Alkindi Sprinkle for Pediatric Patients With Primary Adrenocortical Insufficiency: A Narrative Review.

Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.

Novel agents to treat adrenal insufficiency: findings of preclinical and early clinical trials.

INTRODUCTION: Adrenal insufficiency currently affects over 300/million population, with higher morbidity and mortality compared to the general population. Current glucocorticoid replacement therapy is limited by a lack of reliable biomarkers to guide dosing, inter-patient variation in metabolism and narrow therapeutic window. Increased morbidity and mortality may relate to unappreciated under- or over-exposure to glucocorticoids and impaired cortisol circadian rhythm. New agents are required to emulate physiological cortisol secretion and individualize glucocorticoid dosing. AREAS COVERED: History of glucocorticoid therapy, current limitations, and novel chronotherapeutic glucocorticoid delivery mechanisms. Literature search incorporated searches of PubMed and Embase utilizing terms such as adrenal insufficiency, Chronocort, Plenadren, continuous subcutaneous hydrocortisone infusion (CHSI), and glucocorticoid receptor modulator. EXPERT OPINION: Glucocorticoid chronotherapy is necessary to optimize glucocorticoid exposure and minimize complications. Current oral chronotherapeutics provide improved dosing functionality, but are modifiable only in specific increments and cannot accommodate ultradian cortisol variation. Current data show improvement in quality of life but not morbidity or mortality outcomes. CHSI has significant potential for individualized glucocorticoid dosing, but would require a suitable biomarker of glucocorticoid adequacy to be implementable. Avenues for future research include determining a glucocorticoid sufficiency biomarker, development of interstitial or systemic cortisol monitoring, or development of glucocorticoid receptor modulators.

Glucocorticoids with or without fludrocortisone in septic shock: a narrative review from a biochemical and molecular perspective.

Two randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies.

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.

Rare combination of chronic primary adrenal insufficiency, subclinical hypothyroidism, and bicytopenia as features of systemic lupus erythematosus in a young man: A case report.

Adrenal insufficiency in systemic lupus erythematosus is rarely detected, especially in male patients. Nevertheless, such coexistence can occur, and screening for systemic lupus erythematosus should be considered in primary adrenal insufficiency with symptoms of systemic multiorgan involvement. We report a 22-year-old Asian man, initially diagnosed with bicytopenia, developed severe unintentional weight loss, skin and mucosal hyperpigmentation, along with persistent fatigue. Laboratory examination showed positive antinuclear antibody-indirect immunofluorescence, elevated anti-double-stranded DNA, extremely low morning serum cortisol, and mildly elevated thyroid stimulating hormone with normal free T4. He was diagnosed with systemic lupus erythematosus, manifesting as chronic primary adrenal insufficiency, subclinical hypothyroidism, and bicytopenia. He was treated with mycophenolic acid of 180 mg b.i.d, methylprednisolone of 4 mg q.d, and vitamin D3 1000 IU q.d. Methylprednisolone was given for its anti-inflammatory property and as a simple once-daily regimen to supplement glucocorticoid deficiency. Levothyroxine was not prescribed for our patient since his thyroid stimulating hormone was only mildly elevated, and supplementation of levothyroxine in the setting of adrenal insufficiency might precipitate an adrenal crisis. At the 6-month follow-up, he was no longer fatigued, he regained his body weight, his skin and mucosal hyperpigmentation improved significantly, his thyroid stimulating hormone level normalized (without levothyroxine supplementation), and his complete blood count stabilized, remitting him from the need for transfusion.

Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series.

