between 1991–1994 before the specific cause of their ovarian failure had been identified. One of the women, aged 42 years, did not desire the treatment. Another woman had disseminated lupus and Sjögren's syndrome, and she also abstained from the treatment.
A total of 12 women, mean age 33 years (SD 4.9, range 26–47) at the beginning of the treatment, underwent 1–5 embryo transfers with fresh embryos and 1–3 transfers with frozen–thawed embryos.
The oocyte donors were healthy unpaid volunteers, <35 years of age, who were recruited through the media. The donors underwent down-regulation using intra-nasal buserelin (Suprecur; Hoechst, Frankfurt, Germany), 1200 µg daily, and menopausal gonadotrophin (Pergonal or Fertinorm HP; Serono Nordic, Finland) or FSH (Gonal F; Serono) was given for ovarian stimulation at 150–300 IU/day until the leading follicles were 18 mm in diameter. The oocytes were retrieved using trans-vaginal ultrasound-guided puncture. They were inseminated with the recipient's spouse's sperm or injected with spouse's spermatozoa (ICSI, 1 treatment) depending on sperm quality.
The women with the FSHR mutation were treated with hormone replacement therapy (HRT) using 2–4 mg estradiol valerate (Progynova; Leiras, Turku, Finland) and 20 mg medroxyprogesterone acetate (Gestapuran; Lövens, Ballerup, Denmark) daily to induce menstrual cycles and to prime receptive endometrium before the actual transfer cycle. If the endometrium was <7 mm thick during a test cycle, the dose of estradiol was increased to 6 mg daily. During the planned transfer cycle, bleeding was induced to occur at the same time as the potential donor started her stimulation. Estradiol at 4–6 mg daily was used, and the thickness of the endometrium was monitored after 10–12 days. On the day of oocyte retrieval from the donor, the recipient started intra-vaginal micronized progesterone (Lugesteron; Leiras, Tampere, Finland), 600 mg daily.
Embryo transfer was carried out 2 days after fertilization. The HRT using estradiol and progesterone was continued until a pregnancy test was carried out 2 weeks after the transfer. If the result was positive, HRT was continued until week 12 of pregnancy.
Usually only two embryos, and more recently only one embryo, were transferred at a time. At the beginning of the programme, some women received three fresh embryos, and one received three frozen–thawed embryos. All additional embryos were frozen using propanediol-sucrose as a cryoprotectant for possible treatment during later cycles. If the woman did not have an optimal endometrium, or there were problems in timing, all the embryos were frozen, and frozen–thawed embryos were transferred later. In cycles for frozen–thawed embryo transfer, similar estradiol valerate substitution was given, and vaginal micronized progesterone was started 2 days prior to embryo transfer. The embryos were thawed on the day of transfer.
Surveillance of the pregnancies was initiated with a first ultrasound scan at 5 weeks after embryo transfer. Follow-up was then continued in collaboration with the maternity unit of the teaching hospital to which each woman belonged. Data regarding the pregnancies and deliveries were collected by the units. To follow up the health of the children, all families have voluntarily been in contact with the infertility units of the Family Federation of Finland.
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Results |
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A total of 30 fresh and 15 frozen–thawed embryo transfers were carried out (Table I
). The mean number of oocytes (± SD) received from the donors was 7.7 ± 3.5 (range 3–16), and the mean number of embryos obtained per retrieval was 4.7 ± 2.8 (range 0–12). One to three embryos were transferred at a time. In one cycle, no embryos were obtained due to impaired sperm quality, and this couple was treated by ICSI during the following cycle, with six resulting embryos. The oldest woman received only two cryopreserved embryos in one treatment cycle. Twelve pregnancies resulted from the 30 fresh embryo transfers (40%) and two from the 15 frozen–thawed embryo transfers (13%) (Table I). In addition, two biochemical pregnancies were achieved after fresh embryo transfer.
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The outcome of the pregnancies is presented in Table II
. There were nine deliveries, one miscarriage, and there are three normal ongoing pregnancies. One of the women delivered twice, and two women with ongoing pregnancies are pregnant for the second time after a normal delivery. There were three twin pregnancies. Seven of the pregnancies ended in full-term spontaneous delivery. One of these women had mild pre-eclampsia in her second pregnancy. The mean birth weight of the six singletons was 3539 g. During pregnancy, one of the children was diagnosed as having an atrio-ventricular block, which was treated with a pacemaker immediately after delivery by Caesarean section. His birth weight was 3300 g, and he is otherwise healthy. One of the women with twins had gestational diabetes. She underwent Caesarean section after 37 weeks of pregnancy, and the birth weights of the infants were 2740 and 2490 g. During one twin pregnancy, premature rupture of the membranes occurred after 30 weeks of pregnancy, at which stage the infants were born vaginally, weighing 1740 and 1395g. One of them had pulmonary emphysema, and a lobectomy was carried out at the age of two weeks. The mother had pulmonary embolism, which was treated with heparin, and she made a full recovery. One set of twins was born vaginally at term; the birth weights of these healthy infants were 2940 and 2770 g.
