Mineralocorticoid Replacement Therapy Research Articles

THU609 Timeline For Undetectable Mitotane Plasma Levels In Adrenocortical Carcinoma Patients After Stopping Treatment

Abstract Disclosure: N. Younes: None. P. Hétu: None. A. Lacroix: None. I. Bourdeau: None. Background: Mitotane (o,p’DDD) is an adrenolytic steroidogenesis inhibitor recommended in the treatment of adrenocortical carcinoma (ACC) with a high risk of recurrence. Mitotane has a long plasma elimination half-life, because of its highly lipophilic properties. Objectives: To further explore time to reach undetectable mitotane plasma levels (UM) in treated ACC patients after stopping the medication. Methods: We retrospectively analyzed the medical files of 13 adult patients with ACC who were treated with mitotane during at least 24 months, between 2006 and 2020, in our center. We calculated the duration in months for plasma concentrations of mitotane to be undetectable, from the time of cessation of mitotane in all 13 patients. Baseline demographic characteristics of patients and baseline tumor characteristics were recorded, along with the maximal dose of mitotane used. We also explored the time it took patients to be able to stop glucocorticoid and/or mineralocorticoid replacement therapy following mitotane cessation. Results: The mean age at diagnosis of ACC was 48.2 ± 14.9 years and 69.2% of patients were female. Patients weighted 78.2 ± 27.2 Kg. The mean tumor size and proliferation index Ki67 were 8.1 ± 4.3 cm and 13.3 ± 7.3%. None of the patients had metastasis at diagnosis. They were treated with a mean of 4 ± 2 g of mitotane daily, for 33.5 ± 9 months. Only one patient never had documented therapeutic mitotane range (between 14 and 20 mg/L) during treatment. The time to UM from the time of mitotane cessation was 13.2 ± 7.1 months. All 13 patients were taking glucocorticoid replacement therapy and 5 were able to completely withdraw hydrocortisone 39 ± 14.5 months after stopping mitotane treatment. Only 2 patients out of the 6 patients that were on mineralocorticoid replacement therapy, were able to stop after 34.2 and 59.7 months, respectively. There was no significant relationship found between the duration of exposure to mitotane and the time to UM (p=0.82). On simple linear regression, patients’ weight explained 80% of variance of time to UM. There was a positive relationship between patients’ weight and time to UM (standardized coefficient beta 0.89, p <0.0001). On multiple linear regression, patients’ weight was an independent predictor of time to UM. Conclusion: Mitotane can take up to 13 months to become undetectable in patients’ plasma after cessation. In our cohort, it is mainly influenced by increased weight but not by duration of exposure to the drug. Presentation: Thursday, June 15, 2023

Mineralocorticoid replacement therapy in salt-wasting congenital adrenal hyperplasia.

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.

Assessing treatment adherence is crucial to determine adequacy of mineralocorticoid therapy.

There is no consensus strategy for mineralocorticoid (MC) therapy titration in patients with primary adrenal insufficiency (PAI). We aim to measure serum fludrocortisone (sFC) and urine fludrocortisone (uFC) levels and to determine their utility, alongside clinical/biochemical variables and treatment adherence to guide MC replacement dose titration. Multi-centre, observational, cross-sectional study on 41 patients with PAI on MC replacement therapy. sFC and uFC levels (measured by liquid chromatography-tandem mass spectrometry), plasma renin concentration (PRC), electrolytes (Na+, K+), mean arterial blood pressure (MAP), total daily glucocorticoid (dGC) and MC (dMC) dose, and assessment of treatment adherence were incorporated into statistical models. We observed a close relationship between sFC and uFC (r = 0.434, P = 0.005) and between sFC and the time from the last fludrocortisone dose (r = -0.355, P = 0.023). Total dMC dose was related to dGC dose (r = 0.556, P < 0.001), K+ (r = -0.388, P = 0.013) as well as sFC (r = 0.356, P = 0.022) and uFC (r = 0.531, P < 0.001). PRC was related to Na+ (r = 0.517, P < 0.001) and MAP (r = -0.427, P = 0.006), but not to MC dose, sFC or uFC. Regression analyses did not support a role for sFC, uFC or PRC measurements and confirmed K+ (B = -44.593, P = 0.005) as the most important variable to guide dMC titration. Of the patients, 32% were non-adherent with replacement therapy. When adherence was inserted into the regression model, it was the only factor affecting dMC. sFC and uFC levels are not helpful in guiding dMC titration. Treatment adherence impacts on clinical variables used to assess MC replacement and should be included as part of routine care in patients with PAI.

