Hyperparathyroidism induced by hypothyroidism.

The coexistence of hyperparathyroidism and thyroid tumors and/or chronic thyroiditis has raised the possibility of an etiologic relationship. The present study was designed to test the hypothesis that the chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Three groups of 24 rats each were treated for 12 weeks as follows: group 1 received propylthiouracil (PTU) in their deionized water; group 2 received PTU and thyroid hormone to suppress TSH and to serve as a control group for possible direct effects of PTU; and group 3 was not treated at all and served as another control group. At 12 weeks, 95% of group 1 rats (PTU only) showed hyperplasia of the parathyroids with a 30% mean increase in circulating parathormone.

High phosphate diet-induced primary hyperparathyroidism: an animal model.

Primary hyperparathyroidism (PHPT) is increasing in incidence and detection, primarily because of the aging of our population and the widespread use of automated serum calcium determination. As a result, a substantial number of "early" cases or "biochemical" PHPT are being detected. The indications for parathyroidectomy in such early cases of PHPT are currently under debate, primarily because of economic issues. These factors underscore the importance of research into the basic mechanisms and natural history of PHPT. We investigated an animal model of diet-induced PHPT that retains two crucial aspects of PHPT: elevation of endogenously produced parathyroid hormone (PTH), accompanied by gross and microscopic changes in the native parathyroid glands. Female Long-Evans rats were divided into six groups of 15 each and fed a control diet (Ca/P of 1:2) or a high-phosphate diet (Ca/P of 1:7) for 1-, 2-, or 3-month intervals. Compared with the control animals, serum PTH levels were elevated at all three time intervals in the experimental group, whereas serum calcium levels were decreased at all time intervals. Serum creatine levels were also elevated at all time intervals, whereas serum phosphorus levels did not change. Parathyroid histopathologic studies demonstrated no change at 1 month, whereas nine of 15 experimental animals showed mild hyperplasia at 2 months and 13 of 14 showed mild to moderate hyperplasia with gland enlargement at 3 months compared with control animals. Histopathologic examination of the kidneys showed no change at 1 month but focal parenchymal inflammation with calcium deposition at 2 and 3 months in the experimental groups. In conclusion, the high-phosphate diet successfully induced the earliest changes of PHPT: elevated PTH levels and parathyroid hyperplasia. However, because renal function was mildly compromised early on, some element of early secondary (renal) hyperparathyroidism may have supervened quickly. Because this model is simple, it may be useful to investigate this complex syndrome further, as well as its natural history and the complications it produces in other organs such as the kidneys.

[Hyperparathyroidism and Hashimoto's thyroiditis: coincidence or consequence?]. / L'hyperparathyroïdie et la thyroïdite d'Hashimoto: coïncidence ou conséquence.

Primary hyperparathyroidism is commonly associated with Hashimoto's thyroiditis. The raised TSH levels might induce hyperparathyroidism, as suggested by some experimental data. It might also explain the development of hyperparathyroidism after neck irradiation and lithium therapy.

Altered TSH levels associated with increased serum 1,25-dihydroxyvitamin D3: a possible link between thyroid and parathyroid disease.

The physiologic relationship between the thyroid and parathyroid glands remains poorly understood. A high incidence of coexistent thyroid disease and primary hyperparathyroidism has been well documented. Elevation of serum 1,25-dihydroxyvitamin D3 (vitamin D) has been detected in some patients with primary hyperparathyroidism. A report of specific binding sites and uptake of vitamin D by the thyrotrophs of the anterior pituitary indicates that vitamin D may modulate production or secretion of thyroid-stimulating hormone (TSH). To test this concept, we investigated the influence of elevated serum levels of vitamin D on basal and stimulated TSH. Vitamin D was administered by subcutaneously implanted sustained-release pellets at four dosages. Thyrotropin releasing hormone (TRH) stimulation tests were performed at time zero, 72 hours, 1 week, 2 weeks, and 5 weeks. Animals administered vitamin D became significantly hypercalcemic and demonstrated elevations of vitamin D, which peaked at 72 hours and remained elevated for 2 weeks after pellet implantation. TRH-stimulated TSH levels were significantly elevated at 72 hours and at 1 week and returned to normal after 5 weeks. Parathyroid hormone levels were suppressed at 72 hours and at 1 week and displayed significant elevation at 2 weeks. These results provide in vivo evidence for an interaction and a possible regulatory role of 1,25 on pituitary TSH secretion and parathyroid function.

