Chlamydien haben ein breites Wirtsspektrum und können vielfältige Krankheitssymptome hervorrufen. Obwohl übereinstimmend angenommen wird, dass Chlamydien Fruchtbarkeitsstörungen bei der Sau verursachen, sind zahlreiche Fragen ungeklärt. So ist bisher unbekannt, ob Chlamydien die Eileiter des Schweines besiedeln und krankhafte Veränderungen hervorrufen können. Ziel dieser Arbeit war es deshalb, Eileiter reproduktionsgestörter Sauen auf Chlamydien zu untersuchen und deren mögliche Bedeutung als Infertilitätsursache zu eruieren. Zeitgleich wurden auch Uteri beprobt und diversen differenzialdiagnostisch relevanten Analysen unterzogen. Letztlich sollte durch die Bestimmung von Zearalenon in der Galle das differenzialdiagnostische Spektrum vervollständigt werden. Insgesamt wurden die Genitalorgane von 42 reproduktionsgestörten Sauen (Jungsauen: n=14; Altsauen: n=28; wiederholte Umrausche) aus drei Betrieben auf Chlamydien untersucht. Bei 20 Sauen (Gruppe 1) wurden ein Eileiter und der Uterus, bei weiteren 22 Sauen (Gruppe 2) Ampulle, Isthmus und uterotubale Verbindung beider Eileiter und der Uterus untersucht. Genitalien acht tragender Sauen dienten als Kontrollen. Zum Nachweis von Chlamydien kamen ein kommerzieller IFT (Chlamydia Direct IF Identification) und eine nested PCR (Nachweis des MOMP) mit anschließender Sequenzierung positiver PCR-Produkte zur Anwendung. Eileiter bzw. Eileitersegmente und Uteri wurden histologisch, Uteri fortpflanzungsgestörter Sauen zudem bakteriologisch untersucht. Bei 27 Sauen erfolgte eine Bestimmung von Gesamt-Zearalenon mittels HPLC in der Gallenflüssigkeit. Die IFT- und PCR-Ergebnisse differierten erheblich. Mit dem IFT wurden wesentlich mehr positive Ergebnisse als mit der PCR generiert. Bei 30 (60 %) der insgesamt 50 untersuchten Sauen wurden Chlamydien mittels PCR nachgewiesen. In Gruppe I waren 6 (30 %) der Uteri und 7 (35 %) der Eileiter Chlamydia-positiv, während in der Gruppe II 8 (36,4 %) der Uteri und 12 (54,5 %) der Eileiter als positiv befundet wurden. Tragende Tiere wiesen jeweils 3 (37,5 %) Chlamydia-positive Uteri und Eileiter auf. Nur in einem Fall (12,8 %) konnten Chlamydien ausschließlich im Eileiter detektiert werden. Chlamydien wurden uni- oder bilateral in einem oder mehreren Eileitersegmenten ohne oder mit zeitgleicher Besiedlung des Uterus nachgewiesen. Insgesamt wurden 41 spezifische PCR-Amplifikate aus Eileitersegmenten und Uteri von 26 reproduktionsgestörten Tieren der Gruppen I und II und 4 trächtigen Sauen sequenziert. Am häufigsten wurden Chlamydophila psittaci (n = 24) und Chlamydia suis (n = 10) detektiert. Seltener waren Chlamydophila abortus (n = 4) und Chlamydia trachomatis (n = 3) festzustellen. Insgesamt wiesen 34 (89,5 %) von 38 histologisch untersuchten Uteri entzündliche Veränderungen auf, die zu 94,1 % (n=32) chronisch waren. Entzündliche Infiltrationen mit Immunzellen wurden sowohl in Ampullen (47,9 %) als auch Isthmen (22,9 %) der Eileiter beobachtet. Die Uteri enthielten überwiegend zeitgleich mehrerer Bakterien, die als fakultativ bis obligat pathogen zu beurteilen waren. E. coli dominierte (78,0%). 21 (77,8 %) Sauen wiesen ≥ 50 ng/ml Gesamtzearalenon auf und wurden als positiv bewertet. Es bestanden keine Zusammenhänge zwischen den Chlamydienbefunden und Ergebnissen der übrigen Untersuchungen. Es ist zu schlussfolgern, dass Chlamydien unterschiedlichster Spezies Uterus und Eileiter kolonialisieren. Sie sind in der Schweinepopulation vermutlich weit verbreitet. Da auch tragende Sauen Chlamydien im Genitale enthielten, muss eine Infektion nicht zwangsläufig eine In- bzw. Subfertilität verursachen, noch für zu identifizierende Faktoren vermutlich prädisponierend wirken. Chronische Entzündungen der Uteri sind ähnlich häufig wie entzündlich veränderte Eileiter zu beobachten. Eine direkte Assoziation zwischen genitaler Entzündung und Infektion mit Chlamydien war nicht nachweisbar. Entzündungen von Eileiter und Uterus sind als Sterilitätsursache vermutlich bedeutend. Ob Chlamydien strukturelle und/oder funktionelle Eileiter- und Uterusveränderungen verursachen können, bleibt ebenso wie die Risiken für den Menschen abzuklären, die durch potenziell zoonotische Chlamydien wie Chlamydophila abortus entstehen können.

