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ENDO 2021

Metopirone Treatment in Endogenous Cushing&#39;s Syndrome
Results from a Prospective Multicenter, Open-Label, Phase III/IV Study: PROMPT

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Metopirone Treatment in Endogenous Cushing's Syndrome
Results from a Prospective Multicenter, Open-Label, Phase III/IV Study: PROMPT

technical paper

Background: Based on the CHIASMA OPTIMAL study, oral octreotide capsules (OOC) were recently approved in the US as a long-term maintenance therapy for patients with acromegaly previously responding to injectable octreotide or lanreotide, somatostatin receptor ligands (SRLs). Results on longer-term efficacy and safety of OOC from the first 48 weeks of the open-label extension (OLE) of this study are presented here. Methods: Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period; 90% of patients who received OOC in the DPC period enrolled. All patients entering the OLE were initiated on a 60 mg/day dose of OOC and titrated up or down based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. End points in the OLE were exploratory and included the proportion of patients who completed week 48 of the OLE, the proportion who completed as responders (defined as average IGF-I ≤1.0 × upper limit of normal [ULN] at weeks 46/48), and changes in IGF-I from baseline of DPC and OLE until week 48 of the OLE; multiple imputation (MI) was used for missing data. Results: Forty patients entered the OLE (n=20 each; OOC and placebo). Median exposure to OOC in the OLE was > 1 year for those who had been on placebo in the DPC and ≤ 21 months for those who had been on OOC. Dosing of OOC at the end of their participation in the OLE was 40 mg, n=3; 60 mg, n=10; and 80 mg, n=27. In those who received OOC during the DPC, 90% (n=18) completed 48 weeks of the OLE. Of responders at the end of the DPC period (n=14), 92.6% maintained response at OLE week 48. In patients from the OOC group who completed the DPC on study drug, average IGF-I using MI was 0.91 and 0.90 × ULN at OLE baseline and week 48, respectively. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.06 × ULN in patients who completed the DPC on OOC (n=19). In those who received placebo during the DPC, 70% (n=14) completed 48 weeks of the OLE. Of responders at the end of the DPC (n=5), 100% maintained response at OLE week 48. In patients from the placebo group who completed the DPC and did not revert to prior injectable therapy (n=9), the average IGF-I values were 1.09 and 0.87 × ULN at OLE baseline and week 48 respectively, using MI. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.08 × ULN in patients who completed the DPC on placebo (n=9). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal; most were mild or moderate. The incidence of TEAEs was similar between patients who were on OOC or placebo during the DPC. The safety profile during the OLE did not show new concerns with increased duration of drug exposure. Conclusion: Long term maintenance of biochemical response to OOC is durable as assessed following ≤ 21 months of treatment. The OOC safety profile in the extension study is consistent with that of injectable SRLs but without injection-related AEs.?? 

One-Year Outcomes of the Open-Label Extension of CHIASMA OPTIMAL, a Phase 3 Study of Oral Octreotide Capsules in Acromegaly

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Reduce Fluid Intake in Primary Polydipsia

Background: Studies comparing the timing and pace of puberty in overweight/obese girls (OW/OB) vs normal weight girls (NW) have produced conflicting results; some suggest earlier activation of the central components of the reproductive axis in OB while others are more consistent with a peripheral source of estrogen (e.g. adipose tissue) driving puberty in OB. Importantly, there have been no longitudinal assessments of both clinical and biochemical pubertal markers in OB vs. NW. Methods: 90 healthy pre-menarchal girls (26 OW/OB, 54 NW) from the community, aged 8.2-14.7 years, completed 2.8 ± 1.7 (mean, SD) study visits over the course of 4 years. Visits included dual-energy x-ray absorptiometry to calculate percent total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; stages A-E), pelvic ultrasound, hand x-ray (bone age, BA), blood tests for reproductive hormones, and urine collection to determine a vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. Menarchal status was determined at each visit and via follow-up questionnaires. The effect of TBF on hormones and markers of estrogen action, the pace of breast maturation, and age at menarche were determined using a mixed, multi-state, or Cox proportional hazards model, respectively. Mixed and Cox models controlled for BMORPH at visit 1 (V1) and race. Results: NW girls were older than OW/OB (11.3 vs. 10.2 yrs, p&lt;0.01) at V1, more likely to be non-Hispanic White (66 vs. 40%, p=0.03), and had more advanced breast morphology BMORPH (p&lt;0.01). LH, E2, VMI, BA, and ovarian and uterine volume increased with time with no effect of TBF. There was an interaction between time and TBF for FSH, INHB, E1, Total T, Free T, and A’dione (p&lt;0.05): levels were initially similar in all TBF groups, but after 1 yr, levels increased in girls with higher TBF, plateaued in girls with mid-range TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D (corresponding to growth/arborization of the breast ductal system), more slowly than girls with lower TBF but achieved menarche at a younger age (risk 1.04x higher per 1 unit increase in TBF). Conclusions: Intensive reproductive phenotyping of girls during the pubertal transition reveals that both the neuroendocrine and ovarian components of the axis are generally preserved in girls with higher TBF but that the axis appears to be activated earlier than in girls with lower TBF. In late puberty, however, girls with higher TBF demonstrate subtle differences in standard hormonal (e.g. serum FSH, INHB, and androgen) and clinical (e.g. delayed growth of breast bud) markers of puberty. Investigation of the mechanistic basis for these differences and their potential clinical consequences for girls with higher TBF deserves further study.?? 

