Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly.

BACKGROUND AND PURPOSE: Impaired glucose tolerance and overt diabetes mellitus are frequently associated with acro-megaly. The aim of this study was to find out whether these alterations could be reversed after transsphenoidal surgery. MATERIAL AND METHODS: Two hundred and thirty-nine acromegalic patients were studied before and 6-12 months after transsphenoidal surgery. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient, glucose and insulin concentrations were assessed during the 75 γ oral glucose tolerance test (OGTT). To estimate insulin resistance, we used homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). RESULTS: At the moment of diagnosis, diabetes mellitus was present in 25% of the acromegalic patients. After surgery, the pre-valence of diabetes mellitus normalized to the level present in the general Polish population. We found a statistically significant reduction after surgery in plasma glucose levels both fasting (89.45 ± 13.92 mg/dL vs. 99.12 ± 17.33 mg/dL, p < 0.001) and during OGTT. Similarly, a prominent reduction in insulin secretion was found after surgery compared to the moment of diagnosis (15.44 ± 8.80 mIU/mL vs. 23.40 ± 10.24 mIU/mL, p < 0.001). After transsphenoidal surgery, there was a significant reduction in HOMA-IR (3.08 vs. 6.76, p < 0.0001) and a significant increase in QUICKI (0.32 vs. 0.29, p < 0.001). There were no statistically significant differences after surgery in fasting glucose and insulin levels between patients with controlled and in-adequately controlled disease. CONCLUSIONS: We conclude that in acromegalic patients glucose homeostasis alterations and insulin sensitivity can be normalized after transsphenoidal surgery, even if strict biochemical cure criteria are not fulfilled.

Abnormalities in glucose homeostasis in acromegaly. Does the prevalence of glucose intolerance depend on the level of activity of the disease and the duration of the symptoms?

INTRODUCTION: Acromegaly is characterized not only by disabling symptoms, but also by relevant co-morbidities. Insulin resistance, leading to glucose intolerance is one of the most important contributory factors to the cardiovascular mortality in acromegaly. MATERIAL AND METHODS: We analysed the records of 220 naïve patients with acromegaly diagnosed at our Department in the years 1995-2007. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient glucose and insulin concentrations were assessed when fasting and during the 75 g OGTT. RESULTS: Normoglycaemia existed in 46% of acromegalic patients. Among glucose tolerance abnormalities we found impaired fasting glucose in 19%, impaired glucose tolerance in 15% and overt diabetes mellitus in 20%. There was no statistically significant differences in gender, duration of the disease, basal plasma GH, IGF-1 or fasting insulin concentrations between normoglycaemic patients and those with impairments in glucose tolerance. The groups showed statistically significant differences with respect to age at diagnosis (p < 0.01). There was no significant correlation between GH, IGF-1 concentrations and fasting plasma glucose. There was no correlation between the duration of the disease and fasting plasma glucose. We found a statistically significant correlation between plasma GH, IGF-1 concentrations and HOMA, QUICKI and insulinAUC. CONCLUSIONS: The prevalence of diabetes mellitus among acromegalics is much higher than in the general population. The occurrence of glucose tolerance impairments does not depend on the duration of the disease. In patients with acromegaly insulin resistance and hyperinsulinemia are positively correlated with the level of activity of the disease.

[Pegvisomant--growth hormone receptor antagonist in the treatment of acromegaly]. / Pegvisomant--antagonista receptora hormonu wzrostu w leczeniu akromegalii.

INTRODUCTION: Pegvisomant, growth hormone (GH) antagonist is a new perspective in the treatment of acromegaly. Pegvisomant interferes with GH action by competitive binding to receptor and blocking signal transduction. We present first experiences with treatment acromegaly with pegvisomant in Poland. Aim of the study was to assess pegvisomant efficacy in treatment patients with persistent acromegaly after transspheno-ideal surgery and unsatisfactory disease control with somatostatin analogue octreotide (OCTR). MATERIAL AND METHODS: Material consisted of 10 patients (6 M, 4 F) aged 24-48 with active acromegaly, after neurosurgery, in which OCTR was ineffective in disease control. Patients with glucose metabolism disturbances were assigned to group receiving PEG. Controls were matched for age, sex, disease history, GH and IGF-1 levels. Patients received pegvisomant throughout 12 weeks, then combined therapy with PEG and OCTR-LAR was started for 8 weeks and then OCTR-LAR alone was given for next 8 weeks. Controls were medicated with OCTR-LAR 30 mg each 4 weeks during study. Clinical symptoms and IGF-1 level, fasting glucose and HbA(1c) was measured to assess treatment efficacy. RESULTS: Pegvisomant reduced IGF-1 after first week of therapy from 1270+/-229 to 759+/-223 (40%, p<0.04). Prolonged therapy led to further IGF-1 decrease. After 12 weeks of treatment IGF-1 was significantly lower in comparison to initial as well as to controls (604 mg/l vs. 1270 and 1330, respectively, p<0.02). Combined therapy with PEG and OCTR-LAR was not superior to PEG alone. During treatment with pegvisomant improvement of glucose metabolism was seen, as well as decrease in insulin doses required. No adverse events was recorded. CONCLUSIONS: Pegvisomant--GH receptor antagonist--effectively lowers IGF-1 concentration and improves disease control in patients with acromegaly after unsuccessful surgery and with octreotide unresponsiveness. Significantly improves glucose metabolism. Pegvisomant is indicated in patients with active acromegaly after standard treatment failure, especially in cases of coexistent diabetes mellitus.

