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Frontiers in Bioscience (Landmark... Aug 2023Parathyroid hormone (PTH) is an endocrine peptide found exclusively in the parathyroid glands, whereas parathyroid hormone-related protein (PTHrP) is expressed in a wide... (Review)
Review
Parathyroid hormone (PTH) is an endocrine peptide found exclusively in the parathyroid glands, whereas parathyroid hormone-related protein (PTHrP) is expressed in a wide range of tissues and organs and exerts endocrine, paracrine, and autocrine actions. PTH and PTHrP have a similar homology, sharing the initial 13 amino acid residues at the N-terminus and binding to the same type 1 PTH receptor (PTH1R), which regulates calcium homeostasis. An abnormal increase in PTH production can occur in primary and secondary hyperparathyroidism, whereas PTHrP can be produced in large quantities by malignant cancer cells from solid organs. In addition to increased bone resorption and hypercalcemia, recent evidence suggests that excess PTH and PTHrP can result in protein-energy wasting, malnutrition, and cachexia. Through binding to PTH1R and activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A in white adipose tissue, PTH and PTHrP can stimulate the expression of thermogenic genes causing adipose tissue browning. This change results in an increase in resting energy expenditure, loss of muscle and fat mass, and weight loss. These findings provide a mechanistic link for the long-established relationship between hyperparathyroidism and myopathy, as well as cancer and cachexia. The purpose of this review is to provide a summary of the emerging evidence from both experimental and clinical studies on the role of PTH and PTHrP in protein-energy malnutrition.
Topics: Humans; Adipose Tissue; Cachexia; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Protein-Energy Malnutrition
PubMed: 37664938
DOI: 10.31083/j.fbl2808167 -
Journal of Bone and Mineral Research :... Dec 2022The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a... (Meta-Analysis)
Meta-Analysis
The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a systematic review and meta-analysis of currently available randomized controlled trials to investigate the benefits and harms of PTH therapy and conventional therapy in the management of patients with chronic hypoparathyroidism. To identify eligible studies, published in English, we searched Embase, PubMed, and Cochrane CENTRAL from inception to May 2022. Two reviewers independently extracted data and assessed the risk of bias. We defined patients' important outcomes and used grading of recommendations, assessment, development, and evaluation (GRADE) to provide the structure for quantifying absolute effects and rating the quality of evidence. Seven randomized trials of 12 publications that enrolled a total of 386 patients proved eligible. The follow-up duration ranged from 1 to 36 months. Compared with conventional therapy, PTH therapy probably achieves a small improvement in physical health-related quality of life (mean difference [MD] 3.4, 95% confidence interval [CI] 1.5-5.3, minimally important difference 3.0, moderate certainty). PTH therapy results in more patients reaching 50% or greater reduction in the dose of active vitamin D and calcium (relative risk [RR] = 6.5, 95% CI 2.5-16.4, 385 more per 1000 patients, high certainty). PTH therapy may increase hypercalcemia (RR =2.4, 95% CI 1.2-5.04, low certainty). The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism. Because of limitations of short duration and small sample size, evidence from randomized trials is limited regarding important benefits of PTH therapy compared with conventional therapy. Establishing such benefits will require further studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Hypercalcemia; Hypoparathyroidism; Parathyroid Hormone; Quality of Life; Vitamin D
PubMed: 36385517
DOI: 10.1002/jbmr.4676 -
Journal of Bone and Mineral Research :... Dec 2022The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of...
The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Hypoparathyroidism; Parathyroid Hormone; Quality of Life; Parathyroid Glands
PubMed: 36153665
DOI: 10.1002/jbmr.4714 -
Trends in Endocrinology and Metabolism:... Nov 2019The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of... (Review)
Review
The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to maintain homeostatic control of ionized serum Ca levels and has several unusual signaling features, such as endosomal cAMP signaling, that are well-studied but not structurally understood. In this review, we discuss how recently solved high resolution near-atomic structures of hormone-bound PTHR in its inactive and active signaling states and discovery of extracellular Ca allosterism shed light on the structural basis for PTHR signaling and function.
Topics: Animals; Endosomes; Humans; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31699241
DOI: 10.1016/j.tem.2019.07.011 -
Annals of Saudi Medicine 2023Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that can be lethal. Most patients require parathyroidectomy. (Review)
Review
BACKGROUND
Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that can be lethal. Most patients require parathyroidectomy.
