Genetic testing for familial hyperaldosteronism type 1 in Aotearoa/New Zealand.

BACKGROUND: Primary aldosteronism (PA) is the most common secondary endocrine cause of hypertension with familial hyperaldosteronism type 1 (FH-1), a rare heritable subtype. Timely identification of FH-1 is important because of an increased risk of vascular events in affected individuals and because it provides the opportunity to guide appropriate treatment. Genetic testing is recommended if onset is at a young age (<20 years), there is a family history of PA or early cerebrovascular events occur. AIMS: To assess national rates of testing for FH-1, whether this varied over time and by region. METHODS: De-identified data were obtained on genetic testing performed for FH-1 from 1 April 2010 to 30 October 2023 (163 months) from the Canterbury Health Laboratories database, the sole national testing laboratory for FH-1. RESULTS: A total of 147 tests were performed, of which 19 (12.9%) were positive. Eleven of the positive tests were requested by one region. Testing rates varied from 0.00 to 0.63 per 100 000 people per annum. Most tests were requested by endocrinology services. Testing increased over time from an average of 4.6 tests per annum in the first 5 years of the period studied to 17.7 tests in the most recent 5 years. Limitations include lack of ethnicity data, information on testing indications and testing rates for other familial PA subtypes. CONCLUSIONS: Testing for FH-1 has increased over time but remains low. Testing for familial forms of PA should be considered in those in whom PA was diagnosed at a young age or with a suggestive family history.

Increased Admissions Due to Cardiac Complications of Thyrotoxicosis in Maori.

BACKGROUND: As thyrotoxicosis is a risk factor for atrial fibrillation, current guidelines recommend measuring a thyroid-stimulating hormone level in patients with this disorder. Hyperthyroidism may also be associated with other heart diseases including cardiac ischaemia and cardiac failure. Currently, the prevalence of thyrotoxicosis in cardiac admissions in the absence of a rhythm disorder is unknown. AIMS: The aims of this study were: 1) to calculate the prevalence of admissions for thyrotoxicosis-associated cardiac disease, 2) determine the type of cardiac disease i.e. dysrhythmic, ischaemic or cardiac failure, and 3) to assess whether Maori are over-represented amongst patients admitted to hospital with cardiac complications of thyrotoxicosis. METHODS: A retrospective review of admissions with both thyrotoxicosis and cardiac disease from 1 January 2005 to 31 December 2012 inclusive. RESULTS: Seventy-two patients were identified as being admitted for a cardiac complication of thyrotoxicosis, giving a mean of nine admissions per year. Dysrhythmia was the cause for admission in 32 patients, ischaemia in 12, cardiac failure in 11 and mixed cardiac disease in 17. Graves' disease and amiodarone-induced were the most common causes of the thyrotoxicosis (25 and 19 cases, respectively). Of the cohort 26 (36.1%) were Maori (compared to 16.8% of all cardiac admissions over the same period). Maori were more likely to present with cardiac failure than non-Maori (57.7% vs. 26.1%, p=0.008 respectively). CONCLUSIONS: Maori are over-represented amongst patients admitted with cardiac complications of thyrotoxicosis and more often present with cardiac failure than non-Maori. Measurement of thyroid function should be considered in patients presenting not only with atrial fibrillation but also in patients presenting with cardiac failure, particularly if they are Maori.

Treatment choice, satisfaction and quality of life in patients with Graves' disease.

BACKGROUND: Thyrotoxicosis, most often caused by Graves' disease (GD), when treated inadequately may result in premature mortality. There is little consensus as to which of the 3 treatment options available - antithyroid drugs (ATD), radioactive iodine (RAI) and surgery, is better. AIMS: (i) To assess factors involved in treatment choice and treatment satisfaction in patients treated for Graves' disease; (ii) To assess quality of life (QoL) following treatment of Graves' disease. METHOD: Participants were selected from a prospective study cohort assessing thyrotoxicosis incidence and severity. Of the 172 eligible patients with Graves' disease, 123 treated patients participated (64% had received ATD only, 11% RAI and 25% total thyroidectomy, the latter 2 usually after a period of ATD), along with 18 untreated patients with newly diagnosed Graves' disease (overall participation rate, 73%). Consented patients completed a questionnaire detailing factors involved in treatment choice, QoL and satisfaction with treatment. RESULTS: Participants reported that the most important factors in choosing a treatment were the following: the effects on activities of daily living, concern about use of radioiodine, possibility of depression or anxiety, and doctor's recommendations. Satisfaction levels were high across all 3 treatment types. QoL 1-year following treatment was higher than in untreated patients, and comparable with other international studies. CONCLUSIONS: Patient satisfaction with therapy and QoL does not differ by treatment type. Therefore, clinical and social factors, in combination with patient choice and resource availability, should determine which treatment modality patients with Graves' disease should receive.

Absence of Myostatin Improves Cardiac Function Following Myocardial Infarction.

BACKGROUND: Myostatin inhibits the development of skeletal muscle and regulates the proliferation of skeletal muscle fibroblasts. However, the role of myostatin in regulating cardiac muscle or myofibroblasts, specifically in acute myocardial infarction (MI), is less clear. This study sought to determine whether absence of myostatin altered left ventricular function post-MI. METHODS: Myostatin-null mice (Mstn-/-) and wild-type (WT) mice underwent ligation of the left anterior descending artery to induce MI. Left ventricular function was measured at baseline, days 1 and 28 post-MI. Immunohistochemistry and immunofluorescence were obtained at day 28 for cellular proliferation, collagen deposition, and myofibroblastic activity. RESULTS: Whilst left ventricular function at baseline and size of infarct were similar, significant differences in favour of Mstn-/- compared to WT mice post-MI include a greater recovery of ejection fraction (61.8±1.1% vs 57.1±2.3%, p<0.01), less collagen deposition (41.9±2.8% vs 54.7±3.4%, p<0.05), and lower mortality (0 vs. 20%, p<0.05). There was no difference in the number of BrdU positive cells, percentage of apoptotic cardiomyocytes, or size of cardiomyocytes post-MI between WT and Mstn-/- mice. CONCLUSIONS: Absence of myostatin potentially protects the function of the heart post-MI with improved survival, possibly by limiting extent of fibrosis.

A low incidence of iodine-induced hyperthyroidism following administration of iodinated contrast in an iodine-deficient region.

OBJECTIVE: There are limited data on the incidence of iodinated contrast-induced thyrotoxicosis, particularly in iodine-deficient regions. The aim of this study was to determine the incidence of iodinated contrast-induced thyrotoxicosis and to determine whether thyrotoxicosis was more common in patients ≥70 years compared to those <70 years of age. DESIGN: A prospective study of adult patients undergoing an outpatient CT with iodinated contrast was performed. MEASUREMENTS: Thyroid function tests (TFTs) and urine iodine measurements were performed prior to the scan. TFTs were repeated at 4- and 8-weeks postscan. Changes in TFTs from baseline were analysed. RESULTS: A total of 102 patients were included in the final analysis. Overall, TSH levels dropped (P = 0·0002), and free T3 (FT3 ) levels increased (P = 0·04) between baseline and week 4 with normalization by week 8; however, these changes were not considered clinically significant. No significant differences in free T4 (FT4 ) occurred in the overall group (P = 0·82). There were no differences in TFTs between baseline and 4 or 8 weeks for those patients aged <70 compared to ≥70 years. Two patients developed new subnormal TSH values. Of these, one had a 90-mm follicular variant papillary thyroid carcinoma diagnosed while the other had a normal thyroid assessment and TSH spontaneously normalized by 12 weeks. CONCLUSIONS: Only 2% of patients developed subclinical hyperthyroidism following a standard dose of iodinated contrast for CT investigations. Given the low incidence of iodine-induced thyrotoxicosis, there is no indication for routine pre- and post-CT thyroid function testing in our region.

Retrospective investigation of testosterone undecanoate depot for the long-term treatment of male hypogonadism in clinical practice.

INTRODUCTION: Testosterone undecanoate depot (TUD) administered intramuscularly is an effective form of testosterone replacement therapy (TRT) for male hypogonadism. Because of the ease of administration, TUD therapy may be preferable to subcutaneously implanted extended release T pellet implants (TI). AIM: The primary objective was to retrospectively assess the efficacy and safety of long-term (≥ 2 years therapy) TUD therapy in the clinical setting. The secondary objective was to retrospectively compare TUD with TI therapy. METHODS: Retrospective data were collected from the Waikato Hospital Endocrine Database for 179 hypogonadal men treated with TUD for ≥ 2 years from 1998-2011, with 124 of these men receiving previous TI therapy. MAIN OUTCOME MEASURES: The main outcome measure for efficacy was serum trough total testosterone (TT), and for safety an increase in hemoglobin (Hb) and/or hematocrit (Hct), rise in prostate-specific antigen (PSA) and/or prostatic biopsy and alteration in body mass index and lipid profile. Additional outcome measures were changes in the dosing and/or interval regimens for TUD therapy. RESULTS: Overall, 72% of trough TT levels were in the normal range for TUD therapy compared with 53% of trough TT levels during TI therapy. TUD therapy was well tolerated with 162 men (90.5%) completing 2 years of treatment, and only seven men (3.9%) stopping TUD because of adverse effects. A rise in Hb and/or Hct occurred in 25 men (14%), and a significant rise in PSA in 20 men (13%) at some stage during TUD therapy. At 2 years, 91% of men received the standard 1,000 mg TUD dose with 66% at the standard dosing interval of 10-14 weekly. CONCLUSIONS: TUD is an efficacious, safe, and well tolerated form of TRT, and individual optimisation of the dose and/or interval is only required in the minority of men. Particularly given the ease of administration, TUD was the preferred TRT for both patients and clinicians.

Pregnancy after definitive treatment for Graves' disease--does treatment choice influence outcome?

BACKGROUND: Women requiring thyroid hormone replacement after definitive therapy (surgery or radioiodine) for Graves' disease who later conceive require an early increase in levothyroxine dose and monitoring of thyroid hormone levels throughout pregnancy. In addition, as TSH receptor antibodies (TRAb) can cross the placenta and affect the fetus, measurement of these antibodies during pregnancy is recommended. AIM: To review the management of pregnancies following definitive treatment for Graves' disease in order to assess the rates of maternal hypothyroidism and TRAb measurement. MATERIALS AND METHODS: Retrospective chart review of women who had undergone definitive treatment for Graves' disease at a tertiary hospital and subsequently had one or more pregnancies. RESULTS: A total of 29 women were identified, each of whom had at least one pregnancy since receiving definitive treatment for Graves' disease: there were a total of 49 pregnancies (22 in the surgical group and 27 in the radioiodine group). Both groups had high rates of hypothyroidism documented during pregnancy (47 and 50%, respectively). The surgical group was more likely to be euthyroid around the time of conception. Less than half of the women were referred to an endocrinologist or had TRAb measured during pregnancy. Neonatal thyroid function was measured in one-third of live births. One case of neonatal thyrotoxicosis was identified. CONCLUSIONS: Adherence to the current American Thyroid Association guidelines is poor. Further education of both patients and clinicians is important to ensure that treatment of women during pregnancy after definitive treatment follows the currently available guidelines.

Systematic Review-Type B Insulin Resistance With Isolated Hypoglycemia and Suppressed Insulin.

OBJECTIVE: Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis, characterized by serum autoantibodies to the insulin receptor (AIRAbs). Patients typically present with severe insulin resistance. A mixed hyper- and hypoglycemia phenotype may also occur, as may isolated hypoglycemia. The classic biochemical pattern comprises elevated insulin levels despite hypoglycemia; however, a small proportion of cases demonstrate "isolated hypoglycemia with low insulin." The primary objectives of this systematic review were to identify the clinical characteristics and outcome of this subgroup. DESIGN: Systematic review of cases with hypoglycemia with suppressed insulin. Exclusions: hyperglycemia, elevated insulin, AIRAbs not confirmed. METHODS: PubMed, Medline, and Embase databases were searched up until February 2023 and complemented by manual citation search. The Joanna Briggs Institute critical appraisal checklist for case reports was used to assess bias. RESULTS: A total of 5342 articles were identified after duplicate removal. Eleven, all case reports, met all inclusion criteria and were included. Cases belonging to this subgroup were more diverse in sex, age, and ethnicity when compared with type B insulin resistance as a whole. Of the 11 cases, 3 developed lymphoma. High-dose corticosteroid therapy appeared to be effective therapy for the hypoglycemia, with often rapid response. CONCLUSIONS: Isolated hypoglycemia with low insulin forms a rare subgroup of type B insulin resistance. These patients lack the common characteristics of hyperinsulinemic hypoglycemia and hyperglycemia/insulin resistance. Furthermore, while coexisting autoimmune disease is commonly observed, there is potentially an association with aggressive lymphoma, the onset of which may be delayed.

Systematic Review of Therapeutic Agents and Long-Term Outcomes of Familial Hyperaldosteronism Type 1.

BACKGROUND: Familial hyperaldosteronism type 1 (FH1), previously known as glucocorticoid-remediable aldosteronism, was the first identified monogenic cause of primary aldosteronism. Patients classically develop hypertension at a young age and are at risk of premature vascular complications. A systematic review of FH1 was performed to determine long-term treatment outcomes. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted searches with a patient/population, intervention, comparison and outcomes (PICO) framework using Embase, Medline, PubMed, Scopus, and Web of Science databases to identify patients with FH1 prescribed either no treatment with a minimum 3 months follow-up or medical treatment of at least 3 months duration. RESULTS: A total of 99 FH1 cases were identified from 42 studies. Most had early-onset hypertension but variable hypokalemia, hyperaldosteronism, and hyporeninemia. Of the 62 cases with a reported age of FH1 diagnosis, median age was 18 ± 17.6 years old. Of those treated, 72% received a glucocorticoid for long-term treatment compared with 22% receiving a potassium-sparing diuretic. Data on long-term treatment and disease side effects, complications, and outcomes were seldom reported. However, of 20 patients with reported complications, premature vascular complications were evident with the median age of diagnosis for left ventricular hypertrophy and hypertensive retinopathy 15 and 16.5 years old respectively, the youngest age of aortic dissection age 10 years, and those with reported cerebrovascular history had strokes or transient ischemic attacks before age 40 years. CONCLUSIONS: Major gaps in the literature around FH1 patients' long-term treatment and disease outcomes still exist. Long-term outcome data are required to help inform clinicians of the best long-term treatment for FH1.

Ethnic differences in patients undergoing thyroidectomy for non-toxic multinodular goitre.

BACKGROUND: Maori have an increased incidence of thyrotoxicosis when compvared to non-Maori, however there are limited data on benign non-toxic nodular thyroid disease. AIMS: The aims of this study were to determine the rates of non-toxic multinodular goitre (NTMNG) surgery for Maori and non-Maori and to determine if there were differences in thyroid size between Maori and non-Maori undergoing total thyroidectomy for NTMNG. METHODS: Single centre study of patients undergoing thyroidectomy for NTMNG from 1 December 2006 to 30 November 2016. RESULTS: Maori were overrepresented amongst the 427 patients who underwent surgery for NTMNG at 34% compared to the expected ~17% of the background Maori adult population in the region. At the time of surgery, Maori were younger (P = 0.004) and had a larger thyroid gland (P < 0.001) when compared to non-Maori also undergoing total/near total thyroidectomy. Complication rates were low across all ethnic groups. CONCLUSION: Maori have increased rates of surgery for NTMNG compared to non-Maori and thyroid size is larger at the time of surgery. The reasons for this are currently unknown and more research is required.

Hypercalcaemia due to parathyroid carcinoma presenting in the third trimester of pregnancy.

Primary hyperparathyroidism (pHPT) in pregnancy may be associated with significant maternal and fetal morbidity and mortality. Medical management of pHPT in pregnancy is limited, and surgery is the only definitive therapeutic option. The ideal timing for surgery is mid-second trimester, but surgery may also be safely performed in the third trimester. Delayed parathyroid surgery may result in a hypercalcaemic crisis postpartum owing to loss of active placental calcium transfer. We present a case of parathyroid carcinoma in pregnancy presenting with pre-eclampsia at 32 weeks' gestation.

Systematic Review: Incidence of Pheochromocytoma and Paraganglioma Over 70 Years.

Context: Pheochromocytomas and paragangliomas (PPGLs) are known to be rare. However, there is scant literature reporting their epidemiology, particularly whether the diagnosis of PPGL has increased with advances in medical imaging and biochemical and genetic testing. Objective: The primary objective of this systematic review was to determine the annual incidence of PPGLs and change over time. Design: A systematic review was performed. Medline, Embase, PubMed, and Web of Science Core Collection databases were searched to identify studies reporting PPGL incidence. Studies were eligible for inclusion from the database's inception until August 30, 2021. Results: A total of 6109 manuscripts were identified; 2282 duplicates were excluded, and a further 3815 papers were excluded after abstract and/or full text review. Twelve studies were included in the final review. The incidence of PPGL ranged from 0.04 to 0.95 cases per 100 000 per year. Incidence increased over time, from approximately 0.2/100,000 individuals in studies performed before 2000, to approximately 0.6/100,000 in studies undertaken after 2010. The mode of diagnosis changed over the same time period, with more patients diagnosed from incidental imaging findings, and fewer at autopsy or from symptoms. Conclusion: The annual incidence of PPGL has increased over time. Much of this increase is likely from incidental identification of tumors on imaging. However, the epidemiology of PPGL remains understudied, in particular, in associations with altitude, ethnicity, and genetics. To improve early detection and management guidelines, these gaps should be addressed.

Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications.

Autosomal dominant hypocalcemia type 1 (ADH1) is a disorder of extracellular calcium homeostasis caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR). More than 35% of ADH1 patients have intracerebral calcifications predominantly affecting the basal ganglia. The clinical consequences of such calcifications remain to be fully characterized, although the majority of patients with these calcifications are considered to be asymptomatic. We report a 20-year-old female proband with a severe form of ADH1 associated with recurrent hypocalcemic and hypercalcemic episodes, persistent childhood hyperphosphatemia, and a low calcium/phosphate ratio. From the age of 18 years, she had experienced recurrent myoclonic jerks affecting the upper limbs that were not associated with epileptic seizures, extra-pyramidal features, cognitive impairment, or alterations in serum calcium concentrations. Computed tomography (CT) scans revealed calcifications of the globus pallidus regions of the basal ganglia bilaterally, and also the frontal lobes at the gray-white matter junction, and posterior horn choroid plexuses. The patient's myoclonus resolved following treatment with levetiracetam. CASR mutational analysis identified a reported germline gain-of-function heterozygous missense mutation, c.2363T>G; p.(Phe788Cys), which affects an evolutionarily conserved phenylalanine residue located in transmembrane domain helix 5 of the CaSR protein. Analysis of the cryo-electron microscopy CaSR structure predicted the wild-type Phe788 residue to form interactions with neighboring phenylalanine residues, which likely maintain the CaSR in an inactive state. The p.(Phe788Cys) mutation was predicted to disrupt these interactions, thereby leading to CaSR activation. These findings reveal myoclonus as a novel finding in an ADH1 patient with intracerebral calcifications.

Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is an increasingly used treatment for unresectable neuroendocrine tumours (NETs) that express somatostatin receptors. Normal pituitary tissue expresses somatostatin receptors so patients receiving PRRT may be at risk of developing hypopituitarism. The aim was to assess the prevalence of clinically significant hypopituitarism a minimum of 2 years following radioisotope therapy for metastatic NET. This was a multicentre study (Australia and New Zealand). Sixty-six patients with unresectable NETs were included-34 had received PRRT and 32 comparison patients. Median follow-up after PRRT was 68 months. Male hypogonadism was the most common hormonal abnormality (16 of 38 men [42%]) from the total cohort. Of these, seven men had primary hypogonadism (five from PRRT group) and nine had secondary hypogonadism (six in PRRT group). There was no difference in either male hypogonadism or other hormonal dysfunction between patients who had received PRRT and those that had not. Patients who have received PRRT out to 68 months following treatment do not show concerning hypopituitarism although there may be the suggestion of growth hormone deficiency developing. However, hypogonadism is common in men with NETs so the gonadal axis should be assessed in men with suggestive symptoms as the treatment of testosterone deficiency may improve the quality of life.

Thyrotoxicosis in an Indigenous New Zealand Population - a Prospective Observational Study.

