Clinical And Basic Research On Prolactinomas

Prolactinomas are the most common functional pituitary adenomas, accounting for approximately 40% of all pituitary adenomas, with its incidence as 0.1‰。 Dopamine agonists such as bromocriptine or cabergoline carry a high probability of disease control. However,25% of patients with prolactinomas do not experience a reduction of tumor size or normalization of PRL levels to bromocriptine and 10% to cabergoline. Surgery is another option. Till now, studies on prolactinomas are not rare. In the clinical part, guidelines on the diagnosis and treatment of prolactinomas have been published, in basic medical research, genome sequencing has been fully carried out. Thus, our issues are more focused on the aspect not yet have been cleared reported. In the clinical part, prolactinomas in children are rare, studies now are more focusing on the children less than 18 years old. Since prolactinomas in premature children less than 14 years old are really rare and few studies have been reported before, our subject is trying to analyze the clinical features, diagnosis and treatment experience of these children patients. In basic research, our study set out to explore the relationship between AMPK signal pathways with the bromocriptine resistance mechanisms. And we firstly applied the AMPK signal pathway activator metformin combined with bromocriptine as a new treatment target for the bromocriptine resistant prolactinomas to achieve a more satisfactory result.Part One:Prolactinomas in children under 14. Clinical presentation and long-term follow-upObjective:Pediatric prolactinomas are rare, especially in children under 14 years of age. In this study, we evaluated the clinical presentation and microsurgical outcome of prolactinomas in pre-pubertal children.Methods:Nine patients with prolactinomas who had undergone surgical removal of the tumor before the age of 14 years were included in this retrospective study. Data on their clinical presentation, medications, physical, and laboratory evaluations, radiological findings, and long-time follow-up were obtained from their medical records.Results:The main presenting symptoms in the four female patients were galactorrhea (n=4,100%), whereas the five male patients most commonly presented with headache (n=4,80%) and growth retardation (n=3,60%). Six (66.6%) of the patients who had undergone transsphenoidal surgery were medication-free postoperatively. In three (33.3%) patients with giant adenomas, complete resection of the tumor was not achieved. One (11.1%) patient received radiotherapy after failed surgical and medical treatment. Postoperatively, electrolyte disturbances occurred in five (55.6%) patients, diabetes insipidus in two (22.2%), and thyroid dysfunction in two (22.2%). These complications resolved spontaneously. During follow-up, growth and puberty were usually normal.Conclusions:Tumor compressive symptoms and/or gonadal and growth arrest may be the primary clinical presentations of pediatric prolactinomas. Patients who are not candidates for dopamine-agonist therapy are best treated surgically, based on the low mortality and high cure rates. Hypopituitarism is a rare complication and may resolve spontaneously. Following successful treatment of a prolactinomas, growth and puberty in these children are normal. with headache (n=4,80%) and growth retardation (n=3,60%). Six (66.6%) of the patients who had undergone transsphenoidal surgery were medication-free postoperatively. In three (33.3%) patients with giant adenomas, complete resection of the tumor was not achieved. One (11.1%) patient received radiotherapy after failed surgical and medical treatment. Postoperatively, electrolyte disturbances occurred in five (55.6%) patients, diabetes insipidus in two (22.2%), and thyroid dysfunction in two (22.2%). These complications resolved spontaneously. During follow-up, growth and puberty were usually normal.Conclusions:Tumor compressive symptoms and/or gonadal and growth arrest may be the primary clinical presentations of pediatric prolactinomas. Patients who are not candidates for dopamine-agonist therapy are best treated surgically, based on the low mortality and high cure rates. Hypopituitarism is a rare complication and may resolve spontaneously. Following successful treatment of a prolactinomas, growth and puberty in these children are normal.Part Two:Research by activating AMPK signal pathways in the treatment of bromocriptine resistant prolactinomas.Objective:Adenosine monophosphate-activated protein kinase (AMPK) is an important kinase for energy homeostasis regulation, and AMPK signal pathways play an important role in cellular energy metabolism. Our subject aims to investigate the relationship between AMPK signal pathways with mechanism of bromocriptine resistance.Methods:Our experiments were carried out under three levels as the cells, animal models and human tissue specimens. Firstly, different activation of AMPK signal pathways of human prolactinomas tissues were analyzed in bromocriptine sensitive and resistant groups, and purposed the hypnosis. Then after the activation of AMPK signal pathways by AICAR or metformin, prolactinomas related receptors such as ERα, ERβand D2R expression variation and tumor cell proliferation and apoptosis were analyzed. The MMQ and GH3 xenograft tumor models were used to evaluate the results in cell experiments. The tumor size and serum PRL levels were also evaluated after treatment with bromocriptine only or bromocriptine and metformin combination.Results:D2R receptors expression was relatively decreased in bromocriptine resistant group patients but it was not all. Exception as people with high D2R receptor expression who were resistant to bromocriptine are still existed, but the AMPK activation level was extremely lower in these patients. Experiments on cell levels demonstrated that AICAR and metformin could downregulate the expression of ERaand ERβand thereby inhibit the tumor proliferation and promote apoptosis, and slightly upregulate the D2R expression. In combination with metformin, bromocriptine can distinctly inhibit the tumor growth and PRL levels of animal xenograft models.Conclusion:Activation of AMPK signal pathway could downregulate the ER expression to inhibit the tumor proliferation, prompt the apoptosis. Meanwhile it will slightly upregulate the D2R expression which will increase the sensitivity to bromocriptine.Bromocriptine combined with metformin might be a novel target for the bromocriptine resistant prolactinomas.