Anastrozole as add-on therapy for cabergoline-resistant prolactin-secreting pituitary adenomas: real-life experience in male patients.

INTRODUCTION: Prolactin-secreting adenoma (PRLoma) can present as large and invasive neoplasm, with increased markers of cellular proliferation. First-line approach is Dopamine Agonists (DAs) treatment; however, DA-resistance has been reported, especially in male patients. Estrogens induce lactotroph cell replication and PRL secretion: the use of anti-estrogen treatment in patients with PRLoma have been described in few cases. We reported our experience regarding treatment with the aromatase inhibitor anastrozole (ANA) as add-on therapy for male patients with DA resistant PRLoma. MATERIALS AND METHODS: We describe four male patients (26, 38, 29 and 19 years old at diagnosis), with PRLoma (median diameter 26 mm, PRL 7730 µg/L). They were resistant to cabergoline (CAB, > 2 mg/week) in terms of PRL secretion and tumor size reduction. ANA 1 mg/day was added to the maximum tolerated dose of CAB for at least 1 year. Magnetic Resonance was performed at baseline, after 6 months of CAB + ANA combination and every 12 months afterward. RESULTS: PRL levels decreased in all patients after CAB + ANA (mean - 70%, range - 44/- 97%), achieving a normalization of PRL levels in one case. Tumor size decreased in all cases (mean - 47%, range - 24.5/- 68%). No severe adverse effects have been reported, a moderate weight gain has been observed in two cases. CONCLUSIONS: Addition of an aromatase inhibitor (ANA) to the dopamine agonist therapy improved the control of prolactin levels and induced tumour regression.

Is pasireotide-induced diabetes mellitus predictable? A pilot study on the effect of a single dose of pasireotide on glucose homeostasis.

INTRODUCTION: Pasireotide (PAS) is an effective treatment for Cushing's disease (CD) but its use is burdened by an associated high incidence of diabetes mellitus (DM). The aim of this study was to examine the effect of a single subcutaneous injection of PAS on glucose metabolism in CD, and to identify predictors of DM onset. METHODS: Fifteen patients with CD (13 females, 2 males; median age 43 years [IQR 34-50]) were submitted to an acute PAS test (600 µg s.c.), measuring glucose, insulin, C-peptide, GIP, glucagon, GLP-1, ACTH, and cortisol at the baseline and every 30 min for 2 h. Then they were treated twice daily with PAS 600 µg, and followed up with clinical and hormone assessments for a median of 6 months [2-13]. RESULTS: PAS prompted a significant decrease in all hormonal parameters considered except for glycemia, which increased (as expected), reaching the highest value at 120' (p < 0.0001). Overall, 9/15 patients developed DM within 2 months of starting PAS therapy. There were no differences in age, weight, visceral adiposity, HOMA index, fasting glucose or severity of CD between patients who developed DM and those who did not. Baseline fasting glucagon levels were higher in the DM patients (17.95 [12.45-20.54] vs. 10.53 [8.11-12.33] pmol/L, p = 0.0256), and so were GIP and HbA1c levels (37 [5.5-39.5] vs. 29 [27-31.8] mmol/mol, p = 0.0008). Glucose at 120' was also significantly higher in the DM patients (9.5 [8.65-11.95] vs. 6.85 [4.48-9] mmol/L, p = 0.012). CONCLUSIONS: PAS was rapidly able to suppress insulin and incretin secretion, with a subsequent rise in glucose levels into the diabetic range. It also induced a significant inhibition of glucagon production. The patients at higher risk of DM during PAS therapy were those with higher glucagon levels, HbA1c > 34.5 mmol/mol, and a glucose peak after PAS administration > 9 mmol/L. CD patients with these features given PAS therapy should therefore be monitored more carefully.

Long-course temozolomide in aggressive pituitary adenoma: real-life experience in two tertiary care centers and review of the literature.