INTRODUCTION: There are two major categories of peroxisomal disorders (PDs): peroxisomal biogenesis disorders (PBDs) due to defects in peroxisomal (PEX) genes and deficiency of other peroxisomal enzymes (such as D-bifunctional enzyme deficiency due to HSD17B4). PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA). We aimed to evaluate the clinical phenotype of adrenal insufficiency in patients with PD and to assess any genotype-phenotype correlations with adrenal insufficiency. CASE PRESENTATION: We performed a retrospective electronic medical record review at a single university medical center, of data over 12 years and identified 7 patients with PD. Of the 7 patients identified, 6 patients had a diagnosis of PBD and one had a single peroxisomal enzyme deficiency, HSD17B4. The average age of the patients at diagnosis were 0.61 ± 0.66 years. Four patients (66.7%) had primary adrenal insufficiency: 3, out of the 4, patients had elevated baseline ACTH. Three patients failed to have increased response after the Cortrosyn™ stimulation test. Three patients were on daily hydrocortisone replacement, and 1 patient was on stress-dose hydrocortisone only as needed. Specific genetic variant analysis revealed that all the 3 patients with PBD and adrenal insufficiency who were on steroid supplementation had the compound heterozygous pathogenic variant in exon 13 of PEX1 c.2097dupT (p.Ile700Tyrfs*42) and c.2528G>A (p.Gly843Asp), while the 1 patient with peroxisomal enzyme deficiency and adrenal insufficiency had compound heterozygous pathogenic variants in HSD17B4 c.1369A>T (p.Asn457Tyr) and c.1210 - 1G>A (splice acceptor). Two of these patients with PEX1 variants also required mineralocorticoid supplementation. The 3 PBD patients without adrenal insufficiency did not have a PEX1 variant. DISCUSSION/CONCLUSION: Primary adrenal insufficiency is common in patients with PD. Based on our data, patients with the compound heterozygous PEX1 pathogenic variants of exon 13 (c.2097dupT and c.2528G>A) tend to have adrenal insufficiency. Aldosterone deficiency, though rare, can occur in PD.

Case report: Hypoadrenocorticism crisis complicated by non-cardiogenic pulmonary edema in a dog.

A 6-year-old castrated male Labradoodle was referred in uncompensated hypovolemic shock, with a 72-h history of lethargy, vomiting and diarrhea that had acutely worsened with subsequent development of profuse hemorrhagic diarrhea in the last 24 h after a visit to the groomer. In most respects this case was classic for a patient with a primary hypoadrenocortical crisis. After initial attempts to address hypovolemia and refractory hypotension, no clinical improvement was seen, and the respiratory rate had increased acutely to 80 bpm with crackles detected on thoracic auscultation and serosanguineous fluid began draining from the nose and mouth. An arterial blood gas sample while breathing room air revealed moderate hypoxemia (PaO2 59.9: RI 95-100 mmHg), an elevated alveolar-arterial (A-a) gradient at 54.7 (RI < 15 mmHg) and a PaO2:FiO2 ratio of 285 mmHg. Thoracic radiographs revealed severe bilateral alveolar lung pattern largely limited to the perihilar and caudodorsal lung fields. The radiographic findings, along with signs of ongoing hypovolemia, the lack of evidence of typical long-standing acquired cardiac disease, and the rapid resolution of the pulmonary edema without the need for diuretics or long-term cardiac medications supported non-cardiogenic pulmonary edema. The proposed cause of the non-cardiogenic pulmonary edema was speculated to be neurogenically mediated. Oxygen supplementation along with mineralocorticoid and glucocorticoid replacement therapy was sufficient for the management of the non-cardiogenic pulmonary edema in this case.

Combined Central Hypothyroidism and Adrenal Insufficiency Associated with Retinoic Acid Therapy for Cutaneous T-Cell Lymphoma.

