Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease.

PURPOSE: Cushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11ß-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC). METHODS: LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study. RESULTS: At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control. CONCLUSIONS: Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

Association between biochemical control and comorbidities in patients with acromegaly: an Italian longitudinal retrospective chart review study.

PURPOSE: Achieving biochemical control (normalization of insulin-like growth factor-1 [IGF-1] and growth hormone [GH]) is a key goal in acromegaly management. However, IGF-1 and GH fluctuate over time. The true potential impact of time-varying biochemical control status on comorbidities is unclear and relies on multiple, longitudinal IGF-1 and GH measurements. This study assessed the association between time-varying biochemical control status and onset of selected comorbidities in patients with acromegaly. METHODS: Medical charts of adults with confirmed acromegaly and ≥ 6 months of follow-up at an Italian endocrinology center were reviewed. Patients were followed from the first diagnosis of acromegaly at the center until loss to follow-up, chart abstraction, or death. Biochemical control status was assessed annually and defined as IGF-1 ≤ the upper limit of normal, or GH ≤ 2.5 µg/L in the few cases where IGF-1 was unavailable. Time-varying Cox models were used to assess the association between biochemical control status and comorbidities. RESULTS: Among 150 patients, 47% were female, average age at diagnosis was 43.1, and mean length of follow-up was 10.4 years. Biochemical control was significantly associated with a lower hazard of diabetes (HR = 0.36, 95% CI 0.15; 0.83) and cardiovascular system disorders (HR = 0.54, 95% CI 0.31; 0.93), and a higher hazard of certain types of arthropathy (HR = 1.68, 95% CI 1.04; 2.71); associations for other comorbidities did not reach statistical significance. CONCLUSION: Results further support the importance of achieving biochemical control, as this may reduce the risk of high-burden conditions, including diabetes and cardiovascular system disorders. The association for arthropathy suggests irreversibility of this impairment. Due to limitations, caution is required when interpreting these results.

Treatment of acromegaly with SS analogues: should GH and IGF-I target levels be lowered to assert a tight control of the disease?

BACKGROUND: in acromegaly, the criteria for the cure of the disease after neurosurgery have become tighter and tighter. In contrast, the evaluation of control of disease activity during medical treatment is based upon the normalisation of IGF-I levels and epidemiological criteria, i.e. lessening GH (assessed by RIA) to levels reported to normalise increased mortality. The aim of this study was to evaluate GH and IGF-I suppression during prolonged SS analogues (SA) treatment. The concordance between "safe" GH and normalised IGF-I levels during SA was also assessed, according to gender and gonadal status. DESIGN: multicentre, retrospective. Patients. GH/IGF-I levels were evaluated in 207 acromegalic patients (132 females, aged 20-85 yr) during a prolonged treatment (longer than 12 months) with individually tailored doses of depot SA( lanreotide or octreotide-LAR in 97 and 110 patients, respectively). Final IGF-I levels were transformed in z-scores using data collected in a large cohort of normal subjects of 3 different age groups (20-40 yr old, 41-60 yr old, 61-80 yr old, n=160, 148, 115, respectively), that allowed to set up quartiles of normality (I = 3rd-25th percentile, II = 26th-50th, III = 51th-75th, IV = 76th-97th). RESULTS: fifty-nine and 19.3% of patients achieved GH levels <2.5 and <1 microg/l, respectively. IGF-I were normalised (z-score between 2 and -2) in 58.4% of patients. The distribution of normal IGF-I values among quartiles was uneven: 7%, 19%, 25%, and 49% of values were distributed in the I, II, III, and IV quartile, respectively. The concordance between GH and IGF-I values was poor: 28.4% of patients attaining GH values <2.5 microg/l had still pathological IGF-I (even 12.5% of those with GH <1 microg/l), and 39.3% of those with GH levels still above the "safe" limit had "nor IGF-I. Although proportions of IGF-I normalisation were not different between males and females, the regression line obtained between GH and IGF-I z-score showed the same slope but with a significantly lower intercept in regularly cycling women than in males and in postmenopausal females. Thus for any GH value, cycling females had lower IGF-I than menopausal women and males, and their IGF-I normalisation could be achieved by higher GH values. By ROC analysis, the achievement of normal IGF-I was predicted by the GH value of 1.8 microg/l in males and 2.4 microg/l in females. CONCLUSIONS: in acromegalic patients on SA treatment, GH and IGF-I levels are often not concordant. In addition to age, sex is to be taken into account in the evaluation of hormonal targets. A better refinement of GH and IGF-I targets to be reached while on treatment with SA is warranted.

Gender- and age-related differences in the endocrine parameters of acromegaly.

Acromegaly is a severe slow-developing disease associated with a poor prognosis for cardiovascular disease. To evaluate the impact of age and gender on the severity of the disease, 151 de novo patients with acromegaly (79 women, 72 men, age range 19-77 yr) were included in this open retrospective multi-center cohort study. Basal GH and IGF-I levels, GH response after glucose load and maximal tumor diameter at MRI were measured in all patients at diagnosis. Fasting GH levels and maximal tumor diameter were similar in women and men, while serum IGF-I levels were lower (664.9+/-24.9 vs 755.9+/-32 microg/l; p=0.02) and GH nadir after glucose load was higher (27.5+/-3.7 vs 18.5+/-2.2 microg/l; p=0.04) in women than in men. In both sexes, patients' age was negatively correlated with basal and nadir GH, IGF-I levels and tumor size; fasting GH levels were positively correlated with IGF-I levels and nadir GH after glucose. No interaction between age and gender was found on biochemical and morphological parameters. At diagnosis, elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after glucose load and smaller adenomas than young patients. Women have lower IGF-I levels but higher GH nadir after glucose load than men. These age and gender differences should be considered to appropriately evaluate the activity of acromegaly throughout a life-span.

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.

Occurrence and effects of octreotide antibodies during nasal, subcutaneous and slow release intramuscular treatment.

OBJECTIVE: Previous studies have indicated that antibody formation against octreotide is extremely rare. We examined the occurrence of octreotide antibody formation after treatment with three administration forms in large populations of patients with acromegaly or carcinoid syndrome. DESIGN: (i) Nasally administered octreotide: 70 previously untreated patients and 81 previously s.c. octreotide-treated patients participated. (ii) Subcutaneously administered octreotide: 172 acromegalic patients and 59 patients with carcinoid syndrome treated for up to 12 years participated. (iii) Intramuscularly administered depot octreotide (Sandostatin LAR): 62 acromegalic patients participated. METHODS: Presence of antibodies is defined as increased precipitation by polyethylene glycol of (125)I-octreotide after incubation with serum; this was also used for screening of cross-reaction with somatostatin and lanreotide (Somatuline). RESULTS: In patients who received nasal octreotide for at least 9 and up to 12 months (n=42), the occurrence of octreotide antibodies was 77% and 81% for previously untreated and treated patients respectively. In subcutaneously treated patients it was 63/231 (27%) after a mean exposure of 3 years. In patients treated for more than 5 years (n=53) it was 57% and after 8 years (n=18) 72%. In contrast, no patient could with certainty be identified to be antibody-positive after a mean of 2.5 years intramuscular Sandostatin LAR treatment (n=47). In all populations, the antibody-positive patients were as well controlled as the antibody-negative patients. Octreotide antibodies did not cross-react with native somatostatin (n=141), while about 25% of the antibody-positive sera did cross-react with the somatostatin analogue, lanreotide (Somatuline, Ipstyl, Angiopeptin). CONCLUSIONS: Antibody formation against octreotide is much more frequent than previously believed. It depends primarily on drug exposure time and route of administration. It does not alter the GH/IGF-I status in treated acromegalic patients and induces only mild local reactions in some patients.

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.

Cholelithiasis and acromegaly: therapeutic strategies.

OBJECTIVE: The aims of this study were (i) to evaluate gall-bladder form and contents, (ii) to assess the prevalence of gallstones in acromegalic patients before octreotide treatment and the incidence of gallstone formation in patients with acromegaly during long-term (6-90 months, mean 44 months) octreotide treatment, and (iii) to test the efficacy of ursodeoxycholic acid in preventing and treating octreotide-induced cholelithiasis. DESIGN: Forty-nine patients (23 men and 26 women, aged 19-81 years) were studied by repeated gall-bladder ultrasonography performed at baseline and then every 6 months during octreotide therapy. All ultrasound scans were evaluated by the same radiologist. Statistical analysis was performed using the Chi-squared and regression analysis tests. RESULTS: Asymptomatic stones were recorded in 13/49 patients (26.5%) prior to octreotide treatment (the prevalence of cholelithiasis in the Italian population is 9.5% in men and 18.9% in women). During octreotide therapy gallstones developed in 10/36 patients (27.7%). No significant correlations with sex, age, body mass index, duration of the disease, daily dose and duration of octreotide therapy, altered gall-bladder form, family history of gallbladder stones, basal plasma values of cholesterol and triglycerides were found between the patients (10/36) who developed stones during octreotide treatment and the ones who did not (26/36). Fourteen patients (10 with newly developed stones and four with cholelithiasis diagnosed prior to octreotide) were put on ursodeoxycholic acid at the daily dose of 10 mg/kg. Gallstones completely disappeared in 6/14 patients (42.8%; five patients with newly developed stones and one with stones prior to octreotide therapy) after a mean of 30.8 months of ursodeoxycholic acid treatment. In addition, seven patients were treated with ursodeoxycholic acid at the preventive dose of 450 mg, administered as a once-a-day oral preparation in the evening. However, stones developed in one of these seven patients who was thereafter cured (gallstones completely disappeared) by the therapeutic dose of ursodeoxycholic acid of 10 mg/kg/day after 23 months of treatment. CONCLUSIONS: This study indicates that (i) acromegaly by itself is correlated with a high prevalence of gallbladder stones, (ii) the long-term treatment with octreotide increases the incidence of cholelithiasis, and (iii) ursodeoxycholic acid is useful in the treatment of gallstones in acromegalic patients but its prophylactic effect in patients on octreotide treatment requires further assessment.

Efficacy of a new long-acting injectable form of bromocriptine in hyperprolactinaemic patients.

