Anti-Müllerian hormone in women with hypopituitarism diagnosed before or during adolescence.

In women, anti-Müllerian hormone (AMH) is exclusively expressed in granulosa cells and an established marker of ovarian reserve. In menstrual cycle disorders, low AMH is usually interpreted as an indicator of primary ovarian insufficiency. This study is a case series of 11 patients with hypopituitarism. AMH concentrations were on or below the age-specific 25th percentile in three of the four patients diagnosed in infancy, but not in the remaining seven patients, who were diagnosed during adolescence or later. In patients with hypopituitarism, the detection of low AMH serum concentrations can present a diagnostic pitfall and its value in the interpretation of ovarian reserve in these patients is challenging.

[Multiple hemangiomas, polyposis coli, endometrial and papillary thyroid cancer]. / Multiple Hämangiome, Polyposis coli, Endometrium- und papilläres Schilddrüsenkarzinom.

A 27-year-old female patient presented with multiple lipomas and cavernous hemangiomas of the skin, hemangioma of the parotid gland, polyps of the gastrointestinal tract and endometrial carcinoma. After 1 year the patient presented with papillary thyroid carcinoma and a diagnosis of Cowden syndrome (CS) was made. Genetic testing revealed a pathogenic PTEN gene mutation. Hereditary tumor syndromes, such as CS are underdiagnosed. Clinical management can be adjusted to the needs of CS patients only if an early diagnosis is made. In CS the risk for thyroid, breast and endometrial cancer is severely increased.

Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance.

The effect of insulin and growth factor mediated signaling to gene regulation was investigated in cultured fibroblasts of a patient with a premature aging syndrome (metageria) and severe insulin resistance. Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. Inducibility of the proto-oncogene cfos, a representative endpoint of signaling pathways related to gene expression, by growth factors or insulin was reduced in patient cells. This reduced induction persisted in cfos promoter reporter gene studies indicating that the post receptor defect is localized proximal to the cfos promoter itself. Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. However, basal and inducible phosphorylation of Elk-1 was impaired. In addition, basal and stimulated transcriptional activity mediated by Elk-1 was almost abolished in patient cells. Therefore these results identify a post receptor defect in cFos induction, which appears to be related to a functional alteration of Elk-1. A possible relation of this signal transduction defect to the specific premature aging syndrome remains to be elucidated.

Identification of a novel mutation in the arginine vasopressin-neurophysin II gene in familial central diabetes insipidus.

Familial central diabetes insipidus is an inherited disease of predominant autosomal dominant trait characterized by a deficiency of arginine vasopressin. The arginine vasopressin-neurophysin II ( AVP-NPII) gene consists of three exons and is located on chromosome 20p13 encoding for the precursor protein of AVP. We investigated two Caucasian families with a typical autosomal dominant trait of familial central diabetes insipidus, defined by deficiency of arginine vasopressin. After PCR amplification of exon 1 and exon 2/3, fragments were pooled and purified. Nucleotide sequencing was performed with the Taq DyeDeoxy-terminator cycle sequencing method using nested primers. Two mutations in the coding region of NPII were identified. In family C we found a heterozygous G ==> C missense mutation (AA61) in exon 2 leading to the substitution of cystein with serine. In family D a novel heterozygous nonsense mutation in exon 3 (AA 83, GAG ==> TAG) was indentified, leading to a stop codon instead of glutamine. Both mutations were confirmed by restriction analysis and were found in all affected but not in healthy family members or control subjects. We therefore have identified a missense mutation of the AVP-NPII gene and a novel mutation predicting a truncated protein.

Five cases with central diabetes insipidus and hypogonadism as first presentation of neurosarcoidosis.

OBJECTIVES: We retrospectively reviewed 5 patients with neurosarcoidosis, who all presented with central diabetes insipidus and hypogonadism. DESIGN: This was a single-centre, retrospective analysis of 5 cases with a minimum follow-up of 2 years. METHODS: Case analysis included clinical, biochemical, and endocrinological evaluation and frequent CT/MRI scans of involved organs as primary evaluation and in response to immunosuppressive therapy. RESULT: Neurosarcoidosis was diagnosed in all patients. Two patients had no proven extracerebral manifestation and had a stable disease over 3 and 5 years. One patient showed deterioration with corticosteroids alone but partial remission after additional cyclophosphamide. Pituitary dysfunction remained unchanged in all patients, despite total clinical and radiological remission in two patients. However, one of these patients died of acute granulomatous meningoencephalitis after two years of follow-up. CONCLUSION: Although the presenting symptoms of neurosarcoidosis may vary, the occurrence of central diabetes insipidus associated with typical radiological features is suggestive of neurosarcoidosis. However, there is an increasing number of case reports on lymphocytic hypophysitis. Without the bioptic diagnosis, the differentiation between potentially lethal isolated neurosarcoidosis and lymphocytic hypophysitis is difficult. These cases demonstrate the difficulties in diagnosing neurosarcoidosis and reflect experiences with follow-up parameters.

Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men.

We investigated whether the androgen type or application mode or testosterone (T) serum levels influence serum lipids and lipoprotein levels differentially in 55 hypogonadal men randomly assigned to the following treatment groups: mesterolone 100 mg orally daily ([MES] n = 12), testosterone undecanoate 160 mg orally daily ([TU] n = 13), testosterone enanthate 250 mg intramuscularly every 21 days ([TE] n = 15), or a single subcutaneous implantation of crystalline T 1,200 mg ([TPEL] n = 15). The dosages were based on standard treatment regimens. Previous androgen substitution was suspended for at least 3 months. Only metabolically healthy men with serum T less than 3.6 nmol/L and total cholesterol (TC) and triglyceride (TG) less than 200 mg/dL were included. After a screening period of 2 weeks, the study medication was taken from days 0 to 189, with follow-up visits on days 246 and 300. Before substitution, all men were clearly hypogonadal, with mean serum T less than 3 nmol/L in all groups. Androgen substitution led to no significant increase of serum T in the MES group, subnormal T in the TU group (5.7 +/- 0.3 nmol/L), normal T in the TE group (13.5 +/- 0.7 nmol/L), and high-normal T in the TPEL group (23.2 +/- 1.1 nmol/L). 5 alpha-Dihydrotestosterone significantly increased in all treatment groups compared with baseline. Compared with presubstitution levels, a significant increase of TC was observed in all treatment groups (TU, 14.4% +/- 3.0%; MES, 18.8% +/- 2.5%; TE, 20.4% +/- 3.0%; TPEL, 20.2% +/- 2.6%). Low-density lipoprotein cholesterol (LDL-C) also increased significantly by 34.3% +/- 5.5% (TU), 46.4% +/- 4.1% (MES), 65.2% +/- 5.7% (TE), and 47.5% +/- 4.3% (TPEL). High-density lipoprotein cholesterol (HDL-C) showed a significant decrease by -30.9% +/- 2.8% (TU), -34.9% +/- 2.5% (MES), -35.7% +/- 2.6% (TE), and -32.5% +/- 3.5% (TPEL). Serum TG significantly increased by 37.3% +/- 11.3% (TU), 46.4% +/- 10.3% (MES), 29.4% +/- 6.5% (TE), and 22.9% +/- 6.7% (TPEL). TU caused a smaller increase of TC than TE and TPEL, whereas the parenteral treatment modes showed a lower increase of TG. There was no correlation between serum T and lipid concentrations. Despite the return of serum T to pretreatment levels, serum lipid and lipoprotein levels did not return to baseline during follow-up evaluation. In summary, androgen substitution in hypogonadal men increases TC, LDL-C, and TG and decreases HDL-C independently of the androgen type and application made and the serum androgen levels achieved. Due to the extended washout period for previous androgen medication and the exclusion of men with preexisting hyperlipidemia, this investigation demonstrates more clearly than previous studies the impact of androgen effects on serum lipids and lipoproteins. It is concluded that preexisting low serum androgens induce a "male-type" serum lipid profile, and increasing serum androgens further within the male normal range does not exert any additional effects. The threshold appears to be above the normal female androgen serum levels and far below the lower limit of normal serum T levels in adult men. These findings may have considerable implications for the use of androgens as a male contraceptive and for androgen therapy in elderly men.

Identification of mutations of the arginine vasopressin-neurophysin II gene in two kindreds with familial central diabetes insipidus.

