Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency.

Patients with adrenal insufficiency (AI) receive first glucocorticoid replacement dose after waking, resulting in a 3-5 h delay compared to physiological secretion. Impaired quality of life (QoL) and fatigue might be due to this delayed dose scheme. Modified-release glucocorticoid preparations might have therapeutic advantages. Exploratory pilot study including 14 patients with AI was conducted in a single university center. Patients on morning dose prednisolone (5 mg) were included, switched to modified-release prednisone (5 mg) at 10 PM for 3 months, and then switched back on standard prednisolone. 3 standardized questionnaires (GBB-24, MFI, and AddiQoL) investigating complaints and fatigue were completed at baseline, after 3, and 6 months. Data regarding clinical and hormonal parameters were assessed. Modified-release prednisone showed significant improvement in one of 4 scales of GBB-24 and positive trends to better scores in 3 of 4 scales. The global score of discomfort improved significantly. The MFI showed also significant improvement in 3 of 5 scales and positive trend to better scores in 2 scales. Significant changes to better scores were seen in 4 out of 30 items of the AddiQoL. Modified-release prednisone showed decreased complaints and fatigue compared to standard prednisolone indicating importance of glucocorticoid increase in early morning hours before waking.

Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy.

CONTEXT: Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis. OBJECTIVES: Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women? DESIGN AND PATIENTS: We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients. MAIN OUTCOME MEASURES: BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured. RESULTS: PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m(2) (range, 4.9-19.1) and 15.5 ± 7.8 mg/m(2) (range, 5.7-33.7), respectively. BMD varied within the normal reference range (-2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Ward's region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAI women treated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Ward's region compared to non-DHEA-treated women. CONCLUSIONS: Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addison's women.

Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens.

INTRODUCTION: The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. SUBJECTS AND METHODS: We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. CONCLUSIONS: We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context.

Assessment of suspected insulinoma by 48-hour fasting test: a retrospective monocentric study of 23 cases.

OBJECTIVE: Insulinoma causes fasting hypoglycaemia due to inappropriate insulin secretion. The diagnosis of insulinoma is based on Whipple's triad during a supervised fasting test. The aim of our study was to evaluate retrospectively the percentage of positive 48-hour fasting tests in a large series of patients with insulinoma. DESIGN, PATIENTS AND METHODS: In a retrospective study, we identified 39 patients (24 females, 15 men; average age 47 years [range 12-78 years]) with insulinoma. Sixteen patients were diagnosed by spontaneous hypoglycaemia. Twenty-three patients with insulinoma were tested with a 48-hour fasting test and compared to 31 healthy controls who had a negative fasting test and were followed up for at least two years. RESULTS: The fast was terminated due to neuroglycopenic symptoms in 4 patients (17.4%) at the 12th hour, in 17 patients (73.9%) at the 24th hour, and in 22 patients (95.7%) at the 48th hour. One patient with insulinoma had no neuroglycopenic symptoms, but was diagnosed by glucose and insulin levels during the 48-hour fast. Healthy controls had significantly higher blood glucose and lower insulin levels, and a lower insulin-glucose ratio than patients with insulinoma at the end of the fast. CONCLUSIONS: In conclusion, the 48-hour fasting test was successful in the diagnosis of insulinoma in 95.7% of patients. In this series we did not observe a need for fasting beyond 48 hours.

[Hypogonadism despite of normal testosterone levels]. / Hypogonadismus bei einem jungen Mann mit normalen Testosteronspiegeln.

We report on a 19 year old patient with clinical signs of hypogonadism (small testicles, missing pollutions and diminished beard growth) despite of normal testosterone levels. Further diagnostic procedures revealed panhypopituitarism with insufficiency of the gonadotrope, somatotrope and corticotrope axis due to a beta-HCG-producing suprasellar germinoma with intracerebral metastases. Paraneoplastic production of beta-HCG resulted in sufficient stimulation of Leydig cells with normal production of testosterone, which had partly masked clinical symptoms of gonatrope insufficiency. The patient was treated by combined radiochemotherapy and is in remission since 7 years.

[Hypophyseal ACTH-cell carcinoma after several surgical interventions and radiotherapy]. / Hypophysäres ACTH-Zellkarzinom nach mehreren chirurgischen Eingriffen und Strahlentherapie.

HISTORY AND ADMISSION FINDINGS: A 56-year-old woman was admitted to our hospital with headache, especially on the left temporal side, dizziness and exercise intolerance. She had been operated three times and radiotherapy once because of pituitary adenoma with intermittend hypercortisolism. The clinical examination was without abnormal findings apart from left temporal pain on pressure on the top of the skull. INVESTIGATIONS: Blood tests were entirely normal. At cranial magnet resonance imaging (cMRI) a left temporal tumor of 10 mm diameter was diagnosed. TREATMENT AND COURSE: The first histological study of the excized lesion could not clarify the diagnosis completely. Because of a local recurrent tumor of 20 mm, a second operation was necessary two months later. Due to structural and immunohistological similarities this tumor was identified as a metastasis of a pituitary ACTH-cell carcinoma. The patient was given adjuvant stereotactic radiotherapy. Two years after the treatment, no tumor recurrence was seen by cMRI. CONCLUSION: Carcinomas of the pituitary are very rare. They can be diagnosed only by their metastases. The pathogenesis is still unclear. It is debatable, whether surgery and/or X-ray therapy in the past may influence tumor development.

Enhanced serum prolactin (PRL) in patients with systemic lupus erythematosus: PRL levels are related to the disease activity.

Recent accumulated evidence suggests that prolactin (PRL) is an important immunomodulator and plays a part in the pathogenesis of systemic lupus erythematosus (SLE). The current study assessed the frequency of hyperprolactinaemia in patients with SLE and its association with defined clinical manifestations or serological abnormalities. PRL levels were analysed in 60 patients with SLE including a follow-up of 20 patients, 18 patients with rheumatic autoimmune diseases other than SLE (AID) and in 47 normal healthy subjects (NHS) using ELISA. Clinical manifestations and disease activity (ECLAM) were recorded. Autoantibodies (anti-dsDNA, anti-CL) were determined by standard techniques. In all, 28.3% of the patients with SLE had raised serum PRL. Their PRL levels (17.4+/-15.1 ng/ml, P<0.0001) and those of patients with AID (13.1+/-10.3 ng/ml, P<0.001) were significantly higher compared to NHS (6.3+/-3.2 ng/ml). Anti-dsDNA (r(s) = 0.3, P = 0.04) and anti-CL antibody titres (IgG; r(s) = 0.3, P = 0.03) correlated with PRL level. Furthermore, elevated erytthrocyte sedimentation rate (ESR), anaemia, decrease in C3, fatigue, fever and renal involvement were associated with hyperprolactinaemia. These results were confirmed by follow-up examinations. Moderate hyperprolactinaemia is present in a subset of patients with SLE and serum PRL correlates with clinical and serological disease activity.

A rapid screening for steroid 21-hydroxylase mutations in patients with congenital adrenal hyperplasia. Mutations in brief no. 247. Online.

Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia (CAH). CAH due to 21-hydroxylase deficiency is divided into three classes: salt-wasting (classical), non-classical and simple virilizing, reflecting different degrees of clinical severity. Using polymerase chain reaction (PCR) and allele-specific oligonucleotide hybridisation (ASO), we screened the DNA of 62 Caucasian CAH families (heterozygous parents and children) for 14 different and frequently-found CYP21-mutations (HGMD). Of the 62 patients (21 males, 41 females), 26 females and 11 males had the classical or salt-wasting form, 3 females and 1 male had the non-classical form and 14 females and 7 males had simple virilizing CAH. More than 60% of the patients were compound-heterozygous. We found the mutations on 110 alleles (out of 124 alleles). There were 30 CYP21 gene deletions/conversions, 3 substitutions (P30L) in exon 1, 30 splice mutations (c.93-13A/C>G) in intron 2, 26 point mutations (I172N) in exon 4, one cluster of mutations (I236N, V237E, M239K) in exon 6, 8 mutations (V281L and 1760-1761insT) in exon 7, and 8 nonsense (Q318X) and 4 missense (R356W) mutations in exon 8. Our study supports the case for using this rapid technique for CAH-family screening as long as alleles from both affected patients and parents are screened in parallel.

Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group.

We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.

[18-year-old patient with hypercalcemia, hypophosphatemia, nephrocalcinosis and normal iPTH values. Primary hyperparathyroidism]. / 18jährige Patientin mit Hyperkalziämie, Hypophosphatämie, Nephrokalzinose und im Normbereich gelegenen iPTH. Primärer Hyperparathyreoidismus.

We report an 18-year old woman with surgically proven primary hyperparathyroidism (pHPT) and normal intact parathyroid hormone (iPTH) serum levels. The reason for this rare biochemical presentation are possible biologically active amino-terminal parathyroid hormone polypeptide fragments not detected by the widely used two-site immunoradiometric parathyroid hormone assay (PTH IRMA). Diagnosis and therapy of primary hyperparathyroidism therefore should not exclusively rest on the finding of hypercalcemia coupled with an elevated iPTH level.

Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.

Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin-dependent) diabetes mellitus, we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison's disease.

[The long-term therapy of hypothalamic-hypophyseal Cushing's syndrome with mitotane (o,p'-DDD)]. / Langzeit-Therapie des hypothalamisch-hypophysären Cushing-Syndroms mit Mitotan (o,p'-DDD).

BACKGROUND AND OBJECTIVE: Drug treatment of hypothalamic-pituitary Cushing's syndrome is indicated if standard surgical intervention is not possible or has failed. The question arises whether, after unsatisfactory treatment with various adrenostatic drugs, mitotane (o,p'-DDD), used against adrenal cortical cancer, is efficacious and free of significant side effects when used long-term. PATIENTS AND METHODS: The results of long-term administration of mitotane to six patients, including one pregnant woman, were analysed retrospectively. After a moderate initial dosage of 3.0 g daily a maintenance dose of minimally 0.5 g per week was given or the treatment temporarily interrupted. The concentration of urinary free cortisol served as the main criterion of efficaciousness, together with the clinical course. The plasma concentrations of cortisol, aldosterone and ACTH were also determined, as well as routine clinicochemical parameters. RESULTS: Cortisol excretion became normal in all patients between the 2nd and 10th treatment month, falling from 919 +/- 621.3 nmol daily in the six months before treatment to 162 +/- 93.0 nmol daily in the third six-month treatment period (mean +/- standard deviation). Normal cortisol excretion and regression of symptoms was noted, dose-dependent, as long as the 12th year after start of treatment. Adrenocortical insufficiency occurred in one patient and at times required hormone substitution, followed by lasting remission without special treatment. Significant side effects were not observed other than a reversible increase in gamma-glutamyl transpeptidase. CONCLUSION: Mitotane proved to be an efficacious drug which in exceptional cases can be used without significant side effects in low dosage for the long-term treatment of hypothalamic-pituitary Cushing disease.

[Pregnancy in hyperprolactinemic patients]. / Schwangerschaften bei hyperprolaktinmischen Patientinnen.

In a retrospective study we analysed the outcome of 27 pregnancies in 17 hyperprolactinaemic patients. Cranial CT or MRI scans showed a microadenoma in 9, a macroadenoma in 7 and no change in 1 case. In 5 patients macroadenomas were surgically removed but a residual hyperprolactinaemia remained. In 2 patients with selectively removed microadenomas through the transsphenoidal route only in one case normal prolactin levels could be achieved. This patient became two times pregnant. In 24 patients pregnancy was induced by dopaminergic treatment whereas another patient with microadenoma became spontaneously pregnant after surgery and treatment with bromocriptine. The treatment was discontinued as soon as the pregnancy was recognised. 19 pregnancies were finished by spontaneous delivery and 3 by Caesarean section. Termination of pregnancy was artificially induced in 3 patients. One miscarriage was observed. Another patient was suffering from an extrauterine pregnancy. During pregnancy prolactin levels increased in comparison to basal levels. After delivery and lactation the same prolactin level was found compared to basal levels in patients with microprolactinomas. In patients suffering from macroadenomas prolactin levels decreased in comparison to basal levels. CT of MRI scan evaluations performed after delivery revealed a clinical not relevant increase as well as a decrease of tumor size in 2 cases, respectively. During pregnancy there was no complication due to tumor found in treated patients for hyperprolactinaemia. Only about one half of mothers were able to perform regular breast feeding.

Growth hormone-binding protein-related immunoreactivity in the serum of patients with acromegaly is regulated inversely by growth hormone concentration.

In this report we describe a newly developed radioimmunoassay (RIA) for the determination of the high-affinity growth hormone-binding protein (GHBP) in human blood. Using this RIA for the measurement of GHBP in serum of 29 patients with acromegaly, decreased concentrations were found compared to the normal range, depending on the activity of the disease. Growth hormone-binding protein was correlated inversely to log GH (r = -0.7, p < 0.001). A weaker relationship was shown between the GHBP activity determined in a functional assay based on charcoal separation and log GH (r = -0.51, p < 0.01). While insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) were correlated directly to log GH (r = 0.77 and r = 0.66, p < 0.001), an inverse and weaker relationship was evident between GHBP measured by RIA and IGF-I or IGFBP-3 (r = -0.61 and r = -0.57, p < 0.01). In contrast, no correlation could be detected between data of the functional GHBP assay and IGF-I or IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of insulin-like growth factor I (IGF-I) in normal adults, patients with liver cirrhosis and acromegaly: experience with a new competitive enzyme immunoassay.

A competitive enzyme immunoassay for the determination of human insulin-like growth factor I in microtiter plates was established. Using a polyclonal antiserum raised in rabbits against hIGF-I ovalbumin conjugate the assay system was able to detect IGF-I at a range of 12-800 pg/well with a sensitivity of 10 pg/well. It showed a low (< 0.5%) cross reactivity with hIGF-II. The serum concentrations of IGF-I found by EIA agreed well with those found in a conventional RIA (r = 0.965, p < 0.001). Effects of age and sex on IGF-I levels were studied in 260 normal adults. There was no evidence for sex differences but a steep decline of values from the third to the fourth and from the eight to the ninth decade, respectively. To asses the diagnostic capability of the IGF-I determination in liver cirrhosis, 71 sera of patients classified according to Child classes (A-C) were measured. Although significantly diminished concentrations were found in class B vs A and in class C vs B, the diagnostic sensitivity in cross-sectional examinations proved to be low (class A: 0.33, class B: 0.67). Only in the case of extensively destroyed liver parenchyma (Child C: 0.94) IGF-I was a good indicator of impaired hepatocellular capacity. In 29 patients with acromegaly serum IGF-I levels were investigated. All patients with active acromegaly showed increased IGF-I levels. In contrast, in inactive or weakly active acromegaly values were considerably lower.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnosis and therapy of thyroiditis]. / Diagnostik und Therapie der Thyreoiditis.

In general a heterogeneous group of diseases of the thyroid gland which have a common histological picture of an inflammatory infiltration is referred to as thyroiditis. In the last years increasingly is paid attention to these diseases, since they apparently become more frequent and diagnostics and also therapy have improved. In a review the diagnostic and therapeutic possibilities are discussed, whereby the most frequent forms, the Hashimoto and de Quervain thyroiditis, are described in detail. The individual forms of thyroiditis and particularly the thyroid malignoma are to be distinguished differential-diagnostically.