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Hypertension (HT) during pregnancy is not an infrequent obstetric problem, reaching a prevalence of 5-10%. This condition is highly associated with both maternal and fetal complications if not precisely diagnosed and managed. Even though primary HT, obesity, and preeclampsia are the main causes of HT in this period, other less familiar conditions must be considered during the investigation. Pheochromocytoma and paraganglioma (PPGL) are chromaffin cell tumors that produce, store, and secrete catecholamines, leading to HT and other adrenergic manifestations. Recognition of PPGL is crucial since misdiagnosis and improper management can lead to high morbidity and mortality, particularly during pregnancy. We report on two cases of PPGL diagnosed during pregnancy with different managements. Case 1 is a 25-year-old female at 31 weeks of first pregnancy, whose severe HT and life-threatening symptoms prompted an emergency delivery without previous confirmation or medical treatment of a suspected PPGL. After confirmation, a right adrenal PPGL was surgically resected 4 months later, following 15 days of medical therapy. Case 2 is a 22-year-old female at 18 weeks of pregnancy whose symptomatic PPGL was resected in the second trimester. A next-generation sequencing panel, including 23 PPGL-related genes, found no germline pathogenic variants (GPVs) in case 1 and an exon 1-4 germinative heterozygous deletion of the MAX gene in case 2. Despite the different medical approaches, both cases had satisfactory outcomes. Although uncommon, PPGL should be considered in the differential diagnosis of HT in pregnancy since missing the diagnosis and failing to introduce appropriate and timely treatment may lead to dramatic consequences for the mother and fetus. PPGL diagnosed during reproductive age is likely to result from GPV, prompting genetic investigation and counseling.
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OBJECTIVE: To determine the frequency of "invalid" 1-mg overnight dexamethasone (Dex) suppression tests (DSTs) (1-mg DST) on a large series of patients investigated for hypercortisolism and examine the interference of substances and clinical conditions that may explain low serum Dex levels. METHODS: A retrospective analysis of 1300 Dex-controlled 1-mg DST applied to patients screened for Cushing syndrome or mild autonomous cortisol secretion in a single center for which there were identified invalid tests and distinctive characteristics that may have interfered with the outcome. RESULTS: Among all tests, 146 (11.2%) were considered invalid (serum Dex levels <140 ng/dL, 36 [24.7%] of which were undetectable [<19.5 ng/dL]). In the Dex-undetectable group, 17% failed to take Dex correctly, 25% were on glucocorticoids (GCs), and 20% were on anticonvulsants and moderate CYP3A4 inducers. In the remaining 110 tests (serum Dex 20-140 ng/dL), 6.5% did not take Dex or were using GC, 22% were on anticonvulsants or CYP3A4 inducers, and another 13% had previous gastrointestinal tract abnormalities impairing drug absorption. CONCLUSION: Inappropriately low serum Dex levels during the 1-mg DST may lead to false-positive results. This is associated with recurrent use of CYP3A4-inducing drugs and/or gastrointestinal abnormalities. When serum Dex is undetectable, the key reason is failure to take the medication or the use of GC (when cortisol is suppressed). Simultaneous measurement of serum cortisol and Dex allows for DST validation, improving its accuracy and avoiding unnecessary repetitions. Adherence to verbal/written recommendations and actual use of medication are critical for interpreting the test.
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Síndrome de Cushing , Humanos , Síndrome de Cushing/diagnóstico , Hidrocortisona , Dexametasona/uso terapêutico , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Indutores do Citocromo P-450 CYP3ARESUMO
Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.
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ABSTRACT High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.
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High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.
