Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study.

BACKGROUND: To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS: A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS: Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS: Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00159575.

Twenty years experience with semen cryopreservation in testicular cancer patients: who needs it?

PURPOSE: To evaluate the role of semen cryopreservation (SCP) in the fertility saving management of testicular cancer (TC) patients, treated at the Norwegian Radium Hospital between 1983 and 2002. PATIENTS AND METHODS: 422 of 1388 newly diagnosed TC patients had SCP All patients were followed up for post-treatment paternity. RESULTS: During the 20 years study period, by 2002 an increasing percentage of patients had pre-treatment SCP, reaching 43% after 1994. Twenty-nine (7%) of the 422 patients with SCP had used their frozen semen for assisted reproductive techniques (ART) at least once to achieve fatherhood. Pregnancies were achieved in 16 of these patients' partners, but two of these pregnancies ended in abortions. 67(17%) of 393 men with SCP fathered at least one child without use of frozen semen. The comparable figures for those without SCP were 205 out of 966(21%). Twenty years after orchiectomy the cumulative incidence of first post-treatment fatherhood was 47% for the 393 patients who had SCP but did not use it for ART, and 34% for the 966 patients without SCP (p=0.12). CONCLUSION: If offered, about 50% of the young and middle-aged patients newly diagnosed with TC are interested in pre-treatment SCP. Though our study reveals that a considerable number of TC patients referred to SCP, achieve fatherhood without the use of frozen semen, the psychological impact of pre-treatment cryopreservation is undeniable. Furthermore, for some TC survivors ART with cryopreserved sperm offers the only chance of post-treatment paternity.

Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study.

BACKGROUND: Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation. METHODS: Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection. RESULTS: No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06). CONCLUSIONS: Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.

Gestational age in pregnancies conceived after in vitro fertilization: a comparison between age assessed from oocyte retrieval, crown-rump length and biparietal diameter.

OBJECTIVE: To compare gestational age (GA) and day of delivery estimated from the time of in vitro fertilization (IVF) (oocyte retrieval + 14 days), the ultrasonic measurement of the crown-rump length (CRL) and the biparietal diameter (BPD) in pregnancies conceived in an IVF setting. DESIGN: Included were 208 singletons and 72 twin pregnancies conceived after IVF. GA estimated from the time of IVF was compared with the GA estimated from the ultrasonic measurement of the CRL in the first trimester and the BPD in the second trimester. RESULTS: In singletons the mean difference in gestational age was 0.9 days between IVF and CRL estimates and 2.1 days between IVF and BPD estimates. The gestational age as estimated from CRL or BPD was shorter than the GA estimated from IVF. There was no systematic variation in the mean differences in GA between the methods. In three pregnancies there was a difference of more than 7 days between the gestational age estimated from IVF and CRL and in 22 pregnancies between gestational age estimated from IVF and BPD. A difference of > 14 days for any of the estimates was not found in any case. In singletons there was a high correlation in the gestational age at birth assessed from the time of IVF and from CRL, from the time of IVF and from BPD. CONCLUSION: Assessment of gestational age from the time of IVF, CRL and BPD in pregnancies conceived after IVF shows equally high agreement between the three methods. This supports the use of ultrasound as a reliable method for estimation of gestational age.

[Pregnancy, births and infants after in-vitro-fertilization in Norway, 1988-1991]. / Svangerskap, fødsel og barn etter in vitro-fertilisering i Norge, 1988-91.

We studied 1,165 pregnancies after in vitro fertilization in six public hospitals in Norway in the years 1988-91. The annual number of pregnancies increased from 158 in 1988 to 365 in 1991. The mean number of replaced embryos was reduced from 3.7 to 2.7. The rate of multiple births was not significantly altered in the same period, 24.3% were twin births and 5.7% triplet births. 19.3% of the pregnancies ended in abortion and 8.4% were ectopic. 782 births were registered in the Medical Birth Registry of Norway and compared with all other births during the period. Gestational hypertension, bleeding and preterm birth were observed more often in pregnancies after in vitro fertilization. The proportion of infants with very low birth weight (> 1,500 g) after in vitro fertilization was 9.7%, and nearly 50% of these were triplets. The relative risk of stillbirth and death during the first year of life, adjusted for maternal age and birth order, was 3.1 (95% CI 2.4-4.0) and 2.3 (95% CI 1.5-3.5) for singletons alone. The proportion of multiple births should be reduced.

Formation of antisperm antibodies in women treated with fallopian tube sperm perfusion.

Fallopian tube sperm perfusion (FSP) is a combination of ovarian stimulation and intra-uterine insemination using a large volume (4 ml) of inseminate containing 10(7)-10(8) spermatozoa. The inseminate will flush the Fallopian tubes and some of it will end up in the pouch of Douglas. In the present study, we have investigated whether the FSP method will result in the formation of serum antisperm antibodies in the female. A total of 184 treatment cycles were given to 128 women. The indications for treatment were: unexplained infertility (n = 35), various infertility diagnoses (n = 28) and donor insemination (n = 65). Prior to treatment, 11 (8.6%) women had a positive tray-agglutination test (Friberg) and/or a positive immunobead test. After completing one to four treatment cycles, another six (4.7%) women had developed serum antisperm antibodies. The antibodies induced by the treatment were of isotype IgM and directed against the tail-tip of the spermatozoa. Two of the women, who prior to the treatment had antisperm antibodies, showed an increase in antibody titre during treatment. There was no statistically significant difference in the pregnancy rate between the women with antisperm antibodies and the women without. In our opinion, the small risk of developing antisperm antibodies is no contra-indication for treating infertile couples with FSP.

Fallopian tube sperm perfusion (FSP) versus intra-uterine insemination (IUI) in the treatment of unexplained infertility: a prospective randomized study.

Prospective randomization of 60 couples with unexplained infertility was performed for treatment either with intrauterine insemination (IUI), using a volume of 0.5 ml of the inseminate, or Fallopian tube sperm perfusion (FSP), using a volume of 4 ml of inseminate. The protocols for ovarian stimulation and induction of ovulation were the same in the two groups. The two groups were similar concerning age of the female at the start of treatment and the number of follicles > 15 mm diameter, the serum oestradiol concentrations and the endometrial thickness on the day of human chorionic gonadotrophin (HCG) administration. The mean (+/- SD) number of motile spermatozoa inseminated was significantly higher in the FSP group than in the IUI group (52 +/- 5 x 10(6) and 28 +/- 3 x 10(6) respectively). In the FSP group, 30 women were given a total of 52 treatment cycles; 14 clinical pregnancies occurred in this group, giving a pregnancy rate of 26.9% per cycle and 46.7% per woman. In the IUI group, 28 women were given a total of 51 treatment cycles; five clinical pregnancies occurred, giving a pregnancy rate of 9.8% per cycle and 17.9% per woman. The pregnancy rates per cycle and per woman in the FSP group were significantly higher than in the IUI group (P < 0.05, chi-square test). This study indicates that in the treatment of couples with unexplained infertility, Fallopian tube sperm perfusion (FSP) is more successful than intra-uterine insemination (IUI).

Treatment of unexplained infertility. Fallopian tube sperm perfusion (FSP).

PATIENTS AND METHODS: Fifty-one couples with unexplained infertility were enrolled in the fallopian tube sperm perfusion (FSP) program. FSP is in short a combination of ovarian hyperstimulation, ovulation induction and intrauterine and intrafallopian tube insemination using a sperm suspension of 4 ml volume. RESULTS: One hundred cycles were started; 93 of these were completed, resulting in 27 pregnancies (29.0% per cycle). The pregnancy rate in the first treatment cycle (41.2%) was significantly higher than in the subsequent treatment cycles (14.3%, p < 0.01). Total pregnancy loss was 22.2% (2 ectopic pregnancies and 4 spontaneous abortions). The multiple birth rate was 14.2% (two sets of twins and one set of triplets). Twenty-two couples not conceiving following a maximum of three FSP treatment, were offered IVF treatment. Forty-three IVF cycles were started resulting in 27 embryo replacements in 15 patients. Seven pregnancies occurred in six couples. In 11 of the couples treated, IVF treatment revealed a possible explanation for the infertility; development of multiple small follicles following ovarian hyperstimulation, empty follicle syndrome and partial or total fertilization failure. Only in five of the couples who did not conceive, no cause for the infertility could be found. CONCLUSIONS: In the treatment of couples with unexplained infertility, the FSP procedure seems to give a birth rate of about 40% in less than two treatment cycles. FSP is less invasive and less expensive than alternative procedures such as GIFT, ZIFT and IVF and does not require the expertise and facilities for culturing of human oocytes and embryos.

[Fertilization in vitro--how large a proportion of couples will have a child?]. / In vitro-fertilisering--hvor stor andel av parene får barn?

In Norway, the efficacy and the efficiency of IVF treatment for infertile couples have been questioned. Information about this topic is important for the general public, the infertile population, the gynaecologists and the health authorities. We have followed a cohort of 485 infertile couples accepted for in vitro fertilization treatment. During a 14 month period starting 1 January 1989 a total of 214 women have either delivered or are pregnant in the second or third trimester. This number represents 44% of the 485 women accepted for IVF treatment, irrespective of whether they were treated or not, and 50% of the couples who completed at least one IVF cycle. There was no difference in cycle efficiency (pregnancy rate) between the first to third cycle, but this was significantly lower in cycle 4-6. There was no difference in delivery rate between groups of patients with different diagnoses of female infertility, but an additional male factor reduced the delivery rate significantly. Replacement of cryopreserved/thawed embryos gave a 5% increase in the delivery rate per couple included in the study, and an increase of 13% in the number of deliveries.

The efficacy and efficiency of an in-vitro fertilization programme including embryo cryopreservation: a cohort study.

A cohort of 485 couples starting their first in-vitro fertilization (IVF) attempt between January, 1989 and February, 1991 inclusive, were followed until June 1, 1992. A total of 1086 treatment cycles were initiated (mean 2.2, range 1-6). Of these, 235 (21.8%) cycles were cancelled, giving a total of 851 embryo replacements (mean 1.7, range 1-5). After IVF treatment, 189 women have either delivered or have an ongoing pregnancy in the second or third trimester. This gives a baby take-home rate of 17.4% per started cycle and 22.2% per embryo replacement. For 91 (18.6%) of the couples, the treatment was abandoned prior to completion of the three scheduled IVF attempts and 57 (11.7%) of these had no completed IVF cycles. In the group of couples with reduced sperm quality, the delivery rate was significantly lower than that of the other groups. A total of 193 women had embryos cryopreserved in at least one IVF cycle; 124 of these women started a frozen embryo replacement cycle and 88 had at least one cycle with replacement of frozen/thawed embryos, resulting in 25 deliveries/ongoing pregnancies. Due to the Norwegian law on assisted procreation 65 (33.7%) of the women have had their frozen embryos thawed and discarded after 12 months of storage. The cryopreservation programme, with the limitations of the Norwegian law, gives a 5.2% increase in the baby take-home rate for women entering the IVF programme, an increase of 13.2% in the number of ongoing pregnancies/deliveries and an 11.6% increase in number of children/viable fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Fallopian tube sperm perfusion used in a donor insemination programme.

Ninety-six couples were enrolled in a programme of Fallopian tube sperm perfusion (FSP). FSP is a method combining ovarian stimulation, ovulation induction and intra-uterine insemination with a 4 ml volume of sperm suspension. Frozen/thawed donor semen was used in all cycles. A total of 196 treatment cycles were started and of these 172 were completed. Twenty cycles were cancelled because of maturation of too many follicles, a low ovarian response, or formation of ovarian cysts. Five of the women enrolled in the programme did not have any inseminations. Forty-eight pregnancies occurred (27.9% per cycle) among 45 women (49.5%). There were five spontaneous abortions and one ectopic pregnancy. Sixteen pregnancies are on-going (greater than 12 weeks) and 26 women have delivered (including two sets of triplets and one set of twins). The pregnancy rate declined from the first attempt (34.1%) to the fourth attempt (14.3%). The pregnancy rate was significantly higher in women with three to five mature follicles compared to women with two or fewer mature follicles (P less than 0.05). Cycles in which human chorionic gonadotrophin (HCG) was administered on day 11 or later had a higher pregnancy rate than cycles where HCG was administered on day 10 (P less than 0.01). There was no difference in pregnancy rates between insemination with 8-10 x 10(6) motile spermatozoa and insemination with greater than 30 x 10(6) motile spermatozoa. FSP used in a programme of artificial insemination by donor using frozen/thawed donor semen is relatively simple to perform and gives a high pregnancy rate per cycle.

