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The androgenital syndrome: Don't just think about it in childhood!In adrenogenital syndrome, the body permanently produces too many male sex hormones. Rare, congenital metabolic diseases are usually discovered in infancy and can be treated at an early stage treated at an early stage, but sometimes they only become apparent in adolescence and adulthood.This article provides background knowledge for GPs.
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Síndrome Adrenogenital , Adolescente , Masculino , HumanosRESUMEN
BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81⯱ 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy Xray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (nâ¯= 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low Tscore). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (pâ¯= 0.031) and lower hemoglobin levels (pâ¯= 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.
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Anemia , Hipogonadismo , Osteoporosis , Sarcopenia , Masculino , Humanos , Anciano , Sarcopenia/diagnóstico , Sarcopenia/epidemiología , Sarcopenia/complicaciones , Fuerza de la Mano , Estudios Transversales , Multimorbilidad , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiología , Hipogonadismo/complicaciones , Osteoporosis/diagnóstico , Osteoporosis/epidemiología , Osteoporosis/complicaciones , Anemia/diagnóstico , Anemia/epidemiología , Anemia/complicaciones , TestosteronaRESUMEN
Pituitary insufficiency is a partial or complete failure of secretion of one or more hormones from the pituitary gland. The pituitary gland is located in the hypophysial fossa of the sella turcica of the os sphenoidale and produces ACTH, LH, FSH, GH, TSH, and prolactin. Pituitary insufficiency can be caused by acute damage, such as secondary to traumatic brain injury. It can also be a result of chronic alterations, such as increasing tumor expansion.Pituitary insufficiency often presents with nonspecific symptoms (e.g. fatigue, listlessness, decreased performance, sleep disturbances, weight change) that leads to a challenging and sometimes delayed diagnosis. The symptoms correspond to the failure of the corresponding endorgans. Occasionally, symptoms such as a loss of libido, secondary amenorrhea or nausea in stressful situations are diagnostically indicative.Further clarification includes a clinical examination with endocrinological testing of the pituitary function. Alteration of pituitary hormone secretion can also occur physiologically as in pregnancy, depression or obesity. Substitution therapy of the failed corticotropic, thyrotropic and gonadotropic axis is corresponding to the therapy of a primary endorgan insufficiency. Adequate diagnosis and treatment of pituitary insufficiency is important, as this may prevent life-threatening crises such as an adrenal crisis.
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Hipopituitarismo , Prolactina , Femenino , Embarazo , Humanos , Hipófisis , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Hipopituitarismo/terapia , HormonasRESUMEN
Purpose: In this study we evaluate sleep patterns of patients treated for non-secreting intra- and parasellar tumors and age- and sex-matched healthy controls. Methods: We conducted a self-report cross-sectional case-control study with 104 patients treated for non-secreting intra- and parasellar tumors and 1800 healthy controls in an 1:8 matching. All subjects answered the Munich ChronoType Questionnaire, whereas patients were provided the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Short-Form 36 Health survey, the Beck Depression Inventory and the State-Trait Anxiety Inventory additionally. Results: Patients treated for non-secreting intra- and parasellar tumors go to bed earlier, fall asleep earlier, need less time to prepare to sleep but also to get up. Additionally, they lie and sleep longer. The subgroup analysis showed that patients with secondary adrenal insufficiency compared to controls experienced shorter daily light exposure and longer sleep latency. Higher hydrocortisone dose (>20mg) was associated with worse score in global, physical and mental health, shorter time to prepare to sleep, earlier sleep onset and longer sleep duration. Conclusion: Our study shows that patients treated for non-secreting intra- and parasellar tumors, even if successfully treated, experience altered sleep patterns compared to controls. We suggest that managing clinicians should enlighten these possible sleep alterations to their patients and use specific questionnaires to document sleep disturbances. Additionally, when treating patients surgically, especially by transcranial approach, damaging the suprachiasmatic nucleus should be avoided. Furthermore, circadian hydrocortisone replacement therapy ideally with dual-release hydrocortisone - if possible, in a dose not more than 20mg daily - that resembles physiological cortisol levels more closely may be beneficial and could improve sleep patterns and sleep-related quality of life.
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Neoplasias , Trastornos del Sueño-Vigilia , Humanos , Autoinforme , Estudios de Casos y Controles , Calidad de Vida , Estudios Transversales , Trastornos del Sueño-Vigilia/etiología , Sueño , HidrocortisonaRESUMEN
Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.
