Serial changes in bone mineral density and bone turnover after correction of secondary hyperparathyroidism in a patient with pseudohypoparathyroidism type Ib.

Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and secondary hyperparathyroidism caused by primarily renal resistance to the effects of parathyroid hormone (PTH). However, as an indication of normal PTH responsiveness in bone, some patients with PHP develop skeletal disease because of longstanding secondary hyperparathyroidism. A patient is described with hypocalcemia, hyperphosphatemia, marked secondary hyperparathyroidism, and an increased alkaline phosphatase level. Subsequent evaluation revealed a diagnosis of PHP type Ib. The patient had radiographic evidence of skeletal disease caused by secondary hyperparathyroidism. A urinary level of N-telopeptide cross-links of type I collagen (NTX) was elevated markedly. Bone mineral density (BMD) was in the normal range at all measured sites, with BMD at the spine being higher than at the femur and distal radius. Treatment was initiated with calcium and calcitriol. Seven months later, calcium and PTH levels had normalized. The level of urinary NTX fell by 83%. Spinal BMD improved by 15%, and BMD at the femoral neck improved by 11%. Radial BMD was unchanged. This case emphasizes the importance of evaluating patients with PHP for hyperparathyroid bone disease and shows that correction of secondary hyperparathyroidism in patients with PHP can result in a significant suppression of previously accelerated bone turnover and to substantial gains in BMD at sites containing a major percentage of cancellous bone. The case also implies that assessment of bone turnover with urinary NTX and measurement of BMD with dual-energy X-ray absorptiometry (DEXA) may be useful in following the response of the skeleton to therapy in these patients and suggests the need for more studies of both NTX and BMD in patients with PHP.

Bone density is normal in male rats treated with finasteride.

Bone is an androgen-dependent tissue. It is not known whether normal bony growth and mineralization in males is dependent on testosterone alone, or whether its metabolite, dihydrotestosterone (DHT), also is required. To answer this question, we examined the effect of finasteride, an inhibitor of DHT synthesis, on bone in rats. Three-month-old male rats were treated with placebo, finasteride, or orchidectomy. The bone mineral densities (BMD) of the spine and whole body were measured in vivo by dual x-ray absorptiometry at weeks 0 and 11, and the BMD of the femur and tibia were measured ex vivo at week 11. Histomorphometric analysis was performed on the proximal tibia at week 11. The increase in spine and whole body BMD in finasteride-treated rats did not differ from that in controls, whereas these values were significantly lower in orchidectomized rats. Similarly, the BMD of the femur and tibia and the cancellous bone volume of the proximal tibia in finasteride-treated rats did not differ from those in controls, whereas these values were significantly lower in orchidectomized rats. In summary, bone development and density were normal in rats treated with finasteride. We conclude that selective DHT deficiency is not deleterious to the male rat skeleton.

Finasteride therapy does not alter bone turnover in men with benign prostatic hyperplasia--a Clinical Research Center study.

Benign prostatic hyperplasia is often treated with finasteride, which inhibits the conversion of testosterone to dihydrotestosterone (DHT). Aside from the prostate, other androgen-dependent tissues seem to be unaffected by selective DHT deficiency, but the effect on bone density in humans has not yet been defined. To study this question, we compared indices of bone turnover and bone mineral density in 35 men treated with finasteride with controls. Bone resorption was assessed by measuring urinary excretion of N-telopeptide cross-links of type I collagen and hydroxyproline, and bone formation was assessed by measuring serum osteoncalcin and bone-specific alkaline phosphatase. Bone density of the spine and hip were assessed by dual energy x-ray absorptiometry. We found that finasteride-treated patients had mean DHT levels 81% lower than controls (P < 0.0001). There were no significant differences between the two groups in any of the markers of bone turnover or measures of bone density. These results suggest that testosterone can maintain bone density in men even in the absence of DHT. Although long term studies are needed, our results suggest that men who take finasteride are not at increased risk for bone loss.

The thyroid hormone receptor-beta gene mutation R383H is associated with isolated central resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T4 and T3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received three escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-beta mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation.

The use of fine-needle aspiration biopsy under ultrasound guidance to assess the risk of malignancy in patients with a multinodular goiter.