ODP597 Clinical case of uncomplicated pregnancy in a patient with adrenocortical carcinoma during treatment with mitotane

Abstract Background Mitotane/o,p'DDD is adrenolytic and antitumor therapeutic agent used in the first line drug therapy of advanced adrenocortical carcinoma (ACC) as well as an adjuvant therapy after surgical resection of the primary tumor at moderate/high risk of recurrence. Mitotane is a metabolite of endocrine disruptor DDT and classified among teratogenic compounds. Preterm births and early pregnancy loss have been reported in female patients exposed to mitotane during pregnancy. Clinical Case At age 33, the patient underwent left adrenalectomy for "adrenocortical adenoma". Three years later, she was admitted to our Centre because of rapid development of Cushing's syndrome. Hormonal assessment revealed markedly increased urinary free cortisol level and abnormal overnight dexamethasone suppression test; ACTH was undetectable. Computed tomography revealed lungs and liver secondary masses, as well as tumor mass in the left adrenal bed. According to the above parameters, advanced ACC was suspected. During microscopy and immunohistochemistry of paraffin-embedded tissue blocks, tumor tissue after left adrenalectomy was identified as ACC. The patient started chemotherapy according to EDP-M (etoposide, doxorubicin, and cisplatin) protocol. Prior to chemotherapy initiation, mitotane and oral contraceptive pills were given. She also received glucocorticoid and mineralocorticoid replacement therapy. After three courses of chemotherapy, chest, abdomen and pelvis computed tomography disclosed complete regression of all the tumor masses. The patient continued mitotane, glucocorticoid and mineralocorticoid replacement drugs during the following year. Serial 18F-fluorodeoxyglucose-positron emission tomography scans were negative. One and a half years after cessation of chemotherapy, the patient chose to stop oral contraceptives. Several months later, the patient learned that she was pregnant (12 weeks of gestation) while on mitotane and adrenal replacement therapy. At this point, the patient and her partner were informed of the possible teratogenic effect of mitotane and strongly advised to terminate the pregnancy, but they decided to continue the pregnancy. Mitotane treatment was stopped immediately. The serum concentration of the drug was 16.8 mg/mL, within the therapeutic range (14–20 mg/mL). Glucocorticoid supplementation with hydrocortisone was continued. The course of the pregnancy was uncomplicated. A male infant was delivered breech by cesarean section at a gestation of 39 weeks. Birth weight was 3050 g, length 46 cm, and head circumference 36 cm. Apgar scores were 8, 9 and 9 at 1, 5 and 10 min, respectively. Newborn examination revealed no anomalies and no hyperpigmentation. Blood pressure, heart rate, and temperature were normal. Conclusion To our knowledge, we present the first case of uncomplicated pregnancy in a patient with adrenocortical carcinoma and therapeutic serum concentration of mitotane. Our report suggests that mitotane can not affect normal development of the fetus. Nevertheless, until more data are available, pregnancy should be avoided in women being treated with mitotane for ACC. Presentation: No date and time listed

ODP035 Congenital Adrenal Hyperplasia secondary to 3 beta hydroxydehydrogenase deficiency: Case study and review of literature

