Health-related quality of life in patients with non-functioning pituitary adenoma: a special focus on hydrocortisone replacement dose.

PURPOSE: Patients with non-functioning pituitary adenomas (NFPA) suffer from pronounced impairments in physical and mental measures that result in an impairment of health-related quality of life (HRQOL). The role of secondary adrenal insufficiency (SAI) and especially the one of the hydrocortisone (HC) replacement dose on the HRQOL seems to be conflicting. The primary aim of this study is to assess the HRQOL in patients with NFPA in terms of presence of SAI and in patients without SAI and the secondary to explore the impact of treatment parameters such as daily HC dose. DESIGN/METHODS: In a cross-sectional study we evaluated parameters of HRQOL in 95 patients with NFPA of the Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry in Munich using standardized questionnaires like Short Form (SF-36), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and a self-constructed questionnaire about medical history. RESULTS: We could not find any significant difference between patients with and without SAI in the standardized questionnaires in terms of HRQOL. We could show that higher doses of HC were negatively correlated with HRQOL measured by SF-36 global health score regardless of using BDI or STAI in the block (ß = - 0.397; p = 0.021, ß = - 0.390; p = 0.016, respectively). CONCLUSIONS: NFPA patients with SAI do not have a worse HRQOL than patients with NFPA and intact corticotropic axis. We could show that higher doses of HC are associated with an impaired HRQOL measured by SF-36 global and physical health score, whereas mental health score is not significantly influenced by the HC dose.

Cellular and molecular specificity of pituitary gland physiology.

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.

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.

The USP8 mutational status may predict long-term remission in patients with Cushing's disease.

OBJECTIVE: Almost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin-specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. DESIGN: Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. PATIENTS: Patients with Cushing's disease from a single-centre cohort who underwent TSS between 1991 and 2012. MEASUREMENTS: Long-term remission and recurrence rate after TSS with at least 6 months follow-up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre-operative hormonal levels. USP8 mutational status. RESULTS: Patients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean ± SD 46 ± 10 years vs 53 ± 11 years; P = 0.028) and presented with higher pre-operative 24-hour urinary-free cortisol levels (median IQR µg/24 hours 1174.0, 1184.5 vs 480.0, 405.3; P = 0.045). The incidence of recurrence in a 10-year follow-up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P = 0.026). Recurrence appeared significantly earlier in these patients (months 70, 44-97 95% CI vs 102, 86-119 95% CI; P = 0.019). CONCLUSION: Recurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours.

Desire to Have Children Among Transgender People in Germany: A Cross-Sectional Multi-Center Study.

BACKGROUND: Many trans individuals undergo medical interventions that result in irreversible loss of fertility. Little is known about their desire to have children and attitudes toward fertility preservation options. AIM: To study how the desire for children and the use of fertility preservation options varies among trans women and trans men in different transitioning stages in Germany. METHODS: In this cross-sectional multi-center study, N = 99 trans women and N = 90 trans men were included. Of these, 26 of each sex were just about to start medical treatment. OUTCOMES: Outcome parameter were the prevalence and determinants of a desire to have children in trans persons. RESULTS: Before treatment, a desire for children was significantly higher in trans men compared to trans women (P = .016). In contrast, in those who had already started treatment, a current desire to have children was equally present in about one fourth of participants of both genders while the interest in having children in the future was significantly higher in trans women (69.9%) than in trans men (46.9%; P = .034). Although 76.1% of trans women and 76.6% of trans men indicated that they had at least thought about preserving germ cells before starting medical transition, only 9.6% of trans women and 3.1% of trans men had put this idea into practice. Most trans men in both groups indicated that insemination of a female partner with sperm from an unrelated donor was a suitable option to fulfill their child wish, potentially explaining their low interest in preserving their own germ cells. Finally, a logistic regression analysis accounting for potential confounders revealed that overall trans women were more than twice as likely to have a current desire to have children (odds ratio 2.58), and this wish was on average 5.3% lower with each year of increasing age. CLINICAL TRANSLATION: A low level of fertility preservation among trans persons is contrasted by a high level of desire for children. This highlights the importance of counseling trans individuals regarding fertility preservation options. CONCLUSIONS: To our knowledge, this is the first study that addresses desire to have children in a clinical sample of trans women. It is also the first that investigates this issue among trans men who have not started medical treatment, and the first comparison of both genders. A limitation for the generalization of our results is the special legal context in Germany that forbids oocyte donation for reciprocal in vitro fertilization. Reproductive desire is high among trans individuals, but the use of reproductive options is surprisingly low. Auer MK, Fuss J, Nieder TO, et al. Desire to Have Children Among Transgender People in Germany: A Cross-Sectional Multi-Center Study. J Sex Med 2018;15:757-767.

Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

BACKGROUND: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. METHODS: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD. RESULTS: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145). CONCLUSIONS: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. TRIAL REGISTRATION: NCT number: NCT00934063 . Date of registration: 02 July 2009.

Body Image Perception in Acromegaly Is Not Associated with Objective Acromegalic Changes but Depends on Depressive Symptoms.

OBJECTIVE: Diagnosis of acromegaly is delayed up to 10 years after disease onset despite obvious external/objective changes such as bone and soft tissue deformities. We hypothesized that a lack of subjective perception of the disease state, possibly mediated by psychiatric or cognitive alterations, might contribute to the delayed initiation of a diagnostic workup. DESIGN: Cross-sectional study. METHODS: We investigated perceived body image by standardized questionnaires (FKB-20: Fragebogen zum Körperbild; FBeK: Fragebogen zur Beurteilung des eigenen Körpers) in 81 acromegalic patients and contrasted them to (a) a clinical control group of 60 patients with nonfunctioning pituitary adenomas (NFPA) who lack severe facial and physical alterations and (b) healthy controls. We further evaluated body image in relation to objective acromegalic changes as judged by medical experts and psychiatric pathology, e.g. depression and cognitive impairment. RESULTS: Patients with acromegaly did not lack subjective perception of the disease state; they showed more negative body image, less vitality, more insecurity/paresthesia and more accentuation of the body compared to normal controls. NFPA patients differed from acromegalic patients only in the 'vital body dynamics' scale of the FKB-20, although they hardly exhibit any physical/bodily changes. Depression correlated with worse body image. No associations were found between body image and objective acromegalic changes as judged by medical experts, cognitive decline or treatment status. CONCLUSIONS: Negative body image in acromegalic patients is unrelated to their objective appearance and similar to those of NFPA patients without major bodily changes. Depression, but not cognitive decline or treatment status, contributes to negative body image.

Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.

We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p < 0.05). Over the 10-year study period, a time trend of an overall estimated GH dose increase by 0.06 mg/day (females) and decrease by 0.07 mg/day (males) was shown; this interaction of gender and calendar year was significant (p < 0.0001). In both genders, overall GH dose decreased with increasing age (p < 0.0001). Our study confirms that females and younger patients require higher GH doses compared with males and older patients.

Is insulin-like growth factor-I a good marker for treatment adherence in growth hormone deficiency in adulthood?

OBJECTIVE: There is a paucity of studies on adherence to growth hormone treatment in growth hormone deficient (GHD) adults. Therefore, this study reports on adherence to GH-replacement therapy in adults with GHD, with a special focus on the course and potential predictors of nonadherence. DESIGN: Retrospective single-centre cohort study. PATIENTS: From the local patient database, 179 suitable patients with GHD were identified. MEASUREMENTS: The primary outcome was adherence assessed by calculating the percentage of available prescription data in comparison with recommended GH dosages over a mean follow-up period of 92·4 months. Patients were categorized into five adherence categories ranging from <20% to >80%. RESULTS: Mean overall adherence was 74·0%, with 52·9% of patients falling into the adherence group of >80% and 8·8% of <20%. There was a significant drop in adherence (9·8%) between the first and second years of treatment (P < 0·001). Patients with childhood-onset GHD were significantly less adherent to GH treatment than patients with adult-onset GHD (62·0% vs 77·0%, P = 0·012); however, this finding was no longer significant after including age as a covariate. Frequency of IGF-1 levels lying outside the age- and sex-specific reference range was not a good indicator for adherence. CONCLUSION: Although overall adherence was relatively high in our study sample, there is a significant amount of patients who should be regarded as nonadherent. This applies in particular to younger patients. Treating physicians should be aware of the fact that IGF-1 levels do not seem to be a good indicator for adherence.

