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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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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.

RESUMO

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.

Assuntos

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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.

Assuntos

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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.

Assuntos

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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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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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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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