Rolle der Angiogenese und ihrer Inhibitoren in der Gynäkologie

Angiogenesis describes the neoformation of blood vessels which develop by budding and sprouting of the existing vessel system. Solid tumor growth is dependent on the surrounding growing capillary network providing the tumor with essential nutrients and oxygen. The pathophysiological role of angiogenesis could be shown for multiple benign (endometriosis, menorrhagia, leiomyomatosis, ovarian hyperstimulation syndrome, preeclampsia and placental hypoperfusion syndrome) and malignant (especially metastasized and therapy-refractory breast cancer, ovarian cancer, cancer of the fallopian tube and the primary peritoneal cancer) diseases. Diseases that are very much dependent on (neo) angiogenesis can be treated with various anti-angiogenic agents. Due to the broad spectrum of side effects of established angiogenesis inhibitors which are mostly given in combination with chemotherapeutic agents, this therapeutic approach is mostly limited to malignant diseases, such as breast cancer, ovarian cancer, cancer of the fallopian tube and primary peritoneal carcinoma. This review provides an overview of the current state of knowledge in the anti-angiogenic therapy of gynecological diseases and will give a perspective of potential future implications of new therapeutic agents.     

Neue Aspekte der ovariellen Stimulation

New aspects of ovarian stimulation for assisted reproduction techniques focus on minimizing patient burden and therapeutic risks while maintaining the classic concept of gonadotropin stimulation in combination with gonadotropin releasing hormone (GnRH) analogues. The introduction of a long-acting follicle stimulating hormone (FSH) preparation (corifollitropin alfa) allows dispensing with daily injections during the first week of stimulation while achieving comparable ovarian responses and clinical outcome. Another milestone is the possibility of completely avoiding ovarian hyperstimulation syndrome (OHSS) by the use of GnRH agonists for ovulation induction in a GnRH antagonist protocol for patients with suspected high response. Various treatment modalities are still under discussion to optimize the outcome of infertility therapy in patients with previous or suspected poor response (POR). In summary, the introduction and new combination of preparations allows a more individualized ovarian stimulation in order to optimize treatment outcome and minimize risks and patient burden during assisted reproduction techniques.     

The optic nerve head component of the human ERG.

The local responses of the multifocal ERG reveal continuous changes in the second order waveforms from the nasal to the temporal retina. Scrutiny of these changes suggests the presence of an additive component whose latency increases with the distance of the stimulus from the optic nerve head. This observation led to the hypothesis of a contributing source in the vicinity of the optic nerve head whose signal is delayed in proportion to the fiber length from the stimulated retinal patch to the nerve head. The hypothesis was tested with two independent methods. In Method 1, a set of different local response waveforms was approximated by two fixed components whose relative latency was allowed to vary and the fit of this two component model was evaluated. In Method 2, two signals were derived simultaneously using different placements for the reference electrode. The placements were selected to produce a different ratio of the signal contributions from the retina and the nerve head in the two recording channels. The signals were then combined at a ratio that canceled the retinal component. Method 1 yielded an excellent fit of the two component model. Waveforms and latencies of the hypothetical optic nerve head component derived from the two methods agree well with each other. The local latencies also agree with the propagation delays measured in the nerve fiber layer of the monkey retina. In combination, these findings provide strong evidence for a signal source near the optic nerve head.     

Multifocal electroretinography (MF-ERG) in age-related macular degeneration Beispiel: Altersabh?ngige Makuladegeneration (AMD)

Purpose: Small areas of retinal pathology may pose diagnostic difficulties. The noninvasive multifocal electroretinogram (MF-ERG) provides a topographical mapping of retinal function. Its role in the diagnosis of macular diseases is examined in age-related macular degeneration (AMD). AMD is a main cause of central visual loss in the elderly population, affecting the second eye in 75 %.     

Assessment of early retinal changes in diabetes using a new multifocal ERG protocol

AIMS: To assess early functional retinal changes in diabetics without retinopathy, a new multifocal stimulus paradigm was used that emphasises fast adaptive response contributions. METHODS: 25 normal control subjects (25 eyes) and 11 diabetics without retinopathy (22 eyes) served as subjects. Stimulation and analysis were performed with Veris Science 4.0. A stimulation protocol was used that combines regular multifocal flicker stimulation with a periodic "global" flash inserted between the multifocal stimuli. The multifocal stimuli were presented four video frames apart. The global flash covered the entire screen in the third frame of the four frame interval. The remaining two frames were dark. The periodic global flashes could only contribute to the focal responses if they were affected by the multifocal stimulation. A non-linear component induced by the interaction of the focal and global flashes was observed. The differences between control subjects and diabetics were assessed in both the multifocal responses and their induced effect on the following global flashes. RESULTS: The responses to focal flashes were reduced significantly in diabetics matched in age to the control subjects. The induced components showed large intersubject variability in controls and patients, and did not differ significantly between the two groups. CONCLUSION: The periodic global flashes produce a greater multifocal response reduction in diabetics than in normals, indicating impairment in the rate or magnitude of recovery from the bright preceding stimulus. The new stimulation protocol reveals early changes in retinal function of diabetics.     

Arthroscopic evaluation of anterior cruciate ligament reconstructions

Fourteen patients who underwent anterior cruciate ligament (ACL) reconstruction, using fascia lata or patellar tendon, were examined arthroscopically at a mean time of 16 months following surgery. The postoperative care and rehabilitation program was standardized for all patients. Eleven of these 14 patients were recalled for a functional evaluation. Nine of these 11 patients were satisfied with the outcome of their reconstruction. Two patients complained of an occasional giving way of the knee. The arthroscopic findings were disappointing. Four patients appeared to have viable ligamentous structures in the intercondylar notch. Four patients had lax ligamentous tissue in the notch. In other cases, the notch was filled with varying degrees of amorphous scar tissue. The tissue was tested by palpation with a probe and with an anterior drawer test applied. The scar tissue did develop tension and give a firm end point to the drawer test. Other arthroscopic findings included instances of Grade II, III, and IV chondromalacia of the articular cartilage, adhesions, and capsular scarring not seen at the time of original surgery. While the patient satisfaction and functional results were generally good, we were disappointed with the arthroscopic findings. Based on the generally poor quality of the reconstructed tissue and the articular cartilage lesions, we have changed our surgical technique and postoperative regime.     

Angiogenese – therapeutische Interventionsmöglichkeiten bei rheumatischen Erkrankungen

In contrast to vasculogenesis, angiogenesis is defined as the formation of new vessels from preexisting ones. Physiologically, this multistep process occurs in adults during the reproductive cycle and during pregnancy, pathophysiologically it can be found in wound healing, inflammation and carcinogenesis. The underlying mechanisms are vasodilatation and increasing permeability, destabilization of vessel walls and degradation of extracellular matrix, followed by the proliferation and migration of endothelial cells. Migrated endothelial cells form vascular tubes at sites of ischemia and these tubes are finally stabilized by pericytes and smooth muscle cells. This process is controlled by a complex interaction of angiogenic and angiostatic factors. In contrast to carcinogenesis, the role of angiogenesis for the pathogenesis and therapy of rheumatic diseases is less understood. Two examples for pathologically disturbed angiogenesis, rheumatoid arthritis and systemic sclerosis, are discussed in this review with respect to therapeutic options.