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Hipertensão , Adulto , Adolescente , Humanos , Criança , Hipertensão/etiologia , Aldosterona , HidrocortisonaRESUMO
Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11ß-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11ß-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11ß-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
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Hiperplasia Suprarrenal Congênita , Hiperaldosteronismo , Hiperplasia Suprarrenal Congênita/metabolismo , Androgênios , Citocromo P-450 CYP11B2 , Humanos , Masculino , EsteroidesRESUMO
ABSTRACT Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
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Humanos , Masculino , Hiperplasia Suprarrenal Congênita/metabolismo , Hiperaldosteronismo , Esteroides , Citocromo P-450 CYP11B2 , AndrogêniosRESUMO
INTRODUCTION: Heterozygotes (HZs) for 21-hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complex and narrowly available. Adrenocorticotropic hormone (ACTH)-stimulated serum 17-hydroxyprogesterone (17P) and 21-deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS/MS). OBJECTIVE: This study was performed to reassess former LC-MS/MS-defined post-ACTH 21DF, 17P and cortisol (F) cutoffs in family members at risk for 21OHD. DESIGN AND PATIENTS: Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post-ACTH steroid phenotypes with subsequent genotypes. RESULTS: Post-ACTH 21DF, 17P, F and (21DF + 17P)/F ratio segregate NC, HZ and wild-type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve-defined cutoffs for post-ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty-six of 33 HZ and all 6 NC (82.1%) had post-ACTH 21DF > 60 and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post-ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively. CONCLUSIONS: Reassessed ACTH-stimulated 21DF and 17P cutoffs by LC-MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor-to-product ratio ([21DF + 17P]/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.
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Hiperplasia Suprarrenal Congênita , Hormônio Adrenocorticotrópico , 17-alfa-Hidroxiprogesterona , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Cromatografia Líquida , Cortodoxona , Heterozigoto , Humanos , Estudos Prospectivos , Esteroide 21-Hidroxilase/genética , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Describe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects. DESIGN, SETTING AND PARTICIPANTS: A prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital. METHODS: Collect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography-mass spectrometry (LC-MS): pregnenolone, 17-OH pregnenolone, 17-OH progesterone, 11-deoxycorticosterone, 11-deoxyortisol, 21-deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone. RESULTS: Mean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143-665) nmol/L,(p < .0001), unilateral 268 ± 89 3.2 (range 98-507) nmol/L (p < .019) compared to controls 207 ± 100 (range 72-502) nmol/L. ACTH stimulation showed significantly higher levels in bilateral and unilateral cases compared to controls. After dexamethasone, mean serum cortisol levels suppressed in bilaterals 89 ± 69 (range 30-3) nmol/L (p < .0001), 58 ± 52 (range 16-323) nmol/L in unilateral (p < .01) compared to 26 ± 9 (range 7-46) nmol/L in controls. Mean baseline serum corticosterone was higher in bilateral 9.3 ± 4.8 (range 2.4-18.4) nmol/L (p < .005) and unilateral 7.3 ± 5.7 (range 0.1-30.3) nmol/L (p < .01) compared to controls 4.2 ± 2.4 (range 1.1-10.2) nmol/L, after ACTH stimulation significantly increased to higher levels in bilateral (p < .0002) and unilateral cases (p < .044) compared to controls. After dexamethasone, mean levels were 2.5 ± 2.6 (range 0.5-12.5) nmol/L in bilateral (p < .0006), 1.5 ± 1.6 (range 0.3-9.3) nmol/L in unilateral (p < .09) and 0.75 ± 0.46 (range 0.1-2.1) nmol/L in controls. Mean baseline serum 11-deoxycorticosterone (DOC) was higher in bilaterals 0.32 ± 0.23 (range 0.08-1.1) nmol/L (p < .03) compared to controls 0.15 ± 0.21 (range 0.08-1.1) nmol/L. ACTH stimulation increased levels to 3.27 ± 1.72 (range 0.5-7.4) nmol/L in bilateral cases compared to controls 1.369 ± 1.53 (range 0.1-7.1) nmol/L (p < .0001). Dexamethasone decreased levels to baseline (p ns). There were significant differences in serum 21-deoxycortisol (p < .0002) and serum pregnenolone (p < .004) only after ACTH stimulation. CONCLUSIONS: There is increased activity in several steroid biosynthesis pathways and higher steroid levels in bilateral compared to unilateral cases and evidence of hypercortisolism in 30% unilateral and 62% of bilateral incidentalomas.
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Neoplasias das Glândulas Suprarrenais , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Hormônio Adrenocorticotrópico , Cromatografia Líquida , Dexametasona , Humanos , Hidrocortisona , Espectrometria de Massas , Estudos Prospectivos , EsteroidesRESUMO
Objectives: Physiological hormonal adaptions in athletes and pathological changes that occur in overtraining syndrome among athletes are unclear. The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study evaluated 117 markers and unveiled novel hormonal and metabolic beneficial adaptive processes in athletes. The objective of the present study was to uncover which modifiable factors predict the behaviors of clinical and biochemical parameters and to understand their mechanisms and outcomes using the parameters evaluated in the EROS study. Methods: We used multivariate linear regression with 39 participants to analyze five independent variables-the modifiable parameters (caloric, carbohydrate, and protein intake, and sleep quality and duration of concurrent cognitive activity) on 37 dependent variables-that were elected among the parameters evaluated in the EROS study. Results: Carbohydrate intake predicted quick hormonal responses to stress and improved explosive responses during exercise. Protein intake predicted improved body composition and metabolism and caloric intake, regardless of the proportion of macronutrients, predicted muscle recovery, and alertness in the morning. Sleep quality predicted improved mood and excessive concurrent cognitive effort in athletes under intense training predicted impaired metabolism and libido. Conclusions: The results support the premise that eating, sleep, and social patterns modulate metabolic and hormonal function, clinical behaviors, and performance status of male athletes, and should be monitored continuously and actively to avoid dysfunctions.
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Atletas/psicologia , Transtornos Traumáticos Cumulativos/fisiopatologia , Transtornos Traumáticos Cumulativos/psicologia , Fadiga/fisiopatologia , Fadiga/psicologia , Sono , Fenômenos Fisiológicos da Nutrição Esportiva , Adaptação Fisiológica , Adolescente , Adulto , Composição Corporal , Ingestão de Energia , Exercício Físico , Comportamento Alimentar , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento Social , Esportes , Adulto JovemRESUMO
OBJECTIVE. Adrenal incidentalomas occur in 5% of adults and can produce autonomous cortisol secretion that increases the risk of metabolic syndrome and cardiovascular disease. The objective of our study was to evaluate the relationship between adrenal nodule size measured on CT and autonomous cortisol secretion. SUBJECTS AND METHODS. In a prospective study of 73 patients 22-87 years old with incidentalomas, unilateral in 52 patients and bilateral in 21 patients, we measured maximum nodule diameter on CT and serum cortisol levels at 8:00 am, 60 minutes after the adrenocorticotropic hormone stimulation test, and after the dexamethasone suppression test. We also studied 34 age-, sex-, and body mass index-matched control subjects. Statistics used were Spearman correlation coefficients, t tests, ANOVA test, and multivariate analysis. RESULTS. The mean maximum diameter of unilateral nodules measured on CT was larger on the right (2.47 ± 0.98 [SD] cm) than on the left (2.04 ± 0.86 cm) (p = 0.01). In the bilateral cases, the mean diameter of the right nodules was 2.69 ± 0.93 cm compared with 2.13 ± 0.89 cm on the left (p = 0.06). Mean baseline serum cortisol level was significantly higher in the patients with incidentalomas (bilateral, 13.1 ± 4.5 mcg/dL [p < 0.001]; unilateral, 9.7 ± 3.2 mcg/dL [p = 0.019]) than in the control subjects (7.5 ± 3.6 mcg/dL). After dexamethasone suppression test, serum cortisol levels were suppressed to less than 1.8 mcg/dL in 100% of control subjects, 33% of patients with bilateral incidentalomas, and 62% of patients with unilateral incidentalomas (p < 0.001). There were significant correlations between maximum nodule diameter on CT and serum cortisol levels after the dexamethasone suppression test (ρ = 0.500; p < 0.001) and at baseline (ρ = 0.373; p = 0.003). CONCLUSION. Increasing size of adrenal nodules is associated with more severe hyper-cortisolism and less dexamethasone suppression; these cases need further evaluation and possibly surgery because of increased risks of metabolic syndrome and cardiovascular mortality.
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Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Neoplasias das Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study. METHODS: In this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18-50 years old, males, with BMI 20-30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT. RESULTS: Responses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 µg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1-38.1) vs 4.80 (0.33-27.36) µg/L; p = 0.015], and prolactin [24.3 (10.5-67.45) vs 10.50 (6.21-43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL. CONCLUSIONS: We found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of "hormonal conditioning" in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.
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Atletas/estatística & dados numéricos , Cosintropina/administração & dosagem , Exercício Físico , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Insulina/administração & dosagem , Sistema Hipófise-Suprarrenal/metabolismo , Adolescente , Adulto , Estudos Transversais , Teste de Esforço , Feminino , Hormônios/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prolactina/metabolismo , Adulto JovemRESUMO
CONTEXT: Overtraining syndrome (OTS) and related conditions cause decreased training performance and fatigue through an imbalance among training volume, nutrition, and recovery time. No definitive biochemical markers of OTS currently exist. OBJECTIVE: To compare muscular, hormonal, and inflammatory parameters among OTS-affected athletes, healthy athletes, and sedentary controls. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifty-one men aged 18 to 50 years (14 OTS-affected athletes [OTS group], 25 healthy athletes [ATL group], and 12 healthy sedentary participants [NCS group]), with a body mass index of 20 to 30.0 kg/m2 (sedentary) or 20 to 33.0 kg/m2 (athletes), recruited through social media. All 39 athletes performed both endurance and resistance sports. MAIN OUTCOME MEASURE(S): We measured total testosterone, estradiol, insulin-like growth factor 1, thyroid-stimulating hormone, free thyronine, total and fractioned catecholamines and metanephrines, lactate, ferritin, creatinine, creatine kinase, erythrocyte sedimentation rate, C-reactive protein, lipid profile, hemogram, and testosteroneâ:âestradiol, testosteroneâ:âcortisol, neutrophilâ:âlymphocyte, platelet: lymphocyte, and catecholamineâ:âmetanephrine ratios. Each parameter was statistically analyzed through 3-group comparisons, and whenever P < .05, pairwise comparisons were performed (OTS × ATL, OTS × NCS, and ATL × NCS). RESULTS: Neutrophils and testosterone were lower in the OTS group than in the ATL group but similar between the OTS and NCS groups. Creatine kinase, lactate, estradiol, total catecholamines, and dopamine were higher in the OTS group than in the ATL and NCS groups, whereas the testosteroneâ:âestradiol ratio was lower, even after adjusting for all variables. Lymphocytes were lower in the ATL group than in the OTS and NCS groups. The ATL and OTS groups trained with the same intensity, frequency, and types of exercise. CONCLUSIONS: At least in males, OTS was typified by increased estradiol, decreased testosterone, overreaction of muscle tissue to physical exertion, and immune system changes, with deconditioning effects of the adaptive changes observed in healthy athletes.
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Estradiol/sangue , Exercício Físico/fisiologia , Fadiga , Esportes/fisiologia , Adaptação Fisiológica , Adulto , Atletas , Biomarcadores/análise , Biomarcadores/sangue , Estudos Transversais , Transtornos Traumáticos Cumulativos/complicações , Teste de Esforço/métodos , Fadiga/etiologia , Fadiga/imunologia , Fadiga/metabolismo , Fadiga/fisiopatologia , Humanos , Testes Imunológicos/métodos , Masculino , Pessoa de Meia-Idade , Distúrbios Nutricionais/complicações , Esportes/classificação , Testosterona/sangueRESUMO
Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.
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Síndrome de ACTH Ectópico/diagnóstico , Carcinoma Neuroendócrino/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Síndrome de ACTH Ectópico/etiologia , Hormônio Adrenocorticotrópico/sangue , Adulto , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Amostragem do Seio Petroso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Saliva/metabolismoRESUMO
SUMMARY Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.
Assuntos
Humanos , Feminino , Adulto , Síndrome de ACTH Ectópico/diagnóstico , Carcinoma Neuroendócrino/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Saliva/metabolismo , Síndrome de ACTH Ectópico/etiologia , Hidrocortisona/sangue , Amostragem do Seio Petroso , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/diagnóstico , Hormônio Adrenocorticotrópico/sangue , Diagnóstico Diferencial , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnósticoRESUMO
PURPOSE: Most adrenal incidentalomas (AIs) are nonfunctioning adenomas (NFAs), but up to 30% may secrete cortisol autonomously without clinical evidence of Cushing syndrome (CS), which nevertheless may increase cardiovascular mortality. This subclinical hypercortisolism (SCH) is confirmed by cortisol resistance to a dexamethasone suppression test (DST). Cyclic cortisol secretion occurs in classic CS but was not reported in SCH. OBJECTIVE: Investigate cyclic cortisol production/autonomy in AIs using sequential DSTs. METHODS: A total of 251 patients with AI underwent 487 DSTs over 12 years; patients with at least three DSTs were selected. DSTs were validated by measuring serum dexamethasone. Cyclic SCH was defined when at least two abnormal and two normal DSTs were documented. RESULTS: A total of 44 patients had three or more DSTs during follow-up: 9 of 44 patients (20.4%) had all negative test results (post-DST cortisol ≤1.8 µg/dL) and were classified as NFA; another nine patients had all positive results (cortisol >1.8 µg/dL) and were classified as sustained SCH. The remaining 26 (59.2%) had discordant responses: 8 of 44 (18.3%) had at least two positive and two negative tests, matching the criterion for cyclic SCH, whereas 18 of 44 (40.9%) had only one discordant test and were classified as possibly cyclic SCH. Eleven of 20 (55%) patients initially classified as NFA did not maintain their cortisol pattern. CONCLUSIONS: Extended follow-up with repeated DSTs uncovered an unusual subset of AIs with cyclic SCH. Recurring production of cortisol may affect determination of AI subtypes if based on just one DST. Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk.
RESUMO
The metabolic and hormonal consequences of high-intensity functional training regimens such as CrossFit® (CF) are unclear. Little is known about the triggers and clinical and biochemical features of CF-related overtraining syndrome (OTS). The EROS study compared endocrine and metabolic responses, and eating, social, psychological and body characteristics of OTS-affected (OTS) and healthy athletes (ATL), and non-physically active controls (NPAC). The current study is a post-hoc analysis of the CF subgroups of the EROS study, to evaluate specific characteristics of CF in ATL and OTS. Parameters were overall and pairwise compared among OTS-affected (CF-OTS) and healthy (CF-ATL) athletes that exclusively practiced CF, and NPAC. CF-ATL yielded earlier and enhanced cortisol, GH, and prolactin responses to an insulin tolerance test (ITT), increased neutrophils, lower lactate, increased testosterone, improved sleep quality, better psychological performance, increased measured-to-predicted basal metabolic rate (BMR) ratio and fat oxidation, and better hydration, when compared to NPAC. Conversely, more than 90% of the adaptive changes in CF were lost under OTS, including an attenuation of the hormonal responses to an ITT, increased estradiol, decreased testosterone, and decreased BMR and fat oxidation; the most remarkable trigger of OTS among "HIFT athletes" was the long-term low carbohydrate and calorie intake.
Assuntos
Transtornos Traumáticos Cumulativos/etiologia , Transtornos Traumáticos Cumulativos/metabolismo , Condicionamento Físico Humano/efeitos adversos , Condicionamento Físico Humano/métodos , Adolescente , Adulto , Afeto/fisiologia , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Catecolaminas/urina , Transtornos Traumáticos Cumulativos/fisiopatologia , Técnicas de Diagnóstico Endócrino , Estradiol/sangue , Hormônio do Crescimento Humano/sangue , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiologia , Insulina/sangue , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiologia , Prolactina/sangue , Saliva/química , Sono/fisiologia , Testosterona/sangue , Adulto JovemRESUMO
Objectives: The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study identified multiple hormonal and metabolic conditioning processes in athletes, and underlying mechanisms and biomarkers of overtraining syndrome (OTS). The present study's objective was to reveal independent predictors and linear correlations among the parameters evaluated in the EROS study to predict clinical, metabolic, and biochemical behaviors in healthy and OTS-affected male athletes. Methods: We used multivariate linear regression and linear correlation to analyze possible combinations of the 38 parameters evaluated in the EROS study that revealed significant differences between healthy and OTS-affected athletes. Results: The testosterone-to-estradiol (T:E) ratio predicted the measured-to-predicted basal metabolic rate (BMR) ratio; the T:E ratio and total testosterone level were inversely predicted by fat mass and estradiol was not predicted by any of the non-modifiable parameters. Early and late growth hormone, cortisol, and prolactin responses to an insulin tolerance test (ITT) were strongly correlated. Hormonal responses to the ITT were positively correlated with fat oxidation, predicted-to-measured BMR ratio, muscle mass, and vigor, and inversely correlated with fat mass and fatigue. Salivary cortisol 30 min after awakening and the T:E ratio were inversely correlated with fatigue. Tension was inversely correlated with libido and directly correlated with body fat. The predicted-to-measured BMR ratio was correlated with muscle mass and body water, while fat oxidation was directly correlated with muscle mass and inversely correlated with fat mass. Muscle mass was directly correlated with body water, and extracellular water was directly correlated with body fat and inversely correlated with body water and muscle mass. Conclusions: Hypothalamic-pituitary responses to stimulation were diffuse and indistinguishable between the different axes. A late hormonal response to stimulation, increased cortisol after awakening, and the T:E ratio were correlated with vigor and fatigue. The T:E ratio was also correlated with body metabolism and composition, testosterone was predicted by fat mass, and estradiol predicted anger. Hydration status was inversely correlated with edema, and inter-correlations were found among fat oxidation, hydration, and body fat.
RESUMO
Overtraining syndrome (OTS) is caused by an imbalance between training, nutrition and resting, and leads to decreased performance and fatigue; however, the precise underlying triggers of OTS remain unclear. This study investigated the body composition, metabolism, eating, sleeping patterns and mood states among participants with OTS. Selected participants were divided into OTS-affected athletes (OTS, n = 14), healthy athletes (ATL, n = 25), and healthy non-physically active controls (NCS, n = 12). Compared to ATL, OTS showed decreased sleep quality (p = 0.004); increased duration of work or study (p < 0.001); decreased libido (p = 0.024); decreased calorie (p < 0.001), carbohydrate (p < 0.001) and protein (p < 0.001) intakes; decreased mood states (p < 0.001); decreased basal metabolic rate (p = 0.013) and fat burning (p < 0.001); increased body fat (p = 0.006); decreased muscle mass (p = 0.008); and decreased hydration (p < 0.001). Levels were similar between OTS and NCS, except for worsened fatigue (p < 0.001) and vigour (p = 0.001) in OTS. Reduced calorie intake, worsened sleep, and increased cognitive activity are likely OTS triggers. OTS appears to induce dehydration, increase body fat, decrease libido, and worsen mood.
Assuntos
Composição Corporal , Transtornos Traumáticos Cumulativos/fisiopatologia , Transtornos Traumáticos Cumulativos/psicologia , Metabolismo Energético , Comportamento Alimentar , Sono , Afeto , Ingestão de Energia , Fadiga/etiologia , Humanos , Fenômenos Fisiológicos da Nutrição EsportivaRESUMO
OBJECTIVE: 17α-Hydroxylase deficiency (P450c17D) is characterized by hypogonadism and mineralocorticoid hypertension. We aimed to estimate the relative incidence and spectrum of preliminary misdiagnoses in Brazilian P450c17D patients. METHODS: In this cross-sectional study, we reviewed, updated, and analyzed data of 40 P450c17D patients (21 XY, 19 XX). RESULTS: Complete data were unavailable for 2 patients. Seven patients were relatives of an index case. Of the 31 index cases, 29 (94%) received a total of 16 misdiagnoses (1-4 per patient) before confirmation of P450c17D. Essential hypertension (55%), pure gonadal dysgenesis (35%), and androgen resistance syndrome (21%) were the most frequent misdiagnoses. Median ages at initial and final diagnosis were 13.2 and 16.5 years, respectively, with an average interval to diagnosis of 3.2 years. Initially, 38 (95%) patients had hypertension, and 75% had hypokalemia. Primary amenorrhea and sexual infantilism were present in 95% patients, and 73% were at Tanner stage I. All had low-to-undetectable estrogens and androgens with elevated gonadotropins and progesterone (580 ± 53 ng/dL). Several had recurrent infections in childhood and neurological issues prior to final diagnosis and/or had siblings who died of infectious diseases or unknown causes before puberty. CONCLUSION: The high percentage of prior misdiagnoses in P450c17D patients may be attributable to the rarity of and relative unfamiliarity with the disease, its varied clinical presentation, and the limited access to critical steroid dosages and genotyping. Reduced sex steroids, and elevated gonadotropins and progesterone levels, in addition to mineralocorticoid hypertension, are pathognomonic of P450c17D. CYP17A1 gene mutations provide a definitive diagnosis. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CAH = congenital adrenal hyperplasia CYP17A1 = 17α-hydroxylase enzyme DOC = deoxycorticosterone HH = hypergonadotropic hypogonadism P450c17D = 17α-hydroxylase deficiency TS = Tanner stage.