Diminished pregnancy rates in endometriosis due to impaired uterotubal transport assessed by hysterosalpingoscintigraphy.

OBJECTIVE: To investigate uterotubal transport by means of hysterosalpingoscintigraphy (HSSG) in women with and without endometriosis. DESIGN: A prospective observational study. SETTING: University Hospital, Department of Obstetrics and Gynaecology, Division of Reproductive Medicine and Gynaecologic Endocrinology with 350 in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles and 400 intrauterine insemination (IUI) cycles/year. POPULATION: Cases included 56 infertile women with laparoscopic proven endometriosis and patent fallopian tubes. Twenty-two women with partners suffering from male factor infertility served as controls. METHODS: A diagnostic cycle incorporating HSSG was performed. Subsequently, patients underwent either four cycles of timed intercourse (TI) or IUI in order to achieve pregnancy. If pregnancy did not occur, IVF or ICSI was performed. MAIN OUTCOME MEASURES: Evaluation of uterotubal transport capacity in women with endometriosis and healthy controls. RESULTS: Patients suffering from endometriosis (group I) showed a significant reduction in physiologic uterotubal transport function: While 20 patients (36%) had ipsi- or bilateral uterotubal transport, there was pathological uterotubal transport contralateral to the dominant follicle or a complete failure of transport capacity (negative HSSG) in 36 patients (64%). In the controls (group II), transport function was significantly different: 15 of 22 patients (68%) revealed ipsi- and bilateral tubal demonstration, while 5 patients (22%) showed contralateral transport and 2 patients (10%) showed negative HSSG (P= 0.01). Twenty-three pregnancies were observed (pregnancy rate: 29%). Eleven out of 14 (79%) women with ipsi- or bilateral tubal transport function fell pregnant by means of TI or IUI. In seven of nine patients (78%) with a failure in tubal transport, pregnancy was achieved by IVF/ICSI, despite acceptable semen parameters (P= 0.01). CONCLUSIONS: Endometriosis is significantly associated with a reduction in physiologic uterotubal transport capacity compared with controls. This resulted in diminished pregnancy rates even in women with normozoospermic partners. Therefore, IVF/ICSI may be required even when fallopian tubes are patent or semen quality is normal.

The use of an open-freezing system with self-seeding for cryopreservation of mouse ovarian tissue.

Chemoradiotherapy in young women with cancer has substantially improved life expectancy in these patients, but these treatments often cause infertility. One method of preserving fertility is to cryopreserve ovarian tissue. In this study, an automatic open-vessel freezing system with self-seeding was tested for cryopreservation of murine ovarian tissue; the mouse is a species widely used in human and veterinary medical research. The freezing system concerned, is used for cryopreservation of oocytes and embryos in Europe. Twenty severe combined immunodeficiency (SCID) mice were ovariectomized. The ovarian tissue was either directly transplanted heterotopically into the neck muscle (group 1, n = 6) or cryopreserved after equilibration with 1.5 M dimethylsulphoxide and propanediol. After thawing, the tissue was transplanted in SCID mice (group 2, n = 6). Before and after thawing, a part of the ovarian tissue was examined with the LIVE/DEAD fluorescent viability staining. The count of follicles revealed intact (fresh 24.1%/thawed 21.7%), impaired (fresh 35.1%/thawed 35.4%), and dead follicles (fresh 40.8%/thawed 42.9%). The healthy follicular loss because of the cryopreservation was 10.0%. All recipient mice were killed after 3 weeks. Transplanted ovarian tissue was found macroscopically in all mice. Histological examination showed several growing follicles in all developmental phases in both groups of SCID mice [group 1 (fresh grafts): 315 +/- 76.3 (mean +/- SD); group 2 (cryopreserved grafts): 237 +/- 63.4]. These results demonstrate that the use of an open-freezing system allows the survival of cryopreserved mouse ovarian tissue.

Lipid peroxidation at various estradiol concentrations in human circulation during ovarian stimulation with exogenous gonadotropins.

The aim of our study was to investigate the correlation between serum malondialdehyde levels and serum estradiol concentrations in healthy human female subjects. Nine hundred and fifty-five blood samples, from infertile women undergoing controlled ovarian hyperstimulation treatment with recombinant follicle-stimulating hormone, were collected for estradiol and malondialdehyde measurements. Five groups were formed according to serum estradiol levels: Group I (< 50 pg/ml), group II (50 - 299 pg/ml), group III (300-999 pg/ml), group IV (1000-1999 pg/ml) and group V (> or = 2000 pg/ml). One-way analysis of variance was used for comparisons. Mean malondialdehyde concentrations were 1.74 +/- 0.24 mmol/ml (group I), 1.53 +/- 0.20 mmol/ml (group II), 1.69 +/- 0.24 mmol/ml (group III), 1.77 +/- 0.21 mmol/ml (group IV) and 1.86 +/- 0.20 mmol/ml (group V), respectively. Mean serum malondialdehyde level at physiological estradiol concentrations (50-199 pg/ml, group II) was significantly (p < 0.01) lower than the mean malondialdehyde levels in other groups. Mean malondialdehyde concentrations among the remaining groups did not significantly differ. Our findings suggest that in vivo lipid peroxidation might be increased when circulating estradiol concentrations are below (< 50 pg/ml) or above (> 300 pg/ml) the physiological limits. High blood estradiol levels in human female subjects during ovarian stimulation with exogenous gonadotropins could be associated with increased serum malondialdehyde concentrations.

[Fatal amnioinfusion with previous choriocarcinoma in a parturient woman]. / Patientin mit fataler Fruchtwasserembolie unter der Geburt bei einem überstandenen Chorionkarzinom.

The case of 36-year-old tercipare is described who developed choriocharcinoma in a previous pregnancy. During the first term labour the patient developed cardiac arrest, so reanimation and sectio cesarea was performed. A male new-born was delivered in good condition, but even after intensive therapy and reanimation occurred death of parturient woman with picture of disseminate intravascular coagulopathia (DIK). On autopsy and on histology there was no sign of malignant disease, so it was not possible to connect previous choricarcinoma with amniotic fluid embolism. Maybe was place of choriocarcinoma "locus minoris resistentiae" which later resulted with failure in placentation what was hard to prove. On autopsy we found embolia of lung with a microthrombosis of terminal circulation with punctiformis bleeding in mucous, what stands for DIK.

[Embolization of symptomatic myomas (UAE): technique, indication and results]. / Embolisation bei symptomatischen Uterus-Myomen (UAE): Technik, Indikationsstellung und Ergebnisse.

Presentation of indication, technique and results of transarterial uterine artery embolization (UAE) for the treatment of symptomatic myomas. Technical requirements are presented like DSA, catheters, superselective catheterisation and the different embolization materials as polyvinylalcohol (PVA) or microspheres, as well as the follow-up after UAE. The technical success rate of UAE is documented to range between 98 to 100 % and myomatous symptomatology disappears in 85 to 94 % of the cases. A reduction in the size of the myomata after UAE is observed between 48 to 70 %. A resolution of the hemorrhage disappears in 80 to 96 % of the cases immediately. Particulate embolization of the uterine artery is a new minimally invasive therapy in the management of symptomatic leiomyomas with a high efficiency and low rate of major complications. Further studies may prove the longterm results after UAE, the influence on fertility and possible late complications.

VEGF plasma pattern in ovulation induction: evidence for an episodic secretion and lack of immediate effect of hCG.

Vascular endothelial growth factor (VEGF) is a potent stimulator of vascular proliferation and permeability. Ovarian granulosa cells have been identified as a major source of the cytokine and r-hCG was able to stimulate VEGF mRNA expression in vitro. In this study we have investigated the immediate effect of ovulation induction with hCG on peripheral VEGF levels in 6 women with primary infertility enrolled in the IVF/ET program. The patients underwent a 24-hour continuous blood withdrawal with sampling intervals of 15 minutes starting from 5 hours before ovulation induction with 10.000 IU hCG. Ovulation induction with hCG had no significant immediate effect on mean peripheral VEGF levels. However, VEGF plasma levels did exhibit significant episodic fluctuations with rapid increases every 90-120 minutes without any relation to circulating hCG levels. Taken together, the results of this study suggest that VEGF is released episodically and that systemic VEGF levels are not acutely altered by ovulation induction with hCG.

