United States

Background: Patients with hypopituitarism can have a complete or partial deficiency of pituitary hormones. If not treated adequately, it can result in episodes of myxedema coma or adrenal crisis. Our patient was unique with findings of both myxedema coma and adrenal crisis together on initial presentation.
Clinical Case: A 35-year-old female with a medical history of Sheehan&#39;s Syndrome, transient diabetes insipidus and lyme carditis presented to the emergency department with dizziness, lethargy, and generalized weakness for 1 day. EMS found her blood glucose level to be 21. The patient was given oral glucose. In the ED, her blood glucose level was found to be 34. She confessed she had been noncompliant with her medications for a month. She had no other complaints or possible precipitating factors including illness/trauma/stress. On admission, she was found to be hypothermic to 91.3 deg F, bradycardic to 40-50s, and hypotensive (Systolic 80s-90s/diastolic 50s-60s). On physical examination, she was thin and lethargic but oriented. No gross focal neurological deficits were noted. In addition to the initial hypoglycemia, her laboratory findings were significant for a TSH level of 0.52, T3 level of &lt;30, T4 level of &lt;0.5, eosinophilia as well as normal sodium levels. The sepsis workup was negative. Her VBG showed mild respiratory acidosis. For the myxedema coma and adrenal crisis, she was initially given hydrocortisone 100 mg and levothyroxine 200mcg. Her hypoglycemia improved after administration of these medications and intravenous fluids of dextrose-normal saline. The endocrinology service was consulted, and the patient was admitted to the ICU for monitoring. The next day her hypothermia, hypotension resolved and her lethargy, weakness improved. Once she was stabilized in the ICU, she was transferred to the floors. For the myxedema coma, once stable, she was started on oral levothyroxine 100mcg in accordance with weight-based dosing (1.6 mcg/kg daily) on the following day. Her free T4 level improved from 0.48 to 0.56 to 0.72. Her T3 level improved from &lt;30.0 to 42.7. For the adrenal crisis, after the initial dose of IV hydrocortisone 100mg, it was tapered down to IV hydrocortisone 50 mg, then switched to oral prednisone daily. Eosinophilia from admission was mild which resolved later. Additional management of her history of Sheehan&#39;s Syndrome, her levels of LH 0.5, FSH 1.2, Estradiol &lt;5, and Prolactin 0.6 were all low, so was advised to follow up with hormone replacement therapy outpatient.
Conclusion: This is an interesting case presentation of myxedema coma and adrenal crisis in a patient with a history of Sheehan&#39;s Syndrome. It is important to consider the unique and similar presentations of both myxedema coma and adrenal crisis such as hypotension, bradycardia, hypothermia, hypoglycemia, and lethargy.

ENDO 2022

Unique Case of Combined Presentation of Myxedema Coma and Adrenal Crisis in a Patient With Hypopituitarism or Post Sheehan&#39;s Syndrome

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Background: Patients with hypopituitarism can have a complete or partial deficiency of pituitary hormones. If not treated adequately, it can result in episodes of myxedema coma or adrenal crisis. Our patient was unique with findings of both myxedema coma and adrenal crisis together on initial presentation.
Clinical Case: A 35-year-old female with a medical history of Sheehan's Syndrome, transient diabetes insipidus and lyme carditis presented to the emergency department with dizziness, lethargy, and generalized weakness for 1 day. EMS found her blood glucose level to be 21. The patient was given oral glucose. In the ED, her blood glucose level was found to be 34. She confessed she had been noncompliant with her medications for a month. She had no other complaints or possible precipitating factors including illness/trauma/stress. On admission, she was found to be hypothermic to 91.3 deg F, bradycardic to 40-50s, and hypotensive (Systolic 80s-90s/diastolic 50s-60s). On physical examination, she was thin and lethargic but oriented. No gross focal neurological deficits were noted. In addition to the initial hypoglycemia, her laboratory findings were significant for a TSH level of 0.52, T3 level of <30, T4 level of <0.5, eosinophilia as well as normal sodium levels. The sepsis workup was negative. Her VBG showed mild respiratory acidosis. For the myxedema coma and adrenal crisis, she was initially given hydrocortisone 100 mg and levothyroxine 200mcg. Her hypoglycemia improved after administration of these medications and intravenous fluids of dextrose-normal saline. The endocrinology service was consulted, and the patient was admitted to the ICU for monitoring. The next day her hypothermia, hypotension resolved and her lethargy, weakness improved. Once she was stabilized in the ICU, she was transferred to the floors. For the myxedema coma, once stable, she was started on oral levothyroxine 100mcg in accordance with weight-based dosing (1.6 mcg/kg daily) on the following day. Her free T4 level improved from 0.48 to 0.56 to 0.72. Her T3 level improved from <30.0 to 42.7. For the adrenal crisis, after the initial dose of IV hydrocortisone 100mg, it was tapered down to IV hydrocortisone 50 mg, then switched to oral prednisone daily. Eosinophilia from admission was mild which resolved later. Additional management of her history of Sheehan's Syndrome, her levels of LH 0.5, FSH 1.2, Estradiol <5, and Prolactin 0.6 were all low, so was advised to follow up with hormone replacement therapy outpatient.
Conclusion: This is an interesting case presentation of myxedema coma and adrenal crisis in a patient with a history of Sheehan's Syndrome. It is important to consider the unique and similar presentations of both myxedema coma and adrenal crisis such as hypotension, bradycardia, hypothermia, hypoglycemia, and lethargy.

