Hum. Reprod. Advance Access originally published online on September 30, 2005
Human Reproduction 2006 21(1):175-182; doi:10.1093/humrep/dei310
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Myotonic dystrophy: does it affect ovarian follicular status and responsiveness to controlled ovarian stimulation?
1 Service de Gynécologie-Obstétrique et de Médecine de la Reproduction, 2 Service de Biologie de la Reproduction, Hôpital Antoine Béclère, 157 rue de la Porte-de-Trivaux, 92141 Clamart Cedex and 3 Service de Génétique Moléculaire et Cytogénétique, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France
4 To whom correspondence should be addressed: Service de Gynécologie-Obstétrique et Médecine de la Reproduction, Hôpital Antoine Béclère, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France. E-mail: estelle.feyereisen{at}abc.aphp.fr
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Abstract |
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BACKGROUND: Myotonic dystrophy (MD) is characterized by myotonia, multisystemic lesions and hypogonadism. In women, the relationship between MD and infertility remains controversial. This study investigated the ovarian status and response to controlled ovarian stimulation (COS) in MD women entering our preimplantation genetic diagnosis programme. METHODS: We elected to compare MD patients with X-linked disorders (XLD) carriers, given that XLD have not been shown to affect ovarian status. On the one hand, we analysed all the cycles performed and, on the other hand, we conducted a subanalysis based on only first cycles. RESULTS: MD and XLD groups were similar with regard to women’s ages, day 3 parameters, number of oocytes retrieved, embryos obtained and prevalence of top quality embryos. The day of HCG was significantly delayed and the prevalence of poor quality embryos was higher in the MD group. The subanalysis on first cycles only also showed significantly fewer mature follicles on the day of HCG in MD population. Implantation and pregnancy rates were similar in both groups; however, no pregnancy occurred at the first cycle in MD (0 out of 4), whereas 77% of pregnancies (10/13) occurred at the first attempt in XLD carriers. CONCLUSIONS: These results indicate that the responsiveness to COS was moderately hindered in MD women as compared to controls. Reassuring data about implantation and pregnancy rates support the feasibility of PGD in selected mildly affected MD women.
Key words: myotonic dystrophy/ovarian follicular status/ovarian stimulation/PGD
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Introduction |
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Myotonic dystrophy (MD), also called Steinert disease, is a progressive autosomal dominant genetic disease with an estimated prevalence of 1/25 000 in Europe. The involved gene is the MDY1 gene, cloned in 1992 and located on the long arm of chromosome 19 (19q13.3) (Buxton et al., 1992
). The genetic defect is an amplified trinucleotide (CTG) repeat in the 3' untranslated region of a protein kinase gene (Harley et al., 1992). The severity varies with the number of repeats (Redman et al., 1993): normal individuals have from five to 30 repeat copies (Brook et al., 1992); mildly affected persons, from 50 to 80; and severely affected individuals 
200 copies (
OMIM 160900
[OMIM]
). The phenotypic expression and penetrance of MD are greatly variable, with a wide range of qualitative and quantitative clinical findings. Many obligatory gene carriers are asymptomatic. In families, larger amplification is transmitted to the offspring and explains the anticipation of the disease, with a resulting increase in severity of symptoms in successive generations.
The clinical definition of MD varies from mild disorders that become evident in middle life to congenital MD with neonatal expression and frequent death in the first days of life. With only rare exceptions, it is the mother who transmits the disease in cases of congenital MD (Brunner et al., 1993; Lavedan et al., 1993; de Die-Smulders et al., 1997). Patients born of an affected mother are more severely affected than those born of an affected father (Harper and Dyken, 1972).
Typically, MD is associated with hypotonia of striated and smooth muscle, ophthalmological lesions such as cataracts, cardiac muscle conduction defects and endocrinological disorders. Moreover, hypogonadism is frequently described and MD is associated with decreased fertility. Indeed, in men, MD may cause testicular atrophy and oligozoospermia due to tubular lesions (Vazquez et al., 1990). Yet, in women, the relationship between MD and infertility remains unclear and publications on the subject are controversial. Some investigators have associated MD with an increase risk of ovarian dysfunction (Ulloa-Aguirre et al., 1981), whereas others failed to find a relationship between this multisystemic disease and fertility (Roy et al., 1989).
