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.

Osteoporosis unmasked by hyperthyroidism in a young man with osteogenesis imperfecta.

A young man presented with a vertebral fracture and generalized osteopenia that was initially attributed to coexisting hyperthyroidism. However, the rarity of fractures in young men with hyperthyroidism and the finding of blue sclerae led to the diagnosis of osteogenesis imperfecta. Since vertebral fractures are uncommon in young men with osteogenesis imperfecta, we postulate that the combined effects of the two disorders contributed to his clinical presentation.

The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls.

OBJECTIVE: The intent of this study is to retrospectively evaluate our experience, as well as all published information, regarding the clonidine suppression test to determine its utility, accuracy, and safety in the diagnosis of pheochromocytoma. PATIENTS AND METHODS: All 22 patients (including four with pheochromocytoma) evaluated at a major military referral hospital with the clonidine suppression test for suspected pheochromocytoma for more than 6 years were retrospectively reviewed. All published series of patients similarly evaluated were also critically reviewed. RESULTS: All studies confirm that a nonstressed plasma norepinephrine of more than 2000 pg/mL is diagnostic of pheochromocytoma. In those patients with a plasma norepinephrine of less than 2000 pg/mL, the clonidine suppression test is 92% accurate in diagnosing pheochromocytoma when the normal response to clonidine is defined as total plasma catecholamines of less than 500 pg/mL. Its accuracy diminishes in patients with low baseline plasma catecholamine levels, who may better be tested with a stimulatory test (ie, glucagon). The use of diuretics, beta-blockers, and antidepressants may cause false-positive results or severe hypotension during the clonidine suppression test. Those previously treated with clonidine or with baroreceptor dysfunction may also be prone to severe hypotension, but this complication is otherwise uncommon after acute clonidine ingestion. CONCLUSION: Although it is rarely necessary for the diagnosis of pheochromocytoma, the clonidine suppression test is an accurate and safe test in a select group of patients.

Ectopic thyroid tissue on thallium/technetium parathyroid scan.

The thallium 201/technetium 99m pertechnetate radionuclide study is becoming widely accepted as a means of localizing abnormal or aberrantly located parathyroid tissue. We describe a case in which ectopic retrosternal thyroid tissue appeared as a parathyroid adenoma on thallium-201/technetium-99m pertechnetate scan. Physicians who use this radionuclide study should be aware of the possibility of false-positive images within the mediastinum.

Pancreatic diabetes mellitus.

Diabetes mellitus caused by pancreatic exocrine disease is a unique clinical and metabolic form of diabetes. The diagnosis of pancreatic diabetes caused by chronic pancreatitis may be elusive because it is occasionally painless and often not accompanied by clinical malabsorption until after hyperglycemia occurs. Diabetic patients with pancreatic calcification or clinically demonstrable pancreatic exocrine dysfunction will manifest the unique aspects of pancreatic diabetes described herein. Like other forms of diabetes, the primary hormonal abnormality in pancreatic diabetes is decreased insulin secretion. Patients with this disorder are unique in that they have low glucagon levels that respond abnormally to several physiological stimuli, blunted epinephrine responses to insulin-induced hypoglycemia, and malabsorption. In addition, they often have concomitant alcohol abuse with hepatic disease and poor nutrition. These characteristics result in increased levels of circulating gluconeogenic amino acids, decreased insulin requirements, a resistance to ketosis, low cholesterol levels, an increased risk of hypoglycemia while on insulin therapy, and the clinical impression of brittle diabetes. Retinopathy occurs at a rate equal to that of insulin-dependent diabetes but may be less severe in degree. Other complications of pancreatic diabetes have been less well studied but may be expected to be seen more frequently as these patients survive longer. The characteristics of pancreatic diabetes suggest that a conservative approach be taken in regard to intensive insulin therapy and tight blood glucose control.

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.

The hypothalamic-pituitary-testicular axis in thyrotoxicosis.

The hypothalamic-pituitary-testicular axis was evaluated in seven men with thyrotoxicosis due to Graves' disease. Loss of libido and decreased potency were present in 71% and 56%, respectively. All patients had normal testicular volume (25 ml in all) and gynecomastia was detected in two of seven patients. Total sperm counts were less than 40 million in four of the five men tested. There was an inverse correlation between basal serum 17 beta-estradiol (E2) levels and total sperm count (r = -0.87; P less than 0.05). Mean (+/- SE) total testosterone (T) and E2 levels (1008 +/- 104 ng/100 ml and 104 +/- 16 pg/ml) were significantly higher than in normal men (P less than 0.05). Free T (13.6 +/- 2.4 ng/100 ml) was indistinguishable from normal (15.3 +/- 1.5 ng/100 ml). The mean (+/- SE) response of serum T to hCG administration was blunted (80 +/- 40%) compared to controls (193 +/- 19%; P less than 0.02). Basal plasma LH levels (15.5 +/- 1.5 mIU/ml) were significantly higher (P less than 0.05) than in normal men (9.1 +/- 0.6 mIU/ml) and hyperresponded to 100 microgram LRH iv in five of seven patients. Basal plasma FSH levels and the FSH response to LRH were normal. These results suggest that men with hyperthyroidism have 1) partial Leydig cell failure, 2) impairment of spermatogenesis, and 3) blunting of the feedback effects of E2.

The effects of pyridoxine on pituitary hormone secretion in amenorrhea-galactorrhea syndromes.

Six patients with amenorrhea, five of whom had galactorrhea and elevated PRL levels, were evaluated on a metabolic ward. All had normal sella tomograms, normal thyroid functions, and routine laboratory evaluations. None of the patients had taken any medication in the previous 6 months. On alternate days, five patients received 500 microgram of TRH iv with the measurement of PRL, TSH, FSh, LH, and hGH; 500 mg L-dopa orally with the measurement of PRL, FSH, and LH; a bolus infusion of 300 mg pyridoxine (B6) with measurement of PRL, hGH, TSH, FSH, and LH; and 25 mg chlorpromazine (CPZ) im with the measurement of PRL, LH, and FSH. The patients were then discharged on 600 mg oral pyridoxine/day and were readmitted for a repeat of the complete protocol 21 days later. The patients were continued on 600 mg oral pyridoxine for 3-4 months with monthly evaluations of serum PRL, LH, and FSH levels. These evaluations continued for 3 months after discontinuing pyridoxine. There was no demonstrable change in serum PRL after acute or chronic B6 therapy, mor was there a significant change in the response of PRL to CPZ, L-dopa, or TRH. The mean basal PRL was 97.5 +/- 9.7 ng/ml and after 3-4 months of oral pyridoxine was 97.1 +/- 14.8. In addition, there was no significant change in LH or FSH levels in response to acute or chronic B6, TRH, L-dopa, or CPZ. Neither acute B6 infusion nor chronic B6 therapy had any effect on TSH or the TSH response to TRH. Finally, acute B6 infusion had no effect on hGH levels and there were no paradoxical hGH responses to TRH. Two patients began having regular menses while on chronic pyridoxine. Their hormonal responses did not differ from those of the group, however.

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.

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.

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.

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.

Mild chronic watery diarrhea-hypokalemia syndrome associated with pancreatic islet cell hyperplasia. Elevated plasma and tissue levels of gastric inhibitory polypeptide and successful management with nicotinic acid.

A 46 year old woman is described who had a 13 half year history of watery diarrhea associated with hypokalemia and hypochlorhydria. The diarrhea was secretory as measured by triple lumen tube perfusion and was associated with an increased concentration of fasting plasma immunoreactive gastric inhibitory polypeptide (GIP) of 750 pg/ml which was stimulated to 4,000 pg/ml after a standard meal. The diarrhea decreased after partial pancreatectomy. Diffuse pancreatic islet cell hyperplasia was present and, although GIP was unmeasureable in the pancreas of normal subjects, it was at least 83 ng/g wet weight in this patient. Postoperatively, the patient's diarrhea responded dramatically to the oral administration of nicotinic acid.

Fine needle aspiration of the thyroid. Use in an average health care facility.

Fine needle aspiration of the thyroid is suggested as an initial diagnostic procedure in the evaluation of thyroid nodules. Some proponents of the procedure, however, believe that fine needle aspiration should be restricted to centers in which each operator obtains at least 500 biopsy specimens annually. Reviewed were 155 biopsy specimens obtained over three and one-half years, and the sensitivity of fine needle aspiration was determined to be 100 percent, the specificity to be 47.4 percent, and the accuracy to be 73 percent. A review of the literature revealed the sensitivity in larger series to range between 92 and 98 percent, specificity to range between 52 and 99.5 percent, and accuracy to range between 56.1 and 91.3 percent. The surgical yield of carcinoma was 64 percent in patients evaluated with fine needle aspiration, whereas the yield was 26 percent in those who underwent surgery without fine needle aspiration. These results appear to justify the use of fine needle aspiration in the evaluation of nodular thyroid disease at average-sized health care centers.

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.

Skeletal responsiveness in pseudohypoparathyroidism. A spectrum of clinical disease.

Three cases of pseudohypoparathyroidism with roentgenographic evidence of hyperparathyroid bone disease are described. Renal resistance to exogenous parathyroid hormone (PTH), the hallmark of pseudohypoparathyroidism, was documented by markedly blunted or absent urinary phosphate and cyclic AMP responses to parathyroid extract. At the time of diagnosis all patients were hypocalcemic and hyperphosphatemic with elevated serum alkaline phosphatase levels and subperiosteal resorption noted on skeletal films. Bone biopsy in one patient revealed a histologic appearance consistent with hyperparathyroidism. Serum PTH levels, measured in two patients while they were hypocalcemic, were elevated. None of the patients had short stature, brachydactyly, subcutaneous calcification or mental deficiency. These cases are compared to the 15 well-documented cases previously reported. The presently available information on pseudohypoparathyroidism indicates a variable skeletal response to PTH mediated by several factors extrinsic to bone and suggests that pseudohypoparathyroidism with hyperparathyroid bone disease is one extreme of a clinical spectrum of skeletal responsiveness to PTH. This disorder is part of an expanding clinical picture which makes pseudohypoparathyroidism a diagnostic consideration in any patient with unexplained hypocalcemia, hyperphosphatemia, elevated alkaline phosphatase levels or metabolic bone disease.

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.

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.