Investigating the role of cortisol and growth hormone in fatty liver development: fatty liver index in patients with pituitary adenomas.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is a hallmark of the metabolic syndrome and has been shown to be an independent predictor of cardiovascular mortality. Although glucocorticoids and growth hormone are known to be implicated in its pathophysiology, it has only rarely been investigated in the context of patients with pituitary insufficiency or former cortisol excess. METHODS: Case-control study in patients with biochemically controlled Cushing's disease (CD; N = 33) and non-functioning pituitary adenomas (NFPA; N = 79). NAFLD was estimated by calculating the fatty liver index (FLI) including BMI, waist circumference, GGT and triglyceride levels. RESULTS: Although there was no difference in FLI between patients with NFPA and CD, we identified average daily hydrocortisone (HC) intake in those with adrenal insufficiency to be an independent predictor of FLI (ß = 1.124; p = 0.017), even after adjusting for BMI and waist circumference. In line, those with a FLI > 60 were also taking in average significantly more HC per day than those with a score <60 (21.05 mg ± 5.9 vs. 17.9 mg ± 4.4; p = 0.01). FLI was also the best independent predictor for HbA1c and fasting glucose levels (both p = 0.001). Growth hormone deficiency and replacement therapy were not associated with FLI in either group. CONCLUSIONS: While HC dosage affects FLI as an estimate of NFLD in patients with CD and NFPA, the benefit of GH replacement still needs to be determined. In contrast to reports in CD patients with active disease, NAFLD in those with biochemical control was not different from NFPA patients.

KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors.

OBJECTIVE: KISS1 is a metastasis suppressor gene involved in cancer biology. Given the high expression levels of KISS1 and KISS1R in the hypothalamus and the pituitary respectively, we hypothesized that this system could possibly affect tumor invasiveness and clinical behavior of pituitary tumors. METHODS: Expression levels of KISS1 and KISS1R mRNA were evaluated by RT-PCR. Clinical information pertaining tumor characteristics was extracted from patients' charts. RESULTS: Tumors from 39 patients (21 females, mean age 47.5 years) were examined. KISS1R was expressed in 26 (67%) of samples (94% of NFPA, 42% of GH-, 67% of ACTH-, and 25% of PRL-secreting adenomas) and was found more often in female patients (81 vs. 50% males, p < 0.05); and in NFPA (94 vs. 45.5% in secreting tumors; p = 0.003). Patients expressing KISS1R were older at presentation (50.5 ± 1.4 vs. 38.1 ± 1.3 years; p = 0.008). In the multivariate analysis, factors significantly associated with KISS1R expression included female gender (OR 13.8, 95 % CI 1.22-155.9; p = 0.03) and having a NFPA (OR 24.7, 95% CI 1.50-406.4; p = 0.02). Tumor size, invasiveness and age at presentation were not independently associated with KISS1R expression. Pituitary tumors and normal pituitary were negative for KISS1 mRNA expression. CONCLUSIONS: The majority of human NFPA expressed KISS1R with lower rates of expression in other types of pituitary tumors. KISS1R expression did not impart a clinical beneficial tumor phenotype, as it was not associated with tumor size or invasiveness. Additional studies are required to elucidate the role of KISS1 receptor in pituitary gland physiology and pathology.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

PURPOSE: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. METHODS: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. RESULTS: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. CONCLUSIONS: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Somatostatin receptors: from signaling to clinical practice.

Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.

Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis.

Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC50=87 µM) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 ß acetylation, and a mutation on the GSK3ß-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.

Circulating troponin as measured by a sensitive assay for cardiovascular risk assessment in primary prevention.

BACKGROUND: Measuring circulating cardiac troponin using novel sensitive assays has revealed that even minute elevations are associated with increased mortality in patients with coronary artery disease or even in the general population. Less well defined, however, is the incremental value of measuring circulating cardiac troponin I (cTnI) by a sensitive assay for risk assessment in primary prevention. METHODS: We measured circulating concentrations of cTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) in 5388 individuals free of known cardiovascular disease recruited into the DETECT study, a prospective longitudinal population-based cohort study. We determined the prognostic implications for incident major adverse cardiovascular events (MACE) during 5 years of follow-up. RESULTS: Circulating cTnI was detectable in 19% of the subjects. Increased cTnI concentrations were associated with established risk factors for atherosclerosis and demonstrated a graded relationship with all-cause mortality and incident MACE during 5-year follow-up. A single measurement of cTnI significantly improved risk prediction over established risk factors, and also added prognostic information, when adjusted for serum concentrations of NT-proBNP and hsCRP. CONCLUSIONS: Minute increases in cTnI are associated with increased mortality and incident MACE in a large primary prevention cohort and, thus, identify contributors to cardiovascular risk not fully captured by traditional risk factor assessment.

The influence of gender on the injury severity, course and outcome of traumatic brain injury.

OBJECTIVE: To examine the independent association of gender with injury severity, clinical course, pituitary dysfunction and outcome after traumatic brain injury (TBI). DESIGN: Prospective cohort, analysis of a data sub-set collected as part of the nation-wide database 'The Structured Data Assessment of Hypopituitarism after TBI and SAH'. METHODS AND PROCEDURES: Four hundred and twenty-seven patients following TBI were observed from acute care through neurological rehabilitation. Outcome was measured by Glasgow Outcome Scale (GOS), employment status and living situation post-injury. As a secondary outcome measure anterior pituitary function was assessed. RESULTS: There were no differences in injury severity between men and women. Age had a significant effect on the GCS score (p = 0.0295), but gender did not (p = 0.4105). The outcome was equivalent between men and women once corrected for age. Logistic regression revealed that gender had no effect (p = 0.8008), but age (p = 0.0021) and initial injury severity (p = 0.0010) had an effect on the GOS. After correcting for pre-injury living situation and employment only initial injury severity (p = 0.0005) influenced GOS. Pituitary insufficiency was not affected by sex or age. CONCLUSION: Gender does not seem to influence the course and outcome of TBI. Outcome parameters were affected foremost by initial injury severity and by age, but not by sex.

Sleep patterns in patients treated for non-secreting intra- and parasellar tumors: A self-report case-control study.

Purpose: In this study we evaluate sleep patterns of patients treated for non-secreting intra- and parasellar tumors and age- and sex-matched healthy controls. Methods: We conducted a self-report cross-sectional case-control study with 104 patients treated for non-secreting intra- and parasellar tumors and 1800 healthy controls in an 1:8 matching. All subjects answered the Munich ChronoType Questionnaire, whereas patients were provided the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Short-Form 36 Health survey, the Beck Depression Inventory and the State-Trait Anxiety Inventory additionally. Results: Patients treated for non-secreting intra- and parasellar tumors go to bed earlier, fall asleep earlier, need less time to prepare to sleep but also to get up. Additionally, they lie and sleep longer. The subgroup analysis showed that patients with secondary adrenal insufficiency compared to controls experienced shorter daily light exposure and longer sleep latency. Higher hydrocortisone dose (>20mg) was associated with worse score in global, physical and mental health, shorter time to prepare to sleep, earlier sleep onset and longer sleep duration. Conclusion: Our study shows that patients treated for non-secreting intra- and parasellar tumors, even if successfully treated, experience altered sleep patterns compared to controls. We suggest that managing clinicians should enlighten these possible sleep alterations to their patients and use specific questionnaires to document sleep disturbances. Additionally, when treating patients surgically, especially by transcranial approach, damaging the suprachiasmatic nucleus should be avoided. Furthermore, circadian hydrocortisone replacement therapy ideally with dual-release hydrocortisone - if possible, in a dose not more than 20mg daily - that resembles physiological cortisol levels more closely may be beneficial and could improve sleep patterns and sleep-related quality of life.

TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.

Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release.

Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease.

SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing's disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G(i) α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease.