Der niedrig dosierte Dexamethason-Suppressionstest (LDDST) wird als Screeningverfahren in der Diagnostik des Cushing-Syndroms angewendet. Allerdings können Faktoren wie die variable Resorption, sowie ein gesteigerter Metabolismus von Dexamethason die Testergebnisse beeinflussen und zu falsch positiven Resultaten führen. Ein falsch positives Testresultat wird hierbei insbesondere bei adipösen Patienten häufiger beobachtet. In der vorliegenden Arbeit wurde daher der Einfluss des Körpergewichts auf das Ergebnis des Dexamethason-Suppressionstestes (DST) untersucht. Hierzu wurden hospitalisierte Patienten und ein aus gesunden Probanden bestehendes Kontrollkollektiv rekrutiert und diese einem regulären LDDST unterzogen. Es konnte gezeigt werden, dass übergewichtige Menschen im Rahmen des DST signifikant niedrigere Dexamethasonwerte erreichen als normalgewichtige Personen. Es ist daher davon auszugehen, dass Unterschiede im Body-Mass-Index (BMI) Einfluss auf die Resorptionsrate und den Metabolismus von Dexamethason nehmen und daraus resultierend die Serum-Dexamethasonspiegel wesentlich verringern können. Diese Prozesse scheinen allerdings keinen nachhaltigen Einfluss auf die Cortisolsuppression im DST zu haben, da die Cortisolwerte nach Dexamethasongabe zwischen adipösen und nicht adipösen Testpersonen nicht signifikant differierten. Diese Ergebnisse belegen, dass ein Zusammenhang zwischen BMI-Unterschieden und der Dexamethasonkinetik im LDDST besteht. Die erniedrigten Dexamethasonspiegel bei übergewichtigen Patienten scheinen hierbei insbesondere durch das wesentlich höhere Verteilungsvolumen und durch Unterschiede im hepatogenen Metabolismus bedingt zu sein. Trotz der erniedrigten Dexamethasonwerte bleibt die Feed-Back-Sensitivität der Hypothalamus-Hypophysen-Nebennieren-Achse (HHNA) auch bei Adipositas erhalten, weshalb der LDDST als zuverlässiges Screeningverfahren bei adipösen Patienten mit Verdacht auf Cushing-Syndrom einzustufen ist.

Bipolar disorders and recurrent depressions are two common psychiatric disorders with a life time prevalence of approximately 1% and 8%, respectively. Despite treatment these patients suffer from affective symptoms up to 50% of the time, resulting in lower well-being. The average life length is also reduced with 10-15 years, mainly attributable to suicide and cardiovascular disease. Increased stress is one of many factors that have been shown to be linked to an increased risk for developing affective disorders and some comorbid somatic conditions such as metabolic disturbances and cardiovascular disease. An increased stress level is known to cause hyperactivity of the hypothalamic-pituitary-adrenal-axis (HPA-axis) with increased cortisol secretion. Hyperactivity of the HPA-axis (or hypercortisolism) is one of the most replicated neurobiological finding in depression. In other stress related disorders it has however been shown that prolonged stress over long periods of time can lead to a state of low HPA-axis activity, hypocortisolism. Since persons with recurrent affective disorders such as bipolar disorder and recurrent depression are exposed to a high degree of recurrent and chronic stress it could be expected that in addition to hypercortisolism, a state of hypocortisolism could also develop in these disorders, potentially exerting an influence upon the psychological and somatic wellbeing among these patients. The major aim of this thesis was to evaluate whether hypocortisolism is related to relevant psychiatric and somatic phenotypes in recurrent affective disorders. In bipolar disorder, individuals with hypocortisolism exhibited a higher degree of depression and low quality of life compared to patients with normal HPA-axis activity. In recurrent depression, individuals with hypocortisolism exhibited shorter leukocyte telomere length than patients with normal or high HPA-axis activity, which is an indication of an accelerated aging process. In a sample of both bipolar and recurrent depression patients, hypocortisolism was associated with an increased proportion of obesity, dyslipidemia and metabolic syndrome compared with patients with normal or high HPA-axis activity. Patients with recurrent depression showed a higher occurrence of hypocortisolism than the control sample representative of the general population. Patients with bipolar disorder showed a similar occurrence of hypocortisolism as the control sample. Among bipolar disorder patients with a low degree of lifetime with lithium prophylaxis, there was an inverse correlation between age and HPA-axis activity. In contrast, among patients with a higher degree of lifetime with lithium prophylaxis as well as among the controls, there was no correlation between age and HPA-axis activity. Accordingly, hypocortisolism was most common among older patients with a low degree of lifetime with lithium prophylaxis. In conclusion, hypocortisolism in both recurrent depression and bipolar disorder was associated with multiple clinically-relevant phenotypes. Additionally it was shown for bipolar disorder patients that increasing age was a risk factor for hypocortisolism and that prophylactic lithium treatment was a protective factor. It is argued that the protective effect of lithium towards the HPA-axis is attributable to its mood-stabilizing effect, which in turn reduces the chronic stress level. These results provide new insight into the role of hypocortisolism and chronic stress in recurrent affective disorders warranting further studies and hopefully providing clues to improved treatment strategies.