Abstract Introduction Congenital Adrenal Hyperplasia (CAH) results from one of the five steroidogenic hormonal deficiencies in adrenal steroid synthesis pathway, most commonly caused by 21-hydroxylase deficiency (21-OHD). 3β-hydroxysteroid dehydrogenase (3βHSD) deficiency (def) is very rare cause of CAH, accounting for less than 0.5% of the CAH cases, associated with disorder of sexual development (DSD) and steroidogenesis. We present a case of salt wasting CAH secondary to 3βHSD-def with focus on the management compared with 21-OHD. Case 53yr white female who was diagnosed with salt wasting CAH at birth, started on hydrocortisone replacement. She had oophorectomy at age of 11 due to hemorrhagic changes in ovaries. She was placed on oral contraceptives for most of her life. Her family history is significant for CAH in all of her 3 sisters, with oldest sister having pubic hair at age of 2 with frequent illnesses, triggering extensive workup and was subsequently diagnosed with CAH. Two brothers were also diagnosed with CAH with complete scrotum bifurcation at birth. Her family was subsequently diagnosed with 3βHSD deficiency. Patient's ACTH, Renin, 17-Hydroxyprogesterone (17-OHP) levels have been fluctuating due to skipping of hydrocortisone doses on occasions. Her sleep pattern remains disturbed, going to bed 3-4 AM and waking up at 2-3 PM. Discussion 3βHSD deficiency is very rare cause of CAH with prevalence less than 1 in million cases at birth. First cases were reported by Bongiovanni in 1962. It is autosomal recessive disorder affecting both the sexes. 3βHSD is expressed in adrenal glands and gonadal tissues, where it catalyzes conversion of pregnenolone, 17-hydroxypregnenolone (17OHPreg) and dehydroepiandrosterone (DHEA) into aldosterone, cortisol and androstenedione respectively. Patient with salt-wasting 3βHSD def need mineralocorticoids, glucocorticoids along with sex steroid replacements. Clinical presentation varies with different degrees of salt wasting, incomplete masculinization in males and virilization in females, depending on the severity of the gene mutation. Elevated 17-OHPreg and its ratio with cortisol along with elevated Δ-5 steroids is used for diagnosis with confirmation through genetic testing, compared with 17-OHP levels which are mainly used for 21-OHD diagnosis. Management is challenging with glucocorticoid and mineralocorticoid replacement therapy with risk of under-/over-replacement, some requiring higher doses compared with other forms of CAH. There is higher risk of long term complication such as obesity, reduced adult height, infertility, osteoporosis, TARTs. Compared with 21-OHD, patients with complete 3βHSD def may need sex steroid replacement at puberty including testosterone (males) and cyclic estrogen-progesterone therapy (females). Timing of hydrocortisone should be individualized as higher doses in the morning or evening showed no substantial differences affecting sleep rating, daily activity score, nocturnal BP. DHEA is a useful marker for the adequacy of the therapy along with clinical monitoring. Presentation: No date and time listed

Can serum and urine Fludrocortisone measurements guide mineralocorticoid replacement therapy in primary adrenal insufficiency?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

Пренатальная диагностика врожденной дисфункции коры надпочечников

Enlarged nuchal translucency and nasal bone hypoplasia are considered as markers of chromosomal abnormalities and fetal malformations, although enlarged nuchal translucency can be detected in a healthy fetus and completely disappear by 14–15 weeks’ gestation and can also be observed when the karyotype is normal (in antenatal fetal death, congenital heart disease, miscarriage, preterm birth). The study of markers of chromosomal abnormalities is of practical interest in terms of accumulating information and gaining experience in using them for prenatal diagnosis. A case of accurate sex determination in the fetus with salt-wasting form of congenital adrenal hyperplasia and virilization of the external genitalia (Prader grade IV) at birth is presented. Highly effective prenatal screening including amniocentesis and karyotyping (46XX) at 13 weeks’ gestation ensured that pediatricians were prepared for timely prescription of gluco- and mineralocorticoid replacement therapy. This enabled to prevent the development of acute adrenal crisis and choose adequate management tactics, thereby providing normal puberty and potential fertility. Key words: congenital adrenal hyperplasia, prenatal screening, enlarged nuchal translucency

Evaluation of symmetric dimethylarginine and creatinine in dogs with primary hypoadrenocorticism receiving long‐term mineralocorticoid replacement therapy

To investigate kidney function by determining serum symmetric dimethylarginine (sSDMA) and serum creatinine (sCr) concentrations in dogs with primary hypoadrenocorticism (PH) receiving long-term mineralocorticoid replacement therapy. Dogs with PH receiving a minimum of 12 months of either desoxycorticosterone pivalate or fludrocortisone acetate were included in the study provided that banked frozen serum samples were available for sSDMA analysis. sCr concentrations were retrieved from the medical records. In dogs still alive and presented for regular re-evaluations and in newly diagnosed patients, blood was prospectively collected for sSDMA and sCr determination. Thirty-two dogs met the inclusion criteria. The treatment time ranged from 12 to 146 months after initial diagnosis (median, 55.5 months). The majority of dogs had normal sSDMA and sCr concentrations throughout the hormone replacement treatment. Both sSDMA and sCr concentrations were persistently elevated in three of 32 dogs. Further workup confirmed chronic kidney disease (CKD) in all three dogs. Based on these data, the prevalence of CKD could be higher in dogs with PH receiving long-term mineralocorticoid replacement treatment than in the general dog population. However, additional studies with a larger number of dogs are needed to confirm it.

Enfermedades de la secreción de aldosterona

Hyper- and hypoaldosteronism are caused by an excessive or insufficient adrenal secretion of aldosterone, respectively. Idiopathic bilateral hyperplasia and aldosterone-producing adenoma are the commonest causes of primary hyperaldosteronism. Primary hyperaldosteronism is characterized by hypertension, hypokalemia and metabolic alkalosis; in turn, hypoaldosteronism presents hyperkalemia and metabolic acidosis. The aldosterone/plasma renin activity ratio (ARR) is routinely used as a screening test of primary hyperaldosteronism. Functional tests are recommended if ARR is high (salt-loading, intravenous or oral, and fludrocortisone or captopril suppression). Once diagnostic is confirmed, imaging studies (abdominal computed tomography —CT—) and adrenal vein catheterization (in patients for surgery) have to be performed. Plasma levels of aldosterone and renin activity have to be determined by stimulatory functional tests (response to posture and volume depletion tests). Unilateral laparoscopic adrenalectomy is recommended in primary hyperaldosteronism caused by unilateral hyperplasia or adenoma; mineralocorticoid (spironolactone) receptor antagonists are the first-choice treatment for bilateral cases and in patients considered unfit for surgery. Potassium restriction and mineralocorticoid replacement therapy with fludrocortisone is the treatment of hypoaldosteronism.

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected.

Primary adrenocortical insufficiency (PAI) is an important cause of morbidity in neonates. The most common cause of PAI in neonates is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). Other rarer monogenic cases, for example, adrenal hypoplasia congenita (AHC) or familial glucocorticoid deficiency, also simulate clinical manifestation of 21-OHD, leading to misdiagnosis. The therapies and prognosis of these monogenic cases of PAI are entirely different. This study aimed to compare the differences of clinical data and identify genetic etiologies of PAI cases in the neonatal period. All 7 neonates initially presented with hyperpigmentation, hyponatremia, hyperkalemia, and high serum adrenocorticotropic hormone levels. Only CAH patients showed hyperandrogenism and remarkably elevated serum 17-hydroxyprogesterone levels. All the pathogenic mutations found in CYP21A2 were well known, except c.1069C>T (exon 8). The male patient with AHC had a novel hemizygous deletion of exon 2 in DAX1. The other one with familial glucocorticoid deficiency type 1 had two novel heterozygous mutations in the gene coding melanocortin 2 receptor, c.701C>T (exon 2) and c.119delT (exon 2). Glucocorticoid and/or mineralocorticoid replacement therapy depends on the cause of PAI. Genetic testing can be performed as a alternative diagnostic approach to provide information about therapy, prognosis, and genetic counseling.

Micro- and macrovascular function in patients suffering from primary adrenal insufficiency: a cross-sectional case\u2013control study

BackgroundDespite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function.Methods26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)].ResultsPWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p < .01], whereas no differences in microvascular function could be found. In Reninlow time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p < .05], whereas no differences in IMT and PWV were observed between Reninhigh and Reninlow. No impact of GC dose was observed.ConclusionsMicrovascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Management of congenital adrenal hyperplasia: beyond conventional glucocorticoid therapy.

