Neuropsychiatric and cardiometabolic comorbidities in patients with previously diagnosed Cushing's disease: a longitudinal observational study.

INTRODUCTION: Only few studies have systematically investigated neuropsychiatric aspects in patients with Cushing's disease (CD). Pain syndromes have been described in patients with pituitary adenomas, but so far no systematical investigation has been conducted in patients with CD. Additionally, CD has an association with cardiometabolic comorbidities which ultimately leads to increased morbidity and mortality. Long-term treatment of the hypercortisolic state cannot prevent the persistence of an unfavourable cardiometabolic risk profile. Finally, chronic hypercortisolism is known to impact the health-related quality of life (HRQoL). We aim to systematically investigate the neuropsychiatric and cardiometabolic comorbidities, as well as assess the HRQoL, in patients with previously diagnosed CD in a longitudinal fashion. METHODS AND ANALYSIS: In this longitudinal study, we will assess 20 patients with CD displaying biochemical control 24 months after recruitment in the initial cross-sectional study (n=80). This will be a mixed cohort including patients after surgical, after radiation therapy and/or under current medical treatment for CD. Primary outcomes include changes in mean urinary free cortisol and changes in specific pain patterns. Secondary/exploratory neuropsychiatric domains include depression, anxiety, personality, sleep, body image and quality of life. Secondary/exploratory cardiometabolic domains include anthropometric parameters, cardiometabolic risk biomarkers and insulin resistance. Additional domains will be investigated if warranted by clinical indication. Safety assessment under medical therapy will include liver enzymes, ECG abnormalities and hyperglycaemia. ETHICS AND DISSEMINATION: Risk of damage from study-conditioned measures is very small and considered ethically justified. Dual-energy X-ray absorptiometry may call for detailed fracture risk assessment. However, the radiation dose is very small and only administered on clinical indication; therefore, it is considered ethically justified. This protocol has been approved by the local medical ethics committee.

Specific behaviour, mood and personality traits may contribute to obesity in patients with craniopharyngioma.

INTRODUCTION: Patients with craniopharyngioma (CP) often suffer from obesity, but the underlying causes are still not fully understood. We compared CP to patients with nonfunctioning pituitary adenoma (NFPA) and to a control group (CG) using standardized questionnaires to investigate whether behavioural, mood or personality traits contribute to obesity. METHODS: We compared 31 patients with CP (42% male, 53 ± 15·1 years) to 26 patients with NFPA (71% male, 63·2 ± 10·3 years) and to age- and gender-matched local CG (ratio 2:1). Normative data from the literature are included for reference. Patients were asked to complete eleven standardized questionnaires. Two questionnaires were used to evaluate eating disorders (FEV, EDE-Q), one depression (BDI), one anxiety (STAI), three health-related quality of life (SF-36, EuroQoL, QoL-AGHDA), one sleepiness (Epworth Sleepiness Scale), two personality (EPQ-RK, TPQ) and one body image (FKB-20). RESULTS: Patients with CP scored significantly higher in conscious hunger perception (FEV, CP 5·8 ± 3·2 scores, NFPA 3·6 ± 3·3 scores, CG 3·0 ± 2·5, P < 0·001). They had similar scores for BDI compared with NFPA, but higher scores to CG (P < 0·001, CP 10·6 ± 8·3, NFPA 7·5 ± 5·7, CG 4·96 ± 4·2). CP and NFPA scored higher than CG for anxiety and personality traits such as harm avoidance, fatigability and asthenia and slightly higher for neuroticism. No differences were seen for EDE-Q, quality of life, daytime sleepiness and body image between CP and NFPA. However, differences could be observed to normative data from the literature. CONCLUSION: Obesity in patients with CP might be influenced by eating disorders, negative mood alterations and increased anxiety-related personality traits.

Clinical characteristics of pain in patients with pituitary adenomas.