This study was undertaken to elucidate whether or not there was an ovarian factor associated with the previously noted reduction in fertility in MD patients. In this regard, we undertook a retrospective study among patients seen in our preimplantation genetic diagnosis (PGD) programme. We compared MD patients with women carriers of X-linked disorders (XLD), given that XLD have not been hitherto shown to affect ovarian functions.
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Materials and methods |
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Patients
We analysed the computerized records of the patients selected for PGD in our centre from 2000 to 2004 (inclusive) for those who had MD (n = 52) and were XLD carriers (n = 59). They all went through an initial multidisciplinary consultation that included a geneticist, gynaecologist, embryologist and a psychologist. Of the 52 MD cases, 45 were women and seven were men. The latter were excluded from the study. Medical investigation specially focused on ovarian reserve on day 3 [basal hormonal level and ultrasound examination with antral follicle count (AFC)], status of the uterus (vaginal ultrasound scan, hysteroscopy) and sperm parameters (spermogram, spermocytogram, spermculture). In the MD population, myological, ophthalmological and cardiological assessments were performed. As a result of the initial consultation and the subsequent investigation, some of these couples were advised to consider alternative approaches such as prenatal diagnosis, gamete donation or adoption. In these, PGD was not indicated because of maternal age
40 years, evidence of poor ovarian reserve, and severe medical disorders that contraindicated IVF or pregnancy. Among the 45 couples in which the female partner was suffering from MD, 11 were not included in the PGD programme: seven were excluded for medical reasons and four chose another alternative. Among the four MD women that chose another alternative, there was no evidence of poor ovarian reserve. These couples spontaneously preferred prenatal diagnosis and day 3 explorations have not been performed. Of the 34 eligible to have PGD, 22 couples went through the programme and had a total of 44 initiated COS cycles. The other 12 have not as yet commenced treatment. Unfortunately, with regard to these 12 eligible MD couples that have not started treatment, results of their baseline hormonal and ultrasonographic ovarian exploration are not yet available. For organizational purposes, we schedule these explorations just before patient inclusion for ovarian stimulation treatment.
The 59 couples received in consultation for XLD had various indications as listed in Table I.
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Carriers of fragile X syndrome did not belong to this group because of the well-known premature ovarian failure related to this condition (Murray et al., 1998; Marozzi et al., 2000; Sherman, 2000; Machado-Ferreira et al., 2004). Among the XLD carrier couples, three were excluded at the consultation, including two for evident alteration of the ovarian status on previous examinations (FSH 15 mIU/ml and AFC <10) and one for a medical problem that contraindicated pregnancy; nine others decided against further treatment because of the complexity of the procedure and elected to start spontaneous pregnancies. Concerning the nine couples who chose to start spontaneous pregnancy with prenatal diagnosis, the day 3 explorations have not been performed. Between 2000 and 2004, 42 XLD carrier couples were enrolled in our PGD programme and had a total of 81 initiated COS cycles. The other five eligible have as yet not started treatment and we do not have their day 3 characteristics at the present time.
The objective of this retrospective study was to compare ovarian status and responsiveness to COS in these two different populations of MD and XLD carriers.
IVF protocol
Ovarian stimulation protocol was carried out by using a depot formula of GnRH agonist Decapeptyl 3 mg i.m. (Ipsen Biotech, Paris, France) on day 3 of their menstrual cycle. In our hands, this ‘follicular long protocol’ is as effective as the ‘luteal long protocol’ and its improved flexibility makes the programming of the PGD activity easier at the beginning of the menstrual cycle. Through a rigorous organization, we try, as far as possible, to avoid performing several PGD on the same day, in order to decrease the risk of potential misdiagnosis. After 18 days, the patients underwent a screening transvaginal ultrasound and serum estradiol (E2) concentration assay to document pituitary desensitization. After confirmation of ovarian quiescence, gonadotrophins (150–300 IU) were administered daily, urinary Menopur® (Ferring, Gentilly, France) or recombinant FSH Gonal F® (Serono, Boulogne, France) or Puregon® (Organon, Puteaux, France). The dose of gonadotrophin after day 6 was adjusted to the ovarian response. Since 2003, when recombinant FSH was used, 75 IU recombinant LH (Luveris®; Serono, Boulogne, France) daily was systematically added from the day 6 of stimulation to the day of HCG administration. Monitoring of the cycle was done by assessment of plasma level of LH, E2 and progesterone in conjunction with ultrasonography starting on day 8 of stimulation. The regimen continued until clinical parameters for HCG administration were achieved. HCG 10 000 IU (Human Chorionique Gonadotrophine Endo®; Organon, Puteaux, France) were administered when at least five follicles 16 mm were observed by ultrasound and the E2 plasma level was >1000 pg/ml. In cases at risk for ovarian hyperstimulation syndrome, only 5000 IU of HCG were injected. Patients were cancelled if E2 levels did not reach 1000 pg/ml or if progesterone was >2 ng/ml or if there were fewer than eight growing follicles after 5 days of ovarian stimulation.