Familial central diabetes insipidus is transmitted as an autosomal dominant trait with almost complete penetrance. Twenty-three different mutations of the arginine vasopressin-neurophysin II gene have been reported to date, located within the signal peptide-, the arginine vasopressin-, or the neurophysin II-coding region. In the present study two kindreds with familial central diabetes insipidus were examined. The entire coding region of the arginine vasopressin-neurophysin II gene of one affected subject of each family was amplified by PCR and subcloned into a pUC 18 plasmid, and six positive clones were sequenced. After identification of the mutation, direct sequencing was performed on the respective sequence of family members and 28 healthy control subjects. In family A, a missense mutation (C-->T) at nucleotide position 280 was detected, predicting the substitution of alanine by valine at position -1 of the signal peptide. All affected subjects were heterozygote for the mutation, whereas none of the unaffected family members or control subjects displayed the mutant sequence. In family B, a missense mutation within the neurophysin II-coding sequence was identified (nucleotide 1757, G-->C), predicting the substitution of glycine by arginine at position 23. Again, affected family members were found to be heterozygote for the mutation, which was not observed in unaffected family members or in control subjects. Although the mutation of family A was recently described in 3 other kindreds as well, the mutation within the neurophysin II-coding region represents a novel mutation of the AVP-NP II gene.

[Gynecomastia in men]. / Gynäkomastie beim Mann.

Gynecomastia is a very common symptom of an underlying hormonal imbalance in men. In addition to the three age peaks, a number of pathological conditions can also lead to an increase in the ratio of estrogen to androgen in the male, and thus provoke gynecomastia. While it is not necessary to carry out a thorough diagnostic investigation in every case of gynecomastia, the presence of an underlying tumor needs to be excluded. Should appropriate treatment of associated or causal pathology fail to resolve the problem, drug treatment or surgical options are available.

[The relevance of CDT (carbohydrate-deficient transferrin). Preoperative diagnosis of chronic alcohol abuse in intensive care patients following elective tumor resection]. / Der Stellenwert des kohlenhydratdefizienten Transferrin (CDT). Präoperative Diagnostik des chronischen Alkoholabusus bei intensivmedizinischen Patienten nach elektiver Tumorresektion.

The increase of alcoholism-related problems is associated with vital postoperative clinical complications in chronic alcohol abusers. In particular, the alcohol withdrawal syndrome (AWS) may provoke potentially life-threatening complications in alcohol-dependent patients. Hence, a precise diagnosis of alcohol dependence is mandatory preoperatively, requiring an extensive case history using alcoholism-associated questionnaires. Additional new biological markers for detecting alcoholism could improve the accuracy of preoperative diagnosis. Carbohydrate-deficient transferrin (CDT) reflects increased alcohol consumption. The aim of our interdisciplinary study was to investigate whether the validity of the preoperative diagnosis of chronic alcohol abuse might be improved by measuring CDT. METHODS. A total of 45 patients from the departments of Otorhinolaryngology, Maxillofacial Surgery, and Abdominal and Thoracic Surgery were included in our prospective clinical study. Patients underwent resection of malignant oral, pharyngeal, laryngeal, or oesophageal tumours and were transferred to the intensive care unit for postoperative management. Routine preoperative history, examinations, and laboratory tests including GGT, MCV, ASAT, and ALAT, were supplemented by a specific alcohol-related questionnaire and CDT measurement. The patients were categorised in four groups based on history and the questionnaire: continuously abstinent subjects; sober subjects for at least 7 days; chronic abusers; and dependent subjects. CDT was separated by isocratic anion exchange chromatography and quantified by turbidimetric determination. Statistical analysis was performed by the Kruskal-Wallis test. RESULTS. Preoperatively, 21 patients were at major risk for alcoholism-related complications: 12 were chronic abusers and 9 were diagnosed as dependent. CDT was significantly increased in both groups, and was pathologically elevated in 16 of the 21 patients. Sampling occurred significantly long after the last alcohol intake in the 5 patients with normal CDT values (median: 6.0 days; range: 2-12 days) compared with the 16 with pathologically elevated CDT levels (median: 1.0 day; range: 0-4 days; P = 0.002). The sensitivity of CDT elevation was 16 out of 24 (76%), the specificity 16 out of 16 (100%). Sixteen patients had no previous history of alcohol consumption (sober for at least 7 days) and 8 were definitely abstinent. Both of these groups had normal CDT values. CONCLUSIONS. CDT was a sensitive and specific marker for chronic alcohol consumption in our patient population. Since CDT is a state marker, repeated determinations might be useful to estimate a patient's drinking habits. The combination of CDT and an alcohol-related questionnaire was reliable for detecting alcohol-dependent patients preoperatively.