BACKGROUND: Reported international incidence rates of thyrotoxicosis vary markedly, ranging from 6 to 93 cases per 100 000 per annum. Along with population demographics, exposures, and study design factors, ethnicity is increasingly being recognized as a potential factor influencing incidence. This study aimed to document the epidemiology and clinical presentation of thyrotoxicosis for Maori, the indigenous population in New Zealand. METHODS: A prospective study of adult patients presenting with a first diagnosis of thyrotoxicosis between January 2013 and October 2014 to a single New Zealand center. Demographic data were collected, and detailed clinical assessment performed. RESULTS: With 375 patients, an incidence rate of thyrotoxicosis of 73.0 per 100 000 per annum was identified. Of these, 353 (94.1%) participated in the study. The median age of the cohort was 47 years, 81% were female, and 58% had Graves disease. The overall incidence of thyrotoxicosis for Maori, the indigenous people of New Zealand, was higher than non-Maori (123.9 vs 57.3 per 100 000 per annum). Rates of both Graves disease and toxic multinodular goiter were higher in Maori as compared to non-Maori (incidence rate ratios of 1.9 [1.4, 2.6] and 5.3 [3.4, 8.3], respectively), with this increase being maintained after controlling for age, deprivation, and smoking. CONCLUSIONS: Maori, the indigenous people of New Zealand, have an increased incidence of thyrotoxicosis compared to non-Maori and, in particular, toxic multinodular goiter. A greater understanding of the epidemiology of thyrotoxicosis in other indigenous and marginalized ethnic groups may help to optimize therapeutic pathways, equitable care and outcomes.

Lymphocytic hypophysitis with associated thyroiditis in a man with aseptic meningitis.

OBJECTIVE: Lymphocytic hypophysitis (LH) is a rare chronic inflammatory disorder characterized by lymphocytic infiltration of the pituitary gland commonly affecting women during pregnancy or post-partum period. The pathogenesis remains uncertain, however an autoimmune process is frequently implicated. There is limited data on the occurrence of LH outside the setting of autoimmunity. CASE: We describe a 37-year-old man presenting with diarrhoea, nausea, weight loss, low-grade fever, headache and cerebrospinal fluid analysis consistent with aseptic meningitis. Magnetic resonance imaging (MRI) demonstrated a homogenously enlarged pituitary gland with biochemical testing revealing partial hypopituitarism with adenocorticotrophic hormone and gonadotrophin deficiency. Notably, his free thyroid hormone levels were elevated with a suppressed thyroid-stimulating hormone and a suppressed thyroid technetium scan consistent with thyroiditis. Tissue antibodies including thyroid antibodies were negative. Following introduction of hydrocortisone, he developed transient diabetes insipidus which spontaneously resolved after 4 months. Thyrotoxicosis resolved after 5 weeks and thyroxine was commenced as he developed secondary hypothyroidism. Repeat MRI 3 months later showed a reduction in the size of the pituitary gland which by 6 months had returned to normal size. He remains well on hydrocortisone, thyroxine and testosterone replacement. CONCLUSIONS: Based on clinical and radiological grounds, the diagnosis was consistent with lymphocytic hypophysitis associated with subacute thyroiditis. This is only the second report of this combination in the absence of autoimmunity and the first report of LH and thyroiditis with associated aseptic meningitis in the absence of tissue autoantibodies. We propose a possible viral illness as the unifying aetiological cause.

GH replacement titrated to serum IGF-1 does not reduce concentrations of myostatin in blood or skeletal muscle.

OBJECTIVE: Traditional weight-based regimens of GH replacement are more effective at reversing the loss of skeletal muscle in GH-deficient adults than currently recommended regimens, where the dose of GH is increased to restore serum concentrations of IGF-1. While weight-based regimens increase concentrations of IGF-1 and decrease concentrations of myostatin, it is not known whether the reduced effectiveness of individually titrated GH regimens is due to ongoing hypersecretion of myostatin. Consequently, the aims of this study were to determine whether concentrations of myostatin in blood and skeletal muscle are increased in GH-deficient adults, and whether these concentrations are decreased by GH replacement regimens titrated to restore serum IGF-1. DESIGN: Twenty-six GH deficient adults (18 men and 8 women) were treated with individualised regimens of recombinant human GH aiming to achieve serum concentrations of IGF-1 within one standard deviation of the age- and gender-adjusted mean. Plasma concentrations of myostatin were measured at baseline and after 6 months of treatment were compared to fifteen healthy controls (9 men and 6 women). Skeletal muscle biopsies were performed in 19 of these GH-deficient adults (15 men and 4 women) and 10 of the healthy controls (6 men and 4 women). Expression of IGF-1 and myostatin mRNA was determined by qPCR. RESULTS: Concentrations of IGF-1 in serum and mRNA in skeletal muscle were reduced, and concentrations of myostatin in plasma and mRNA in skeletal muscle were increased in GH-deficient adults at baseline (P < .05 versus healthy controls). Despite restoring concentrations of IGF-1, GH replacement did not reduce concentrations of myostatin in either blood or skeletal muscle. Concentrations of IGF-1 and myostatin in both blood and skeletal muscle were positively correlated in GH-deficient adults at baseline (P < .05), but not in GH-replete adults. CONCLUSIONS: Concentrations of myostatin in blood and skeletal muscle are increased in GH-deficient adults. Despite normalising concentrations of IGF-1, individualised regimens of GH replacement do not reduce concentrations of myostatin in blood or skeletal muscle. Ongoing hypersecretion of myostatin may explain why individually titrated GH replacement regimens are less effective than higher weight-based regimens in increasing skeletal muscle mass.

