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PURPOSE: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. METHODS: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. RESULTS: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). CONCLUSIONS: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.
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Insuficiencia Suprarrenal , Síndrome de Cushing , Humanos , Síndrome de Cushing/tratamiento farmacológico , Hidrocortisona/uso terapéutico , Resultado del Tratamiento , LógicaRESUMEN
PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.
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Síndrome de Cushing/tratamiento farmacológico , Cetoconazol/uso terapéutico , Adulto , Síndrome de Cushing/patología , Femenino , Humanos , Hidrocortisona/uso terapéutico , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Calidad de Vida , Somatostatina/uso terapéuticoRESUMEN
BACKGROUNDS: The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known. METHODS: We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum ('Single VHL tumour' cohort), 70 patients with multiple tumours of the VHL spectrum ('Multiple VHL tumours' cohort), 76 patients with a VHL disease as described in the literature ('VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants. RESULTS: Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum. CONCLUSIONS: VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.
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Predisposición Genética a la Enfermedad , Paraganglioma/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/genética , Adulto , Anciano , Exones/genética , Femenino , Pruebas Genéticas , Mutación de Línea Germinal/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Paraganglioma/epidemiología , Paraganglioma/patología , Linaje , Adulto Joven , Enfermedad de von Hippel-Lindau/epidemiología , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
Catecholamines are physiological regulators of carbohydrate and lipid metabolism during stress, but their chronic influence on metabolic changes in obese patients is still not clarified. The present study aimed to establish the associations between the catecholamine metabolites and metabolic syndrome (MS) components in obese women as well as to reveal the possible hidden subgroups of patients through hierarchical cluster analysis and principal component analysis. The 24-h urine excretion of metanephrine and normetanephrine was investigated in 150 obese women (54 non diabetic without MS, 70 non-diabetic with MS and 26 with type 2 diabetes). The interrelations between carbohydrate disturbances, metabolic syndrome components and stress response hormones were studied. Exploratory data analysis was used to determine different patterns of similarities among the patients. Normetanephrine concentrations were significantly increased in postmenopausal patients and in women with morbid obesity, type 2 diabetes, and hypertension but not with prediabetes. Both metanephrine and normetanephrine levels were positively associated with glucose concentrations one hour after glucose load irrespectively of the insulin levels. The exploratory data analysis showed different risk subgroups among the investigated obese women. The development of predictive tools that include not only traditional metabolic risk factors, but also markers of stress response systems might help for specific risk estimation in obesity patients.
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Metanefrina/orina , Análisis Multivariante , Normetanefrina/orina , Obesidad/orina , Adolescente , Adulto , Anciano , Biomarcadores/orina , Análisis por Conglomerados , Diabetes Mellitus Tipo 2/orina , Femenino , Humanos , Síndrome Metabólico/orina , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Circunferencia de la CinturaRESUMEN
11ß-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH11ß). In females, the clinical phenotype of CAH11ß classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11ß-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH11ß have also been briefly discussed. The presented case of an adult woman with CAH11ß shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility.
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Hiperplasia Suprarrenal Congénita/genética , Infertilidad Femenina/genética , Mutación , Esteroide 11-beta-Hidroxilasa/genética , Acné Vulgar/genética , Adulto , Femenino , Estudios de Seguimiento , Hirsutismo/genética , Humanos , Trastornos de la Menstruación/genética , Persona de Mediana EdadRESUMEN
Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.
