Hypothalamic and pituitary function

The thyroid gland is under the control of thyroid-stimulating hormone (TSH) from the pituitary. It secretes thyroxine (T₄) and triiodothyronine (T₃). Iodine is essential for the synthesis of thyroid hormones. T₄ is probably converted to T₃ in peripheral tissues. Thyroid hormones have a role in growth and development, but their principal effect is the control of basal metabolic rate. Deficiency or excess affects all the tissues of the body, reducing or increasing the metabolic rate, resulting in hypothermia or hyperthermia, respectively. Deficiency during development produces mental retardation. Lack of iodine leads to thyroid swelling (goitre) caused by continuing stimulation by TSH. Calcium is one of the most tightly controlled ions in the body; abnormalities can produce muscle paralysis. Bone is the major store of calcium. Calcium reabsorption by the kidney is controlled by parathyroid hormone (PTH) produced by the parathyroid glands, which lie in the posterior part of the lobes of the thyroid gland. PTH secretion is controlled by blood calcium concentrations. Phosphate metabolism is intimately bound up with the control of calcium levels, as is the metabolism of vitamin D, which stimulates the absorption of calcium from the gastrointestinal tract and, in part, from the kidney.     

Thyroid and parathyroid hormones and calcium homeostasis

The thyroid gland is under the control of thyroid stimulating hormone (TSH) from the pituitary. It secretes thyroxine (T4) and triiodothyronine (T3). Iodine is essential for the synthesis of thyroid hormones. T4 is probably converted to T3 in peripheral tissues. Thyroid hormones have a role in growth and development but their principal effect is the control of basal metabolic rate. Deficiency or excess affects all the tissues of the body, reducing or increasing the metabolic rate, resulting in hypothermia or hyperthermia, respectively. Deficiency during development produces mental retardation. Lack of iodine leads to thyroid swelling (goitre) caused by continuing stimulation by TSH. Calcium is one of the most tightly controlled ions in the body; abnormalities can produce muscle paralysis. Bone is the major store of calcium. Calcium reabsorption by the kidney is controlled by parathyroid hormone (PTH) produced by the parathyroid glands, which lie in the posterior part of the lobes of the thyroid gland. PTH secretion is controlled by blood calcium concentrations. Phosphate metabolism is intimately bound up with the control of calcium levels, as is the metabolism of vitamin D, which stimulates the absorption of calcium from the gastrointestinal tract and, in part, from the kidney.     

Thyroid and parathyroid hormones and calcium homeostasis

The thyroid gland is under the control of thyroid-stimulating hormone (TSH) from the pituitary. It secretes thyroxine (T4) and triiodothyronine (T3). Iodine is essential for the synthesis of thyroid hormones. T4 is probably converted to T3 in peripheral tissues. Thyroid hormones have a role in growth and development but their principal effect is the control of basal metabolic rate. Deficiency or excess affects all the tissues of the body, reducing or increasing the metabolic rate, resulting in hypothermia or hyperthermia, respectively. Deficiency during development produces mental retardation. Lack of iodine leads to thyroid swelling (goitre) caused by continuing stimulation by TSH. Calcium is one of the most tightly controlled ions in the body; abnormalities can produce muscle paralysis. Bone is the major store of calcium. Calcium reabsorption by the kidney is controlled by parathyroid hormone (PTH) produced by the parathyroid glands, which lie in the posterior part of the lobes of the thyroid gland. PTH secretion is controlled by blood calcium concentrations. Phosphate metabolism is intimately bound up with the control of calcium levels, as is the metabolism of vitamin D, which stimulates the absorption of calcium from the gastrointestinal tract and, in part, from the kidney.     

Thyroid,parathyroid hormones and calcium homeostasis

The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3) in response to thyroid-stimulating hormone release from the anterior pituitary gland. Iodine is essential for the synthesis of thyroid hormones. T4 and T3 increase the basal metabolic rate, heat production, and help to maintain normal growth and development. Serum calcium levels are under very tight control. The majority of calcium is found in bones. Calcium and phosphate levels are maintained by four hormones – parathyroid hormone (PTH), calcitonin, vitamin D and fibroblast growth factor 23. PTH is produced by the parathyroid glands and its secretion is determined by serum calcium levels.     

Thyroid,parathyroid hormones and calcium homeostasis

The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3) in response to thyroid-stimulating hormone (TSH) released from the anterior pituitary gland. Iodine is essential for the synthesis of thyroid hormones. T4 and T3 increase basal metabolic rate, heat production and help to maintain normal growth and development. The parathyroid glands are essential for maintaining normal levels of serum calcium, which is necessary to maintain normal cellular function via calcium acting as a secondary messenger. Calcium is also involved in the coagulation of blood, transmission of nerve impulses and muscular contraction. Calcium is provided by various dietary sources and plasma levels are altered by varying absorption in the gut, mobilization from bone and excretion by the kidney.     

Disorders of calcium and magnesium balance: a physiology-based approach

Disorders of calcium and magnesium balance are physiologically interesting and clinically challenging. In this review, we attempt to bridge the gap between physiology and practice by providing a physiology-based approach to understanding hypocalcemia, hypercalcemia and hypomagnesemia. Calcium and, to a lesser extent, magnesium balance is achieved through a complex interplay between the parathyroid gland, bone, the intestine and the kidney. Our understanding of the molecular physiology of calcium and magnesium balance has grown considerably following the discovery of the calcium-sensing receptor (CaSR) and the main intestinal and renal transporters for calcium and magnesium, namely, the transient receptor potential channels TRPV5, TRPV6 and TRPM6. The regulation of parathyroid hormone (PTH) secretion by CaSR and the subsequent effects of PTH and vitamin D on TRPV5 constitute an increasingly characterized regulatory loop. In contrast, no truly magnesiotropic hormones have been identified, although the recently established interactions between the epidermal growth factor and TRPM6 suggest a possible candidate. Overall, the aim of this review is to illustrate the clinical disorders of calcium and magnesium balance from the perspective of their integrated physiology.     

Thyroid function after radiotherapy and laryngectomy for carcinoma of the larynx

Total levels of thyroxine (T₄) and thyroid-stimulating hormone (TSH) were measured in 37 patients who had previously had carcinoma of the larynx treated by radiotherapy and total laryngectomy with thyroid lobectomy. Ten percent of the patients had clinical features of hypothyroidism and 30% had total T⁴ levels below the lower limit of normal. A further 40% had results in the low normal range. Forty-four percent of patients had raised TSH levels, 90% of these having low or low normal T₄ levels. The histology of the thyroid gland was normal in all 37 patients. Attention should be given to preserving intact the vasculature of the contralateral thyroid lobe whenever it is necessary to remove the ipsilateral thyroid lobe during a laryngectomy. Proper postoperative assessment of thyroid gland function is desirable in all these patients to identity those at risk of hypothyroidism and to avoid unnecessary morbidity.     

Phosphorus reduces renal receptivity for parathyroid hormone in rats

Changes in kidney calcium concentration and secreted parathyroid hormone were studied in weanling male rats (n = 12) fed diets containing either 0.5% (n = 6) or 1.5% (n = 6) total phosphorus. Calcium and phosphorus concentrations in the kidney of rats fed a high-phosphorus diet were markedly greater than those in rats fed a control diet. In addition, urinary excretion of phosphorus increased gradually after administration of a high-phosphorus diet, but there was no similar tendency of phosphorus/creatinine excretion, which decreased gradually from the starting day of feeding to the end of the feeding period. The high-phosphorus diet also produced greater serum parathyroid hormone (PTH) without urinary cyclic adenosine monophosphate (cAMP) excretion stimulated by PTH. The mean values of serum 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) concentrations were significantly increased 1 h after injection of 2.77 g rat PTH(1–34) in all rats. However, in rats fed a high-phosphorus diet, the rise of serum 1,25(OH)₂D stimulated by exogenous PTH was lower than that in rats fed a control diet.     

