Randomised controlled trial of preconception lifestyle intervention on maternal and offspring health in people with increased risk of gestational diabetes: study protocol for the BEFORE THE BEGINNING trial.

INTRODUCTION: Gestational diabetes mellitus (GDM) is associated with increased risk for type 2 diabetes in the mother and cardiometabolic diseases in the child. The preconception period is an optimal window to adapt the lifestyle for improved outcomes for both mother and child. Our aim is to determine the effect of a lifestyle intervention, initiated before and continued throughout pregnancy, on maternal glucose tolerance and other maternal and infant cardiometabolic outcomes. METHODS AND ANALYSIS: This ongoing randomised controlled trial has included 167 females aged 18-39 years old at increased risk for GDM who are contemplating pregnancy. The participants were randomly allocated 1:1 to an intervention or control group. The intervention consists of exercise (volume is set by a heart rate-based app and corresponds to ≥ 1 hour of weekly exercise at ≥ 80% of individual heart rate maximum), and time-restricted eating (≤ 10 hours/day window of energy intake). The primary outcome measure is glucose tolerance in gestational week 28. Maternal and offspring outcomes are measured before and during pregnancy, at delivery, and at 6-8 weeks post partum. Primary and secondary continuous outcome measures will be compared between groups based on the 'intention to treat' principle using linear mixed models. ETHICS AND DISSEMINATION: The Regional Committees for Medical and Health Research Ethics in Norway has approved the study (REK 143756). The anonymised results will be submitted for publication and posted in a publicly accessible database of clinical study results. TRIAL REGISTRATION NUMBER: Clinical trial gov NCT04585581.

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

Polycystic ovary syndrome (PCOS) is characterized by the presence of insulin resistance, and women with PCOS have high prevalence of gestational diabetes (GDM). Both conditions have been associated with increased risk for pregnancy complications such as preterm birth, preeclampsia and increased offspring birth weight. We aimed to estimate the prevalence of GDM in women with PCOS using both previous and new diagnostic criteria, and to analyse whether the risk of pregnancy complications increased with the presence of GDM. In addition, we aimed to assess the response to metformin treatment in PCOS women with GDM. We performed post-hoc analysis of three prospective, double blinded studies of altogether 791 pregnant women with PCOS randomized to either metformin or placebo treatment from first trimester to delivery. Glucose data allowing GDM classification after previous (WHO 1999) and new (WHO 2013 and Norwegian 2017) diagnostic criteria were available for 722 of the women. Complications such as preeclampsia, late miscarriage and preterm birth, birth weight and gestational age were correlated to the presence of GDM and metformin treatment. The prevalence of GDM was 28.3% (WHO 1999), 41.2% (WHO 2013) and 27.2% (Norwegian 2017). Having GDM already in first trimester associated with increased risk for late miscarriage (p<0.01). Having GDM according to newer criteria correlated to increased maternal age and BMI (p<0.001). Otherwise, having GDM (any criteria) correlated neither to the development of preeclampsia, nor to birth weight z-score or the proportion of offspring being large for gestational weight. Maternal age and BMI, parity and gestational weight gain, but not GDM or metformin treatment, were determinants for birth weight z-score. Conclusion: in pregnant women with PCOS, having GDM did not increase the risk for other pregnancy complications except for an increased risk for late miscarriage among those with GDM already in the first trimester.

Pituitary Adenoma and Non-acute Headache: Is There an Association, and Does Treatment Help?

