Non-Hunner's Interstitial Cystitis Is Different from Hunner's Interstitial Cystitis and May Be Curable by Uterosacral Ligament Repair.

BACKGROUND: The posterior fornix syndrome (PFS) was first described in 1993 as a predictably occurring group of symptoms: chronic pelvic pain (CPP), urge, frequency, nocturia, emptying difficulties/urinary retention, caused by uterosacral ligament (USL) laxity, and cured by repair thereof. SUMMARY: Our hypothesis was that non-Hunner's interstitial cystitis (IC) and PFS are substantially equivalent conditions. The primary objective was to determine if there was a causal relationship between IC and pelvic organ prolapse (POP). The secondary objective was to assess whether other pelvic symptoms were present in patients with POP-related IC and if so, which ones? How often did they occur? A retrospective study was performed in 198 women who presented with CPP, uterine/apical prolapse (varying degrees), and PFS symptoms, all of whom had been treated by posterior USL sling repair. We compared their PFS symptoms with known definitions of IC, CPP, and bladder symptoms. To check our hypothesis for truth or falsity, we used a validated questionnaire, "simulated operations" (mechanically supporting USLs with a vaginal speculum test to test for reduction of urge and pain), transperineal ultrasound and urodynamics. KEY MESSAGES: 198 patients had CPP and 313 had urinary symptoms which conformed to the definition for non-Hunner's IC. The cure rate after USL sling repair was CPP 74%, urge incontinence 80%, frequency 79.6%, abnormal emptying 53%, nocturia 79%, obstructive defecation 80%. Our findings seem to support our hypothesis that non-Hunner's IC and PFS may be similar conditions; also, non-Hunner IC/BPS may be a separate or lesser disease entity from "Hunner lesion disease". More rigorous scientific investigation, preferably by RCT, will be required.

Symptoms of voiding dysfunction and other coexisting pelvic floor dysfunctions: the impact of transvaginal, mesh-augmented sacrospinous ligament fixation.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the prevalence for voiding dysfunction and if symptom improvement can be achieved by adequate pelvic floor surgery. METHODS: We evaluated the Propel Study data from 281 women with pelvic organ prolapse (POP) stage 2-4. Bother caused by obstructive micturition, voiding dysfunction, and coexisting pelvic floor symptoms were assessed using the Pelvic Floor Distress Inventory (PFDI) preoperatively and 6, 12, and 24 months after vaginal prolapse repair. Successful reconstruction (Pelvic Organ Prolapse Quantification [POP-Q] stage 0-I throughout the 2-year follow-up at all compartments, "responders"), was compared with all others ("non-responders"). RESULTS: Prevalence of voiding dysfunction was significantly reduced after surgery for all patients with "moderate" to "quite a bit" of bother ("R2") regarding all examined PFDI questions. Defects of the posterior/apical compartment and lower stage defects were found to cause obstructive micturition, which improved significantly after POP surgery. Six months after surgery, the prevalence of R2 for voiding dysfunction symptoms was reduced significantly for responders compared with non-responders. Significant reduction of R2 in patients with rectoceles could be shown for some PFDI questions, whereas the rate was lower in patients with cystoceles. Other pelvic floor symptoms often coexisted in patients with voiding dysfunction symptoms and improved significantly after surgery as well. CONCLUSIONS: Symptoms of voiding dysfunction are frequent in female patients with POP and can significantly improve after vaginal mesh-augmented prolapse repair even for posterior and minor defects. Before counseling patients to undergo POP surgery because of their obstructive symptoms, other causes of voiding dysfunction must first have been ruled out.

The impact of sacrospinous ligament fixation on pre-existing nocturia and co-existing pelvic floor dysfunction symptoms.

INTRODUCTION AND HYPOTHESIS: To evaluate whether nocturia and coexisting pelvic floor symptoms in women with pelvic organ prolapse (POP) can be improved by ligamentous fixation of apical vaginal prolapse to the sacrospinous ligament. METHODS: We evaluated the PROPEL study data from 281 women with pelvic organ prolapse stage > 2. Bothersome nocturia and coexisting pelvic floor symptoms were assessed with the Pelvic Floor Disorder Inventory (PFDI) questionnaire preoperatively and at 6, 12 and 24 months after successful vaginal prolapse repair. Women with successful reconstruction (POP-Q stage < 1 at all compartments throughout the 2-year follow-up), defined as anatomical "responders," were compared to the anatomical "non-responders." RESULTS: Among the patients completing all PFDI questions (N = 277), anatomical responders and non-responders were the groups of interest for our analysis. We found the occurrence rates of "moderate" or "quite a bit" of nocturia was significantly reduced after surgery in all subgroups (48.7% at baseline vs. 19.5% after 24 months). The occurrence of nocturia was halved for responders compared to non-responders (45.4% and 48.3% at baseline vs. 14% and 29.5% after 24 months). Anatomical non-responders still had a relevant improvement of POP-Q stages, especially in the apical compartment. Prevalence rates of co-existing over- and underactive bladder, fecal incontinence, defecation disorders and pain symptoms were also significantly reduced postoperatively. CONCLUSION: Nocturia can be associated with symptomatic POP, with improvements seen following vaginal ligamentous prolapse repair. We caution providers, however, when advising patients of the possible resolution of nocturia following POP reconstruction, that all other traditional etiologies of nocturia must first be ruled out.

Can surgical reconstruction of vaginal and ligamentous laxity cure overactive bladder symptoms in women with pelvic organ prolapse?

OBJECTIVE: To examine the extent and intensity of the coexistence of overactive bladder (OAB) symptoms in women with pelvic organ prolapse (POP) and to evaluate the likelihood of OAB symptom improvement after surgical POP reconstruction over a period of 2 years. PATIENTS AND METHODS: The effectiveness of the transvaginal, single-incision 'Elevate' technique for anatomical cure of anterior/apical and posterior/apical vaginal prolapse has been previously reported in a prospective, multicentre study. This technique uses mesh arms attached to the sacrospinous ligaments to recreate apical ligamentous support. Using the same sample population as that used in the multicentre study (n = 281), we conducted the present sub-analysis focusing on estimating the extent of comorbidity between POP and OAB symptoms, as well as the effects of subsequent pelvic floor reconstruction on OAB symptoms over a long period. Assessments of POP and OAB symptom severity before and after surgery at 6, 12 and 24 months were obtained using the Pelvic Floor Distress Inventory (PFDI) questionnaire. RESULTS: Preoperatively, 70% of all POP patients reported moderate to severe OAB symptoms, with almost half (49.5%) noting severe OAB bother ('quite a bit bothersome') for one or more of the classic OAB symptom domains on the PFDI: 'daytime urinary frequency'; 'urinary urgency'; 'urinary urgency incontinence'; and/or 'nocturia'. In fact, across all four OAB symptom domains evaluated, there were significantly more severe symptoms ('quite a bit bothersome') than moderate ('moderately bothersome') or mild ('somewhat bothersome'): 26-31%, 13-21%, and 17-19% of patients, respectively. In patients with symptomatic POP >stage 2, there was no relationship between further degree of prolapse and presence of severity of OAB symptoms; however, patients with POP stage 2 had significantly more complaints regarding the items 'daytime urinary frequency' and 'urinary urgency incontinence' compared with those with stage 3-4 POP. Pelvic floor reconstructive surgery resulted in significant improvement in all OAB symptoms, which seemed to be stable over time. The cure rate of moderate-to-severe OAB complaints ranged between 60% and 80%, which was a durable improvement noted throughout 24 months. CONCLUSION: Results showed that POP was to a high degree accompanied by moderate-to-severe OAB complaints. Significant long-lasting improvements in bothersome OAB symptoms occurred after adequate surgical reconstruction of anterior/apical and posterior/apical vaginal support.

Clinical score system in the treatment of Cushing's disease: failure to identify discriminative variables from the German Cushing's Registry.

PURPOSE: To develop a multidimensional and integrated clinical scoring instrument, that encompasses, summarizes and weights appropriately the desired clinical benefits of a treatment for Cushing's disease (CD). METHODS: A panel of 42 variables potentially relevant to the clinical course of CD was predefined by endocrinology experts taking into account relevant literature. Variables as well as biochemical disease activity assessed as urinary free cortisol (UFC) levels were evaluated at baseline and at least after 12 months in patients treated between 2012 and 2016 in two Munich-based academic centres of the German Cushing's Registry. The primary endpoint was the identification of variables whose changes from baseline to follow-up visit(s) could characterize well biochemical cured from not cured patients after 12 months. RESULTS: Ninety nine patients with at least two consecutive visits were enrolled. Biochemical data were available for 138 visit-pairs among which UFC was not controlled in 48 (34.8%) and controlled in 90 (65.2%) first visits. In 41 (29.7%) consecutive visits (visit-pairs) changes in biochemical activity categories was observed between visits; concretely: in 17 (12.3%) consecutive visits changing from previously controlled to not controlled, and in 24 (17.4%) from uncontrolled to controlled biochemical activity. Multivariate statistical analyses (especially analyses of variance) based on data of the 138 visit-pairs were performed in order to proof possible effects of biochemical activity on clinical benefits. However, in none of the considered 42 variables corresponding to quality of life-dimensions, laboratory, anthropometric, musculo-skeletal or other clinical areas any statistically significant differences between different categories of biochemical activity were observed. CONCLUSION: It was not possible to provide clinical key parameters in our population of patients with CD discriminating biochemical cured from non-cured patients and to construct a clinical scoring system reflecting clinical treatment benefits.

Cure of Underactive and Overactive Bladder Symptoms in Women by 1,671 Apical Sling Operations Gives Fresh Insights into Pathogenesis and Need for Definition Change.

INTRODUCTION: To check evidence that symptoms identical with those constituting "underactive bladder" (UAB) and "overactive bladder" (OAB) are caused by apical prolapse and cured by repair thereof. MATERIAL AND METHODS: After repair of apical prolapse by mesh tape reinforcement of lax uterosacral ligaments (USL) data form 1,671 women were retrospectively examined to determine the presence of OAB and UAB symptoms and to check, how many were cured surgically. Thereby 3 different techniques were performed: elevate (n = 277), "Posterior IVS" (n = 1,049), and TFS cardinal (CL)/USL (n = 345). RESULTS: Symptoms identical with those comprising UAB and OAB were cured in up to 80% of cases following surgical repair of the CL/USL complex. CONCLUSIONS: These symptoms may be consistent with symptoms of the posterior fornix syndrome, which comprises 4 main symptoms: micturition difficulties, urge/frequency, nocturia, chronic pelvic pain, all consequent on USL laxity. Surgical cure of OAB and UAB is inconsistent with existing definitions, which imply pathogenesis of the detrusor muscle itself. A reconsideration and reformulation of existing definitions may be required. Altering UAB definition to "bladder emptying difficulties" and return to former definitions for OAB such as "detrusor" or "bladder instability" may help to restore compatibility with surgical cure of these conditions.

No effects of antidepressants on negative symptoms in schizophrenia.

Negative symptoms are common in schizophrenia, but often difficult to differentiate from depression. They are associated with long-term impairment and do not respond well to current treatment approaches. Even though antidepressants are commonly prescribed in schizophrenia, their beneficial effect is still under debate. In the present study, we aimed to investigate the effect of serotonergic versus noradrenergic antidepressant add-on therapy on negative symptoms in schizophrenia. Fifty-eight patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and with predominant negative symptoms were randomized in a double-blind design to add-on treatment with citalopram, reboxetine, or placebo for 4 weeks. Analysis of covariance with repeated-measures design was used to compare improvement between treatment groups in scores of the Positive and Negative Syndrome Scale and the Hamilton Rating Scale for Depression. A χ² test was used to compare responder rates between treatment groups. Repeated-measures analysis of covariance revealed no differences between treatment groups over time (treatment × time, not statistically significant) for Positive and Negative Syndrome Scale subscales. Although a subgroup analysis in subjects fulfilling the criteria for minor depression was suggestive of higher responder rates in the citalopram group compared with reboxetine, the results did not reach significance level. Our findings do not support a beneficial effect of adjunctive antidepressant treatment on negative symptoms in schizophrenia. However, depressive symptoms are reduced in patients with minor depression by citalopram but not reboxetine, which is in line with previous findings.

Distraction versus focusing during VR exposure therapy for acrophobia: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: The therapeutic mechanisms of exposure therapy are not well understood. Research suggests that focusing on the most feared aspect might not be necessary, and that distraction with a low cognitive load (e.g., conversation) might enhance exposure. We aimed at systematically testing the efficacy of exposure therapy with focusing vs. conversational distraction, hypothesizing that distracted exposure would yield superior effects. METHODS: Thirty-eight patients with acrophobia (specific phobia of heights; clinician-determined) (free from relevant somatic or other mental disorders) were randomly assigned (1:1) to one virtual reality (VR) session of either focused (n = 20) or distracted exposure (n = 18). This monocentric trial took place at a psychiatric university hospital. RESULTS: Both conditions resulted in a significant reduction of acrophobic fear and avoidance, and a significant increase of self-efficacy (primary outcome variables). However, condition did not have a significant effect on any of these variables. Effects were stable at four-week follow-up. Heart rate and skin conductance level indicated significant arousal, but did not differ between conditions. LIMITATIONS: Eye-tracking was unavailable, nor did we assess emotions other than fear. Power was limited due to sample size. CONCLUSIONS: A balanced exposure protocol combining attention to fear cues with conversational distraction, while not being superior, might be as effective as focused exposure for acrophobia, at least during the initial stages of exposure therapy. These results support previous findings. This study demonstrates how VR can be exploited for therapy process research, as VR supports dismantling designs and the incorporation of online process measures.

Sleep disturbances in highly stress reactive mice: modeling endophenotypes of major depression.

BACKGROUND: Neuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days. RESULTS: Differences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle. CONCLUSIONS: The HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.

Effects of chronic posttraumatic stress disorder on metabolic risk, quality of life, and stress hormones in aging former refugee children.

It is still unclear whether the association between traumatic stress and physical disease is mediated by posttraumatic stress disorder (PTSD). Therefore, we examined the long-term consequences of PTSD on cardiovascular risk, stress hormones, and quality of life in a sample of former refugee children who were severely traumatized more than six decades ago. In 25 subjects with chronic PTSD and 25 trauma-controlled subjects, we measured the variables of metabolic syndrome supplemented by the ankle-brachial index and highly sensitive C-reactive protein. Quality of life was assessed using the 36-item Short-Form Health Survey. Cortisol, adrenocorticotropin-releasing hormone (ACTH), and dehydroepiandrosterone (DHEA) were measured using the low-dose-dexamethasone suppression test. In addition, salivary cortisol was assessed at 8:00 a.m., 12:00 p.m., 4:00 p.m., and 8:00 p.m. We found a significant group effect between participants with and without PTSD regarding quality of life but not in any metabolic parameter including the ankle-brachial index or cortisol, ACTH, and DHEA in plasma before and after dexamethasone or salivary cortisol. The postulated association between traumatic stress and physical illness does not appear to be mediated by PTSD in this population. Nevertheless, the search for subgroups of PTSD patients with childhood traumatization leading to different metabolic and endocrine long-term consequences in aging PTSD patients is needed.

[Long-term consequences of flight and expulsion in former refugee children]. / Langzeitfolgen von in der Kindheit am Ende des II. Weltkrieges erlebter Flucht und Vertreibung.

Little is known about long-term consequences of flight and expulsion during childhood. The aim of this study was to interview aging former refugee children about their recollection of traumatic experiences and to screen for full and partial posttraumatic stress disorder (PTSD) and their differential impact on today's quality of life and mental health. In 502 participants from the former German eastern territories who were displaced as children at the end of World War II (at the age of 5-12 years) we examined traumatic experiences, posttraumatic stress symptoms (PDS), comorbid symptoms (SCL-90-R), depressive symptoms (BDI) and quality of life (SF-36). 31.5% participants reported posttraumatic stress symptoms indicating current full PTSD, and 33.7% fulfilled the criteria of a current partial PTSD. Participants with full and partial PTSD reported a significantly reduced quality of life, often depressive and comorbid symptoms and were compromised in their well-being compared to participants without PTSD. The study demonstrates the long-term consequences of flight and expulsion during childhood in aging former refugee children more than 60 years later. Posttraumatic stress symptoms play a prominent role for quality of life and well-being in this population.

Atrial natriuretic peptide (ANP) as an endogenous anxiolytic in patients with heart failure? - No replication of previous results showing an inverse association of anxiety and plasma ANP parameters.

OBJECTIVE: An acute anxiolytic-like effect of atrial natriuretic peptide (ANP) has been demonstrated in several preclinical and clinical studies. In a so far singular study (Herrmann-Lingen et al., 2003), patients with congestive heart failure, who pathognomonicly display increased plasma ANP, showed a significant inverse association of anxiety symptoms and pro-ANP levels, giving rise to speculations about ANP as an endogenous anxiolytic. We tried to replicate and extend this preliminary finding. METHODS: In 56 patients suffering from heart failure with reduced left ventricular ejection fraction we measured ANP, mid-regional pro-ANP (MR-proANP) and cyclic guanosine monophosphate (cGMP) as plasma parameters of ANP functioning and characterized anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) and in addition the State Trait Anxiety Inventory (STAI) for state anxiety. Spearman rank correlation coefficients were calculated. RESULTS: None of our plasma ANP parameters showed a significant association with anxiety symptoms as per HADS ratings. The same picture emerged with STAI state anxiety. ANP, MR-proANP and cGMP significantly correlated with each other. CONCLUSION: In another sample of patients with heart failure we were unable to replicate previous and preliminary cross-sectional findings of low anxiety in subjects with high plasma pro-ANP. Direct measurement of effector hormone ANP and its second messenger as well did not support our hypothesis. Chronically elevated ANP in heart failure might attenuate its potential anxiolytic effects. Longitudinal studies experimentally increasing ANP levels in anxious heart failure patients are needed to test if this approach has clinical psychotropic utility.

Sleep and active renin levels--interaction with age, gender, growth hormone and cortisol.

AIMS: In young normal male subjects, plasma renin activity (PRA) shows large oscillations with a distinct association to the cyclic occurrence of rapid eye movement (REM) and non-REM (NREM) periods. Until now the sleep-related course of active renin levels is unknown. Furthermore, there are no data on the effects of age and gender on nocturnal renin and the interaction between these variables, sleep, growth hormone (GH) and cortisol. METHODS: We investigated simultaneously sleep EEG (23:00-07:00 h) and the plasma concentrations (23:00-07:00 h) of active renin (in 10-min intervals) and of GH and cortisol (in 20-min intervals) in 47 healthy volunteers (24 women and 23 men) aged 19-69 years. RESULTS: In the total sample, significant positive correlations were found between renin concentrations and NREM sleep and the sleep efficiency index, whereas a significant negative correlation exists to wakefulness. Renin shows also a positive correlation to GH levels which is restricted to the younger subjects (<40 years) during NREM sleep. No association exists between renin and cortisol. The averaged nocturnal mean renin levels were significantly lower in female than in male subjects, and in subjects older than 40 years than in younger subjects. Oscillations of active renin levels were found with increases during NREM periods and decreases during REM periods. CONCLUSIONS: In all, nocturnal averaged renin levels are lower in women than in men, decrease during ageing and correlate positively with GH, whereas the interaction between renin and sleep is independent from age and gender.

Decreased recognition of negative affect after selective serotonin reuptake inhibition is dependent on genotype.

Selective serotonin reuptake inhibitors (SSRIs) are known to influence the information processing of emotional material in depressed patients and healthy controls. The functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with the effectiveness of serotonin reuptake inhibitors. It is not known whether 5-HTTLPR has an influence on emotional processing in healthy controls. We report first data with long-term SSRI administration after genetic characterization of 5-HTTLPR in a randomized, double-blind, placebo-controlled, crossover design. In 30 healthy controls, 15 homozygous for the long and 15 for the short allele of 5-HTTLPR, emotionally valent images were used to elicit positive or negative emotions. We found a diminished perception of sad and fearful information under SSRI which was significant in the long allele group. These findings emphasize the importance of genetic variance in emotion processing research.

Cortisol, DHEA and DHEA-S during exposure therapy in patients with obsessive-compulsive disorder - secretion patterns and prediction of treatment response.

The cortisol response in patients with obsessive-compulsive disorder (OCD) during exposure with response prevention (ERP), a stressful but very effective psychotherapeutic treatment, has shown contradictory findings in three prior studies with low sample sizes. In a larger cohort of 51 patients with OCD we repeatedly measured subjective units of distress (SUD) and the adrenocortical stress hormones cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) in saliva during the very first session of ERP and on the day before. Expectedly, SUD were increased on the ERP day before the session and further rose during ERP, but salivary cortisol and DHEA were statistically indistinguishable from the comparison condition. Interestingly, DHEA-S was significantly elevated throughout the ERP versus the comparison day, but did not further increase in acute response to ERP. According to an explorative analysis in a subsample, hormone levels on the comparison or the ERP day did not predict anti-OCD treatment response one month later. These results corroborate our prior findings of cortisol non-response despite considerable subjective stress in ERP. The role of DHEA-S in anticipatory anxiety and the effects of augmentative cortisol therapy in ERP need further study.

A low cost artisan tension-free tape technique cures pelvic organ prolapse and stress urinary incontinence - proof of concept.

INTRODUCTION: The primary cause of pelvic organ prolapse (POP) is weak cardinal/uterosacral (CL/USL) ligaments and for stress urinary incontinence, weak pubourethral ligaments (PUL). MATERIAL AND METHODS: A 1 cm wide tape cut from a mesh sheet was applied tension-free to reinforce already plicated CL/USLs for cure of prolapse and directly to PUL for cure of stress urinary incontinence (SUI). 40 tapes were inserted, 10 midurethrally for SUI and 30 for 2nd/3rd degree prolapse: 15 to uterosacral ligaments and 15 to cardinal ligaments. RESULTS: At 12 months follow-up there was 72% cure for POP, 70% for SUI and improvement in urge/nocturia symptoms in 82% of patients.At 36 months 8/15 patients were evaluated. Anatomic cure for POP III was 2/4, for POP I-II 6/6. CONCLUSIONS: Though a 'proof of concept' study, our results may be sufficient to provide, in time, an alternative individual pathway for surgeons wishing to provide more certainty to a prolapse repair than 'native tissue' for an individual patient. The method questions whether expensive mesh kits are really necessary: our data though small, actually part of a learning curve, was within 15 percentage points of more sophisticated, more expensive tensioned slings. Intraoperative complications were low with no tape erosions seen at 12 months. Further validation with larger prospective and comparative trials is required.

Sleep in pituitary insufficient patients compared to patients with depression and healthy controls at baseline and after challenge with CRH.

Sleep disturbances are prevalent in both patients with pituitary insufficiency and with depression. The role of corticotropin releasing hormone (CRH), involved in sleep regulation, has not been fully clarified. Pituitary insufficiency is an ideal model for studying sleep-endocrine effects since no consecutive hormone releases and feedback effects occur after hormone administration. 11 male patients with a chronic insufficiency of the anterior pituitary gland (PI) and under stable hormonal substitution were studied during three consecutive nights in the sleep laboratory. The first night served for adapting to laboratory setting, during the second night placebo was administered and during the third night 4 × 50 µg CRH were injected in pulsatile fashion. Sleep parameters were additionally compared with those of 15 healthy male controls (C) and 15 male patients with depression (D). CRH administration was associated with a numerical increase of wake time (115 ± 15 to 131 ± 13 min) and a decrease of REM sleep (89 ± 8 to 80 ± 8 min), REM latency (69 ± 14 to 55 ± 9 min) and slow wave sleep (66 ± 16 to 57 ± 15 min). Yet, none of these changes reached statistical significance. PI showed a worse sleep profile as compared to both control groups, e.g. indicated by a significantly lower sleep efficiency index (PI:0.80 ± 0.03 vs. C:0.94 ± 0.01 vs. D:0.87 ± 0.03). In conclusion sleep-EEG changes after CRH in PI patients resemble those found in in part in patients with depression. Sleep in anterior pituitary insufficiency was impaired despite full hormonal substitution possibly suggesting an alteration of the receptor organisation of brain structures involved in sleep regulation.

Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.

Somatostatin analogs (SSA) with their potent antisecretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine tumors, such as gastroenteropancreatic and acromegaly-associated growth hormone secreting pituitary tumors. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal control is not achieved in a sizeable proportion of these patients. The reasons for this incomplete response to SSA treatment are unclear. We have found that the tumor suppressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to determine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF-I and presence of tumor shrinkage). All tumors displayed ZAC1 immunoreactivity [weak (+; n = 15), moderate (++; n = 16) and strong (+++; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF-I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at diagnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shrinkage and hormone normalization.

Ghrelin suppresses secretion of FSH in males.

BACKGROUND: Ghrelin decreases the secretion of LH probably by suppressing the release of hypothalamic GnRH. So far however, there is no evidence that ghrelin affects also the secretion of FSH in humans, the other gonadotrophin regulated by GnRH. OBJECTIVE: Our objective was to study the effect of ghrelin on secretion of FSH in humans. DESIGN/STUDY SUBJECTS: Nocturnal (20:00-07:00 h) secretion profiles of FSH were measured in 10 healthy males (25.3 +/- 3.2 years) twice, receiving 50 microg ghrelin or placebo at 22:00, 23:00, 24:00, and 01:00 h, in this single-blind, randomized, cross-over study. RESULTS: Mean FSH plasma levels were significantly (P < 0.05) lower with ghrelin than placebo between 01:00 and 02:20. Consistently, a significant decrease from baseline was only observed in the ghrelin but not in the placebo condition. CONCLUSION: This study provides first evidence that ghrelin suppresses the secretion of FSH in humans.

The selective serotonin re-uptake inhibitor escitalopram modulates the panic response to cholecystokinin tetrapeptide in healthy men depending on 5-HTTLPR genotype.

Selective serotonin re-uptake inhibitors, such as escitalopram, are currently the treatment of choice for patients with panic disorder. The panic response to intravenous cholecystokinin tetrapeptide, a potentially useful paradigm for volunteer translational studies, has so far not been investigated in healthy man after respective pre-treatment. In a double-blind, placebo-controlled, randomized, within subject cross-over design 30 healthy young men, 15 each with the long/long or short/short genotype for the serotonin transporter linked polymorphic region, were pre-treated with 10mg/d of escitalopram orally for six weeks and then challenged with 50 microg of cholecystokinin tetrapeptide. The primary outcome measure was the increase of Acute Panic Inventory ratings by cholecystokinin tetrapeptide. The increase of anxiety, tension and stress hormone secretion were secondary outcome measures. A significant treatment by genotype effect on the increases of Acute Panic Inventory ratings emerged. Panic induced by cholecystokinin tetrapeptide was significantly more pronounced in the short/short genotype subjects under escitalopram vs. placebo pre-treatment. With the exception of significantly elevated serum prolactin after escitalopram, no effects in the secondary outcome measures were detected. Contrary to our expectation, no inhibitory effect of escitalopram upon panic symptoms elicited by choleystokinin tetrapeptide could be demonstrated in healthy men. These findings do not support the potential usefulness of this panic model for proof-of-concept studies. The biological underpinnings of the increased panic symptoms after escitalopram in our volunteers with short/short genotype need further research.