The most common enzyme defect associated with congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency (21OHD). Glucocorticoid therapy aiming to suppress adrenocorticotrophic hormone (ACTH)-mediated hyperandrogenemia and to replace glucocorticoid deficiency, if indicated, remains the first line of management in CAH with or without mineralocorticoid replacement therapy and salt supplementation. We review interventions that may address unmet needs in the management of CAH. Although the objective of this review is to highlight some potential benefits of supplemental therapies, the authors do not recommend for or against the use of the reviewed therapies. In the review, the terms 'male' and 'female' refer to 'genetic male (46,XY)' and 'genetic female (46,XX)' respectively. Supplemental therapies, some of which appear to be promising, attempt to address CAH-associated morbidity but long-term efficacy and safety data are still lacking. We highlight main ideas behind the use of interventions that target an improvement in physiological glucocorticoid replacement, adult height outcome, and management of female genital virilization in CAH.

Identifying a disease-specific renin-angiotensin-aldosterone system fingerprint in patients with primary adrenal insufficiency.

In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case-control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients. AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

Plasma renin levels are associated with cardiac function in primary adrenal insufficiency

BackgroundDespite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, primary adrenal insufficiency (AI) is associated with an increased mortality, mainly due to cardiovascular disease. The role of MC replacement is not known. Therefore, we assessed whether renin concentrations during routine GC and MC substitution therapy are associated with heart function and morphology.MethodsThirty two patients with primary AI were included in a cross-sectional case–control study. In total, 17 patients and 34 healthy controls (age: 48 ± 12 vs. 46 ± 18 years; BMI: 23 ± 3 vs. 24 ± 3 kg/m2) underwent magnetic resonance spectroscopy and imaging measurements to assess cardiac function, morphology, ectopic lipids, and visceral/subcutaneous fat mass. Patients were divided according to their actual plasma renin concentration at the study visit (Actual-Reninlow vs. Actual-Reninhigh) and their median plasma renin concentration of previous visits (Median-Reninlow vs. Median-Reninhigh).ResultsEjection fraction was higher (67 ± 5 vs. 55 ± 3%; p = 0.001) and left ventricular mass was lower (60 ± 9 vs. 73 ± 10 g/m2; p = 0.025) in Actual-Reninhigh. Median-Reninhigh was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m2; p = 0.029). Blood pressure, glucose, and lipid metabolism, as well as ectopic lipid content, pericardial fat mass, and visceral/subcutaneous fat were not different between the groups. Compared with controls, ejection fraction was significantly lower in patients with AI (56 ± 4 vs. 63 ± 8%; p = 0.019). No differences were found in patients with ≤20 mg compared with >20 mg of hydrocortisone per day.ConclusionsHigher renin concentrations are associated with more favorable cardiac function and morphology in patients with primary AI.

Optimizing mineralocorticoid replacement therapy in patients with congenital adrenal hyperplasia and Addison's disease

Optimizing mineralocorticoid replacement therapy in patients with congenital adrenal hyperplasia and Addison's disease

Treatment of Addison's disease during pregnancy.

SummaryAddison’s disease, or primary adrenocortical insufficiency, is a long-term, potentially severe, rare endocrine disorder. In pregnancy, it is even rarer. We report the case of a 30-year-old pregnant patient with Addison’s disease, referred to Obstetrics-Endocrinology specialty consult at 14 weeks gestation. She had been to the emergency department of her local hospital various times during the first trimester presenting with a clinical scenario suggestive of glucocorticoid under-replacement (nausea, persistent vomiting and hypotension), but this was interpreted as normal pregnancy symptoms. Hydrocortisone dose was adjusted, and the patient maintained regular follow-up. No complications were reported for the remainder of gestation and delivery. Pregnant patients with Addison’s disease should be monitored during gestation and in the peripartum period by multidisciplinary teams. Adjustments in glucocorticoid and mineralocorticoid replacement therapy are often necessary, and monitoring should be based mainly on clinical findings, which becomes increasingly difficult during pregnancy. Patient education and specialized monitoring are key to avoiding complications from under- or over-replacement therapy in this period.Learning points:An increase in glucocorticoid replacement dose is expected to be necessary during pregnancy in a woman with Addison’s disease.Patient education regarding steroid cover and symptoms of acute adrenal crisis are fundamental.Monitoring in this period is challenging and remains mainly clinical.The increase in hydrocortisone dose often obviates the need to increase fludrocortisone dose.

