Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Control of acromegaly in more than 90% of patients after 10 years of pegvisomant therapy: an European referral centre real-life experience.

PURPOSE: Pegvisomant (PEG) efficaciously controls IGF-I excess in acromegaly and possesses a positive impact on glucose metabolism. Data on very prolonged PEG treatment are still limited, therefore, we investigated the effects of 10-years PEG on disease control, maximal tumour diameter (MTD), and metabolic profile in consecutive patients resistant to somatostatin analogues (SRLs) followed in an European referral centre for acromegaly. METHODS: Since the 2000s, we collected data on anthropometric, hormonal and metabolic parameters, and MTD of patients receiving PEG. In the current study, we included 45 patients (19 men, 26 women, 46.8 ± 11 years) treated for at least 5 years with PEG mono or combined therapy, analyzing data before, after 5- and 10-years PEG. RESULTS: After10 years, 91% of patients showed full disease control and in 37% a significant decrease in MTD was found. Diabetes prevalence was slightly increased, whereas HbA1c remained stable over the decade. Transaminases remained stable and no case of cutaneous lipohypertrophy was recorded. A different metabolic impact between mono- or combined therapy was found. Patients in monotherapy showed significantly lower fasting glucose (p = 0.01), fasting insulin (p = 0.008), HbA1c (p = 0.007), HOMA-IR (p = 0.001), and significantly higher ISI0 (p = 0.002), whereas patients under combined therapy showed significantly lower total (p = 0.03), and LDL cholesterol (p = 0.007). Acromegaly duration before PEG was inversely related to ΔFG (r = - 0.46, p = 0.03) and ΔFI (r = - 0.54, p = 0.05). CONCLUSIONS: PEG is effective and safe in long term. In patients resistant to SRLs, early beginning of PEG allows a wider gluco-insulinemic improvement.

Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity.

OBJECTIVE: Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. DESIGN: Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. RESULTS: For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 µg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001). CONCLUSIONS: Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia.

Perioperative cortisol can predict hypothalamus-pituitary-adrenal status in clinically non-functioning pituitary adenomas.

BACKGROUND: Peri-operative steroids are administered routinely to patients with pituitary adenoma undergoing transsphenoidal adenomectomy (TSA). AIM: To evaluate hypothalamic-pituitary-adrenal (HPA) axis before and after programmed endoscopic TSA (E-TSA) in patients with clinically non-functioning pituitary macroadenoma (NFPA). DESIGN: Open prospective. SETTING: Tertiary referral hospitals. PATIENTS: Seventy-two consecutive patients (20-87 yr, 37 males). INTERVENTIONS: Adrenal steroid replacement therapy (ASRT) was given only in patients with hypocortisolism [08:00 h cortisol (F) <8 microg/dl]. MAIN OUTCOME MEASUREMENTS: After ETSA, achieving wide (>90%) selective resection of the adenoma in all, F and clinical picture were checked at day 2. The low-dose (1 microg) ACTH test (LDACTH) was performed at 6 weeks and repeated at 12 months. RESULTS: Hypocortisolism was present pre-operatively in 14 patients (19.4%), persisted post-operatively in all but one, and was detected de novo at the post-operative day 2 control in 6 (10.3%). In all but one the post-operative day 2 basal F and peak F during LDACTH test were concordant. No patient whose F was > 8 microg/dl was treated with ASRT or developed symptoms of adrenal failure during the follow-up (1-11 yr, median 5). CONCLUSIONS: HPA function is usually preserved in NFPA and is infrequently impaired after complete tumor removal by E-TSA. The 08:00 h. plasma cortisol evaluation before and 2 days after surgery, using as cut-off the value of 8 microg/dl, allows full evaluation of HPA status. Peri-operative steroid treatment should be given only in patients with hypocortisolism.

Somatostatin analogs and gallstones: a retrospective survey on a large series of acromegalic patients.