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Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Adenoma/genética , Corticotrofos/patología , Humanos , Antígeno Ki-67 , Mutación/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Cushing's disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing's disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing's disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.
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Neoplasias , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Animales , Corticotrofos/metabolismo , Endopeptidasas/genética , Endopeptidasas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Humanos , Ratones , Neoplasias/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Somatostatina/análogos & derivados , Somatostatina/farmacología , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/uso terapéutico , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
OBJECTIVE: Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context. DESIGN: Cross-sectional single-center study. METHODS: Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage. RESULTS: Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement. CONCLUSION: Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.
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Craneofaringioma , Endocannabinoides/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Neoplasias Hipofisarias , Hormona Adrenocorticotrópica/metabolismo , Adulto , Ácido Araquidónico/metabolismo , Ácidos Araquidónicos/metabolismo , Estudios de Casos y Controles , Craneofaringioma/metabolismo , Craneofaringioma/fisiopatología , Estudios Transversales , Entrenamiento Aeróbico , Ejercicio Físico/fisiología , Femenino , Glicéridos/metabolismo , Glicopéptidos/metabolismo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patología , Hipotálamo/fisiopatología , Masculino , Persona de Mediana Edad , Ácidos Oléicos/metabolismo , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/fisiopatología , Alcamidas Poliinsaturadas/metabolismo , Adulto JovenRESUMEN
PURPOSE: To evaluate safety and effectiveness of biosimilar recombinant human growth hormone (rhGH; Omnitrope®) in adults with growth hormone deficiency (GHD), using data from the PATRO Adults study. METHODS: PATRO Adults was a post-marketing surveillance study conducted in hospitals and specialized endocrinology units across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope® treatment. Effectiveness was evaluated as a secondary objective. RESULTS: As of January 2020, 1447 patients (50.9% male) had been enrolled from 82 centers in 9 European countries. Most patients had adult-onset GHD (n = 1179; 81.5%); 721 (49.8%) were rhGH-naïve at study entry. Overall, 1056 patients (73.0%) reported adverse events (AEs; n = 5397 events); the majority were mild-to-moderate in intensity. Treatment-related AEs were reported in 117 patients (8.1%; n = 189 events); the most commonly reported (MedDRA preferred terms) were arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10). In total, 495 patients (34.2%) had serious AEs (SAEs; n = 1131 events); these were considered treatment-related in 28 patients (1.9%; n = 35 events). Mean (standard deviation) IGF-I SDS increased from - 2.34 (1.47) at baseline to - 0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 3 years). Body mass index remained stable between baseline and 3 years. CONCLUSION: Data from PATRO Adults indicate biosimilar rhGH (Omnitrope®) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice.
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Vigilancia de Productos Comercializados , Biosimilares Farmacéuticos/efectos adversos , Enanismo Hipofisario , Femenino , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Estudios Longitudinales , Masculino , Proteínas RecombinantesRESUMEN
BACKGROUND: The rates of incomplete surgical resection for pituitary macroadenomas with cavernous sinus invasion are high. In growth hormone-producing adenomas, there is a considerable risk for persistent acromegaly. Thus, effective treatment options are needed to limit patient morbidity and mortality. This multicenter study assesses the efficacy and safety of robotic radiosurgery (RRS) for patients with cavernous sinus-invading adenomas with persistent acromegaly. METHODS: Patients who underwent RRS with CyberKnife for postoperative acromegaly were eligible. RESULTS: Fifty patients were included. At a median follow-up of 57 months, the local control was 100%. The pretreatment insulin-like growth factor 1 (IGF-1) levels and indexes were 381 ng/mL and 1.49, respectively. The median dose and prescription isodose were 18 Gy and 70%, respectively. Six months after RRS, and at the last follow-up, the IGF-1 levels and indexes were 277 ng/mL and 1.14, as well as 196 ng/mL and 0.83, respectively (p = 0.0001 and p = 0.0002). The IGF-1 index was a predictor for biochemical remission (p = 0.04). Nine patients achieved biochemical remission and 24 patients showed biochemical disease control. Three patients developed a new hypopituitarism. CONCLUSIONS: RRS is an effective treatment for this challenging patient population. IGF-1 levels are decreasing after treatment and most patients experience biochemical disease control or remission.
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BACKGROUND: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.