Longitudinal Investigation of Pubertal Milestones and Hormones as a Function of Body Fat in Girls

Backround:Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with asymmetric short stature (e.g. Kniest dysplasia, spondyloepiphyseal dysplasia). Less is known about nonsyndromic collagenopathies - data about their frequency and subtle phenotypic signs are sparse, the information about their response to growth hormone (GH) treatment is lacking completely.?Aim:To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response.?Methods:Out of 522 individuals treated in our center with GH from the indication of primary GH deficiency (GHD) or small for gestational age short stature (SGA-SS), 87 children with FSS fulfilled the inclusion criteria (pre-treatment height ≤-2 SD in both patient/their shorter parent, signed written informed consent) and were enrolled to the study. Next-generation sequencing was performed to search for variants in COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 and COL11A2 genes. The results were evaluated using ACMG guidelines. The phenotype of children with (likely) pathogenic variants was described including the short-term GH treatment response (growth velocity and body-height SDS increase over three years of treatment). For statistical evaluation, parametric tests were used, p-values <0.05 were considered significant.?Results:A (likely) pathogenic variant in one of the collagen genes was found in 10/87 (11.5%) children. Their age was 12.5 years (median, range 6-17 years), their pre-treatment height was -3.1 SD (-2.4 to -4.3 SD). Their birth length (median -2.8 SD; range -0.7 to -4.1 SD) was more severely affected than birth weight (median -2.1 SD; range -1.0 to -2.7 SD). Eight children were treated with GH from SGA-SS indication, the remaining 2 were classified as mild GHD (maximal stimulated GH concentration 8.0 and 9.7 ug/l, normal brain MRI and examination of other pituitary hormones). Detailed anthropometric examination described mild asymmetry with shorter limbs and mild bone dysplasia signs (scoliosis, more pronounced lumbar lordosis, genua valga, limited elbow extension) in 2/10 and 4/10 affected children, respectively. Growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment (p<0.001, paired-sample T-test), height improved from a median of -3.1 SD to -2.2 SD after three years of therapy (p=0.001, ANOVA repeated measures analysis of variants).?Conclusion:Nonsyndromic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.?Supported by the Ministry of Health, Czech Republic, grant number NV18- 07-00283 and by the research project of the Grant Agency of Charles University of Prague, GAUK 976718. ?? 