[Disturbed utero-tubal transport in hysterosalpingoscintigraphy as a predictive functional test for IVF therapy]. / Gestörte uterine Transportfunktion in der Hysterosalpingoszintigraphie (HSSG) als prädiktiver Funktionstest für die Durchführung einer IVF-Therapie.

Hysterosalpingoscintigraphy (HSSG) is a simple method to evaluate the transport function of uterus and fallopian tubes. There is a quick uptake of radionuclides into the uterus and a transport to the side bearing the dominant follicle in 70 % of the patients in the late follicular phase of the cycle. Uptake and transport of the immotile radionuclides imitate the directed sperm transport through the female genital tract at the time of ovulation. 214 of 796 infertility patients with proven patency of fallopian tubes (27 %) showed only an uptake of the particles without a transport towards the fallopian tubes (negative HSSG). In these patients no spontaneous pregnancy occurred and pregnancy rate remained low by the means of timed intercourse or insemination. Indeed, the pregnancy rate (8.4 %) was significantly lower compared with the patients who became pregnant by timed intercourse, insemination or spontaneously and had a positive HSSG before (15 %; p=0.001). However, the pregnancy rate that could only be achieved by methods of ART was significantly higher in the group of patients with negative HSSG (57 % vs. 25 %, p=0.05). Our data suggest that HSSG is a new method to evaluate the integrity of the inner genital tract's transport function, especially in patients suffering from idiopathic infertility. Impaired transport function (negative HSSG) should be considered as an indication for IVF-treatment.

The detrimental role of colloidal volume substitutes in severe ovarian hyperstimulation syndrome: a case report.

Although, the mechanisms for the development of ovarian hyperstimulation syndrome (OHSS) are still not clear, the symptoms usually correlate with the levels of serum estradiol and ovarian enlargement. We report a case, where the clinical course was unusually prolonged. When menstrual bleeding had already occurred, serum estradiol was less than 10 pg/ml and the ovaries were almost normal in size, the patient developed pleural effusion and a significant alteration in blood-coagulation. This was most likely caused by an over-infusion of hydroxyethyl starch (HES) over 10 days. The pleural effusion contained high levels of HES, reaching 74% of the plasma concentration as measured by a novel method after acidic hydrolysis of HES. Carbohydrates as dextran and HES are well known to interact with the blood-coagulation system. Increase capillary permeability, typical of OHSS, leads to loss of colloidal substances into the third space, where HES is slowly degraded and osmotic pressure is high. This might prolong and aggravate the urine of OHSS.

Peripheral levels of vascular endothelial growth factor (VEGF) are higher in gonadotropin stimulated as compared to natural ovarian cycles.

The purpose of the present study was to investigate the stability of vascular endothelial growth factor (VEGF) in plasma samples and the influence of ovarian hyperstimulation on systemic levels of VEGF. Stability assays for VEGF in plasma samples revealed significant increases following even short incubations of samples at room temperature (< or = 2 h, p < 0.001). To investigate a possible impact of controlled ovarian hyperstimulation (COH) on peripheral VEGF levels, serial blood collection over one menstrual cycle was performed in unstimulated as well as in gonadotropin-stimulated cycles for in vitro fertilisation/embryo transfer (IVF/ET) (10 women each). Peripheral levels for VEGF were significantly higher in gonadotropin stimulated cycles as compared to non-stimulated cycles (p < 0.001). There was no significant difference between follicular phase and luteal phase levels in either group. VEGF levels tended to correlate with the number of follicles detected by vaginal sonography prior to oocyte aspiration (p = 0.051). In conclusion, VEGF levels are elevated in gonadotropin-stimulated IVF/ET cycles as compared to natural cycles.

Influence of pneumoperitoneum and patient positioning on preload and splanchnic blood volume in laparoscopic surgery of the lower abdomen.