Unique Case of Combined Presentation of Myxedema Coma and Adrenal Crisis in a Patient With Hypopituitarism or Post Sheehan's Syndrome

technical paper

The anterior pituitary controls growth, metabolism, reproduction and stress responses through the synthesis and secretion of specific hormones. Distinct cell lineages within the anterior pituitary generate specific hormones. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. Our recent work has implicated the stem cell determinant and sequence-specific mRNA binding protein, Musashi, as a regulator of pituitary cell plasticity. The mechanisms by which Musashi controls pituitary cell plasticity are unknown. In this study, we have sought to identify the mRNA regulatory targets of Musashi in the adult mouse pituitary. Through the use of Musashi-RNA-immunoprecipitation we report a cohort of 1192 pituitary mRNAs that specifically interact with Musashi. mRNAs specific to each of the hormone-producing cell lineages were identified, as well as mRNAs specific to immature stem and progenitor cell lineages. The biological pathways encoded by the Musashi-enriched mRNAs include cell adhesion, cellular homeostasis, unfolded protein responses, protein trafficking, endocrine processes and female pregnancy. Functional analysis of validated mRNAs reveals both activating and inhibitory control of mRNA translation by Musashi. Together, our findings indicate a broad and complex role for Musashi in the post-transcriptional regulation of adult pituitary function.

Insight into Integrated Control of Pituitary Function Revealed Through Analysis of Musashi Target mRNAs

Medical treatment of acromegaly is based on either suppressing pituitary GH secretion or inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of IGF1. AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) with a KD of 1.9nM for the human GHR, and 18.5nM for the rat GHR. The circulating half-life of AZP-3813 in the rat is 11.2 hours. In previous studies, AZP-3813 was demonstrated to suppress IGF1 secretion in juvenile rats in a dose-related manner, and to maintain IGF1 suppression when given over 4 days. To examine the ability of chronic AZP-3813 treatment to maintain suppression of IGF1 levels, we injected normal, 5-week old (~150g), male Sprague Dawley rats subcutaneously either with vehicle or with AZP-3813 at doses of either 10 or 30mg/kg QD for 19 days (n=7/group). Blood samples were collected immediately prior to either vehicle or AZP-3813 injection on days 1, 2, 3, 7, 10, 15 and 19, and 24h after the last injection (day 20). Samples were assayed for total IGF1 content by radioimmunoassay, and samples collected on days 2, 10 and 19 were also analyzed for AZP-3813 content by LC-MS/MS. At the initiation of treatment, the average body weight of the rats was 150.3 + 3.0g, and over the 20 days of the study animals treated with vehicle gained an average of 158.4 + 4.9g. In contrast, rats treated QD with 10 or 30mg/kg AZP-3813 gained 23.6 + 2.1 and 27.9 + 2.2% less weight than the vehicle-treated controls, respectively. Accumulation of AZP-3813 levels in the blood was observed with repeated daily injections of both 10 and 30mg/kg, increasing from day 2 levels by 107.1 + 12.5 and 125.2 + 36.3%, respectively, by day 19. In the vehicle-treated control rats, IGF1 levels increased from an initial 395.1 +16.3ng/ml to 674.4 + 19.8ng/ml by day 20. Twenty-four hours after the first injections of 10 and 30mg/kg AZP-3813, IGF1 levels were suppressed by 27.6 + 3.4 and 29.2 + 3.3%, respectively, versus vehicle-treated control levels, and, with continued treatment, a similar magnitude of IGF1 suppression was maintained through day 20 despite the progressively increasing levels of IGF1 observed in the vehicle-treated rats. At study termination on day 20, animals treated with 10 and 30mg/kg AZP-3813 were observed to have 4.1 and 4.6% shorter femur length, 1.1 and 3.6% shorter body length, and 7.7 and 13.3% less liver weight, respectively, as compared with vehicle-treated control rats. These results demonstrate that with continued treatment, the potent GHR antagonist activity exhibited by AZP-3813 translates to sustained in vivo suppression of IGF1 levels and associated parameters, and support its development as a potential therapy for acromegaly.