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Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Evaluación de Resultado en la Atención de Salud , Péptidos Cíclicos/farmacología , Somatostatina/análogos & derivados , Acromegalia/sangre , Adulto , Austria , Femenino , Geles , Alemania , Hormona de Crecimiento Humana/sangre , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/administración & dosificación , Somatostatina/administración & dosificación , Somatostatina/farmacología , SuizaAsunto(s)
Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/terapia , Calidad de Vida , Hormona Adrenocorticotrópica/metabolismo , Animales , Humanos , Hidrocortisona/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnósticoRESUMEN
INTRODUCTION: Growth hormone (GH) deficiency (GHD) in adults is characterized by abnormal body composition, unfavorable cardiovascular risk factors, and poor quality of life. The diagnosis is made within appropriate clinical settings and according to established guidelines. Numerous studies have shown that GH treatment improves body composition, cardiovascular risk factors, physical capacity, and quality of life while issues on safety, in particular long-term safety, remain. AREAS COVERED: Short- and long-term safety of GH replacement in adults with GHD. EXPERT OPINION: Adults with GHD are an inhomogeneous group of patients and GH replacement requires individual considerations. Most adverse effects are mild and transient and related to fluid retention and GH dose. In patients without comorbidities long-term GH treatment is safe and development of diabetes, cardiovascular disease, or tumors are not increased. Furthermore, mortality is not increased. Patients with risk factors should be identified before GH treatment is initiated and an optimal balance between benefit and risk established. Studies with sufficient duration and power to identify the development of cardiovascular diseases and cancers are still awaited. Effective management of comorbidities can be expected to decrease morbidity and mortality and improve quality of life. Studies with long-acting GH formulations are ongoing and available data indicate similar effects and short-time safety.
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Terapia de Reemplazo de Hormonas/efectos adversos , Hormona de Crecimiento Humana/efectos adversos , Adulto , Composición Corporal , Terapia de Reemplazo de Hormonas/métodos , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/deficiencia , Humanos , Calidad de Vida , Proteínas Recombinantes , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: To assess the safety (particularly the occurrence of malignancies) of growth hormone (GH) replacement (Omnitrope®) in adults with GH deficiency, using data from the ongoing PATRO Adults post-marketing surveillance study. METHODS: PATRO Adults is being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ⩾1 dose of Omnitrope® are included in the safety population. Malignancies are listed as adverse events under the MedDRA System Organ Class 'neoplasms, benign, malignant and unspecified (including cysts and polyps)'. RESULTS: As of July 2018, 1293 patients had been enrolled in the study and 983 (76.0%) remained active in the study. Approximately half [n = 637 (49.3%)] of the patients were GH treatment-naïve on study entry. The majority of enrolled patients had multiple pituitary hormone deficiency (n = 1128, 87.2%). A total of 41 on-study malignancies were reported in 33 patients (2.6%; incidence rate 7.94 per 1000 patient-years). The most common cancers were basal cell carcinoma (n = 13), prostate (n = 6), breast, kidney and malignant melanoma (each n = 3). Treatment with Omnitrope® was discontinued following diagnosis of malignancy in 16 patients. The tumors occurred after a mean of 79.4 months of recombinant hormone GH (rhGH) treatment overall. CONCLUSION: Based on this snapshot of data from PATRO Adults, Omnitrope® treatment is tolerated in adult patients with GH deficiency in a real-life clinical practice setting. Our results do not generally support a carcinogenic effect of rhGH in adults with GH deficiency, although an increased risk of second new malignancies in patients with previous cancer cannot be excluded based on the current dataset.
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PURPOSE: Patients with non-functioning pituitary adenomas (NFPA) suffer from pronounced impairments in physical and mental measures that result in an impairment of health-related quality of life (HRQOL). The role of secondary adrenal insufficiency (SAI) and especially the one of the hydrocortisone (HC) replacement dose on the HRQOL seems to be conflicting. The primary aim of this study is to assess the HRQOL in patients with NFPA in terms of presence of SAI and in patients without SAI and the secondary to explore the impact of treatment parameters such as daily HC dose. DESIGN/METHODS: In a cross-sectional study we evaluated parameters of HRQOL in 95 patients with NFPA of the Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry in Munich using standardized questionnaires like Short Form (SF-36), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and a self-constructed questionnaire about medical history. RESULTS: We could not find any significant difference between patients with and without SAI in the standardized questionnaires in terms of HRQOL. We could show that higher doses of HC were negatively correlated with HRQOL measured by SF-36 global health score regardless of using BDI or STAI in the block (ß = - 0.397; p = 0.021, ß = - 0.390; p = 0.016, respectively). CONCLUSIONS: NFPA patients with SAI do not have a worse HRQOL than patients with NFPA and intact corticotropic axis. We could show that higher doses of HC are associated with an impaired HRQOL measured by SF-36 global and physical health score, whereas mental health score is not significantly influenced by the HC dose.
