Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

Long-term effects of metreleptin in Rabson-Mendenhall Syndrome on glycemia, growth, and kidney function

Context Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that one year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. Objective Determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. Design/Participants/Intervention/Setting Comparison of patients with RMS during non-randomized open-label treatment with metreleptin (≥0.15 mg/kg/day) versus no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main Outcome Measure(s) A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, BMI, and IGF-1; growth hormone (GH), estimated glomerular filtration rate Results Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P=0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. GH increased after metreleptin treatment vs. control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher GH, while reduced A1c predicted higher IGF-1. Conclusions Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.

Bipolar Androgen Therapy in the management of prostate cancer

Introduction and purpose: Prostate cancer (PCa) as one of the most frequent neoplasms in men remains a challenge for oncologists. The main strategy of its treatment is the Androgen Deprivation Therapy (ADT) the principle of which is an inducement of hypogonadism. The lack of testosterone is not only a factor greatly contributing to a decrease of quality of life overall, but additionally it increases the odds of the complications, including low libido and erectile disfunction, metabolic abnormalities, high cardiovascular risk, osteoporosis, anaemia, or depression. ADT also has the potential of inducement of castration resistance (CRPC), which significantly worsen patients prognosis. The main purpose of this review is to explore the Bipolar Androgen Therapy (BAT), which has the potential to solve the aforementioned problems. State of knowledge: The mechanism of BAT action has been described. BAT is effective not only against CRPC, but androgen-dependant PCa as well. BAT reverses the hormone resistance in CRPC, thus allowing the rechallenging of the ADT. It has the direct cytotoxic effect on cancer cells. Additionally BAT increases the exponents of the general quality of life of the patients. There is a number of active clinical trials regarding BAT. Conclusions: BAT is a safe therapeutic strategy with the high efficacy in reversing hormone resistance in CRPC patients, thus significantly increasing their health prognoses and it allows to alleviate or avoid the adverse effects of ADT.

A Case of macro-TSH masquerading as subclinical hypothyroidism

A 47-year-old man was commenced on levothyroxine following a diagnosis of subclinical hypothyroidism with nonspecific symptoms. Despite increasing doses of levothyroxine, his thyroid-stimulating hormone (TSH) remained elevated and he was referred for further assessment as he was unable to tolerate further titration. On assessment, his thyroid function demonstrated an elevated TSH and elevated free-T4. The initial impression was of iatrogenic thyrotoxicosis, with possible underlying thyroid hormone resistance, TSHoma or assay interference. After discontinuation of levothyroxine, free-T4 normalised but TSH remained elevated. There was a normal response to thyrotropin-releasing hormone (TRH) testing. T3 suppression testing demonstrated free-T4 reduction but persistently high TSH. THRβ sequencing was normal. TSH measurement by alternative assays revealed discrepant results. Gel filtration chromatography revealed the presence of high-molecular weight TSH variant alongside normal TSH. Macro-TSH is a rare phenomenon with spuriously elevated TSH and which may mimic subclinical hypothyroidism. Recognition of macro-TSH avoids misdiagnosis and prevents inappropriate treatment.

Optimal integration of CDK4/6 inhibitors for treatment of hormone receptor-positive metastatic breast cancer

The paper analyzes the effectiveness of a new class of medications — CDK4/6 cyclin-dependent kinases inhibitors and discover the mechanism of its action. The article describes the general results of studies on palbociclib, ribociclib and abemaciclib* for the first- and subsequent-line of the therapy of HR-positive/HER2-negative metastatic breast cancer. The profile of adverse events of approved CDK4/6 inhibitors are considered. The combination of CDK4/6 inhibitors with endocrine therapy was shown to have benefits in survival, potentiality to reduce hormone resistance and great perspectives to improve clinical results of hormone receptor-positive metastatic breast cancer.

Thyroid Hormone Resistance Syndrome Presenting as Exercise Induced Asthma

Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter. Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G>A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise. Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.