The role of calcitonin in the development and treatment of osteoporosis.

CT is a peptide hormone produced predominantly by thyroid C cells and probably to a lesser extent by extrathyroidal tissues. Although its physiological function has not yet been established, it is a pharmacological inhibitor of osteoclastic bone resorption. There is currently no convincing evidence that naturally occurring or iatrogenic CT deficiency is involved in the pathogenesis of osteoporosis; however, a selective examination of patients with various rates of bone turnover would help to resolve this issue. As a pharmacological inhibitor of bone resorption, CT has potential usefulness in the therapy of osteoporosis. CT has been shown to stabilize or modestly increase indices of cortical and trabecular bone mass and total body calcium when administered to patients with established osteoporosis for periods of 1-2 yr. The increments in bone mass seen in some studies appear to be transient and are likely due to reductions in bone resorption with bone formation remaining unaffected until remodeling spaces are filled. The duration and magnitude of these increases are probably limited by the eventual decline in bone formation as remodeling equilibrium is reestablished. Therefore, reduction in the rate of bone loss with maintenance of the existing skeletal mass, rather than significant sustained increases in bone mass, should be considered the most realistic therapeutic goal with this agent. Whether or not a reduction in the rate of bone loss persists for longer periods needs further evaluation as does the important issue of subsequent fracture rates. The identification of patients with increased bone resorption rates (high turnover osteoporosis) should help provide a basis for more selective treatment of those patients who would be most likely to respond to this form of therapy. Whether there is additional benefit to using intermittent CT concurrently or sequentially with bone formation stimulating agents (coherence therapy) also needs to be explored. CT may also be of benefit in the prevention of osteoporosis, particularly in postmenopausal women who are unable or unwilling to take estrogen replacement. These potential benefits must be weighed carefully against the current cost of CT and the inconvenience of it having to be given by injection, problems which should be solved by future research.

Familial hyperinsulinism presenting in adults.

Two adult siblings presented with recurrent syncope due to severe hyperinsulinemic hypoglycemia. Exploratory laparotomy in the elder sibling showed a grossly normal pancreas, but histologic examination revealed islet cell hyperplasia. Neither sibling has any evidence of the multiple endocrine neoplasia type 1 syndrome, nor is there any other family history to suggest this diagnosis. To our knowledge, this is the first report of adult-onset familial hyperinsulinism without other manifestations of multiple endocrine neoplasia type 1 syndrome. A simple provocative test for hyperinsulinism was also suggested by these cases. Because the initial patient related his symptoms to exercise, we used treadmill exercise in both patients to diagnose hyperinsulinism and observe its response to therapy.

Glucose tolerance in granuloma annulare.

Granuloma annulare (GA) may be associated with glucose intolerance. Twenty-one patients with GA were evaluated. Four patients were found to have frank diabetes mellitus and 2 were excluded from the data analysis because of obesity. The remaining patients and 14 age- and weight-matched controls had oral and intravenous glucose tolerance tests (GTT). During the oral GTT the fasting plasma glucose, the 2-h plasma glucose, the area of the glucose curve, the 1-h serum insulin, and the area of the insulin curve were all significantly greater in the GA patients than in the controls. During the intravenous GTT the immediately releasable insulin pool was intact, while the fasting plasma glucose and the area of the glucose curve were greater in the GA patients than in the controls. The data taken together suggest that glucose tolerance may be reduced in GA and that insulin resistance may exist.

Effects of mild asymptomatic primary hyperparathyroidism on bone mass in women with and without estrogen replacement therapy.

Primary hyperparathyroidism (HPT) presents most commonly as a mild elevation of the serum calcium concentration in an asymptomatic individual. There are conflicting data regarding the effects of mild primary HPT on bone mass. This cross-sectional study was conducted to examine this question further and to determine whether estrogen replacement therapy (ERT) in postmenopausal women with primary HPT might be beneficial. We measured bone mass in 59 women with mild asymptomatic primary HPT, of whom 43 (HPT) had never taken and 16 (estrogen-replaced HPT) were currently taking ERT. We also studied 84 healthy normocalcemic women who were not on ERT (controls) and 45 who were on ERT (estrogen-replaced controls). After adjustment for age, height, and weight, mean bone mass values in the HPT group were significantly reduced in the midradius (20%), distal radius (20%), lumbar spine (17%), and femoral neck (11%) compared with the controls. The estrogen-replaced HPT group had mean bone mass values greater than those in the HPT group, similar to those in the controls, and lower than those in the estrogen-replaced controls. Mild asymptomatic primary HPT results in bone loss from both the appendicular and axial skeleton, and ERT in postmenopausal women with primary HPT may ameliorate this loss.