OBJECTIVE: The objective of this study was to assess the relationship of different doses of a long-acting bromocriptine preparation (Parlodel LAR) to the degree and duration of PRL suppression. We also measured circulating bromocriptine levels and altered tolerability of the drug. DESIGN: A double-blind randomized study of three different doses 25, 50 and 100 mg of Parlodel LAR. PATIENTS: Twenty-one female patients (seven patients/dose) with both tumoral and non-tumoral hyperprolactinaemia. MEASUREMENTS: After a single injection of Parlodel LAR 25, 50 or 100 mg, serum PRL and plasma bromocriptine levels were assessed during a follow-up of 60 days together with changes in clinical symptoms and signs of hyperprolactinaemia. RESULTS: Serum PRL levels normalized in 19 of 21 patients. The suppression of PRL secretion lasted 28 days in four of seven patients treated with either 25 or 50 mg Parlodel LAR and in five of seven patients who received Parlodel LAR 100 mg. In five of seven patients treated with the 100 mg dose, serum PRL levels were still within the normal range on day 60. Plasma bromocriptine levels remained therapeutically active for 28 days in all three groups. On day 60 they were within the therapeutic range only in the 100 mg group. Clinical data show a rapid disappearance of symptoms and signs of hyperprolactinaemia. Adverse events were mostly mild and transient. CONCLUSIONS: These data support the excellent efficacy and good tolerability of Parlodel LAR in patients with hyperprolactinaemia.

A new oral slow release form of bromocriptine, Parlodel SRO, in the chronic treatment of 26 hyperprolactinemic patients.

Parlodel SRO, a new slow release form of bromocriptine, was studied in 26 patients with tumoral and non-tumoral hyperprolactinemia. Prior to the treatment, serum prolactin (PRL) levels ranged from 45 ng/ml to 7000 ng/ml and they decreased to within the normal range in all but one patient after 7 days-1 year of treatment with this new formulation of bromocriptine. The clinical improvement paralleled the normalization of PRL secretion. Tolerability was rated good or very good in 24 patients, even in the three patients who had been intolerant of oral Parlodel. In conclusion, Parlodel SRO administered as a single daily dose resulted in very effective lowering of serum PRL in patients with hyperprolactinemic disorders.

Hypocalcemic effects of rectal and intramuscular administration of synthetic salmon calcitonin.

To assess the acute biological activity of a new rectal form of synthetic salmon calcitonin (SMC), 10 healthy subjects were randomly assigned, according to a crossover design, to single doses of either 50 IU SMC intramuscularly or 100 IU SMC rectally. Ionized and total calcium were measured as SMC bioactivity indicators in blood samples collected during a 6-hour period after the administration of the drug. In all the subjects, rectal administration of 100 IU of SMC induced falls in both plasma total calcium and whole blood ionized calcium: similar levels were observed after intramuscular injection of 50 IU of SMC. The pharmacodynamic bioavailabilities for total and ionized calcium of the 100 IU suppository and the 50 IU intramuscularly were 106% and 60%. The total and ionized calcium AUCs were the same after i.m. injection and suppository. We conclude that, in normal subjects, synthetic salmon calcitonin administered by the rectal route at the dose of 100 IU is effective and has the same biological effects as 50 IU of SMC given intramuscularly. Therefore, this new rectal form may be a useful alternative to parenteral injection.

Medical management of acromegaly: effects of SMS 201-995 in 30 patients.

The effect of chronic administration of SMS 201-995, a long acting analogue of somatostatin, has been studied in 30 acromegalic patients (pts). CT-scan showed pituitary adenoma in 20/30 pts, empty sella in 9/30 pts and no sign of pituitary tumor in one case. SMS 201-995 was administered subcutaneously every 8 hours at the daily dose of 150-900 micrograms. Blood samples for GH, insulin and blood glucose were taken hourly from 04:00 to 20:00 h before treatment, after 15 days and then monthly or fortnightly. IGF-I plasma levels were assayed at 08:00 h in the same day as GH determinations. CT-scan controls were carried out after 12-24 months of treatment in 16/20 pts. GH plasma levels were normalized in 16/30 pts after 0.5-9 months of SMS treatment, whereas in 14/30 pts they were reduced by about 50%. In 10/16 pts the CT-scan examination showed a shrinkage of the tumor size of 20-55%, while no variation of the tumor mass was observed in the 2 pts. In conclusion our data show that SMS 201-995 is a very effective medical treatment in acromegalic patients.

Insulin secretion and glucose tolerance in non-insulin dependent diabetic patients after chronic nifedipine treatment.

The effect of nifedipine 40 mg.day-1 for 3 months on glucose tolerance, insulin and C-peptide secretion after an oral glucose tolerance test (OGTT), intra-venous glucose tolerance test (IVGTT) and glucagon stimulatory test, has been studied in 8 moderately hypertensive women suffering from non-insulin dependent diabetes mellitus (NIDDM). No significant variation in glucose metabolism was noted after nifedipine treatment, except for a slight improvement in insulin secretion after OGTT at the end of the study. There was an increase in cholesterol as a collateral effect.