Transvaginal ultrasound-guided oocyte retrieval was scheduled for 36 h after HCG administration under local or general anaesthesia. All oocytes obtained were inseminated by ICSI to prevent residual contamination with sperm DNA (Liebaers et al., 1998).
After fertilization, the zygotes were cultured in specific culture media ISMI and ISM2 (Medi Cult, Lyon, France) until their biopsy.
Biopsy procedure
The biopsy was carried out on cleavage stage at day 3 in ISM2 medium (Medi Cult, Lyon, France) using a no-contact laser (Fertilase; MTG, Germany) for zona drilling (De Vos and Van Steirteghem, 2001). One or two blastomeres were gently aspirated. In order to reduce the possibility of misdiagnosis, two blastomeres were systematically removed and used for PGD analysis if the embryo had at least six cells and whenever it was possible (Ray et al., 1998).
PGD techniques
PCR analysis
Amplification protocols were described by Ray et al. (2000, 2001, 2002). Results were obtained 6–12 h after embryo biopsy. PCR is usually performed for the analysis of single gene defects (Wells and Sherlock, 1998). It has been used for all MD PGD and whenever it was feasible (identified mutation) for XLD (Gigarel et al., 2004).
Fluorescent in situ hybridization (FISH) analysis
When specific PCR diagnosis for XLD was not technically possible, embryo sexing by FISH analysis was performed (Harper et al., 1994; Staessen et al., 1999). In these situations, PGD aimed at selecting potentially affected XY male embryos, to avoid replacing them in the uterine cavity. The probes were specific centromeric probes of each X and Y chromosomes, labelled with different fluorochromes. Centromeric probes for X were labelled with green fluorescein (FITC–12-dUTP), whereas centromeric Y probes were labelled with red rhodamine (tetramethyl-rhodamine-5-dUTP). The biopsied blastomeres were spread on slides (Superfrost Plus) by the HCL–Tween method according to Coonen et al. (1996). Following the hybridization, the slides were washed and analysed using a Leica fluorescence microscope fitted with a Photometrics camera. Only the blastomeres with two evident green signals were defined as ‘normal’ and the two blastomeres from an embryo had to demonstrate the same pattern. If not, the embryo was considered as mosaic and was not transferred.
Embryo quality assessment
On day 3 embryos were classified as A, B, C, D on the basis of their morphology. Criteria included cell number, size of blastomeres and the percentage of anucleated fragments (Frydman et al., 2004). The embryos with grade A or B were considered as high grade embryos (TOP embryos).
Embryo transfer procedure
Embryo transfers were carried out on day 4 using a Frydman catheter 4.5 (CCD, Paris, France). As in regular IVF cycles, the age of the patient, the number of previous attempts and embryo quality determined the number of embryos transferred, with a maximum of three embryos replaced. Exceptionally, there were supernumerary unaffected embryos which were cryopreserved. Luteal phase support was systematically given by daily vaginal administration of micronized progesterone (Estima G; EFFIK, Bievres, France) until a negative serum pregnancy test or until 8 weeks of gestation. A clinical pregnancy was noted when an intrauterine gestational sac was seen on vaginal ultrasound 5 weeks after the embryo replacement. An ongoing pregnancy was defined as a clinical pregnancy with a fetal heartbeat >12 weeks.
Statistical analysis
The data were analysed using the non-parametric Mann–Whitney test and the 
2-test. We compared the observed ovarian follicular status in MD patients with that observed in XLD carriers. We also compared results observed during COS and the outcome of PGD in both populations. P < 0.05 was considered statistically significant.
