Comparison of #Enzian classification and revised American Society for Reproductive Medicine stages for the description of disease extent in women with deep endometriosis.

STUDY QUESTION: How is endometriosis extent described by the #Enzian classification compared to the revised American Society for Reproductive Medicine (rASRM) stages in women undergoing radical surgery for deep endometriosis (DE)? SUMMARY ANSWER: The prevalence and severity grade of endometriotic lesions and adhesions as well as the total number of #Enzian compartments affected by DE increase on average with increasing rASRM stage; however, DE lesions are also present in rASRM stages 1 and 2, leading to an underestimation of disease severity when using the rASRM classification. WHAT IS KNOWN ALREADY: Endometriotic lesions can be accurately described regarding their localization and severity by sonography as well as during surgery using the recently updated #Enzian classification for endometriosis. STUDY DESIGN, SIZE, DURATION: This was a prospective multicenter study including a total of 735 women between January 2020 and May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Disease extent in women undergoing radical surgery for DE at tertiary referral centers for endometriosis was intraoperatively described using the #Enzian and the rASRM classification. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 735 women were included in the study. Out of 31 women with rASRM stage 1, which is defined as only minimal disease, 65% (i.e. 20 women) exhibited DE in #Enzian compartment B (uterosacral ligaments/parametria), 45% (14 women) exhibited DE in #Enzian compartment A (vagina/rectovaginal septum) and 26% (8 women) exhibited DE in #Enzian compartment C (rectum). On average, there was a progressive increase from rASRM stages 1-4 in the prevalence and severity grade of DE lesions (i.e. lesions in #Enzian compartments A, B, C, FB (urinary bladder), FU (ureters), FI (other intestinal locations), FO (other extragenital locations)), as well as of endometriotic lesions and adhesions in #Enzian compartments P (peritoneum), O (ovaries) and T (tubo-ovarian unit). In addition, the total number of #Enzian compartments affected by DE lesions on average progressively increased from rASRM stages 1-4, with a maximum of six affected compartments in rASRM stage 4 patients. LIMITATIONS, REASONS FOR CAUTION: Interobserver variability may represent a possible limitation of this study. WIDER IMPLICATIONS OF THE FINDINGS: The #Enzian classification includes the evaluation of DE in addition to the assessment of endometriotic lesions and adhesions of the ovaries and tubes and may therefore provide a comprehensive description of disease localization and extent in women with DE. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. All authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The Prevention of Positioning Injuries During Gynecologic Surgery. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/077, October 2020).

Purpose Positioning injuries are relatively common, forensically highly relevant complications of gynecologic surgery. The aim of this official AWMF S2k-guideline is to provide statements and recommendations on how to prevent positioning injuries using the currently available literature. The literature was evaluated by an interdisciplinary group of experts from professional medical societies. The consensus on recommendations and statements was achieved in a structured consensus process. Method The current guideline is based on the expired S1-guideline, which was updated by a systematic search of the literature and a review of relevant publications issued between February 2014 and March 2019. Statements were compiled and voted on by a panel of experts. Recommendations The guideline provides general and specific recommendations on the prevention, diagnosis and treatment of positioning injuries.

Adenomyotic glands are highly related to endometrial glands.

RESEARCH QUESTION: How closely related are adenomyotic and endometrial glands? DESIGN: In this study, the mRNA and protein database www.proteinatlas.org was searched for proteins expressed predominantly in the endometrial glands. Specificity was tested with tissue microarrays. Biopsy specimens of endometrial, adenomyotic tissue, or both, were collected after surgery from 21 women without endometriosis, 20 women with endometriosis, 18 women with adenomyosis together with endometriosis and 12 women with adenomyosis alone. Tissue expression was analysed by immunohistochemistry. RESULTS: Two proteins were identified: calcyphosine (CAPS), and msh homeobox 1 (MSX1). A high abundance and good specificity in endometrial glands were found. Both proteins, CAPS and MSX1, showed a high specificity for endometrium and are both localized in the luminal cells and epithelial cells of the glandular and adenomyotic glands. No significant differences were found between CAPS- and MSX1-positive endometrial glands between cases with and without endometriosis. Also, no cycle-specific different expression was found. Furthermore, a close relationship between the adenomyotic glands and the endometrial glands for CAPS (range 63.0-98.3%) and for MSX1 (range 87.1-99.3%) could be demonstrated. Only 11.2% and 6.8% negative glands for CAPS and MSX1 were identified in all tissues from all patients, respectively; none were negative for both proteins. CONCLUSIONS: Taken together, our results show that the protein expression pattern of adenomyosis is nearly identical to those of the endometrium with and without endometriosis, thus suggesting endometrial glands as the main source for adenomyotic glands.