PURPOSE: Fine-needle aspiration biopsy (FNAB) is a commonly performed procedure used in the evaluation of solitary thyroid nodules, in which the risk of malignancy is approximately 5% in most patients. Recently, the use of ultrasound (US) guidance in FNAB has been shown to enhance the diagnostic efficacy of this procedure. However, the risk of malignancy in thyroid nodules occurring within a multinodular goiter (MNG) has not been completely clarified, nor has the optimal means of investigating such nodules using FNAB. SUBJECTS AND METHODS: We performed a retrospective study of all patients seen over a 4-year period with a MNG that had one or more nodules who underwent FNAB under US guidance. The results from the history and physical examination, thyroid function and antibody tests, radionuclide studies, thyroid sonogram, cytology of aspirated nodules, and surgical pathology were recorded and analyzed. RESULTS: A total of 93 nodules were aspirated in 61 patients with MNG. Adequate material was obtained in 96% of aspirates on the first attempt. Sixty-seven aspirates in 44 patients yielded benign cytology and 22 aspirates in 15 patients yielded suspicious cytology. All patients with suspicious cytology underwent thyroid surgery. Thyroid cancer was found in 5 of these nodules, including 4 cases of papillary cancer and 1 case of Hürthle cell cancer, and 1 additional patient had occult papillary cancer discovered. The overall malignancy rate in thyroid nodules among the patients with MNG was approximately 5%. CONCLUSIONS: FNAB under US guidance is a useful diagnostic modality in the evaluation of thyroid nodules in selected patients with MNG. Because the risk of thyroid malignancy in these nodules is comparable to that which exists in solitary thyroid nodules, the possibility of thyroid malignancy should be considered in all patients with MNG.

Diagnosis of Candida thyroiditis by fine needle aspiration.

Infective thyroiditis is an uncommon condition, and fungal infection of the thyroid gland is rare. We present a case of Candida thyroiditis in a patient with leukaemia and review the three previous reports of this entity in the world's literature. We conclude that Candida thyroiditis should be considered in immunosuppressed patients with known infection who develop fever and neck pain, that gallium scanning may help localise the infection to the thyroid gland; that fine needle aspiration is a useful diagnostic test, and that thyroid dysfunction is common with Candida thyroiditis.

Course and outcome of pregnancy in a patient with mild, asymptomatic, primary hyperparathyroidism diagnosed before conception.

Primary hyperparathyroidism (PHP) during pregnancy is well known to confer an increased risk of complications to both the mother and the fetus. However, the risks and optimal management of patients with mild, asymptomatic disease during pregnancy are much less clear. We observed a patient with mild, asymptomatic PHP who was diagnosed before conception through pregnancy. The patient remained asymptomatic through the first 22 weeks of pregnancy, and her calcium levels remained under 11 mg/dL. This occurred despite a dramatic elevation in the level of 1,25-dihydroxyvitamin D and marked hypercalciuria. Parathyroid surgery was performed at 22 weeks of gestation and a parathyroid adenoma was removed. Postoperatively, the patient's calcium level normalized and the rest of the pregnancy was uncomplicated. The patient delivered a healthy baby at 40 weeks of gestation. The neonatal course was unremarkable. We conclude that mild, asymptomatic PHP during early pregnancy is compatible with normal fetal development and an uncomplicated pregnancy and that the serum calcium level in such patients can remain stable with medical management alone, despite the marked changes in maternal calcium metabolism that characterize normal pregnancy.

Case report: postpartum hypopituitarism in a patient with sickle cell trait.

The authors report a case of hypopituitarism in a 28-year-old woman who appeared to develop this in conjunction with a pregnancy 4 years previously. The patient had clear-cut evidence of secondary hypoadrenalism and secondary hypothyroidism. A magnetic resonance imaging scan revealed a partially empty sella of normal size. The patient had no prior evidence of peripartum hypotension or other obstetrical catastrophe. Her only recognizable risk factor was the presence of sickle cell trait. The authors speculate that her sickle trait predisposed her to develop pituitary infarction during her first pregnancy. The authors also review three previous cases linking sickle cell syndromes with hypopituitarism and suggest that this case further supports the concept that sickle cell syndromes can predispose affected individuals to pituitary infarction and ultimately to subsequent hypopituitarism.

Idiopathic giant-cell granulomatous hypophysitis mimicking acute meningitis.

A 32-year-old woman presented with severe headache, photophobia, fever, nausea, vomiting, and worsening vision. She had also noted several months of amenorrhea. She was febrile to 38.9 degrees C. Laboratory evaluation revealed a markedly elevated erythrocyte sedimentation rate. Lumbar puncture revealed a cerebrospinal fluid lymphocytic pleocytosis and an elevated protein level. Endocrine studies revealed evidence of panhypopituitarism without diabetes insipidus. A magnetic resonance imaging study showed a 2-cm pituitary mass with optic chiasmal compression. The patient had a trans-sphenoidal resection of the mass. Pathology revealed multinucleated giant cells in necrotic debris, but no evidence of pituitary tumor. Studies looking for evidence of systemic granulomatous disease were negative. The patient was considered to have idiopathic giant-cell granulomatous hypophysitis. After surgery, the patient's vision improved and hormone replacement therapy was initiated. This case illustrates that idiopathic giant-cell granulomatous hypophysitis should be considered in the differential diagnosis of a patient presenting with a pituitary mass, hypopituitarism, and meningitis-like symptoms.

