Initiation of ovarian stimulation independent of the menstrual cycle: a case-control study.

PURPOSE: In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. METHODS: This was a prospective, case-control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18-36 years; ≤3 previous IVF/ICSI attempts; BMI 20-30 kg/m(2); regular cycle (28-35 days); luteal phase progesterone >7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle®) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19-21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150-225 rFSH or HP-HMG/day. RESULTS: The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m(2), of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: -29.2-22.2 %, p = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7). CONCLUSIONS: Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.

Influence of acetic acid on a pap smear of dysplastic lesion.

BACKGROUND: Cervical cancer prevention is performed by taking Pap smears. The correct execution of the smear is crucial as an inadequate smear might result in underdiagnosis. The second means of cervical cancer prevention is visual inspection of the cervix uteri with acetic acid, while often both methods are combined. We investigated whether the application of acetic acid compromises the Pap smear. PATIENTS AND METHODS: A total of 100 patients with dysplasia were prospectively included; Pap smears were obtained before and after the application of acetic acid. RESULTS: We observed an alteration of the result of the Pap smear after acetic acid application in 41%. However, these alterations did not result in a dysplastic case being classed as a normal smear or vice versa. CONCLUSION: The application of acetic acid to the transformation zone of the cervix uteri may enhance changes of the Pap smear in dysplasia, however, the changes affect subgroups of dysplasia and thus do not change therapeutic management.

Are there changes in characteristics and therapy of young patients with early-onset breast cancer in Germany over the last decade?

PURPOSE: The objective of the study is to investigate recent changes in patient characteristics and treatment procedures of young breast cancer patients over the last 10 years in Germany. METHODS: The study describes the data of 518 patients who were treated adjuvantly between 2008 and 2011 and participated in a resident mother-child program for rehabilitation (cohort II). The data includes TNM-categories, biology of tumor and therapies. This population is compared to a cohort of 535 patients, who were treated between 2002 and 2006 (cohort I). Characteristics and treatment of cohort II are compared with a normally age distributed cohort. RESULTS: 51.5 % of the patients in cohort II were diagnosed with tumor category pT1, 36.9 % pT2, 4.4 % pT3 and 1.2 % pT4. 3.3 % had merely DCIS. 58.1 % of the patients were pN0, 28.4 % pN1 and 13.5 % had a more intense manifestation of lymph nodes. 45.8 % of the tumors showed a grading classified as G3, 69.3 % were estrogen and progesterone hormone receptor positive and 21.8 % Her2 positive. 24.5 % of the examined patients showed a triple negative carcinoma. 66.2 % of the patients with pT1 or pT2 underwent breast-conserving surgery. Overall 19.2 % of the women received mastectomy only and 17.4 % received mastectomy with subsequent reconstruction. 98.6 % of the patients received axillary surgery, 87.6 % chemotherapy. Overall, 21.0 % of the patients received their chemotherapy in connection with clinical studies. 88.0 % of the patients with hormone receptor positive tumors received endocrine therapy, 25.5 % of them with GnRH-analogs. In comparison with cohort I the tumors in cohort II were detected with a higher proportion of negative lymph nodes (48.8 %/58.1 %, p = 0.008) and G1 grading (4.9/5.6 %, p = 0.001). On the other hand the percentage of triple negative tumors increased from 21.0 % to 24.5 % (p = 0.018). Operative therapy has adjusted to a more moderate way. Breast-conserving therapy with pT1 and pT2 increases from 57.3 % to 66.2 % (p = 0.006), sentinel lymph node biopsy only from 24.5 % to 47.5 % (p[Symbol: see text]0.001) over the years. The percentages of chemotherapy, radiation, endocrine therapy and antibody therapy with positive receptor have stayed stable over the last decade. Comparing cohort II with a normally age distributed group (DMP II 2007-2009) the young patients have still a much lower portion of negative lymph nodes (58.1 %/67.9 %) and positive hormone receptor status (69.3 %/85.1 %). The percentage of a high grading G3 is 45.8 % in cohort II versus 24.7 % in DMP II. The portion of breast-conserving therapy with pT1 is with 68.9 versus 82.2 % still comparatively low. Young patients received more axillary surgery (98.6 %/81.5 %) but less endocrine therapy with hormone receptor positive tumors (93.3 %/94.7 %). CONCLUSION: Young breast cancer patients in Germany can still be regarded as a special group. Although tumors are now more often detected before reaching the lymph nodes than 10 years ago, an even bigger percentage is triple negative. Operative treatment has improved to a less aggressive way. Still operative and medical treatments have to be chosen after very careful evaluation.

Fetal intra-abdominal tumors: assessment of spectrum, accuracy of prenatal diagnosis, perinatal outcome and therapy at a tertiary referral center.

OBJECTIVE: To describe the varieties and ultrasound characteristics of prenatally diagnosed fetal abdominal tumors and to scrutinize the accuracy of prenatal diagnosis as well as the postnatal outcome and therapy of affected pregnancies. STUDY DESIGN: Retrospective study of 354 fetuses found to have abdominal tumors on prenatal sonogram, identified from 1993 to 2009 at a tertiary referral center for prenatal medicine. The cohort was classified into subgroups according to the sonographic appearance of the fetal tumor and the affected anatomic structure (urinary, gastrointestinal and genital tracts and other locations). Sensitivity, specificity, positive predictive value and false-positive rate of ultrasonography in identifying the system of origin were calculated. Relationships between relevant outcome domains and the different subgroups were assessed using the chi-square test and Fisher's exact test. RESULTS: Our cohort comprised 222 urinary tract lesions, 37 genital tract lesions, 80 gastrointestinal lesions and 15 tumors of other origins. The mean gestational age at diagnosis was 26+0 wks. The prenatally established diagnosis was exactly concordant with postnatal findings in 88.9%. Sensitivity, specificity, positive predictive value and false-positive rate of ultrasonography in identifying the system of origin (urinary, gastrointestinal, genital tracts and other locations) were 98.3%, 97.6%, 92.6% and 2.4%, respectively. The favorable postnatal outcome rate was highest among fetuses with genital tract lesions (95%) and lowest among those with tumors of the urinary tract (62%, p=<0.001). Twenty per cent of tumors regressed spontaneously, mostly gastrointestinal tumors (36%, p=<0.001). In 75/354 cases (21%) the parents opted to terminate the pregnancy: intra-uterine fetal demise and neonatal death were each noted in 4%. Prenatal therapy was performed in 24 of 354 cases (7%) and postnatal surgery in 64 cases (18%). CONCLUSION: The majority of fetal abdominal anomalies were accurately diagnosed and the vast majority of affected fetuses had a favorable outcome, some tumors even resolved with advancing pregnancy. Pre- and post-natal invasive surgical interventions were mandatory in only a small number of cases.

The effects of cetrorelix and triptorelin on the viability and steroidogenesis of cultured human granulosa luteinized cells.

BACKGROUND: We investigated the effects of the gonadotropin-releasing hormone (GnRH) agonist triptorelin as well the GnRH antagonist cetrorelix those of on the viability and steroidogenesis in human granulosa luteinized (hGL) cell cultures. MATERIALS AND METHODS: The hGL cells were obtained from 34 women undergoing ovarian stimulation for IVF treatment. The cells were cultured for 48 h with or without 1 nM or 3 nM of cetrorelix or triptorelin in serum-free media. The cell viability was evaluated by the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. The concentrations of estradiol and progesterone in culture supernatants were measured by ELISA. RESULTS: Treatment with triptorelin slightly increased cell viability, whereas treatment with 3 nM cetrorelix led to a significant decrease. Estradiol concentrations were reduced with 3 nM triptorelin. Cultures treated with high-dose of either cetrorelix or triptorelin tended to secrete less progesterone than controls. CONCLUSION: Cetrorelix significantly reduces the viability of hGL cells. Triptorelin and cetrorelix may have minor effects on steroidogenesis. These results suggest that GnRH analogues may influence ovarian functions.

Blood loss after caesarean section: depending on the management of oxytocin application?

PURPOSE: Oxytocin donation in caesarean section is used to reduce postpartum blood loss. Cardiovascular side effects such as tachycardia, hypotension and decreased cardiac output are known and seem to depend on the way of application, whereas the blood loss is said to be similar. We aimed to examine that extent of haemorrhage in our own patients. METHOD: In July 2011, the perioperative oxytocin management was changed and the postpartum was oxytocin bolus abolished. Retrospectively, we reviewed the pre- and postpartum haemoglobin in all women who had undergone caesarean section in the year 2011 at the University Hospital of Schleswig-Holstein, Campus Luebeck. RESULTS: We found a significantly higher blood loss in those patients who were treated without oxytocin bolus but only with oxytocin infusion (-10.5 vs. -9 g/dl). CONCLUSION: We recommend to do further studies to clarify the advantage and contraindications of using oxytocin boluses and until to use the oxytocin bolus again in healthy patients but to avoid it in patients with cardiovascular risk.

Characteristics and therapy of premenopausal patients with early-onset breast cancer in Germany.

PURPOSE: The objective of the study is to investigate what kind of tumors young, premenopausal breast cancer patients in Germany show at diagnosis and how they are treated adjuvantly in comparison with a normally distributed cohort. METHODS: The study describes the data of 535 patients who were treated adjuvantly between 2002 and 2006 and participated in a resident mother-child program for rehabilitation (Groemitz cohort). The data includes TNM categories, biology of tumor and therapies. This population is being compared to an age-heterogeneous cohort from the state of Schleswig-Holstein and the DMP-report of the state of North Rhine-Westphalia. RESULTS: 45.8 % of the patients were diagnosed with tumor category pT1, 37 % pT2, 7.3 % pT3 and 1.9 % pT4. 5 % had merely DCIS. 48.8 % of the patients were pN0, 31.4 % pN1 and 17.4 % had a more intense manifestation of lymph nodes. 43.5 % of the tumors showed a grading classified as G3, 64.3 % were estrogen and progesterone hormone receptor positive and 26.2 % Her2 positive. 21 % of the examined cohort members/patients showed a triple negative carcinoma. 59.1 % of the patients with pT1 underwent breast-conserving surgery, 56.1 % of those with pT2 and 25.6 % of those with pT3. Overall 31.0 % of the women received mastectomy and 14.8 % received mastectomy with subsequent reconstruction. 97.6 % of the patients received axillary surgery, 89.9 % chemotherapy. Overall 23.7 % of the patients received their treatment in connection with clinical studies. 95.3 % of the patients with hormone receptor positive tumor received endocrine therapy, 61.3 % of them with GnRH-analogs. In comparison with the OVIS and DMP cohorts patients of the Groemitz cohort were on average 20 years younger. Their tumors were of bigger size and had more often reached the axillary lymph nodes (pN0 48.8 % Groemitz/62.0 % OVIS/66.7 % DMP). The hormone receptor status was more often negative (35.7/16.6/16.5 %) and tumor grading higher (G3 43.5/29.0/28.5 %). Surgery was more extensive even with small tumors (breast conserving surgery with tumor stage pT1 59.1/81.2/77.6 %) and axillary surgery was performed more often in the young collective (97.6/89.3/62.5 %). More patients of the young collective received chemotherapy (89.9/58.4 %/unknown) and more patients of the young collective with hormone receptor positive tumor received endocrine therapy (95.3/77.4/90.6 %). CONCLUSION: Our study shows that young breast cancer patients in Germany can be regarded as a special group. At the time of diagnosis the tumor has frequently reached a more advanced stage, and carcinomas are more aggressive. Operative and medical treatment will often be more aggressive.

Total laparoscopic hysterectomy without uterine manipulator at big uterus weight (>280 g).

METHODS: The retrospective study included the total laparoscopic hysterectomy without uterus manipulator at big uterus >280 g (Group A), proceeding the same technique as known to show feasibility and safety of its technique, compared with a randomized patient group of a uterus weight below 280 g (Group B). Statistical measurement was proceeded in typical clinical parameters. RESULTS: No statistical differences in age, body mass index, further abdominal surgery, blood loss, and hospital stay were observed. Operating time was significantly different favouring the uterus below 280 g (111.74 min Group A/90.68 min Group B). No increase in intra- or postoperative complications in both groups was observed. CONCLUSION: Total hysterectomy at big uterus (>280 g) is safe and feasible. Statistical analysis shows a significant shorter operating time only in one parameter (Group B). The technique of hysterectomy without uterus manipulator offers a surgical advancement also at vaginal stenosis, early staged cervix, or endometrial cancer and exhibits an opportunity for laparoscopic advancement in these cases too.