Sustained Suppression of IGF1 with AZP-3813, a Bicyclic 16-Amino Acid Peptide Antagonist of the Human Growth Hormone Receptor and a Potential New Treatment for Acromegaly

Introduction:
Diabetes insipidus (DI) is a rare complication of subarachnoid hemorrhage (SAH) and associated with worse prognosis and increased mortality. We present a case of combined nephrogenic and central DI together with osmotic diuresis as a result of SAH and discuss the pathophysiology.
Case:
A 63-year-old female without significant past medical history was found unresponsive. CT head followed by angiography confirmed extensive SAH arising from a saccular anterior communicating artery (Acoma) aneurysm. She underwent emergent coil embolization and right frontal external ventriculostomy drain placement. Postoperatively, she developed polyuria (300-400 mL/hour) and hypernatremia (156 mEq/L) concerning for the development of DI. Serum osmolality was elevated at 316 mOsm/kg, urine osmolality inappropriately low relative to serum osmolality at 289 mOsm/kg but also unexpectedly high for complete DI, serum potassium 2.9 mEq/L and urine potassium elevated urine at 9 mEq/L. Serum copeptin was 6 pmol/L and inappropriately low for nephrogenic DI, suggesting a mixed central and peripheral process as well as contribution from osmotic diuresis. Intravenous (IV) desmopressin (DDAVP) only slightly reduced the polyuria. Management was complicated by adypsia and persistent hypokalemia requiring ongoing replacement. IV fluid, which had initially consisted of high-osmolality Plasma-Lyte (294 mOsm/L), matched to urine output, was switched to D5W, leading to a significant decrease in polyuria. On post-operative day 17, DDAVP was discontinued with normalization of sodium (137 mEq/L), potassium (3.8 mEq/L) and urine output. Three months post-operatively, she was asymptomatic with intact pituitary function and no hypokalemia.
Discussion:
Hypokalemia in patients with SAH is thought due to acute intracellular shift of potassium caused by excessive β2-adrenergic activity generated endogenously by the sympathetic nervous system. In our patient, there was also likely contribution from distal tubular delivery of sodium from osmotic diuresis, leading to increased urinary potassium losses and hypokalemia-induced partial nephrogenic DI which was further complicated by partial central DI as suggested by the inappropriately low copeptin level for nephrogenic DI in face of a high serum osmolality and inappropriately low urine osmolality. As the vascular supply to anterior hypothalamus is derived from the Acoma, rupture may compromise perfusion affecting neuronal populations in the lamina terminalis that regulate thirst and AVP secretion in response to hyperosmolarity. Early detection of DI is critical because hypovolemia can predispose to cerebral vasospasm and worsen outcomes. This case also depicts the importance of careful consideration of sources of osmolar loads such as the composition of administered IV fluids, and aggressive potassium replacement to maintain DDAVP sensitivity.
Conclusion:
DI should be considered in polyuria syndrome with hypernatremia after a neurosurgical event. Nephrogenic and central DI and adypsia can manifest following SAH, with sources of iatrogenic osmolar load further complicating the clinical picture. Early recognition and treatment may reduce morbidity and mortality.

Subarachnoid Hemorrhage Complicated by Nephrogenic and Central Diabetes Insipidus

Background
Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD.
Methods
Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available.
Results
A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of >14 years (girls) or >16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals.
Conclusions
Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy.

Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial

BACKGROUND:
Somatrogon is a long-acting recombinant human growth hormone (hGH) currently in development as a once-weekly injectable treatment for children with growth hormone deficiency (GHD). In a phase 2 (NCT01592500) and a phase 3 (NCT02968004) study, patients received either once-weekly somatrogon or once-daily Genotropin.

