Comparison of aspirating pipettes and hysteroscopy with curettage.

PURPOSE: In this prospective study, endometrial biopsy by pipette was compared with hysteroscopy with curettage in patients with an abnormal uterine bleeding (ABU) (hypermenorrhea, intermediate bleeding, continuous bleeding, postmenopausal bleeding) and patients with a sonographically abnormal endometrium. METHODS: 176 patients were included. The pipette samples were taken during the usual planned procedure under general anaesthesia. Thereafter, the planned hysteroscopy with curettage was completed. The study was performed as a double-blind study. The obtained histologies (of pipelle and curettage) were sent separately to the same pathologist. The pipelle material was encoded by a specific number without any patient data. RESULTS: In 97% of the cases using the biopsy with pipette were obtained an adequate sample. The biopsy with pipette had a sensitivity and specificity of 100% in the diagnosis of endometrial carcinoma and atypical hyperplasia. Pipette showed a significantly lower accuracy with a sensitivity of 28% in the diagnosis of endometrial hyperplasia without atypia. Pipette showed the lowest sensitivity for polyps, myomas and atrophic endometrium. CONCLUSION: The study shows that pipette sampling is a safe, accurate, low-cost ambulatory procedure with high sensitivity for the detection of atypical endometrial hyperplasia and endometrial carcinoma. In the case of sonographically definable findings (polyp, myoma), hysteroscopy with curettage is preferred.

Array-comparative genomic hybridization analysis in patients with Müllerian fusion anomalies.

Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic-multifactorial inheritance can be assumed but autosomal-dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array-comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1ß as well as in 22q11.21 have already been observed in MRKHS (Mayer-Rokitansky-Küster-Hauser syndrome). In summary, we (1) detected causative micro-rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies.

The use of cyproterone acetate/ethinyl estradiol in hyperandrogenic skin symptoms - a review.

INTRODUCTION: Hyperandrogenism affects approximately 10-20% of women of reproductive age. Hyperandrogenic skin symptoms such as hirsutism, acne, seborrhea and alopecia are associated with significant quality of life and psychological impairment. Women with abnormalities in androgen metabolism may have accompanying anovulation and/or polycystic ovary syndrome (PCOS), both of which have reproductive and metabolic implications if left untreated. Cyproterone acetate (CPA), combined with ethinylestradiol (EE), is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism, in women of reproductive age. OBJECTIVE: To review the data on the efficacy and safety of CPA 2 mg/EE 35 µg for the treatment of hyperandrogenic skin symptoms in women. METHODS: A non-systematic narrative review based on a literature search of the PubMed database. RESULTS: Seventy-eight studies were identified. The majority of sufficiently powered studies show a high efficacy of CPA 2 mg/EE 35 µg in the treatment of severe acne and hirsutism. Studies show that therapeutic response in women with hirsutism requires a long-term approach and that hyperandrogenic skin symptoms in patients with PCOS are efficiently treated. Additional benefits include cycle control and, in some women, improvement in mood and perception of body image. Safety and tolerability data are summarized by the pharmacovigilance risk assessment committee (PRAC) of the European Medicine's Agency's (EMA). CONCLUSIONS: This review provides a comprehensive overview about the efficacy of CPA 2 mg/EE 35 µg in the treatment of hyperandrogenic skin symptoms, thus allowing both health care professionals and women to balance the risks and benefits of treatment based on evidence.

Indications and Route of Hysterectomy for Benign Diseases. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry No. 015/070, April 2015)

Background: Official guideline "indications and methods of hysterectomy" to assign indications for the different methods published and coordinated by the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (OEGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). Besides vaginal and abdominal hysterectomy, three additional techniques have been implemented due to the introduction of laparoscopy. Organ-sparing alternatives were also integrated. Methods: The guideline group consisted of 26 experts from Germany, Austria and Switzerland. Recommendations were developed using a structured consensus process and independent moderation. A systematic literature search and quality appraisal of benefits and harms of the therapeutic alternatives for symptomatic fibroids, dysfunctional bleeding and adenomyosis was done through MEDLINE up to 6/2014 focusing on systematic reviews and meta-analysis. Results: All types of hysterectomy led in studies to high rates of patient satisfaction. If possible, vaginal instead of abdominal hysterectomy should preferably be done. If a vaginal hysterectomy is not feasible, the possibility of a laparoscopic hysterectomy should be considered. An abdominal hysterectomy should only be done with a special indication. Organ-sparing interventions also led to high patient satisfaction rates, but contain the risk of symptom recurrence. Conclusion: As an aim, patients should be enabled to choose that therapeutic intervention for their benign disease of the uterus that convenes best to them and their personal life situation.