OBJECTIVE
Report experience in managing this severe disease.
DESIGN
Retrospective chart review of case series.
SETTING
Tertiary health care center.
PATIENTS AND METHODS
We reviewed data on patients managed for NSHPT from June 2001 to January 2023. Demographic, clinical, and follow-up data were collected, and descriptive data were generated.
MAIN OUTCOME MEASURES
Pre- and postoperative levels of parathyroid hormone (PTH) and serum calcium, and effect of autotransplantation.
SAMPLE SIZE
19.
RESULTS
The 13 males and 6 females had a a mean age of 46 days at referral. The mean preoperative parathyroid hormone (PTH) and serum calcium levels were 996 ng/L and 4.54 mmol/L, respectively. Twelve patients underwent ultrasonography preoperatively. Of these, six had prominent glands, while no glands were seen in the other six. A Sestamibi scan was done for 15 patients, of which nine showed negative results and six showed positive results, with three glands observed in the neck and three in the sublingual area. Nineteen patients underwent renal ultrasonography, with nine showing nephrocalcinosis. The mean age at surgery was 5.2 months. Total parathyroidectomy (four glands) was performed in 17 patients, and 15 underwent concurrent auto-transplantation. One patient had three glands removed, in addition to auto-transplantation. Another underwent single gland excision as a redo-surgery after previous surgery elsewhere. The mean postoperative follow-up duration was 6 years. The mean postoperative PTH and calcium levels were 25 ng/L and 1.64 mmol/L, respectively. Ultimately, all the patients were required to initiate calcium and vitamin D supplements, except for two patients who had undergone auto-transplantation. Molecular genetic screening of the calcium-sensing receptor gene reported likely pathogenic/pathogenic mutations in 16 of 19 patients (13 were homozygous, two were heterozygous, one was negative, and data was unavailable for the remaining three patients).
CONCLUSIONS
Surgical treatment of NSHPT is effective. Preoperative radiological localization studies did not impact the treatment plan. Auto-transplantation proved ineffective in maintaining independence from medical supplements.
LIMITATIONS
The retrospective nature of the study may imply inaccuracybut since the data are gathered from electronic medical records, we believe it is highly accurate. The small sample size limits generalizability.
Topics: Male; Infant, Newborn; Female; Humans; Infant; Parathyroid Glands; Calcium; Retrospective Studies; Hyperparathyroidism, Primary; Parathyroid Hormone
PubMed: 37916585
DOI: 10.5144/0256-4947.2023.01.11.1200 -
Physiological Research Nov 2021Parathyroid hormone (PTH) increases the release of serum calcium through osteoclasts, which leads to bone resorption. Primary, PTH stimulates osteoblasts leading to... (Review)
Review
Parathyroid hormone (PTH) increases the release of serum calcium through osteoclasts, which leads to bone resorption. Primary, PTH stimulates osteoblasts leading to increase RANKL (receptor activator for nuclear factor kappa-B ligand) expression and thus differentiation of osteoclasts. In kidneys, PTH increases calcium and decrease phosphate reabsorption. In kidneys, PTH stimulates 1alpha-hydroxylase to synthesize active vitamin D. Primary hyperparathyroidism (PHPT) is characterized by skeletal or renal complications. Nowadays, the classical form of PHPT is less seen and asymptomatic or subclinical (oligo symptomatic) forms are more frequent. Previously, it was thought that cortical bone is preferably affected by PHPT and that predispose bones to fracture at sites with a higher amount of cortical bone. However, an increased risk of vertebral fractures has been found by most of the studies showing that also trabecular bone is affected. Bone Mass measurement (BMD) at all skeletal sites is advised, but another specific tool for fracture assessment is needed. Trabecular bone score (TBS), an indirect measure of trabecular bone, maybe a useful method to estimate fracture risk. TBS is associated with vertebral fractures in PHPT regardless of BMD, age, BMI and gender. Furthermore, there is an association between TBS and high resolution peripheral quantitative computed tomography (HR-pQCT) parameters in the trabecular and cortical compartment. However, studies considering the effect of PHPT treatment on TBS are more conflicting. Secondary hyperparathyroidism caused by vitamin D deficiency was associated with impaired bone microarchitecture in all age categories, as measured by TBS and Hr-pQCT with further improvement after treatment with vitamin D.
