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15.05.2004
 
Newsletter No. 27
 
Early pregnancy
  1. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations.

Gynaecologic Oncology

  1. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women.
  2. Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial

  1. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study
  2. Lifetime expression of stem cell markers in the uterine endometrium.

Gynaecologic Endocrinology and Reproductive Medicine

  1. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection.
  2. Fallopian tube sperm perfusion versus intrauterine insemination in unexplained infertility: a randomized, prospective, cross-over trial.
  3. Initiation of the gonadotropin-releasing hormone antagonist ganirelix for in vitro fertilization cycles in which the lead follicle is >14 mm.
  4. Blastocyst versus early cleavage embryo transfer: a retrospective analysis of 4,165 transfers.
  5. Single blastocyst transfer: a prospective randomized trial.
  6. Blastocyst-stage embryo transfer in patients who failed to conceive in three or more day 2-3 embryo transfer cycles: a prospective, randomized study.

1. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations.

The study was performed o determine whether the miscarriage rate in recurrent miscarriage patients with an abnormal karyotype, especially reciprocal translocations, in either partner is worse than without an abnormal karyotype. One thousand and two hundred eighty-four couples with a history of 2 or more (2 to 12) consecutive first-trimester miscarriages were included in the study. Patients with antiphospholipid antibodies were treated with low-dose aspirin and combined therapy. Subsequent miscarriages were compared for cases with and without an abnormal karyotype in either partner. A karyotype analysis was also conducted for each aborted conceptus and offspring of 95 pregnancies of 47 patients with reciprocal translocations. Of the total of 1,284 couples, 58 (4.5%) had translocations, 11 being Robertsonian translocations. Eleven of the 18 cases (61.1%) where the husband had a reciprocal translocation suffered further miscarriage; this also was the case for 21 of the 29 cases (72.4%) where the wives had a reciprocal translocation. Those with reciprocal translocations in either partner miscarried significantly more frequently than those without an abnormal karyotype. Only one infant with an unbalanced translocation was found in 34 cases of successful pregnancy following habitual abortion.
CONCLUSION(S): The pregnancy prognosis with either maternal or paternal reciprocal translocations is poorer than without them. The presence of a reciprocal translocation is thus a risk factor in couples who have recurrent miscarriages.

Reference

Sugiura-Ogasawara M, Ozaki Y, Sato T, Suzumori N, Suzumori K. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations. Fertil Steril. 2004 Feb;81(2):367-73.

2. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women.

A comparative, randomized, evaluator-blinded study was conducted in thirty-seven postmenopausal women to compare changes in mammographic density and the expression of markers of proliferation (Ki67) and apoptosis (Bcl-2) after 1 year of treatment with tibolone and continuous conjugated equine estrogens combined with medroxyprogesterone acetate (CEE-MPA). Tibolone (2.5 mg; n = 18) or continuous conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (5 mg; n = 19) was given for 1 year. Mammographic density (BI-RADS density score), expression of immunohistochemical markers Ki67 and Bcl-2 were determined. Mean breast density score decreased significantly from 2.22 to 1.67 in the tibolone group, compared with a significant increase in the CEE-MPA-treated group from 1.84 to 2.63. Ki67 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 1 of 19, 15 of 19, and 3 of 19 subjects, respectively, in the CEE-MPA group. Bcl-2 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 5 of 19, 9 of 19, and 5 of 19 subjects, respectively, in the CEE-MPA group.
CONCLUSION(S): One-year treatment with tibolone induced a decrease in breast density, with a reduction in proliferation and a stimulation of apoptosis, whereas 1-year treatment with CEE-MPA induced an increase in breast density, with stimulation of proliferation and inhibition of apoptosis, indicating that tibolone effects on the breast are different from those of CEE-MPA.

Reference

Valdivia I, Campodonico I, Tapia A, Capetillo M, Espinoza A, Lavin P. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women. Fertil Steril. 2004 Mar;81(3):617-23.

3. Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial

Mortality due to breast cancer has been reported to be the same or even lower in HRT users than in non-users. This has been attributed to earlier diagnosis and to better prognosis. Nevertheless, more advanced disease in HRT users was reported recently by the Women's Health Initiative (WHI) study. The objective of this study was to assess, using a systematic review of current literature, whether the data of the WHI study are in contradiction to observational data. Twenty-five studies ere selected, for which we evaluated the methodology, the characteristics of the studied populations, confounding breast cancer risk factors and prognostic indicators. The WHI study, showing a worsening of some prognostic parameters, is in contradiction to most published observational studies. Most observational studies are retrospective, not well matched and did not consider most confounding factors. Their methodology and selection criteria varied considerably and the number of patients was often small. No differences in the distributions of histology, grade or steroid receptors were observed in the WHI trial, while this was the case in some of the observational studies. Other parameters (S phase, protein New, Bcl-2 gene, protein p53 and E-adhering, catharsis D) were not reported in the WHI trial.
CONCLUSIONS: In view of these data, the current clinical message to patients should be changed: one can no longer declare that breast cancers developed while using HRT are of better prognosis.

Reference

Antoine C, Lieges F, Curly B, Pasting A, Rosenberg S. Women's Health Initiative. Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial. Hum Reprod. 2004 Mar;19(3):741-56. Epub 2004 Jan 29.

4. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study.

To determine the role of an aromatase inhibitor, letrozole, in the treatment of reproductive-age women with endometriosis and associated chronic pelvic pain a phase 2, open-label, nonrandomized proof-of-concept study was conducted. Ten patients with endometriosis, all previously treated both medically and surgically, with unsatisfactory results were included. Endometriosis was diagnosed by biopsy and scored from an initial diagnostic laparoscopy performed within 1 month before treatment was begun. Oral administration of letrozole (2.5 mg), the progestin norethindrone acetate (2.5 mg), calcium citrate (1,250 mg), and vitamin D (800 IU) was done daily for 6 months. Within 1-2 months after completion of the treatment, a second-look laparoscopy was performed to score and biopsy endometriosis. Changes in American Society for Reproductive Medicine (ASRM) scores for endometriosis, pelvic pain assessed by visual analog scale, serum hormone levels (FSH, LH, E(2), and estrone [E(1)]), and bone density (DEXA scan) were determined. No histologically demonstrable endometriosis was present in any patient during the second-look laparoscopy. ASRM and pelvic pain scores decreased significantly in response to treatment. Overall, no significant change in bone density was detected. Gonadotropin levels were not significantly altered by treatment, and although circulating E(2) and E(1) levels were reduced, the decrease was not statistically significant.
CONCLUSION(S): The combination of letrozole and norethindrone acetate achieved marked reduction of laparoscopically visible and histologically confirmed endometriosis in all 10 patients and significant pain relief in nine out of 10 patients who had not responded previously to currently available treatments. On this basis, letrozole should be a candidate for the medical management of endometriosis.

Reference

Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004 Feb;81(2):290-6.

5. Lifetime expression of stem cell markers in the uterine endometrium.

A descriptive, controlled study was performed in forty archived uterine endometrial samples to identify stem cells in uteri from the fetal to the postmenopausal period. Immunohistochemistry with c-kit/CD117, CD34, bcl-2, and Ki67was performed. C-kit/CD117, CD34, bcl-2, and Ki67 were consistently expressed in the stroma of the basalis layer. Bcl-2 was restricted to the fetal uterine endometrium.
CONCLUSION(S): By studying the immunolocalization of stem cell markers (i.e., c-kit, CD34, and bcl-2), we found that stem cells are present continuously in the uterine endometrium from the fetal period. The cells seem to be located mainly in the stroma of the basalis and to be independent of hormonal regulation to avoid cyclic shedding. A small number of latent stem cells dormant in the stroma of the basalis were found to have the potential for mesenchymal differentiation.

Reference

Cho NH, Park YK, Kim YT, Yang H, Kim SK. Lifetime expression of stem cell markers in the uterine endometrium. Fertil Steril. 2004 Feb;81(2):403-7.

6. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection.

In a retrospective, matched-control study from January 2000 to October 2001 two hundred forty-five women with subserosal and/or intramural fibroids that did not compress the uterine cavity (fibroid group) and 245 women with no evidence of fibroids anywhere in the uterus (control group) were compared to further evaluate the effects of intramural and subserosal uterine fibroids on the outcome of IVF-ET, when there is no compression of the endometrial cavity. There was no correlation between location and number of uterine fibroids and the outcomes of IVF-ICSI. Patients with subserosal or intramural fibroids <4 cm had IVF-ICSI outcomes (pregnancy, implantation, and abortion rates) similar to those of controls. Patients with intramural fibroids >4.0 cm had lower pregnancy rates than patients with intramural fibroids CONCLUSION(S): Patients having subserosal or intramural leiomyomas of <4 cm not encroaching on the uterine cavity have IVF-ICSI outcomes comparable to those of patients without such leiomyomas. Therefore, they might not require myomectomy before being scheduled for assisted reproduction cycles. However, we recommend caution for patients with fibroids >4 cm and that such patients be submitted to treatment before they are enrolled in IVF-ICSI cycles. Whether or not women with fibroids > 4 cm would benefit from fibroid treatment remains to be determined.

Reference

Oliveira FG, Abdelmassih VG, Diamond MP, Dozortsev D, Melo NR, Abdelmassih R. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection. Fertil Steril. 2004 Mar;81(3):582-7.

7. Fallopian tube sperm perfusion versus intrauterine insemination in unexplained infertility: a randomized, prospective, cross-over trial.

A randomized, prospective, cross-over study to compare the results of fallopian tube sperm perfusion (FSP) versus standard intrauterine insemination (IUI) in 56 patients with unexplained infertility undergoing controlled ovarian hyperstimulation (COH). COH was induced by recombinant FSH and monitored by serial transvaginal ultrasound. On the day of hCG administration during the first treatment cycle, patients were randomized to either IUI or FSP. Thereafter, in case no pregnancy was achieved, patients went on being treated with FSP and IUI in alternate cycles. A maximum of four treatment cycles per couple was performed. FSP was performed using a pediatric Foley's catheter inseminating 4 mL of sperm-enriched suspension; a Kremer-Delafontaine catheter delivering 0.5 mL of sperm suspension was used for IUI. One hundred twenty-seven cycles (58 FSP, 69 IUI) were performed. The clinical pregnancy rate per cycle was 21.7% for IUI and 8.6% for FSP, respectively. No major adverse effects were recorded for either technique.
CONCLUSION(S): After COH, FSP is less effective than IUI in couples with unexplained infertility.

Reference

Biacchiardi CP, Revelli A, Gennarelli G, Rustichelli S, Moffa F, Massobrio M. Fallopian tube sperm perfusion versus intrauterine insemination in unexplained infertility: a randomized, prospective, cross-over trial. Fertil Steril. 2004 Feb;81(2):448-51.

8. Initiation of the gonadotropin-releasing hormone antagonist ganirelix for in vitro fertilization cycles in which the lead follicle is >14 mm.

The initiation of GnRH antagonists when the lead follicle is >14 mm does not adversely affect IVF success rates and leads to a shortened duration of GnRH antagonist administration.

Reference

Klipstein S, Reindollar RH, Regan MM, Alper MM. Initiation of the gonadotropin-releasing hormone antagonist ganirelix for in vitro fertilization cycles in which the lead follicle is >14 mm. Fertil Steril. 2004 Mar;81(3):714-5.

9. Blastocyst versus early cleavage embryo transfer: a retrospective analysis of 4,165 transfers.

A retrospective analysis of all the ovarian stimulation-in vitro fertilization-embryo transfer cycles was performed at the Centre for Human Reproduction, Athens, Greece, between June 1997 and December 2001 to compare the clinical outcomes after the transfer of blastocysts versus early cleavage embryos in assisted reproduction technologies (ART). The number of blastocysts transferred per ET was significantly lower compared to that of all early cleavage embryos. The implantation rate of blastocysts was significantly higher compared to that of all other modes of transfer. Clinical pregnancy rate after the transfer of blastocysts was significantly increased compared to that after transfer of any early cleavage embryo. The viable pregnancy rate after the transfer of blastocysts was significantly increased only compared to that after the transfer of day-2 embryos. There were no significant differences regarding the multiple gestation rates among the various modes of transfer.
CONCLUSION:The use of blastocysts in ART is beneficial when compared to that of day-2 embryos and at least comparable to that of day-3 embryos. Blastocyst culture and transfer remains a favourable and promising option in ART.

Reference

Pantos K, Makrakis E, Karantzis P, Stavrou D, Grammatis M, Chronopoulos K. Blastocyst versus early cleavage embryo transfer: a retrospective analysis of 4,165 transfers. Clin Exp Obstet Gynecol. 2004;31(1):42-4.

10. Single blastocyst transfer: a prospective randomized trial.

A prospective randomized trial was conducted in 48 women undergoing IVF-embryo transfer with day 3 FSH 12 mm in diameter on day of hCG administration in order to determine the efficacy of single blastocyst transfer. Embryo culture to the blastocyst stage was performed in sequential media G1/G2 followed by transfer of either one or two blastocysts. The transfer of a single blastocyst resulted in an implantation and ongoing pregnancy rate of 60.9% with no twins. The transfer of two blastocysts resulted in an implantation rate of 56%, an ongoing pregnancy rate of 76% with a 47.4% incidence of twins.
CONCLUSION(S): Single blastocyst transfer is an effective method of eliminating multiple births while maintaining high pregnancy rates in this selected group of patients.

Reference

Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004 Mar;81(3):551-5.

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11. Blastocyst-stage embryo transfer in patients who failed to conceive in three or more day 2-3 embryo transfer cycles: a prospective, randomized study.

A prospective, randomized study was conducted to compare blastocyst-stage embryo transfers (ETs) with day 2-3 ETs in 54 patients with an adequate ovarian response who failed to conceive in three or more day 2-3 IVF/ET cycles. Ovarian down-regulation was obtained using GnRH agonist, and controlled ovarian hyperstimulation was achieved using daily administration of gonadotropins. The rate of blastocyst formation, ET cancellations, pregnancies, implantation, multiple gestation, and live births were determined. The clinical pregnancy rates per oocyte retrieval were 21.7% and 12.9% per blastocyst and day 2-3 ETs, respectively. Although there was a significantly higher implantation rate for blastocyst embryos (21.2%) as compared with 48- to 72-hour embryos (6%), the multiple-pregnancy rate was not significantly different between both groups. An ET cancellation rate of 26% and 6.4% for blastocyst and day 2-3 ETs, respectively, was observed. The presence of two or more 8-cell embryos on day 3 in culture carried a high probability of obtaining blastocysts for transfer.
CONCLUSION(S): This prospective randomized study suggests that in patients with an adequate ovarian response who failed to conceive in at least three IVF/ET cycles [1]. transfer of blastocyst-stage embryos carries a significantly higher implantation rate; [2]. the pregnancy rate per oocyte retrieval and ET are higher in the blastocyst-stage group, even if it did not reach statistical significance; [3]. a higher ET cancellation rate was observed in the whole blastocyst-stage group; [4]. the ET cancellation rate was reduced significantly if the decision to proceed to blastocyst transfer was made on day 3 after oocyte retrieval, which is a post hoc conclusion.

Reference

Blastocyst-stage embryo transfer in patients who failed to conceive in three or more day 2-3 embryo transfer cycles: a prospective, randomized study. Fertil Steril. 2004 Mar;81(3):567-71.

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Gerhard Leyendecker