Background/Objective: Although retinoid-associated central hypothyroidism has been reported on several occasions, there are very few studies on retinoid-associated central adrenal insufficiency. Here, we present the case of a patient with alitretinoin-induced central hypothyroidism and adrenal insufficiency. Case Report: An 86-year-old man with a diagnosis of cutaneous T-cell lymphoma, treated with oral alitretinoin 30 mg po daily, topical steroids, and ultraviolet light therapy presented to the emergency department with generalized weakness, decreased energy, orthostasis, and unexplained falls. Thyroid-stimulating hormone (TSH) was 0.31 mIU/L (normal range: 0.4-4.4) from 1.93 before alitretinoin therapy, whereas free thyroxine was 5.7 pmol/L (normal range: 8-18) and the AM cortisol was 40 nmol/L (normal range: 120-535); these values were suggestive of central hypothyroidism and adrenal insufficiency. Adrenocorticotropic hormone (ACTH) was not measured because of a laboratory error. Alitretinoin was stopped, and one dose of hydrocortisone 100mg IV was initiated, followed by maintenance doses of oral hydrocortisone 20mg qam and 10mg qpm. Levothyroxine (50µg ) daily was started 24 hours later. After stopping hydrocortisone for 24 hours, the AM cortisol and ACTH levels were 406 nmol/L and 2.18 pmol/L (normal range:1.6-13.9), respectively. He was discharged on thyroid hormone replacement therapy and glucocorticoids. Repeat thyroid function tests 6 weeks later showed a TSH of 0.4 mIU/L, and free thyroxine of 9.7 pmol/L. Discussion: Alitretinoin activates nuclear receptors called retinoic acid receptors and retinoid X-receptors. Retinoic acid receptors and retinoid X-receptors are widely expressed in the anterior pituitary gland. RXR-selective ligands such as retinoids can suppress TSH secretion, resulting in central hypothyroidism. Retinoids have also been shown to decrease ACTH secretion, which can result in central adrenal insufficiency. Conclusion: Although central adrenal insufficiency and hypothyroidism have not been commonly reported in patients taking retinoids, they should always be considered when caring for these patients.

Autoimmune Polyglandular Syndrome Type 1: A Report of Rare Case of a 16-Year-Old Asian Female Patient With Respiratory Manifestations.

Autoimmune Polyglandular Syndrome (APS) spans three types of autoimmune disorders, categorized as APS type 1, type 2, and type 3. APS type 1 (APS-1) is the rarest type of the three. Complications of APS-1 can affect the bones, joints, skin, nails, gonads, eyes, thyroid, and several internal organs. We report a case of APS-1 in a 16-year-old female patient, who presented with complaints of oral thrush, tingling and numbness in her peripheries, and rash with multiple patches on the whole body with an infection of the nails, all around the age of 11 years, progressively worsening with time. In the next two years, she developed a bilateral decrease in visual acuity and dryness of the eyes as well as seizures, which have previously been seen in APS-1 patients. Laboratory results revealed hypocalcemia and hypoparathyroidism, but normal morning cortisol. Her mucocutaneous candidiasis and hypoparathyroidism fulfilled the criteria required for diagnosing APS-1. Her case, however, was made unique by her respiratory manifestations of frequent respiratory tract infections, which started around the age of 15 years, with a high-resolution CT scan (HRCT) revealing bronchiectasis, not commonly found amongst APS-1 patients. She was prescribed antibiotics for her respiratory tract infection exacerbations, oral calcium, vitamin D supplements, oral fluconazole, as well as an extensive eye care regimen. We report this case to add to the knowledge of this rare disease and look at its usual as well as unusual manifestations.

ADRENAL HISTOPLASMOSIS: AN EASTERN INDIAN PERSPECTIVE.