OBJECTIVE: Clinical presentation of pituitary adenomas frequently involves pain, particularly headache, due to structural and functional properties of the tumour. Our aim was to investigate the clinical characteristics of pain in a large cohort of patients with pituitary disease. DESIGN: In a cross-sectional study, we assessed 278 patients with pituitary disease (n=81 acromegaly; n=45 Cushing's disease; n=92 prolactinoma; n=60 non-functioning pituitary adenoma). METHODS: Pain was studied using validated questionnaires to screen for nociceptive vs neuropathic pain components (painDETECT), determine pain severity, quality, duration and location (German pain questionnaire) and to assess the impact of pain on disability (migraine disability assessment, MIDAS) and quality of life (QoL). RESULTS: We recorded a high prevalence of bodily pain (n=180, 65%) and headache (n=178, 64%); adrenocorticotropic adenomas were most frequently associated with pain (n=34, 76%). Headache was equally frequent in patients with macro- and microadenomas (68 vs 60%; P=0.266). According to painDETECT, the majority of the patients had a nociceptive pain component (n=193, 80%). Despite high prevalence of headache, 72% reported little or no headache-related disability (MIDAS). Modifiable factors including tumour size, genetic predisposition, previous surgery, irradiation or medical therapy did not have significant impact neither on neuropathic pain components (painDETECT) nor on headache-related disability (MIDAS). Neuropathic pain and pain-related disability correlated significantly with depression and impaired QoL. CONCLUSIONS: Pain appears to be a frequent problem in pituitary disease. The data suggest that pain should be integrated in the diagnostic and therapeutic work-up of patients with pituitary disease in order to treat them appropriately and improve their QoL.

The effect of the ANKK1/DRD2 Taq1A polymorphism on weight changes of dopaminergic treatment in prolactinomas.

Treatment with dopamine agonists in patients with prolactinomas has been associated with weight loss in short term studies. However, long-term studies on weight changes are lacking. Taq1A is a restriction fragment length polymorphism considered as a gene marker for the DRD2 gene. The presence of at least one A1 allele is linked to reduced brain dopaminergic activity due to reduced receptor binding and lower density of the dopamine 2 receptor. We aimed at testing the hypothesis that the dopaminergic treatment in prolactinoma patients leads to sustained weight loss and that the presence of diminished weight loss response under dopamine agonists is associated with the minor A1 allele of Taq1A.We included n = 44 patients (17 male and 27 female, 26 macroadenomas and 18 microadenomas) with prolactinomas treated with dopamine agonists. Outcome measures were weight and body mass index (BMI) change under dopaminergic treatment after 2 years with regard to Taq1A status and sex. We observed that the dopaminergic treatment leads to a significant mean weight loss of 3.1 ± 6.25 kg after 2 years. Regarding Taq1A polymorphisms, 21 patients were carriers of at least one A1 allele and 23 patients had a genotype of A2/A2. However, the presence of the A1 allele was neither associated with the mean BMI at baseline nor with an altered weight loss response under dopamine agonist therapy. Our results implicate that the dopaminergic treatment leads to a sustained weight loss in patients with prolactinomas after 2 years. However, there was no association to the A1 allele of Taq1A, observation that needs to be analysed in larger cohorts.

PIK3CA and APC mutations are synergistic in the development of intestinal cancers.

Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (ß-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.

Factores de riesgo para el desarrollo de delirium postoperatorio en pacientes adultos mayores: estudio clínico prospectivo analítico / Risk factors for the development of postoperative delirium in elderly patients: prospective analytical trial

Determinar si existe asociación entre algunos factores de riesgo en el desarrollo de delirium en la población adulta mayor de dos servicios quirúrgicos del Hospital Regional de Talca. Material y Método: Se realizó un estudio clínico prospectivo, que incluyó todos los pacientes mayores de 65 años que se sometieron a cirugía traumatológica o urológica electiva en un período de 3 meses. Para evaluar cuantitativamente el delirium se utilizaron el Test Mental Abreviado (TMA) y el test “Confussion Assessment Method” (CAM). Se midió la incidencia de delirio y se analizó su relación con deterioro cognitivo previo, edad, analfabetismo, enfermedades crónicas, fractura de cadera, uso de benzodiazepinas y tiempo quirúrgico. Resultados: De un total de 81 pacientes (55 por ciento hombres; rango de edad 74,9 +/- 7,9), el 39,5 por ciento presentó delirium. De los factores de riesgo incluidos en el estudio sólo tienen asociación estadísticamente significativa, la edad (p = 0,033) y el analfabetismo (p = 0,000). Conclusión: El delirium postoperatorio es una complicación frecuente del paciente adulto mayor que se somete a cirugía, donde la edad y el analfabetismo son factores predisponentes, los que deben ser considerados en la evaluación preanestésica con el objetivo de disminuir la incidencia de este cuadro...

Objective: Evaluate the association of some possible risk factors in the development of post surgery delirium in the elderly population at two surgical services at the Regional Hospital of Talca. Materials and Methods: We performed a prospective clinical study, which included all patients older than 65 years who underwent elective orthopedic surgery or urological surgery in a period of 3 months. Two tests were administered to quantitatively evaluate the delirium: Abbreviated Mental Test (AMT) and Confusion Assessment Method (CAM). We analyzed the association between delirium and possible risk factors such as prior cognitive impairment, age, illiteracy, chronic disease, hip fracture, use of benzodiazepines and surgical time. Results: Of a total of 81 patients (55 per cent male, age range 74.9 +/- 7.9), 39.5 per cent had delirium. Of the risk factors included in the study only statistically significant association with age (p = 0.033) and illiteracy (p = 0.000). Conclusions: Postoperative delirium is a common complication of elderly patient who undergoes surgery, where age and illiteracy are predisposing factor, should be considered in the preanesthetic assessment in order to reduce the incidence of this condition...

Increased prevalence of anxiety-associated personality traits in patients with Cushing's disease: a cross-sectional study.

BACKGROUND/AIMS: Chronic hypercortisolism in Cushing's disease (CD) has been suggested to contribute to an altered personality profile in these patients. We aimed to test this hypothesis and attempted to determine the effects of disease- and treatment-related factors that might moderate an altered personality in CD. METHODS: We assessed 50 patients with CD (74% biochemically controlled) and compared them to 60 patients with non-functioning pituitary adenomas (NFPA) and 100 age- and gender-matched mentally healthy controls. Personality was measured by two standardized personality questionnaires, TPQ (Cloninger personality questionnaire) and EPQ-RK (Eysenck personality questionnaire-RK). RESULTS: Compared to mentally healthy controls, CD patients reported significantly less novelty-seeking behaviour, including less exploratory excitability and less extravagance. On harm avoidant subscales, they presented with more anticipatory worries and pessimism, higher fear of uncertainty, shyness with strangers, fatigability and asthenia. Moreover, CD patients appeared to be less extraverted, more neurotic and socially desirable. CD patients differed from NFPA patients in terms of higher neuroticism scores, and NFPA patients did not show altered novelty-seeking behaviour or extraversion. In the subgroup analysis, CD patients with persistent hypercortisolism displayed significantly higher fear of uncertainty, fatigability and asthenia, indicating high harm avoidance in total, than those in biochemical remission. CONCLUSION: Patients with CD showed a distinct pattern of personality traits associated with high anxiety in combination with traits of low externalizing behaviour. Such personality changes should be taken into account in the diagnosis and treatment of CD patients, as they might interfere with the patient-physician communication and/or challenge the patients' social and psychological functioning.

Efecto de la sedación en el desarrollo de delirium en pacientes adultos mayores sometidos a cirugía con anestesia espinal: estudio clínico prospectivo / Effect of sedation in the development of delirium in elderly patients undergoing surgery with spinal anesthesia: a prospective clinical study

Determinar la ocurrencia de delirium postoperatorio en pacientes adultos mayores sometidos a cirugía con anestesia espinal con y sin sedación. Material y Método: Se realizó un estudio clínico prospectivo descriptivo, que incluyó todos los pacientes mayores de 65 años que se sometieron a cirugía traumatológica o urológica electiva con anestesia espinal en un período de 3 meses. Para evaluar cuantitativamenteel delirium se utilizaron 2 herramientas: Test Mental Abreviado (AMT, por sus siglas en inglés) y Confussion Assessment Method (CAM) durante el postoperatorio inmediato, a las 24, 48 y 72 h; y se comparó la ocurrencia de delirium en los grupos con y sin sedación. Resultados: La incidencia de delirium postoperatorio fue del 50 por ciento en pacientes con sedación versus un 36,8 por ciento en quienes no la recibieron, lo que no demostró ser significativamente mayor (p = 0,268). Sin embargo, se encontró en ambos grupos un patrón de presentación temporal del delirium diferente, que si bien no fue significativo (p = 0,136), muestra una clara tendencia. Conclusiones: El delirium postoperatorio en el paciente anciano es una complicación frecuente, en el cual el uso de benzodiazepinas podría jugar un rol, tanto en su incidencia como en sus características temporales...

Determining the occurrence of postoperative delirium in elderly patients undergoing surgery with spinal anesthesia with or without sedation. Materials and Methods: We performed a prospective clinical study, which included all patients older than 65 years who underwent elective urological surgery or trauma with spinal anesthesia in a period of three months. To quantitatively evaluate delirium using 2 tools: Abbreviated Mental Test (AMT) and Confusion Assessment Method (CAM) during the immediate postoperative period, at 24, 48 and 72 hours, and compared the occurrence of delirium in the groups with and without sedation. Results: The incidence of postoperative delirium was 50 percent in patients with sedation versus 36.8 percent in those who did not, which is not shown to be significantly higher (p = 0.268). However, both groups found a pattern of temporal presentation of delirium different, but was not significant (p = 0.136), showing a clear trend. Conclusions: Postoperative delirium in the elderly is a common complication in which the use of benzodiazepines may play a role in both its incidence and temporal characteristics...

Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas.

INTRODUCTION: Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. MATERIALS AND METHODS: We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. RESULTS: i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. DISCUSSION: This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Distinct dopaminergic personality patterns in patients with prolactinomas: a comparison with nonfunctioning pituitary adenoma patients and age- and gender-matched controls.

INTRODUCTION: Personality patterns such as extraversion and novelty seeking have been associated with an altered dopaminergic activity in healthy subjects. Patients with prolactinomas have been described as exhibiting an altered dopaminergic tone and are often treated with dopamine agonists. Little is known about the personality traits of this patient group. Hence, we aimed at examining whether patients with prolactinomas exhibit modified personality patterns compared to patients with nonfunctioning pituitary adenomas and healthy controls. SUBJECTS/METHODS: In this cross-sectional study, 86 patients with prolactinomas and 58 patients with nonfunctioning pituitary adenomas (NFPA) were compared with 172 mentally healthy age- and gender-matched controls. To assess personality traits, standardized personality questionnaires (Eysenck personality questionnaire-EPQ-RK and Tridimensional Personality Questionnaire devised by Cloninger-TPQ) were administered. RESULTS: Patients with either prolactinomas or NFPA showed a distinct personality profile compared to the normal population, characterized by increased neuroticism and they also answered in a socially desirable mode. On harm-avoidant total and subscales, they presented with a higher fear of uncertainty and also increased fatigability and asthenia. The prolactinoma patients, when contrasted with the 'clinical' control group of patients with NFPA and after post hoc tests for multiple comparisons following the Bonferroni-Holm procedure showed significantly reduced extraversion (p = 0.044) and increased shyness with strangers (p = 0.044), tending to be more neurotic and present lower scores in the novelty seeking subscale impulsiveness. CONCLUSION: This is, to our knowledge, the first study providing new evidence of an altered personality profile of prolactinoma patients which might affect the patient-doctor relationship, treatment and patient's quality of life.

The effect of acute application of pegvisomant alone and in combination with octreotide on endogenous GH levels during a 6-h test in patients with acromegaly on constant pegvisomant treatment.