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Results |
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During 5 years of PGD activity, 44 MD cycles were started, including 22 couples, resulting in 27 oocytes retrievals, 24 embryo biopsies and 18 embryo transfers. Seventeen MD cycles were cancelled, including 10 for poor response. During the same period, 81 XLD cycles were started, including 42 couples, leading to 53 oocytes retrievals, 48 embryo biopsies and 41 embryo transfers. Twenty-eight XLD cycles were cancelled, including 19 for poor response. Among the 48 biopsies performed in XLD carriers, 20 PGD were done by FISH analysis and 28 by PCR. Spontaneous fertility status was comparable in the two populations. In the MD group, there were one case of azoospermia and two subfertile couples who had previously conceived after intrauterine inseminations or simple ovarian stimulation. Among the XLD carriers, there were four cases of male infertility (oligozoospermia), two cases of unexplained infertility and one case of polycystic ovary syndrome.
The two groups were also similar with regard to women’s ages [31 (26–36) versus 31 (24–38) years respectively].
The analysis of day 3 ovarian follicular status failed to demonstrate any statistical difference between the MD and XLD populations: FSH [5.9 (3.3–12.8) versus 6.0 (2.5–9.4) mIU/ml], E2 [37.0 (10–139) versus 43.0 (10–180) pg/ml] and AFC [12.5 (5–40) versus 15.0 (5–46) follicles] respectively. Only the inhibin B levels were significantly higher in the XLD group [85 (15–260) pg/ml] versus 60 (15–182) pg/ml (P = 0.001) in the MD group (Table IIa).
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Our cycle-wise instead of couple-wise analysis can introduce a risk of bias by over- or under-representation of particularly good or bad ovarian reserves and responses. In order to avoid this problem, we conducted a subanalysis on first cycles only. Of the 22 first MD cycles started, 13 OR were performed, leading to 12 embryo biopsies and six embryo transfers. Of the 42 first cycles started in XLD carriers, 31 OR were performed, leading to 29 embryo biopsies and 24 embryo transfers. Considering the results of this subanalysis, no significant difference was found in the day 3 parameters between the two populations (Table IIb).
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The results of monitoring are summarized in Table IIIa. Both MD and XLD groups were comparable with regard to cycle cancellation rate for poor ovarian response [23% versus 24%), E2 levels on day 6 [186 (36–1848) versus 238 (50–1364) pg/ml], E2 levels on day 9 [590.0 (53–4980) versus 902.5 (81–4289) pg/ml] and E2 levels on the day of HCG administration [2807 (1481–4962) versus 3033 (882–6223) pg/ml]. Endometrial thickness [9.4 (4.7–14) versus 10.0 (6–13.8) mm] and number of 16 mm follicles were similar on the day of HCG administration [9 (4–14) versus 9 (5–24)] respectively. Significant differences were found with regard to progesterone levels [1.10 (0.16–3.20) versus 0.78 (0.14–2.82) pg/ml] the day of HCG administration [13 (10–16) in MD group versus 12 (9–15) in XLD group; P = 0.001] and the total FSH or HMG required [2787.5 (1200–4500) IU in MD women versus 2100.0 (1050–3600) IU in XLD women; P = 0.009]. The subanalysis of the monitoring data and of the responsiveness to COS (Table IIIb) showed a significantly delayed response to COS in the MD group; the median day of HCG administration occurred on day 12.5 (11–15) in MD patients whereas it occurred on day 11.5 (9–15) in the XLD group (P = 0.02). The same subanalysis failed to confirm a significant difference with regard to progesterone levels on the day of HCG administration and the amount of FSH or HMG injected between our two populations. Significantly more mature follicles 16 mm were obtained on the day of HCG administration in the XLD group in this subanalysis [10.5 (5–24) follicles in XLD carriers versus 8.0 (4–10) in the MD population; P = 0.01].
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Both MD and XLD populations were similar with regard to number of oocytes retrieved [11.5 (6–25) versus 14.0 (3–32)], number of oocytes inseminated [10.5 (4–21) versus 13.0 (1–26)], embryos obtained [7.0 (0–15) versus 9.0 (1–19)] and the prevalence of top quality embryos (38 versus 40%) respectively. The prevalence of TOP quality embryos was comparable in the two populations, but significantly more grade D embryos were observed in MD patients (26.5 versus 14.5% in XLD carriers; P = 0.0002). Statistically significant differences were found between the MD and XLD populations in terms of average number of biopsied embryos [4.5 (0–14) versus 6.0 (0–16); P = 0.03]. The number of transferred embryos was lower in MD patients but the difference was not significant [1.0 (0–2) versus 2.0 (0–3); P = 0.05] (Table IVa). The subanalysis on first cycles showed a non-significant trend towards inferiority in the outcome of COS treatment in the MD group with regard to the number of oocytes retrieved [9 (6–20) in MD patients versus 15.0 (3–32) in XLD carriers; P = 0.07], oocytes inseminated [8.5 (4–17) versus 13.0 (1–26) respectively; P = 0.11] and embryos obtained [5.0 (0–14) versus 9 (1–19) respectively; P = 0.12]. In the subanalysis, the number of transferred embryos was significantly lower in MD women [1 (0–2)] versus [2 (1–3)] in XLD carriers (P = 0.002) (Table IVb).