Age related correlation between serum TSH and thyroid C cell hyperplasia in Long-Evans rats.

The purpose of the present investigation was to determine whether there is a correlation between the serum levels of thyroid stimulating hormone (TSH), parafollicular cell (C) population in the thyroid and calcitonin (CT) secretion in aging Long-Evans (L-E) rats. Serum TSH and CT values were determined in 50 male rats at ages 2, 6, 12, 18 and 24 months and 50 female rats at 18, 21 and 24 months. The animals were sacrificed at the end of the experiment to evaluate thyroid C cell pathology. Male rats showed an increase in the serum TSH values at 6 and 12 months of age, a decline at 18 months and a significant increase from 18 to 24 months of age. In female rats, a significant increase in serum TSH concentration was also noted from 18 to 24 months of age. In both sexes, 24 month old animals with thyroid C cell hyperplasia (CH+ group) had a significantly higher level of serum TSH as compared to animals with normal distribution of C cells (CH- group). Concentration of serum CT showed a progressive increase with age in both sexes. Male rats with thyroid C cell pathology had significantly higher levels of serum CT at 24 months of age as compared to rats with normal C cell distribution. In female rats, however, serum CT concentrations in two groups were not statistically significant. We conclude from these studies that in aged L-E rats, serum TSH concentration has an influence on thyroid C cell population.

Radioiodine sensitivity of parafollicular C cells in aged Long-Evans rats.

An earlier study from our laboratory demonstrated that the incidence of thyroid C cell neoplasia in aging Long-Evans rats was high. When radioactive iodine was administered to 8-week-old Long-Evans rats, this incidence was reduced, although thyroid follicular cell neoplasia was increased. The aim of this study was to determine whether iodine-131 (131I) administered to an aged population of Long-Evans rats with established C cell hyperplasia would have a C cell ablative effect as pronounced as that observed in studies of young rats. For this study, 180 18-month-old Long-Evans rats (90 male and 90 female) were used. Baseline serum calcitonin levels were determined, and control and experimental groups containing equal numbers of animals were designated. 131I was administered by intraperitoneal injection to the experimental group, while equal volumes of saline solution were given to the control group. Blood samples for determination of serum calcitonin levels were obtained at 6-week intervals until the rats were 24 months old. Thyroid glands were then removed, and tissues were fixed, sectioned, and stained with hematoxylin and eosin and with peroxidase-antiperoxidase (PAP) using an anticalcitonin antibody. Examination of thyroid tissues showed that the incidence of C cell neoplasia was significantly reduced in irradiated animals as compared with nonirradiated controls (chi 2 analysis, p less than 0.05). PAP staining demonstrated diminished intracytoplasmic calcitonin in the radiation-treated group. Analysis of serum calcitonin levels over time showed significantly lower levels in the irradiated rat group than in the nonirradiated group (p less than 0.006).

Sex hormone modulation of serum TSH levels.

This study was undertaken to determine the effects of estrogen and testosterone on baseline and thyrotropin-releasing hormone (TRH)-stimulated serum thyroid-stimulating hormone (TSH) levels in rats. Seven groups of 20 rats each were studied: intact males (group I), intact females (group II), castrated males (group III), castrated females (group IV), castrated males with testosterone replacement (group V), castrated females with testosterone supplement (group VI), and intact females with testosterone supplement (group VII). Two weeks after initiation of these hormone treatments, blood samples for TSH levels were obtained before and 10 minutes after TRH injection. Testosterone levels were also determined to verify hormone release. The results of these studies indicated that (1) testosterone has a primary, stimulatory role in the control of TSH concentration in that it causes elevation of both baseline and TRH-stimulated TSH levels, (2) endogenous estrogens have no such direct effect on TSH levels, and (3) in the presence of testosterone, endogenous estrogens partially inhibit the TSH-elevating effect of the androgen. As TSH stimulation is considered requisite for thyroid carcinogenesis, the different effects of testosterone and estrogen on TSH levels, demonstrated in this study, may in part explain differences in incidence and prognosis of thyroid carcinoma observed between the sexes in both rats and human beings.