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Adrenalectomía , Hormona Adrenocorticotrópica/metabolismo , Terapia Combinada/historia , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Hidrocortisona , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Pituitary adenomas (PAs) show a broad clinicomorphological spectrum. The proliferation activity, evaluated by MIB-1 labelling index (LI), and p53 expression have been pointed as predictive markers for invasiveness and progression. The aim of this study was to evaluate the proliferation rate and p53 expression and to look for any relationships with the clinical behaviour and follow-up results in a series of Bulgarian patients with PAs. A total of 93 patients with PAs (81 hormone-secreting, 12 non-functioning), who were operated on and followed up for a period of five years, were included. The MIB-1 LI and p53 expressions were determined by immunohistochemistry and correlated with various clinical and tumour variables. The whole group of PAs showed a low proliferation rate with evident variations in a small number of cases (MIB-1 LI - 0.50 ± 0.56, from 0.1 to 3.30). MIB-1 LI correlated with tumour size (p = 0.012) and was positively related with male gender (p = 0.23) and partial surgical resection (p = 0.036). We found no significant differences regarding the age, functional activity, invasion (n = 33), expansion (n = 37) and tumour recurrences (seven cases). Only 10 cases (10.8%) showed a focal, nuclear p53 immunoreactivity. The p53 positive tumours had higher proliferation rate (p = 0.0001) but no relationship with the other clinical and tumour variables. Among all cases, there was only one case with higher MIB-1 LI (3.3%), positive p53 expression and tumour recurrence after surgery. Our results show that most PAs have a low proliferation rate and lack of p53 expression, as well as no relationship with tumour invasion or postsurgical progression.
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AIMS: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. METHODS: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. RESULTS: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. CONCLUSIONS: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.
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PURPOSE: This preliminary study aimed to analyze and identify differentially expressed miRNAs in Bulgarian patients with non-functioning pituitary neuroendocrine tumors (NFPitNET). The relationship between deregulated miRNAs and tumor invasiveness, recurrence, and size was determined. METHODS: Twenty patients with NFPitNET were selected and fresh pituitary tumor tissues were collected. RNA containing miRNAs were isolated using miRNAeasy mini kit and analyzed by quantitative real-time polymerase chain reaction (PCR) using LNA miRNA Cancer-Focus PCR Panel (Qiagen). RESULTS: Three miRNAs (miR-210-3p, miR-149-3p, and miR-29b-3p) were deregulated in invasive compared to non-invasive NFPitNETs. Differential expression of four-miRNA signatures - miRNA-17, miR-19, miR-106a, and miR-20, correlated with patient recurrence. CONCLUSION: This prospective pilot study selected a unique miRNA expression profile, that correlates with invasiveness and recurrence in non-functioning pituitary neuroendocrine tumors. Moreover, some of the selected miRNAs are reported for the first time in patients with this disease, shedding light on the molecular mechanisms involved in pituitary pathogenesis. The identified miRNAs demonstrate potential as biomarkers, deserving further investigation in a larger cohort to validate their clinical applicability.
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MicroARNs , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/metabolismo , Masculino , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Proyectos Piloto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
PURPOSE: Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls. METHODS: Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated. RESULTS: Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064-1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001-1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = -0.245; p = 0.029), HOMA-IR (r = -0.250; p = 0.030), free testosterone (r = -0.303; p = 0.006) levels. systolic (r = -0.294; p = 0.008) and diastolic (r = -0.342; p = 0.002) blood pressure. CONCLUSIONS: Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications.
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Síndrome del Ovario Poliquístico , Humanos , Femenino , Metanefrina , Andrógenos , Factor de Crecimiento Nervioso , Hormona AntimüllerianaRESUMEN
INTRODUCTION: Several retrospective and cross-sectional studies have revealed a higher prevalence of autoimmune thyroid diseases (AITD) with a predominance of autoimmune hypothyroidism in prolactinoma patients compared to the general population. To date, we have no data on the clinical course of AITD in these patients. The aim of this prospective study was to assess the clinical course of AITD in female patients with prolactinomas compared to an age- and thyroid-risk factors-matched control group. MATERIALS AND METHODS: The study population consisted of 144 females (71 patients/73 controls) who underwent approximately a 6-year follow-up. Physical examination, thyroid ultrasound and laboratory testing (measurement of antibodies to thyroglobulin, thyroid peroxidase, TSH-receptor; serum TSH and FT4 levels) were performed twice - at the baseline and at the follow-up visits. RESULTS: AITD were diagnosed in 26.8% (n=19) of the patients and 9.6% (n=7) of the controls (p=0.007) at baseline visit. At the end of the follow-up (FU), these percentages increased to 33.8% (n=24) among the patients versus 12.3% (n=9) in the control group (p=0.002). Hypothyroidism was significantly more frequent in prolactinoma patients than in controls at the end of the study (19.7% vs. 4.1%; p=0.003). Two prolactinoma patients had hyperthyroidism at the baseline visit and restored euthyroid state with negative TSH-receptor antibodies during the follow-up. We did not observe hyperthyroidism in the control group. Among the hypothyroid subsets, the average daily levothyroxine dose at FU visit varied from 25 to 200mcg in the prolactinoma group compared to 25 to 50mcg in the control group. CONCLUSIONS: Female patients with prolactinomas seem to be prone to autoimmune hypothyroidism. As a pathogenetic mechanism, we could suggest the selective immunomodulatory action of PRL predominantly on cell autoimmunity, complement activation and antibody-dependent cytotoxicity, resulting in earlier and more rapid progression of Hashimoto's thyroiditis towards hypothyroid state in genetically predisposed individuals.