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Outcomes of the PGD procedure were comparable with regard to implantation rates (13.3% in MD versus 15.6% in XLD carriers) and ongoing pregnancy rates per embryo transfer (22% in MD population, versus 31.7% in the XLD group). Four single clinical and ongoing pregnancies were obtained in MD women. XLD women had 14 clinical pregnancies, including one miscarriage and 13 ongoing pregnancies (12 singletons and one twin) (Table IVa). The subanalysis on first cycles showed that 77% of ongoing pregnancies (10/13) were obtained at the first attempt for XLD carriers, whereas no pregnancy (0/4) was obtained at the first attempt for MD women (Table IVb).
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Discussion |
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Our study demonstrated that women affected with MD exhibit a relatively poor response to COS compared to XLD carriers whose response appears normal. Women with MD required a significantly greater amount of FSH or hMG, with delay in the day of HCG administration. The MD patients needed significantly more gonadotrophins (P = 0.009) to yield the same number of follicles. The use of higher quantities of FSH could well be biased by a higher starting dose based on the earlier impression of reduced ovarian reserve in some MD cases. In addition, the subanalysis on first cycles did not confirm this finding but did show significantly fewer mature follicles
16 mm on the day of HCG administration in the MD group (P = 0.01). There was no significant difference in the number of oocytes retrieved, embryos obtained and the percentage of top embryos. The non-significant trend towards inferiority observed in the subanalysis in the MD group in terms of oocytes retrieved, inseminated and embryos obtained has to be underlined: our results did not reach significance but this may be due to the number of cases in our series.
Surprisingly, inhibin B levels on day 3 were significantly lower in MD women, whereas values for other day 3 parameters (FSH, E2, AFC) were similar. The subanalysis of first cycles did not confirm these results and failed to show a difference in the day 3 parameters between the two populations. No woman with evident poor ovarian reserve enters our PGD programme on account of the inherently reduced IVF outcome. This characteristic was shared by both study groups. It represents a limitation of our methodology as we could not evaluate the ovarian status and response to COS of women who were previously excluded. At the present time, our data do not allow us to conclude that the follicular status is decreased in the MD population but the responsiveness to COS of MD women is inferior to XLD carrier controls.
There appears to be a consensus in the medical literature about the risk of decreased fertility in MD men. Indeed, many studies found hypogonadism with sperm count defects (Hortas et al., 2000), testicular atrophy in 65.5% of patients (Vazquez et al., 1990) and damage to the seminiferous tubules as evident on biopsy specimens (Takeda and Ueda, 1977). In women, the correlation between fertility and MD remains unclear. Most of the studies report no significant correlation between ovarian status and the disease (Henriksen et al., 1978), whereas others, many of which are case reports, report a decreased fertility due to the multisystemic disorders in MD (Ulloa-Aguirre et al., 1981). Epidemiological studies did not show evidence of subfertility in female MD population. These case–control analyses were all performed in the Saguenay region, located in the North-east of the province of Quebec in Canada and known for its exceptionally high prevalence of the disease (1/475) (Bouchard et al., 1988; Roy et al., 1989; Veillette et al., 1989; Dao et al., 1992).
The results of our study allow us to affirm a moderately decreased fertility in MD women. Nevertheless, the mechanisms by which MD damages testicular functions while being relatively sparing of ovarian function remains to be elucidated. So far, it is well demonstrated that the number of CTG repeats broadly correlates with the overall severity of the disease. CTG repeat number seems to have a predictive value only in the case of some clinical symptoms, and pathogenic mecanisms of MD may differ depending on the tissue (Marchini et al., 2000). The severity of male hypergonadotrophic hypogonadism in MD appears to be related to (CTG)n triplet mutation (Mastrogiacomo et al., 1994).