Randomized clinical trial of intraoperative parathyroid gland angiography with indocyanine green fluorescence predicting parathyroid function after thyroid surgery

Background

Hypoparathyroidism, the most common complication after thyroid surgery, leads to hypocalcaemia and significant medical problems. An RCT was undertaken to determine whether intraoperative parathyroid gland angiography with indocyanine green (ICG) could predict postoperative hypoparathyroidism, and obviate the need for systematic blood tests and oral calcium supplementation.

Methods

Between September 2014 and February 2016, patients who had at least one well perfused parathyroid gland on ICG angiography were randomized to receive standard follow‐up (measurement of calcium and parathyroid hormone (PTH) on postoperative day (POD) 1 and systematic supplementation with calcium and vitamin D; control group) or no supplementation and no blood test on POD 1 (intervention group). In all patients, calcium and PTH levels were measured 10–15 days after thyroidectomy. The primary endpoint was hypocalcaemia on POD 10–15.

Results

A total of 196 patients underwent ICG angiography during thyroid surgery, of whom 146 had at least one well perfused parathyroid gland on ICG angiography and were randomized. None of these patients presented with hypoparathyroidism, including those who did not receive calcium supplementation. The intervention group was statistically non‐inferior to the control group (exact 95 per cent c.i. of the difference in proportion of patients with hypocalcaemia –0·053 to 0·053; P = 0·012). Eleven of the 50 excluded patients, in whom no well perfused parathyroid gland could be identified by angiography, presented with hypoparathyroidism on POD 1, and six on POD 10–15, which was significantly different from the findings in randomized patients (P = 0·007).

Conclusion

ICG angiography reliably predicts the vascularization of the parathyroid glands and obviates the need for postoperative measurement of calcium and PTH, and supplementation with calcium in patients with at least one well perfused parathyroid gland. Registration number: NCT02249780 ( http://www.clinicaltrials.gov ).     

The effects of recombinant human TSH on bone turnover in patients after thyroidectomy

Thyrotropin receptors are expressed in several extrathyroidal tissues including bone. We investigated whether the increase of thyroid-stimulating hormone (TSH) levels, under stable thyroid hormone levels, affects the bone markers. Thirty-two postmenopausal women, with papillary thyroid carcinoma, previously treated with near-total thyroidectomy and I¹³¹ remnant ablation underwent routine evaluation for residual disease by using injections of recombinant human TSH (rhTSH) without withdrawal from thyroxine therapy. Changes in TSH levels and various serum and urine markers of bone metabolism were followed before and 1, 2, 5, and 7 days after the rhTSH injections. A transient, significant decrease in serum calcium and urinary excretion of C- and N-terminal telopeptides of type I collagen was observed after the injections of rhTSH. Serum parathyroid hormone (PTH) started to rise along with TSH, but a significant increase of PTH was only reached on Day 5 when the TSH concentration had fallen more than 80% of the peak value. Bone alkaline phosphatase and osteocalcin did not show any significant change over time. There was no significant correlation between TSH concentration and the various parameters we measured. The study provides evidence that rhTSH produces a transient inhibition of bone resorption, as well as an attenuation of osteoblast response in spite of the PTH activation. Additional studies are needed to resolve the mechanisms by which TSH alters the response of the bone cells.     

Compensatory parathyroid hypertrophy after hemiparathyroidectomy in rats feeding a low calcium diet

Summary The functional and anatomic compensatory response of the parathyroid gland was examined in hemiparathyroidectomized (HPTx) rats whose parathyroid hormone (PTH) secretion was stimulated by a low calcium diet. These responses were compared with those observed in the thyroid gland of hemithyroidectomized (HTx) rats. Rats kept on a low calcium diet for 10 days were subjected to HPTx, HTx, or sham operations. Throughout the experiment (up to 28 days after surgery), serum calcium levels of HPTx rats were lower than the basal, with Δ values (mg/dl, mean±SEM) of −0.66±0.17 and −0.84±0.17, (P<0.05) 3 and 28 days after surgery, respectively. Serum PTH decreased significantly from 7 to 21 days after HPTx, reaching normality at day 28 after surgery. In HTx rats, serum thyroxine (T4) levels diminished significantly 7 days after surgery, and attained normality thereafter. The mitotic index (number of metaphases/1,000 cells) in parathyroid glands of colchicine-treated HPTx rats increased significantly in comparison to sham-operated controls, when examined 2 or 40 days after surgery. The mitotic index of thyroid follicular cells was significantly higher than that of their respective controls, 2 but not 40 days after HTx. These results indicate that after HPTx, a delayed compensatory response is found when the animals are kept under a low calcium diet. Parathyroid response is both delayed and of a minor degree compared to that found in the thyroid gland after HTx.     

Anatomy and physiology of the parathyroids: A practical discussion for surgeons

Normal parathyroid glands vary in macroscopic appearance, number, and location. Adequate surgical treatment of hyperparathyroidism often depends on identification of all glands, which requires precise knowledge of the normal anatomy and embryology of organs derived from the third and fourth branchial pouches. The following questions form the basis of surgical strategy: (a) Is this a normal parathyroid gland? (b) Where should the surgeon look for a normal gland? (c) How many parathyroid glands are there? (d) Where should the surgeon look for a missing gland? About 80% of patients have 4 glands. The upper pair is usually near the point where the recurrent nerve enters the larynx. The lower pair is more variable in location and may be found between the inferior thyroid artery and the thymus. Normal glands may be ectopically located along the path of embryologic migration, adjacent to or embedded in organs of similar origin. Parathyroid hormone (PTH), vitamin D, and calcitonin maintain calcium levels which modify intestinal absorption, renal excretion, and bone turnover. PTH secretion responds promptly to calcium changes acting upon vitamin D synthesis, tubular reabsorption of phosphates, calcium renal excretion, and bone reabsorption. Vitamin D controls intestinal calcium absorption. Calcitonin stimulates bone accretion. Excess PTH tilts this balance toward hypercalcemia, hypercalciuria, and bone décalcification; hypercalcemia and detectable PTH levels coincide only in hyperparathyroidism. In treating patients with hyperparathyroidism, delicate surgical technique is essential, but the ingenuity of the surgeon in developing a plan of action based on thorough knowledge of normal anatomy and embryology is the key to successful therapy.     

Physiology of the pituitary,thyroid, parathyroid and adrenal glands

The pituitary gland is made of clusters of cells producing specific hormones that control growth (growth hormone), thyroid function (triiodothyronine (T₃) and thyroxine (T₄)), adrenal function (adrenocorticotrophic hormone (ACTH)) and gonadal function (follicle-stimulating hormone and luteinizing hormone). In addition, the neurons that join the posterior pituitary (neurohypophysis) secrete vasopressin – the antidiuretic hormone involved in maintaining water balance.     

Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics

The identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important implications for understanding the pathogenesis and evolution of secondary hyperthyroidism in chronic kidney disease (CKD). Signaling through the CaSR has direct effects on three discrete components of parathyroid gland function, which include parathyroid hormone (PTH) secretion, PTH synthesis, and parathyroid gland hyperplasia. Disturbances in calcium and vitamin D metabolism that arise owing to CKD diminish the level of activation of the CaSR, leading to increases in PTH secretion, PTH synthesis, and parathyroid gland hyperplasia. Each represents a physiological adaptive response by the parathyroid glands to maintain plasma calcium homeostasis. Studies of genetically modified mice indicate that signal transduction via the CaSR is a key determinant of parathyroid cell proliferation and parathyroid gland hyperplasia. Because enlargement of the parathyroid glands has important implications for disease progression and disease severity, it is possible that clinical management strategies that maintain adequate calcium-dependent signaling through the CaSR will ultimately prove useful in diminishing parathyroid gland hyperplasia and in modifying disease progression.     

Phosphocalcic metabolism: regulation and explorations

Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances.     

