Hormone Stimulation Test Research Articles

Is Gadolinium Contrast Necessary for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

Introduction: Short stature is a common concern that necessitates pediatric endocrinology evaluation. Growth hormone deficiency (GHD) is a commonly considered etiology. Brain and pituitary magnetic resonance imaging (MRI) with gadolinium-based contrast agents (GBCAs) is the most widely used imaging in assessing patients with GHD. Given the significant strides made in MRI technology, the need for contrast material should be reassessed. Method: We performed a retrospective review of healthy patients with short stature and/or GHD who underwent brain and pituitary MRI with and without contrast to assess the added value of contrast administration. Results: 227/318 identified patients underwent growth hormone (GH) stimulation testing; 28 (12.3%) with normal GH response and 62 (27.3%) with severe GHD. We found a low incidence of sellar and suprasellar pathologies. When comparing noncontrast and contrast MRI, we found perfect agreement in detecting abnormal posterior pituitary bright spots (kappa:1.0) and substantial agreement in detecting pars intermedia cysts and posterior superior sellar cysts (kappa: 0.74 and 0.71, respectively). Initially, only moderate agreement was found in detecting infundibular abnormalities (kappa: 0.51), although a revised noncontrast MRI protocol with high-resolution 3D images enabled visualization of the infundibulum. Conclusion: The MRI evaluation of healthy patients with short stature and/or isolated GHD may be completed without the use of GBCAs. The slight overestimation of pituitary stalk interruption by noncontrast images can be overcome by adding newer high-resolution sequences.

Diagnosing Growth Hormone Deficiency: Can a Combined Arginine and Clonidine Stimulation Test Replace 2 Separate Tests?

ObjectiveGiven the large number of false-positive growth hormone deficiency (GHD) diagnoses from a single growth hormone (GH) stimulation test in children, 2 different pharmacologic tests, performed on separate days or sequentially, are required. This study aimed to assess the reliability and safety of a combined arginine-clonidine stimulation test (CACST). MethodsThis was a retrospective, single-center, observational study. During 2017-2019, 515 children aged >8 years underwent GH stimulation tests (CACST: n = 362 or clonidine stimulation test [CST]: n = 153). The main outcome measures used to compare the tests were GH response (sufficiency/deficiency) and amplitude and timing of peak GH and safety parameters. ResultsPopulation characteristics were as follows: median age of 12.2 years (interquartile range [IQR]: 10.7, 13.4), 331 boys (64%), and 282 prepubertal children (54.8%). The GHD rate was comparable with 12.7% for CACST and 14.4% for CST followed by a confirmatory test (glucagon or arginine) (P = .609). Peak GH was higher and occurred later in response to CACST compared with CST (14.6 ng/mL [IQR: 10.6, 19.4] vs 11.4 ng/mL [IQR: 7.0, 15.8], respectively, P < .001; 90 minutes [IQR: 60, 90] vs 60 minutes [IQR: 60, 90], respectively, P < .001). No serious adverse events occurred following CACST. ConclusionOur findings demonstrate the reliability and safety of CACST in detecting GHD in late childhood and adolescence, suggesting that it may replace separate or sequential GH stimulation tests. By diminishing the need for the second GH stimulation test, CACST saves time, is more cost-effective, and reduces discomfort for children, caregivers, and medical staff.

The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls.