OBJECTIVE: Headache is a controversial indication for treatment of pituitary adenoma. We studied the possible relationship between pituitary adenomas and headache as well as the symptomatic effects of treatment. METHODS: Current and prior headache complaints were assessed in structured telephone interviews in 201 patients with pituitary adenoma. Clinical variables and headache history were retrieved from medical records. Headache prevalence among patients was compared with a regional population-based cohort. RESULTS: The presence of headache was higher in patients before the diagnosis of pituitary adenoma compared with the general population (P < 0.001). At follow-up, overall prevalence was lower (P < 0.001), but chronic headache was more prevalent (P = 0.001) than in the general population. With the exception of family history, no associations between headache and clinical or radiologic variables were identified. At follow-up evaluation, 77% of patients with headache reported improvement, 5% reported worsening, and 11% reported new headaches. Patients with nonfunctional adenoma who underwent surgical treatment reported improvement more often (85%) than patients who did not undergo surgery (58%) (P = 0.042). CONCLUSIONS: In a cohort with both treated and untreated patients with pituitary adenoma, headache prevalence was low compared with the general population. We found no link between clinical or radiologic variables and headache. Although a higher proportion of patients who underwent surgical treatment reported symptomatic relief, most patients who did not undergo treatment also improved. We believe that the unpredictable dynamics of headache over time and the lack of predictive and modifiable tumor-related variables associated with headache or treatment of headache weaken headache as a sole indication for pituitary adenoma treatment.

Gene expression profiling identifies ESRP1 as a potential regulator of epithelial mesenchymal transition in somatotroph adenomas from a large cohort of patients with acromegaly.

CONTEXT: The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking. OBJECTIVE: We hypothesized that characterization of EMT-related transcripts in somatotroph adenomas could identify novel therapeutic targets in individuals with poor response to SA treatment and provide more knowledge of the mechanism of EMT progression. PATIENTS: Fifty-three patients with acromegaly participated in the study. RESEARCH DESIGN AND METHODS: We performed microarray analysis of 16 adenomas, eight with high expression and eight with low expression of E-cadherin, in order to identify EMT-related transcripts. Candidate transcripts were further explored in vivo in 53 adenomas and in vitro in a rat pituitary GH-producing cell (GH3) after exploring three models for reducing E-cadherin and inducing a mesenchymal phenotype. RESULTS: In vivo E-cadherin mRNA expression in tumor tissue is associated negatively with tumor size and invasiveness and positively with GH and IGF-I levels in serum and response to SA treatment. Microarray and subsequent PCR analysis identify several EMT-related genes associated with E-cadherin expression. In vitro, few of these EMT-related genes were regulated by silencing E-cadherin or by TGF-ß1 treatment in GH3 cells. In contrast, silencing Esrp1 in GH3 cells regulated many of the EMT-related transcripts. CONCLUSION: These results indicate that ESRP1 could be a master regulator of the EMT process in pituitary adenomas causing acromegaly.

KIT protein expression and mutational status of KIT gene in pituitary adenomas.

KIT protein expression and mutational status of KIT gene in different types of tumours have been intensively studied since Imatinib Mesylate, KIT/PDGFRA tyrosine kinase inhibitor became available. However, only one immunohistochemical study on KIT expression in pituitary adenomas has been published. There are currently no reports on mutational status of KIT gene in pituitary adenomas. We have immunohistochemically investigated KIT expression in 252 pituitary adenomas and found cytoplasmic reactivity in 52.4% and membranous reactivity in 8.3% of all adenomas. There was statistically significant difference in KIT expression between clinically non-functioning, growth hormone- and adrenocorticotroph hormone-producing adenomas. The group with membranous expression was dominated by somatotropinomas and clinically non-functioning adenomas. KIT expression in a subset of adenomas was also confirmed by western blot analysis of 48 adenomas. Immunohistochemical KIT expression was correlated with basic clinical data and in a cohort of acromegalic patients with additional data (somatostatin receptor type 2A expression, response to somatostatin analogue treatment and mutational status of gsp oncogene). Exons 9, 11, 13 and 17 of KIT gene were searched for mutations in the tumours with membranous KIT expression and in a minority of tumours with cytoplasmic KIT expression using denaturing high-performance liquid chromatography and in suspected cases sequencing of one or more exons. No mutations in the examined exons were found. Our results may suggest a role of KIT in the pathogenesis of a subset of pituitary adenomas and point out the need for further research to find out if KIT-reactive adenomas could be sensitive to Imatinib Mesylate.

Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly.

CONTEXT: Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas. OBJECTIVES: To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment. DESIGN/SETTINGS/PATIENTS: Seventy-eight patients with active acromegaly were included. Long-term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E-cadherin and SSTR2a. Protein levels of E-cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas. RESULTS: DG adenomas and the transitional group had higher serum levels of IGF-1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long-term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E-cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG. CONCLUSIONS: Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response.

CONTEXT: Appropriate cell-to-cell adhesion is fundamental for the epithelial phenotype of pituitary cells. Loss of the adhesion protein E-cadherin has been associated with invasiveness, metastasis, and poor prognosis in cancers of epithelial origin. In somatotroph adenomas, a variable and reduced expression of E-cadherin has been demonstrated. In addition, nuclear translocation of E-cadherin was found to correlate with pituitary tumor invasion. OBJECTIVE: The objective was to examine the protein expression of E-cadherin in somatotroph pituitary adenomas in relation to adenoma size, invasiveness, and somatostatin analog (SMS) efficacy. PATIENTS AND METHODS: Eighty-three patients were included, and 29 were treated preoperatively with SMS. Adenoma E-cadherin protein expression was analyzed by Western blot (61 patients) and immunohistochemistry (IHC) (80 patients) with antibodies directed against both extracellular and intracellular domains (IHC). The acute (direct surgery group) and long-term (preoperatively treated group) SMS responses were evaluated. Baseline tumor volume and invasiveness were measured on magnetic resonance imaging scans. RESULTS: Membranous E-cadherin was lost in several adenomas. Nine of these were nuclear E-cadherin positive. The E-cadherin protein expression correlated negatively to tumor size and positively to acute SMS response. Low E-cadherin levels (preoperatively treated group only) and loss of membranous E-cadherin correlated to tumor invasiveness. The E-cadherin level correlated positively to tumor reduction after SMS treatment, and adenomas with nuclear E-cadherin staining had lower IGF-I reduction and tumor shrinkage. Preoperatively treated adenomas had reduced E-cadherin protein levels, but the IHC expression was unaltered. CONCLUSION: Reduced E-cadherin expression may correlate to a dedifferentiated phenotype in the somatotroph pituitary adenomas.

Low levels of raf kinase inhibitory protein in growth hormone-secreting pituitary adenomas correlate with poor response to octreotide treatment.

CONTEXT: Excessive GH production by pituitary tumors causes acromegaly. Medical treatment of acromegaly with somatostatin analogs (SMSs), like octreotide, is well established, but the clinical effect is variable. One mechanism for octreotide effect is inhibition of the MAPK signaling pathway after binding to the G protein-coupled somatostatin receptor. Nonphosphorylated Raf kinase inhibitory protein (RKIP) binds to and inhibits Raf1 kinase, and thereby attenuates MAPK signaling, whereas phosphorylated RKIP inhibits G protein receptor internalization and degradation due to inhibition of G protein receptor kinase 2. OBJECTIVE: Our objective was to study RKIP levels in pituitary somatotroph adenomas, and relate them to clinical characteristics and response to octreotide treatment in patients with acromegaly. PATIENTS AND METHODS: RKIP level was analyzed by Western blot of proteins extracted from somatotroph tumors frozen a short time after surgery in 51 patients with active acromegaly. An acute somatostatin test was performed in 46 of the patients, and in 21 the IGF-I level before and 6 months after SMS treatment was available. RESULTS: The adenoma RKIP level correlated significantly to both the acute and the long-term octreotide responses on serum levels of GH and IGF-I, respectively. In multiple regression analyses, the RKIP level was a significant determinant for both the GH reduction in the acute test and the IGF-I reduction after approximately 6 months. CONCLUSION: The RKIP level in somatotroph adenomas seems to be important for the clinical effect of SMS treatment, in which low levels of RKIP correlate to poor clinical response to SMSs.