Effect of theophylline on calcium metabolism and circulating vitamin D metabolites.

Theophylline has been shown to induce the hepatic microsomal enzyme system. These same enzymes increase the metabolism of vitamin D and 25-hydroxyvitamin D when induced by chronic barbiturate or phenytoin administration. To assess the long-term effects of theophylline on vitamin D and calcium metabolism, young rats were treated for 4 weeks with constant subcutaneous theophylline infusions. Theophylline-treated animals had a significantly increased urinary calcium excretion (p less than 0.0001), a significantly decreased total body calcium per gram body weight (p less than 0.05), and significantly decreased serum 25-hydroxy-vitamin D concentrations (p less than 0.002) when compared to control animals. These alterations in the concentration of 25-hydroxyvitamin D may impair the ability to increase 1,25-dihydroxyvitamin D-dependent intestinal calcium absorption to compensate for excessive urinary calcium losses. These data suggest that theophylline promotes skeletal calcium loss, and its use may be a risk factor for the development of osteopenia in humans.

Thyroid adaptation to chronic tetraglycine hydroperiodide water purification tablet use.

Tetraglycine hydroperiodide tablets purify water by liberating 8 mg free iodine/tablet. The effects of ingesting four tablets daily for 3 months on thyroid size, function, and radioactive iodine uptake were studied prospectively in eight healthy volunteers. Serum inorganic iodide increased from 2.7 to approximately 100 micrograms/dL. Urinary iodide excretion rose 150-fold from a pretreatment mean of 0.276 to 40 mg/day. Radioactive iodine uptake was less than 2% after 7 days and remained below 2% in all subjects at 90 days. Mean serum T4 and T3 declined after 7 days. T4 remained below baseline, whereas T3 had recovered by the end of the treatment period. Serum TSH and the TSH response to TRH rose significantly after 7 days and remained elevated at 3 months. The average thyroid volume, determined by ultrasound, increased by 37%. Neither hyperthyroidism nor hypothyroidism was observed. The mean thyroid volume in seven subjects available for repeat determinations an average of 7.1 months after the study was not different from the baseline value. In normal subjects, a reversible TSH-dependent thyroid enlargement occurs in response to the iodine load from daily use of tetraglycine hydroperiodide water purification tablets.

Reduced bone mineral content in totally thyroidectomized patients: possible effect of calcitonin deficiency.

To further investigate the relationship between calcitonin deficiency and osteoporosis, we have measured bone mineral content (BMC) by single photon absorptiometry in patients made iatrogenically calcitonin deficient by prior total thyroidectomy for thyroid cancer. Compared to sex-, age-, height-, and weight-matched normal controls, male patients had a significantly lower mean BMC at the midradius (1.162 +/- 0.02 vs. 1.301 +/- 0.05 g/cm; P less than 0.02) and the distal radius (1.180 +/- 0.04 vs. 1.338 +/- 0.04 g/cm; P less than 0.01). Female patients also had a significantly lower BMC at the midradius compared to those of a similarly matched group of normal controls and a group of patients on L-T4 suppression for nodular goiters (0.791 +/- 0.04 vs. 0.896 +/- 0.05 vs. 0.891 +/- 0.03 g/cm; P less than 0.025). We conclude that calcitonin deficiency from surgical thyroidectomy is associated with significant decreases in bone mineral content in both sexes. This lends further support to the concept that calcitonin deficiency may be an important causative factor in the development of osteoporosis.

Antideoxyribonucleic acid antibodies in Graves' disease.

Antidouble stranded DNA (dsDNA) antibodies have been detected by a sensitive RIA in the sera of 28-100% of patients with Graves' disease, but it remains unclear whether these assays have detected authentic dsDNA antibodies. We have obtained sera from 42 patients with active Graves' disease and no known connective tissue disorders. All sera were tested for dsDNA antibodies by 2 quantitative RIAs (Farr assay and Millipore filter assay; normal, less than 20% for both assays) and by an enzyme-linked immunosorbant assay for antibodies to dsDNA and to single stranded DNA (ssDNA). All sera were negative for dsDNA antibodies by the Farr assay and by enzyme-linked immunosorbant assay, 2 of 42 had mildly elevated levels (33% and 23%) by the Millipore filter assay, and 7 of 42 were positive for ssDNA antibodies. The 2 positive sera for dsDNA antibodies were also tested using the Crithidia luciliae indirect immunofluorescence assay, and both were negative. Patients with Graves' disease have been reported to have an increased prevalence of antinuclear antibodies, but the more recent findings of dsDNA antibodies in these patients is of interest because dsDNA antibodies are considered to be specific for systemic lupus erythematosus. Our data suggest that true immunoglobulin G dsDNA antibodies are not elevated during active Graves' disease, and positive assay results may be due to measurement of ssDNA antibodies, immunoglobulin M dsDNA antibodies, or nonantibody DNA binding.

Evidence of endocrine involvement early in the course of human immunodeficiency virus infection.

Adrenal, gonadal, and thyroid function were assessed in 40 asymptomatic subjects in whom infection with the human immunodeficiency virus (HIV) had recently been documented. None of the patients had historical or clinical evidence of endocrine dysfunction. Their mean serum hormone levels were also within the expected ranges, but several differences were noted compared to those of seronegative controls. Basal cortisol, basal aldosterone, and ACTH-stimulated cortisol were significantly lower in the HIV group. One subject (2.5%) had a subnormal cortisol response, and two (5%) had abnormal aldosterone responses to ACTH. PRA tended to be higher, and serum angiotensin-converting enzyme levels somewhat lower in the HIV group. Serum free testosterone was markedly elevated in the HIV patients and was associated with an exaggerated LH response to GnRH, but PRL, estradiol, and basal and peak GnRH-stimulated FSH did not differ between groups. Three subjects (8%) had subclinical hypothyroidism. Serum thyroid hormone levels were normal, but basal T3 was lower in the HIV group compared to control values. While of little immediate clinical importance, many subtle endocrine aberrations are evident very early in the course of HIV infection. These findings obtained in HIV-seropositive subjects without infections or tumors and who were not receiving medical therapy suggest an effect of HIV on each of the endocrine systems examined.

The effects of theophylline and nifedipine on corticotropin-stimulated cortisol secretion.

The adrenal cortisol response to corticotropin appears to involve both calcium and cyclic adenosine 3',5'-monophosphate (cAMP) as intracellular mediators. In 10 healthy male volunteers, the short-term administration of theophylline, which affects both intracellular calcium and cAMP, lowered basal cortisol levels but augmented the in vivo cortisol response to short-term corticotropin stimulation. Short-term administration of nifedipine, a calcium channel antagonist, had no effect on basal or peak cortisol levels but reduced the incremental cortisol response to corticotropin. The effects of both theophylline and nifedipine, although statistically significant, were modest and of questionable clinical significance but should be considered in the interpretation of the clinical corticotropin stimulation test. They may also provide some insight into the post-receptor actions of corticotropin.

Thyroid hormone resistance syndromes.

The thyroid hormone resistance syndromes are disorders in which the body's tissues are resistant to the effects of thyroid hormone. Generalized resistance to thyroid hormone (GRTH) is characterized by resistance in the pituitary gland and in most or all of the peripheral tissues. Affected individuals have elevated serum thyroid hormone levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary resistance to thyroid hormone (PRTH) is characterized by resistance in the pituitary gland but not in peripheral tissues. Patients have elevated serum thyroid hormone levels and normal or elevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, but current choices are not completely satisfactory. Selective peripheral resistance to thyroid hormone (PerRTH) is characterized by resistance in peripheral tissues but not in the pituitary. The only patient thus far described had normal serum thyroid hormone and TSH levels but was clinically hypothyroid and improved with thyroid hormone administration. All of these disorders are probably more common than is generally recognized and are often misdiagnosed and inappropriately treated. GRTH, in most cases studied, results from a mutation in the thyroid hormone receptor beta gene causing an amino acid substitution in or a partial or complete deletion of the thyroid hormone-binding domain of the receptor. The causes of PRTH and PerRTH remain to be determined.

Lithium-associated thyrotoxicosis.