AIMS:
Compare the phase 2 and 3 study results with growth data from published literature and a database of children treated with once-daily Genotropin.

METHODS:
In the 12-month main portion of the phase 2 study (004), patients were randomized to 1 of 3 once-weekly somatrogon doses (0.25, 0.48, and 0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 004, patients continued into the open-label extension (OLE), consisting of an additional 12 months at the original somatrogon dose (Genotropin recipients were randomized to 1 of the 3 somatrogon dose regimens), after which all patients received somatrogon at 0.66 mg/kg/week. In the 12-month main portion of the phase 3 study (006), patients were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 006, all patients received somatrogon (0.66 mg/kg/week) in an OLE. Four year growth data from 004 and 006 were pooled and analyzed, then compared with growth data from matched subsets of hGH-treated patients as reported by Ranke and Lindberg1 (Genotropin dose: 0.22-0.31 mg/kg/week) and Bakker et al,2 (hGH dose: most patients received 0.3 mg/kg/week) and with data from a matched cohort from the Pfizer International Growth Study Database (KIGS), in which patients received once-daily Genotropin (0.20-0.28 mg/kg/week).

RESULTS:
The combined mean height velocity (HV) at the end of the 12-month main portions of study 004 and 006 was 10.37 cm/year for somatrogon-treated patients. The Year 1 mean HV reported by Ranke and Lindberg for children with a chronological average-centered age of 7.5 years was 9.4 cm/year and 8.3 cm/year for children with severe and moderate GHD, respectively. The Year 1 mean HV reported by Bakker et al for children with idiopathic GHD aged 7.5 years at the beginning of hGH therapy was ~10 cm/year (for males and females). The mean annual HVs during the OLE period were 9.37, 8.97, and 9.03 cm/year at OLE Year 1, 2 and 3 in somatrogon-treated patients, which were numerically greater than HVs of 7.09, 6.35, and 6.08 cm/year at the corresponding annual visit in the matched KIGS cohort (Genotropin dose: 0.20–0.28 mg/kg/week).

CONCLUSIONS:
Comparisons with published literature and the KIGS database indicate that children treated with once-weekly somatrogon (0.66 mg/kg/week) showed good growth, compared with children treated with once-daily hGH, strengthening the expectation that somatrogon-treated children are likely to achieve a satisfactory final adult height.

References
1.Ranke and Lindberg. JCEM. 2010;95(3): 1229-1237.
2.Bakker, Frane, et al. JCEM. 2008;93(2): 352-357.

Growth outcomes from the phase 2 and phase 3 studies of once weekly somatrogon vs daily genotropin in pediatric patients with growth hormone deficiency: comparisons with published literature and an international growth study database

The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD.

REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension.

At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively.

During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in <10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group.

In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified.

Once-Weekly Somapacitan in Growth Hormone Deficiency: 4-Year Efficacy and Safety Results from REAL 3, a Randomised Controlled Phase 2 Trial

Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial.
The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters.
Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups.
In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment.

Once-Weekly Somapacitan Versus Daily Growth Hormone in Children Born Small for Gestational Age: Results From a Randomized Phase 2 Trial

Background
MRIs of the brain in patients with short stature have shown a number of abnormalities. Some of these radiological findings can have clinical significance. Here we have looked at MRI results in such a population.

Objective
To review the value and significance of the prevalence of all abnormal MRI findings of children with short stature who are to undergo growth hormone therapy (GHT).

Materials and methods
This study involved a retrospective review of MRI findings in all children prescribed GHT within a pediatric health network's database from Jan 2020 to Aug 2021. Post-gadolinium contrast enhanced brain and pituitary MRIs utilizing 2 mm slices were used to calculate pituitary volume. Pituitary volume was calculated using the ellipsoid formula (LxWxH/2). Pediatric patients diagnosed with non-acquired GHD or ISS, with MRIs having been performed between Jan 2020 and Aug 2021 and having been prescribed GHT by Aug 2021 were included in this study. Patients who experienced other endocrine abnormalities such as SGA, Turner Syndrome, and Noonan Syndrome were excluded. Patients with obstruction of sellar and parasellar religion due to movement artifacts or magnetic interference on their MRIs were also excluded.