Mutations in WNT9B are associated with Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a well-known malformation pattern of the Müllerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b-/- mice show a MRKHS-like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls. One nonsense mutation and five likely pathogenic missense mutations were detected in WNT9B. Five of these mutations were found in cases with MRKHS accounting for 4.6% of the patients with this phenotype. No pathogenic mutations were detected in the control group (p = 0.017). Interestingly, all of the MRKHS patients with a WNT9B mutation were classified as MRKHS type 1, representing 8.5% of the cases from this subgroup. In previous studies, two of the patients with a WNT9B mutation were found to carry either an additional deletion of LHX1 or a missense mutation in TBX6. We conclude that mutations in WNT9B were frequently associated with MRKHS in our cohort and some cases may be explained by a digenic disease model.

The Prevention of Positioning Injuries during Gynecologic Operations. Guideline of DGGG (S1-Level, AWMF Registry No. 015/077, February 2015).

Purpose: Official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). Positioning injuries after lengthy gynecological procedures are rare, but the associated complications can be potentially serious for patients. Moreover, such injuries often lead to claims of malpractice and negligence requiring detailed medical investigation. To date, there are no binding evidence-based recommendations for the prevention of such injuries. Methods: This S1-guideline is the work of an interdisciplinary group of experts from a range of different professions who were commissioned by DGGG to carry out a systematic literature search of positioning injuries. Members of the participating scientific societies develop a consensus in an informal procedure. Afterwards the directorate of the scientific society approves the consensus. The recommendations cover.

Treatment of Iron Deficiency in Women.

Iron deficiency with and without anaemia is a common cause of morbidity, particularly in women. Iron deficiency is generally the result of an imbalance between iron loss and iron absorption. In women with symptoms suspicious for iron deficiency, it is important to confirm or exclude the suspicion using proper tests. The use of serum ferritin levels is considered the gold standard for diagnosis. Although the ideal ferritin levels are not unknown the current consent is that levels < 40 ng/ml indicate iron deficiency, which needs to be treated in symptomatic patients. However, symptoms can already occur at ferritin levels of < 100 ng/ml and treatment must be adapted to the individual patient. Iron supplementation is only indicated in symptomatic patients diagnosed with iron deficiency whose quality of life is affected. It is important to treat iron deficiency together with its causes or risk factors. For example, blood loss from hypermenorrhea should be reduced. Women also need to receive information about the benefits of an iron-rich diet. If oral treatment with iron supplements is ineffective, parenteral iron administration is recommended.

The accessory spleen: prevalence and imaging findings in 1,735 consecutive patients examined by multidetector computed tomography.

OBJECTIVE: To analyze the prevalence and CT findings of accessory spleens in the normal population. MATERIAL AND METHODS: CT-examinations of 1735 consecutive patients, all examined by triple phase 16-row multidetector computed tomography (MDCT) of the abdomen, were retrospectively analyzed with special emphasis on the presence, location and imaging aspects of accessory spleens. RESULTS: 199 patients showed an accessory spleen (11%). Size of accessory spleens ranged from 3 to 20 mm (mean 10 mm). In 60% the accessory spleen was located at the level of the splenic hilum and in 33% at the level of the lower pole. In 46% the accessory spleen was located medially and in 43% ventrally. 19 patients presented with two (1.1%) and seven patients with three accessory spleens (0.4%), respectively. One patient showed splenosis and one patient showed an enlarged accessory spleen (5 cm) secondary to a splenic apoplexy (i.e. hemorrhagic infarction) of the accessory spleen, caused by torsion. CONCLUSION: Accessory spleens may be identified by MDCT in about 11% of patients. Familiarity with normal imaging findings and knowledge on differential diagnoses, possible pathologies and potential pitfalls helps to differentiate from other findings in the upper abdomen.

Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial.

BACKGROUND: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E(2)V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology. METHODS: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E(2)V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90-day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. RESULTS: The intention-to-treat population comprised 231 women. The E(2)V/DNG response rate was much higher than with placebo (P < 0.0001). The mean reduction in MBL volume in E(2)V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E(2)V/DNG (95% confidence interval 490, 255 ml; P < 0.0001). Significant improvements in iron metabolism parameters were observed with E(2)V/DNG but not placebo. Overall, 14 women (9.7%) treated with E(2)V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E(2)V/DNG and placebo groups (each n = 2). CONCLUSIONS: E(2)V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E(2)V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801.

Seven years of safety and efficacy of the recombinant human growth hormone Omnitrope in the treatment of growth hormone deficient children: results of a phase III study.

AIM: This phase III clinical study in growth hormone deficiency (GHD) children with growth retardation was designed to compare efficacy and safety of Omnitrope((R)) with Genotropin((R)) and assess the long-term safety and efficacy of Omnitrope((R)). The results of 7 years of treatment with Omnitrope((R)) are presented. PATIENTS AND METHODS: Eighty-nine treatment-naïve, prepubertal children with GHD were randomized (part 1) to Omnitrope((R)) lyophilisate (group A, n = 44) or Genotropin((R)) (group B, n = 45) for 9 months and received a subcutaneous dose of 0.03 mg/kg/day. In part 2, patients receiving Omnitrope((R))lyophilisate continued the same treatment for a further 6 months, while patients on Genotropin((R)) were switched to Omnitrope((R)) liquid for the subsequent 6 months. In part 3, patients in both groups received Omnitrope((R))liquid for a period up to 69 months. RESULTS: The development of the 4 auxological parameters (height, height SD score, height velocity and height velocity SD score) and IGF-1 and IGFBP-3 levels were comparable between both groups of patients and confirmed the well-known growth response of GHD children to recombinant human GH treatment. Omnitrope((R)) was well tolerated and safe over 7 years of treatment. CONCLUSION: The clinical comparability between Omnitrope((R)) and Genotropin((R)) was demonstrated within 9 months of treatment. Long-term safety and efficacy of 7 years of treatment with Omnitrope((R)) was proven.

Efficacy and safety of a new ready-to-use recombinant human growth hormone solution.

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rh- GH, somatropin), approved as the first 'biosimilar' in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy endpoints and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was -0.20 cm/yr (95% confidence interval (CI) [-1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [-0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.

Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: abnormal processing causes signaling deficiency.

Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig cell hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.

[Prophylaxis of Postoperative Nausea and Vomiting FollowingGynaecological Laparoscopy]. / Mono- und Kombinationsprophylaxe von Ubelkeit und Erbrechen nach gynäkologischen Laparoskopien.

OBJECTIVE: Compared to other procedures, gynaecological laparoscopies are followed rather frequently by postoperative nausea and vomiting (PONV). Therefore, we investigated the prophylactic antiemetic efficacy of metoclopramide and droperidol under general anaesthesia with isoflurane (part 1). Given the rather unsatisfying results of this monoprophylaxis we examined the effects of a quintuple prophylaxis in this setting (part 2). METHODS: Part 1: Following ethical committee approval and written informed consent 120 patients scheduled for elective gynaecological laparoscopy were allocated prospectively, randomly and observer-blinded to the following groups: group P (placebo): 2 ml NaCl 0.9 %, group D: 2.5 mg droperidol, group M: 10 mg metoclopramide. Part 2: Subsequently 50 patients scheduled for elective gynaecological laparoscopy and bearing a minimum risk of 25 % to experience postoperative vomiting were allocated prospectively and blinded to the observers to a quintuple prophylaxis group: group X: 10 mg metoclopramide, 2.5 mg droperidol, 12.5 mg dolasetron, 62.5 mg dimenhydrinate, 8mg dexamethasone. Part 1 and 2: Anaesthesia was induced with fentanyl, etomidate and succinycholine and maintained with isoflurane/N2O, fentanyl and cisatracurium. The antiemetics were applied intravenously 20 min prior to end of surgery. RESULTS: Within the first 24 h postoperatively vomiting occurred more frequently in group P (44 %) compared to group D (21 %, p = 0.046) and group M (33 %, n. s.). Nausea also occurred more frequently in group P (61 %) compared to group D (24 %, p = 0.003) and group M (48 %, n. s.). Intensity of nausea was reduced both in group D and group M compared to group P (p = 0.03). Likewise the requirements for antiemetics as a rescue medication were reduced in group D (p = 0.02) and group M (p = 0.047) compared to group P. In group X no patient suffered from postoperative vomiting, no patient required a rescue antiemetic. CONCLUSIONS: Whereas droperidol provides a reliable antiemetic effect, the prophylactic effect of metoclopramide is rather uncertain. Therefore, further studies regarding a dose response-relationship for metoclopramide are deemed necessary. Since a monoprophylaxis with droperidol or metoclopramide failed to attain a satisfying PONV-prophylaxis in patients at high risk for PONV, the quintuple antiemetic combination might be an effective and safe solution.

Treatment of a torqued hematosalpinx in the thirteenth week of pregnancy using gasless laparoscopy.

Laparotomy and carbon dioxide laparoscopy are relatively traumatic and high-risk operations for patients. They may have negative effects on pregnancy, especially in advanced pregnancy. Gasless laparoscopy was performed on torqued hematosalpinx in a woman in the thirteenth week of pregnancy. After salpingectomy, the pregnancy proceeded normally.

IGFBP-1 and glycodelin serum levels before and after hysterectomy with and without bilateral oophorectomy in premenopausal women.

OBJECTIVES: The aim of our study was to investigate the role of the intact endometrium and ovaries for serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) and glycodelin. STUDY DESIGN: In 35 premenopausal patients with a planned hysterectomy, serum measurements of IGFBP-1 and glycodelin were done before surgery and 1, 3, 5, and 10 days after surgery. Patients were divided into three groups according to the kind and time of operation: (1) hysterectomy with bilateral adnexectomy in the luteal phase and (2) hysterectomy without adnexectomy in the follicular phase or (3) the luteal phase. RESULTS: IGFBP-1-we could not show any differences in IGFBP-1 serum levels before and after hysterectomy with or without bilateral oophorectomy. Glycodelin-hysterectomized and oophorectomized patients showed decreasing serum levels up to day 3. After day 5, circulating concentrations of glycodelin increased continuously but remained below pre-operative levels. In both non-adnexectomized groups we saw a reduction up to day 5 but a rise at day 10. None of the results reached statistical significance. CONCLUSION: The results indicate that endometrium and ovary are not the only sources of IGFBP-1 and glycodelin.

Raman spectroscopic evaluation of the effects of diet and lipid-lowering therapy on atherosclerotic plaque development in mice.

Quantitative characterization of atherosclerotic plaque composition with standard histopathological methods remains limited to sectioned plaques. Raman spectroscopy enables nondestructive quantification of atherosclerotic plaque composition. We used Raman spectroscopy to study the effects of diet and lipid-lowering therapy on plaque development in apolipoprotein (APO) E*3-Leiden transgenic mice. Raman spectra were obtained over the full width and entire length of the ascending aorta and aortic arch. Spectra were modeled to calculate the relative dry weights of cholesterol and calcium salts, and quantitative maps of their distribution were created. In male mice (n=20) that received a high-fat/high-cholesterol (HFC) diet for 0, 2, 4, or 6 months, Raman spectroscopy showed good correlation between cholesterol accumulation and total serum cholesterol exposure (r approximately 0.87, P<0.001). In female mice (n=10) that were assigned to an HFC diet, with or without 0.01% atorvastatin, a strong reduction in cholesterol accumulation (57%) and calcium salts (97%) (P<0.01) was demonstrated in the atorvastatin-treated group. In conclusion, Raman spectroscopy can be used to quantitatively study the size and distribution of depositions of cholesterol and calcification in APOE*3-Leiden transgenic mice. This study encourages Raman spectroscopy for the quantitative investigation of atherosclerosis and lipid-lowering therapy in larger animals or humans in vivo.

Anticardiolipin antibodies in ectopic pregnancies.

BACKGROUND: Anticardiolipin auto-antibodies are known to be inflicted in recurrent pregnancy losses and other adverse outcomes of pregnancy. However, their role in extrauterine pregnancies is unknown. OBJECTIVE: To clarify the association between anticardiolipin antibodies and extrauterine pregnancies. PATIENTS AND METHODS: About 30 patients with ectopic pregnancies confirmed histologically and 40 control subjects with intrauterine pregnancies were studied. Mean duration of pregnancy was 38 and 39 days, respectively. Serum levels of IgG, IgA, and IgM antibodies against cardiolipin were measured. In addition, measurements of human chorionic gonadotropin (beta hCG) and progesterone were made. RESULTS: Mean levels of IgA and IgM but not IgG antibodies were significantly higher in patients with ectopic pregnancies than in normal pregnant women. Distribution frequency histograms revealed that a subgroup of ectopic pregnancies exhibit antibody titers corresponding to that of intrauterine pregnancies, and others showing elevated levels. Markedly elevated antibody levels were observed in patients having low levels of beta hCG and/or progesterone. CONCLUSION: In view of the inflammatory events associated with some cases of ectopic pregnancies, elevated levels of anticardiolipin auto-antibodies may give clues to pathogenesis. Determination of IgM antibodies may help discriminate ectopic pregnancies with auto-immune pathogenesis from those caused by other factors.

Conservative treatment of ectopic pregnancy in a cesarean section scar with methotrexate: a case report.

Ectopic pregnancies sited in dehiscent cesarean section scars have a high risk of rupture and bleeding. Attempts at operative therapy frequently end in loss of the uterus. A connection with the cavum uteri justifies an attempt at dilatation and curettage. We describes a patient with combined systemic and local intra-amniotic methotrexate (MTX). The uterus was preserved.