Regulation of murine skeletal muscle growth by STAT5B is age- and sex-specific.

BACKGROUND: Sexually dimorphic growth has been attributed to the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis, particularly GH-induced activation of the intracellular signal transducer and activator of transcription 5B (STAT5B), because deletion of STAT5B reduces body mass and the mass of skeletal muscles in male mice to that in female mice. However, it remains unclear why these effects are sex- and species-specific, because the loss of STAT5B retards growth in girls, but not in male mice. Our objectives were to determine whether sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice and investigate the mechanisms by which STAT5B regulates sexually dimorphic growth. METHODS: Blood and skeletal muscle were harvested from male and female STAT5B-/- mice and their wild-type littermates from the onset of puberty to adulthood. RESULTS: Growth of the skeleton and skeletal muscles was retarded in both sexes of STAT5B-/- mice, but more so in males. Although reduced, sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice with an oxidative shift in the composition of myofibres in both sexes. Concentrations of IGF1 in blood and skeletal muscle were reduced in male STAT5B-/- mice at all ages, but only in female STAT5B-/- mice at the onset of puberty. Expression of androgen receptor (AR) and oestrogen receptor alpha (ERα) mRNA and protein was reduced in skeletal muscles of male and female STAT5B-/- mice, respectively. Loss of STAT5B abolished the sexually dimorphic expression of myostatin protein and Igf1, Ar, Erα, suppressor of cytokine signalling 2 (Socs2), and cytokine-inducible SH2-containing protein (Cis) mRNA in skeletal muscle. CONCLUSIONS: STAT5B appears to mediate GH signalling in skeletal muscles of male mice at all ages, but only until puberty in female mice. STAT5B also appears to mediate the actions of androgens and oestrogens in both male and female mice, but sexually dimorphic growth persists in STAT5B-/- mice.

Inequitable Long-Term Outcomes for an Indigenous Population After Definitive Treatment of Patients With Graves Disease.

BACKGROUND: Maori, the indigenous people of Aotearoa/New Zealand, have an increased incidence of Graves disease and often require more than one radioiodine (RAI) dose, raising the question as to whether surgery may be preferable in this population. However, there is a lack of outcome data after definitive therapy in an indigenous population. AIM: To assess ethnic differences in thyroid status after definitive therapy for Graves disease. METHODS: Single-center retrospective review of patients treated by RAI or thyroidectomy from 1 December 2001 to 31 March 2013. TSH levels at 1, 2, 5, and 10 years after treatment were recorded. RESULTS: A total of 798 patients were included: 589 received RAI, and 209 underwent surgery. Overall, 48% of patients were euthyroid at 1 year after definitive treatment, and 63.5% were euthyroid by 10 years. Maori were less likely to be euthyroid when compared with Europeans at all time points (e.g., 29.7% vs 57.3% at 1 year and 52.2% vs 70.9% at 10 years, P < 0.0005). Maori were more likely to receive more than one dose of RAI compared with Europeans (30.2% vs 14.2%, P < 0.0005). Persistent thyrotoxicosis at 1 year after RAI was seen in 25.8% of Maori compared with 8.3% of Europeans (P < 0.0005). CONCLUSIONS: Maori have lower rates of optimal thyroid levels than their European counterparts at all time points studied. Early disparity was associated with a higher RAI failure rate. Late differences were due to higher rates of untreated hypothyroidism. Overall, euthyroid rates were low, indicating the need for improvement in care, particularly for indigenous peoples.

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.