Context: The clinical presentation of histoplasmosis is varied. Due to its propensity for adrenal involvement, histoplasmosis is an important differential diagnosis in any patient presenting with adrenal mass, bilateral in particular. Objective: Data on clinical presentation, pattern of adrenal involvement, radiological appearance and long-term follow-up of adrenal histoplasmosis are relatively sparse; hence we looked at it. Design: This record based single-centre retrospective study was conducted in one of the tertiary care hospitals, situated in eastern India catering the Gangetic delta. Subjects and methods: Data on demographic characters, presenting manifestations, biochemical & hormonal parameters and radiological appearance of confirmed adrenal histoplasmosis cases (n=9), admitted between 2015-2019 have been retrieved. The treatment outcome and condition of patients after 1-4 years of follow-up has also been discussed. Results: Four out of the nine (44.4%) patients had predisposing immunocompromised conditions in the form of diabetes and/or chronic alcoholism while rest were immunocompetent. Seven out of nine patients (77.8 %) had signs and symptoms suggestive of adrenal insufficiency, while two (22.2%) presented with only pyrexia of unknown origin. All of them had bilateral adrenal mass, though the radiologically appearances were different. All patients received anti-fungal agents with/without hydrocortisone and/or fludrocortisone. One patient died (11.1%), while majority responded favourably to treatment. Adrenocortical function did not recover completely. Conclusions: The possibility of adrenal histoplasmosis should always be considered in patients presenting with bilateral adrenal mass, irrespective of adrenal morphology. Treatment is effective, but many of them require supplemental hydrocortisone for quite a long period, if not lifelong. Mineralocorticoid deficiency, however, is not permanent.

CIRMI-a new term for a concept worthy of further exploration: a narrative review.

Background and Objective: Critical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major pathophysiological events; dysregulation of the hypothalamic-pituitary-axis, altered cortisol metabolism, and tissue corticosteroid resistance. Similar changes are evident with regard to mineralocorticoid dysfunction in critical illness. Hyperreninemic hypoaldosteronism describes a sub-population of critically ill patients with an impaired adrenal aldosterone response to increased levels of renin. In the light of the recent demonstration of significant mortality improvements associated with adjunctive glucocorticoid treatment in combination with fludrocortisone in septic shock, and the suggestion that angiotensin II is effective in treating vasodilatory shock, the clinical relevance of mineralocorticoid dysfunction in critical illness requires further exploration. This interpretative review considers hyperreninemic hypoaldosteronism, a concept worth re-examining in the light of the potential mortality benefit of mineralocorticoid supplementation in critical illness. We compare the pathophysiological and clinical characteristics of CIRCI and hyperreninemic hypoaldosteronism, two syndromes that represent corticosteroid and mineralocorticoid dysfunction in critical illness. We highlight gaps in the literature and give novel insights into the limitations of assessment, diagnosis and treatment. Methods: English language abstracts and articles published before June 2021 were identified through PubMed and Google Scholar. Randomized trials, observational studies, basic sciences studies, systematic and narrative reviews were considered. Reference lists of articles were searched for further relevant material. Key Content and Findings: Difficulties are encountered in interpreting measures of gluco- and mineralo-corticoid activity in critical illness. Aldosterone levels, like cortisol, have been shown to be increased in sepsis and hemorrhagic shock. The finding of hyperreninemia and hyperaldosteronism with an aldosterone/plasma renin activity ratio below 2 should prompt consideration of hyperreninemic hypoaldosteronism, a finding, which likely signifies the loss of negative feedback control of the renin-angiotensin-aldosterone system. Conclusions: As there is evidence to suggest that in acute critical illness, hyperreninemic hypoaldosteronism, is associated with poor outcomes, co-administration of hydrocortisone with fludrocortisone in patients with septic shock should be considered. In keeping with the concept of CIRCI, we suggest the term critical illness-related mineralocorticoid insufficiency as a more appropriate description of the impaired aldosterone response to increased levels of renin seen in this group of patients.

Neonatal bilateral adrenal hemorrhage and adrenal insufficiency accompanied by Subgaleal hematoma: a case report with brief review of literature.

BACKGROUND: Neonatal adrenal hemorrhage (NAH) is an almost infrequent phenomenon (0.2-0.55%). Mechanical compression and alterations of venous pressure during delivery are considered the most probable explanations. Approximately 10% of the cases might have bilateral involvement. Clinical symptoms include abdominal mass, poor feeding, vomiting, prolonged jaundice, and anemia. Subgaleal hemorrhage (SGH) is one of the most clinically remarkable and potentially hazardous postnatal cranial injuries. CASE PRESENTATION: An early-term Iranian male neonate who was born through spontaneous vaginal delivery and experienced shoulder dystocia was diagnosed with bilateral NAH leading to adrenal insufficiency requiring glucocorticoid and mineralocorticoid supplementation. The SGH and jaundice were other postnatal complications. Serial monthly abdominal and brain ultrasound revealed complete regression of lesions after 70 days. However, after 16 months, the neonate has been still treated with hydrocortisone and fludrocortisone for the adrenal insufficiency diagnosis. He has a lower limit weight for age; however, developmental milestones have been appropriate for age. DISCUSSION AND CONCLUSION: Adrenal hemorrhage and SGH should be examined and looked for, particularly with proven evidence of difficult delivery and asphyxia in at-risk newborns. Clinical and ultrasound follow-up is mandatory for the assessment of hemorrhage resolution and conservative management. The early detection and treatment of adrenal insufficiency by laboratory examination is strongly recommended in bilateral cases. Furthermore, the early recognition of postnatal SGH to prevent clinical and neurological outcomes seems essential.

Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis.

Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.

Prevalence of Endocrine Disorders Among 6078 Individuals With Down Syndrome in the United States.

Findings from a recent study describing prevalence of common disease conditions in the largest documented cohort of individuals with Down syndrome (DS) in the United States strongly suggested significant disparity in endocrine disorders among these individuals when compared with age- and sex-matched individuals without DS. This retrospective, descriptive study is a follow-up report documenting prevalence of 21 endocrine disorder conditions, across 28 years of data, from 6078 individuals with DS and 30,326 age- and sex-matched controls, abstracted from electronic medical records within a large integrated health system. Overall, individuals with DS experienced higher prevalence of adrenal insufficiency and Addison's disease; thyroid disorders, including hypothyroidism, hyperthyroidism, Hashimoto's disease, and Graves' disease; prolactinoma/hyperprolactinemia; diabetes insipidus; type I diabetes mellitus; and gout. Conversely, those with DS had lower prevalence of polycystic ovary syndrome and type II diabetes mellitus. Many prevalences of endocrine conditions seen in individuals with DS significantly differ relative to their non-DS matched counterparts. These varied findings warrant further exploration into how screening for and treatment of endocrine conditions may need to be approached differently for individuals with DS.

Possible Adrenal Involvement in Long COVID Syndrome.

Background: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. The most frequent symptoms are fatigue and cognitive dysfunction. We describe a patient suffering from Long COVID in whom adrenal involvement was highlighted. Methods: The patient described Long COVID symptoms that persist 3 months after the negativization of the molecular swab test. The main symptoms were weakness, brain fog, dizziness, and muscular and joint pain. All routine lab panels for inflammation, anemia, and thyroid and liver function were conducted. Moreover, salivary cortisol and DHEA-S determinations were used to compute the adrenal stress index (ASI). Results: All tests were negative, except the ASI that showed very low levels of free cortisol. The patient started hydrocortisone acetate supplementation. Conclusion: Long COVID symptoms could be explained by an adrenal involvement, due to a COVID-19 action on adrenal glands and by a iatrogenic side effect of high glucocorticoid therapy during the COVID-19 infection. Salivary cortisol determination is effective for establishing a correct recovery plan.

Vitamin D status and its associations with clinical and laboratory parameters in patients with Addison's disease.