Results
Of one hundred and twelve patients found, eighty one met criteria for inclusion in this study. Of the eighty one MRIs reviewed, twenty eight children, 34.6%, had normal pituitary anatomy and fifty three, 65.4%, had a pituitary abnormality. Out of the fifty three with a pituitary abnormality, forty three subjects, 81.1%, were determined to have a small pituitary volume, including significant pituitary hypoplasia. Ten subjects (18.9%) had an enlarged pituitary volume (pituitary hyperplasia). Of these ten patients who had an enlarged pituitary volume, eight were pubertal (80%). Nine children with a pituitary abnormality (16.9%) had additional structural anomalies on their MRIs. One had a small left frontal developmental venous anomaly. Two had Rathke's cleft cysts. Two had pars intermedia cysts. One had a small right parietal developmental venous anomaly. One had a small left parietal developmental venous anomaly. One had a left cerebellar tonsillar ectopia bordering on chiari malformation (.5 mm away on the coronal plane). One had a small lobulation (semi-bulbous projection) of the anterior pituitary gland, superior and anterior to the infundibular stalk.

Conclusion
Prevalence of brain abnormalities in children with short stature who are to undergo GHT is significant and warrants MRI evaluations in these subjects.

The Prevalence of Abnormalities in Cranial MRIs in Children with Short Stature Prior to Growth Hormone Therapy

Background: Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study.
Methods: Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms.
Results: A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference.
Conclusions: The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition.

Medical History of Children Enrolled in PROPEL: A Prospective Clinical Assessment Study in Children with Achondroplasia

Background: Families often seek medical care for a child's short stature due to concerns about how short stature affects psychosocial function in childhood and projected into adulthood. However, height is a poor predictor of psychosocial adjustment, and there is a critical gap in our understanding of how patient and parent characteristics alter the potential impact of being short.
Hypothesis: We hypothesized that among healthy youth undergoing medical evaluation for short stature, youth quality of life (QoL) and self-esteem would be associated with youth and parental characteristics rather than height.
Methods: Healthy youth aged 8-14 years who underwent provocative GH testing in our Growth Center and a parent participant each completed surveys at or around the time of testing. Surveys collected demographic data; youth and parent report of youth health-related QoL (PedsQL and Quality of Life in Short Stature Youth [QoLISSY]); youth reports of self-esteem (Self-Perception Profile for Children [SPP]), coping skills (Coping Strategies Inventory), and social support (Social Support Scale for Children); and parent reports of perceived environmental threats (World Out There), goals for their child (Achievement Goals), and autonomy support (Parents As Social Context Questionnaire). Clinical data were extracted from the patients' electronic health records. Continuous variables were summarized as mean ± SD. Univariate models with Holm-Bonferroni correction of significance level 0.05 assessed the marginal effect of each factor on QoL and self-esteem outcomes. Multivariable linear regression models with stepwise selection approaches were used to identify significant predictors of QoL and self-esteem.
Results: Participants included 60 youth (15 female/45 male; age 11.77 ± 1.93 years; 50% prepubertal, 37% Tanner 2, 13% Tanner 3; height Z-score -2.18 ± 0.61) and their parents (55 female/5 male; age 45.65 ± 7.25 years). In multivariable regression, the youth PedsQL physical domain was associated positively with grade in school and perceived friend support. The youth PedsQL psychosocial domain was associated positively with perceived support from classmates and friends, but negatively with disengaged coping. The youth QoLISSY total score was associated positively with perceived support from classmates. Youth's global self-esteem (SPP) was associated positively with perceived classmate support and mid-parental height Z-score. Parent report of youth psychosocial QoL (PedsQL) was associated positively with perceived classmate support. None of the other analogous parent assessment outcomes were associated with the QoL or self-esteem outcomes. Neither youth height nor height Z-score was associated with any of the QoL or self-esteem outcomes.
Conclusions: Perceived social support and coping skills were associated with QoL and self-esteem in healthy short youth, whereas youth height was not, and constitute an important potential area of clinical intervention.

Unique Case of Combined Presentation of Myxedema Coma and Adrenal Crisis in a Patient With Hypopituitarism or Post Sheehan's Syndrome

Downloads

Next from ENDO 2022

Insight into Integrated Control of Pituitary Function Revealed Through Analysis of Musashi Target mRNAs

Similar lecture

Late Breaking Tools and Targets in Basic Endocrinology Research

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES