The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.
Bernhard Mayr, Dirk Schnabel, Helmuth-Günther Dörr and Christof Schöfl
Flavius Zoicas, Michael Droste, Bernhard Mayr, Michael Buchfelder and Christof Schöfl
Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease.
Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment - insulin resistance (HOMA-IR), HbA1c and lipids were assessed.
Eight patients experienced substantial weight loss (−13.1±5.1 kg (range −9 to −22)). Insulin resistance (HOMA-IR −3.2±3.5 (range −9.1 to 0.8)) and HbA1c values (−1.3±1.4% (range −4.5 to 0.0)) improved under treatment (24.3±18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks.
GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations.
Bernhard Mayr, Rolf Buslei, Marily Theodoropoulou, Günter K Stalla, Michael Buchfelder and Christof Schöfl
GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level.
In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.
The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%).
Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.
Matthias Möhlig, Martin O Weickert, Elham Ghadamgadai, Andrea Machlitt, Bettina Pfüller, Ayman M Arafat, Andreas F H Pfeiffer and Christof Schöfl
Objective: Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS.
Design: Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women.
Results: A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = −0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP.
Conclusions: Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.
Hiroyoshi Akutsu, Jürgen Kreutzer, Gerald Wasmeier, Dieter Ropers, Christian Rost, Matthias Möhlig, Henri Wallaschofski, Michael Buchfelder and Christof Schöfl
Information about the risk and course of coronary artery disease (CAD) in acromegaly is limited.
To evaluate CAD risk in acromegalic patients at diagnosis and after successful treatment during follow-up.
Subjects and methods
Twenty-five consecutive patients (age 45.1±10.6 years, 15 women) were studied at the time of diagnosis, and 19 patients were re-evaluated after 4.6±1.1 years. The European Society of Cardiology (ESC) risk score was calculated, and a cardiac computed tomography was performed for detection and quantification (Agatston score (AS)) of coronary artery calcium (CACs). Fifty age-, sex-, and CAD risk-matched subjects and CAC data from the population-based Heinz Nixdorf Recall (HNR) study served as controls.
In 21 of the 25 patients, the 10-year risk of developing CAD according to the ESC risk score was low (<10%) and high (>20%) in four patients. The AS was lower than in controls (2.6±7.9 vs 66±182; P=0.014) and less patients had a positive CAC (AS>0) (20 vs 48%, P=0.024), which in the acromegalic patients was less than expected from the HNR study. The AS did not correlate with GH excess or disease duration. In 19 acromegalic patients, who were in remission and re-evaluated after 4.6±1.1 years, the ESC risk (P=0.102) and the AS (P=0.173) did not change significantly and no symptomatic CAD event occurred.
CAD risk in newly diagnosed acromegalic patients was low and remained stable after successful treatment. CAC was lower than in controls suggesting that GH excess per se does not carry an additional CAD risk.
Matthias Möhlig, Martin O Weickert, Elham Ghadamgahi, Ayman M Arafat, Joachim Spranger, Andreas F H Pfeiffer and Christof Schöfl
Adiposity, insulin resistance (IR), and hyperandrogenism are features of polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4) secreted from adipose and liver tissues has been linked to IR. The impact of RBP4 on IR in PCOS and its usability to identify women with metabolic syndrome (MS) or impaired glucose tolerance ((IGT) or diabetes) were investigated.
Plasma RBP4 was determined in 115 consecutive PCOS women. Associations with IR, body composition, and hyperandrogenemia were investigated by correlation and multiple linear regression analyses in 110 non-diabetics. Receiver operating characteristic curve analysis was used to evaluate RBP4 as a parameter for identifying MS and IGT or diabetes.
RBP4 increased over tertiles of IR (P=0.009). RBP4 correlated with HOMA %S (R=−0.286, P= 0.002), waist-to-hip ratio (WHR) (R=0.233, P=0.034), and dual energy X-ray absorptiometry (DEXA)-lean body mass (R=0.282, P=0.016) but not with body mass index (BMI), DEXA-total or -trunk fat mass, hsCRP, free testosterone, DHEAS, androstenedione, and 17β-estradiol. Adjusted for age, BMI, smoking, and IGT, the association between RBP4 and HOMA %S remained significant (P=0.032). RBP4 explained 4.6% of the variation in HOMA %S. RBP4 was higher in MS and IGT or diabetes, but its ability to identify these women was low (area under the curve, AUC=0.631, P=0.041 or AUC=0.660, P=0.016).
In PCOS, RBP4 has a small independent impact on IR. It is not correlated with hyperandrogenemia, 17β-estradiol, other adrenal steroids, or with markers of adiposity in general. Furthermore, RBP4 does not appear suitable for screening MS or impaired glucose metabolism (IGT or diabetes).