Many studies have shown steroid hormone changes in adrenal incidentalomas with subclinical hypercortisolism and various forms of Cushing's syndrome. The aim of our work was to measure, using novel steroid GC-MS/MS measurement procedure, complex picture of many steroids in these patients. With the knowledge of these changes we could better explain causal pathophysiologic changes. In the study on patients with adrenal incidentalomas we described complex steroid changes in patients with subclinical hypercortisolism. Previous studies showed decrease of DHEAS in subclinical hypercortisolism. We confirmed this finding and described a decrease in other androgens and their metabolites. We also evaluated their sensitivity and specificity when compared to routinely used parameters for diagnosis of subclinical hypercortisolism. Furthermore, we looked at the alterations in all measured steroids and their changes in the 1 mg dexamethasone suppression test. In another study, we analyzed steroid changes in various forms of Cushing's syndrome. We confirmed the decrease of adrenal androgens in the ACTH independent forms and mild increase in the ACTH dependent forms. We also described elevations of mineralocorticoid precursors in central and ectopic forms of ACTH secretion. In the distinction of ectopic and central...

Made available in DSpace on 2015-07-22T20:49:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-06-27. Added 1 bitstream(s) on 2015-08-11T03:25:48Z : No. of bitstreams: 1 Publico-10871.pdf: 288428 bytes, checksum: 1c97fa2e91133c59ce89adf43ddcefed (MD5) / A sindrome de Cushing (SC) endogena e rara. Pacientes com SC subclinica (SCS) apresentam hipercortisolismo sem manifestacoes clinicas. SC ocorre em 2-3% de diabeticos mal controlados. Estudamos 103 pacientes adultos obesos ambulatoriais com diabetes mellitus tipo 2 para avaliar alteracoes do cortisol e SCS. Todos coletaram cortisol salivar as 23:00h e cortisol salivar e serico apos teste de supressao com 1mg de dexametasona (DST). Pacientes cujos resultados de qualquer teste estavam no quintil superior (253ng/dL, 47ng/dL e 1,8ƒÊg/dL, respectivamente para cortisol salivar 23:00h e salivar e serico pos-DST) foram reavaliados. Os valores medios desse grupo encontravam-se 2,5 vezes acima dos valores dos demais pacientes. Apos um teste confirmatorio com 2mgx2dias DST a investigacao da SC foi encerrada para 61 pacientes com todos os testes normais e 33 com apenas um teste (falso) positivo. Todos os 8 pacientes com dois testes alterados apresentaram cortisol urinario normal, mas 3 deles mostraram maior probabilidade diagnostica de SCS (hipercortisolismo e alteracoes em exames de imagem). Contudo, o diagnostico final nao pode ser confirmado por cirurgia ou patologia em nenhum deles. Embora nao confirmatorios, os resultados deste estudo sugerem que a prevalencia de SCS seja maior em populacoes de risco do que na populacao geral. / Endogenous Cushing’s syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00h and salivary and serum cortisol after a 1mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253ng/dL, 47ng/dL and 1.8ìg/dL, respectively for the 23:00h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5- fold higher than in the remaining patients. After a confirmatory 2mgx2day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population. / TEDE / BV UNIFESP: Teses e dissertações

Der niedrig dosierte Dexamethason-Suppressionstest (LDDST) wird als Screeningverfahren in der Diagnostik des Cushing-Syndroms angewendet. Allerdings können Faktoren wie die variable Resorption, sowie ein gesteigerter Metabolismus von Dexamethason die Testergebnisse beeinflussen und zu falsch positiven Resultaten führen. Ein falsch positives Testresultat wird hierbei insbesondere bei adipösen Patienten häufiger beobachtet. In der vorliegenden Arbeit wurde daher der Einfluss des Körpergewichts auf das Ergebnis des Dexamethason-Suppressionstestes (DST) untersucht. Hierzu wurden hospitalisierte Patienten und ein aus gesunden Probanden bestehendes Kontrollkollektiv rekrutiert und diese einem regulären LDDST unterzogen. Es konnte gezeigt werden, dass übergewichtige Menschen im Rahmen des DST signifikant niedrigere Dexamethasonwerte erreichen als normalgewichtige Personen. Es ist daher davon auszugehen, dass Unterschiede im Body-Mass-Index (BMI) Einfluss auf die Resorptionsrate und den Metabolismus von Dexamethason nehmen und daraus resultierend die Serum-Dexamethasonspiegel wesentlich verringern können. Diese Prozesse scheinen allerdings keinen nachhaltigen Einfluss auf die Cortisolsuppression im DST zu haben, da die Cortisolwerte nach Dexamethasongabe zwischen adipösen und nicht adipösen Testpersonen nicht signifikant differierten. Diese Ergebnisse belegen, dass ein Zusammenhang zwischen BMI-Unterschieden und der Dexamethasonkinetik im LDDST besteht. Die erniedrigten Dexamethasonspiegel bei übergewichtigen Patienten scheinen hierbei insbesondere durch das wesentlich höhere Verteilungsvolumen und durch Unterschiede im hepatogenen Metabolismus bedingt zu sein. Trotz der erniedrigten Dexamethasonwerte bleibt die Feed-Back-Sensitivität der Hypothalamus-Hypophysen-Nebennieren-Achse (HHNA) auch bei Adipositas erhalten, weshalb der LDDST als zuverlässiges Screeningverfahren bei adipösen Patienten mit Verdacht auf Cushing-Syndrom einzustufen ist.