ObjectiveTo evaluate the characteristics and significance of serum kisspeptin and makorin ring finger protein 3 (MKRN3) levels for the diagnosis of central precocious puberty (CPP) in girls.MethodThirty four individuals with CPP, 17 individuals with premature thelarche (PT), and 28 age-matched prepubertal girls as normal control (NC) were recruited in this case–control study. Physical measurements included BMI and tests for breast, bone, and sexual characteristics. Biochemical measurements included serum LH, FSH, estradiol, insulin-like growth factor-1, MKRN3, and kisspeptin. Blood samples were taken from individuals with CPP and PT before the gonadotrophin-releasing hormone stimulation test and at 30, 60, 90, and 120 min after injection with triptorelin.ResultsSerum kisspeptin levels were higher in the CPP group when compared to the NC group (P = 0.020), while serum MKRN3 levels were lower in the two groups (P = 0.028). There were no significant differences between the CPP and PT groups as well as the PT and NC groups (all, P > 0.05). The cut-off value of serum kisspeptin differentiating patients with CPP from those without CPP was 0.40 nmol/L, with 82.4% sensitivity and 57.1% specificity, while the cut-off value of serum MKRN3 was 0.33 pmol/L, with 79.4% sensitivity and 53.6% specificity. The area under the curves (AUCs) of both kisspeptin and MKRN3 for differentiating those girls with CPP from PT were less than 0.5.ConclusionsSerum levels of kisspeptin and MKRN3 may play an auxiliary role in predicting CPP. However, the two measurements were not able to differentiate girls with CPP from PT and prepubertal control. This study emphasizes the need to search for markers to simplify the accurate diagnosis of CPP in girls.

Pituitary Macroadenoma and Severe Hypothyroidism: The Link between Brain Imaging and Thyroid Function

In case of primary hypothyroidism, reactive pituitary hyperplasia can manifest as pituitary (pseudo) macroadenoma. We report the case of a 12-year-old boy who was evaluated for impaired growth velocity and increased body weight. Because of low insulin-like growth factor 1 levels and poor response to the growth hormone stimulation test, brain magnetic resonance imaging was performed and a pituitary macroadenoma was found. Treatment with levothyroxine was started, and thyroid function was evaluated approximately every 40 days to titrate the dosage. After few months of therapy, the size of the macroadenoma decreased and growth hormone secretion normalized. The pituitary returned to normal size in approximately 5 years. The boy went through puberty spontaneously and reached a normal adult height. In a patient affected by primary hypothyroidism, reactive pituitary hyperplasia can cause growth hormone deficiency; however, growth hormone secretion usually normalizes after starting levothyroxine treatment. Pituitary macroadenoma can be difficult to distinguish from severe pituitary hyperplasia; however, pituitary macroadenomas are rare in childhood, and our clinical case underlines how the hormonal evaluation is essential to achieve a correct diagnosis and prevent unnecessary surgery in a context of pituitary mass.

Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction

Blue light therapy can be used in horses to alter the natural photoperiod and inhibit winter hair coat growth. Seasonal increases in ACTH occur in the fall season but are exaggerated in horses with pituitary pars intermedia dysfunction (PPID). Additionally, PPID horses frequently present with hypertrichosis. Thus, blue light therapy was proposed as a potential management tool for hypertrichosis and for investigating the impact of photoperiod manipulation on ACTH. Eighteen PPID horses, aged 18 to 31 yr, from a university-owned research herd were selected and assigned to either the control group (n = 10) or the treatment (blue light therapy) group (n = 8) based on age and clinical history, which included the results of multiple endocrine tests. Consistent daylength of approximately 14.5 h was maintained for the treated horses from July 15 through approximately late October via the extension of natural daylength using wearable masks that provided short wavelength blue light (465 nm) to 1 eye. The control group was exposed to only the natural photoperiod during this time. All horses were housed on the same farm and remained on pasture for the duration of the study. On Day 0, thyrotropin-releasing hormone (TRH) stimulation tests were performed to confirm PPID status; there were no differences between the 2 groups in resting plasma ACTH or plasma ACTH at 10 min after TRH administration. To determine an effect of treatment on ACTH, blood was collected via jugular venipuncture for measurement of ACTH at sequential timepoints over a 16-h period in mid-October. Hair weights were also assessed throughout the study. No differences in resting plasma ACTH were observed between the 2 groups across the seasonal analysis (July and October) or during the 16-h testing. The PPID horses receiving blue light therapy had lighter hair weights compared to the PPID control horses. These results suggest that blue light therapy does not alter ACTH concentrations but could potentially be used as an additional management tool for hypertrichosis in PPID horses. Manipulation of the photoperiod using blue light therapy did not affect seasonal changes in ACTH in this study.