Matthias Möhlig, Joachim Spranger, Michael Ristow, Andreas F H Pfeiffer, Thilo Schill, Hans W Schlösser, Lothar Moltz, Georg Brabant and Christof Schöfl
Objective: Polycystic ovary syndrome (PCOS) is a risk factor for type 2 diabetes mellitus and screening for abnormal glucose metabolism has been recommended by an oral glucose tolerance test (OGTT). This procedure is time-consuming and inconvenient, limiting its general use. Therefore, an easy method is wanted to separate PCOS women with normal from those with potentially abnormal glucose metabolism.
Design: Simple parameters obtained from 101 consecutive PCOS patients were assessed by receiver operating curve analysis for their ability to predict abnormal glucose metabolism.
Results: Comparing discriminating parameters at defined sensitivities revealed that, assessed by homeostasis model assessment (HOMA), insulin resistance (HOMA%S) had the highest specificitiy. At a cut-off point of 73.1%, HOMA%S had a sensitivity of 95.5% and a specificity of 51.9%. Applying this cut-off separated 59 women who had a high probability of abnormal glucose metabolism from 42 women who were at low risk (less than 2.5%). Fasting insulin was the second-best parameter and had a similar specificity. A screening strategy which applies HOMA%S or fasting insulin could almost halve the number of OGTTs by directing them to those PCOS women most likely to be suffering from abnormal glucose metabolism. The negative predictive value of this strategy was 97%. The strategy was tested and confirmed in a second and independent cohort of 264 PCOS women.
Conclusions: HOMA%S, or to a lesser extent fasting insulin, appears to allow for stratified metabolic screening of PCOS women with OGTT.
Christof Schöfl, Holger Franz, Martin Grussendorf, Jürgen Honegger, Cornelia Jaursch-Hancke, Bernhard Mayr, Jochen Schopohl and the participants of the German Acromegaly Register
Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under ‘real life’ conditions are scarce.
To describe biochemical long-term outcome of acromegaly patients in Germany.
Design and methods
Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0–52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range.
Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25–443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0–44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy.
The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.
Christof Schöfl, Martin Grussendorf, Jürgen Honegger, Anke Tönjes, Daniel Thyroke-Gronostay, Bernhard Mayr, Jochen Schopohl and the participants of the German Acromegaly Register
Disease control is a prime target in acromegaly treatment. This should be achievable in the vast majority of patients by available treatment options. For unknown reasons, however, a significant number of patients do not achieve disease control.
To investigate reasons for failure to achieve disease control in long-standing acromegaly.
Design and methods
Survey based on the German Acromegaly Registry database (1755 patients in 57 centres). Questionnaires were sent to 47 centres treating 178 patients with elevated disease markers (IGF1 and GH) at the last documented database visit out of 1528 patients with a diagnosis dated back ≥2 years. Thirty-three centres returned anonymised information for 120 patients (recall rate 67.4%).
Median age of the 120 patients (58 females) was 57 years (range 17–84). Ninety-four patients had at least one operation, 29 had received radiotherapy and 71 had been previously treated medically. Comorbidities were reported in 67 patients. In 61 patients, disease activity had been controlled since the last documented database visit, while 59 patients still had biochemically active disease. Reasons were patients' denial to escalate therapy (23.3%), non-compliance (20.6%), fluctuating insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels with normal values at previous visits (23.3%) and modifications in pharmacotherapy (15.1%). Therapy resistance (9.6%), drug side effects (4.1%) and economic considerations (4.1%) were rare reasons.
Main reasons for long-standing active acromegaly were patients' lack of motivation to agree to therapeutic recommendations and non-compliance with medical therapy. Development of patient education programmes could improve long-term control and thus prognosis of acromegalic patients.
Matthias Möhlig, Ayman M Arafat, Martin A Osterhoff, Frank Isken, Martin O Weickert, Joachim Spranger, Andreas F H Pfeiffer and Christof Schöfl
Low circulating testosterone concentrations have been associated with insulin resistance (IR). Androgen action is mediated by the androgen receptor (AR) whose activity is modulated by a polymorphic CAG repeat sequence within exon 1. An interaction between testosterone and CAG repeat length (CAG length) with respect to IR has been described in women.
We investigated such a putative interaction between testosterone and the CAG length with respect to IR in men with normal glucose tolerance.
In 113 non-diabetic men calculated free testosterone, the CAG length, and a multiplicative interaction term were investigated by multiple linear regression analysis for an association with IR, as indicated by homeostasis model assessment (HOMA %S).
In a multivariate regression analysis adjusted for age and body mass index, free testosterone, CAG length, and a multiplicative interaction term were significantly associated with IR (P=0.001, P=0.001, P=0.01 respectively). The model explained 36.6% of the variation of IR and predicted that in carriers with a CAG length of 23, changes in testosterone would only minimally affect IR. For CAG lengths longer than 23, however, an increase in testosterone would improve IR, namely the longer the CAG length, the greater the effect. In contrast, in the case of CAG lengths shorter than 23, the effect of increasing testosterone would be the opposite.
In men, testosterone and the AR CAG repeat length polymorphism interacted with respect to IR. The interpretation of the association between testosterone and IR seems to require consideration of the AR CAG repeat polymorphism.