CONTEXT: Development of gallstones (GS) is reported during the use of somatostatin analogs (SA) that are at present the mainstay for the medical treatment of acromegaly. OBJECTIVE: To review the prevalence and clinical and biochemical correlates of GS in acromegalic patients. DESIGN AND SETTING: Retrospective survey on hospital records in acromegalic patients followed up in the last 20 yr in tertiary referral centers. PATIENTS: Four hundred and fifty-nine patients (272 females). MAIN OUTCOME MEASURES: According to SA use and GS occurrence, patients were divided in 4 groups: 1) treated with SA without GS (SA+GS-), 2) GS developed while on SA (SA+GS+), 3) GS without SA use (SA-GS+), 4) neither GS nor SA (SA-GS-). RESULTS: Patients were unevenly distributed in the 4 groups: 232, 125, 38, 64, respectively, pointing to a prevalence of GS in acromegaly of 8.3% at diagnosis with an additional 35% developing GS during SA. GS occurred after 3 months-18 yr (median 3 yr) of SA treatment, were diagnosed after symptoms in 17.6%, were associated to steatosis, ultrasound biliary dilation, and biochemical cholestasis, in 25.6%, 12.8%, and 4% of patients, respectively. Ursodehoxicolic acid was administered after GS occurrence, causing their dissolution in 39% of patients after 3-48 months (median 12). Cholecystectomy was performed in 16.8%of patients in group 2. At multivariate analysis obesity, dyslipidemia, and SA treatment were independent predictors of GS onset, whereas gender and age were not. CONCLUSIONS: GS are a frequent occurrence in acromegalic patients treated with SA, may occur at any time, but are seldom symptomatic or prompt acute surgery. Obesity and dyslipidemia appear to play a major role in the occurrence of GS in acromegalic patients on SA treatment.

Long-lasting suppression of prolactin secretion and rapid shrinkage of prolactinomas after a long-acting, injectable form of bromocriptine.

Since Corenblum reported in 1975 the first documented reduction of tumor size in two patients with macroprolactinoma, evidence has accumulated that bromocriptine causes shrinkage of PRL-secreting adenomas in most patients. Recently a long-acting form of bromocriptine (bromocriptine LA) was developed. A single dose of 50 mg i.m. decreases basal and sleep-related PRL secretion in normal subjects for 28 days. We treated 13 patients (8 women, 5 men) with PRL secreting tumors (5 macroadenomas and 8 microadenomas) with a single dose (50 mg) of bromocriptine LA. In the 5 patients with macroprolactinomas plasma PRL levels decreased markedly within 12 hours, reaching normal levels in only one patient. In all patients the suppression of PRL secretion lasted at least 28 days and the tumor size was reduced by 20% to 59% within 21 days after the injection. Visual fields improved in all 3 patients with abnormal vision prior to the injection. In one patient with bitemporal hemianopsia an almost normalization of the visual field was noted 24 hours after bromocriptine LA administration. In 7/8 patients with microprolactinomas plasma PRL levels decreased to within the normal range within 12 hours after the administration of bromocriptine LA. The normalization of PRL secretion lasted for at least 28 days. Menses resumed in all 6 women 7 to 41 days after the injection, galactorrhea disappeared in all 4 patients, and libido and potency become normal in both men with microprolactinomas. Patients treated with bromocriptine LA reported only short-lasting (1 hour - 2 days) mild or moderate adverse effects, consisting of dizziness (4 patients) and nausea (4 patients). Long-acting bromocriptine should be considered as the initial management for patients with PRL-secreting tumors. The use of bromocriptine LA could also overcome the compliance problems that occur in many patients soon after the initiation of oral bromocriptine therapy.

Growth hormone binding protein and growth hormone availability in acromegalic patients treated with long-acting octreotide (Sandostatin-LAR).

OBJECTIVE: In the medical treatment of acromegaly different factors are influential; among these the impact on growth hormone binding protein (GHBP) has not been clarified. DESIGN: Twenty acromegalic patients and nineteen age- and gender-matched normal subjects participated in this study. The patients were treated for 21 months with depot long-acting microsphere-enclosed octreotide (Sandostatin-LAR). Previously, all the patients were treated s.c. with octreotide t.i.d. After a 2-week wash-out period (baseline) the patients received the first i.m. injection of the long-acting octreotide. The first two injections were administered at 60-day intervals; thereafter the injections were at 28-day intervals. METHODS: The levels of GHBP, complexed GHBP, growth hormone (GH) and insulin-like growth factor-I (IGF-I) were determined in fasting serum samples. RESULTS: In the 2-week wash-out period GHBP levels decreased from 1.13 +/- 0.17 to 0.92 +/- 0.15 nmol/l (P < 0.05). During the 21-months treatment, GHBP increased again to 1.10 +/- 0.16 nmol/l. In the age- and gender-matched control group GHBP levels were significantly higher at all times (1.95 +/- 0.21 nmol/l. P(all) < 0.02). Mean levels of 8-h GH decreased from 12.6 +/- 2.58 microg/l at baseline to 1.97 +/- 0.20 microg/l after 21 months of treatment (P < 0.05). Mean 8-h GH levels were unchanged during long-acting octreotide treatment compared with levels during s.c. treatment (1.97 +/- 0.20 microg/l and 1.90 +/- 0.20 microg/l respectively). In fasting blood samples GH-complexed GHBP ranged from 13.8 +/- 2.4% (9 months) to 25.4 +/- 4.5% (baseline) of total GHBP. Serum IGF-I increased from 367 +/- 45 to 764 +/- 80 microg/l (P < 0.05) during the 2-week wash-out period and decreased to 290 +/- 35 microg/l (P < 0.05) after 21 months of treatment with long-acting octreotide. IGF-I levels after 21 months were significantly lower than during s.c. octreotide treatment (P < 0.05). CONCLUSION: Serum GHBP levels are similar during treatment with long-acting octreotide as compared with regular octreotide. Furthermore, significant changes in GHBP can occur within 2 weeks. Finally, in addition to the lowering effect on GH levels, the induced increase in GHBP levels may imply a further advantage in octreotide treatment of acromegaly. circulating GH bound to GHBP may less readily reach the tissues.

Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients.

OBJECTIVE: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.

Diffusion model of pain language and quality of life in orofacial pain patients.

AIMS: To address the following questions: (1) Which words are preferred by different groups of orofacial pain patients to describe their pain experience? (2) Is it possible, based on such descriptions, to obtain a clinical differential diagnosis in these patients? (3) Is there any relationship between the verbal description of pain and self-rated quality of life (QOL)? (4) Can a pattern of modulation of pain language by affective variables (diffusion model) be recognized in orofacial pain patients, as it has in other chronic pain patients? and (5) If so, what might be the clinical usefulness of assessing pain language in these patients? METHODS: A total of 332 consecutive orofacial pain patients filled out an Italian Pain Questionnaire (the Italian analog of the McGill Pain Questionnaire) and were then divided into 6 diagnostic subgroups (sample 1) based on history and clinical findings. In a double-blind setting, the distribution of pain descriptors and indexes was statistically evaluated. From sample 1, a randomly selected sample of 121 patients (sample 2) also filled out a QOL categorical scale. The results of both tests in this sample were compared statistically. RESULTS: Some significant differences among diagnostic subgroups were found for choice of descriptors and for pain intensity. When a patient's pain description was compared to the corresponding self-evaluation of QOL, a self-perceived worsening of QOL revealed a good correlation with an increase in the number of words chosen, pain intensity, and affective and sensory pain descriptors. A similar significant association was found between self-assessed anxiety and/or depression and the same items. CONCLUSION: Although trends in patients' choice of descriptors were evident, differential diagnosis based on only a pain questionnaire was not possible in the different groups of orofacial pain patients examined in this study. The present study suggests the presence of a phenomenon of diffusion in the language of those patients who were experiencing a worsening of their QOL as a result of pain and consequent psychologic distress. This observation can be of clinical usefulness by enhancing the sensitivity of the clinician to the suffering and affective distress experienced by the patient, and it also can be helpful in refining the therapeutic approach for each individual patient.

[Synthetic PH-RH as a pituitary function test in anorexia nervosa]. / Il GN-RH sintetico come test di funzionalità ipofisaria nella anoressia nervosa

The hypophyseal gonadotrophin LH reserve was studied in 9 adult women, 5 of whom were suffering from nervous anorexia (N.A.) and 4 normal, by means of subcutaneous injection of 50 mcg of synthetic GN-RH. Basal values of plasmatic LH proved to be significantly lower in N.A. than in the controls where the response to GN-RH was prompt. In patients with N.A., on the other hand, response was practically absent and differences were significant at all stages of the test. The parallel study of basal steroiduria and following methopirone confirmed the torpid hypophyseal response in N.A. These findings confirm previous personal reports and indicate that the GN-RH test is a useful technique for diagnostic and prognostic definition of N.A.

[The vanishing testis syndrome. Considerations on a case]. / La sindrome del testicolo evanescente. Considerazioni su di un caso

The aetiopathogenesis and clinical and diagnostic features of bilateral absence of the testicles in 46XY subjects are briefly reviewed. A eunuchoid 25-yr-old patient with male sex chromatin, 46 XY genotype, plasma testosterone slightly below normal, normal urinary 17-KS unaltered by gonadotropin stimulation, and bilateral absence of the testicles is presented. Examination of the inguinal canal showed a funiculus and ductus deferens residue terminating in an adipose mass. Section of the fibrous duct showed that this mass was full of capillaries and venules. Lesion between the 14th and 16th week of pregnancy is postulated.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.