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Hipertiroidismo , Hipotiroidismo , Neoplasias Hipofisarias , Prolactinoma , Humanos , Femenino , Prolactinoma/complicaciones , Prolactinoma/tratamiento farmacológico , Prolactinoma/epidemiología , Estudios Prospectivos , Estudios Retrospectivos , Receptores de Tirotropina , Estudios Transversales , Autoanticuerpos , Hipotiroidismo/epidemiología , Hipertiroidismo/epidemiología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/epidemiología , Progresión de la EnfermedadRESUMEN
The purpose was to assess the level of medication adherence (MA) and related factors among individuals with acromegaly. The secondary goal was to assess the quality of life of patients and whether and how it correlates with the level of adherence. A prospective one-year study was conducted among patients with acromegaly diagnosed, treated, and monitored in the reference center for rare endocrine diseases in Bulgaria in 2021. Clinical data, patients reported outcomes, and health economics data were collected to define the predictors of non-adherence to medicines. Medication adherence level was assessed through a free Morisky-Green 4-item questionnaire. A total of 179 patients with acromegaly were observed. Approximately 62% were female, 50% were between 41 and 60 years, and the mean age at diagnosis was 40.4 years. The response rate to the questionnaires was 53% (n = 95; mean age 53.5 years, 73% female and 26% male). Patients with high levels of MA reported higher median values for the 36-Item Short Form Health Survey (SF-36) in comparison with those with low levels: 65.5 vs. 48.5 (p = 0.017). Similar results for EQ-5D-3L (3-level EuroQol 5D version) values and the level of MA were found: 0.656 vs. 0.796 (p = 0.0123). A low level of adherence was revealed in 34.7% of the patients, with no difference among different age groups. A significant positive determinant for adherence was years lived with acromegaly (OR = 5.625, 95% CI 1.7401-18.1832, p = 0.0039), as shorter duration was related to higher odds for high level of adherence. The current study demonstrates the importance of MA assessment for patients with acromegaly in Bulgaria. The medication adherence to the prescribed therapy among the observed group of patients with acromegaly varied as the percentage of adherent patients was around 65%. Still, there are low-adherent patients, and the responsible factors should be further investigated.
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OBJECTIVE: To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach, and management strategies in patients with Cushing's syndrome (CS) included in the European Registry on Cushing's Syndrome (ERCUSYN). DESIGN: Cohort study. METHODS: We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS), and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years old) and 175 (9.8%) as older (≥65 years old). RESULTS: Older patients were more frequently males and had a lower Body Mass Index (BMI) and waist circumference when compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism, and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism, and bone fractures than younger patients, regardless of sex (P < .01 for all comparisons). Measurement of urinary free cortisol supported the diagnosis of CS less frequently in older patients when compared with the younger (P < .05). An extrasellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (P < .01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (P < .01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly when compared with their younger counterpart (P < .05). CONCLUSIONS: Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated.
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Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Masculino , Humanos , Anciano , Síndrome de Cushing/diagnóstico , Hidrocortisona , Estudios de Cohortes , Sistema de RegistrosRESUMEN
Introduction: Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar). Methods: We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas ("unselected", n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39). Results: AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups. Discussion: AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.