Testosterone enhancement of thyroid carcinoma in rats: the role of TSH.

Radiation treatment of Long-Evans male rats (40 mu Ci Na131I at the age of 2 months) led to a high incidence of thyroid follicular carcinomas at the age of 24 months; castration of males before irradiation caused a significant reduction in incidence of this tumor. In this study, replacement testosterone (T) was administered to castrated male rats by means of implanted, slow-release hormone-containing pellets (T-physiologic dose). Three testosterone doses (0.1T, 1.0T, and 30T) were used to treat groups of castrated irradiated and castrated nonirradiated rats from 2 to 18 months of age. The incidence of thyroid follicular carcinoma at 18 months in irradiated rats depended on the dose of replacement testosterone used. Tumor incidence was 8%, 14%, 41%, and 50% after treatment with 0T, 0.1T, 1.0T, and 30T, respectively. The incidence of thyroid follicular carcinoma in nonirradiated rats ranged from 0 to 7%. Mean serum thyroid-stimulating hormone (TSH) values in irradiated animal groups were elevated significantly above those for age-matched nonirradiated animals. The degree of TSH elevation in irradiated animals was related directly to the testosterone-replacement level. All rat groups showed age-dependent decreases in serum T4 levels, and T4 levels were also lowered by replacement testosterone in nonirradiated castrated animals. In aging irradiated animals, serum T4 levels were similarly decreased by testosterone, despite elevated TSH levels in these groups. In this study, testosterone appeared to act indirectly to promote development of irradiation-induced thyroid tumors by early and prolonged elevation of TSH levels.

Androgen-mediated development of irradiation-induced thyroid tumors in rats: dependence on animal age during interval of androgen replacement in castrated males.

When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred, depending on the time interval for hormone replacement. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was generally associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. Thus an indirect effect of T via early stimulation of TSH may be at least partly responsible for the high incidence of irradiation-induced thyroid tumors in rats.

Serum calcium metabolism in acute experimental pancreatitis.

Serum calcium changes in severe pancreatitis were studied in 23 dogs. Twelve dogs underwent duodenotomy and served as controls. Pancreatitis was induced in the other 11 by autologous bile injection (1 ml/kg) into the pancreatic duct. Serum amylase, total calcium, ionized calcium, albumin, magnesium, chloride, phosphorous, parathyroid hormone (PTH), and calcitonin were measured at 0, 1/2, 1, 3, 6, 24, 48, and 72 hours after duodenotomy or bile injection. Serum amylase levels became significantly elevated in all dogs with pancreatitis at 30 minutes (p less than 0.01) and remained so throughout the entire experiment. Total calcium levels dropped significantly 30 minutes after pancreatitis was induced from 10.0 +/- 0.3 mg/dl compared with 8.8 +/- 0.4 mg/dl in control dogs (p less than 0.05) and remained statistically lower for as long as 1 hour. Ionized calcium levels were significantly lower than were those of control dogs at 1/2, 1, 3, and 6 hours (p less than 0.05). Serum magnesium and chloride levels showed no significant changes between both groups. The only significant difference in phosphorus values was at 6 hours when they were higher in dogs with pancreatitis than in controls (6.2 +/- 0.3 mg/dl versus 4.8 +/- 0.4 mg/dl; p less than 0.05). Serum albumin levels remained unchanged throughout the study except for 48 hours when they were significantly lower in animals with pancreatitis (p less than 0.02). PTH levels were significantly greater in dogs with pancreatitis than in controls at 1, 3, 6, and 24 hours (p less than 0.05). There was no significant difference in calcitonin levels between both groups. Ionized calcium is a more reliable indicator of calcium fluxes in acute experimental pancreatitis since it remains depressed longer than total serum calcium. The time course of PTH elevation indicates a reaction to hypocalcemia, and failure of PTH secretion is not the cause of hypocalcemia in pancreatitis. This study does not support elevation of calcitonin as a cause of hypocalcemia in acute pancreatitis.

Parathyroid cysts: a report of eleven cases including two associated with hyperparathyroid crisis.

