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Summary Background Congenital adrenal hyperplasia caused by classic 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH-stimulated values of 17-hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21-Deoxycortisol (21DF), an 11-hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ. Objective To determine the discriminating value of basal and ACTH-stimulated serum levels of 21DF in comparison with 17OHP in a population of HTZ for 21OHD (n = 60), as well as in NC patients (n = 16) and in genotypically normal control subjects (CS, n = 30), using fourth generation tandem mass spectrometry after HPLC separation (LC-MS/MS). Results Basal 21DF levels were not different between HTZ and CS, but stimulated values were increased in the former and virtually nonresponsive in CS. Only 17·7% of the ACTH-stimulated 21DF levels overlapped with CS, when compared to 46·8% for 17OHP. For 100% specificity, the sensitivities achieved for ACTH-stimulated 21DF, 17OHP and the quotient [(21DF + 17OHP)/F] were 82·3%, 53·2% and 87%, using cut-offs of 40, 300 ng/dl and 46 (unitless), respectively. Similar to 17OHP, ACTH-stimulated 21DF levels did not overlap between HTZ and NC patients. A positive and highly significant correlation (r = 0·846; P

Summary objective Abnormal corticosteroid-binding globulin (CBG) is an extremely rare condition and only three mutations have been described in four families. The molecular basis of an abnormal CBG in a Brazilian family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined. subjects All 10 family members, comprising three generations, and nine healthy volunteers were studied. measurements Genomic DNA was extracted from white blood cells from all family members. The human cbg exons 2–5 were amplified by PCR, submitted to automatic sequencing. Cortisol and CBG levels in serum were measured by radioimmunoassay (RIA). CBC in serum was determined using tritiated cortisol and other cortisol binding parameters were calculated through Scatchard analysis. results A missense mutation in exon 5 of cbg (1254G → A; Asp367Asn), recently described as CBG Lyon, was found in all family members. The proband and one sister were homozygous whereas all other family members, including parents, were heterozygous for this mutation. Cortisol levels in the only two homozygotes were lower than in heterozygotes and both were significantly lower as compared to controls (69 and 182 nmol/l vs. 267 ± 129 nmol/l vs. 459 ± 195 nmol/l, respectively, P

Summary objective Hyperprolactinaemia is caused by high levels of monomeric, dimeric or macro forms of prolactin in circulation, the monomeric form being predominant in patients with prolactinomas. Macroprolactinaemia, however, is common and is associated with asymptomatic cases. In this study, we reviewed our records regarding clinical and imaging investigations in patients who were found to have hyperprolactinaemia predominantly due to the presence of macroprolactin and compared them with the findings observed in patients whose prolactin molecular size consisted predominantly of the monomeric form. patients and methods We conducted a retrospective study of 113 consecutive patients (nine men and 104 women, aged 19–67 years, median age 39 years) with hyperprolactinaemia who were screened for the presence of macroprolactin by polyethylene glycol precipitation and/or chromatography and submitted to pituitary magnetic resonance imaging (MRI) and/or computerized tomography (CT). results Fifty-two of 113 patients (46%) had hyperprolactinaemia due to macroprolactin, whereas the remaining 61 patients (54%) had their hyperprolactinaemia confirmed by the predominance of the monomeric form. Both groups shared similar mean prolactin levels (79·9 ± 63·6 µg/l, median of 62·0 µg/l, and 97·9 ± 155·4 µg/l, median of 61·0 µg/l, respectively). Of the patients with macroprolactinaemia, 46% had no symptoms of hyperprolactinaemia, whereas only 10% of the patients who screened negative for macroprolactin were asymptomatic. There was an association between macroprolactinaemia and negative pituitary imaging findings: normal pituitary images were found in 78·9% of patients who had macroprolactinaemia and in 25% of patients with monomeric hyperprolactinaemia. In addition, none of the patients with macroprolactinoma (seven cases) had macroprolactinaemia. conclusions The presence of macroprolactinaemia does not exclude the possibility of a pituitary adenoma and consequently may not prevent pituitary imaging studies. However, our data demonstrate that all asymptomatic patients who screened positive for macroprolactin had normal pituitary imaging studies. Patient samples showing hyperprolactinaemia should be first tested for macroprolactin, before the patient is submitted to imaging studies. We suggest that imaging studies should be ordered in patients with macroprolactinaemia when indicated by clinically relevant features. As a result, unnecessary anxiety and costly medical procedures may be prevented.

Due to the increasing availability and sensitivity of diagnostic methods, biochemical and imaging abnormalities of pituitary function and anatomy are becoming more frequent. Hyperprolactinaemia was found in three women without any prolactin (PRL) related clinical features. All three patients had normal libido, regular menses with evidence of ovulation, no galactorrhoea, and normal FSH, LH, TSH and free T4 serum levels. Magnetic resonance imaging (MRI) of the sellar region showed images that were compatible with pituitary microadenomas in all three cases. Due to the discordance between laboratory and clinical features, we searched for the presence of PRL aggregates with high molecular weight and low biological activity (macroprolactinaemia). Initially, we screened with a polyethylene glycol precipitation method, and then confirmed the presence of macroprolactinaemia by chromatography. All three cases screened positive for the presence of macroprolactinaemia. MRI alterations, compatible with pituitary microadenomas, may be due to true microincidentalomas, normal anatomical variations or imaging artefacts. In conclusion, we have described the presence of double diagnostic pitfalls that might lead to unnecessary medical or surgical intervention.