OBJECTIVE: Co-treatment with somatostatin analogues and growth hormone receptor antagonists in acromegaly might be a new treatment option abolishing the negative effects of monotherapy. Nevertheless, little is known about the acute effect of the combined treatment on endogenous GH and pegvisomant levels. DESIGN: Ten acromegalic patients on constant pegvisomant therapy were included. Two 6-h GH secretion profiles were performed once after pegvisomant alone (P), the other after an additional 100 microg octreotide sc injection (PO). After 180 min, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. In addition, insulin and glucose were measured. RESULTS: In the combined profile PO, a significant decrease of median endogenous GH was seen (p<0.01, median percentage decline 75.2%, range 23.7-88.2), which was not seen in profile P. Seven of 10 patients had a decline >70% and might be seen as responders. After meal, endogenous GH significantly decreased only in profile P (p<0.01). Pegvisomant levels did not differ significantly between profiles and did not change significantly during the tests. After meal, glucose levels rose higher and later and insulin levels lower and later in profile PO than in profile P. CONCLUSION: During pegvisomant treatment, endogenous GH can be reduced significantly by acute application of a somatostatin analogue. Therefore, in acromegalic patients on pegvisomant therapy GH regulation due to somatostatin analogues seems to be preserved.

Personality in patients with pituitary adenomas is characterized by increased anxiety-related traits: comparison of 70 acromegalic patients with patients with non-functioning pituitary adenomas and age- and gender-matched controls.

OBJECTIVE: Although neuropsychiatric and morphological brain alterations in acromegalic patients have been described and a distinct disease personality is clinically suspected, this has never been systematically investigated. We examined whether patients with acromegaly showed an altered personality profile compared with patients with non-functioning pituitary adenomas and healthy controls. DESIGN AND METHODS: In this cross-sectional study, 70 acromegalic patients and 58 patients with non-functioning pituitary adenomas were compared with 140 mentally healthy population controls, matched for age and gender. Personality traits were measured by standardized personality questionnaires (Eysenck personality questionnaire-RK and tridimensional personality questionnaire). RESULTS: Compared with healthy controls, acromegalic patients described themselves as distinctly more harm avoidant and neurotic and presented themselves with high social conformity. On harm avoidant subscales, they reported more anticipatory worries and pessimism, higher fear of uncertainty, higher fatigability and asthenia. This personality pattern was not specific for acromegaly, but could similarly be observed in patients with non-functioning pituitary adenomas. However, specific for patients with GH-producing adenomas was an even more reduced novelty-seeking behaviour, especially in terms of lower impulsiveness, compared with patients with non-functioning pituitary adenomas. CONCLUSION: Patients with pituitary adenomas show a distinct pattern of increased anxiety-related personality traits compared with the general population, potentially as a result of the pituitary lesion and/or associated hormonal dysregulations and comorbidities. Acromegaly is additionally associated with reduced impulsivity and novelty-seeking behaviour, which might affect patients' management and their quality of life.

High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels.

OBJECTIVE: The estimated prevalence of acromegaly is 40-125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels. DESIGN: A cross-sectional, epidemiological study (the DETECT study). Patients A total of 6773 unselected adult primary care patients were included. MEASUREMENTS: We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS). RESULTS: Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients. CONCLUSIONS: Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.

Pituitary imaging abnormalities in patients with and without hypopituitarism after traumatic brain injury.

Recent evidence suggests that patients with traumatic brain injury (TBI) are at substantial risk of hypopituitarism. The pathomechanisms, however, are not completely understood yet. Little is known about the association of morphological changes in the sella region with pituitary function in TBI. In this study, we assessed morphological abnormalities of the sella region in patients with TBI and their relation to endocrine function. We studied magnetic resonance (MR) or computed tomography (CT) scans of 22 patients with TBI [17 men, 5 women, age (mean+/-SD) 43.5+/-10.6 yr, time after trauma 17.4 +/-15.0 yr]. Of these, 15 patients had some degree of hypopituitarism. We found abnormalities of the sella region in 80% of the patients with hypopituitarism and 29% of those without hypopituitarism (Fisher's exact test, p=0.032). The most common abnormality was loss of volume or empty sella, followed by native signal inhomogeneities, perfusion deficit, and lack of neurohypophyseal signal. Our results indicate that pituitary imaging abnormalities are more common in TBI patients with hypopituitarism than those without. Both immediate trauma-induced pathology as necrosis and hemorrhage as well as multifactorial mid- to long-term changes may underlie these abnormalities.

New aspects in the diagnosis and treatment of Cushing disease.

Cushing disease, which is caused by the excessive production of ACTH, is a rare and complex endocrine disorder that still represents a major challenge for the physician in terms of accurate diagnosis and efficient treatment. Diagnosing Cushing syndrome and its etiology is an elaborate procedure and no single test is sensitive and specific enough to provide sufficient accuracy. Therefore, an ordered cascade of tests is necessary recommended by a consensus statement in 2002. The proposed diagnostic algorithm will be summarized in the following section. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the treatment of choice for the reduction of ACTH secretion. However, not all patients can be cured by surgery. In the present article, we examine recent studies that have investigated the therapeutic potential of new generations of drugs for the treatment of Cushing disease such as cabergoline and SOM230. The role of nuclear receptors: retinoic acid receptors and peroxisome proliferator-activated receptor-gamma as new approaches for treating pituitary tumors is also discussed.

[The genetics of hypogonadotropic hypogonadism in the male]. / Hypogonadotroper Hypogonadismus beim Mann. Abklärungskaskade vom Hirn bis ins Genom.

Underlying causes of hypogonadotropic hypogonadism are acquired or congenital disorders of the hypothalamus or pituitary (e.g. pituitary adenoma, craniopharyngioma, prior radiotherapy, trauma, severe general diseases, extreme stress, genetic mutations). In addition to a comprehensive history and physical examination, the diagnostic work-up includes measurement of testosterone, LH and FSH, with the aim of differentiating between primary and secondary hypogonadism. Where indicated, investigation of pituitary function, the use of imaging procedures, possibly an olfactory test, a GnRH stimulation test or genetic analyses may be added. Depending upon the indication, treatment is effected with testosterone, GnRH or gonadotropines.

Pulmonary leiomyomatosis in women after hysterectomy for uterine myoma. Benign metastasizing leiomyoma?

INTRODUCTION: Leiomyomas, which usually occur multilocular in uterus, can develop even if rarely in other organs with smooth muscle cells. The tumour is considered benign; 2 case reports supports the hypothesis that uterus myoma could metastasize, and in the metastasis sites grow invasively. METHODS: 2 female patients 44 y. and 29 y. old were admitted to our clinic for MPL. Due to increasing tumor size respectively dypnea, they were operated on. Multiple nodules of the left lung in one case, and a mediastinal tumour in the other were resected; resected tumour was histologically examined. RESULTS: In both cases it was a matter of well-differentiated leiomyosarcoma. The mediastinal tumour has already invade the N. phrenicus. Postoperatively there were no complications. Patients discharged in well-doing state, medical control one year later revealed no new growth. CONCLUSION: Multiple pulmonary leiomyomas are rare, they occur in sexually mature women in coincidence with uterus myoma. Even though many authors assume that MPL is a lung metastasis of benign tumours, the pathogenesis is still hypothetical. Supporting this thesis is the hormone dependence of both the uterine and the pulmonary tumours; against it, is that extrapulmonary locations are too rarely observed. The still open pathogenetical question has no therapeutical consequence. Whenever technically possible, a radical, parenchyma-saving surgical therapy should be the first choice. Otherwise hormon-ablation is a good alternative.

Stable thiyl radicals in dried yeast Cu(I)6-thionein.

It was of interest to obtain long-lived thiyl radicals embedded in organic matrices. Solid thiol compounds including penicillamine, glutathione, and cysteine were UV irradiated under anaerobic conditions at 293 K for 60 min. The formed radicals were identified by electron paramagnetic resonance (EPR) (g = 2.0265 +/- 0.0015) at 293 K as thiyl radicals. The blue-colored radical species were subjected to reflection spectrometry (lambda max = 601 +/- 3 nm). The color and the EPR signal remained unchanged for six months. At the same time, the UV irradiation of lyophilisized yeast Cu(I)6-thionein generated stable EPR detectable thiyl was seen when the Cu(I)-thiolate was used. No EPR detectable thiyl radicals radicals at a g-value of 2.026 +/- 0.001. Unlike irradiated cysteine, a five times higher concentration of thiyl radicals were measured in the Cu(I)-thiolates of penicillamine, glutathione, and thiophenole, indicating that the hexanuclear copper arrangement in Cu(I)-thionein is most suitable for both the formation and stabilization of this sulfur radical species.