INTRODUCTION: There is increasing evidence that several autoimmune diseases, as well as their activity, are associated with vitamin D (VD) deficiency. Our study aimed to evaluate the prevalence of VD insufficiency in patients with Addison's disease (AD), as well as to evaluate associations between VD concentrations and various clinical and laboratory parameters of the disease. MATERIALS AND METHODS: We retrospectively analyzed medical records of 31 adult patients diagnosed with autoimmune Addison's disease, in whom serum VD was measured. We assessed correlations between serum VD and various clinical and laboratory parameters. R e s u l t s: 90.3% of AD patients had inadequate VD concentrations (<30 ng/mL), and 19.3% of them were found to be severely VD deficient (<10 ng/mL). Among assessed laboratory variables, only serum calcium concentrations significantly correlated with VD status (r = 0.53, p = 0.006). The mean serum VD concentration was significantly lower in patients with severe fatigue (15.17 ± 8.41 vs 26.83 ± 12.29 ng/mL, p = 0.011) and limited exercise capacity (12.38 ± 6.9 vs 21.63 ± 10.87 ng/mL, p = 0.016). C o n c l u s i o n s: This study demonstrates a high prevalence of VD deficiency in AD patients, as well as the association between low VD concentrations with symptoms such as severe fatigue or limited exercise capacity. Further studies are needed to clarify if impaired VD status is a risk factor in the pathogenesis of AD and to assess if VD supplementation improves the quality of life of AD patients.

Novel function of adrenocorticotropic hormone in the stimulation of vascular endothelial growth factor release in healthy children and adolescents: a proof-of-concept study.

PURPOSE: To assess the effect of adrenocorticotropic hormone (ACTH) on plasma vascular endothelial growth factor (VEGF) levels in healthy children and adolescents and to inform future work on the effects of ACTH on VEGF in bone. METHODS: An Institutional Review Board-approved prospective study of 10 healthy subjects, ages 9-17, was conducted to assess the effect of ACTH on plasma VEGF levels. VEGF levels were collected at baseline and every 30 minutes for 3 hours. Cosyntropin (a synthetic ACTH analogue) was administered at a low-dose (1 µg) given at t=0 minutes and a high-dose (250 µg) given at t=60 minutes. A Friedman test was performed comparing baseline to peak VEGF levels after stimulation with low-dose and high-dose cosyntropin. RESULTS: Peak plasma VEGF levels significantly increased after high-dose cosyntropin compared with baseline (P=0.042). Peak plasma VEGF levels did not significantly increase after low-dose cosyntropin compared to baseline. CONCLUSION: To our knowledge, this is the first study to demonstrate that ACTH administration causes a significant increase in plasma VEGF levels in humans. This finding may have important implications in the protective effects of ACTH on bone. Decreased bone mineral density and adrenal suppression are common side effects of glucocorticoid use in pediatrics. VEGF increases vascularity and may play a role in reducing glucocorticoid-induced bone disease. Animal studies have shown that ACTH stimulates release of VEGF in osteoblasts, though this effect has yet to be evaluated in humans.

Consideraciones en el manejo del adulto con Hiperplasia Suprarrenal congénita clásica por déficit de 21-Hidroxilasa / Management considerations for the adult with congenital adrenal hyperplasia due 21-hydroxylase deficiency

La Hiperplasia Suprarrenal Congénita (HSRC) corresponde a un grupo de defectos genéticos en la síntesis de cortisol. El 95% de ellas son debidas al déficit de 21-hidroxilasa por lo que nos referiremos solo a esta deficiencia. La hiperplasia suprarrenal congénita clásica (HSRC-C) debuta en recién nacidos o lactantes con insuficiencia suprarrenal primaria, diferentes grados de hiperandrogenismo clínico en mujeres y puede coexistir con hipotensión, hiperkalemia e hiponatremia si hay un déficit clínico de aldosterona. El objetivo de este artículo es actualizar el conocimiento y enfoques sugeridos para el manejo de la HSRC-C desde el inicio de sus controles en la etapa adulta. El diagnóstico diferencial en retrospectiva de la HSRC-C y la no clásica (HSRC-NC) a veces resulta difícil ya que esta enfermedad es un espectro fenotípico continuo. La insuficiencia suprarrenal y la dependencia a terapia corticoidal son los eventos principales para diferenciar estas dos patologías que tienen enfoques terapéuticos diferentes. El tratamiento de la HSRC-C en adultos abarca 2 objetivos primarios: la adecuada sustitución de la falla suprarrenal y el control de hiperandrogenismo mediante el uso de corticoides en sus dosis mínimas efectivas. En la mujer existen terapias complementarias para el control del hiperandrogenismo como anticonceptivos y otras que se encuentran en diferentes fases de investigación. Esto permite disminuir las dosis de corticoides en algunos casos. Es importante a la vez abordar tres objetivos secundarios: controlar el riesgo cardiometabólico propio de la enfermedad, evitar el sobre tratamiento corticoidal y manejar la infertilidad. La correcta monitorización del tratamiento en adultos tomando en cuenta los objetivos descritos permite una mejor calidad de vida en estos pacientes. Finalmente el consejo genético debe realizarse en todos los pacientes con HSRC que deseen fertilidad y en sus parejas. El estudio requiere de secuenciación del gen CYP21A2 y debe realizarse en un laboratorio de experiencia.