Primary hypothyroidism developed in a 57-year-old woman treated for eight years with lithium carbonate for manic-depressive illness, and nine months later she became thyrotoxic. Although autoimmune disease appeared to be responsible, lithium was suspected to play a contributory role in both phases of her illness. This is the first reported case of hyperthyroidism following hypothyroidism in a lithium-treated patient. The 24 reported cases of lithium-associated thyrotoxicosis and the possible mechanisms that may explain this poorly understood phenomenon are also reviewed.

Radioiodine-induced thyroid storm. Case report and literature review.

Thyroid storm developed following radioiodine therapy in a 43-year-old man with Graves' disease, weight loss, myopathy, severe thyrotoxic hypercalcemia, and a pituitary adenoma. The hypercalcemia may have been a significant, and previously unreported, predisposing factor for the radioiodine-associated thyroid storm. This case and 15 other well-documented cases of radioiodine-associated storm found in the literature are reviewed, as are several other cases of less severe exacerbations of thyrotoxicosis associated with radioiodine therapy. Although not often seen, these complications are often fatal. High-risk patients, such as the elderly, those with severe thyrotoxicosis, and those with significant underlying diseases, may benefit from preventive measures such as the judicious use of thyrostatic medications during the periods before and after isotope administration.

Pure primary hyperaldosteronism due to adrenal cortical carcinoma.

A 47-year-old woman is described who had pure primary hyperaldosteronism due to an adrenal cortical carcinoma. This may represent the first such case in which modern laboratory tests allowed specific diagnosis and exclusion of hypersecretion of other adrenal steroids, and also the first reported case in which modern localizing procedures have been utilized. Other interesting facets of the case include calcification of the tumor, visualization with 131l iodomethylnorcholesterol , metaplastic histologic changes, and coexistent bilateral renal artery fibromuscular disease.

Central hyperthyroidism.

Central hyperthyroidism is a rare condition in which thyrotoxicosis results from primary overproduction of TSH by the pituitary gland with subsequent thyroid enlargement and hyperfunction. The two known causes of central hyperthyroidism are TSH-producing pituitary tumors (TSHomas) and the syndrome of PRTH. Both of these entities are characterized by clinical thyrotoxicosis, diffuse goiters, elevated circulating levels of free T4 and T3, and a nonsuppressed serum TSH. It is critical to distinguish central hyperthyroidism from the much more common types of primary hyperthyroidism, all of which have undetectable TSH values. TSHomas and PRTH can usually be differentiated from one another by measuring the serum alpha-subunit and the TSH response to intravenous TRH or exogenous thyroid hormone, and by pituitary imaging studies. TSHomas are usually benign adenomas arising from the monoclonal expansion of neoplastic thyrotropes. Causative oncogenes have not yet been convincingly identified. PRTH is a nonneoplastic disorder caused by inherited mutations in the gene for the thyroid hormone receptor beta; it is a poorly understood variant of GRTH. For unclear reasons, in PRTH, the pituitary gland is resistant to the feedback inhibitory effects of circulating thyroid hormones while peripheral tissues respond normally, causing patients to experience the toxic peripheral effects of thyroid hormone excess. TSHomas are best treated by transphenoidal surgical removal. Radiotherapy is indicated for inoperable or incompletely resected tumors. Octreotide administration is a useful adjunct for preoperatively reducing tumor size and for the medical management of surgical treatment failures. PRTH is ideally treated by chronically suppressing TSH secretion with medications such as D-thyroxine, TRIAC, octreotide, or bromocriptine. If such therapy is ineffective or unavailable, thyroid ablation with radioiodine or surgery may be employed with subsequent close monitoring of both thyroid hormone status and pituitary gland size.

Functional interactions of an upstream enhancer of the mouse glycoprotein hormone alpha-subunit gene with proximal promoter sequences.

Transcription of the glycoprotein hormone alpha-subunit gene in the pituitary is governed by different promoter elements in thyrotropes and gonadotropes. We recently identified an upstream enhancer that directs a high level of cell type specific expression in transgenic mice and stimulates proximal promoter activity in cultured alphaTSH and alphaT3 cells. To assess the contribution of promoter sequences that functionally interact with the enhancer, we mutated two proximal elements shown to be important in both thyrotrope and gonadotrope cells. Disruption of the pituitary glycoprotein hormone basal element (PGBE), which binds a LIM homeodomain protein, resulted in a decrease in basal promoter activity in both alphaTSH and alphaT3 cells. Enhancer function was completely abolished by the PGBE site mutation in alphaT3 gonadotropes, whereas some stimulatory activity remained in alphaTSH thyrotropes. Mutation of the gonadotrope specific element (GSE), which binds SF1 and is important for basal activity in gonadotropes and TRH response in thyrotropes, resulted in declines in basal and enhanced promoter activity only in alphaT3 cells and not in alphaTSH cells. Despite this decrease in enhanced activity, the GSE mutated promoter still retained some enhancer stimulated activity, suggesting that the PGBE site still functionally interacts in the absence of an intact GSE. This mutation had no effect in alphaTSH cells. These data suggest that although the enhancer works in both cell types it exhibits cell type specific functional characteristics.