STUDY OBJECTIVE: To determine the hemodynamic effects of pneumoperitoneum and patient positioning during laparoscopic surgery of the lower abdomen. DESIGN: Prospective study. SETTING: University-affiliated medical center. PATIENTS: 10 ASA physical I and II female patients scheduled for laparoscopic surgery of the lower abdomen. INTERVENTIONS: Patients were anesthetized with propofol and an alfentanil infusion, then intubated, and normoventilated. MEASUREMENTS: After intubation, a transesophageal multiplane probe for measurements of right (RVESA) and left (LVESA) ventricular end-systolic and end-diastolic areas (RVEDA and LVEDA) and ejection fraction area (RVEFa, LVEFa) was introduced; heart rate (HR) and noninvasive blood pressure (BP) were recorded every minute. Ventilation was not changed during the measurements. A transvaginal ultrasound probe was inserted to measure the diameter of the common iliac vein. Measurements were performed 15 minutes after induction of anesthesia and while patients were in the supine position (P 0), 10 minutes after CO(2) insufflation to 10 mmHg IA pressure (P 10), 10 minutes after a further increase to 15 mmHg (P 15), 10 minutes after 20 degrees Trendelenburg (P 15 T), and 20 degrees reverse Trendelenburg positions (P 15 RT). Data are shown as medians, 25th to 75th percentiles, and comparisons between P 0, P 10, P 15, and P15 T were made with the Friedman test, followed by Wilcoxon test, when significant. Data at P 15 T, P 15 RT, and P 15 were compared using the Wilcoxon test, with a p-value < 0.05 regarded as significant. MAIN RESULTS: Pneumoperitoneum at 10 mmHg abdominal pressure caused a significant increase of LVESA by 78% (RVESA: 61%) and LVEDA by 48.5% (RVEDA: 45%). The diameter of the common iliac vein was decreased by 6%. A further increase of abdominal pressure to 15 mmHg led to an additional increase of 20% (LVESA) and 17% (LVEDA). Mean arterial pressure increased by a significant 7% at P 10, decreasing subsequently by 5% at P 15. The Trendelenburg position did not alter any hemodynamic findings. Reverse Trendelenburg position, however, caused a significant LVEDA-and RVEDA-decrease by 18% and 27%, respectively, and an increase in the diameter of the common iliac vein by 22%. The LVEFa and RVEFa decreased significantly after abdominal CO(2) insufflation by 18% each (P 10) without further change. CONCLUSIONS: The lithotomy position and subsequent pneumoperitoneum increased preload, probably as a result of blood shifting from the abdomen to the thorax by compression of splanchnic vessels caused by the pneumoperitoneum. Careful fluid management, maintaining low abdominal pressure, and use of the reverse Trendelenburg position are favored to prevent adverse hemodynamic effects in laparoscopic surgery.

Role of hysteroscopy in detection and extraction of endometrial polyps: results of a prospective study.

OBJECTIVE: The aim of this study was to determine whether hysteroscopy improves the detection and extraction of endometrial polyps in postmenopausal women. This method was compared with curettage complemented by Randall polyp forceps. STUDY DESIGN: In a prospective study hysteroscopy was performed before and after curettage in postmenopausal women. In addition to curettage, the Randall polyp forceps was used to extract endometrial polyps. Curettage and polyp extraction by Randall forceps were performed by a second surgical team that did not know the results of hysteroscopy. RESULTS: A total of 83 patients were included in the study because of either postmenopausal bleeding (n = 40) or ultrasonographic abnormal endometrium (n = 37), or both (n = 6). Thirty-two patients received either hormone replacement therapy or tamoxifen. Hysteroscopy revealed endometrial polyps in 51 patients. Polyps were diagnosed by curettage alone in 22 (43%) cases. In 18 of these 22 cases remnants of polyps were extracted by Randall forceps, and in another 23 cases polyps were only found by use of the Randall forceps. Thus in 45 (88%) of 51 patients the detection of endometrial polyps by curettage and Randall forceps was possible. A second hysteroscopy procedure revealed remnants of polyps or polyps in 31 cases. These patients with incomplete curettage predominantly had a preoperative endometrial thickness of > or =10mm. CONCLUSIONS: Curettage alone in postmenopausal patients is not sufficient for detection and extraction of endometrial polyps. Additional use of Randall forceps improves detection of polyps considerably. However, with both procedures complete extraction of polyps was not achieved in a considerable number of patients. Hysteroscopy-controlled extraction was superior, especially in those patients with an endometrial thickness of >10 mm.