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Nine of the 12 treated women now have children, four of them have two, and three are still pregnant (one for the first time and two for the second time), which means that 10 of the 12 women became pregnant. Two of the women have finished their treatment without becoming pregnant. One of them was 47 years old. She was offered treatment because her younger sister was being treated, and she underwent only one unsuccessful treatment using frozen–thawed embryos. After that she finished her treatment, being pleased to have been given a chance. The other woman had been treated with four fresh and three frozen–thawed embryo transfers.
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Discussion |
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Twelve children were born after oocyte donation to nine women with an inactivating mutation in the FSHR, and three are still pregnant (one for the first time and two for the second time). Hence, 10 women out of 12 became pregnant. These pregnancies show that FSH action is not essential in achieving pregnancy if donated oocytes are used, and that it is possible to have normal pregnancies without FSH action. The endometria of the women with the FSHR mutation responded normally to HRT with estradiol and micronized progesterone, and the placentas appeared to function similarly to that after oocyte donation in general (Söderström-Anttila et al., 2001
). Normal spontaneous delivery also proved possible.
FSH is the central hormone of human reproduction. It acts by binding to specific receptors localized exclusively in the gonads. In the female, FSH binding has been localized to the granulosa cells (Simoni et al., 1997). Recent reports have indicated the possible presence of FSHR protein and mRNA in cultures of human myometrial smooth muscle cells (Kornyei et al., 1996). Thus, it might be possible that FSH exerts its action also in other female reproductive tissues, including decidua and placenta. This localization is in contrast with the expression pattern observed for the LH receptor, which can be demonstrated in a variety of tissues. The subjects with the FSHR mutation appear to have normal LH action, but they have high circulating LH concentrations.
The pregnancies of these women were not without complications. However, the problems seen in our subjects were typical of pregnancies resulting from donated oocytes (Abdalla et al., 1990; Sauer and Paulson, 1990; Pados et al., 1992; Söderström-Anttila et al., 1998;Söderström-Anttila, 2001). Women with an FSHR defect are generally healthier than those having Turner's syndrome, but we have obtained similarly good pregnancy results (22 pregnancies in 18 individuals) with some pregnancy complications (pre-eclampsia and hypertension) among women with Turner's syndrome (Foudila et al., 1999; Hovatta, 1999). The mild pre-eclampsia, gestational diabetes, and premature rupture of the membranes with pulmonary embolism were all different types of complication. They were probably more associated with oocyte donation treatment than with the FSHR mutation.
Although the Finnish-type FSHR mutation seems to be rare in other populations, new inactivating mutations have been identified in subjects from other countries (Beau et al., 1998; Touraine et al., 1999). It is important to note that women who have these mutations, and probably also other genetic causes of ovarian failure, can be successfully helped using donated oocytes. Women with the FSHR mutation, however, differ from many other women with primary ovarian failure in having primary and occasionally early secondary follicles in their ovaries (Aittomäki et al., 1996).
In the future, in-vitro maturation of oocytes from ovarian cortical tissue might enable the treatment of these women, using their own oocytes. Cryopreservation of human ovarian tissue is already feasible (Hovatta et al., 1996; Newton et al., 1996). Ovarian cortical tissue might hence be cryopreserved at a young age, and oocytes matured at the time when the woman desires children. Fresh ovarian tissue could also be used if the woman is young enough to have good numbers of follicles at that time.
To obtain mature oocytes from ovarian tissue without FSH activity is a challenging task. In the mouse, mature oocytes and one live, though not healthy, pup have already been obtained starting from primordial follicles (Eppig and O'Brien, 1996). In humans, primordial follicles can be regularly cultured to secondary, and occasionally to early antral, stage when ovarian cortical tissue slices are cultured within extracellular matrix (Hovatta et al., 1999), but improvements in culturing oocytes are needed before meiotically competent oocytes are obtained, which could then be matured for fertilization. However, even if this could be achieved with donated normal tissue, it may not be feasible with FSHR-deficient follicles, as FSH probably regulates the expression of a number of genes in the granulosa cells, the target cells of FSH action in developing follicles. This is of relevance for oocyte maturation, as important interactions are likely to occur between the oocyte and granulosa cells (Picton and Gosden, 2000).
We have not routinely tested any healthy male partners or oocyte recipients for the mutation, because the carrier frequency (1 in 85) means that the risk for a child to be homozygous for this mutation, and hence infertile, is lower than 1%. This makes it also acceptable to use the affected woman's own oocytes in this recessive disorder. All the couples are receiving genetic counselling, and testing can be offered for those who desire it.
For the time being, the present results show that these women can be helped by using donated oocytes.
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Acknowledgements |
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We thank Nicholas Bolton for revising the language. We also thank the personnel of the IVF Units of the Family Federation of Finland for participating in the treatment of these women.
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Notes |
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6 To whom correspondence should be addressed at: Karolinska Institutet, Department of Obstetrics and Gynaecology, Huddinge University Hospital, S-141 86 Stockholm, Sweden. E-mail: outi.hovatta{at}klinvet.ki.se
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Submitted on June 26, 2001; accepted on September 18, 2001.
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