Does GH replacement therapy in adult GH-deficient patients result in recurrence or increase in size of pituitary tumours?

OBJECTIVE: Hypopituitary GH-deficient patients have an increased cardiovascular mortality and GH replacement in this population has resulted in considerable therapeutic benefit. GH replacement involves administration of a potentially mitogenic substance to patients with a previous or residual pituitary tumour. Our objective was to evaluate whether GH replacement results in an increase in the size of pituitary tumours. METHODS: This was a non-randomised observational study on patients recruited from the endocrine clinic. All subjects had GH deficiency, proven on an insulin tolerance test and were divided into those who were or were not receiving long-term GH replacement. Comparison of change in pituitary size was made with interval radiological imaging of the pituitary. RESULTS: Seventy-five patients (40 men and 35 women) were in the study, 47 were on long-term GH replacement and there were 28 controls. The average length of treatment for the treated group was 3.6 patient years. Thirty-nine patients in the treated group had at least 2 years of GH treatment between imaging studies of the pituitary. Two patients in the treated group had an increase in pituitary size (non-functioning adenomas) and two in the control group (one functioning and one non-functioning adenoma adenoma). None of these four patients required further treatment. There was no statistically significant difference between the two groups. CONCLUSION: Using a representative cohort of hypopituitary patients attending an endocrine clinic, GH replacement was not associated with an increased pituitary tumour recurrence rate. Although the results are not conclusive, in the period of observation GH had little adverse effect but longer studies are required to be certain.     

Recombinant hGH replacement therapy and the hypothalamus–pituitary–thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?

OBJECTIVE: Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD. DESIGN: Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. MEASUREMENT AND STUDY SUBJECTS: Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study. RESULTS: Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels (P < 0.01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups. CONCLUSION: Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD.     

Two years of growth hormone replacement therapy in a group of patients with Sheehan’s syndrome

To investigate the effects of GH replacement on lipid profile, carotid artery intima-media thickness (IMT), glucose metabolism and visceral fat in patients with Sheehan’s syndrome, ten patients, mean age 44.8 ± 9.5 yr, compared with 10 controls matched for age and body mass index were studied. Total cholesterol, Triglycerides (TG), HDL-c, LDL-c, Apolipoprotein A and B (apoA and apoB) and Lipoprotein (a), serum IGF-1, ultrasonography of the carotid arteries, oral glucose tolerance test (OGTT), HOMA insulin resistance index, insulin sensitivity index (ISI)-composite and abdominal CT scan were performed. When compared to a control group, patients presented lower HDL concentrations (p = 0.05) and 2-h OGTT insulin levels (p < 0.04) and increased TG levels (p < 0.04). After 24 months of GH replacement a reduction in the relation ApoB/ApoA (p = 0.04) was observed, as well as an increase in HDL (p < 0.004). A decrease in carotid artery IMT and in visceral fat over time was found, p < 0.03 and p < 0.04 respectively, though without any significant differences during post hoc comparisons of means, which may be explained by the small number of cases studied, but there was a tendency, p = 0.08 and p = 0.09 respectively. The 2-h OGTT insulin levels increased (p < 0.02) as well as the prevalence of glucose intolerance (prevalence = 42.8%, p < 0.05). GH replacement therapy promoted favorable effects on carotid artery IMT, lipid profile and visceral fat in patients with Sheehan’s syndrome. On the other hand, patients developed abnormal glucose tolerance probably due to an increase in insulin resistance, demonstrated by higher insulin levels, despite favorable changes in body composition.     

Withdrawal of dopamine agonist therapy in prolactinomas: In which patients and when?

Purpose

The aim of the study was to assess the effect of dopamine agonist (DA) withdrawal, the current recurrence rate of hyperprolactinemia, and possible factors that predict recurrence in patients with prolactinoma.

Methods

We evaluated DA withdrawal in 67 patients with prolactinoma (50 female/17 male) who received DA treatment for at least 2 years and showed normalization of prolactin (PRL) levels and tumor disappearance or ≥50 % tumor shrinkage, retrospectively. Accordingly, patients were divided into two groups as remission and recurrence groups, and factors that predict recurrence were evaluated.

Results

The overall remission rate was 46 %; the remission ratios were 65 % in microprolactinomas and 36 % in macroprolactinomas. Remission rates were 39 % in the bromocriptine withdrawal group and 55 % in the cabergoline withdrawal group. The maximum tumor diameter and baseline PRL levels were significantly higher in the recurrence group (p = 0.001 and p = 0.003, respectively). The mean duration of DA therapy was significantly longer in the remission group (88.7 ± 48.1 and 66.7 ± 30.4 months, respectively, p = 0.026).The mean time to recurrence was 5.3 ± 3.2 months. The mean PRL levels at recurrence time were significantly lower than baseline PRL levels (p = 0.001).