Congenital Adrenal Hyperplasia (CAH) are a group of genetic defects characterized by impaired cortisol synthesis. 95% of them are due to 21-hydroxylase deficiency. We will discuss only this enzyme's deficiency. Classic congenital adrenal hyperplasia (CAH-C) debuts in newborns or infants with primary adrenal insufficiency, some degree of clinical hyperandrogenism in newborn females, and can coexist with hypotension, hyperkalemia, and hyponatremia if there is a clinical aldosterone deficiency. The objective of this article is to update the knowledge and suggested approaches for the management of CAH-C from the beginning of its controls in the adult stage. The retrospective differential diagnosis of CAH-C and non-classical (CAH-NC) is sometimes difficult because this disease is a continuous phenotypic spectrum. Adrenal insufficiency and dependence on corticosteroid therapy are the main events to differentiate these two pathologies that have different therapeutic approaches. In adults, the treatment of CAH-C must include 2 primary objectives: adequate the replacement of adrenal failure and control of hyperandrogenism, through the use of corticosteroids in their minimum effective doses. In women there are complementary therapies for the control of hyperandrogenism, such as contraceptives and others that are in different phases of research. This makes it possible to reduce the doses of corticosteroids in some cases. It is important at the same time to address three secondary objectives: control the cardiometabolic risk of the disease secondary to corticosteroid treatment, avoid corticosteroid overtreatment and manage infertility. The correct monitoring of treatment in adults and taking in to account the objectives described, allows a better quality of life in these patients. Finally, genetic counseling must be carried out in all patients planning for children, with any type of CAH and in their partners. The study requires sequencing of the CYP21A2 gene and must be performed in a certified laboratory.

Unwanted Hormonal and Metabolic Effects of Postoperative Adjuvant Mitotane Treatment for Adrenocortical Cancer.

Mitotane is widely used for the treatment of adrenocortical cancer (ACC), although the drug-related toxicity complicates its use. The aim of this study is to assess comprehensively the different endocrine and metabolic unwanted effects of the drug, and to provide data on the supportive therapies. We retrospectively analyzed 74 ACC patients adjuvantly treated with mitotane for ≥12 months. During the treatment period (40 months, 12-195), 32.4% of patients needed replacement therapy for mineralocorticoid deficit, 36.2% for hypothyroidism and 34.3% for male hypogonadism. In fertile women, hypogonadism was uncommon, while 65.4% of women developed ovarian cysts. Although no significant change in low-density lipoprotein (LDL) was observed, statins were started in 50% of patients for a significant increase in total cholesterol and triglycerides. Dyslipidemia occurred early, after a median time of 6 months from mitotane start. Conversely, testosterone replacement was usually started after >2 years. In many cases, ranging from 29.4% to 50% according to the side effect, toxicity occurred well before the achievement of the target mitotane concentrations. Supportive therapies were able to revert the biochemical alterations induced by mitotane, although higher doses were needed for a likely pharmacokinetic interaction of exogenous steroids and statins with mitotane. In conclusion, adjuvant mitotane therapy is associated with a spectrum of unwanted effects encompassing the function of different endocrine glands and requires a careful clinical and biochemical assessment associated with the therapeutic drug monitoring.