Interdisciplinary Laparoscopic Implantation of Neuromodulation Leads to the Sacral Plexus for Therapy of Chronic Pelvic Pain and Neurogenic Bladder Dysfunctions.

OBJECTIVE: The aim of this study was to report on the use of laparoscopic implantation of leads on the branches of the sacral plexus for neuromodulation in the treatment of chronic pelvic pain (CPP) in a multidisciplinary setting with the help of electrophysiological neuromonitoring. MATERIALS AND METHODS: Between 2012 and 2019, six female patients complaining of chronic pain and bladder and bowel dysfunctions underwent laparoscopic exposure and nerve identification with the help of electrophysiological neuromonitoring. A lead was placed laparoscopically in direct contact with the affected nerve. Pain intensity (numerous ranking scale [NRS]), generic health status (EQ-5D-5L), Becks Depressions Inventory (BDI-V), Pain Catastrophizing Scale (PCS), and Client Satisfaction Questionnaire (CSQ-8) were assessed pre-/postoperatively as well as three and six months after surgery. Statistical analysis was performed using Mann-Whitney U and Wilcoxon rank-sum test. RESULTS: The median age was 36.5 years. NRS improved from a median of 9.5 preoperatively to 3.0 (p < 0.001) at six-month follow-up. Median EQ-5D-5L index value before treatment was 0.18, indicating a notably lowered quality of life and increased up to 0.83 after six months (p < 0.001). Preoperative median BDI-V scores indicated a major depressive mood and improved from a median of 46.0 to 12.0 after six months (p = 0.007). Preoperative PCS was elevated with a median score of 41.0 and decreased to 4.0 after six months (p < 0.001). CSQ showed that patients were satisfied with the treatment. CONCLUSIONS: This unique method is an alternative and effective treatment option for CPP even years after primary endometriosis surgery.

Localization of claudin-2 and claudin-3 in eutopic and ectopic endometrium is highly similar.

PURPOSE: Claudins as the major components of tight junctions are important in maintaining cell-cell integrity and thus function as a barrier. Dysregulation of the claudins is often associated with loss of the epithelial phenotype, a process called epithelial-mesenchymal transition (EMT), which most often results in gain of migrative and invasive properties. However, the role of claudins in the endometrium or endometriosis has only rarely been examined. METHODS: In this study, we investigated localization of claudin-2 and claudin-3 in the eutopic and ectopic endometrium with immunohistochemistry. A detailed quantification with HSCORE was performed for claudin-2 and claudin-3 in endometrium without endometriosis and in cases with endometriosis compared to the three endometriotic entities: peritoneal, ovarian, and deep-infiltrating endometriosis. RESULTS: We found a preferential localization of both claudins in the glandular and the luminal epithelial cells in the endometrium with and without endometriosis. Quantification of localization of both claudins showed no differences in eutopic endometrium of control cases compared to cases with endometriosis. Furthermore, both claudins are localized highly similar in the ectopic compared to the eutopic endometrium, which is in clear contrast to previously published data for claudin-3. CONCLUSION: From our results, we conclude that localization of claudin-2 and claudin-3 is highly stable in eutopic and ectopic endometrium without any loss of the epithelial phenotype and thus do not contribute to the pathogenesis of endometriosis.

Similar Characteristics of Endometrial and Endometriotic Epithelial Cells.

Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial and acquisition of mesenchymal cell characteristics. Our aim was to assess the epithelial phenotype in the pathogenesis of endometriosis with epithelial and mesenchymal markers. We used 2 structural (keratin-18, -19 [K18, K19]), 1 membrane-associated (mucin-1 [MUC1]), and 2 mesenchymal proteins (vimentin; zinc finger E-box-binding homeobox 1, [ZEB1]) to compare epithelial and mesenchymal characteristics in eutopic endometrium with the 3 endometriotic entities, peritoneal, ovarian, and deep infiltrating endometriosis (DIE). Quantitation showed no differences for K18, K19, and MUC1 between endometrium with and without endometriosis. Also, K18 was not different between endometrium and endometriotic lesions. In contrast, K19 and MUC1 were modestly but significantly decreased in the endometriotic lesions compared to endometrium. However, the maintained expression of epithelial markers in all investigated tissues, regardless of the pathological condition, clearly indicates no loss of the epithelial phenotype. This is further supported by the reduced presence of epithelial vimentin in endometriotic lesions which is in contrast to an increase in stromal vimentin in ectopic endometrium, especially in ovarian endometriosis. The ZEB1 increase in endometriotic lesions, especially in DIE, on the other hand suggests a role of partial EMT in the development of endometriotic lesions, possibly connected with the gain of invasive capabilities or stemness. Taken together, although we found some hints for at least a partial EMT, we did not observe a severe loss of the epithelial cell phenotype. Thus, we propose that EMT is not a main factor in the pathogenesis of endometriosis.