Conclusion

The most important predictors of recurrence were maximum tumor diameter and baseline PRL levels in this study. The remission rate in our study group was higher, which was thought to be associated with the longer duration of DA treatment and that our patients were selected according to certain criteria. Despite these positive results, close monitoring is necessary for detection of early and late recurrence, especially within the first year after DA withdrawal.

     

Cardiac function in growth hormone deficient patients before and after 1 year with replacement therapy: a magnetic resonance imaging study

Assessed by conventional echocardiography the influence of growth hormone deficiency (GHD) and effects of replacement therapy on left ventricle (LV) function and mass (LVM) have shown inconsistent results. We aimed to evaluate cardiac function before and during replacement therapy employing the gold standard method cardiac magnetic resonance imaging (CMRI) and measurements of circulating levels of B-type natriuretic peptides. Sixteen patients (8 males and 8 females, mean age 49 years (range 18–75)) with severe GHD and 16 matched control subjects were included. CMRI was performed at baseline and after 1 year of GH replacement therapy. IGF-I, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) were measured after 0, 1, 2, 3, 6 and 12 months of treatment. IGF-I Z-score increased from (median (IQR)) −2.3 (−3.8 to −1.4) to 0.5 (−0.3 to 1.7). LVM index (LVMI), ejection fraction (range 63–80%), cardiac output index and levels of BNP and NT-proBNP were similar at baseline in patients compared to controls (P-values from 0.09 to 0.37). The patients had significantly smaller LV end-diastolic volume index (P = 0.032) and end-systolic volume index (P = 0.038). No significant change in LV systolic function or LVM occurred during 1 year of GH treatment. BNP levels were unchanged (P = 0.88), whereas NT-proBNP tended to decrease (P = 0.052). Assessed by the highly sensitive and precise CMRI method, untreated GHD was not associated with impaired systolic function or reduced LVMI and 1 year of GH replacement using physiological doses did not influence cardiac mass or function.     

How much, and by what mechanisms, does growth hormone replacement improve the quality of life in GH-deficient adults?

The majority of studies (but not all) have demonstrated that adults with hypopituitarism of both childhood and adult onset have a diminished quality of life (QOL) in comparison with the normal population. Reductions in physical and mental energy, dissatisfaction with body image and poor memory have been reported most consistently. A specific role for growth hormone (GH) deficiency, as opposed to multiple pituitary hormone deficiency, has been observed for the memory deficit, which extends to both short- and long-term memory. Comparisons with normal siblings have confirmed the reduced QOL, although differences have been small. There is less consensus for a reduction in QOL when hypopituitary subjects are compared with patients with other chronic diseases, with studies supporting (in comparison with diabetics) and refuting (in comparison with patients following mastoid surgery) the reduction in QOL. GH replacement in adults has improved QOL, particularly in the domains of energy level and self-esteem, and memory has improved. The social impact of these changes may be considerable, with patients requiring fewer days' sick leave. A major placebo effect is present, however, and neutral results as well as positive have been reported in placebo-controlled trials. Where a positive effect has been observed, it has been more likely to occur in patients with a low QOL at the outset. It is otherwise impossible to predict at the outset those who will benefit from GH replacement. GH treatment has effects on body composition, exercise capacity, muscle strength, total body water and intermediary metabolism which would be expected to improve QOL. Replacement therapy also has side-effects, and it is the variable balance of the positive and negative effects, coupled with the difficulties of measuring QOL, which have led to the disparate results in the literature. There is probably also a true inter-individual variation, although the mechanisms of this are currently unknown.     

Does muscle inflammation influence recovery of muscle strength and function in patients undergoing total hip replacement?

BackgroundGenetic markers of muscle inflammation (eg, tumour necrosis factor α [TNFα] and interleukin [IL] 6 are downregulated following repeated transient increases after bouts of exercise. Total hip replacement (THR) typically resolves preoperative pain, although strength deficits of 10–21% persist in the affected hip at 1 year postoperatively. This study assessed whether mRNA expression of TNFα and IL6 in the vastus lateralis (VL) of the operated leg was related to changes in the strength of the operated leg quadriceps in patients following THR.MethodsTen patients were recruited prospectively after ethical approval. Distal VL (5 cm proximal to lateral suprapatellar pouch) biopsy samples were obtained intraoperatively and at 6 weeks postoperatively, with maximal voluntary contraction of the operated leg quadriceps (MVCOLQ) in Newtons (N), assessed preoperatively and at 6 weeks postoperatively. RT-PCR was used to assess mRNA expression in the biopsy samples and associations evaluated with Spearman's correlation coefficient.FindingsMean mRNA relative quotient (RQ) for comparison of 6 week intraoperative VL samples was 6·23 [SD 12·85] for TNFα and 17·10 [47·46] for IL6. Preoperatively, mean MVCOLQ was 188·90 N [76·84] and at 6 weeks it was 217·00 N [53·91]. There was no significant relation between TNFα or IL-6 RQ and absolute MVCOLQ at 6 weeks (r=0·115 [p=0·376] and ?0·491 [p=0·075], respectively). No statistically significant relation existed between TNFα mRNA RQ and the improvement in MVCOLQ at 6 weeks (r=–0·498, p=0·071) nor with IL6 and the same measure (r=0·091, p=0·401).InterpretationThere is a trend to correlation that exists for improvement in MVCOLQ with a reduction in TNFα mRNA expression, as well as between absolute MVCOLQ and reduction in IL-6 mRNA expression at 6 weeks postoperatively. Improvement in muscle strength may be mediated by reduced muscle inflammation and the associated reduction in pain in patients with severe osteoarthritis.FundingWales Deanery and Betsi Cadwaladr University Health Board Small Grants Scheme.     