NOVEL DAX-1 (NR0B1) MUTATION IN A THAI BOY WITH X-LINKED ADRENAL HYPOPLASIA CONGENITA (AHC): A FIRST REPORT

Background:Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of adrenal development resulting in hypoplasia of adrenal gland and inability to produce glucocorticoids, mineralocorticoids and sex steroids. X-linked AHC is the most common form and is caused by mutation of the DAX1 gene. Here we report a case of 4-year-old Thai boy with X-linked AHC, the first case of genetically confirmed novel DAX1 mutation in Thailand. Patient and Method:A 4-year-old Thai boy presented with fever and vomiting for 3 days. He was the fifth child of unrelated parents. The past medical history was unremarkable except his skin had been progressively more pigmented since early infancy. Physical examination revealed normal genital development and addisonian hyperpigmentation which prominent at skin crease, gum and knuckles. Laboratory investigations showed hyponatremia, hyperkalemia, and hypochloremia. Hormonal evaluation revealed low baseline cortisol level which is not rising after 250 mg ACTH stimulation test. ACTH level and plasma renin activity were elevated. A diagnosis of X-linked AHC was established. Glucocorticoid and mineralocorticoid replacement therapy were initiated. Molecular analysis by direct DNA sequencing of the DAX1 gene was performed in the patient and family members. Result:Mutation analysis revealed a novel hemizygous GG deletion (c.1148_1149delGG) resulting in a premature termination codon at the position 387 (p.Gly383Aspfs*5). This frameshift mutation was predicted to encode a truncated DAX1 protein missing a portion of ligand binding domain. The mutation identified in our proband was inherited from his carrier mother. Conclusion:We report a case of classical X-linked AHC with established a novel frameshift mutation in the DAX1 gene. Genetic analysisis important not only for diagnostic confirmation in the index case but also for carrier detection in his mother which provided a proper management and appropriate genetic counseling for this famity.

Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy.

Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.

Contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism

BackgroundWe aimed to determine whether a greater degree of contralateral suppression of aldosterone secretion at adrenal venous sampling predicted the development of postoperative hyperkalemia after unilateral adrenalectomy for primary aldosteronism. MethodsA retrospective analysis of patients undergoing unilateral adrenalectomy for primary aldosteronism between 2004-2015 was performed. Clinical and biochemical parameters of patients who developed hyperkalemia (≥5.2 mmol/L) after unilateral adreanlectomy were compared with those who remained normokalemic. The contralateral suppression index was defined as the aldosterone-to-cortisol ratio from the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio from the external iliac vein. ResultsOf 192 patients who met criteria for inclusion, 12 (6.3%) developed hyperkalemia (median serum potassium 5.5 mmol/L, range 5.2-6.2 mmol/L), with a median time to onset of 13.5 days (range 7-55 days). Five patients had transiently increased serum potassium concentrations that normalized spontaneously. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 vs 1.0 mg/dL, P = .01), higher postoperative creatinine (1.3 vs 1.0 mg/dL, P = .02), lesser median contralateral suppression index (0.14 vs 0.27, P = .03), and larger adenomas (1.9 vs 1.4 cm, P = .02). On multivariable logistic regression, the contralateral suppression index remained the only significant predictor of postoperative hyperkalemia (P = .04) with an optimal cut-off of <0.47. ConclusionHyperkalemia after unilateral adrenalectomy for primary aldosteronism is uncommon and usually transient, but may require mineralocorticoid supplementation. Patients with a contralateral suppression index of <0.47 require meticulous follow-up and monitoring of serum potassium concentrations after unilateral adrenalectomy.