Molecular biological examination of somatotroph pituitary adenomas related to clinical data from patients with acromegaly

Definition and epidemiology The first historical description of acromegaly could be the story of David and Goliath described both in The Old Testament and in the Koran. Goliath was a giant, but David defeated him by sneaking up on him, maybe in his visual field defect, and hitting him with a stone in the forehead using a sling. The connection between gigantism and the pituitary, hence with the possibility of visual disturbances, was not recognized until 1884, published in a book by Fritzsche and Klebs. Two years later, Pierre Marie introduced the name acromegaly and a clinical description of the syndrome. He had several suggestions for the aetiology; none included the pituitary. Acromegaly is a clinical syndrome due to chronic exposure to supra-physiological levels of growth hormone (GH), in almost all cases caused by a GH producing somatotroph pituitary adenoma. When the GH overproduction occurs before the fusion of the growth plates, it results in increased and continuous length growth, termed gigantism. However, the disease usually develops later in life, with a median age of diagnosis at 40-50 years, men being a little younger than females. The incidence of acromegaly is reported to be 2-4 new cases per million inhabitants per year, but the prevalence is markedly higher, varying between 36 and 125 patients per million inhabitants in recent publications. The reports with the lowest numbers for both incidence and prevalence are from national registers of acromegaly, where the results from different regions are highly variable. This could be due to registration bias and underestimation in some of the regions, and hence an underestimation of total incidence and prevalence. Clinical characteristics The clinical features and symptoms of acromegaly develop slowly, and the diagnosis is usually delayed by several years. The median time from start of symptoms to diagnosis has been reported to 4 to 6 years in recent studies. This diagnostic delay did not change in patients diagnosed between 1992 and 2003, compared to 1981 – 1991. A published patient’s journey is an illustrating example of how long the way to correct diagnosis can be. The symptoms of acromegaly are due to tumour mass or hormone hypersecretion. The symptoms caused by the expanding tumour mass are similar for all pituitary tumours, and include headache and compression of the optic nerve tract or chiasm causing visual field defects. In larger adenomas, various degrees of pituitary insufficiency can occur due to suppression of the other hormone producing cells in the pituitary. The elevated level of GH leads to increased production of insulin-like growth factor 1 (IGF-1), both in the liver causing increased systemic IGF-1, and locally. The effects of elevated GH and IGF-1 include acral and soft tissue hyperplasia, causing enlarged and swollen hands and feet, carpal tunnel syndrome, coarse facial features and macrognathia, macroglossia, sleep apnoea and deepening of the voice. Arthropathy with joint pain is common, developing to irreversible osteoarthritis in a later stage. Metabolic changes like increased insulin resistance causing impaired glucose tolerance or diabetes mellitus are not unusual. Commonly reported are also increased sweating, fatigue and physical weakness. A recent study reported higher incidence of affective disorders, particularly depressions, in patients with acromegaly, also compared to patients with other chronic diseases. Cardiac hypertrophy occurs even in patients shortly exposed to GH hypersecretion, and can develop further to cardiomyopathy and heart failure in untreated acromegaly. Arterial hypertension, arrhythmias and atherosclerosis are other manifestations. A schematic overview of symptoms is given in table 1. Diagnosis Single GH measurements are not reliable in the diagnostic evaluation of acromegaly due to the normal pulsatile GH secretion. However, IGF-1 is a function of the integrated 24-h serum GH level and a single measure can be used as screening procedure. In acromegaly, serum IGF-1 will be elevated compared to the normal age related reference range. The diagnosis are confirmed with an oral glucose tolerance test (OGTT), where hyperglycaemia will fail to suppress GH sufficiently in the case of acromegaly. A magnetic resonance imaging (MRI) scan of the pituitary will usually identify the adenoma

The effect of surgery on fat mass, lipid and glucose metabolism in mild primary hyperparathyroidism

Context: Mild primary hyperparathyroidism has been associated with increased body fat mass and unfavorable cardiovascular risk factors. Objective: To assess the effect of parathyroidectomy on fat mass, glucose and lipid metabolism. Design, patients, interventions, main outcome measures: 119 patients previously randomized to observation (OBS; n = 58) or parathyroidectomy (PTX; n = 61) within the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, an open randomized multicenter study, were included. Main outcome measures for this study were the differences in fat mass, markers for lipid and glucose metabolism between OBS and PTX 5 years after randomization. Results: In the OBS group, total cholesterol (Total-C) decreased from mean 5.9 (±1.1) to 5.6 (±1.0) mmol/L (P = 0.037) and LDL cholesterol (LDL-C) decreased from 3.7 (±1.0) to 3.3 (±0.9) mmol/L (P = 0.010). In the PTX group, the Total-C and LDL-C remained unchanged resulting in a significant between-group difference over time (P = 0.013 and P = 0.026, respectively). This difference was driven by patients who started with lipid-lowering medication during the study period (OBS: 5; PTX: 1). There was an increase in trunk fat mass in the OBS group, but no between-group differences over time. Mean 25(OH) vitamin D increased in the PTX group (P < 0.001), but did not change in the OBS group. No difference in parameters of glucose metabolism was detected. Conclusion: In mild PHPT, the measured metabolic and cardiovascular risk factors were not modified by PTX. Observation seems safe and cardiovascular risk reduction should not be regarded as a separate indication for parathyroidectomy based on the results from this study

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.© 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0

Attenuated RORC expression in the presence of EMT progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery.

Somatostatin analogs (SA) have been established as the first line medical treatment for acromegaly, but following long-term treatment, SA normalizes GH and IGF-I levels in only 40-60% of patients. The epithelial marker E-cadherin plays a crucial role in the epithelial mesenchymal transition (EMT) and is associated with a poor response to SA treatment. We hypothesized that the characterization of transcripts regulated by SA in somatotroph adenomas with high and low E-cadherin expression may identify signaling pathways and mediators that can explain the poor response to SA treatment. We performed a microarray analysis of sixteen adenomas with different levels of E-cadherin and SA treatment to identify regulated transcripts. Candidate transcripts were further explored in vivo in sixty-five adenomas, and interactions between SA treatment and EMT progression on mRNA expression profiles and associations with clinical recovery were assessed. Finally, the effects of SA treatment on adenoma cells in vitro from acromegalic patients were determined. Microarray analysis of selected adenomas with differential E-cadherin expression, as a marker of EMT progression, identified 172 genes that displayed differential expression that was dependent on SA treatment. The validation of selected candidates in the entire cohort identified 9 transcripts that showed an interaction between E-cadherin expression and SA treatment. Further analysis of the impact of these genes suggests that attenuated RORC expression in somatotroph adenomas is associated with increased tumor size and a blunted clinical response. Our study indicates that attenuated RORC may be involved in the poor clinical response to SA treatment in patients with acromegaly

Matrix scatter plots between <i>RORC</i> and the response to the acute SA test, tumor size, tumor size reduction and IGF-I reduction.

<p>Matrix scatter plots between <i>RORC</i> and the response to the acute SA test, tumor size, tumor size reduction and IGF-I reduction.</p

Associations between selected transcipts and clinical variables.

a<p>Univariate, Pearson correlation: r (p = ). <b>^b</b>Multivariate, Stepwise linear regression: B (SE), t = , p = . NA, not applicable.</p

Demographics of the study population.

<p>Unless stated, data are given as median (25^th, 75^th percentile).</p>†<p>p<0.05 vs. Preoperative SA.</p>#<p>During acute octreotide test in patients not preoperatively treated with a somatostatin analog;</p>*<p>after median 6 months (range 2–32 months) preoperative SA treatment.</p