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Adenoma/tratamiento farmacológico , Adenoma/psicología , Hidrocortisona/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/psicología , Calidad de Vida/psicología , Estudios Transversales , Femenino , Humanos , Hidrocortisona/farmacología , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
The authors present current findings on transsexualism and its treatment. According to the ICD-10, transsexualism is defined as the "desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex." Synonyms of transsexualism are terms such as gender dysphoria reflecting the distress that persons feel due to a mismatch between their gender identity and their sex assigned at birth.The prevalence of transsexualism is estimated to be about 0,6â%. The diagnosis of transsexualism is made by psychiatrists, but at least five more medical specialties (endocrinologist, surgeon, ear, nose and throat specialist, speech therapist and dermatologist) are involved when treating transsexual persons. Hormonal therapy is a very important element of the treatment process; due to the complexity of transsexualism it should be undertaken by endocrinologists with experience and expertise in this field.
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Medicina Interna/educación , Transexualidad , Femenino , Identidad de Género , Hormonas Esteroides Gonadales/uso terapéutico , Humanos , Masculino , Grupo de Atención al Paciente , Transexualidad/diagnóstico , Transexualidad/terapiaRESUMEN
The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.
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Acromegalia/complicaciones , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer , Tamizaje Masivo , Monitoreo Fisiológico , Neoplasias de la Tiroides/diagnóstico , Acromegalia/diagnóstico , Acromegalia/epidemiología , Acromegalia/terapia , Adenoma/complicaciones , Adenoma/diagnóstico , Adenoma/epidemiología , Adenoma/terapia , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/epidemiología , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/normas , Endocrinología/métodos , Endocrinología/normas , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Humanos , Tamizaje Masivo/métodos , Tamizaje Masivo/normas , Oncología Médica/métodos , Oncología Médica/normas , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/normas , Vigilancia de la Población/métodos , Guías de Práctica Clínica como Asunto/normas , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/epidemiologíaRESUMEN
CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. OBJECTIVE: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1â ≤â 1.3â ×â ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. DESIGN: Retrospective multicenter study. SETTING: Eight participating European centers. METHODS: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. RESULTS: Lower IGF-1 concentration at baseline (odds ratio (OR)â =â 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, Pâ =â .0073) and lower bodyweight (ORâ =â 0.99, 95% CI 0.98-0.99 kg, Pâ =â .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (ORâ =â 1.40, (1.19-1.65) IGF-1 ULN, Pâ ≤â .0001), the presence of type 2 diabetes (oral medication ORâ =â 2.48, (1.43-4.29), Pâ =â .0013; insulin therapy ORâ =â 2.65, (1.02-6.70), Pâ =â .045), and higher bodyweight (ORâ =â 1.02, (1.01-1.04) kg, Pâ =â .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (ORâ =â 0.96, (0.94-0.99) year, Pâ =â .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (ßâ =â 0.90, standard error (SE)â =â 0.02, Pâ ≤â .0001 and ß â =â 0.002, SEâ =â 0.001, Pâ =â .014, respectively). CONCLUSION: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.
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Acromegalia/tratamiento farmacológico , Biomarcadores Farmacológicos , Modelos Teóricos , Receptores de Somatostatina/agonistas , Somatostatina/análogos & derivados , Acromegalia/sangre , Acromegalia/diagnóstico , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/metabolismo , Estudios de Cohortes , Europa (Continente) , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ligandos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Octreótido/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Pronóstico , Estudios Retrospectivos , Somatostatina/uso terapéutico , Resultado del TratamientoRESUMEN
Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted.
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Subunidad RIIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Hipofisarias/genética , Activación Transcripcional/genética , Línea Celular Tumoral , Subunidad RIIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunoglobulinas/genética , Fosforilación/genética , Neoplasias Hipofisarias/patología , Transducción de Señal/genética , Hipoxia Tumoral/genéticaRESUMEN
Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing's disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing's disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.