Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women.

INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.

Effect of Single-Dose Imipramine on Anal Sphincter Tone in Healthy Women: A Randomized, Placebo-Controlled Study Using Anal Acoustic Reflectometry.

INTRODUCTION AND HYPOTHESIS: Despite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method. METHODS: In a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days' washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine. RESULTS: All participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH2O (95% confidence interval [CI] 2.0-28.2 cmH2O, p = 0.03) in the resting state and 15.1 (95% CI 4.2-26.0 cmH2O, p = 0.01) cmH2O during squeezing. CONCLUSIONS: The findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function.

Psychiatric morbidity among men using anabolic steroids.

OBJECTIVE: The purpose of this study was to investigate the psychiatric morbidity among men with abuse of anabolic steroids. METHODS: The design is a retrospectively matched cohort study. Five hundred and fourty-five males, who tested positive for anabolic steroids in Danish fitness centers during the period January 3, 2006 to March 1, 2018, were matched with 5450 randomly chosen male controls. Data was cross-referenced with seven national registers pertaining to information about education, employment status, and psychiatric comorbidity. Main outcomes and measures were prescription of psychopharmacological treatment. RESULTS: The incidence of treatment with anxiolytics (HR: 2.34, 95% CI: 1.62-3.38) and antipsychotics (HR: 2.69, 95% CI: 1.99-3.63) displayed a remarkable increase in the years following doping sanction, compared to the control group. The prevalence of antidepressant use was already markedly elevated several years before doping sanction, but also displayed a higher incidence in the years following sanction (HR: 1.65, 95% CI: 1.28-2.13). The associations remained highly significant after controlling for socioeconomic factors. CONCLUSION: Anabolic steroids use is strongly associated with psychiatric morbidity.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AIMS: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. METHODS: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine ), 8 mg reboxetine (and placebocitalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). RESULTS: Compared to placebo, citalopram increased OUP by 6.6 cmH2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition. CONCLUSION: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Effect of reboxetine and citalopram on anal opening pressure in healthy women: A randomized, double-blind, placebo-controlled crossover study.

BACKGROUND: In placebo-controlled clinical trials, reboxetine, a selective noradrenaline reuptake inhibitor, increases urethral pressure and relieves stress urinary incontinence symptoms in women. Considering the close connection in neural regulation of the external urethral and anal sphincters, we hypothesized that reboxetine may also enhance anal sphincter pressure. Conversely, it is believed that selective serotonin reuptake inhibitors may contribute to fecal incontinence by reducing anal sphincter pressure. In this study, we investigated the effect of reboxetine and citalopram on anal opening pressure in healthy female volunteers. METHODS: In a double-blind, three-way crossover trial, 24 female participants received single doses of 40 mg citalopram, 8 mg reboxetine, and matching placebos, with a minimum of 8-day washout between sessions. Using anal acoustic reflectometry, we measured anal opening pressure during both resting and squeezing conditions at the estimated time of peak plasma concentration for both study drugs. KEY RESULTS: Compared with placebo, reboxetine increased anal opening pressure with 23.4 cmH2O (95% confidence interval [CI] 16.5-30.2, p < 0.001) during rest and with 22.5 cmH2O (95% CI 15.2-29.8, p < 0.001) during squeeze. Citalopram did not change anal opening pressure statistically significantly compared to placebo. CONCLUSIONS & INFERENCES: An 8-mg dose of reboxetine increased anal opening pressure substantially in healthy women, suggesting potential benefits for fecal incontinence symptoms. In contrast, a 40-mg dose of citalopram showed a marginal and statistically insignificant effect on anal opening pressure, indicating that selective serotonin reuptake inhibitors do not contribute to fecal incontinence by reducing anal sphincter tone.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency.

PURPOSE: Studies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure. METHODS: Prospective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC. OUTCOMES: Diurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure. RESULTS: After the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: -55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (-1.6 and -1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (-1.5 and -0.5 kg, P = 0.003 and 0.02), HbA1c (-1.2 mmol/mol, P = 0.02), and osteocalcin decreased (-7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged. CONCLUSION: This study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones. CLINICAL TRIAL REGISTRATION: EudraCT201400203932.

Quality of life in thyroid cancer.

To explore the impact of differentiated thyroid cancer (DTC) on quality of life (QoL) a clinical analytical framework was developed. Based on the clinical analytical framework, a systematic literature search was performed to identify studies applying patient-reported outcomes (PRO) instruments among patients with DTC. Subsequently, the scope was narrowed down to studies comparing scores on the Medical Outcomes Study (MOS) Short form 36 (SF-36) to a reference population (clinical interpretability criterion). Further, the currently available thyroid cancer (TC) specific QoL PROs were review in accordance with the standards of the International Society of Quality of Life Research. In the initial search, 213 studies were included. The additional 'clinical interpretability'-criteria, limited the final study sample to 16 studies, 13 cross-sectional and 3 longitudinal. QoL was impacted across all SF-36 scales. The impact was generally modest and the impact was impeded by time since diagnosis and treatment. Four TC specific instruments were identified. Generally, the documentation of their measurement properties, particularly content validity and clinical validity, including substantial quantitative validation, was scarce. As was the cross-cultural applicability of the currently available instruments. This restricted, focused, clinically founded review showed an impact on a broad range of QoL issues. There is a need for large-scale measurement of QoL outcome longitudinally, using well-validated PRO instruments in order to identify with certainty the impact on subgroups.

The adverse reactions of anabolic steroid abuse.

Anabolic steroid abuse is a growing health concern due to its relatively prevalent use and adverse health effects. These drugs cause significant disturbances of the body's endocrine system, and the most common somatic adverse drug reactions are gynaecomastia, infertility, testicular dysfunction, and acne. Furthermore, the use of anabolic steroids is associated with a variety of psychiatric disorders and antisocial behaviour as summarised in this review.

The effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments.

PURPOSE: Replicating the physiological cortisol secretion is key in the treatment of glucocorticoid insufficient individuals and optimization may enhance quality of life. The study investigates fatigue measured by ecological momentary assessments in patients treated with conventional hydrocortisone compared with once-daily dual-release hydrocortisone (Plenadren). METHODS: A 21-week open-label switch pilot trial included 30 patients with adrenal insufficiency due to hypopituitarism. Fatigue was assessed four times daily for 20 days using a momentary item version of the Multidimensional Fatigue Inventory on patients' usual hydrocortisone regimen. Participants switched treatment to an identical daily dose of Plenadren for 16 weeks where fatigue assessments were repeated. Change in fatigue and diurnal variation of fatigue was analyzed using mixed models for repeated measurements. RESULTS: In four out of five fatigue subscales fatigue was significantly reduced 0.7-1.1 points (scales ranging from 4 to 20), when treated with Plenadren compared with conventional hydrocortisone, corresponding to small effect sizes below the scale-specific minimal important changes. However, 33% of the participants completing the study (9/27) experienced reductions in fatigue above the minimal important change. On Plenadren, we found larger between-person variances and smaller within-person variances. Finally, we identified diurnal fatigue curves for both treatments. CONCLUSIONS: The Plenadren-related reduction in fatigue was significant but not necessarily of clinical importance when looking at a group level. However, there was a large interindividual variation in treatment effect, why patients with a large benefit in quality of life should be identified. Future RCTs should be powered to detect the effect magnitudes identified here.

Anabolic-androgenic steroids and the risk of imprisonment.

BACKGROUND: The use of Anabolic-Androgenic Steroids (AAS) has been associated with increased aggressiveness and violent behavior. We therefore investigated the proposed correlation between the use of AAS and criminality while controlling for important socio-economics covariates and for psychiatric comorbidity. METHODS: The primary endpoints were prison sentences, and time to first prison sentence. A retrospective matched cohort study design consisting of 545 males, who tested positive for AAS in Danish gyms during the period January 3, 2006 to January 31, 2017. They were matched with 5450 randomly chosen male controls. Data were cross-referenced with national register information on education, employment status, substance abuse and psychiatric comorbidity. In addition, 638 males sanctioned because they rejected to participate in the doping control and 6380 controls were used as a replication cohort. RESULTS: Already at baseline, 20.6% of the AAS users had a previous prison sentence whereas the rate was 3.7% in the control cohort (p < 0.0001). During the follow-up period the cumulative prevalence increased to 29.5% and 4.9%, respectively (unadjusted HR 9.15, 95% CI 6.33-13.20). The associations remained highly significant after controlling for socio-economic factors, drug abuse and psychiatric comorbidity. The results could be replicated in a similar cohort. CONCLUSION: Our study shows that AAS users have a 9-fold increased risk of being convicted of a crime compared to matched controls, randomly chosen from the general population. This association could not be explained by common socioeconomic factors or by psychiatric comorbidity.

PlenadrEMA: effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments: a study protocol for an open-label switch pilot study.

INTRODUCTION: Patients with adrenal insufficiency have impaired health-related quality of life (QoL). The dual-release hydrocortisone preparation, Plenadren, has been developed to mimic the physiological cortisol release more closely than conventional hydrocortisone treatment. Plenadren has been shown to improve QoL, in particular fatigue, in patients with primary adrenal insufficiency. However, the effect has not been investigated in patients with secondary adrenal insufficiency; furthermore, no study has taken the diurnal variation of fatigue into account. To assess diurnal variations, it is necessary to use repeated daily measurements, such as ecological momentary assessments (EMAs). This study aims to evaluate EMAs of fatigue as outcome in future large-scale randomised clinical trials. METHODS AND ANALYSIS: The PlenadrEMA trial is an investigator-initiated open-label switch pilot trial of the effect of Plenadren versus conventional hydrocortisone on fatigue in patients with secondary adrenal insufficiency. The trial will include 30 participants. After 5 weeks on their usual hydrocortisone treatment, patients will be shifted to Plenadren for 16 weeks. Fatigue will be assessed using momentary versions of the Multidimensional Fatigue Inventory (MFI-20). Items will be administered to participants via a smartphone application four times daily during 20 days. Assessments will be performed before treatment shift and repeated after 12.5 weeks on Plenadren. The study will identify the best suited outcome for future randomised clinical trials, and in addition, estimate the variability and difference in fatigue between the two treatments to perform power calculations. ETHICS AND DISSEMINATION: The trial will be conducted in accordance with the Declaration of Helsinki and has been approved by the Regional Scientific Ethical Committee in Copenhagen (ID: H-1-2014-073). All patients will receive written and verbal information about the trial and will give informed consent before enrolment. Findings will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: EudraCT201400203932.

General practitioners do not systematically adhere to regional recommendations on treatment of uncomplicated urinary tract infections.

INTRODUCTION: Uncomplicated urinary tract infection (uUTI) is a common reason for seeing a GP. In Denmark, it is debated if sulfamethizole or pivmecillinam should be recommended for empirical treatment of uUTIs. We evaluated sulfamethizole and pivmecillinam use in the five Danish regions from 2007 to 2011 and explored if the choice of antibiotic in primary care was in accordance with the regional recommendations for uUTI. MATERIAL AND METHODS: Regional drug use data on pivmecillinam and sulfamethizole from 2007 to 2011 were retrieved from the Registry of Medicinal Product Statistics. Regional recommendations from the same period were identified. We calculated differences in consumption based on defined daily doses per 1,000 inhabitants per day (DID) of pivmecillinam and sulfamethizole between the five regions, and intraregional developments. RESULTS: Four regions had recommendations on uUTI in 2011. From 2007 to 2009, sulfamethizole was the only antibiotic recommended. Pivmecillinam was recommended along with sulfametizole in one of four regions from 2010, which increased to two regions in 2011. During the five-year period, sulfamethizole consumption decreased in all regions. The absolute decrease ranged from 0.4 to 0.6 DID. Pivmecillinam consumption increased steadily; the absolute increase ranged from 1.5 to 2.5 DID. During the whole period, the total pivmecillinam consumption was higher than the total sulfamethizole consumption. CONCLUSION: Pivmecillinam dominated the treatment of uUTIs, whereas sulfamethizole prevailed in the regional recommendations, which suggests a lack of adherence to regional recommendations. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.