Orsalia Alexopoulou

Divergence between growth hormone and insulin-like growth factor-i concentrations in the follow-up of acromegaly.

CONTEXT Divergence between GH and IGF-I values is regularly observed in treated acromegalic patients, and its significance is unclear. OBJECTIVES The objective of the study was to explore the frequency and identify potential determinants of discordant serum GH and IGF-I concentrations in noncured acromegalic patients. PATIENTS Two hundred twenty-nine noncured acromegalic patients of the Belgian acromegaly registry (AcroBel) were grouped according to their mean GH level (< or = or > 2 microg/liter) and IGF-I z-score (< or = 2 or > 2). Clinical and metabolic parameters were compared between groups with active disease (high GH and IGF-I; n=81),high GH (with normal IGF-I; n=25), high IGF-I (with normal GH; n=55), and controlled disease (GH and IGF-I normal; n=68). RESULTS Compared with the high IGF-I group, the high GH group was characterized by younger age (52 vs. 58 yr, P < 0.05), female predominance (72 vs. 36%, P < 0.01), and lower body mass index (25 vs. 31 kg/m(2); P < 0.001), fasting glucose (91 vs. 99 mg/dl; P < 0.05), and glycated hemoglobin levels (5.7 vs. 6.1%; P < 0.01). There was no difference among the groups regarding baseline characteristics of pituitary adenoma, current medical treatment, or symptom score. CONCLUSIONS Thirty-five percent of noncured acromegalic patients exhibit a discordant GH and IGF-I pattern. The high GH phenotype was found predominantly in younger estrogen-sufficient females, implying a possible role for age, gender, and estrogens in this biochemical divergence. The high IGF-I phenotype was associated with a worse metabolic profile, suggesting that high IGF-I, rather than high GH, is indicative of persistently active disease.

Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients

CONTEXT Adequate postoperative management of nonfunctioning pituitary macroadenomas (NFMAs) remains a challenge for the clinician. OBJECTIVE To identify predictive factors of NFMA relapse after initial surgery. PATIENTS AND METHODS This retrospective study included 142 patients operated for an NFMA in two academic centers (CHU Bicêtre in France and UCL St Luc in Belgium). The rate of tumor relapse, defined as recurrence after total surgical resection or regrowth of a surgical remnant, as well as predictive factors was analyzed. RESULTS During a mean follow-up of 6.9 years, 10 out of 42 patients (24%) who had complete macroscopic resection of their tumor had recurrence, and 47 out of 100 patients (47%) with a surgical remnant experienced regrowth. The overall relapse rates were 25, 43, and 61% at 5, 10, and 15 years respectively. Invasion of the cavernous sinus, absence of immediate radiotherapy after the first neurosurgery, and immunohistochemical features of the tumor (mainly positive immunostaining for several hormones or for hormones other than gonadotropins) were independent risk factors for tumor relapse. Incomplete excision was only associated with relapse when invasion was withdrawn from the analysis, suggesting that these two factors are closely linked. CONCLUSION NFMAs frequently recur/regrow after initial surgery, particularly when tumor is invasive, precluding complete removal. Immunohistochemical features such as positive immunostaining for several hormones or for hormones other than gonadotropins could help to predict undesirable outcomes.

Endocrine and metabolic disorders in young adult survivors of childhood acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL)

Background  Treatments of acute lymphoblastic leukaemia (ALL) and non‐Hodgkin lymphoma (NHL), involving various combinations of chemotherapy (chemo), cranial irradiation (CI) and/or bone marrow transplantation after total body irradiation (BMT/TBI), are often successful but may have several long‐term harmful effects.

Bone density and markers of bone remodeling in type 1 male diabetic patients

AIMS To assess the prevalence and severity of bone disease in type 1 diabetic patients and to determine serum markers of bone remodeling as well as their relationship with bone mineral density (BMD). METHODS BMD [by dual energy x-ray absorptiometry (DXA)] and serum markers of bone remodeling [osteocalcin, c-terminal telopeptide of type I collagen (CTX)], leptin and osteoprotegerin (OPG) were measured in 42 adult males with type 1 diabetes. Twenty-four non-diabetic subjects served as controls. RESULTS In 40% of the patients, osteopenia at the lumbar spine (L1-L4) and/or at the left hip was found, and 7% met criteria for osteoporosis. L1-L4 BMD z-score was correlated with age (r=0.365, P=0.018) and a similar trend was observed at left hip. L1-L4 BMD z-score was negatively correlated with CTX and osteocalcin (r=-0.343, P=0.028; r=-0.376, P=0.024, respectively). A significant correlation was evidenced between BMD z-score at both lumbar spine and left hip and leptin values (r=0.343, P=0.03; r=0.395, P=0.012, respectively) but after adjustment for weight this correlation was no longer significant. Osteocalcin, CTX and leptin concentrations were comparable between patients and controls, while OPG concentrations tend to be higher in diabetic subjects (P=0.08). CTX was negatively correlated with age (r=-0.390, P=0.012) and positively correlated with osteocalcin (r=0.696, P<0.001). OPG was positively correlated with age (r=0.507, P=0.001). CONCLUSION Our results suggest that in diabetic subjects osteopenia is a relatively frequent complication but bone loss is attenuated with age progression. Whether this is also mediated by OPG and/or leptin remains to be confirmed.

Outcome of prolactinoma after pregnancy and lactation: a study on 73 patients

Prolactinoma is the most frequent pituitary tumour among women of child‐bearing age. Only a few studies have addressed the outcome of prolactinoma after pregnancy.

Optimalization and cost management of lanreotide-Autogel therapy in acromegaly

BACKGROUND Lanreotide-Autogel is a depot formulation of the somatostatin analog lanreotide used in the treatment of acromegaly. We investigated whether prolonging or shortening the interval between injections would offer any benefit. SUBJECTS AND METHODS The interval was prolonged from once every 4 weeks to once every 6 weeks when patients (n=9) had normal IGF-I and GH concentrations. When patients (n=12) had still elevated IGF-I or GH on the maximal dose of 120 mg every 4 weeks, the interval was shortened to once every 3 weeks. Serum IGF-I and GH were measured after 12 and 24 weeks to allow for dose adaptation. Symptoms and tumor volume were evaluated at baseline and after 36 weeks. RESULTS In seven of the nine subjects with normal IGF-I and GH, the interval could be extended to 6 weeks without loosing efficacy on IGF-I (195 vs 213 microg/l; not significant, NS) and GH concentrations (1.4 vs 1.3 microg/l; NS). The weekly dose could significantly be reduced (from 23.3 to 17.8 mg; P=0.002). In only 1 of the 12 not-controlled patients, reducing the interval to once every 3 weeks induced normalization of IGF-I and GH. CONCLUSION In subjects whose acromegaly is well controlled using lanreotide-Autogel, prolonging the time interval between injections can often be increased 4 to 6 weeks without loss of efficacy, thereby improving the subjects comfort and reducing the cost of treatment. On the other hand, in subjects whose acromegaly is not controlled on a dose of 120 mg every 4 weeks, reducing the interval to every 3 weeks is rarely beneficial.

Evaluation of the respective influence of thyroid hormones and TSH on blood coagulation parameters after total thyroidectomy

BACKGROUND Several hemostatic abnormalities have been described in hypothyroidism, such as modification of coagulation proteins and bleeding tendency. Although thyroid hormone deficiency is considered to be responsible for these changes, the underlying mechanisms have not yet been established. OBJECTIVE To evaluate the respective influence of peripheral thyroid hormones (free thyroxine) and TSH on blood clotting by assessing coagulation parameters in patients with a history of total thyroidectomy for thyroid cancer, under three different conditions: induced hypothyroidism, euthyroid state, and following recombinant human TSH (rhTSH) administration. METHODS Coagulation parameters (platelet count, fibrinogen, international normalized ratio, prothrombin time, thrombin time, activated partial thromboplastin time (APTT), factor VIII activity ((FVIII:C), as well as von Willebrand factor antigen (VWF:Ag) and VWF activity using collagen binding assay (VWF:CBA)) were measured in patients with severe hypothyroidism following withdrawal of thyroid hormone replacement therapy, and in the same patients with euthyroidism after restoring replacement treatment (group A), and before and after administering rhTSH (group B). RESULTS FVIII:C, VWF:Ag, and VWF:CBA were significantly decreased (P<0.001), whereas APTT was significantly increased (P<0.001) in patients with severe hypothyroidism compared with patients in the euthyroid state. No changes in clotting parameters were observed in patients who received rhTSH therapy. CONCLUSION This prospective study shows that severe short-term hypothyroidism is associated with significantly lower levels of VWF:Ag, VWF:CBA, and FVIII:C. Administration of exogenous TSH has no effect on coagulation parameters. These findings suggest that thyroid hormone deficiency is likely to be the main cause of coagulation alterations in patients with hypothyroidism.

Evolution of Glucose Tolerance After Treatment of Acromegaly: A Study in 57 Patients.

The aim of our study was to evaluate the evolution of glucose metabolism in 57 patients after treatment of their acromegaly and to determine risk factors for the persistence of abnormal glucose tolerance. Therefore, we performed IGF-I measurements, oral glucose tolerance tests (OGTTs), and HOMA to evaluate insulin sensitivity (HOMA-S) and β-cell function (HOMA-β) at diagnosis and at last visit (median follow-up 7 years). At diagnosis of acromegaly, 14 patients (25%) were diabetic and 15 (26%) had impaired glucose tolerance, whereas at the last visit, 32% were diabetic and 26% remained glucose intolerant. There was a decrease in fasting glucose (median - 7.0 mg/dl) in the 20 patients cured by surgery, whereas it increased in the 28 patients controlled under medical therapy (median + 2.0 mg/dl; p<0.05 vs. cured group) and in the 9 patients with active disease (median + 4.0 mg/dl). Loss of β-cell function was more pronounced in the patients under medical treatment (median - 87.9%) vs. the cured group (median - 30.4%; p<0.05). There was a decrease in HbA1c between diagnosis and last visit in patients under pegvisomant (mean - 19.2 mmol/mol) vs. a small increase in patient treated by somatostatin analogues (+ 3.4 mmol/mol; p<0.05). Independent risk factors for persistent abnormal glucose tolerance were the glucose tolerance status at diagnosis and ongoing treatment with somatostatin analogues. In conclusion, we found that more than 50% of patients still have IGT or diabetes after treatment of acromegaly. Improvement of glucose metabolism is mainly observed in cured patients and in patients treated with pegvisomant.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

Treatment of adult growth hormone deficiency: who, why and how? A review.

Abstract Adult growth hormone deficiency (AGHD) is nowadays recognized as a distinct clinical entity and replacement therapy has become a standard practice. Reflecting on the accumulated evidence, questions nevertheless arise. Should all AGHD patients be treated? What dose of GH should be given and for how long? What are the real long-term benefits, in particular regarding life expectancy? If the diagnosis of severe GHD is firmly established and if there is no contra-indication (such as an active cancer or uncontrolled diabetes), it is worthwile initiating GH replacement therapy. Treatment can indeed correct the abnormal body composition, improve various adverse cardiovascular parameters and risk factors, increase muscle strength and bone mineral density and, although to a variable degree, improve the patient’s quality of life and psychological well-being. Treatment should be started with very low doses to avoid side-effects related to fluid retention and should then be gradually titrated against IGF-I values, clinical response and individual tolerance. There is unfortunately no confirmed predictive factor for the overall therapeutic response in a given individual. Thus, the decision to whether or not pursue the therapy will depend on the ratio of perceived and expected benefits over cost and risks of treatment, as well as on the persistent motivation of the patient.