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Neoplasias Hipofisarias , Prolactinoma , Humanos , Masculino , Agonistas de Dopamina , Células Germinativas , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/terapia , Prolactina , Prolactinoma/tratamiento farmacológico , Prolactinoma/genética , Receptores de Hidrocarburo de ArilRESUMEN
Objective: The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response. Design: The study design is an OLE of a double-blind placebo-controlled (DPC) trial. Methods: Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported. Results: Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time. Conclusions: Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.
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Acromegalia , Adulto , Humanos , Acromegalia/tratamiento farmacológico , Octreótido/efectos adversos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Resultado del Tratamiento , Método Doble CiegoRESUMEN
Endogenous/exogenous Cushing's syndrome is characterized by a cluster of systemic manifestations of hypercortisolism, which cause increased cardiovascular risk. Its biological basis is glucocorticoid excess, acting on various pathogenic processes inducing cardiovascular damage. Hypertension is a common feature in Cushing's syndrome and may persist after normalizing hormone excess and discontinuing steroid therapy. In endogenous Cushing's syndrome, the earlier the diagnosis the sooner management can be employed to offset the deleterious effects of excess cortisol. Such management includes combined treatments directed against the underlying cause and tailored antihypertensive drugs aimed at controlling the consequences of glucocorticoid excess. Experts on endocrine hypertension and members of the Working Group on Endocrine Hypertension of the European Society of Hypertension (ESH) prepared this Consensus document, which summarizes the current knowledge in epidemiology, genetics, diagnosis, and treatment of hypertension in Cushing's syndrome.
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Síndrome de Cushing , Hipertensión , Antihipertensivos/uso terapéutico , Consenso , Síndrome de Cushing/complicaciones , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Glucocorticoides/uso terapéutico , Humanos , Hidrocortisona , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológicoRESUMEN
Background: Adherence to therapy is one of the most important elements during the therapeutic process ensuring the predefined therapeutic outcomes. The aim is to analyze the need and importance of treatment adherence guideline for acromegaly patients and the possibilities for its development and implementation in Bulgaria. Methods: A set of methods was applied: (1) a literature review in the electronic database for identification of articles and guidelines related to adherence and acromegaly; (2) analysis of Bulgarian legislative documents; (3) a pilot study for assessment of the level of treatment adherence among hospitalized Bulgarian acromegaly patients in 2018; (4) a plan for development and implementation of specific guideline was created entitled BULMEDACRO - BULgarian guideline for MEdication aDherence assessment and improvement in ACROmegaly. Results: No specific guidelines for evaluation, monitoring, reporting and/or improving adherence in acromegaly patients has been found in the literature. Requirements for regular assessment of the level of adherence, application of appropriate methods for improvement and monitoring are not sufficiently formulated and mandatory. The pilot study confirmed that therapy adherence among Bulgarian patients with acromegaly is relatively high as almost 90% of patients report that they strictly comply with their prescribed treatment regimen. It is necessary, however, a specific guideline focused on the methods for assessment and improvement of adherence, in order to ensure monitoring and follow-up of acromegaly patients. Conclusions: Patients with acromegaly should be the focus of specially designed national programs, initiatives and/or guidelines for regular evaluation and improvement of the adherence level. Despite the difficulties and the lack of an adequate legal basis, successive steps initiated by different stakeholder are needed.
Asunto(s)
Acromegalia , Acromegalia/diagnóstico , Bulgaria/epidemiología , Protocolos Clínicos , Humanos , Cooperación del Paciente , Proyectos PilotoRESUMEN
Background: Cushing's syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS. Methods: SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases. Results: Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal. Conclusions: Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM. Clinical Trial Registration: (ClinicalTrials.gov), NCT01838551.
Asunto(s)
Síndrome de Cushing/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Cetoconazol/administración & dosificación , Adulto , Anciano , Glucemia/metabolismo , Síndrome de Cushing/complicaciones , Síndrome de Cushing/metabolismo , Complicaciones de la Diabetes/metabolismo , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Cetoconazol/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.