The utility of thyroid nuclear imaging and other studies in the detection and treatment of underlying thyroid abnormalities in patients with endogenous subclinical thyrotoxicosis.

PURPOSE: Endogenous subclinical thyrotoxicosis is diagnosed when a patient who is not taking exogenous thyroid hormone has a suppressed level of thyroid-stimulating hormone with normal levels of the free thyroid hormones thyroxine and triiodothyronine and other known causes of a suppressed thyroid-stimulating hormone level have been excluded. Although such a condition is caused by underlying thyroid disease, the specific nature and relative prevalence of these disorders and the utility of nuclear imaging and other studies in their detection remains unclear. PATIENTS AND METHODS: The authors performed a retrospective study of 50 patients with endogenous subclinical thyrotoxicosis. The results of the history and physical examination, thyroid nuclear scan, radioactive iodine uptake measurement, and thyroid antibody studies were reviewed. The results of the nuclear imaging and thyroid antibody studies were combined in an attempt to establish an underlying diagnosis for each patient. RESULTS: The thyroid nuclear imaging and antibody studies were used to establish a specific thyroid disorder in most of the patients (n = 39). These disorders included most commonly toxic multinodular goiter, various forms of autoimmune thyroid disease, and solitary toxic adenoma. A specific diagnosis was not determined in 11 patients. Therapy with I-131 radioactive iodine was administered to 14 of these patients, 13 of whom subsequently achieved a normal thyroid-stimulating hormone level. CONCLUSIONS: Most patients with endogenous subclinical thyrotoxicosis have underlying thyroid abnormalities that can be determined by nuclear imaging and, in selected cases, thyroid antibody studies.

Use of the dopamine agonists bromocriptine and cabergoline in the management of risperidone-induced hyperprolactinemia in patients with psychotic disorders.

Risperidone is a novel antipsychotic agent that blocks both dopaminergic and serotonergic receptors. In several reports, clinically significant hyperprolactinemia has been reported in patients on this agent. However, the optimal management of risperidone-induced hyperprolactinemia has not been clarified. We reviewed the records of 5 patients with psychotic disorders who were evaluated for risperidone-induced hyperprolactinemia. There were 4 females and 1 male patient, aged 30-45 yr. All patients had significant hyperprolactinemia, with prolactin (PRL) levels ranging from 65.5 to 209 microg/l. All but 1 of these patients had manifestations of hypogonadism. In these 4 patients, risperidone therapy was continued and the dopamine agonists bromocriptine or cabergoline were added. In 3 out of 4 patients, such additional therapy reduced the PRL level and alleviated hypogonadism. None of the patients treated with these agents had a worsening of psychosis. We conclude that risperidone can cause clinically significant hyperprolactinemia in patients treated with this drug. If risperidone therapy must be continued in such patients, addition of the dopamine agonists bromocriptine or cabergoline may successfully alleviate hyperprolactinemia and the associated manifestations without worsening psychotic symptoms.

Differentiating between orchiectomized rats and controls using measurements of trabecular bone density: a comparison among DXA, histomorphometry, and peripheral quantitative computerized tomography.

In studies of rat bone metabolism, trabecular bone density should be measured. Three established methods of measuring trabecular bone include trabecular bone volume by histomorphometry (BV/TV%), trabecular bone density by peripheral quantitative computerized tomography (pQCT), and areal bone density of trabecular-rich regions by dual x-ray absorptiometry (DXA). We compared the ability of these three methods to discriminate between orchiectomized (orchidectomized) rats and controls. Sixteen male Sprague-Dawley rats (400-425 g) were orchiectomized, and 16 others were controls. In vivo spine bone mineral density (BMD) was measured at the beginning of the study and again after 11 weeks. Rats were sacrificed, and ex vivo BMDs of the right femur and tibia were measured by DXA, followed by trabecular bone density of the right proximal tibia by pQCT. BT/TV% of the left proximal tibia was measured by histomorphometry. Differences between groups were detected by all three methods, but both the magnitude of the difference between groups and the variance of the measurements was much greater for histomorphometry and pQCT than for DXA. Consequently, the statistical significance for the difference between groups was comparable for all three methods. Of the sites measured with DXA, the proximal tibia had the greatest statistical significance for the difference between groups. In summary, all three methods can demonstrate the effect of orchiectomy on trabecular bone. The large differences between groups seen by histomorphometry are also seen by pQCT but not by DXA. We conclude that trabecular bone density by pQCT may be a reasonable surrogate for measurements by histomorphometry.

A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of RTH, which only leads to abnormal pituitary TSH secretion (PRTH), is unclear. In a patient with PRTH, a novel mutation of a conserved arginine residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced function on stimulatory thyroid hormone response elements found in peripheral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a member of the nuclear receptor superfamily that selectively abolishes hormone-dependent inhibition and localizes a novel C-terminal domain necessary for this property.