OBJECTIVE We have investigated the effects of the inhaled corticosteroid flunisolide on bone metabolism and adrenal function in patients with moderate asthma. SUBJECTS AND DESIGN Twenty ambulatory patients (13 females, 7 males, mean age ± SD of 36.4 ± 12.4 years) with moderate asthma were recruited. None had taken corticosteroids for at least 1 month. Flunisolide 500 μg was given twice a day for 10 weeks, without any other medication. Blood and urine were collected before and at the end of treatment course. Cortisol (basal and 1 h after ACTH 250 μg i.v.) was measured to evaluate adrenal function. A peak cortisol response of 496 nmol/l was considered an adequate response. Serum ionized calcium, intact PTH, plasma osteocalcin (OC) and urinary pyridinoline (Pyr) and deoxy-pyridinoline (D-Pyr) were measured to evaluate bone metabolism. Wilcoxon paired test was performed for statistical analysis. Results are expressed as mean ± SD. RESULTS In most patients (85%), there was no difference after treatment with flunisolide on basal and stimulated cortisol levels. We found a significant decrease of OC (3.55 ± 1.42 to 2.97 ± 1.05 nmol/l) and Pyr (66.4 ± 20.0 to 59.5 ± 24.9 pmol/μmol creatinine) levels after treatment (P

OBJECTIVE The frequency of gonadoblastoma is high in patients with Turner's syndrome bearing cells with Y or partial Y-chromosome. About 60% of patients with Turner's syndrome have a 45,X karyotype. In 30% of them a Y-sequence is disclosed by DNA analysis. To identify patients at risk of developing gonadoblastoma, a PCR based assay with SRY, ZFY and DYZ3 specific primers was carried out to detect different Y-sequences in the DNA of peripheral lymphocytes from patients with Turner's syndrome. DESIGN AND PATIENTS Peripheral blood karyotypes from 36 patients with Turner's syndrome were studied. Patients with proven Y-chromosomal material were excluded. Genomic DNA was extracted from peripheral blood. SRY and ZFY genes and DYZ3 repetion of Y-chromosome were amplified by PCR. Patients with clinical signs of hyperandrogenism or with positive Y-sequences by PCR underwent gonadectomy. The gonadal tissues were examined for Y-sequences using PCR, morphology and immunohistochemical study. MEASUREMENTS Turner's syndrome and signs of hyperandrogenism were evaluated both clinically and through laboratory tests. Haematoxylin and eosin staining was employed in gonadal morphology studies. The presence of testosterone was detected by immunohistochemistry using a monoclonal antibody. RESULTS Two patients who had Y-positive blood samples and three hyperandrogenic (2 hirsutes, 1 virilized) Y-negatives underwent gonadectomy. PCR was carried out on their gonadal tissue. The tissue from the two patients without hyperandrogenism was Y-positive. The gonadal tissue from the three hyperandrogenics was Y-negative. Gonadal morphology disclosed hilus cell hyperplasia in the 3 hyperandrogenic Y-negatives and in one Y-positive patient; stromal luteoma and hyperthecosis in the virilized patient, cystadenofibroma in one hirsute patient and gonadoblastoma in one Y-positive. Testosterone was detected immunohistochemically in the hilus cell hyperplasia, stromal luteoma and hyperthecosis found in the hyperandrogenic patients. CONCLUSIONS The molecular study was sensitive and useful in the evaluation of patients at risk of developing gonadoblastoma. Other nontumour, gonadotrophin-dependent and Y-independent mechanisms which deserve the same medical approach may be involved in the genesis of hyperandrogenic signs in Turner's syndrome.

OBJECTIVE Since panhypopituitarism in patients with Sheehan's syndrome is due to massive pituitary necrosis with only minor hypothalamic involvement, we hypothesized that serum TSH levels would be low but its circadian rhythm preserved in these patients. DESIGN AND PATIENTS Basal and TRH-stimulated mean afternoon (1500–1700 h) and nocturnal (0100–0300 h) TSH levels were determined in 10 patients with Sheehan's syndrome before and during T4/glucocorticoid replacement and in seven controls. MEASUREMENTS Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radioimmunoassay; TSH, GH, PRL and LH were determined by immunofluorimetric assay. RESULTS Afternoon TSH levels were markedly increased in Sheehan's syndrome patients compared with controls (3.3 ± 1.0 vs 0.5 ± 0.15 mU/l, respectively, P = 0.002). At night, TSH levels remained unchanged in Sheehan's syndrome patients (3.3 ± 1.1 mU/l) but rose significantly in controls (1.1 ± 0.34 mU/l, P = 0.016). The nocturnal TSH increment was significantly higher in controls than in patients (143 vs−4.9%, respectively, P = 0.0001). In eight patients with normal serum fT4 levels during treatment, basal TSH levels decreased to 0.16 ± 0.05 mU/l (P≤ 0.008), being barely detectable or undetectable in four patients. In the six patients with detectable TSH during treatment, nocturnal TSH increments were normal in four and blunted in two. There was a strong correlation between pre- and post-treatment basal TSH (r = 0.82, P = 0.012) and between pre- and post-treatment peak TSH after TRH (r = 0.91, P = 0.0017), but no significant correlation between TSH and thyroid hormone levels. The per cent ratio of peak TSH after TRH between treated patients and controls, an estimate of the relative size of the functional thyrotroph pool in Sheehan's syndrome patients, was 7%. CONCLUSIONS Loss of TSH rhythm in Sheehan's syndrome is usually secondary to hormonal deficiency and results from maximally increased secretory activity of a decreased pool of thyrotrophs. The paradox of increased TSH levels and decreased thyroid function in Sheehan's syndrome could result from decreased TSH bioactivity and/or from a critically reduced thyrotroph population that fails to sustain sufficient TSH secretion in the face of rising serum thyroid hormone levels.