PGE2 receptor (EP4) agonists: Potent dilators of human bronchi and future asthma therapy?

BackgroundAsthma and chronic obstructive pulmonary disease are characterized by inappropriate constriction of the airway smooth muscle. In this context, the physiological response of the human airways to selective relaxant agonists like PGE₂ is highly relevant. The aim of this study was thus to characterize the PGE₂ receptor subtypes (EP₂ or EP₄) involved in the relaxation of human bronchial preparations.MethodsHuman bronchial preparations cut as rings were mounted in organ baths for isometric recording of tension and a pharmacological study was performed using selective EP₂ or EP₄ ligands.ResultsIn the presence of a thromboxane TP receptor antagonist and indomethacin, PGE₂ induced the relaxation of human bronchi (E_max = 86 ± 04% of papaverine response; pEC₅₀ value = 7.06 ± 0.13; n = 6). This bronchodilation was significantly blocked by a selective EP₄ receptor antagonist (GW627368X, 1 and 10 μmol/L) with a pK_B value of 6.38 ± 0.19 (n = 5). In addition, the selective EP₄ receptor agonists (ONO-AE1-329; L-902688), but not the selective EP₂ receptor agonist (ONO-AE1-259), induced potent relaxation of bronchial preparations pre-contracted with histamine or anti-IgE.ConclusionPGE₂ and EP₄ agonists induced potent relaxations of human bronchial preparations via EP₄ receptor. These observations suggest that EP₄ receptor agonists could constitute therapeutic agents to treat the increased airway resistance in asthma.     

Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a two-year open, prospective study in young adult men and women with severe GH deficiency

CONTEXT: GH secretion and response to GH replacement are gender-related. OBJECTIVE: The objective of this study was to investigate the effects of GH deficiency (GHD) and replacement on the cardiovascular system according to gender. DESIGN: The design was open and prospective. SETTING: The study was conducted at a university hospital. SUBJECTS: Subjects included 36 severe adult-onset GHD patients (18 men, 20 women, aged < 45 yr); 36 gender-, age-, and body mass index-matched healthy subjects served as controls. INTERVENTIONS: Subjects received GH replacement at a median dose of 6.5 microg/kg.d in men and 7.7 microg/kg.d in women for 2 yr. MAIN OUTCOME MEASURES: Homeostasis model assessment index, total to HDL cholesterol ratio, fibrinogen and C-reactive protein levels, left ventricular mass index, blood pressure, heart rate, diastolic filling, and systolic function at rest and at peak exercise and intima-media thickness (IMT) at common carotid arteries were measured. RESULTS: Basal prevalence and/or degree of insulin resistance, lipid alterations, compromised cardiac function, and IMT were similar in women and men. Diastolic dysfunction was more prevalent in men (61 vs. 25%, P = 0.036). After GH replacement, IGF-I levels normalized in all patients. Lipid profile, fibrinogen, and C-reactive protein levels normalized in all cases. The total to HDL ratio (P = 0.04) was higher in women than men. The homeostasis model assessment index persisted higher in GHD patients than controls and decreased only in GHD men (P = 0.017). Left ventricular mass index normalized during treatment in both women and men, abnormal diastolic function persisted in three women (P = 0.031), and abnormal systolic performance persisted in six women and one man (P = 0.13). IMT decreased similarly in women and men, persisting higher than in controls. Exercise performance normalized in all. CONCLUSIONS: Two-year GH replacement has similar beneficial effects on cardiac and exercise performance and atherosclerosis in women and men with severe GHD.     

Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post‐liver transplant is excellent, with 1‐year survival rate >90% and 5‐year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child‐Turcotte Pugh score ≥9 or a model for end‐stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1‐year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra‐hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non‐alcoholic fatty liver disease‐associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future.