Die vorliegende Arbeit stellt die Powerdopplersonographie an Hand von Vergleichen und Gegenüberstellungen in deskriptiver Weise als nicht invasive Methode vor. Insgesamt wurden bei sechs klinisch-gynäkologisch gesunden Warmblutstuten 16 abgeschlossene, spontane und regelmäßige Zyklen mittels transrektalem Ultraschall aufgezeichnet. Es wurden 10590 dopplersonographische Messdaten ausgewertet, hinzu kamen 9601 powerdopplersonographische Bilddateien, die mittels Pixelanalysesoftware ANALYSIS PRO 1.1 analysiert wurden.

Im Mittelpunkt dieser Untersuchung stand die Frage, inwieweit der Feldhasenrückgang (Lepus europaeus) auf eine verminderte Reproduktion zurückzuführen ist. Zur Klärung dieser Frage wurden dabei erstmals in Deutschland die jährliche Reproduktionsleistung von Häsinnen durch den Nachweis von Plazentationsstellen (BRAY, 1998), erfasst. Die Alterbestimmung erfolgte über die etablierte Methode der Augenlinsenwägung (ANDERSON u. JENSEN, 1972; SUCHENTRUNK, 1991). Die Probenentnahme erfolgte auf den jährlichen Feldhasenjagden in 15 verschiedenen Revieren in den Jahren 1997 und 1998 im Zeitraum Oktober bis Dezember. Untersucht wurden 311 Uteri, 183 von adulten und 128 von juvenilen Häsinnen. 84% der adulten Weibchen waren nachweislich reproduktiv, bei den Junghäsinnen (unter einem Jahr alte) lag der Anteil bei 0,8%. Alle Individuen der jüngsten Altersklasse der Adulten (1-1,5 Jahre) waren fortpflanzungsaktiv, während in der Klasse der 1,5-3 Jahre alte Tiere bereits nur noch 90% reproduziert hatten. Bei Häsinnen im Alter von 3-5 Jahren lag der Wert bei 86%. Bei der ältesten Klasse (> 5 Jahre) sank der Anteil deutlich auf 54% ab. Von den 30 nichtreproduktiven adulten Häsinnen wiesen 21 pathologische Uterusveränderungen auf. Auffällig war das hohe Durchschnittsalter der nichtreproduktiven, das bei über vier Jahren lag, im Vergleich zu den reproduktiven Tieren. Im Durchschnitt wurden 9,2 Plazentationsstellen pro Uterus bei den adulten Häsinnen (nichtreproduktive miteinbezogen) gezählt. Dieser Wert entspricht den aus der Literatur bekannten Angaben. Hinweise auf eine verminderte Fertilität weiblicher Tiere als Ursache für den kontinuierlichen Rückgang der Feldhasenpopulation und dessen gleichzeitige Überalterung konnten aus diesen Ergebnissen nicht abgeleitet werden. Zu vermuten sind erhöhte Sterblichkeitsraten von Junghasen als Ursache für den bedenklichen Rückgang der Feldhasenpopulation. / The present study focuses on the question, whether the decrease in numbers of European hares (Lepus europaeus) could be due to a decrease in reproduction within that species. In order to clarify this hypothesis, this study investigated the annual reproduction performance of female European hares by counting the number of placentation sites that have been detected with a method described by (BRAY, 1998). In addition, the females agea were determined using the established method of eye lens weight as an age index (ANDERSON u. JENSEN, 1972; SUCHENTRUNK, 1991). The analysis was carried out in the years 1997 an 1998. This field investigation is the very first study addressing this question in Germany. Uterine probes were sampled on the annual hares huntings from October to December. Reproduction performance was analysed in 311 uteri, with 183 from adult and 128 from juvenile animals, respectively. While 84% of the adult animals (age: more than 1 