Topics: Bone Density; Bone and Bones; Humans; Parathyroid Hormone; Tomography, X-Ray Computed
PubMed: 34918524
DOI: 10.33549/physiolres.934779 -
Rhode Island Medical Journal (2013) Oct 2022Primary hyperparathyroidism (PHPT) is a common endocrine disorder that results in excess parathyroid hormone (PTH) secretion and hypercalcemia. PHPT is usually caused by...
Primary hyperparathyroidism (PHPT) is a common endocrine disorder that results in excess parathyroid hormone (PTH) secretion and hypercalcemia. PHPT is usually caused by an adenoma and its presentation is often asymptomatic, though it can negatively impact the skeleton via osteoporosis mostly affecting cortical bone and fracture. The diagnosis of PHPT is made by clinical presentation and biochemical and hormonal assessment. Surgical treatment guided by ultrasound sonography and/or 99mTc-sestamibi scintigraphy is generally curative. Normocalcemic hyperparathyroidism (NPHPT) is a variant of hyperparathyroidism defined by normal serum calcium and persistently elevated serum PTH levels. Limited data exist on NPHPT's effects on the skeleton, though current evidence suggests a positive correlation between the disorder and the presence of osteoporotic fractures. Taken together, patients affected by the various manifestations of hyperparathyroidism and their associated homeostatic disturbances represent a not insignificant portion of fracture patients seen in a fracture liaison service.
Topics: Calcium; Fractures, Bone; Humans; Hyperparathyroidism; Parathyroid Hormone; Radiopharmaceuticals; Technetium Tc 99m Sestamibi
PubMed: 36173907
DOI: No ID Found -
The Journal of Clinical Investigation May 2023The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of...
The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of the proximal tubule. Yoon et al. demonstrated the intracellular mechanism by which parathyroid hormone (PTH) increases production of 1,25-vitamin D. Activation of PTH receptor 1/cAMP/PKA signaling inhibited salt-inducible kinase 2 (SIK2) and SIK3, which increased CYB27B1 transcription and 1,25-vitamin D production. Replication of these effects with small-molecule SIK inhibitors suggests possible therapeutic applications for patients with disorders characterized by 1,25-vitamin D deficiency. Zhou et al. discovered that proximal tubule glycolysis acts as a phosphate sensor that regulates fibroblast growth factor 23 production in bone. They described several kidney-specific metabolic modifications that enabled glycolysis to be deployed as a phosphate sensor. The provocative results raise intriguing questions with implications for patients with disorders of phosphate homeostasis, including chronic kidney disease.
Topics: Humans; Kidney; Kidney Tubules, Proximal; Parathyroid Hormone; Phosphates; Vitamin D
PubMed: 37115697
DOI: 10.1172/JCI169607 -
Frontiers in Endocrinology 2022
Topics: Humans; Calcium; Parathyroid Hormone; Hypocalcemia; Homeostasis
PubMed: 36644693
DOI: 10.3389/fendo.2022.1124762 -
Frontiers in Endocrinology 2023The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D (1,25(OH)D). Early research efforts focused on... (Review)
Review
The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D (1,25(OH)D). Early research efforts focused on PTH and 1,25(OH)D and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)D and FGF23; the regulation of PTH by 1,25(OH)D, however, remains obscure. We review here our molecular understanding of how PTH induces expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)D. FGF23 and 1,25(OH)D, on the other hand, function by suppressing production of 1,25(OH)D. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of . PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied sites. The negative actions of both FGF23 and 1,25(OH)D appear to suppress expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at , the gene encoding the enzyme that degrades 1,25(OH)D, thereby contributing to the overall regulation of blood levels of 1,25(OH)D. Relative to PTH regulation, we summarize what is known of how 1,25(OH)D regulates PTH suppression. These studies suggest that it is not 1,25(OH)D that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an approach that furthers our understanding of the regulation of expression by PTH and 1,25(OH)D and provide the first evidence that P may act to induce expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.
Topics: Humans; Calcitriol; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Parathyroid Hormone; Kidney; Calcium
PubMed: 37441497
DOI: 10.3389/fendo.2023.1213361