Familial Short Stature - a Novel Phenotype of Growth Plate Collagenopathies

Introduction: The genetic basis of human growth regulation has only been partly elucidated thus far. Therefore, finding causative genes in patients with short stature help in understanding precise pathophysiological mechanisms, establishing genotype-phenotype relationships and optimizing treatment. In order to extend our knowledge about the genes involved in short stature, we studied a unique cohort of consanguineous families with children with short stature from Sulaymani in Kurdistan, Iraq. Patients and Methods: Fifty-five consanguineous families, with children shorter than -2.3SDS at the time of examination (median height -3.3SDS, range -2.3 to -15SDS), who were examined at the endocrine outpatient clinic of the Department of Pediatrics, Sulaymani University College of Medicine between January 2018 and February 2020, were included in the study. In families with more than one child with short stature, the shorter sibling was selected as the proband (median age 8 years, range 1 - 15 years). Three probands were subsequently excluded due to the diagnosis of Turner’s syndrome and Edward’s syndrome. Consent was obtained from all families and probands’ DNA was analyzed by Whole Exome Sequencing (WES) methods. The data were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Selected potentially pathogenic variants were confirmed using Sanger sequencing methods and evaluated by the American College of Medical Genetics (ACMG) standards and guidelines. Results: A monogenic cause of short stature, which explained the patient phenotype, was elucidated in 13 of 26 families who were analyzed thus far. Seven families had multiple affected children making a total of 22 patients with a positive genetic diagnosis. Pathogenic or likely pathogenic variants (according to the ACMG standards) were found in genes involved in the GH-IGF-1 axis (GHR), in the extracellular matrix of the growth plate (COL1A2, MMP13, LTBP3, and ADAMTS17), in the regulation of chondrocytes (NPR2 and CTSK), transporter coding genes (SLC34A3), and other genes (PTCH1, GALNS, DNACJ21, ZSWIM6, GNPTG). Among them, there are 9 novel variants and 10 homozygous variants including variants in genes causing syndromic short stature. Unexpectedly, we successfully identified three cases of autosomal dominant short stature (variants in genes NPR2, COL1A2, PTCH1) as well. The remaining probands from 26 families are still being analyzed. Conclusion: With the help of NGS methods, we have successfully elucidated the genetic cause of short stature in nearly 50% of patients who were analyzed thus far. These results further strength the concept that genes affecting the growth plate (chondrocytes and the extracellular matrix) play a crucial role in growth regulation. Acknowledgements: The study was co-funded by grants AZV 18-07-00283 and GAUK 340420.?? 

Growth Plate Genes Are Key Regulators of Growth: Lessons Learned From Children of Consanguineous Families From Kurdistan, Iraq

Surgical approach of atypical genitalia according to adult patients with Differences of Sexual Development. Introduction: Differences of sexual development (DSD) define congenital diseases in which there is an atypical development of chromosomal, gonadal or anatomical sex, and may present varying degrees to genital atypia. There has been a discussion about the ideal time for surgical approach of atypical genitalia. S, because some non-governmental entities argue that the surgical approach should be delayed until adulthood after the patient's consent. Objective/methodology: To analyze the perspectives of adult DSD patients followed at a reference center in São Paulo on the surgical approach to correct atypical genitalia, through a semi-directed interview. Results: Thirty-seven adult patients with atypical genitalia were interviewed. Patients’ mean age was 36 years. 70% of them had atypical genitalia diagnosed at birth. The patients’ median age at the genitoplasty approach was 5 years (1 to 35 years). The median time interval between the beginning of the follow-up at the referral center and the surgical procedure was 1.9 years. When asked about the ideal period/age for genitoplasty, 72.2% considered the childhood, 16.7% cited when they’re teenagers, 8.3% in adulthood and 2.8% did n’t know. The discomfort reported by the patients related to atypical genitalia decreased after the surgical approach: from 3.8 to 2.9 p < 0.01 (on a scale of 1 “without discomfort’ to 4 “extreme discomfort”). Insecurity about the appearance of genitalia and functionality during sexual intercourse influences negatively affective relationships. Four (10.8%) patients presented gender dysphoria, all of them with 46 ,XY DSD, three with partial gonadal dysgenesis (all approached surgically before being admitted to our referral service) and one with 5-alpha-reductase 2 deficiency. Conclusion: Most 46 ,XY DSD patients considered childhood the ideal time to correct their atypical genitalia. An early follow-up in a reference center and an adequate evaluation by a multidisciplinary may influence the positive results associated to the surgical approach of the atypical genitalia in childhood and the low prevalence of gender dysphoria in adulthood.?? 

Self-Reported Feelings of Adult Patients With Differences of Sex Development (DSD) Regarding Genital Surgical Procedures

Gnas Heterozygous Inactiviation Affects Calcitonin Receptor Bioactivity in a Mouse Model of Albright Hereditary Osteodystrophy based upon Parental Inheritance