Incidentally, no woman with severe MD disorders entered our PGD programme on account of the inherently high risk pregnancy. Seven women were excluded because of severe cardiac defects that contraindicated pregnancy. The day 3 explorations have not been performed in these cases. All our patients had only mild deficiencies and usually the only clinical sign of the disease was a weakness involving facial muscles and distal muscles of the extremities. For 10 couples, MD was only diagnosed after the birth of an affected child. In our study, of the 22 MD couples, eight women had <500 repeat copies, 12 had between 500 and 1000 and only two had a number of repeats >1000. However, we found no statistically significant correlation between the ovarian status, response to COS, or cancellation rate for insufficient response and (CTG) triplet repeats. It would be interesting to investigate the impact of the CTG repeat number on the infertility of MD women within a defined age group, with sufficient numbers of subjects.
In our study, significantly fewer embryos were biopsied in the MD population compared to the XLD group, whereas the total number of embryos obtained and the percentage of TOP embryos were similar. However, a significant increase of low grade embryos (grade D) was observed in the MD group, suggesting an initial oocyte abnormality possibly linked to the disease. Further follow-up of more MD patients in the future may confirm or refute this assumption. In addition, it is particularly striking to note that no pregnancy was obtained at the first treatment cycle in MD patients, whereas the ongoing pregnancy rate was 41.6% (10/24) per embryo transfer at the first attempt in XLD carriers.
A statistically significant difference in regard to embryos suitable for transfer was expected, since in the MD group 50% of embryos would be affected. On the other hand, in XLD, 50% of embryos are expected to be affected when sexing by FISH (20/48 cases, 41.6%), and 75% of embryos are expected to be unaffected if PCR is used (28/48 cases, 58.3%). Indeed in our study, 50.7% (65/128) of MD patients’ embryos were affected, against only 30.4% (100/329) in XLD carriers (P < 0.005).
The outcome of PGD cycles in our MD women is similar to those reported by the PGD ESHRE Consortium (ESHRE PGD Consortium Steering Committee, 2005). MD is the most common indication for autosomal dominant disorders noted by the European Consortium. The most striking difference between our results and those of the Consortium lies in the cancellation rate (8% between 1999 and May 2001 and 14% between May and December 2001 reported by the Consortium versus 38% in our study). This underlines the rigorous patient selection in our centre, which permits a greater success rate associated with IVF and PGD cycles (22% ongoing pregnancies per embryo transfer in our MD population).
In our study, despite the fact that no pregnancy occurred during the first treatment cycle in MD patients, global implantation and pregnancy rates in MD are similar to controls and support the feasibility of successful PGD in selected women suffering from mild MD.
However, PGD may not be an option for all MD women and all patients who are referred for a PGD cycle should be counselled about the success rate, which depends largely on the number of cumulus–oocyte complexes retrieved (Vandervorst et al., 1998). That is the reason why the screening results of the initial multidisciplinary consultation are important—to assess, as far as possible, the chances of a successful response to COS and to counsel couples appropriately.
In summary, subject to appropriate selection, MD patients have an acceptable pregnancy rate. This rate was not significantly different from XLD patients but there is a trend towards inferiority in MD (22% ongoing pregnancies versus 31.7% in the XLD group): this may be due to the selection of mildly affected women that were accepted into our PGD programme and/or to the number of cases in our series, despite the fact that our results were superior to those reported before.
In conclusion, the present study is the first one using the PGD tool to assess a gonadal failure in MD women. Responsiveness to COS was moderately hindered as compared to controls, even if no difference was found with regard to the ovarian follicular status. Ovarian potential remains relatively intact as compared to the severe defects described in men. The mechanisms of the gonadal insufficiencies in MD have still to be explored. On the other hand, PGD outcome is reassuring and supports the feasibility of PGD in women with MD.
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We would like to thank all personnel for their help and assistance. We are indebted to many colleagues of the clinical, scientific, laboratory, nursing, secretarial and technical staff of the Antoine Béclère Hospital Centre for Reproductive Medicine and of the Necker Hospital Department of Medical Genetics, without whom the PGD programme could not function. The authors wish to express their thanks to Prof. Victor Gomel for his helpful suggestions made while editing and translating the English text.
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References |
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Submitted on April 25, 2005; resubmitted on August 10, 2005; accepted on August 16, 2005.
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