Impaired Localization of Claudin-11 in Endometriotic Epithelial Cells Compared to Endometrial Cells.

Claudins are the major components of tight junctions and are often deregulated in human cancer, permitting escape of cancer cells along with the acquisition of invasive properties. Similarly, endometrial cells also show invasive capabilities; however, the role of tight junctions in endometriosis has only rarely been examined. In this study, we analyzed the protein expression and localization of claudin-7 and claudin-11 in human eutopic and ectopic endometrium and endometrial cell lines. We identified claudin-7 primarily at the basolateral junctions of the glandular epithelial cells in eutopic endometrium as well as in the ectopic lesions in nearly all glands and cysts. Quantification of claudin-7 localization by HSCORE showed a slight increase in peritoneal and deep infiltrating endometriosis (DIE) compared to eutopic endometrium. In contrast, claudin-11 was localized mainly in the apicolateral junctions in nearly all glandular epithelial cells of the eutopic endometrium. Interestingly, we observed a deregulation of claudin-11 localization to a basal or basolateral localization in ovarian (P < .001), peritoneal (P < .01), and DIE (P < .05) and a moderately decreased abundance in ovarian endometriosis. In endometrial cell lines, claudin-7 was only present in epithelial Ishikawa cells, and silencing by small-interfering RNA increased cell invasiveness. In contrast, claudin-11 could be demonstrated in Ishikawa and endometriotic 12Z and 49Z cells. Silencing of claudin-11 decreased invasiveness of 12Z slightly but significantly in 49Z. We suggest that although claudin-7 and claudin-11 can be found in nearly all eutopic and ectopic epithelial cells, the impaired localization of claudin-11 in ectopic endometrium might contribute to the pathogenesis of endometriosis.

Lysophosphatidic acid triggers cathepsin B-mediated invasiveness of human endometriotic cells.

Extracellular lysophosphatidic acid (LPA) and the G-protein-coupled LPA receptors (LPAR) are involved in cell migration and invasion and found in the human endometrium. However, underlying mechanisms resulting in cellular invasion have been rarely investigated. We used stromal endometrial T-HESC, epithelial endometriotic 12Z, 49Z and Ishikawa cells. Interestingly, proliferation of T-HESC cells was strongly increased after LPA treatment, whereas the epithelial cell lines only showed a moderate increase. LPA increased invasion of 12Z and 49Z strongly and significantly. The LPAR inhibitor Ki16425 (LPAR1/3) attenuated significantly LPA-induced invasiveness of 12Z, which was confirmed by LPAR1 and LPAR3 siRNAs, showing that both LPA receptors contribute to invasiveness of 12Z cells. Investigation of cell invasion with an antibody-based protease array revealed mainly differences in cathepsins and especially cathepsin B between 12Z compared to the less invasive Ishikawa. Stimulation with LPA showed a time- and dose-dependent increased secretion of cathepsin B which was inhibited by the Gq inhibitor YM-254890 and Gi/o inhibitor pertussis toxin in the 12Z cells, again highlighting the importance of LPAR1/3. The activity of intracellular and secreted cathepsin B was significantly upregulated in LPA-treated samples. Inhibition of cathepsin B with the specific inhibitor CA074 significantly reduced LPA-increased invasion of 12Z. Our results reveal a novel role of LPA-mediated secretion of cathepsin B which stimulated invasion of endometriotic epithelial cells mainly via LPAR1 and LPAR3. These findings may deepen our understanding how endometriotic cells invade into ectopic sites, and provide new insights into the role of LPA and cathepsin B in cellular invasion.

Selective Progesterone Receptor Modulators for the Medical Treatment of Uterine Fibroids with a Focus on Ulipristal Acetate.

Uterine fibroids are the most frequent benign tumours in women of child-bearing age. Their symptoms are diverse and the quality of life of the women affected can be significantly impaired. While treatment to date has been primarily by means of surgical intervention, selective progesterone receptor modulators (SPRMs) open up new medication-based treatment options. EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has recently completed its review of ESMYA® (ulipristal acetate, 5 mg), following reports of serious liver injury, including liver failure leading to transplantation in postmarketing settings. We will provide some information on the PRAC's recommendations to minimize this risk. Nevertheless, the effectiveness and safety of the SPRM ulipristal acetate (UPA), both with regard to preoperative administration and with regard to an intermittent administration as long-term treatment for patients with symptomatic uterine fibroids, have been shown in several clinical studies (PEARL I-IV).

Patterns of missing data in the use of the endometriosis symptom diary.

BACKGROUND: Endometriosis is a common, chronic condition in women of reproductive age that is characterized by the presence of functional endometriotic lesions outside the uterus. The Endometriosis Symptom Diary (ESD) is an electronic patient-reported outcome (ePRO) instrument that assesses women's experience of endometriosis symptoms, with pain scored using a 0-10 numeric rating scale. This study investigated patterns of data missing from the ESD in the VALEPRO study. METHODS: Post hoc analyses of missing data were conducted. RESULTS: Of 272 participants using the ESD, 26.5% had no missing diary entries, 46.7% had > 0-5% of entries missing, 13.2% had > 5-10% of entries missing and 13.6% had > 10% of entries missing over the entire study period. The duration of missing episodes (defined as ≥1 consecutive days with missing diary entries) was generally short; most (81.4%) were 1 day. The difference in mean worst pain scores between missing and complete episodes per participant was - 0.1, suggesting that missing episodes were not related to severity of pain. Entries were significantly more likely to be missing on Fridays (18.5%) and Saturdays (22.9%) compared with other days of the week (p < 0.0001). Participants in the USA had significantly more long missing episodes than those in Germany (proportions of missing episodes longer than 1 day, 22.6 and 10.5%, respectively; p < 0.0001). The proportions of women with ≥1 missing entry were 50.0, 70.2 and 79.8% for women with elementary education, secondary education, and a college or university education, respectively. The proportions of women with ≥1 missing entry were similar for those with and without children (72.2 and 74.3%, respectively). CONCLUSIONS: Most participants were highly compliant with entering data in the ESD and the amount of missing data was low. Entries were significantly more likely to be missing on Fridays and Saturdays compared with other days of the week, and participants in the USA had significantly more long missing episodes than participants in Germany. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01643122 , registered 4 July 2012.

Corrigendum to "Selective Progesterone Receptor Modulators for the Medical Treatment of Uterine Fibroids with a Focus on Ulipristal Acetate".

[This corrects the article DOI: 10.1155/2018/1374821.].

Composition of the Stroma in the Human Endometrium and Endometriosis.

To analyze whether the endometrial and endometriotic microenvironment is involved in the pathogenesis of endometriosis, we characterized the stromal composition. We used CD90 for fibroblasts, α-smooth muscle actin for myofibroblasts as well as CD10 and CD140b for mesenchymal stromal cells. Quantification of eutopic endometrial stroma of cases without endometriosis showed a high percentage of stromal cells positive for CD140b (80.7%) and CD10 (67.4%), a moderate number of CD90-positive cells (57.9%), and very few α-smooth muscle actin-positive cells (8.5%). These values are highly similar to cases with endometriosis showing only minor changes: CD140b (76.7%), CD10 (63%), CD90 (53.9%), and α-smooth muscle actin (6.9%). There are no significant differences in the composition of CD140b- and CD10-positive stromal cells between the eutopic endometrial stroma and the 3 different endometriotic entities (ovarian, peritoneal, and deep infiltrating endometriosis), except for a significant difference between CD10-positive stromal cells in peritoneal lesions compared to ovarian lesions. However, the percentage of CD90-positive stromal cells was reduced in the 3 different endometriotic entities compared to the endometrium, especially significant in the ovarian lesions. In contrast, the percentage of α-smooth muscle actin-positive cells in the ovary was moderately increased. Taken together, the marker signature of eutopic endometrial and endometriotic stromal cells resembles mostly mesenchymal stromal cells. Our results show clearly that the proportion of the different stromal cell types in the endometrium with or without endometriosis does not differ significantly, thus suggesting that the stromal eutopic endometrial microenvironment does not contribute to the pathogenesis of endometriosis.

Termination of Pregnancy for Medical Indications under Sec. 218a Para. 2 of the German Criminal Code - Real-life Data from the "Gießen Model".

Background Following the legal provisions on the termination of pregnancies in Art. 13 of the SFHG (Law on the Assistance for Pregnant Women and Families, passed on 27.07.1992, BGBl. I, p. 1398) the so-called embryopathic indication for termination was abandoned. Since then, sec. 218a para. 2 of the German Criminal Code (StGB) states that for late terminations, i.e., terminations after the 12th week of gestation post conception, the pregnant woman must be in exceptional distress "according to medical opinion". Method Between 01.05.2012 and 25.07.2016, a total of 160 pregnancy terminations were carried out in Gießen University Hospital under sec. 218a para. 2 StGB. The following data were obtained from the patients' files: age of the pregnant woman, number of pregnancies, type of fetal disease or malformation, time of diagnosis, medical and psychosocial counseling given to the pregnant woman, time of termination or delivery, type of termination, fetal gender. Results 160 pregnant women (mean age: 31.6 years) underwent termination of pregnancy between the 13th - 37th week of gestation. Chromosomal anomalies were diagnosed prenatally in 60 cases, and anomalies were diagnosed on ultrasonography in 100 cases, with the preponderance of cases presenting with developmental disorders of the central nervous system and cardiovascular system. Conclusion In addition to recording intrauterine fetal disorders, when pregnancies are terminated under sec. 218a para. 2 StGB, treating physicians are expected to give plausible reasons why "according to medical opinion" the pregnancy represents a danger to the life of the pregnant woman or of grave injury to her physical or mental health and enter these reasons in the patient's medical records.

PAI-1 secretion of endometrial and endometriotic cells is Smad2/3- and ERK1/2-dependent and influences cell adhesion.

In the endometrium transforming growth factor-betas (TGF-ßs) are involved mainly in menstruation and endometriosis. After binding of the ligands to the high-affinity receptors, TGF-ß receptors (TBR1 and TBR2), TGF-ßs activate Smad signaling to modulate gene expression and cellular functions. However, recently also Smad-independent pathways have been studied in more details. To evaluate both pathways, we have analyzed TGF-ß signaling in human endometrial and endometriotic cells. Although endometrial and endometriotic cells secrete TGF-ß1, secretion by stromal cells was higher compared to epithelial cells. In contrast, secretion of TGF-ß2 was higher in endometriotic stromal and endometriotic epithelial cells compared to normal endometrial cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-ß1 or TGF-ß2 increased Smad-dependent secretion of plasminogen activator inhibitor-1 (PAI-1) dramatically in all three cell lines. Of note, endometriotic cells secreted clearly higher levels of PAI-1 compared to endometrial cells. Whereas a TBR1 kinase inhibitor completely blocked the TGF-ß1 or TGF-ß2-induced PAI-1 secretion, an ERK1/2 inhibitor only partially reduced PAI-1 secretion. This inhibition was not dependent on epidermal growth factor receptor (EGFR) activation by phosphorylation but on kinase activity of the TBR1. Finally, treatment of endometrial and endometriotic cell lines with recombinant PAI-1 showed reduced cell adhesion, especially of the endometrial cells. In summary, our results demonstrate that both Smad-dependent and TBR1-dependent ERK1/2 pathways are necessary for TGF-ß-dependent high level secretion of PAI-1, which might increase cellular deadhesion.

Analysis of Clusterin and Clusterin Receptors in the Endometrium and Clusterin Levels in Cervical Mucus of Endometriosis.

Clusterin (CLU) is expressed in tissues and body fluids and is altered in some pathologies. In endometriosis, a noninvasive test is still lacking, thus, we analyzed CLU in mucus samples of patients. Additionally, we investigated localization of CLU and the putative CLU receptors (apolipoprotein E receptor 2 [ApoER2], megalin, very low-density lipoprotein receptor [VLDLR], and transforming growth factor ß receptor type I and II [TßR1/TßR2]). In mucus samples, CLU levels are modestly, but not significantly, higher in cases with endometriosis compared to cases without endometriosis, however, CLU levels are significantly (P = .02) reduced in patients with endometriosis receiving contraception compared to cases with endometriosis without contraception. Analysis of CLU and CLU receptors showed CLU mainly in the uterine epithelial cells in the majority of glands, but also in endothelial cells. Similarly, ApoER2 and TßR1 could also be found preferentially in the endometrial glands. Whereas ApoER2 staining was strong in the vessels, TßR1 was modestly expressed in vessels and muscle cells. In contrast, staining of VLDLR and TßR2 was modest in the glands but stronger in vessels and muscle cells. Megalin staining was faint in the glands. A similar pattern for these proteins could be observed in adenomyosis. We demonstrate for the first time high concentrations of CLU in mucus samples and significantly reduced CLU levels in cases with endometriosis receiving contraception compared to cases with endometriosis without contraception. Furthermore, we identified uterine epithelial and endothelial cells as the main source of CLU and found different preferential CLU receptor complexes on glands, vessels, and smooth muscle cells.

Low bone mineral density and vitamin d deficiency correlated with genetics and other bone markers in female Turkish immigrants in Germany.

Patients with osteoporosis have a low bone mass resulting in an increased risk for bone fractures, morbidity and mortality. One hundred thirty-one female pre-menopausal participants (98 Turkish immigrants living in Germany in comparison with 33 age-matched healthy Germans) were recruited for this study which explored vitamin D deficiency and specific genetic modifications of bone metabolism. The subjects were investigated for their femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) of the right total femur and the lumbar spine. Serum levels of osteologic parameters were determined: parathormone (PTH), calcium (Ca), osteocalcin (OC), phosphate (P), alkaline phosphatase (AP), beta-crossLaps (CL), tartrate-resistant acid phosphatase isoform 5b (TRAP5b), and 25-vitamin D3 (25-OH D3). The Bsml- and Fokl-polymorphisms of the vitamin D receptor (VDR) gene and the collagen type I alpha 1 (COLIA1)-gene polymorphism were also genotyped. An extremely high prevalence of vitamin D deficiency could be found in the immigrant cohort (87.8 %). Osteoporosis but not osteopenia was more prevalent in this group. Among immigrants with osteoporosis, TRAP5b was elevated in 42.9 % and beta-CL in 28.6 %. Only the Fokl FF-genotype of the VDR polymorphism was significantly more prevalent among the Turkish women, Ff-genotyped immigrants showed significantly decreased BMD. A significant correlation between the COLIA1-gene polymorphism and BMD could not be identified in the two groups. Vitamin D deficiency and osteoporosis appear to be dominant and unrecognized problem among female Turkish immigrants in Germany. Therefore, in this population, osteologic parameters and BMD should be routinely analyzed and deficiencies be treated immediately.

Targeting of Peptide Cytotoxins to LHRH Receptors For Treatment of Cancer.

Receptors for LHRH (luteinizing hormone-releasing hormone) are expressed in about 80% of human endometrial, ovarian and prostate cancers and are also found in more than 50% of breast cancers including triple negative breast cancers. In the human body, LHRH receptors are found at significant levels in the pituitary and reproductive organs. Other benign tissues or hematopoietic stem cells express only low levels of receptors for LHRH or no receptors. Thus LHRH receptors are promising targets for a receptor- mediated chemotherapy with cytotoxic hybrid molecules. Cytotoxic analogs of LHRH consist of a LHRH agonist, which is used as a carrier peptide and DOX or its derivatives. Cytotoxic analogs of LHRH, AEZS-108 (formerly known as AN-152) and AN-207, exhibit anti-cancer activity in various in vitro and in vivo models of LHRH-receptor positive cancers. In AEZS-108 (zoptarelin DOX) DOX is covalently linked to the LHRH agonist [D-Lys(6)]LHRH. Results of phase I and II clinical studies in patients with breast, endometrial and ovarian cancers demonstrated good anticancer activity with moderate toxic side effects and without any sign of cardiotoxicity so far. AEZS-108 is also being evaluated in phase I/II studies in castration resistant prostate cancer and metastatic bladder cancer. Because of the very promising phase II results in endometrial cancer, a multinational, multicenter phase III study of this malignancy has been initiated and is currently recruiting patients.

Infertility today: the management of female medical causes.

It has to be suspected that some environmentally hazardous substances have genotoxic properties, revealing their reproductive toxicity at a later stage only. Cancer, including childhood cancer, is more common than usually expected. Undesirable side effects of surgery, chemotherapy, and/or radiation can be premature ovarian failure or even premature menopause. In cases of autoimmune disease, autoantibodies can directly affect maturation of oocytes in the follicle, fertilization, and implantation. Spontaneous abortions are more common in patients with autoimmune disease. Thrombophilia is known to display a higher rate of spontaneous abortions as well as pre-eclampsia and intrauterine growth retardation. Infections are a common threat to pregnancy. Metabolic syndrome is increasingly frequent in western countries and often associated with hyperandrogenemia and polycystic disease. Women with inflammatory bowel disease such as Crohn disease or ulcerative colitis usually have no problems conceiving. In conclusion, even though infertility is a multifactorial disease, various medical and non-medical conditions can be attributed to it.