Introduction: In the United States, non-Hispanic white (NHW) children are disproportionately over-represented relative to children of racial and ethnic minorities in pediatric growth hormone (GH) treatment registries. This study sought to determine if this racial inequity is due to differences in GH stimulation testing and/or GH prescribing patterns in children referred for endocrine evaluation of short stature.?Methods: Retrospective chart review was performed including children aged 2-16 years, with height z-score ≤ -1.5, and of NHW, non-Hispanic black (NHB) or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 1, 2012 and December 31, 2019. Age, sex, anthropometry, GH stimulation test results and GH treatment data were extracted. Comparisons between NHB, NHW and Hispanic children were performed using analysis of variance, chi-squared tests, Mann Whitney U and logistic regression tests.?Results: This study included 7,425 patients (5,905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI 1.04 - 1.8) times more likely than NHB children and 1.7 (95% CI 1.2 - 2.2) times more likely than Hispanic children to undergo GH stimulation testing. NHB children treated with GH had: 1) lower median peak GH concentration when compared with NHW (p=0.02) and Hispanic (p=0.08) children (NHB 4.7 [1.2, 8.3] ng/ml, NHW 7.2 [4.9, 9.7] ng/ml, Hispanic 7.1 [4.3, 11.9] ng/ml); 2) lower median height z-scores than NHW (p=0.01) but not Hispanic children (p=0.5); and 3) a greater height deficit from mid-parental height when compared with NHW (p=0.01) and Hispanic (p=0.002) children?Discussion: Racial and ethnic disparities are present in the evaluation and treatment of children with disordered growth. This likely results from both over-investigation of NHW children as well as under-investigation and under-treatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is unfortunately not current practice.?? 

Racial/Ethnic Disparities in the Investigation and Treatment of Pediatric Growth Hormone Deficiency

Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety, and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS.?Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8.?Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient.?In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.?? 

Topline Results of the CARE-PWS Phase 3 Study: Intranasal Carbetocin Improves Hyperphagia and Anxiety and Distress Symptoms in Prader-Willi Syndrome (PWS)

The timing of puberty in females is highly sensitive to metabolic cues and energy reserves. Epidemiologic studies indicate a relationship between increased body mass index and earlier puberty in girls. In contrast, a significant delay in puberty and menarche is seen in girls who have diminished body fat. Multiple peripheral hormones are responsible for transmitting metabolic information to hypothalamic kisspeptin and GnRH neurons. Sufficient levels of leptin, an adipose tissue hormone with a permissive/stimulatory effect on the metabolic control of reproduction, are required for puberty onset, reproductive function and fertility. Loss-of-function mutations in the Delta-like homolog 1 (DLK1) gene have been described in girls with central precocious puberty (CPP) and increased body fat, suggesting a link between metabolism and reproduction. DLK1 is a paternally expressed gene located on human chromosome 14q32.2 in a locus associated with Temple syndrome (TS). Dlk1 knockout mice display pre- and postnatal growth retardation, a phenotype that overlaps with TS. We have shown that Dlk1 deficient female mice achieved puberty at the same age as wild type mice, despite a considerably lower body weight (BW) (“relative precocious puberty”). To date, the mechanisms of action of Dlk1 in determining pubertal onset remain unknown. In this study, we used a Dlk1 deficient mouse model to explore the influence of Dlk1 in the regulation of reproductive axis, particularly its effects on leptin and/or kisspeptin, a major excitatory factor of the reproductive axis. By RT-qPCR and Western blot, we confirmed that both Dlk1 mRNA and protein were undetectable in the mediobasal hypothalamus (MBH) of Dlk+/p- (which inherited the mutant allele from their father), but it was present in Dlk+/+ mice. White adipose tissue (WAT) and blood were collected from Dlk+/p- and Dlk+/+ female mice at postnatal day (PND) 26, and MBH tissue was obtained from both groups at PND 15, 26 and 60. Quantification of total WAT showed no significant difference between Dlk1+/p-and Dlk1+/+ mice (p=0.8) at PND26, even after correction for total BW (p=0.29). Hypothalamic mRNA levels of Kiss1 and Socs3, a downstream mediator of leptin signaling, were measured by RT-qPCR. Kiss1 mRNA levels were significantly reduced in the MBH of Dlk1+/p- mice at PND15 and PND60, but no significant difference was found at PND 26. Socs3 expression was significantly lower in Dlk1+/p- mice (p=0.04) as a result of the reduced circulating levels of leptin (ELISA) observed in these mice at PDN26 (p=0.01). Our findings suggest that the absence of Dlk1 may attenuate the metabolic effects of low body weight and low leptin levels on puberty onset and that, as seen in humans, DLK1 is an important link between body weight and pubertal development. Finally, Dlk1 deficiency leads to activation of the reproductive axis despite lower levels of kisspeptin.?? 

Metopirone Treatment in Endogenous Cushing's Syndrome Results from a Prospective Multicenter, Open-Label, Phase III/IV Study: PROMPT

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