Fallopian tube sperm perfusion: first clinical experience.

We have developed an insemination method using a large (4 ml) volume of the inseminate. This method incorporates ovarian stimulation, isolation of an optimal number of motile spermatozoa and, finally, Fallopian tube sperm perfusion (FSP). In a clinical study, 139 couples with various causes of infertility, had a total of 239 treatment cycles. The pregnancy rate per treatment in groups with endometriosis, ovulation disorders, tubal impairment, combined male and female factors and subnormal sperm quality were low, ranging from 2.7% to 7.7%. In patients with unexplained infertility, the pregnancy rate per treatment was 26.9% and for this group, the pregnancy rate in the first treatment cycle was 37.3%. In the cervical hostility group, two pregnancies occurred after five treatments. FSP seems to be a favourable treatment for couples with cervical hostility or unexplained infertility. About half of the women in these groups conceived after three treatment cycles. FSP is easier to perform and is less expensive than other methods of assisted procreation, such as in vitro fertilization and gamete intra-Fallopian transfer.

IVF in the Nordic countries 1981-1987: a collaborative survey.

This report concerns the development of in-vitro fertilization (IVF) in the Nordic countries from the start of 1981 to January 1, 1988. All the 24 clinics in the Nordic countries which treat infertile couples with IVF participated in the study. The number of IVF clinics in the Nordic countries has increased from four in 1981 to 24 in 1987. In the same period, the number of people who spent some of their professional time as a part of an IVF team increased from 17 to 150. The majority of the clinics (19) based their activity mainly on governmental funding, while five of the clinics were private. During the period from 1981 to 1987, the Nordic clinic changed their methods of oocyte retrieval. In 1981, all oocyte retrievals were done using laparoscopy. Transvesical, ultrasound-guided follicular punctures domainated in 1985 and transvaginal ultrasound-guided punctures were used in 81.5% of the retrievals in 1987. A total of 852 pregnancies were reported. Of these, 313 (36.8%) were miscarriages, including 66 (7.7%) ectopic pregnancies. At January 1, 1988, 433 babies had been born, including 48 sets of twins, 14 sets of triplets and two sets of quadruplets. This gave a multiple birth rate of 18.2%. Premature births (less than 36 weeks of gestation) were reported in 14.6% of the births. Five babies (1.1%) died in the neonatal period and five (1.1%) were born with various types of malformation. One hundred and eight-eight pregnancies were in progress at January 1, 1988.

[Freezing, thawing and transfer of human embryos]. / Nedfrysing, tining og tilbakesetting av humane embryoer.

We present our experience of cryopreservation of human embryos from 1 July 1987 to 1 July 1989. During this period, 667 in vitro fertilizing cycles were completed. In 173 (26%) of these cycles, a total of 805 surplus embryos were cryopreserved. 516 embryos were thawed and 247 of these were transferred to the uterine cavity in a total of 110 replacement cycles. This resulted in 22 (20%) pregnancies in which a total of 28 gestational sacs could be verified by ultrasound. Seven of the pregnancies aborted spontaneously in the first trimester and one pregnancy was ectopic. By 1 July 1989, five singleton pregnancies were in progress and 13 babies had been born from nine deliveries (one set of triplets and two sets of twins). 25% of the patients whose embryos were cryopreserved became pregnant in the in vitro fertilizing cycle after replacement of fresh embryos.

[Chlamydia trachomatis and infertility in women]. / Chlamydia trachomatis og infertilitet hos kvinner.

Humoral IgG antibodies to Chlamydia trachomatis were determined in 131 infertile women, 102 with fallopian tube disorders and 29 with other infertility diagnosis and normal fallopian tubes. Chlamydia antibodies were identified significantly more often among women with abnormal fallopian tubes (89%) than among women with other infertility diagnosis (48%). Among Chlamydia antibody positive subjects the mean index was significantly higher among subjects with tubal disorders than among subjects with normal tubes (3,4 versus 2,2; p less than 0.01). This study indicates a close association between anti-bodies to Chlamydia trachomatis and tubal infertility.