PURPOSE: Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful. METHODS: We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150-200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles. RESULTS: Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD. CONCLUSIONS: TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+ PAs and PCs, when further therapies may be unsuccessful.

Decrease in salivary cortisol levels after glucocorticoid dose reduction in patients with adrenal insufficiency: A prospective proof-of-concept study.

BACKGROUND AND AIM: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement therapy. Cortisol measurement in saliva is increasingly being used: we assessed salivary cortisol rhythm in outpatients with AI, to provide new insights regarding the management of GC treatment. MATERIALS AND METHODS: Nineteen AI outpatients collected six saliva samples from awakening (Fa , before taking the morning GC therapy), during the day (F1.5 h , F6 h before the afternoon GC dose, F8.5 h , F12 h ) until bedtime (Fb ). We measured daily cortisol exposure by calculating the area under the curve (AUCFa→Fb ). Saliva samples were collected at baseline and one year after GG dose reduction (by at least 5 mg of hydrocortisone). RESULTS: Hydrocortisone equivalents decreased from median 25 mg/d (baseline, interquartile range IQR 20-27.5) to 15 mg/d (IQR 15-20, P < .01). As expected, we observed a reduction in both daily cortisol exposure (AUCFa→Fb 23 982 nmol·h/L, IQR 12 635-45 369, to 14 689 nmol·h/L, IQR 7168-25 378, P < .001) and salivary cortisol levels at F6 h (24.8 nmol/L, IQR 20.1-35.7, to 21 nmol/L, IQR 8.7-29.2, P < .05) and Fb (8.7 nmol/L, IQR 3.4-20.2, to 3.7 nmol/L, IQR 3.0-5.8, P < .05). None of the patients developed signs or symptoms consistent with AI after GC reduction. Median diastolic blood pressure (DPB) values fell from baseline to the end of follow-up (87.5 mm Hg, IQR 80-90, to 80 mm Hg, IQR 80-85, P < .05). The AUCFa→Fb of patients at baseline was above the reference value (90th percentile of controls) in 12 patients (60%); after the dosage reduction, 30% of patients normalized their daily cortisol exposure (AUCFa→Fb ). CONCLUSIONS: The reduction in GC treatment in patients with AI resulted in better control of daily cortisol rhythm, measured with salivary cortisol, and in an improvement of DPB. Further studies are needed to ascertain if salivary cortisol could be used as a biomarker to manage GC replacement therapy.

Clinical presentation and management of acromegaly in elderly patients.

BACKGROUND AND AIM: Acromegaly is a rare disease with a peak of incidence in early adulthood. However, enhanced awareness of this disease, combined with wide availability of magnetic resonance imaging (MRI), has increased the diagnosis of forms with mild presentation, especially in elderly patients. Moreover, due to increased life expectancy and proactive individualized treatment, patients with early-onset acromegaly are today aging. The aim of our study was to describe our cohort of elderly patients with acromegaly. MATERIALS AND METHODS: This is a cross-sectional retrospective study of 96 outpatients. Clinical, endocrine, treatment, and follow-up data were collected using the electronic database of the University Hospital of Padova, Italy. RESULTS: We diagnosed acromegaly in 13 patients, aged ≥65 years, presenting with relatively small adenomas and low IGF-1 secretion. Among them, 11 patients were initially treated with medical therapy and half normalized hormonal levels after 6 months without undergoing neurosurgery (TNS). Remission was achieved after TNS in three out of four patients (primary TNS in two); ten patients presented controlled acromegaly at the last visit. Acromegaly-related comorbidities (colon polyps, thyroid cancer, adrenal incidentaloma, hypertension, and bone disease) were more prevalent in patients who had an early diagnosis (31 patients, characterized by a longer follow-up of 24 years) than in those diagnosed aged ≥65 years (5 years of follow-up). CONCLUSIONS: Elderly acromegalic patients are not uncommon. Primary medical therapy is a reasonable option and is effectively used, while the rate of surgical success is not reduced. A careful cost-benefit balance is suggested. Disease-specific comorbidities are more prevalent in acromegalic patients with a longer follow-up rather than in those diagnosed aged ≥65 years.

Pituitary-adrenal axis and peripheral cortisol metabolism in obese patients.

BACKGROUND AND AIM: A close relationship between adiposity and increased cortisol levels is well established in patients with endogenous hypercortisolism. Nevertheless, hypothalamic-pituitary-adrenal (HPA) axis regulation in overweight subjects is still a matter of concern. We studied free cortisol (urinary free cortisol, UFC and late night salivary cortisol, LNSC), pituitary feedback (serum cortisol after 1 mg dexamethasone suppression test, 1 mg DST) and peripheral cortisol metabolism (urinary cortisol to cortisone ratio, F/Eratio) in a large series of overweight subjects without Cushing's Syndrome. MATERIALS AND METHODS: We considered 234 patients divided in 5 BMI classes, matched for age and gender (BMI ≤ 25 kg/m2n = 38; 25-30 n = 58; 30-35 n = 52; 35-40 n = 52; >40 n = 34). UFC, LNSC and urinary F/Eratio were assessed with LC-MS. RESULTS: We collected 183 LNSC, 176 UFC, 152 1 mg DST and 64 F/Eratio tests. UFC levels were higher in lean subjects, and they decreased according to the BMI classes (p = 0.022). Non-suppressed cortisol levels (>50 nmol/L) after 1 mg DST were observed especially in patients with normal weight or mild obesity. Patients with BMI ≥ 35 kg/m2 revealed a reduced F/Eratio (0.39 vs. 0.61, p = 0.006). The specificity of tests (false positive results) was higher considering 1 mg DST or UFC in obese patients, on the contrary impaired cortisol rhythm (LNSC above normality) was observed in 47 subjects, irrespective of weight. CONCLUSIONS: Overweight and obese subjects are characterised by an original regulation of HPA axis (reduced UFC levels, increased suppression after 1 mg DST) and peripheral cortisol metabolism (reduced F/Eratio), suggesting an effort to counteract hypercortisolism.

Age and the metabolic syndrome affect salivary cortisol rhythm: data from a community sample.

OBJECTIVE: Measurement of cortisol levels in saliva is a marker of free hormone. How salivary cortisol rhythm is affected by age, gender, the metabolic syndrome and estrogen-progestin therapy was evaluated in a community sample of adults. SUBJECTS AND METHODS: One hundred twenty volunteers recruited from the Hospital staff and family members of the Endocrinology Unit were instructed to collect 7 salivary samples: the first on awakening (F(0)) and 6 more (F(1.5), F(5), F(6), F(10), F(11.5) and F(14)) over the next 14 hours. Each volunteer also underwent a complete physical evaluation and a comprehensive medical history was taken. Salivary cortisol was measured using a radioimmunometric assay. Daily cortisol secretion was evaluated computing the Area Under the Curve (AUC(F0)(→)(F14)); the F(14)/F(0) ratio was calculated as a marker of cortisol rhythm. RESULTS: Median F(14) levels were higher in the subjects in the third tertile of age than in those falling in the second or in the first age tertile (respectively, 2.09 vs 1.33 vs 1.25 ng/mL, p=0.023 and p=0.006), in the hypertensive volunteers (2.44 vs 1.44 ng/mL, p=0.030) and in those with the metabolic syndrome (2.95 vs 1.4 ng/mL, p=0.002), with an elevated median F(14)/F(0) ratio (0.48 vs 0.19, p=0.006). According to the Kruskal-Wallis analysis of variance, the most important factor affecting F(14) value was age (p=0.001). AUC(F0)(→)(F14) was not influenced by gender, age, metabolic syndrome or estrogen-progestin therapy. CONCLUSIONS: While it did not affect the daily cortisol rate, late-night salivary cortisol levels were found to be increased in the subjects in the higher age tertile and in those with the metabolic syndrome.