Freezing of human ovarian tissue--not the oocytes but the granulosa is the problem.

The freezing of human ovarian tissue may be the key for restoring fertility after systemic therapy of cancer. In contrast to others we investigated the survival rate of whole follicles, and had a special look at the granulosa cells. Ovarian tissue was collected laparoscopically (n = 10) and divided into equal parts for freezing (n = 1570) or as control (n = 1660). The cryopreservation was done slowly, or as a ultrarapid freezing. After thawing the number of follicles, oocytes and granulosa cells surviving was counted and corrected for equal volumina of the samples. While 84.5% of the oocytes survived freezing, only 40.4% of the follicles were intact after thawing. The data show that the procedure damaged follicles, which mainly affected the granulosa cells. As the intactness of follicles may play a critical role for the maturation of the oocytes after thawing the protocols should be optimised to meet the needs of oocytes and granulosa cells.

Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis.

The regulation of human implantation is still unknown. Evidence from mice suggests an essential role for several paracrine mediators but species differences with implantation in the human preclude the extrapolation of these concepts to humans. An intrauterine microdialysis device (IUMD), consisting of microdialysis tubing glued into a balloon catheter on one side and into a polypropylene tube on the other, allows a dynamic and accurate in-vivo measurement of uterine paracrine interactions in humans. Inserted into the uterine cavity in the form of a loop, it can be continuously perfused with saline to reveal a number of relevant cytokines and growth factors in uterine effluents of non-pregnant women in both follicular and luteal phases. These included interleukin (IL)-1alpha, IL-1beta, IL-6, leukaemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), epidermal growth factor, vascular endothelial growth factor (VEGF), insulin-like growth factor binding protein-1 (IGFBP-1), prolactin, and human chorionic gonadotrophin (HCG). The source of intrauterine HCG is unclear since endometrial mRNA for the HCG beta-subunit is not revealed using reverse transcriptase polymerase chain reaction analysis. Applying urinary HCG locally via the IUMD profoundly alters endometrial secretory parameters. Prolactin, IGFBP-1, and M-CSF are significantly inhibited and VEGF is regulated in a biphasic manner involving early stimulation followed by inhibition of intrauterine levels. Use of the IUMD has thus shown that the urinary HCG preparations routinely used for ovulation induction and luteal support may directly alter endometrial function.

Should add-back therapy for endometriosis be deferred for optimal results?

Add-back hormone replacement therapy has been shown to alleviate some of the hypo-oestrogenic side effects associated with gonadotrophin-releasing hormone agonists, including demineralisation of bone. Studies on patients with uterine fibroids have shown that concomitant add-back therapy reduced the efficacy of these agents, but that deferred administration was less detrimental. This trial set out to investigate if deferred add-back therapy could offer any advantages to patients with endometriosis compared with immediate therapy. Zoladex [goserelin acetate (3.6 mg every 4 weeks)] was given for 24 weeks either with placebo, with medrogestone (10 mg/day) for 24 weeks (immediate add-back therapy), or with placebo for 12 weeks followed by medrogestone (10 mg/day) for 12 weeks (deferred add-back therapy) to 123 patients. The number of responders measured using the Revised American Fertility Society score (decrease in this score of > or = 50%) was greatest in the immediate add-back therapy group, although there were no significant differences between groups. All three treatment groups showed significant decreases in bone mineral density compared with baseline but smaller losses were generally observed in the add-back groups. A significantly smaller number of patients in the immediate add-back group reported hot flushes during the first 12 weeks of treatment compared with the deferred add-back group. In conclusion, it appears that there is no extra advantage to patients with endometriosis being treated with goserelin in delaying the start of add-back therapy.

Substitution with testosterone as aromatizable substrate for induction of follicular maturation, estradiol production and ovulation in a patient with 17 alpha-hydroxylase deficiency.

17 alpha-Hydroxylase Deficiency (17 alpha-OHDS) is a rare defect of steroid biosynthesis, characterized by the inability to synthesize cortisol, androgens or estrogens, by the complete absence of follicular maturation, hypergonadotropic hypogonadism, primary amenorrhea and hypertension. Since the ovaries of such patients contain numerous primordial follicles, we hypothesized that the absence of spontaneous follicular maturation could be due to a lack of aromatizable substrate. To provide this substrate, testosterone was administered either by intra-ovarian injection or by vaginal administration. Ovarian stimulation was performed with human urinary gonadotropins. Follicular maturation and ovulation could be induced by this treatment, as determined from ultrasonography, the analysis of LH, estradiol and progesterone serum levels and the aspiration of oocytes from the mature follicles. Fertilization of these oocytes in vitro, however, did not succeed. We conclude that follicular maturation can be induced in 17 alpha-OHDS by gonadotropins when testosterone is provided as an aromatizable substrate and that estrogens are a necessary component of follicular maturation.

[Age specific and age corrected mortality in gynecological carcinoma--including breast carcinoma]. / Altersspezifische und alterskorrigierte Mortalität gynäkologischer Karzinome--einschl. Mamma-Karzinom.

Quality of life and life span are parameters which characterise a successful tumour diagnosis and therapy. We found out that the age-specific death rate and standardised death rate concerning gynaecological cancers and carcinoma of the breast in Bavaria increased and we compared different years. The standardized mortality ratio increased between 1977 and 1990 from 91 to about 108% Neither diagnostics using update equipment nor an individualised therapy improved the situation. The slightly increasing incidence rate does not explain the present rate of deaths in cancer. An important factor is the younger age and the endocrine situation of women at the time of the primary disease. 50% of our patients are less than 55 years old and pre- or perimenopausal. Estrogen-gestagen combinations used in contraceptives and hormone replacement therapy (HRS) seem to have a stimulating effect (Henderson). The significant decrease in cervical cancer is encouraging, but does not compensate the increase in breast cancer. No significant change is seen in ovarian cancer.

[Ovarian stimulation with gonadotropins in undetected tubal pregnancy within the scope of in vitro fertilization]. / Ovarielle Stimulation mit Gonadotropinen bei unentdeckter Eileiterschwangerschaft im Rahmen der In-vitro-Fertilisation.

The authors report on a patient who was pretreated with a depot GnRH-analog previous to exogenous gonadotropin stimulation before in-vitro fertilisation (IVF). The patient had an undiagnosed ectopic pregnancy. Folliculogenesis and the hormone profile were normal. In patients with patent tubes, contraception (non-hormonal) in the cycle previous to IVF should be performed.

[Extension of the concept of extracorporeal fertilization by cryopreservation of impregnated oocytes]. / Die Erweiterung des Konzepts der extrakorporalen Befruchtung durch die Kryokonservierung imprägnierter Eizellen.

Cryopreservation of human embryos within in-vitro fertilization treatment was already proposed in 1977 by Edwards and Steptoe. Today, this procedure is used worldwide by several teams as a standard method to enhance the success rate of IVF. In spite of this, there are many disadvantages of the freezing of embryos, furthermore it is legally prohibited in Germany. We report on a new concept for treatment, which includes the freezing of impregnated oocytes after IVF and their transfer in subsequent cycles. From 109 out of 120 patients who were treated with a long acting GnRH analogue or a contraceptive pill before IVF stimulation, "supernumerary" impregnated oocytes could be frozen. Twenty-three pregnancies resulted after immediate embryo transfer, and thirty patients, who returned for the transfer of cryopreserved oocytes, became pregnant. Neither the IVF pre-treatment, nor the stimulation in the transfer cycles of frozen oocytes with clomiphene citrate, influenced the success rate significantly. Combining the 53 pregnancies, a cumulative pregnancy rate of 49% can be calculated per IVF stimulation treatment. This means a doubling of the success rate, compared with routine IVF treatment. Although there are still problems to be solved, as, for instance, the insufficient implantation rate of 7% after the transfer of frozen/thawed cells, we consider cryopreservation of pronuclear oocytes a useful and promising supplement of IVF treatment. There is no further need for the freezing of embryos.