Influence of testosterone on breathing during sleep.

Apneas and hypopneas during sleep occur more frequently in men than women. Disordered breathing is also reported to increase in hypogonadal men following testosterone administration. This suggests a hormonal influence on sleeping respiratory pattern. We therefore studied respiratory rhythm during sleep in 11 hypogonadal males both on and off testosterone-replacement therapy. In four subjects the anatomy (computerized tomography) and airflow resistance of the upper airway were also determined on both occasions. Sleep stage distribution and duration were unchanged following androgen administration. However, both apneas and hypopneas increased significantly during testosterone replacement so that the total number of disordered breathing events (apneas + hypopneas) per hour of sleep rose from 6.4 +/- 2.1 to 15.4 +/- 7.0 (P less than 0.05). This was a highly variable event with some subjects demonstrating large increases in apneas and hypopneas when androgen was replaced, whereas others had little change in respiration during sleep. Upper airway dimensions, on the other hand, were unaffected by testosterone. These results suggest that testosterone contributes to sleep-disordered breathing through mechanisms independent of anatomic changes in the upper airway.

Massive extracapsular hemorrhage from a parathyroid cyst.

A 32-year-old man had a giant cervical mass, dysphagia, dyspnea, and severe hypercalcemia. A computed tomographic scan showed the mass to extend from the left mandible to the level of the aortic arch. Exploratory surgery of the neck revealed a ruptured parathyroid cyst complicated by massive hemorrhage into the cervical tissues and mediastinum. The postoperative course was uncomplicated with prompt resolution of the hypercalcemia. Although a rare occurrence, extracapsular parathyroid hemorrhage should be considered in the differential diagnosis of all rapidly evolving cervical and mediastinal masses, especially when hypercalcemia is present.

Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients.

Prospective studies are not available to address various issues commonly encountered in the management of hypothyroid patients. We have conducted a case-based mail survey of American Thyroid Association (ATA) members and primary care providers (PCP) regarding hypothyroidism management issues. A majority of ATA members and a minority of PCPs used antithyroid antibody testing in the evaluation of hypothyroidism. Approximately 2/3 of all respondents indicated that they would treat patients with mild thyroid failure when antithyroid antibodies are negative; 77% of PCPs and 95% of ATA members recommended treatment when antibodies are positive. For a young patient with mild thyroid failure, 71% of ATA members would initiate a full levothyroxine (LT4) replacement dose of 1.6 microg/kg per day or slightly lower; PCPs were more likely to start with a low dose and titrate upwards. For a young patient with overt hypothyroidism, 42% of PCPs and 51% of ATA respondents recommended an initial full LT4 replacement dose. The majority of all respondents would start with a low LT4 dose and adjust the dose gradually in an elderly patient, regardless of the severity of thyroid hormone deficiency. More than 40% of ATA respondents chose a target thyrotropin (TSH) range of 0.5-2.0 microU/mL for a young patient while 39% favored a goal of 1.0-4.0 microU/mL for an elderly patient. PCPs more often chose a broader TSH goal of 0.5-5.0 microU/mL. In conclusion, the current practice patterns of PCPs and ATA members that were elicited in this survey differ significantly in regard to the evaluation and management of hypothyroidism.

Hyperthyroidism following hypothyroidism.

Two patients are presented who developed autonomous thyrotoxicosis following a diagnosis of primary hypothyroidism. In one of these patients, antibodies to the TSH receptor were typical of Graves' disease when measured as thyrotropin binding inhibitor immunoglobulins (TBII) and as human thyroid adenylate cyclase stimulating (HTACS) activity, while a needle biopsy of the thyroid gland was consistent with lymphocytic thyroiditis. Twenty-one other reported cases of this unusual sequence found in the literature are reviewed. This occurrence is more common than is generally appreciated.