[Cushing's syndrome caused by paraneoplastic ACTH secretion 11 years after occurence of a medullary thyroid carcinoma]. / Cushing-Syndrom durch paraneoplastische ACTH-Sekretion 11 Jahre nach medullärem Schilddrüsenkarzinom.

HISTORY AND ADMISSION FINDINGS: A 47-year-old man, with known and treated hypertension for 2 years, was admitted because of recent marked weight gain. Eleven years before a medullary thyroid carcinoma had necessitated removal of his thyroid and parathyroids. He was not receiving levothyroxine, calcium and vitamin D. Physical examination revealed florid Cushing's syndrome with a "buffalo hump", plethora, truncal obesity and red striae. Both his mother and a maternal male cousin were reported to have had a medullary thyroid carcinoma. INVESTIGATIONS: Plasma ACTH was 80 pg/ml (normal 10-70 pg/ml), urinary cortisol 764 microgram/24 h (normal 20-100 microgram/24 h). ACTH rose to 93.1 pg/ml after dexamethasone, with little suppression of serum cortisol (reduced from 34.4 to 22.1 microgram/dl; normal 7-25 microgram/dl. Magnetic resonance imaging did not detected an abnormal hypophysis. Petrosal sinus catheterization revealed hypophyseal suppression of ACTH, without evidence of focal peripheral ACTH production. Calcitonin was 24 000 pg/ml (normal < 8.8 pg/ml). Computed tomography showed multiple round lesions in the liver (histology: metastasis of a C-cell carcinoma). Genetic test showed a multiple endocrine neoplasm type IIa. DIAGNOSIS, TREATMENT AND COURSE: The findings indicated Cushing's syndrome, most likely due to paraneoplastic ACTH secretion from a metastasis of the C-cell carcinoma. In the absence of a site of paraneoplastic ACTH secretion, bilateral adrenalectomy was performed. The plethora and striae regressed postoperatively and it was possible to reduce markedly the antihypertensive medication. CONCLUSION: An ectopic site of ACTH should be included in the differential diagnosis of Cushing's syndrome. This is the first reported case of a medullary thyroid carcinoma and ectopic ACTH production in which the paraneoplastic ACTH secretion had been delayed for 11 years.

Abnormal pentagastrin response in a patient with pseudohypoparathyroidism.

The case of a 25 year old female patient with pseudohypoparathyroidism type I (PHP) and hypercalcitoninaemia is reported. She was referred to our clinic because of recurrent hypocalcaemia associated with paraesthesias and muscle cramps. She had no signs of Albright hereditary osteodystrophy (AHO), a normal mental status and no family history of hypocalcaemia or any other endocrine disease. Considering the laboratory results with hypocalcaemia, hyperphosphataemia, normal vitamin D and normal creatinine with an extraordinary elevated PTH we diagnosed pseudohypoparathyroidism type I. She had delayed pubertal development with menarche in the age of 20 and hypothyroidism with an atrophic thyroid since she was 22 years old. Calcitonin (CT) was increased and the performed pentagastrin test showed an excessive CT-response with a peak of 725 pg/ml after 2 min. Up to now there are only three reports of patients with PHP and hypercalcitoninaemia. An abnormal pentagastrin response is known to be a specific marker for medullary thyroid carcinoma, but there were no signs of any malignant disease, even after one year of follow-up. The most reasonable cause for the pathological pentagastrin response might be chronic hypocalcaemia. When interpreting a pathological pentagastrin test in a patient with PHP the specifity of the test might be diminished and a careful observational strategy might be appropriate.

Suppressed levels of serum cortisol following high-dose oral dexamethasone administration differ between healthy postmenopausal females and patients with established primary vertebral osteoporosis.

