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Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone Thomas Römer, Johannes Bitzer, Christian Egarter et al. Geburtsh Frauenheilk. doi:10.1055/a-1471-4408 In the e-first version of this article the name of the co-author was incorrect. Correct is: Katrin Schaudig

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 – 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive. Hormonelle Kontrazeptiva stellen eine effektive und sichere Methode der Schwangerschaftsverhütung dar. Die Gestagene, die in der Kontrazeption verwendet werden, sind entweder Bestandteil kombinierter hormoneller Kontrazeptiva (Tabletten, Pflaster oder Vaginalringe) oder werden als einzelner Wirkstoff in Gestagen-Monopräparaten (Tabletten [im englischen Sprachgebrauch „POP“ = Progestin-only-Pill], Implantate, Intrauterinsysteme oder Depotpräparate) eingesetzt. Gestagene sind in der Langzeitverhütung bei adäquater Anwendung höchst effektiv und haben ein sehr gutes Sicherheitsprofil mit nur wenigen Kontraindikationen. Kürzlich wurde ein neuer östrogenfreier Ovulationshemmer (POP) in den USA und der EU zugelassen. Das Gestagen-Monopräparat enthält 4 mg Drospirenon (DRSP), welches antigonadotrope, antimineralokortikoide und antiandrogene Eigenschaften aufweist. Das Einnahmeschema mit 24-tägiger Hormonanwendung, gefolgt von einem 4-tägigen hormonfreien Intervall, wurde gewählt, um die Blutungskontrolle zu verbessern, die Estradiolspiegel auf dem Niveau der frühen Follikelphase zu halten und somit einen Estrogenmangel zu vermeiden. Klinische Studien belegten die hohe kontrazeptive Wirksamkeit, ein sehr geringes Risiko für kardiovaskuläre Nebenwirkungen und ein günstiges Blutungsmuster. Aufgrund der langen Halbwertszeit von DRSP (30 – 34 Stunden), bleibt die Wirksamkeit des Präparats selbst bei einmaligem Vergessen der Pilleneinnahme erhalten. Die Aufrechterhaltung der Ovulationshemmung bei möglichem Vergessen einer Pilleneinnahme wurde in Studien mit geplanten 24-stündigen Einnahmeverzögerungen gezeigt. Nach einem Überblick über den aktuellen Stand der estrogenfreien Kontrazeption beschreibt die vorliegende Arbeit das klinische Entwicklungsprogramm des 4-mg-DRSP-Monopräparats und die daraus resultierenden Daten zur Wirksamkeit und Sicherheit dieses neuen estrogenfreien oralen hormonellen Kontrazeptivums.

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to womenʼs individual needs, take account of her personal circumstances, and have few or no side effects.

Introduction Would adolescent girls in Germany choose a different method of contraception to the combined oral contraceptive if provided with the appropriate information? Is there a need for long-acting contraception among our adolescent girls? How satisfied are female patients with the information they receive at their respective gynaecology practices, and how much do the girls know about different methods of contraception? Materials and Methods In the study “Thinking About Needs in COntraception” (TANCO), not only female patients, but also their respective gynaecologists were surveyed online about current methods of contraception, their satisfaction with these methods, and also their level of knowledge concerning the individual methods of contraception, the situation related to advice about different contraceptive options and their general satisfaction with gynaecological care. This article presents the data from the subset of adolescent girls aged 14 to 19 years (n = 2699) out of the total of 18 521 women surveyed. Results The girls surveyed were familiar with at least the name of more than five different methods of contraception (average 5.3). The doctors assumed that the respondents would know only 4.2 different methods. When asked explicitly about how the individual methods of contraception work, clear deficits became evident. This applies not only to the entire population of respondents, but also the users of the respective contraceptive method. In addition, a strong interest in long-acting contraception emerged from the survey, particularly among young women. Discussion The data from the TANCO study reveal a clear discrepancy between the existing contraception almost exclusively in the form of the contraceptive pill and the contraceptive options considered by adolescent girls if they are thoroughly informed. The need for education into alternatives to the pill is high, as is the willingness to use such alternatives after receiving information – much higher than the figures suggested by the gynaecologists.

Skizziert wird, wie in der Folge der Befreiung der Sexualitat von gesellschaftlichen und moralischen Zwangen und der Liberalisierung weiblicher Lebenswelten die Entwicklung einer eigenstandigen weiblichen Identitat fur junge Madchen haufig verkurzt und erschwert wird. Pravention ist ein klassisches Feld arztlichen Handelns, und im Bereich Madchengesundheit konnen Gynakologinnen und Gynakologen eindrucksvolle Optionen fur primare Pravention anbieten. Ausgehend von einem ganzheitlichen Verstandnis von sexueller Gesundheit konnen sie junge Madchen in einer turbulenten Lebensphase kompetent und behutsam dabei begleiten, den eigenen Korper kennen, schatzen und schutzen zu lernen.

Patients with the Mayer–Rokitansky–Küster–Hauser syndrome (MRKH) have a congenital utero–vaginal cervical aplasia, but normal or hypoplastic adnexa and develop with normal female phenotype. Some reports mostly demonstrated regular steroid hormone levels in small MRKH cohorts including single MRKH patients with hyperandrogenemia and a clinical presentationof hirsutism and acne has also been shown. Genetically a correlation ofWNT4mutations with singular MRKH patients and hyperandrogenemia was noted. This study analyzed the hormone status of 215 MRKH patients by determining the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, 17-OH progesterone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone–binding globulin (SHBG) and prolactin to determine the incidence of hyperandrogenemia and hyperprolactinemia in MRKH patients. Additional calculations and a ratio of free androgen index and biologically active testosterone revealed a hyperandrogenemia rate of 48.3%, hyperprolactinemia of 9.8% and combined hyperandrogenemia and hyperprolactinemia of 4.2% in MRKH patients. The rates of hirsutism, acne and especially polycystic ovary syndrome (PCOS) were in the normal range of the population and showed no correlation with hyperandrogenemia. A weekly hormone assessment over 30 days comparing 5 controls and 7 MRKH patients revealed high androgen and prolactin, but lower LH/FSH and SHBG levels with MRKH patients. The sequencing ofWNT4,WNT5A,WNT7AandWNT9Bdemonstrated no significant mutations correlating with hyperandrogenemia. Taken together, this study shows that over 52% of MRKH patients have hyperandrogenemia without clinical presentation and 14% hyperprolactinemia, which appeals for general hormone assessment and adjustments of MRKH patients.

The aim of this study was to determine the extent to which women’s choice of contraceptive method depends on the advice received from their gynecologist and whether more intensive counseling might lead to more frequent use of long-acting reversible contraception (LARC). A total of 1089 physicians and 18,521 women responded to 32 or 37 questions, respectively, using an online questionnaire. The women were asked about their current use of contraceptive methods, the extent of their satisfaction with them, their satisfaction with the counseling they had received, and whether they wanted to have more information about contraception. The physicians were similarly asked which contraceptive methods were being used, how satisfied with them they were, how they would assess their patients’ satisfaction with them, and whether the women wanted to have more information. The results showed that 61% of the women were using oral contraceptives, and a total of only 9% were using behavior-independent long-term contraceptive methods. However, 60% of the women stated that long-term contraception would be an option for them if they had more information about it. Gynecologists underestimated this figure, at only 18%. Whereas 66% of the gynecologists believed that their patients never forgot to take the pill, nearly, half of the women stated that they had forgotten it at least once during the previous 3 months. The small number of women who use long-term contraception is in clear contrast to the fact that many women want to have a very safe but also behavior-independent method.

Background Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. Methods The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1–23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3–5, 5–7, 7–9, 9–11, 11–13, 13–15, and 15–17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. Results Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p

Der verantwortungsvolle Umgang mit Patientinnen in der Kinder- und Jugendgynakologie bedarf eines speziellen Wissens uber die embryonale Entwicklung des inneren und auseren Genitales, uber Besonderheiten in den einzelnen Hormonphasen und Ablaufe in der Pubertat mit ihren Normvarianten. Die haufigste Diagnose des Kleinkindes ist die Labiensynechie, eine Verklebung der kleinen Schamlippen, die einfach zu diagnostizieren ist. Haufigster Vorstellungsgrund im Kindesalter ist die Vulvovaginitis, bei deren Diagnostik die verschiedenen Hormonphasen und mogliche Differenzialdiagnosen wichtig sind. Bei Jugendlichen sind Blutungsstorungen ein wichtiger Vorstellungsgrund. Hier kann durch die Erhebung der Pubertatsstadien einfach auf Ursachen geschlossen werden (primare/sekundare/tertiare Ovarialinsuffizienz). Bei Madchen mit primarer Amenorrho, normal abgelaufener Pubertatsentwicklung und Einsetzen der Thelarche vor > 2,5 Jahren muss an eine genitale Fehlbildung gedacht werden.

Purpose: This guideline of the German Society of Pediatric Endocrinology and Diabetology (DGKED) is designed to be expertsʼ opinion on the current concept of prenatal therapy for congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). Several scientific medical societies have also participated in the guideline. It aims to offer guidance to physicians when they counsel affected families about prenatal therapy. Methods: The experts commissioned by the medical societies developed a consensus in an informal process. The consensus was subsequently confirmed by the steering committees of the respective medical societies. Recommendations: Prenatal CAH therapy is an experimental therapy. We recommend designing and using standardized protocols for the prenatal diagnosis, therapy and long-term follow-up of women and children treated prenatally with dexamethasone. If long-term follow-up is not possible, then prenatal therapy should not be performed.

Background The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. Methods We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. Results Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling’s families to date. Conclusion Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated. Electronic supplementary material The online version of this article (10.1186/s12884-018-2091-8) contains supplementary material, which is available to authorized users.

Background Daysy is a fertility monitor that uses the fertility awareness method by tracking and analyzing the individual menstrual cycle. In addition, Daysy can be connected to the application DaysyView to transfer stored personal data from Daysy to a smartphone or tablet (IOS, Android). This combination is interesting because as it is shown in various studies, the use of apps is increasing patients´ focus on their disease or their health behavior. The aim of this study was to investigate if by the additional use of an App and thereby improved usability of the medical device, it is possible to enhance the typical-use related as well as the method-related pregnancy rates. Result In the resultant group of 125 women (2076 cycles in total), 2 women indicated that they had been unintentionally pregnant during the use of the device, giving a typical-use related Pearl-Index of 1.3. Counting only the pregnancies which occurred as a result of unprotected intercourse during the infertile (green) phase, we found 1 pregnancy, giving a method-related Pearl-Index of 0.6. Calculating the pregnancy rate resulting from continuous use and unprotected intercourse exclusively on green days, gives a perfect-use Pearl-Index of 0.8. Conclusion It seems that combining a specific biosensor-embedded device (Daysy), which gives the method a very high repeatable accuracy, and a mobile application (DaysyView) which leads to higher user engagement, results in higher overall usability of the method. Electronic supplementary material The online version of this article (10.1186/s12978-018-0479-6) contains supplementary material, which is available to authorized users.

Introduction Endometriosis is associated with hyperperistalsis and dysperistalsis in the uterus, and it has been shown that progesterone leads to a decrease in uterine contractility. The synthetic gestagen dienogest is often administered in women who are receiving conservative treatment for endometriosis, and it may be the treatment of choice. The present study investigated the effects of dienogest on uterine contractility in comparison with the known inhibitory effect of progesterone. Material and methods Eighty swine uteri were examined using an established extracorporeal perfusion model. The uteri were perfused for at least 4 hours with progesterone, dienogest, or a modified Krebs-Ringer solution as the control group, with uterine contractions being measured using an intrauterine microchip catheter. The amplitude and frequency of contractions and the area under the curve (AUC), reflecting overall contractility, were measured at two separate locations (the isthmus and fundus). Results Progesterone led to a significant decrease in the amplitude of uterine contractions and to reduced overall pressure (AUC) at the isthmus and fundus. Dienogest led to a significant decrease in the amplitude of contractions and overall pressure (AUC) in the area of the isthmus, but the decrease near the fundus was not significant. The frequency of uterine contractions was not influenced by either progesterone or dienogest. Conclusions These results confirm the known inhibitory effect of progesterone on uterine contractility (relative to amplitude of contractions and overall contractility), affecting the whole organ. Perfusion of the uterus with dienogest also led to a general decrease in uterine contractility similar to the effect of progesterone.

Aim The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. Methods This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). Recommendations The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities. Ziel Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) publiziert und zusammen mit der Deutschen Gesellschaft für Urologie (DGU) sowie Deutschen Gesellschaft für Reproduktionsmedizin (DGRM) koordiniert wurde, ist es, durch die Evaluation der relevanten Literatur konsensbasierte Handlungsempfehlungen für die Beratung und den Einsatz von fertilitätserhaltenden Maßnahmen bei präpubertären Mädchen und Jungen sowie für Patienten/-innen im reproduktiven Alter zu geben. Im Folgendem werden die Statements und Empfehlungen für Mädchen und Frauen dargestellt. Die Statements und Empfehlungen für Jungen und Männer sind nicht Inhalt dieser Publikation. Methoden Diese S2k-Leitlinie wurde durch einen strukturierten Konsens von repräsentativen Mitgliedern verschiedener Fachgesellschaften (n = 40) im Auftrag der Leitlinienkommission der DGGG, DGU und DGRM entwickelt. Empfehlungen Es werden Empfehlungen zur Beratung und dem Einsatz von fertilitätserhaltenden Maßnahmen bei Patientinnen unter Berücksichtigung der Lebensumstände, der geplanten onkologischen Therapie und des individuellen Risikoprofils dargestellt sowie über das Vorgehen bei ausgewählten Tumorentitäten.

Background In March 2018, Dr. Martin C. Koch and colleagues published an analysis purporting to measure the effectiveness of the Daysy device and DaysyView app for the prevention of unintended pregnancy. Unfortunately, the analysis was flawed in multiple ways which render the estimates unreliable. Unreliable estimates of contraceptive effectiveness can endanger public health. Main body This commentary details multiple concerns pertaining to the collection and analysis of data in Koch et al. 2018. A key concern pertains to the inappropriate exclusion of all women with fewer than 13 cycles of use from the Pearl Index calculations, which has no basis in standard effectiveness calculations. Multiple additional methodological concerns, as well as prior attempts to directly convey concerns to the manufacturer regarding marketing materials based on prior inaccurate analyses, are also discussed. Conclusion The Koch et al. 2018 publication produced unreliable estimates of contraceptive effectiveness for the Daysy device and DaysyView app, which are likely substantially higher than the actual contraceptive effectiveness of the device and app. Those estimates are being used in marketing materials which may inappropriately inflate consumer confidence and leave consumers more vulnerable than expected to the risk of unintended pregnancy. Prior attempts to directly convey concerns to the manufacturer of this device were unsuccessful in preventing publication of subsequent inaccurate analyses. To protect public health, concerns with this analysis should be documented in the published literature, the Koch et al. 2018 analysis should be retracted, and marketing materials on contraceptive effectiveness should be subjected to appropriate oversight.

The goal of this study was to compare a traditional slow-freeze method (TF) with an open unidirectional slow freeze cooling system (UF) for whole ovary cryopreservation. Therefore, whole pig ovaries were randomly assigned to (A) fresh control, (B) traditional slow freeze (TF) or (C) unidirectional slow freeze (UF). Ovaries were perfused with 10% DMSO in Krebs-Ringer. For TF, whole ovaries were placed in specimen jars containing 10% DMSO and placed into a specialized container for freezing filled with propan-2-ol. For UF, whole ovaries were placed within a specially designed container containing 10% DMSO and transferred to a specialized freezing machine (CTE 920). Histological evaluation demonstrated intact morphology of follicles in all groups; however, an overall decrease of follicle numbers in TF (46%) and UF (50%) compared to fresh control. Live/dead assay indicated significantly lower populations of live cells in both TF (60%) and UF (58%) compared to fresh tissue (74%). TUNEL assay confirmed a difference in percentage of apoptotic follicles between fresh and TF, but there was no significant difference between fresh and UF. To improve the structural and functional integrity of whole ovaries, further investigation, especially into directional freezing, is needed. Whole ovary cryopreservation could provide opportunities for women facing fertility loss due to chemo- or radiotherapy treatment.

This article is about a new project that combines clinical data intelligence and smart data. It provides an introduction to the “Klinische Datenintelligenz” (KDI) project which is founded by the Federal Ministry for Economic Affairs and Energy (BMWi); we transfer research and development results (R&D) of the analysis of data which are generated in the clinical routine in specific medical domain. We present the project structure and goals, how patient care should be improved, and the joint efforts of data and knowledge engineering, information extraction (from textual and other unstructured data), statistical machine learning, decision support, and their integration into special use cases moving towards individualised medicine. In particular, we describe some details of our medical use cases and cooperation with two major German university hospitals.

Die Uberlebensraten von Krebspatientinnen haben sich mittels moderner Behandlungsmethoden in den letzten Jahren merklich erhoht. Allerdings fuhren die Therapien sehr haufig zu einer Sterilitat und viele Frauen mussen sich nach erfolgreicher Therapie mit dem Verlust ihrer Fruchtbarkeit auseinandersetzen. Dies lasst Fragen nach Moglichkeiten zum Erhalt oder Wiederherstellung der Fertilitat dieser Patientinnen aufkommen. Neben der Transposition der Gonaden vor einer Radiotherapie, dem medikamentosen Gonadenschutz durch GnRH-Analoga und der Kryokonservierung von befruchteten und unbefruchteten Eizellen hat sich vor allem die Kryokonservierung von Ovarialgewebe als Methode der Fertilitatsprotektion etabliert, uber die wir im Folgenden berichten mochten.

In this guideline, recommendations and standards for optimum diagnosis and treatment of endometriosis are presented. They are based on the analysis of the available scientific evidence as published in prospective randomized and retrospective studies as well as in systematic reviews. The guideline working group consisted of experts from Austria, Germany, Switzerland, and the Czech Republic.

Das Ullrich-Turner-Syndrom (UTS) ist eine genetische Erkrankung, die mit einem kompletten oder partiellen Verlust eines X-Chromosoms einhergeht. Kinder oder erwachsene Patientinnen mit UTS leiden haufig unter metabolischen, kardiovaskularen, renalen, gastrointestinalen Komorbiditaten, unter Ostrogenmangelerscheinungen und psychosozialen Problemen. Wahrend der Kindheit werden die Patienten traditionell in spezialisierten Kinderklinken behandelt, aber es fehlt noch ein Konzept fur die weiterfuhrende Behandlung in der Transitionsperiode und danach. Im Artikel werden die wichtigsten publizierten Empfehlungen zur Behandlung von Madchen und Frauen mit UTS aufgefuhrt. Ein besonderer Fokus liegt auf der Transition. Vorgestellt werden ebenfalls die Ergebnisse eines interdisziplinaren Expertentreffens fur ein strukturiertes Behandlungskonzept. Analysiert man die bisherigen Publikationen, lassen sich die Mangel in der Nachsorge der UTS-Frauen auf folgende Punkte zusammenfassen: fehlende Gesamtkonzepte in der Weiterbetreuung, Unsicherheiten und Uberforderung bei der Betreuung der UTS-Frauen durch manche Hausarzte, aber auch das fehlende Krankheitsbewusstsein bei einigen Betroffenen. Komorbiditaten bei erwachsenen UTS-Patientinnen sind vielfaltig und umfassen metabolische, kardiovaskulare, gastrointestinale und renale Erkrankungen, Hormonmangelerscheinungen, gynakologische sowie psychosoziale Probleme. Die notwendige Hormonsubstitutionstherapie, u. a. mit Ostrogen und Gestagenen, erfordert eine Langzeitbetreuung durch erfahrene Spezialisten. Empfohlen wird eine ausfuhrliche Diagnostik zum Zeitpunkt der Transition sowie konsequente Untersuchungen, nach Klinik und Risikoprofil, 1- bis 5-jahrlich.

Extracting ovarian tissue before oncologic therapy and transplanting it afterwards are increasingly being used to preserve fertility in women. This study describes standardized and safe operative procedures, with few complications, and reports the resulting ovarian function and pregnancy rates. The standardized operative techniques for removing and transplanting ovarian tissue used at the Erlangen center are: for tissue removal, one-third to half of the tissue from one ovary is excised with scissors, without tissue coagulation; for subsequent transplantation, pieces of ovarian tissue are placed in a retroperitoneal pocket without closure of the pocket. Between January 2007 and December 2015, ovarian tissue was extracted in 399 women and transplanted following cancer therapy in 38. No surgical complications were observed within 28 days. To date, there have been ten pregnancies and nine live births after transplantation in seven different women; 26 of the 38 women developed hormonal activity, confirmed by a menstrual cycle or raised serum estradiol levels. The techniques for laparoscopic removal and transplantation of ovarian tissue described here provide a standardized method with a very low risk of complications. The pregnancy rate after ovarian tissue transplantation, currently 15–30%, can be expected to rise further in the near future.

Moderne Behandlungsmethoden ermoglichen besonders auch jungen Krebspatientinnen ein Uberleben ihrer schweren Erkrankung, fuhren jedoch haufig zu einer Sterilitat. Dies lasst Fragen nach Moglichkeiten zum Erhalt oder Wiederherstellung der Fertilitat dieser Patientinnen aufkommen. Als eine der Optionen hat sich die Kryokonservierung von Ovarialgewebestuckchen etabliert. Prinzipiell gibt es drei Moglichkeiten fur eine spatere Schwangerschaft mit kryokonserviertem Ovarialgewebe: In-vitro-Kultur des Ovarialgewebes mit anschliesender In-vitro-Fertilisation der im Brutschrank gewonnenen Eizellen, die Xenotransplantation, d. h. die „Kultur“ des Gewebes in einem Tier und die Retransplantation des Gewebes nach uberstandener Krebserkrankung. Im Moment ist nur letztere Option realisierbar. Zurzeit sind mehr als 25 Geburten nach Retransplantation von kryokonserviertem Gewebe dokumentiert, darunter 2 aus Deutschland, wo die Retransplantation an der Frauenklinik in Erlangen stattgefunden hat. Der Ubersichtsartikel geht auf klinische Aspekte der Retransplantation ein, wie Wahl des Transplantationsortes, Nachverfolgung der Patientinnen und Sicherheit der Methode.

Aggressive medikamentose Therapien und Radiotherapie fuhren haufig zu Infertilitat. In den vergangenen Jahren wurden deshalb Strategien zur Fertilitatsprotektion entwickelt. Dazu gehoren die Kryokonservierung von unbefruchteten Eizellen und die Kryokonservierung von Ovarialgewebe. Die Kryokonservierung von unbefruchteten Eizellen ist technisch schwieriger als die von Embryonen, hat aber fur jungere Patientinnen den Vorteil, dass zum Zeitpunkt der Eizellentnahme kein mannlicher Partner benotigt wird. Neuere Studien zeigen, dass zur Konservierung der unbefruchteten Eizellen die Methode der Vitrifikation der des langsamen Einfrierens vorzuziehen ist. Eine grosere Anzahl von Eizellen kann jedoch erst nach Stimulationstherapie gewonnen werden, was eine Verschiebung der Therapie bedingt. Zudem ist die Methode nicht fur prapubertare Madchen geeignet. Dabei und um eine Verschiebung der Chemotherapie zu vermeiden bietet sich die Kryokonservierung von Ovarialgewebe an. Dies ist technisch gut durchfuhrbar und erfolgreich, was die ersten Geburten von Kindern in Deutschland 2011/2012 nach Anwendung der Methode belegen. Auch bei der Gefahr der Kontamination des Gewebes mit Krebszellen, die eine Retransplantation verbietet, ist die Kryokonservierung des Ovarialgewebes sinnvoll, da die Entwicklung innovativer Methoden zur In-vitro-Reifung sehr wahrscheinlich ist, sodass kunftig auch diesen Frauen zu einem eigenen Kind verholfen werden kann.

Congenital genital malformations occurring in the female population are estimated to be 5 per 1000 and associate with infertility, abortion, stillbirth, preterm delivery and other organ abnormalities. Complete aplasia of the uterus, cervix and upper vagina (Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome) has an incidence of 1 per 4000 female live births. The molecular etiology of congenital genital malformations including MRKH is unknown up to date. The homeobox (HOX) genes HOXA10 and HOXA13 are involved in the development of human genitalia. In this investigation, HOXA10 and HOXA13 genes of 20 patients with the MRKH syndrome, 7 non-MRKH patients with genital malformations and 53 control women were sequenced to assess for DNA variations. A total of 14 DNA sequence variations (10 novel and 4 known) within exonic and untranslated regions were detected in HOXA10 and HOXA13 among our cohorts. Four HOXA10 and two HOXA13 DNA sequence variations were found solely in patients with genital malformations. In addition to mutations resulting in synonymous amino acid substitutions, in the HOXA10 gene a missense mutation was identified and predicted by computer analysis as probably damaging to protein function in two non-MRKH patients, one with a bicornate and the other patient with a septated uterus. A novel exonic HOXA10 cytosine deletion was also identified in a non-MRKH patient with a septate uterus and renal malformations resulting in a premature stop codon and loss of the homeodomain helix 3/4. This cytosine deletion and the missense mutation in HOXA10 were analysed by real time PCR and sequencing, respectively, in two additional larger cohorts of 103 patients with MRKH and 109 non-MRKH patients with genital malformations. No other patients were found with the cytosine deletion however one additional patient was identified regarding the missense mutation. Rare DNA sequence variations in the HOXA10 gene could contribute to the misdevelopment of female internal genitalia.

Summary The active transport of sperm through the female genital tract is a very important factor in the fertilisation process. There is conflicting evidence as to whether seminal plasma has a positive or a negative effect on reproductive performance regarding the sperm transport in the female genital tract. In this study, we investigated if the perfused swine uterus is an appropriate model to study the effect of human seminal plasma on uterine contractility. It was found that repeated application of human seminal plasma caused a significantly higher rise in pressure and frequency of contractions in perfused swine uteri compared to buffer [a 1.8-fold and 1.5-fold pressure rise (Δt1SP, P = 0.025; Δt2SP, P = 0.004)] after the first and second application of seminal plasma respectively, and even a 2-fold pressure rise after the third application with a statistical significance of P = 0.007. The pressure rise caused by the seminal plasma over the entire period of application was calculated using a mathematical programme and was represented by the integral of the pressure curve over time. This perfusion model as well as the use of pressure-time integrals is suitable for patho-physiological studies of the uterus.

Thyroid disorders have a great impact on fertility in both sexes. Hyperthyroidism and hypothyroidism cause changes in sex hormone-binding globulin (SHBG), prolactin, gonadotropin-releasing hormone, and sex steroid serum levels. In females, thyroid hormones may also have a direct effect on oocytes, because it is known that specific binding sites for thyroxin are found on mouse and human oocytes. There is also an association between thyroid dysfunction in women and morbidity and outcome in pregnancy. In males, hyperthyroidism causes a reduction in sperm motility. The numbers of morphologically abnormal sperm are increased by hypothyroidism. When euthyroidism is restored, both abnormalities improve or normalize. In women, the alterations in fertility caused by thyroid disorders are more complex. Hyper- and hypothyroidism are the main thyroid diseases that have an adverse effect on female reproduction and cause menstrual disturbances--mainly hypomenorrhea and polymenorrhea in hyperthyroidism, and oligomenorrhea in hypothyroidism. In recent studies, it has become evident that it is not only changes in serum levels of SHBG and sex steroids that are responsible for these disorders, but also alterations in the metabolic pathway. Adequate levels of circulating thyroid hormones are of primary importance for normal reproductive function. This review presents an overview of the impact of thyroid disorders on reproduction.

Objective To identify genetic causes of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Design Prospective laboratory study. Setting University hospital. Patient(s) Fifty-six patients with MRKH syndrome. Intervention(s) Identification of microdeletions and –duplications in a group of 48 MRKH patients by array-CGH. Results obtained by array-CGH were confirmed by RT-qPCR. Sequential analysis of two candidate genes LHX1 and HNF1B in a group of 56 MRKH patients. Main Outcome Measure(s) Identification of chromosomal regions and genes (recurrent and private) associated with MRKH syndrome. Result(s) We could delineate three definitively relevant regions (1q21.1, 17q12, and 22q11.21) and suggest that LHX1 und HNF1B are candidate genes for MRKH syndrome, because we identified recurrent deletions affecting these genes and a possible causative missense mutation in LHX1 . Conclusion(s) Our findings suggest that different chromosomal regions are associated with MRKH syndrome.

Background Congenital malformations involving the Mullerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Mullerian aplasia or Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. Methods In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Mullerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. Results A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Mullerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Mullerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Mullerian aplasia. Conclusion The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Mullerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Mullerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

Objective To evaluate the impact of smoking on endocrine, metabolic, and clinical parameters in women with polycystic ovary syndrome (PCOS). Design Cohort analysis. Setting University hospital. Patient(s) 346 women with PCOS, including 98 smokers and 248 nonsmokers. Intervention(s) Screening panel, including physical examination, weight and height measurement, and ultrasound examination of the ovaries, and hormone and insulin measurements. Main Outcome Measure(s) Clinical, metabolic, and endocrine parameters, oral glucose tolerance test, calculation of insulin resistance indexes. Result(s) In women with PCOS, smoking was associated with statistically significantly increased levels of fasting insulin and calculated free testosterone (cFT) and with a raised free androgen index (FAI) score, which resulted in aggravated scores on the homeostatic model for assessment of insulin resistance (HOMA-IR). However, no differences were observed between the smoking and nonsmoking groups with regard to the clinical parameters for hirsutism, acne, ovulatory function (classified as eumenorrhea, oligomenorrhea, and amenorrhea), or polycystic ovaries using the ultrasound criteria recommended according to the Rotterdam definition. Conclusion(s) In women with PCOS, smoking is associated with increased free testosterone and fasting insulin levels, resulting in aggravated insulin resistance. However, there were no differences between smokers and nonsmokers when clinical parameters were compared.

Introduction: The aim of this study was to evaluate long-term changes in endocrine and metabolic parameters and body mass index in women with polycystic ovary syndrome (PCOS) who were treated with metformin over 2 years without caloric restriction. Material and Methods: Twenty-six obese women with PCOS were treated with metformin over 2 years without caloric restriction. Clinical, metabolic and endocrine parameters and the body mass index were measured and an oral glucose tolerance test was carried out to calculate insulin resistance indices at the beginning and at the follow-up after 2 years. The Homeostatic Model for Assessment of Insulin Resistance (HOMA-IR) was calculated. Results: No significant changes in body mass index or HOMA-IR were observed. However, a significant decrease in fasting and 2-h insulin levels was observed. Women showed a significant increase in sex hormone-binding globulin (SHBG) levels, while total testosterone (TT) levels and the free androgen index decreased significantly. Furthermore a significant decrease in Hirsutism was observed. There was a decrease in cholesterol and an increase in high-density lipoprotein. Conclusions: Long-term treatment with metformin in women with PCOS appears to reduce androgen excess due to increased SHBG and decreased TT levels resulting in improvement of Hirsutism as a clinical sign of androgen excess. Furthermore a significant decrease in fasting and 2-h insulin levels and slightly improved insulin resistance indices were observed.

OBJECTIVE: It is postulated that the establishment of specialized centers with certification can be used as a marketing tool, in addition to its quality-assurance effect, and that it influences patients' choice of a hospital. One prerequisite for this, however, must be an awareness on the part of patients about both the purpose and the availability of a specialized center. The present study investigated the extent to which patients are familiar with specialized centers. METHODS: The data were gathered from 1073 patients of the Department of Gynecology, the University Breast Center Franconia (UBF; certified in accordance with DIN EN ISO 9001, DKG, DGS, EUSOMA, ESGO, EBCOG), and the University Perinatal Center Franconia (UPF; certified in accordance with DIN EN ISO 9001; level 1, defined by GBA regulations) by means of questionnaire. Of these patients, 46.7 % (n = 501) had breast cancer. The reason for presentation was obstetric in 31.9 % (n = 342) of cases, while 18.5 % of the patients (n = 198) had benign gynecological disease. Topics investigated included whether each patient knew she would be treated in a specialized center and whether there were any differences between obstetric patients and those with breast cancer. Moreover, they were asked about whether specialized certified centers were important to them. RESULTS: Out of all the patients questioned, 34.4 % did not know what the definition of a specialized center is; 37.7 % stated that they did know, and 27.9 % stated that they knew “a little”. A total of 289 patients provided specific descriptions. While only 46.1 % of the obstetric patients knew precisely or to a minor degree what a certified specialized center is, 78.2 % of the patients at the breast center knew what it was (p < 0.001). Prior to presentation, 52.3 % of all patients knew that it was a specialized center, although only 37.5 % of the obstetric patients had this prior information, compared with 65.8 % of patients with breast cancer (p < 0.001). When compared directly, the probability of having prior information was more than three times higher among oncology patients (HR 3.19 [95 % CI 2.35 to 4.34]). When asked about importance of receiving care at a specialized certified center, this was found to be very significantly more important for patients with breast cancer (HR 6.82 [95 % CI 3.09 to 15.04]). CONCLUSION: This survey shows that obstetric patients are often unaware of the definition of a specialized certified center. Oncology patients with breast cancer are much better informed about the definition and availability of a specialized center. While the establishment of centers currently appears to be inappropriate as a marketing tool for obstetric patients, the specialization and certification of a breast center can be used for oncology patients.