year) showed reproduction, in contrast only 0,8% of the juvenile female hares (age: less than 1 year) were reproductive. Within the group of the youngest adult female hares (age: 1 to 1,5 years) all animals showed reproduction performance, however, reproduction proved to be already reduced to 90% in the group of 1,5 – 3 years old animals. In the group of female hares in the age from 3 – 5 years 86% displayed a reproduction performance, while finally in the oldest adult female hares (age: more than 5 years) only 54% showed signs of reproduction. Interestingly, out of 30 adult female hares that showed no sign of reproduction, 21 animals in a age older than 4 years showed pathological uterine alterations. The average number of placentation sites per uteri was 9,2 (nonreproductives include). This value is consitant with reports from the literature. Therefore, it is unlikely that cause for the decrease in population within that wild life species is due to a reduce fertility of female European hares. It seems that the higher deathrate of young hares may be the cause for the decrease of hares population

Objective: Reductions in sodium pump (SP) abundance can give rise to increases in contractile force in uterine and vascular smooth muscle as well as an increased secretion in secretory cells, including potentially those of the placenta. To determine whether the mouse might serve as a model for human pregnancy in terms of the SP and to determine whether changes in SP abundance anticipate or follow labor, we studied pregnant mice over the final trimester of their pregnancy. Study Design: C57Bl6 dams (n=46) were bred and studied during their pregnancy. Animals (n=4) were sacrificed at specific gestational time points. Other mice had labor induced with LPS on Gestational day 15 and were then studied at specific time points after induction. Specimens were studied for mRNA abundance as well as protein abundance using methods such as Real time RT-PCR and Western blot analysis. Data were analyzed by ANOVA with post hoc Duncan's pair-wise comparisons. Results: Levels of uterine SP α3 isoform mRNA were most abundant on day 14 near the beginning of the third trimester. There was a significant fall in SP &alpha3 mRNA abundance by day 18 with a slightly lower level on the day of birth but an increased SP α3 mRNA abundance by one day post partum. Contrary to the uterus, SP α3 mRNA levels in the placenta increased over the last trimester, from day 14 to the day of birth. Western blot analysis on the two tissues demonstrated a somewhat similar pattern. In the LPS studies of uterus and placenta, the SP α3 isoform protein abundance appeared to fall when compared to the 2 hour time point. Those animals which were injected with a vehicle control showed very little change in SP α3 abundance after injection. While protein levels were reduced, there was no significant reduction in mRNA for all specimens. Conclusion: Uterine SP α3 isoform protein expression fell late in mouse pregnancy but prior to labor and appeared to be mediated by reductions in its mRNA. These reductions paralleled changes observed in term pregnant women. Such reductions would increase the sensitivity of the uterus to agents causing contraction but may directly increase the force, duration and frequency of contractions. Placental SP α3 isoform protein expression had no significant change over the final trimester. However, unlike uterine protein, the placental protein may not be mediated by its mRNA. Reductions in SP α3 protein abundance were also seen in preterm labor produced by LPS induction. These changes may not be mediated by mRNA. Taken together, changes in the SP α3 isoform may represent a fundamental mechanism in the initiation and/ or progression of term labor and in preterm in mouse and potentially in human.

Placenta accreta spectrum disorder (PASD) is the adherence of the placenta caused by an abnormal trophoblast invasion into the myometrium. It is classified as placenta accreta, placenta increta, and placenta percreta depending on the extent of the invasion. Placenta accreta, defined as the superficial invasion of the placenta to the myometrium, accounts for 75% of PASD. Placenta increta is characterized by chorionic villi invasion deep into the myometrium. Placenta percreta involves placental invasion through the uterus and serosa and into the peritoneal cavity or surrounding viscera. Maternal morbidity and mortality can occur secondary to hemorrhage, disseminated intravascular coagulation, risks associated with blood transfusion, and pelvic and abdominal viscera injury. The standard of care in a known diagnosis of PASD is a cesarean delivery followed by hysterectomy with the placenta in situ. We report a case in which the diagnosis of focal PASD was not known antenatally but suspected after vaginal delivery. The patient subsequently underwent conservative management with uterine preservation and did not require laparotomy.

Although prostaglandins (PG) and oxytocin are crucial mediators of uterine contractility, their receptor-mediated effects during the menstrual cycle, pregnancy and labour are not fully understood. The aim of this thesis was to elucidate the functional expression of EP, FP, TP and oxytocin receptors in isolated human myometrium relative to myocyte mRNA and signal transduction pathways. Myometrial samples were obtained from consenting non-pregnant and pregnant donors. Functional techniques were used to determine isometric muscle contractions. Primary uterine myocytes and fibroblasts were cultured at term to identify stimulated changes in calcium (Ca2+), cyclic adenosine monophosphate (cAMP) and mRNA. Myometrial strips exhibited spontaneous contractions, which were most active midcycle under oestrogenic conditions. At this time intrinsic contractility and responsiveness to uterotonins decreased towards the fundus. PGE2 produced bellshaped responses with predominant utero-relaxant effects mediated via the EP2 subtype. Although activity was partially restored by PGE2 through EP3/1 receptors, tissue excitation was more pronounced at FP, TP and oxytocin receptors. Despite high FP mRNA expression, the lower segment uterus was particularly responsive to U46619 and oxytocin at term pregnancy. Even so, Ca2+ mobilisation by oxytocin was greater via principal release from intracellular stores. Incubations with atosiban, progesterone and a rho-kinase inhibitor reduced oxytocin-stimulated Ca2+ transients. EP2 also attenuated oxytocic effects but this appeared to be mediated through cAMP rather than Ca2+ signalling pathways. With advancing labour, intrinsic myogenic activity declined in parallel with oxytocin desensitisation. However, TP-induced contractions were continued in the lower parturient uterus. These findings demonstrate that PG and oxytocin receptor expression are regulated in a hormone-dependent temporal and spatial manner. EP2-mediated cAMP formation appears to promote uterine quiescence, whilst TP receptors may control muscle tonus during parturition. These receptors and their messenger systems represent effective tocolytic targets for uterine hypercontractile disorders, such as dysmenorrhoea and preterm labour. / Allergan Inc.

In the human uterus prostaglandins (PG) PGE2, PGD2, PGI2, PGF2¿ and Thromboxane A2 (TXA2), also termed prostanoids, are synthesised and deactivated to 15-keto PGE2, J2 metabolites, 6-keto-PGF1¿, 15-keto PGF2¿ and TXB2 respectively. However, not all metabolites have been analysed simultaneously within the same tissue. The primary objective of this thesis was to determine full uterine prostanoid profiles in human non-pregnancy, pregnancy and parturition, to better understand these processes and find suitable tocolytic targets. In addition, ten cytokines in human cervico-vaginal fluid (CVF) were measured according to interval to labour to test their suitability as labour onset predictors, with a view to developing a test to determine women at risk of preterm labour. Prostanoid analysis was carried out in endometrium (n=9) and myometrium (n=15- 16) donated by non-pregnant women and lower segment myometrium obtained from pregnant women (before (n=14) and after labour onset (n=7)) by liquid chromatography coupled with electrospray ionisation mass spectrometry (LC/ESIMS/ MS). Cytokines produced by CVF collected from pregnant donors (20-41 weeks gestation, n=2-10) were investigated using Enzyme-Linked Immunosorbent Assay (ELISA) or Luminex®. Human endometrium produced greater concentrations of TXB2, PGE2 and PGF2¿ than myometrium in vitro (p<0.05). Fifteen prostanoids were detected in human myometrium. Production of 6-keto-PGF1¿, PGE1 and PGF1¿ increased whilst 15- keto PGE2 and PGJ2 decreased at term pregnancy (37-41 weeks gestation) versus non-pregnancy (p<0.05). Myometrium from parturient donors synthesised TXB2 and PGE2 more abundantly than the non-labouring equivalent. Cytokine concentration was greatest in CVF sampled the week before labour, in particular Interleukin-6 (IL-6), Macrophage Inflammatory Protein-1¿ (MIP-1¿) and Monocyte Chemotactic Protein-1 (MCP-1) (p<0.05). Endometrial TXB2, PGE2 and PGF2¿ could aid in proliferation of glandular epithelium prior to ovulation. Prostacyclin may facilitate prolongation of pregnancy to term and thromboxane could contribute to uterine stimulation during labour. Cervical dilation may be influenced by PGE2 in lower segment myometrium. MCP- 1, MIP-1¿ and IL-6 could mark a short interval to labour onset. / Allergan Inc.

All human lives start with pregnancy. A pathological pregnancy can be physically, mentally, and financially detrimental to newborns and families. Preterm labor and birth (PTB) is one of the most serious pathological conditions associated with pregnancy. PTB affects 10% of global births and is the leading cause of death in children under five years of age. Multiple etiologies are identified for causing PTB and three major reproductive tissues are involved: the uterus, the cervix, and the feto–maternal interface. Throughout pregnancy, these reproductive tissues change in response to various signals, a process called remodeling. Timely and appropriate remodeling of these tissues is needed for a healthy pregnancy. One central element of remodeling is a change in tissues’ mechanical properties, the focus of this work. This dissertation investigates the mechanical environment of pregnancy by characterizing the remodeling of three reproductive tissues of primates (humans and Rhesus macaque monkeys) and computationally simulating pregnancy physiology. I combine comprehensive mechanical testing with digital image correlation (DIC) to capture the material behavior of reproductive tissues, characterize the architecture of these tissues’ fiber networks by optical coherence tomography (OCT), implement a microstructurally-inspired constitutive mate- rial model, conduct inverse finite element analysis (IFEA) to quantify observed remodeling, and finally use finite element analysis (FEA) to simulate pregnancy anatomy and physiology. Results presented here demonstrate that the non-human primate (NHP) cervix, human uterus, and NHP feto–maternal interface all undergo remodeling during pregnancy and experience com- plex stress conditions. In general, the NHP cervix becomes softer and more extensible, with distinct stages. While the ground substance compressibility stays approximately the same throughout gestation, the fiber network steadily becomes more extensible, though rapidly becomes less stiff and more dispersed during the second trimester. The human uterus late in gestation is softer and more extensible compared to its NP state; most of its remodeling involves changes to fiber network extensibility and architecture. The NHP feto–maternal interface adhesion strength reaches a peak early in the third trimester. Lastly, I generated preliminary subject-specific finite element models of NHP by using a workflow developed for human data. By doing this, the complex stress and stretch conditions that reproductive tissues undergo during pregnancy can be visualized. Future work advancing our understanding of pregnancy and women’s health should include the characterization of the time-dependent properties of reproductive tissues, investigation of the relationship between quantitative ultrasound measurements and tissues’ mechanical properties, and improvements to the current FEA workflow.

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