The clinical and preclinical research interests of the group are closely related to the diseases treated in our neuroendocrinological outpatient clinic. Because most of the more than 2000 patients annually examined suffer from pituitary disturbances (pituitary insufficiency, pituitary tumors etc.), the exploration of the underlying pathomechanisms of these diseases represents a major research focus of our group. In addition, we perform clinical and preclinical research projects that are associated with other endocrine disorders such as transsexualism or metabolic diseases. In this context, studies on the pathogenesis of metabolic disorders have emerged as a new research focus. These studies are also of high impact for metabolic disturbances which often occur during the use of anti-depressant treatment for patients with major depression.
Neuropsychiatric, neurological and metabolic aspects of pituitary disorders
In close cooperation with psychiatrists, psychologists and neurologists of the institute as well as external centers, we conduct clinical studies to investigate neuropsychiatric, neurologic and metabolic alterations in patients with pituitary hormone excess or deficiency and how they change during treatment.
We could show that patients with endocrine-active pituitary adenomas exhibit neuropsychiatric (e.g. cognition, sleep, quality of life), morphologic (brain architecture) and neurologic (sensation of pain) changes, which improve after successful therapy (tumor resection, pharmacologic hormone suppression). Further studies related to these aspects are in progress.
Pituitary insufficiency is sometimes observed in patients with traumatic brain injury (TBI) or subarachnoidal hemorrhage (SAH). In close collaboration with neurological rehabilitation centers we investigate whether adequate hormone substitution can improve the multiple clinical problems of hormone-deficient patients with TBI or SAH. In another project we examine whether hormone substitution mimicking circadian rhythms benefits patients in comparison to bolus application. For some hormones, the latter can cause psychiatric or metabolic disturbances, which may potentially be avoided when hormone substitution mimics physiological circadian variations of hormone production and thus blood hormone levels.
Influence of sex hormones on the stress reactivity of transsexual patients
The hyper-activation of the HPA-axis by chronic stress may be one of the most relevant factors for the induction of depression. However, due to the higher prevalence of depression in women, sex hormones also seem to play an important causative role. In a collective of transsexual patients we will study whether the cross-gender sex therapy has an influence on the basal and stimulated activity of the HPA axis and whether this is potentially responsible for the higher prevalence of depression in male-to-female transsexual patients.
Supported by the „Bundesministerium für Bildung und Forschung (BMBF)“, the collaboration of several competence centers for neuroendocrine tumors including pituitary adenomas has been founded, and is known as the excellence network for neuroendocrine tumors (NeoExNET). We are currently collecting a large amount of data from affected patients in order to perform clinical studies in an extensive collective of patients. These studies aim to identify diagnostically relevant biomarkers or prognostic factors and to develop new therapeutic concepts for the treatment of pituitary tumors. In this way, we aim to achieve optimal patient care and quality control.
Pathogenesis and pharmacological therapy of pituitary adenomas
In pituitary adenomas, tumor cells, stromal cells, vessel cells and immune cells interact among each other through direct cell-to-cell contacts and/or soluble factors. These interactions play important roles in tumor neovascularisation through angiogenesis or immune-neuroendocrine processes. The identification of the mechanisms involved in these processes will aid in the development of anti-angiogenic or immunosuppressive therapeutic concepts. In this context, we are currently focusing our research interests on the sumoylation enhancer RSUME, which regulates key factors of both immune-neuroendocrine and angiogenic processes.
Pharmacologically active ligands of the somatostatin receptor type 2 (SSTR2) sensitize pituitary tumor cells to treatment with chemotherapeutic compounds. The combined therapy of SSTR2 ligands and mTOR inhibitors has given first promising results and will be continued.
We have shown that HSP90 inhibitors inhibit growth and ACTH secretion of corticotroph pituitary tumors both in vitro and in vivo and largely revert pathophysiological changes in an animal model. The investigations on the mechanism of action will be continued. The approval of the efficacy of the HSP90 inhibitors at a clinical level is planned.
Pathogenesis of metabolic syndrome and obesity
Elements of the IGF-1 system as well as FKBP immunophilines, in particular FKBP5/FKBP51, are important components of the physiology of adipocytes. If, and how the deregulation of these substances in adipocytes contributes to the development of the metabolic syndrome and of obesity is currently under investigation.
A further project deals with the role of the posttranslational process of neddylation in adipogenesis, lipid metabolism and adipositas. Neddylated proteins are strongly expressed in adipocytes, whereas the expression changes during adipogenesis. In addition, first results suggest that the neddylation is of importance for the lipolysis and thus the biology of adipocytes. In current in vitro and in vivo experiments we will identify the mechanisms through which neddylation affects the genesis and the biology of adipocytes.