In acromegaly, increased bone mineral density (BMD) is determined by GH-excess, gonadal function and gender.

OBJECTIVES: The aim of our study was to evaluate bone metabolism and bone mineral density (BMD), and to indicate the main determinants of these parameters in a large group of patients with active acromegaly. METHODS: A group of 121 active acromegalics, aged 23-80 years, from a single endocrinological center was studied. Serum GH, IGF-I, LH, FSH, PRL, estradiol/testosterone, osteocalcin (OC), type I collagen carboxyterminal telopeptide (ICTP) as well as BMD by DXA at spine L2-L4, femoral neck, Ward's triangle and trochanter were measured. RESULTS: Serum OC and ICTP concentrations were elevated (mean+/-SEM: 31.7+/-2.2 microg/L, p<0.001; 7.3+/-0.5 microg/L, p<0.001, respectively), and positively correlated with each other, as well as with IGF-I. BMD (Z-scores) was increased at L2-L4, femoral neck and trochanter (0.35+/-0.15, p=0.016; 0.60+/-0.11, p<0.001 and 0.59+/-0.13, p<0.001; respectively). The main determinants of Z-scores and ICTP were gonadal status and gender, while of OC was IGF-I. Eugonadal acromegalics had higher than normal serum OC and ICTP, as well as Z-scores at all measured sites. Hypogonadal patients (2/3 of the population) had significantly higher serum ICTP concentrations and lower BMD at all sites, when compared to eugonadal acromegalics. Thirty five percent of hypogonadal subjects had T-score<-1. Men had significantly higher serum ICTP and lower Z-scores than women. CONCLUSIONS: (i) In active acromegaly, enhanced IGF-I-dependent bone turnover and increased BMD is observed. (ii) In hypogonadal acromegalics, high bone resorption decreases BMD and may lead to osteoporosis. (iii) There is a smaller increase in bone resorption and greater increase in BMD in women with acromegaly than in men.

ACTH responses to somatostatin, valproic acid and dexamethasone in Nelson's syndrome.

OBJECTIVE: Pituitary tumours occurring in patients bilaterally adrenalectomized because of Cushing's disease (Nelson's syndrome) are frequently invasive and a complete their resection is not possible in most of them. Administration of the drugs decreasing ACTH secretion could be helpful in such unresectable tumours. We tried to evaluate the influence of somatostatin and valproic acid, compared to dexamethasone, in short-term studies, on plasma ACTH levels in Nelson's syndrome (NS). MATERIAL AND METHODS: Basal ACTH levels were determined within 18 h after last dose of hydrocortisone and next, 1 and 2 hours following oral administration of 20 mg of hydrocortisone. Somatostatin was injected s.c. in two patients with NS while sodium valproate and dexamethasone were administered orally for three days in three patients with NS (two with an invasive pituitary tumour and one with a localized, intrasellar adenoma). The blood for ACTH and cortisol determination was drawn before the tests (two hours after 20 mg of hydrocortisone ingestion) as well as 1 and 2 hours following somatostatin injection and after 3 days of valproic acid or dexamethasone administration. RESULTS: High plasma ACTH levels were found before the tests. Somatostatin lowered ACTH levels in both patients, more effectively in the patient with non-invasive pituitary adenoma. Valproic acid decreased moderately ACTH concentration in two patients, while following dexamethasone administration a fall in ACTH levels was observed in all three patients, the most evident in the patient with a non-invasive Nelson's adenoma. CONCLUSION: Somatostatin seemed to be more effective in its inhibitory action on ACTH secretion than valproic acid, thus its administration in invasive cases of NS could be tried as a supplementary method to neurosurgery. The response to dexamethasone administration indicates that a feed-back regulation, although impaired, exists in these cases.

[Hyperprolactinaemia--pitfalls in PRL assessment]. / Hiperprolaktynemia--pulapki w oznaczaniu PRL.

Prolactin (PRL) is one of the most commonly assessed hormones, and hyperprolactinaemia seems to be often endocrine disorder. Hyperprolactinaemia is not a disease, but only a symptom indicating relevant medical conditions to be diagnosed and properly treated. Laboratory findings should be always cautiously interpreted with reference to clinical context. Possible problems could be evoked by errors during sampling and assessment itself. While interpreting laboratory results, one have to pay attention on pulsate secretion profile of PRL (within hours), and shows marked diurnal cycle (with maximum during sleep period). PRL level depends also on emotional status (stress amplifies PRL secretion), and also on dietary habits and stimulants. Lastly, a growing body of evidence proven that in some cases elevated PRL level could be caused by presence of polymeric form of PRL--so called "macroprolactin". This form has diminished receptor-binding specificity and weak, if any, biological effect while immunoreactivity is preserved. In clinical practice, in cases of macroprolactinaemia high level of circulating hormone does not correlate with slight, if even, clinical symptoms. To avoid errors in prolactin assessment blood should be drawn fasting, preferentially in series or during dynamic test after dopaminergic blockade with metoclopramide. Interpretation must parallel include clinical data. It is essential that PRL level is proportional to pituitary lactotroph tumor size. Extremely high PRL concentration could exceed technical capability of laboratory equipment and remain underestimated, or even undiagnosed. Beneath presented algorithm could be useful in planning diagnostic and therapeutic procedures.