Influence of calcitriol on prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cell lines.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a potential molecular prognostic factor for breast cancer, and calcitriol [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is a promising target in breast cancer therapy. MATERIALS AND METHODS: The influence of calcitriol on the proliferation and the effects of calcitriol on the expression of prostaglandin- and vitamin D-metabolising enzymes were examined in benign and malignant breast cells. RESULTS: Calcitriol inhibited the proliferation of MCF-10F and MCF-7 cells but not of invasive MDA-MB-231 cells and reduced the expression of COX-2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in the benign breast cell line MCF-10F. Furthermore, dysregulation in vitamin D-metabolising proteins was detected, especially in MDA-MB-231 cells. CONCLUSION: These results suggest dysregulation of vitamin D metabolism and a lack of a possible influence of calcitriol on the metabolism of prostaglandins in the malignant breast cell lines.

Expression of prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cells.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a crucial role in prognosis of malignancy and has been associated with carcinogenesis, particularly neoangiogenesis and tumor progression. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol [1,25(OH)(2)D(3)] mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. MATERIALS AND METHODS: The expression of prostaglandin (PG)-metabolizing enzymes, vitamin D-metabolising enzymes and VDR were determined in benign and malignant breast cell lines using western blot analysis. RESULTS: We detected an inverse correlation between the two types of metabolism, a reduced VDR expression in the malignant breast cell lines, and therefore an insufficient induction of 24-hydroxylase in the malignant cells. CONCLUSION: We suggest the possibility of dysregulation of vitamin D-metabolizing enzymes in malignant breast cell lines.

Incidence of testicular malignancies and correlation to risk factors in a TESE population of subfertile men.

INTRODUCTION: In recent years, researchers have postulated a decreasing fertility potential of males and a rising incidence of testicular malignancies. MATERIALS AND METHODS: In this retrospective observational diagnostic multicenter study, 302 patient files of subfertile men whose testes were biopsied for TESE procedure were analysed. All patients referred to reproductive medicine centres in Northern Germany and they were identified by the cycle data collected by the German IVF register. A total of 280 patients (436 cycles) treated for intracytoplasmatic sperm injection after TESE procedures were eligible to be analysed. RESULTS: Our findings: 13.0% overall paternity rate before TESE procedure, 45.9% smokers, maldescensus testis was found on occasion (12.9%), and mumps orchitis previously occurred to 10 patients (3.6%). The tumour incidence rate at the time of testicle biopsy was 1.81% (= 5 pts.). Two of these patients had an anamnesis for maldescensus testis and one patient acquired mumps orchitis in childhood. CONCLUSION: Our data even reflects that tumour patients express an interest in having children after completion of cancer treatment, presenting four patients who had testicular biopsies after a previous malignancy. Moreover, there is evidence suggesting that environmental factors are causative for the trends in occurrence of male reproductive health problems. Within our highly selected population, the testicular tumour incidence rate is 100-fold higher than in a standard population. Supposing that the incidence rate of testicular malignancies among infertile men continues to increase in comparison to the incidence rate of the general male population, one has to count on an incremental number of males suffering from subfertility and testicular tumours.

Impact of cyclooxygenase-2 in breast cancer.

Prostaglandin metabolism plays a pivotal role in inflammatory processes and has also been demonstrated to have a role in carcinogenesis, tumor differentiation and tumor growth in breast cancer. Cyclooxygenase-2 (COX-2) is the key involved enzyme, as it triggers prostaglandin synthesis. We reviewed the current literature regarding the impact of prostaglandin metabolism on breast cancer and illustrated the current evidence of the COX-2 influence on breast cancer, delineating possible future prophylactic and therapeutic strategies.

Intraoperative assessment of surgical margins during breast conserving surgery of ductal carcinoma in situ by use of radiofrequency spectroscopy.

Assessment of margins when excising ductal carcinoma in situ (DCIS) of the breast is difficult. Frozen section is unreliable and specimen intraoperative radiography only provides information regarding the extent of the visualized lesion or the microcalcifications. A multi-center, single arm study was conducted to evaluate the benefit of a novel device (MarginProbe) in intraoperative margin assessment during breast conserving surgery (BCS) of DCIS, and the associated reduction of re-excisions. We present results for 22 patients, from those enrolled in our institution. The device was used as an adjunctive tool to current practice. Based on permanent histology reporting, the rate of successful procedures was 86%. The improvement in intraoperative assessment with device use was associated with a reduction in re-excision rates, from 38.8 to 18%.

Spontaneous uterine rupture at the 21st week of gestation caused by placenta percreta.

PURPOSE: To describe the management of a ruptured uterus caused by placenta percreta in the 21st week of gestation. METHODS: We present a case report of a 33-year-old patient with a ruptured uterus in the 21st week of gestation who presented at the Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Campus Luebeck. Therapeutic management was performed by laparoscopy, and consecutive laparotomy and hysterectomy. RESULTS: A 33-year-old patient presented with severe abdominal pain in the 21st week of gestation at the department of abdominal surgery. A laparoscopy was performed to exclude appendicitis. There was about one liter of blood in the peritoneal cavity and a small, bleeding lesion in the fundus uteri was found which was coagulated. The blood was evacuated and the patient returned to department of gynecology. One hour after the first operation, the patient developed signs of hypovolemic shock and ultrasound showed absent fetal heart beat. An immediate laparotomy was performed and a ruptured uterus was detected. The fetus was removed and a hysterectomy performed. Pathology results showed a placenta percreta. After a few days in hospital and transfusion of 4 liters of blood the patient was discharged in a healthy condition. CONCLUSIONS: In a pregnant woman with severe abdominal pain even in the 21st week of gestation a placenta percreta has to be considered as a differential diagnosis. If there is no evidence of other causes, laparoscopy may help to confirm the diagnosis and hysterectomy is a life saving intervention.

Ovarian stimulation: from basic science to clinical application.

Treatment for infertility, including ovarian stimulation, was first introduced almost 100 years ago. At this time, radiation therapy became an established treatment, and it was only some decades later that the problem of radiation-induced cancer emerged. Non-human gonadotrophins, such as pregnant mare serum gonadotrophin (PMSG), and human pituitary gonadotrophins (HPG), were commonly used for hormonal stimulation procedures. However, use of PMSG led to antibody formation, and it was therefore only useful for the first treatment cycle. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease. The first hormonal product from human menopausal urine to be used was human menopausal gonadotrophin (HMG), followed later by purified preparations of this product. All of these preparations contained a high percentage of unknown urinary proteins, which interfered with batch-to-batch consistency. This changed with the introduction of recombinant gonadotrophins, produced from an immortalized/standardized mammalian cell line (CHO). More recent developments include the introduction of long-acting gonadotrophin formulations. The development of gonadotrophin-releasing hormone (GnRH) analogues and more recently the use of GnRH antagonists has helped to improve ovarian stimulation protocols by optimizing their efficacy, and making them easier to administer.

Coexistent parathyroid adenoma and thyroid papillary carcinoma in pregnancy.

BACKGROUND: Primary hyperparathyroidism in pregnant women is a rare antenatal complication. Maternal symptoms include nephrolithiasis, bone disease, pancreatitis, hyperemesis, muscle weakness, mental status changes, and hypercalcemic crisis. Fetal complications comprise intrauterine growth retardation, low birth weight, preterm delivery, intrauterine fetal death, postpartum neonatal titanic crisis, and permanent hypoparathyroidism. CASE: A 23-year-old gravida was referred to our clinic with severe hyperemesis and weight loss at 32 gestational weeks. She was diagnosed with primary hyperparathyroidism because of parathyroid adenoma and treated with surgery where a synchronous thyroid papillary carcinoma was detected. After right parathyroidectomy and right subtotal lobectomy of the thyroid, the patient was stable and laboratory and clinical findings normalized. The fetus' state was monitored via reassuring non-stress cardiotocography and repeated sonographic exams until birth. Delivery was induced at 35 weeks of gestation because of preeclampsia. CONCLUSION: Parathyroid adenoma in pregnancy is a rare maternal condition with potential impact on the advancing pregnancy. Generally, a surgical approach is recommended with thorough inspection of the thyroid gland so that any irregular structure might be removed during the same surgical intervention for diagnostic reasons. In this reported case, a coexistent papillary carcinoma of the thyroid was detected accidentally and removed successfully.