Ciclesonide Impacts Clinicopathological Features of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergen-mediated disease of the esophagus. Pharmacologic treatment has largely relied on repurposing corticosteroids. Ciclesonide (CIC) is a corticosteroid for the treatment of asthma with biochemical properties that improve topical potency. To determine whether CIC decreased clinicopathological features of EoE. We performed a retrospective cohort study of patients with EoE treated with CIC at a pediatric hospital from 2010 to 2019. Data were extracted from the electronic health record. Patients who were prescribed CIC with pre- and post-CIC endoscopic and histological data available were included for analysis. A total of 281 patients were treated with CIC and 81 met criteria for inclusion. Use of CIC was associated with reduced symptoms including dysphagia (P < .001), abdominal pain (P < .001), vomiting (P= .01), heartburn (P= .02), and behavior changes (P= .02). Average composite endoscopic reference scores decreased from 2.54 to 1.37 (P < .001), with improvement in exudates, edema, and furrows (all P < .001). Peak eosinophil counts decreased from 48 to 23 eosinophils/hpf (P < .001). Forty-three patients (53%) achieved remission (<15 eosinophils/hpf). Esophageal Candida was reported in 1 patient. Fasting morning cortisol concentrations were low in 10 of 31 patients tested. Six of these 10 patients had abnormal adrenocorticotropic hormone stimulation testing, 5 of 6 diagnosed with adrenal insufficiency before transition to CIC and 3 of 6 with subsequent normalization of adrenal function on CIC therapy. Patients with EoE treated with CIC experienced significant reductions in clinicopathological features of EoE. CIC can be considered an alternative therapy in patients with known adrenal insufficiency or at risk of developing adrenal insufficiency.

Corticosteroid‐associated hypothalamic–pituitary–adrenal axis suppression in brain tumours: a focus on dosing and tapering

AbstractBrain tumours are among the most challenging malignancies to treat. The majority of brain tumours are associated with perifocal oedemas and disturbances in the cerebrospinal fluid (CSF) flow. Glucocorticoids (GC) are the mainstay supportive therapy for a variety of disorders associated with brain tumours such as vasogenic oedema, intracranial pressure, headache, and vomiting. In contrast, prolonged exposure to GC has been associated with suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Moreover, abrupt tapering and sudden stopping of GC therapy are the most common causes of HPA axis suppression leading to secondary adrenal insufficiency (SAI). Furthermore, a variety of well‐established dynamic tests have been used to diagnose and assess the integrity of the HPA axis, such as the insulin tolerance test, the metyrapone stimulation test and the adrenocorticotropic hormone stimulation test. Hydrocortisone replacement is the recommended therapy for SAI as it provides the physiological circadian cortisol rhythm. In the context of brain tumours, limited evidence exists to guide clinical practice regarding the optimal dosing of GC with regard to side effects, duration of therapy, withdrawal regimen or quality of life. In this review, we summarise the current status of HPA axis suppression and the SAI associated with GC therapy in brain tumours.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Non-Classic Congenital Adrenal Hyperplasia in Two Adolescents With Gender Dysphoria

The care of transgender individuals is multidisciplinary including medical, surgical, psychiatric, and psychological health professionals. We here report 2 cases of nonclassic congenital adrenal hyperplasia (CAH) coincidently discovered during the clinical and biochemical evaluation prior to hormonal treatment for gender dysphoria. Elevated 17-OH-progesterone and androstenedione led to further investigations including adrenocorticotropic hormone stimulation test and genetic evaluation of 21CYPA2 confirming the diagnosis of CAH in both individuals. The findings may have implications for future surgical treatment and in the case of transwomen for the choice of antiandrogenic treatment. These cases therefore confirm the importance of thorough clinical and biochemical evaluation of transgender individuals before initiation of hormone therapy.

A young man with abdominal pain and intestinal distension

A 20-year old man of Balkan descent presented to the emergency department with abdominal pain and constipation of several days‘ duration. On clinical examination, he was afebrile and normotensive. The abdomen was distended with reduced bowel sounds. Laboratory investigations were significant for hyponatraemia (129 mmol/l) and elevated aminotransferases in the double digits; inflammatory markers were normal. Abdominal ultrasound was unrevealing as to a specific cause but meteorism was noted. Cortisol response to an adrenocorticotrophic hormone stimulation test was normal.

The Use of Morning Urinary Gonadotropins and Sex Hormones in the Management of Early Puberty in Chinese Girls.

ContextAlthough gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP), it is invasive, expensive, and time-consuming, requiring multiple blood samples to measure gonadotropin levels.ObjectiveWe evaluated whether urinary hormones could be potential biomarkers for prepuberty or postpuberty, aiming to simplify the current diagnosis and prognosis procedure.MethodsWe performed a cross-sectional study of a total of 355 girls with CPP in National Clinical Research Center for Child Health in China, including 258 girls with positive and 97 girls with negative results from GnRHST. Twenty patients received GnRH analogue (GnRHa) treatment and completed a 6-month follow up. We measured luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, progesterone, testosterone, and human chorionic gonadotropin in the first morning voided urine samples.ResultsTheir urinary LH levels and the ratios of LH to FSH increased significantly with the advancement in Tanner stages. uLH levels were positively associated with basal and peak LH levels in the serum after GnRH stimulation. A cutoff value of 1.74 IU/L for uLH reached a sensitivity of 69.4% and a specificity of 75.3% in predicting a positive GnRHST result. For the combined threshold (uLH ≥ 1.74 + uLH-to-uFSH ratio > 0.4), the specificity reached 86.6%. After 3 months of GnRHa therapy, the uLH and uFSH levels decreased accordingly.ConclusionuLH could be a reliable biomarker for initial CPP diagnosis and screening; uLH could also be an effective marker for evaluating the efficacy of clinical treatment.

Adrenocortical Function in Children With Brain Tumors and Pediatric Hematopoietic Cell Transplantation Recipients.

Adrenocortical insufficiency (AI) is a clinical condition defined by deficient production of glucocorticoids that can result in life-threatening complications. We examined the prevalence of AI in children with brain tumors and those undergoing hematopoietic cell transplantation. Adrenocorticotropic hormone stimulation (stim) testing was used for the assessment of adrenocortical function. On the basis of 155 stim tests in 117 patients, AI was diagnosed in 27.4% of patients with brain tumors and in 21% of hematopoietic cell transplantation recipients. A number of risk factors associated with AI were identified. Adrenocorticotropic hormone stim testing led to a definitive diagnosis of AI or recovery of adrenal function and unambiguous medical management.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

Single random measurement of urinary gonadotropin concentration for screening and monitoring girls with central precocious puberty.

PurposeThe gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, time-consuming, and inconvenient. This study evaluated whether a single random measurement of urinary luteinizing hormone (LH) concentration could substitute for the GnRHST in diagnosing and monitoring central precocious puberty (CPP) in girls.MethodsFifty-five girls with breast buds before 8 years of age were assessed by both the GnRHST and urinary gonadotropin assays. Based on the GnRHST results, 29 girls were assigned to the CPP group (peak LH≥5 IU/L), and 26 were placed in the premature thelarche (PT) group (peak LH<5 IU/L). Auxological data and urine and serum samples were collected at baseline and after treatment with a GnRH agonist for 12 and 24 weeks.ResultsAlthough the auxological data did not differ between the 2 groups, the serum levels of insulin-like growth factor-1, basal LH, follicle-stimulating hormone (FSH), estradiol, and peak LH; urinary LH; and peak serum LH/FSH and urinary LH/FSH ratios were higher in the CPP group than in the PT group. Pearson correlation analysis showed a positive correlation between the urinary and serum LH concentrations (r=0.660, P<0.001). Receiver-operating characteristic curve analyses showed that a urinary LH concentration of 0.725 IU/L was a cutoff that significantly predicted positivity on the GnRHST. Urinary LH and FSH concentrations declined significantly during GnRH agonist treatment.ConclusionsA single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.