Thyroid function and lipid concentration after thyroidectomy in rats

The purpose of this study was to determine whether subjects with high serum thyrotropin (TSH) levels and low-normal serum thyroxine (T₄) levels are euthyroid, as a result of the increased TSH stimulation of the thyroid, or hypothyroid. As a model to study this clinically important problem we analyzed serum cholesterol (Chol), triglyceride (Tg), TSH, T₄, and triiodothyroxine (T₃) before and 7, 10, and 12 weeks after sham operation (SO), hemithyroidectomy (Htx), and total thyroidectomy (Ttx) in 33 male Sprague—Dawley rats. By 7 weeks after Ttx serum TSH levels increased from 861 ± 84 to 9657 ± 644 ng/ml, T₄ decreased from 3.7 ± 0.18 to 0.84 ± 14 ng/ml, and T₃ decreased from 0.317 ± 0.026 to 0.217 ± 0.007 ng/ml (P < 0.001). Serum Chol increased from 69.6 to 112.5 mg/dl, whereas Tg decreased from 70.93 ± 3.56 to 50.54 ± 4.18 mg/dl (P < 0.01). After Htx serum TSH levels were higher than before operation and were higher than in the SO group (P < 0.05); serum T₄ and T₃ levels tended to be lower than before Htx and lower than in the SO group, but this decrease was only significant for both T₄ and T₃ 10 weeks after operation (P < 0.05); serum Chol and Tg levels were the same in Htx and SO animals. Thus, after Ttx (1) serum T₃ and T₄ levels decrease, (2) serum TSH levels increase, (3) serum Chol levels increase, and (4) serum Tg levels decrease. After Htx (1) serum TSH levels increase, (2) serum T₃ and T₄ levels are low-normal or slightly low, (3) serum Chol and Tg levels are normal. It appears that increased TSH stimulation of the thyroid gland can maintain normal serum lipid levels in the presence of low-normal or slightly low thyroid hormone concentrations. Thus, animals with increased serum TSH levels and low-normal or slightly low thyroid hormone levels are either not hypothyroid or serum lipid levels are an insensitive indicator of hypothyroidism.     

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T₃) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen‐replete, 46 estrogen‐deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone‐specific alkaline phosphatase (BAP), cross‐linking terminal C‐telopeptide of type I collagen (CTX), procollagen type 1 amino‐terminal propeptide (P1NP), and cross‐linked N‐telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25‐hydroxyvitamin D, parathyroid hormone (PTH), thyroid‐stimulating hormone (TSH), and free triiodothyroxine (T₄) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild‐type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone. © 2010 American Society for Bone and Mineral Research     

The effect of ionized calcium, pH, and temperature on bioactive parathyroid hormone during and after open-heart operations

Normal myocardial function is dependent on the metabolic balance of a number of electrolytes and hormones. The calcium ion plays a major role in muscle contraction and is rigorously controlled within narrow limits. Open-heart surgery imposes metabolic disturbances on both electrolytes and hormones, especially ionized calcium. Normally, ionized calcium levels are controlled by parathyroid hormone with a negative feedback from the ionized calcium controlling the system, but the results from this study suggest that during open-heart procedures, ionized calcium does not impose its normal negative feedback on bioactive parathyroid hormone secretion. The low blood pH levels that occurred during the operative conditions of the patients studied and the level of hypothermia imposed on the circulating blood during cardiopulmonary bypass appeared to influence the control of parathyroid hormone secretion, causing high levels of hormone to be secreted during this period.     

A semimechanistic model of the time‐course of release of PTH into plasma following administration of the calcilytic JTT‐305/MK‐5442 in humans

JTT‐305/MK‐5442 is a calcium‐sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT‐305/MK‐5442 binds to CaSRs, thus preventing receptor activation by Ca²⁺. In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time‐course relationship between JTT‐305/MK‐5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT‐305/MK‐5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca²⁺ binding, and a second source released more slowly following hours of reduced Ca²⁺ binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (E_max) functions of JTT‐305/MK‐5442 concentration. Our model describes both the dose‐dependence of PTH time of occurrence for maximum drug concentration (T_max) and maximum concentration of drug (C_max), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT‐305/MK‐5442 administration.