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15.07.2000

Newsletter No. 4

No principle morphological difference between endometriosis and adenomyosis Infertility in endometriosis: hormonal treatment? Increased risk of early pregnacy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction Assisted zonal hatching (AZH) or transfer of zona-free embryos? 1. No principle morphological difference between endometriosis and adenomyosis Sampson’s theory of the pathogenesis of endometriosis according to which pelvic endometriosis would result from the transtubal shedding of endometrial tissue by means of retrograde menstruation finally lead to the view that endometriosis and adenomyosis are pathogenically different entities. Not only the different localizations (uterus versus pelvic peritoneum) but also the cellular composition of the two lesions would characterise them as different entities. Endometriotic lesions were glandular and adenomyotic lesion were musculo-glandular in character. Adenomyotic lesions are also found at extrauterine sites such as the bowel, the sacro-uterine ligaments and the recto-vaginal septum. Such lesions are referred to as "deep infiltrating" endometriosis. Recently, the view was advanced that superficial endometriosis could not develop into deep endometriosis, because they were different entities. While superficial endometriosis would result from the transtubal shedding of endometrial cells and tissue of the zona functionalis by retrograde menstruation deep infiltrating endometriosis would originate from the basal endometrium as does adenomyosis. Deep infiltrating endometriosis, therefore, should be considered as adenomyosis. Recent immunocytochemical studies using monoclonal antibodies directed against muscle-specific actin, however, demonstrated the presence of muscular tissue in nearly all lesions of superficial endometriosis. Thus, the definition of distinct endometriotic entities based on the difference in the tissue composition of the lesions (endometriotic nodules versus adenomyotic nodules) is inconsistent with the very frequent presence of smooth muscle cells in endometriosis irrespective of its localization. These data add to the view that endometriosis and adenomyosis can be considered as a pathogenic entity. References Brosens IA, Brosens JJ (2000) Is deep endometriosis a progressive disease? Hum. Reprod. 15: 1-3 Anaf V, Simon Ph, Fayt I, Noel J-C (2000) Smooth muscles are frequent components of endometriotic lesions. Hum. Reprod. 15: 767-771 Kunz G, Beil D, Huppert P, Leyendecker G (2000) Structural abnormalities of the uterine wall in women with endometriosis and infertility visualised by vaginal sonography and magnetic resonance imaging. Hum. Reprod. 15: 76-82 Leyendecker G (2000) Endometriosis is an entity with extreme pleiomorphism. Hum Reprod. 15: 4-7 TOP 2. Infertility in endometriosis: hormonal treatment? According to the ESHRE Capri Workshop Group there seems to be enough available evidence to suggest that drugs suppressing ovulation are of no benefit to infertile women with endometriosis and their use only delays potential conceptions in comparison with expectant management or alternative therapies such as assisted reproduction. In the light of this scenario, hormonal drugs should no longer be prescribed, either alone or in combination with surgery, with the aim of increasing the pregnancy rate in infertile women. References The ESHRE Capri Workshop Group (2000) Optimal use of infertility diagnostic tests and treatments. Hum. Reprod. 15: 723-732 TOP 3. Increased risk of early pregnacy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction. Pituitary downregulation with GnRH-analogues in the long protocol results in a strong suppression of gonadotropin serum levels. The impact of suppressed concentrations of circulating luteinizing hormone (LH) during ovarian stimulation on the outcome of in-vitro fertilization or intracytoplasmatic sperm injection treatment in 200 consecutive, normogonadotropic women (couples) was analysed retrospectively. A standard stimulation protocol with mid-luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation and ovarian stimulation with recombinant follicle-stimulating hormone (FSH) was used in all cases. Blood was sampled from each woman on stimulation days 1 and 8 for analysis of oestradiol and LH in serum. A threshold value of serum of 0.5 IU/l on stimulation day 8 (S8) was chosen to discriminate between women with low or ‘normal’ LH concentrations. Low concentrations of LH on S8 (<0.5 IU/l) were found in 49% of the women. This group of women was comparable with the normal LH group with regard to pre-treatment clinical parameters, and to parameters characterizing the stimulation protocol with the exception of serum oestradiol concentrations, which on S8 was significantly lower than in the normal LH group (P < 0.001). The proportion of positive pregnancy tests was similar in the two groups (30% versus 34% per started cycle), but the final clinical treatment outcome was significantly different, with a five-fold higher risk of early pregnancy loss (45% versus 9%) in the low LH group and consequently a significantly poorer chance of delivery than in the ‘normal’ LH group. It is concluded that a substantial proportion of normoganodotrophic women treated with GnRH agonist down-regulation in combination with FSH, devoid of LH activity, experience LH suppression, which compromises the treatment outcome. Whether theses women would benefit from supplemention with recombinant LH or human menopausal gonadotrophin during ovarian stimulation, remains to be proven with future prospective randomized trials. References Westergaard LG, Laursen SB, Andersen CY (2000) Increased risk of early pregnacy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction. Hum. Reprod. 15: 1003-1008 TOP 4. Assisted zonal hatching (AZH) or transfer of zona-free embryos? Assisted zona hatching (AZH) has being used in IVF programmes for several years and controversially discussed with respect to its benefit to increase pregnancy rates in elder women. Recently, successful pregnancies have been reported after transfer of zona-free blastocysts. It was the study of Mansour and co-workers to evaluate outcomes after transfer of zona-free day 3 embryos. Two groups of women undergoing ICSI were included in the study. Group A consisted of 52 women under the age of 40 years undergoing their first ICSI attempt. They were alternately randomized to receive zona-free embryos (27 women) and zona-intact embryos (25 Women). The second group (group B) included 71 women with a poor prognosis, as defined by age 40 years or more, and/or at least two previously failed IVF/ICSI attempts. They were randomized in a 3:4 ratio (30 zona-free, 41 zona intact). Acid Tyrode’s solution was used to remove the zona pellucida before embryo transfer on day 3 after oocyte collection. The pregnancy rate in group A was not significantly improved when the zona pellucida was removed. However, in the poor prognosis group B, zonal removal resulted in a significantly higher pregnancy rate when compared with controls (23 versus 7.3%). We conclude that complete removal of the zona pellucida can improve pregnancy rates in women with poor IVF/ICSI prognosis. There was no indication that zona pellucida removal increased the chance of monocygotic twinning. References Mansour RT, Rhodes CA, Aboulgar MA, Serour GI, Kamal A (2000) Transfer of zona-free embryos improves outcome in poor prognosis patients: a prospective randomized controlled study. Hum. Reprod. 15: 1061-1064

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