Eleven parathyroid cysts were found in 325 patients who underwent parathyroid operations. Ten cysts were located in the neck and one was located in the mediastinum. The cysts ranged in size from 1.6 to 10 cm with a mean of 3.9 cm. The patients who had cysts included six women and five men, and their ages ranged from 28 to 72 years with a mean of 51 years. In contrast to other reports that have suggested that most parathyroid cysts are nonfunctional, all but one of our patients had hyperparathyroidism, as evidenced by hypercalcemia, hypophosphatemia, and elevated parathyroid hormone level, which was corrected by cyst removal. The nonfunctional cyst first appeared to be an asymptomatic neck mass. Two patients had acute hyperparathyroid crises, which required emergency operations. It is postulated that the crises may have been the result of spontaneous necrosis of preexisting parathyroid adenomas. This is supported by the pathologic findings of degeneration and early organization as well as by the presence within the cyst of sanguineous fluid that contained a parathormone concentration greater than 100 times normal serum levels.

Effects of radiation on parafollicular C cells of the thyroid gland.

While radiation has well-recognized effects on follicular cells of the thyroid gland, those on parafollicular C cells are not yet established. Low-dose radiation that has been proved to be nonablative and carcinogenic to follicular cells was administered to 8-week-old Long-Evans rats to study the changes in C cell number and function. Circulating calcitonin levels were significantly reduced in animals that had undergone radiation at age 24 months. Mean calcitonin values were 0.66 (+/- 0.20) ng/ml and 1.64 (+/- 0.59) ng/ml for control males and females compared with 0.14 (+/- 0.06) ng/ml and 0.11 (+/- 0.01) ng/ml for males (P less than 0.05) and females (P less than 0.001) that had undergone radiation, respectively. These levels correlated well with C cell population density in thyroid glands in the control group and in the group that had undergone radiation as evidenced by light microscopy. Routine hematoxylin and eosin staining showed C cell hyperplasia in 77% of control animals of both sexes compared with 4% in animals that had undergone radiation (P less than 0.005). Immunoperoxidase staining with an anticalcitonin antibody showed virtual absence of C cells in most animals that had undergone radiation compared with diffusely scattered cells in animals in the control group. Medullary carcinomas occurred in 14% of animals in the control group compared with 3% of animals that had undergone radiation (P less than 0.05). These data indicate that the radiation dosage that is carcinogenic to the follicular epithelium causes lethal injury to C cells and thus suggest that C cells are more sensitive to radiation than are follicular cells. This increased sensitivity could explain the virtual absence of C cells, decrease in calcitonin levels, and reduced numbers of medullary carcinomas in the animals that had undergone radiation.

Successful autotransplantation of parathyroid adenomas in seven patients.

The autotransplantation of normal as well as adenomatous parathyroid tissue is currently being used with increasing frequency. In the present report, we describe our experiences with the successful transplantation of adenomatous or hyperplastic parathyroid tissue in seven patients. Prior to transplant surgery, six of these patients had recurrent or persistent primary hyperparathyroidism. The last patient was on hemodialysis for chronic renal failure and was presumed to have tertiary hyperparathyroidism. A large superior mediastinal parathyroid adenoma was found at a second neck exploration. In all patients, the only remaining parathyroid tissue was either adenomatous or hyperplastic. A total of 30 to 75 mg of this parathyroid tissue was diced and transplanted into single subfascial pockets of the forearm muscles (6) or sternocleidomastoid muscle (1). Following transplantation, all patients required transient calcium and vitamin D supplements for six to 12 weeks. In follow-up studies of ten months to 12 years, all patients have remained eucalcemic with normal parathyroid hormone levels. The use of a single subfascial pocket (versus the popular method of multiple implants) may explain the lack of recurrent hyperparathyroidism in our small population.

Subtotal parathyroidectomy for primary hyperparathyroidism. Long-term results in 292 patients.

Subtotal parathyroidectomy was performed in a consecutive series of 292 patients with primary hyperparathyroidism. We evaluated the long-term postoperative results during a period of 16 years. Patients ranged in age from 14 to 83 years and included 176 women and 116 men. Of these, 16% had a history of exposure to radiation in childhood or adolescence, while thyroid disease requiring some form of thyroidectomy coexisted in 91 (31%) of the patients. Histologic information on three or more parathyroid glands was obtained in 73% of the cases. We considered 285 patients (97.6%) cured after their first operation. The remaining seven patients (2.4%) had persistent hyperparathyroidism. However, five were cured after a sternum-splitting mediastinal exploration and one after a second neck exploration. The seventh remains hypercalcemic despite a subsequent mediastinal exploration. Temporary postoperative hypoparathyroidism occurred in 10% of our cases and permanent hypoparathyroidism in 1%. There have been no instances of recurrent hyperparathyroidism.

Castration induces a marked reduction in the incidence of thyroid cancers.

Although thyroid disease in humans predominates in females, the prognosis of thyroid cancer in males is much less favorable. To further explore the role of male sex hormones, we utilized the experimental model of radiation-induced follicular cancer in the rat, studying the effects of castration on tumor development. Microscopic evidence of tumor formation was correlated with the biochemical parameters serum thyroxine (T4), thyrotropin (TSH), and thyrocalcitonin (TC) at 24 months. The incidence of follicular carcinomas in intact males ws 58%, compared to 28% in comparable females. Castration of males caused a reduction in the incidence to 22%. Mean circulating levels of TSH were markedly elevated in all three irradiated groups. Mean T4 levels were reduced significantly only in irradiated castrated animals. TC levels were reduced in all irradiated groups. We conclude that although elevated levels of TSH probably play a significant role in the development of radioactive iodine-triggered follicular thyroid neoplasms in the rat, male sex hormone may also play an important role beyond their known effect on basal and thyrotropin-releasing hormone-stimulated TSH.

Hyperparathyroid crisis. Successful treatment of ten comatose patients.

Hyperparathyroid crisis is a rare disease manifested by elevated serum calcium, weakness, nausea and vomiting, altered states of consciousness, and elevated circulating parathormone. This hypercalcemic state is noted for a frequently acute presentation and associated high mortality rate, approaching 60% in some series. Ten patients in parathyroid crisis were observed in a consecutive personal series of 325 cases of operatively proved hyperparthyroidism. All 10 patients were successfully treated. Each patient remained or lapsed into persistent coma despite extensive medical management and normalization of serum calcium in some instances. An emergency parathyroidectomy was performed in all cases. Reversal of the comatose state was noted in all patients within 24 hours, followed by gradual normalization of serum calcium. Serum calcium ranged from 15 to 19.6 mg/dl. The blood urea nitrogen level was elevated in six patients. A single adenoma was found in nine patients and multiglandular disease involving the neck and the mediastinum in one. All patients survived. The successful treatment of this disease demands prompt and accurate diagnosis coupled with vigorous medical therapy and emergency parathyroidectomy if the patient's status continues to deteriorate.

Hypothalamic LH may play a role in control of pituitary LH release.

We have recently reported immunoassayable luteinizing hormone (LH) in several areas of the rat brain and conspicuously present in the hypothalamus. In this report, we focus on the presence of LH in the hypothalamus and its potential role in regulation of pituitary LH release. In adult female rats, examined during the course of the estrous cycle, a significant fall in hypothalamic LH coincides with the surge in pituitary and serum LH at the time of proestrus, signaling ovulation. Ovariectomized adult rats show no change in hypothalamic LH at a time when there is a dramatic rise in both anterior pituitary and serum LH. These data support the concept that hypothalamic LH is not of pituitary origin and that it may play a role in the short-loop negative feedback system controlling the surge in anterior pituitary LH release, and event initiating ovulation.

Subtotal parathyroidectomy: normalization of circulating parathormone.

Subtotal parathyroidectomy was performed in 52 consecutive patients with primary hyperparathyroidism. The postoperative results, 6-24 months following the operation, were evaluated according to a calcium-parathormone normogram. In 48 patients the values returned to the normal zone. Two patients had persistent hypercalcemia. The other two patients remained in the hyperparathyroid zone of the normogram, with moderate elevations of serum parathormone, in spite of normocalcemia. The significance of the failure to achieve normal circulating parathormone levels in patients with postoperative eucalcemia is discussed. The importance of serum parathormone and calcium relationship in the evaluation of patients following parathyroidectomy is emphasized.