Hypercortisolism and glucocorticoid treatment, even in a low dose or administered topically, may influence bone metabolism. It was the aim of this study to investigate whether there might be differences in the regulation of endogenous cortisol secretion between patients with established primary vertebral osteoporosis and healthy controls. Suppressed morning serum cortisol concentrations in a 3 mg dexamethasone overnight suppression test were compared in well-defined healthy postmenopausal women (n = 149) and osteoporotic patients classified as having established primary vertebral osteoporosis with no clinical features of hypercortisolism (n = 78). Suppressed cortisol in the healthy controls was 1.08 +/- 0.44 microg/dl and in the primary osteoporotics 1.58 +/- 1.42 microg/dl (p < 0.0001). Of the investigated primary osteoporotics 15.4% (n = 12) had suppressed cortisol levels above the 97.5th percentile (1.96 microg/dl) of the healthy controls. Subgroup analysis regarding the influence of gonadal steroid hormone replacement in both groups and gender in the osteoporotic group did not change the results. Four of the 12 patients with incomplete suppressive cortisol underwent adrenal endosonography, unilateral adrenal nodular hyperplasia being detected in three cases. In two patients the diagnosis was confirmed by histology and normalisation of a dexamethasone suppression test following endoscopic adrenalectomy. These data yield evidence for a difference in the regulation of cortisol secretion following high-dose dexamethasone administration between healthy subjects and a subgroup of patients with primary osteoporosis. This might be due to a relevant amount of autonomous cortisol secretion in some of these patients; however, even cortisol resistance has to be taken into account.

[Micromorphological findings in jaw bone after radiotherapy. Confocal laser scanning microscopy and fluorescence darkfield microscopy studies]. / Mikromorphologische Kieferveränderungen nach Bestrahlung. Untersuchungen durch konfokale Laser-Scanning-Mikroskopie und Fluoreszenzdunkelfeldmikroskopie.

Early radiation effects on human bone may lead to osteoradionecrosis (ORN). Direct bone cellular lesions [28] as well as fibrous degeneration of blood vessels [21] are considered to be pathologically relevant. Only few data on initial subclinical radiation effects are available. Patients were grouped according to the dose of radiation and clinical findings. Group 1: sound human bone of lower jaw, mostly collected during orthodontic surgery (n = 10 patients); group 2: specimens of lower jaw from patients with ORN (n = 12 patients); group 3: specimens of lower jaw from patients with head and neck cancer who were preoperatively treated with 36 Gy radiation; group 4: specimens of lower jaw from patients with head and neck cancer (n = 9) who were treated with 60-70 Gy radiation. Specimens were studied by confocal laser scanning microscopy (CLSM), by conventional light microscopy (DL) and by fluorescence darkfield microscopy (DFM) after bisbenzimide staining (H 33258) of the viable cellular nuclei. For the correlating study of identical areas in CLSM and DL the specimens were prepared according to the sawing and grinding technique [8]. All the radiated bony specimens, regardless of the dose of radiation, showed areas of extensive or total loss of vitality of the osteocytes. This finding was also evident after 36 Gy and a short interval between radiation and sample collection (group 3). Additionally, in CLSM micromorphologic lesions of the lamellate structure were seen. With these results we can confirm the loss of vitality of the osteocytes as an initial radiation effect as described earlier [10, 23, 28]. In addition to these findings, alteration of the lamellate microstructure was found in the early phase after radiation. The functional and mechanical significance of these findings should be the subject of further studies.

Confocal laser scanning microscopy: A nondestructive subsurface histotomography of healthy human bone.

Microscopy of bony tissue usually requires special treatment for decalcification and processing of thin sections. Confocal laser scanning microscopy (CLSM) allows the nondestructive histotomography of organic hard tissue. The aim of this study was to visualize healthy human bone structures and to correlate identical areas in CLSM and conventional light microscopy. Each sample of healthy human lower jaw (n = 20) was divided into three parts: (1) fresh, untreated bony blocks studied by CLSM; (2) MMA-embedded thin sections (without decalcification), HE stained and studied by CLSM and conventional light microscopy (correlation of identical areas); (3) decalcificated, HE stained, histological sections studied by conventional light microscopy. In untreated bony blocks, microstructures such as osteocytes and lamellae were identified by CLSM. These structures could be correlated with conventional light microscopy. In CLSM, subcellular structures cannot yet be interpreted, whereas cytoplastic processes of osteocytes were seen with high contrast. With CLSM, nondestructive histology of cortical bone can be obtained. The risk of artifacts due to pretreatment is minimized, and subsurface visualization does not affect the interpretation.

[Confocal laser scanning microscopy (CLSM) for validation of non-destructive histotomography of healthy bone tissue]. / Konfokale Laser-Scanning Mikroskopie (CLSM) Validierung der zerstörungsfreien Histotomographie gesunden Knochengewebes.

OBJECTIVES: Fixation (formalin), decalcification (sections) or mechanical treatment (grinding) all bear the risk of artifacts occurring during hard-tissue histology. Because studies on the etiology of pathological changes mostly focus on subclinical lesions, artifacts can simulate early changes or even be superimposed on existing changes. The objective of this study was to determine how artifacts can be reduced. MATERIAL AND METHODS: In confocal laser scanning microscopy (CLSM) a focused laser beam scans the surface of the specimens and penetrates into the tissue. The intensity of the remitted light is recorded. The confocal effect is due to an extremely small aperture (pin-hole), excluding light from out-of-focus planes of the sample. By stepwise movement of the object table, a tomographic series of tomographic images is obtained. Sound cortical bone samples of the lower jaw (n = 20) were studied by light microscopy and by CLSM, visualizing identical areas of a ground sectioned sample after H&E staining. Additionally, embedded and fresh blocks of tissue of the same bone sample were studied histotomographically in the CLSM. RESULTS: (1) Light microscopic micromorphology of cortical bone can be visualized adequately in the CLSM; (2) many structures that can be visualized by light microscopy only after special staining (e.g., osteozyte processes) can be visualized by the CLSM using sample blocks without pretreatment. CONCLUSION: (1) Nondestructive subsurface histotomography by CLSM totally excludes mechanical artifacts; (2) physicochemical artifacts can be handled more easily because fresh samples can be studied; (3) pseudo-three-dimensional imaging allows histological interpretation of the tissue that is equivalent to macroscopic tomographic techniques (CT, MRT).

Effect of long-term treatment with GH on bone metabolism, bone mineral density and bone elasticity in GH-deficient adults.

OBJECTIVE: Adults with GH deficiency (GHD) commonly have subnormal bone mineral density (BMD), and have been reported to have an increased risk of fractures. It has been suggested that GH replacement therapy may have beneficial effects on bone in such patients. The aim of this study was to investigate the effects of long-term GH replacement therapy on bone metabolism, BMD and bone elasticity in adults with GHD. DESIGN: At the start of the study, 20 adults with GHD were randomized to receive either GH, 0.25 IU/kg/week (the 'GH group') or placebo (the 'placebo group'). After 6 months, patients in the placebo group were switched to GH therapy, and all patients received GH for a further 42 months. PATIENTS: Of the 20 patients included in the study, 11 were male and nine were female. Mean age at the start of the study was 42.5 +/- 10.1 years. All patients had been GH-deficient for at least 2 years before the start of the study. MEASUREMENTS: Rates of bone resorption and formation were assessed by measuring serum levels of type I collagen carboxyterminal cross-linked telopeptide (ICTP) and carboxyterminal propeptide of type I procollagen (PICP), respectively. BMD was measured at the lumbar spine by dual-photon absorptiometry (DPA) and at the non-dominant forearm by single-photon absorptiometry (SPA). Bone elasticity was assessed by measuring apparent phalangeal ultrasound transmission velocity (APU). RESULTS: The main results in the GH group were as follows. The rate of bone resorption increased significantly during the first 6 months of treatment and remained significantly elevated above its baseline level thereafter. The rate of bone formation also rose during the first 6 months of treatment and remained elevated thereafter, but was significantly higher than at baseline only after 24 months of treatment. At both sites measured, BMD was subnormal at baseline, decreased during the first 6 months of treatment, and increased progressively for the rest of the study, eventually rising well above its baseline level. Bone elasticity decreased during the first 6 months of treatment, but had returned to its baseline level after 24 months. CONCLUSIONS: Our results support previous findings that BMD is subnormal in adults with GHD, that GH replacement therapy can stimulate bone turnover in such adults and that, in the long term, such stimulation results in a significant increase in BMD. In addition they show, for the first time, that BMD may continue to rise even after GH replacement therapy has been administered for 4 years, and indicate that bone elasticity is not adversely affected by long-term GH therapy.

Bone mineral density and bone metabolism in diabetes mellitus.

The effect of diabetes mellitus on bone metabolism and bone mineral density is discussed controversially. Diabetes mellitus due to an autoimmune process seems to be associated with low turnover osteopenia either in the animal model or in children and adolescents. A number of factors are discussed as being involved, but in this age group clinical symptoms are missing. Adult patients of either sex with IDDM show a reduced bone mineral density when measured at peripheral sites such as the distal forearm or the femoral neck, diabetic complications such as neuropathy and microangiopathy seem to pronounce the deficit of bone mass. In these patients, osteopenia is accompanied by a high turnover situation of bone metabolism, possibly due to microvascular complications. In contrast, patients with NIDDM and here especially overweight women have a normal or even increased bone mineral density. Up to now, there is no convincing evidence for an increased incidence of osteoporotic fractures in diabetic patients. Systemic diabetic osteopenia therefore does not seem to be of great epidemiological relevance.

Growth hormone substitution in growth hormone-deficient adults: effects on collagen type I synthesis and skin thickness.

Growth hormone stimulates collagen type I synthesis. Collagen type I is a common matrix compound in a large number of connective tissues. The aim of our study was to prove whether a stimulation of collagen type I synthesis might be accompanied by a deposition of collagen type I in the skin (cutis). Twenty growth hormone-deficient hypopituitary patients were included in a randomised, double-blind, placebo controlled, prospective, twelve-month study (eighteen patients assessable at the end of the study). The patients were treated with recombinant human growth hormone 0.25 U/kg/week subdivided in daily subcutaneous injections beginning with half the dosage during the first four weeks. During the first six months half of the patients were treated with placebo. PICP, the indicator of collagen type I synthesis, was increased after six months of therapy when compared to placebo. Skin thickness measured by ultrasound at the forearm and mechanically at the dorsum of the hand with strong compression of the skin both increased significantly following growth hormone substitution. Our data indicate that the stimulation of collagen type I synthesis by growth hormone substitution is followed by a deposition of collagen type I in the skin.

Validation of a mechanical method for measuring skin thickness: relation to age, body mass index, skin thickness determined by ultrasound, and bone mineral density.

In a number of endocrine disorders, typical changes in skin thickness can be observed which make measurement of skin thickness interesting in this field. A newly developed mechanical method for measuring skin thickness is presented. Using a digital measuring screw on the dorsum of the hand with a defined measuring force of 10 newton and a resulting tissue compression of 1500 mm Hg, highly reproducible results were obtained (mean coefficient of variation 2.56%). In 129 women, 37 to 78 years old, body mass index < 30 kg/m2, there was no significant relation between body mass index and skin fold thickness. A negative correlation between skin fold thickness and age (r = 0.37, p < 0.001) was detected. This has been shown for skin by other methods previously and is well known to occur in bone, another tissue whose matrix as well as dermis consists mainly of collagen type I. In 30 subjects, half hypopituitary patients, half healthy subjects (17 women, 13 men; 43.3 +/- 10.5 years old), skin fold thickness measured mechanically and sonographically determined skin thickness correlated with r = 0.46 (p < 0.01). A significant correlation between bone mineral density measured by single photon-absorptiometry at the ultradistal forearm and skin fold thickness measured mechanically was found and skin fold thickness measured mechanically was found (r = 0.36, p < 0.05), whereas this was not the case for sonographically determined skin thickness and bone mineral density (r = 0.13, n.s.). This newly developed method might be useful in clinical studies on endocrine disorders affecting skin (and bone) metabolism and the regulation of collagen type I metabolism in general.

In-vivo investigation of material quality of bone tissue by measuring apparent phalangeal ultrasound transmission velocity.

The square of ultrasound transmission velocity in a material is related to the modulus of elasticity, which is known to be an indicator of stability in bone. The aim of our study was to use ultrasound transmission velocity to obtain information about the material properties of bone tissue, keeping other factors possibly influencing ultrasound transmission as constant as possible. Apparent phalangeal ultrasound transmission velocity (APU) measured in 54 isolated, fresh pig phalanges was shown to be independent of bone mineral density (BMD) measured by SPA. Fastest sound transmission led exclusively through cortical bone so that intertrabecular connectivity in spongious bone could not influence the result. In humans APU was measured in the mediolateral direction at the midphalanx of the middle finger. In 53 healthy subjects (15-81 years old; 27 women, 26 men), there was a decrease of APU with age (r = -0.30, p < 0.05). Further, when comparing the results of both hands intraindividually almost identical values indicated constant intraindividual architecture of bone at this location. There was no evidence for a relation of APU to physical load comparing dominant and nondominant hand and relating the results to subjectively estimated physical load. In a second group of 43 perimenopausal women (47-60 years old), APU, which again decreased with age (r = -0.33, p < 0.05), was found not to be correlated to BMD measured by SPA at the distal forearm (cortical bone).(ABSTRACT TRUNCATED AT 250 WORDS)