Effect of body mass index on peak growth hormone level after growth hormone stimulation test in children with short stature.

PurposeThe aim of this study is to evaluate the effect of body mass index (BMI) on peak serum growth hormone (GH) level after GH stimulation test in children with short stature.MethodsData were obtained from retrospective medical record reviews of those who visited the pediatric endocrine clinic at St. Vincent’s Hospital of Catholic University for short stature from January 2010 to June 2019. A total of 115 children (66 boys and 49 girls) whose height was less than the third percentile according to age and sex underwent GH stimulation testing.ResultsOf the 115 subjects, 47 were diagnosed with GH deficiency (GHD) and 68 were diagnosed with idiopathic short stature (ISS). In patients with GHD, weight standard deviation score (SDS) (P<0.001) and BMI SDS (P≤0.001) were higher, and free thyroxine (T4) level (P=0.012) was lower than those in the ISS group. In total subjects, peak serum GH level after GH stimulation test showed negative correlations with weight SDS (r=-0.465, P<0.001), BMI SDS (r=-0.398, P<0.001), and thyroid stimulating hormone (r=-0.248, P=0.008) and a positive correlation with free T4 (r=0.326, P<0.001). In multiple regression analysis, BMI SDS (P=0.003) was negatively associated with peak serum GH level in GH stimulation testing after adjusting for age, sex, pubertal status, and type of pharmacological stimulus.ConclusionsThe BMI SDS influences peak serum GH level after GH stimulation testing. We should consider BMI factors when interpreting the results of GH stimulation testing.

The Dexamethasone-CRH Stimulation Test: A Single-Center Experience

Background: The diagnostic value of adding a Corticotropin Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. We hypothesized that adding CRH to LDDST would provide additional case detection in patients suspected of having Cushing’s disease (CD). Methods: We identified 118 patients who underwent the Dex-CRH test to evaluate ACTH-dependent CS from a prospectively maintained pituitary database over 12 years. Seven patients were excluded (2 lost to follow up, 2 were on Dilantin with no available Dexamethasone (Dex) level, 2 had cyclic CD, and 1 suspected noncompliance with Dex intake). Three patients with ectopic ACTH Syndrome had very high cortisol levels after both LDDST and Dex-CRH tests. The remaining 108 patients are the subjects of this analysis. Patients were instructed to take 8 doses of Dex 0.5 mg PO every 6 hours starting at noon with the last dose of Dex taken at 6 AM. Ovine CRH injection (1 µg/kg, max 100 mcg) was given IV 2 hours afterwards. Cortisol was measured 2 hours after the last Dex dose prior to and 15 minutes after CRH administration. CD diagnosis was made based on positive ACTH staining on pituitary pathology and/or development of hypocortisolism postoperatively. Patients with no Cushing disease (NCD) are the group of patients in whom CD diagnosis could not be confirmed after a minimum follow up of 30 months. Results: Among 108 patients who underwent Dex-CRH test, 66 had CD and 42 had NCD. The female sex ratio, and median (range) for each of age, BMI, and follow-up duration in months were as follows with no statistically significant difference between the two groups: CD: 83%, 40 (15–82), 34 (30–42) and 63 (24–102). NCD: 88%, 40 (20–71), 37 (31–43) and 52 (30–67). Among 66 patients with CD, 5 patients (7.6%) had a cortisol level ≤ 1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of these three patients the LDDST was normal (cortisol post-Dex was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cut-off value of > 1.4 µg/dL at 15 min during Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded from the analysis (n=74), the sensitivity did not change but specificity and accuracy of Dex-CRH test further increased to 97% and 99%, respectively. Conclusion: The CRH test addition to the 2-day LDDST provided additional case detection in 5/66 (7.6%) of patients with CD. It resulted in one additional false-positive case compared to LDDST. Measurement of Dex level provided improved diagnostic accuracy of DEX-CRH test.

TRH Stimulation Testing in Older Individuals with Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration

Abstract Background: Subclinical hypothyroidism is common in older individuals. To better understand the underlying physiology, we examined the pituitary-thyroid axis using thyrotropin releasing hormone (TRH) stimulation testing both at baseline and after levothyroxine (LT4) and liothyronine (LT3) supplementation. Methods: We conducted a randomized, double-blind, cross-over study in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. The primary outcome measures were TSH serum concentration area under the curve (AUC), maximum TSH serum concentration (Cmax), and change in free thyroxine (∆FT4) and total triiodothyronine (∆TT3) levels following TRH stimulation, each measured at three time points: once at baseline and once each after achieving euthyroid TSH levels with the two thyroid preparations. The maximal change in TSH (∆TSH); FT4 and TT3 AUCs; and time to maximal TSH, FT4, and TT3 (Tmax) were also analyzed. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed TRH stimulation testing at baseline and after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day and LT4 dose was 34 (9) µg/day. After TRH stimulation, the mean TSH AUC (0-180) at baseline was 3099.5 (1424.4) µIU*min/mL, and significantly decreased after both LT4 [631.4 (315.2), p&amp;lt;0.001] and LT3 [631.5 (317.3), p&amp;lt;0.001]. There was no difference in TSH AUC (0-180) between LT4 and LT3 treatment arms. Baseline mean TSH Cmax was 27.2 (14.5) µIU/mL and significantly decreased after LT4 [5.5 (3.0), p&amp;lt;0.001] and LT3 [5.4 (2.9), p&amp;lt;0.001], with no difference between the LT4 and LT3 treatment arms. The ∆FT4 was 0.11 (0.07) ng/dL at baseline and decreased significantly on LT3. The ∆TT3 was 0.32 (0.09) ng/mL at baseline and significantly decreased on both LT4 and LT3, with no difference between treatment arms. Conclusions: Older individuals with antibody-negative persistent subclinical hypothyroidism have a heterogeneous TSH response to TRH stimulation. Our data show a significantly diminished response to TRH stimulation after thyroid hormone replacement, and they support the pharmacodynamic equivalence of LT4 and LT3 treatment.

Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of <7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity. Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism. Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study. 1Murray etal (2018) JCI Insight 3(7): e93247

Pharmacokinetics and Pharmacodynamics of Macimorelin Acetate (AEZS-130) in Paediatric Patients With Suspected Growth Hormone Deficiency (GHD)

Abstract Growth hormone deficiency (GHD) in children is a rare, aetiologically diverse condition that results in growth failure and short stature. Inadequate response to two different growth hormone stimulation tests (GHST) is required for the diagnosis of GHD. Macimorelin acetate, a potent, orally administered growth hormone (GH) secretagogue, is approved by the FDA and EMA for the diagnosis of adult GHD. Study AEZS-130-P01 is the first of two studies to investigate macimorelin acetate as a diagnostic test in children with suspected GHD. This was an open-label, group comparison, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single-dose 0.25, 0.5 and 1 mg/kg oral macimorelin acetate in paediatric subjects with suspected GHD. The macimorelin GHST was administered between two standard GHST, conducted as per local clinical practice, with a recovery period of 7-28 days between tests. Blood samples were collected pre-dose (±15 min) and 15, 30, 45, 60, 90, 120 and 360 minutes after macimorelin acetate intake. Overall, 24 paediatric subjects (8 per cohort [C1, C2, C3]) were included in the pharmacokinetic/pharmacodynamic (PK/PD) analysis. Five males and 3 females were observed in C1 and C2, 7 males and 1 female in C3. In all three cohorts, at least 3 subjects represented Tanner stages I or II. All 24 subjects (100%) were white, with a median age of 9.8, 9.0 and 10.5 years (range 4-15 years) and a median body-mass index of 16.1 kg/m2 (12.4-21.4 kg/m2) at screening. Overall, 88 adverse events were reported, many related to the standard GHST; none were considered related to the macimorelin test. Maximum plasma concentrations for macimorelin were mainly observed between 30-45 min. The mean Cmax values were 3.46, 8.13 and 12.87 ng/ml for C1, C2, and C3, respectively. The AUCs increased with dose; the mean AUC0-6 values were 6.69, 18.02 and 30.92 h*ng/mL. The mean elimination half-lives were 1.22, 1.61 and 1.71 h, respectively. PK and PD profiles for all three cohorts were comparable, with peak GH levels mainly observed within 30-60 min following macimorelin intake. Macimorelin acetate was safe and well tolerated in all dosing cohorts. A dose-dependent increase in macimorelin Cmax and AUC in children and adolescents correlated well with data from adult subjects. A robust dose-proportional GH response was also achieved. PD results showed that GH response was comparable in all dose groups, with a slight shift to earlier tmax at higher macimorelin doses.

Impact of IGF-1 Normative Datasets on Indication and Outcome of Growth Hormone Stimulation Testing

In the Netherlands, the diagnosis of growth hormone deficiency in children follows the Dutch national guidelines for Triage and Diagnosis of Growth Disorders in Children. Initial biochemical evaluation includes an IGF-1 measurement as screening parameter for growth hormone deficiency. Based on the clinical probability of growth hormone deficiency and the IGF-1 Z-score, a growth hormone stimulation test is performed if serum IGF-1 Z-score is < 0 SD in case of a high probability and if serum IGF-1 Z-score is < -1 SD in case of low probability. An IGF-1 Z-score > 0 SD virtually excludes a growth hormone deficiency disorder. The interpretation of growth hormone stimulation testing is dependent on both the peak growth hormone concentration, but also on the baseline IGF-1 Z-score, particularly in cases of partial deficiency. Although, nation wide, Dutch laboratories have harmonized their measurement for IGF-1 (as was previously done for growth hormone), a Dutch harmonized normative data set has not been widely adopted. Moreover a clinical evaluation of the implementation of this dataset based on dynamic testing has not been published. To assess the impact of choice of a particular normative dataset on the diagnosis of growth hormone deficiency we recalculated Z-scores of IGF-1 measurements between 2016 and 2019, using our home reference values based on de normative dataset by Elmlinger (E)1, and using the normative datasets defined by Bidlingmaier (B)2 and by the Dutch IGF-1 harmonization program (NL). Based on these three Z-scores, the outcomes of growth hormone stimulation tests performed in this period (n=86) were reassessed according to the interpretation described in the Dutch guideline. Using all three normative datasets the same 4 patients were identified as likely to have a growth hormone deficiency, whereas 10(E), 10(B), or 8(NL) patients were identified as possible partial growth hormone deficiency. In 70(E), 66(B) or 72(NL) patients the growth hormone stimulation test was unaffected. Using normative dataset B, 6 patients displayed a pattern associated with a possible growth hormone resistance, or of bio-inactive growth hormone syndromes, which based on its incidence would be unlikely for a secondary care setting. A striking observation was however, that of all patients with a normal stimulation test 9 (E)/16 (B) or 30 (NL) had a IGF-1 Z-score of > 0 SD. This implies that, for the diagnosis of growth hormone deficiency, it is safe to implement the Dutch harmonized dataset, which in addition could result in a reduction in the number of growth hormone stimulation tests that have to be performed.