Consensus on criteria for acromegaly diagnosis and remission.

PURPOSE: The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy. METHODS: Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes. RESULTS: In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches. CONCLUSION: Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.

Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

A Pituitary Society update to acromegaly management guidelines.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.

Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency.

INTRODUCTION AND BACKGROUND: Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al. OBJECTIVE: To investigate whether normative data of the VARIETE cohort lead to differences in Z-scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al. DESIGN: We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH-deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al. RESULT: Before GH treatment, Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al: -2.40 (-4.52 to +1.31) (mean [range]) vs. -1.41 (-3.14 to +1.76); P < .001). After 12 months of GH treatment, again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al: -0.65 (-4.32 to +2.79) vs 0.21 (-3.00 to +3.28); P < .001). CONCLUSION: IGF-I Z-scores in 102 GH-deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice, this would most likely have led to different clinical interpretations and GH dose adjustments.

Efficacy and safety of bariatric surgery for craniopharyngioma-related hypothalamic obesity: a matched case-control study with 2 years of follow-up.

BACKGROUND: Hypothalamic obesity is a devastating consequence of craniopharyngioma. Bariatric surgery could be a promising therapeutic option. However, its efficacy and safety in patients with craniopharyngioma-related hypothalamic obesity remain largely unknown. OBJECTIVES: We investigated the efficacy of bariatric surgery for inducing weight loss in patients with craniopharyngioma-related hypothalamic obesity. In addition, we studied the safety of bariatric surgery regarding its effects on hormone replacement therapy for pituitary insufficiency. METHODS: In this retrospective matched case-control study, we compared weight loss after bariatric surgery (that is, Roux-en-Y gastric bypass and sleeve gastrectomy) between eight patients with craniopharyngioma-related hypothalamic obesity and 75 controls with 'common' obesity during 2 years of follow-up. We validated our results at 1 year of follow-up in a meta-analysis. In addition, we studied alterations in hormone replacement therapy after bariatric surgery in patients with craniopharyngioma. RESULTS: Mean weight loss after bariatric surgery was 19% vs 25% (difference -6%, 95% confidence of interval (CI) -14.1 to 4.6; P=0.091) at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity compared with control subjects with 'common' obesity. Mean weight loss was 25% vs 29% (difference -4%, 95% CI -11.6 to 8.1; P=0.419) after Roux-en-Y gastric bypass and 10% vs 20% (difference -10%, 95% CI -14.1 to -6.2; P=0.003) after sleeve gastrectomy at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity vs control subjects with 'common' obesity. Our meta-analysis demonstrated significant weight loss 1 year after Roux-en-Y gastric bypass, but not after sleeve gastrectomy. Seven patients with craniopharyngioma suffered from pituitary insufficiency; three of them required minor adjustments in hormone replacement therapy after bariatric surgery. CONCLUSIONS: Weight loss after Roux-en-Y gastric bypass, but not sleeve gastrectomy, was comparable between patients with craniopharyngioma-related hypothalamic obesity and control subjects with 'common' obesity at 2 years of follow-up. Bariatric surgery seems safe regarding its effects on hormone replacement therapy.

Acylated and unacylated ghrelin during OGTT in Prader-Willi syndrome: support for normal response to food intake.

BACKGROUND: Prader-Willi syndrome (PWS) is characterized by hyperphagia with impaired satiety. PWS patients have very high acylated ghrelin (AG) with normal unacylated ghrelin (UAG) levels, resulting in an elevated AG/UAG ratio, suggesting an intrinsic defect in the ghrelin regulation. Normally, food intake induces satiety and a drop in AG and UAG levels, but it is unknown if these levels also decline in PWS. OBJECTIVE: To evaluate whether the high AG levels in PWS decline in response to glucose intake during an oral glucose tolerance test (OGTT), and to investigate the effects of growth hormone (GH) treatment on this response. METHOD: Serum levels of AG, UAG and AG/UAG ratio during an OGTT were determined in 24 GH-treated patients with PWS (median age 19·0, range 14·2-25·9 years) and in 10 GH-stop patients (of whom five were in GH-treated group; 18·5, 14·5-20·3 years). RESULTS: In GH-treated and GH-stop young adults with PWS, there was a sharp decline of AG levels and a decrease of UAG levels in the first 30 min after the glucose load, which resulted in a lower AG/UAG ratio. GH-treated patients had significantly lower AG levels than GH-stop patients at baseline and during the OGTT. All UAG levels and AG/UAG ratios were lower in the GH-treated patients, although not significantly. CONCLUSIONS: In young adults with PWS, an oral glucose load significantly reduces AG and UAG levels, suggesting normal regulation of the ghrelin axis by food intake. GH treatment results in lower AG levels at baseline and during OGTT, suggesting a more favourable metabolic profile. Our findings might suggest that the impaired satiety is not the result of an abnormal response of the orexigenic ghrelin to food intake.

Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes.

AIM: To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP-531, designed to improve glycaemic control and reduce weight. METHODS: Assessments, including glucose measurements, were performed in a three-part randomized study. In Part A, healthy subjects [n = 44, age 18-50 years, body mass index (BMI) 20-28 kg/m(2) ] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP-531 or placebo. In Part B, overweight/obese subjects (n = 32, age 18-65 years, BMI 28-38 kg/m(2) ) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18-65 years, BMI 20-40 kg/m(2) , glycated haemoglobin (HbA1c) 7-10%] received AZP-531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively). RESULTS: AZP-531 was well tolerated. Single- and multiple-dose pharmokinetic variables were similar. Maximum AZP-531 concentrations were typically reached at 1 h post-dose. Observed maximum concentration (Cmax ) and area under the curve were dose-proportional. The mean terminal half-life (t1/2 ) was 2-3 h. In Part B, AZP-531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin-sensitizing effect. AZP-531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In Part C, glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP-531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo). CONCLUSIONS: AZP-531 was well tolerated in this first-in-human study. Its pharmacokinetic profile, suitable for once-daily dosing, and metabolic effects support further clinical development for T2D.

The effect of hypopituitarism on fatigue after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) survivors often complain of fatigue, which is disabling. Fatigue is also a common symptom of pituitary dysfunction (PD), in particular in patients with growth hormone deficiency (GHD). A possible association between fatigue after SAH and long-term pituitary deficiency in SAH survivors has not yet been established. METHODS: A single center observational study was conducted amongst 84 aneurysmal SAH survivors to study the relationship between PD and fatigue over time after SAH, using mixed model analysis. Fatigue was measured with the Fatigue Severity Scale and its relationships with other clinical variables were studied. RESULTS: Three-quarters of respondents (76%) have pathological fatigue directly after SAH and almost two-thirds (60%) of patients still have pathological levels of fatigue after 14 months. The severity of SAH measured with a World Federation of Neurosurgical Societies (WFNS) score higher than 1 (P = 0.008) was associated with long-term fatigue. There is no statistically significant effect of PD (P = 0.8) or GHD (P = 0.23) on fatigue in SAH survivors over time. CONCLUSIONS: Fatigue is a common symptom amongst SAH survivors. WFNS is a usable clinical determinant of fatigue in SAH survivors. Neither PD nor GHD has a significant effect on long-term fatigue after SAH.

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults.

PURPOSE: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). METHODS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. RESULTS: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. CONCLUSIONS: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

Pituitary dysfunction after aneurysmal subarachnoid haemorrhage: course and clinical predictors­the HIPS study.

OBJECTIVE: We describe the occurrence and course of anterior pituitary dysfunction (PD) after aneurysmal subarachnoid haemorrhage (SAH), and identify clinical determinants for PD in patients with recent SAH. METHODS: We prospectively collected demographic and clinical parameters of consecutive survivors of SAH and measured fasting state endocrine function at baseline, 6 and 14 months. We included dynamic tests for growth-hormone function. We used logistic regression analysis to compare demographic and clinical characteristics of patients with SAH with and without PD. RESULTS: 84 patients with a mean age of 55.8 (±11.9) were included. Thirty-three patients (39%) had PD in one or more axes at baseline, 22 (26%) after 6 months and 6 (7%) after 14 months. Gonadotropin deficiency in 29 (34%) patients and growth hormone deficiency (GHD) in 26 (31%) patients were the most common deficiencies. PD persisted until 14 months in 6 (8%) patients: GHD in 5 (6%) patients and gonadotropin deficiency in 4 (5%). Occurrence of a SAH-related complication was associated with PD at baseline (OR 2.6, CI 2.2 to 3.0). Hydrocephalus was an independent predictor of PD 6 months after SAH (OR 3.3 CI 2.7 to 3.8). PD was associated with a lower score on health-related quality of life at baseline (p=0.06), but not at 6 and 14 months. CONCLUSIONS: Almost 40% of SAH survivors have PD. In a small but substantial proportion of patients GHD or gonadotropin deficiency persists over time. Hydrocephalus is independently associated with PD 6 months after SAH. TRIAL REGISTRATION NUMBER: NTR 2085.

Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY.

OBJECTIVE: To evaluate use of pegvisomant, a growth hormone (GH) receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites). METHODS: A descriptive analysis of safety, magnetic resonance imaging (MRI) reading, and treatment outcomes in 710 subjects who received at least 1 pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY. RESULTS: Subjects received a mean of 5.4 years of pegvisomant and were followed in ACROSTUDY for a mean of 3.8 years. A total of 1,255 adverse events (AEs) were reported in 345 subjects (48.6%). Serious AEs (SAEs) were reported in 133 (18.7%) subjects, including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least 1 liver function test (LFT) reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases >3 times the upper limit of normal (ULN). No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, insulin-like growth factor 1 (IGF-1) level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy. CONCLUSIONS: ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective for patients with acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit-risk of pegvisomant therapy.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing's disease.

Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

What is active acromegaly and which parameters do we have?

Disease activity of acromegaly can be measured in many ways. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations are the main biochemical markers used to measure the response to treatment. Both GH and IGF1 have been associated with prognosis, in particular mortality. In this review, we discuss the available parameters to assess disease activity in acromegaly.

Effects of chronic slow release-lanreotide treatment on insulin-like growth factor system and metabolic parameters in acromegalic patients.

Insulin and IGF binding protein (IGFBP)-1 are linked by negative association. Somatostatin (SS) reduces insulin secretion by acting on pancreatic ß-cell and also by decreasing GH secretion. SS analogues in acromegaly reduce total IGF-I levels inhibiting GH hypersecretion, but they also reduce free IGF-I bioactivity increasing IGFBP-1 levels by inducing insulin decrease. In 13 acromegalic patients we studied GH, IGF system, insulin, and glucagon levels at baseline and at 7 days, 1 and 6 months under treatment with slow release (SR)-lanreotide (LAN) (60 mg im monthly). The hormonal and metabolic response to arginine (ARG) (0.5 g/kg iv in 30 min) was also studied at each time point. LAN decreased GH, total IGF-I, and IGFBP-3 levels at each time point. Insulin and glucagon levels were reduced, while IGFBP-1 and free IGF-I levels were increased by LAN at day 7 and after 1 month only. LAN did not modify the GH, insulin, glucagon, glucose, and IGFBP-1 responses to ARG. At each time point ARG-induced insulin increase was coupled to increase in glucagon and IGFBP-1 levels. This study shows that acromegalic patients under chronic treatment with LAN display: a) inhibition of GH and total IGF-I levels, not coupled to persistent decrease in free IGF-I levels; b) persistent decrease in IGFBP- 3 but transient decrease and increase in insulin and IGFBP- 1, respectively; c) unchanged hormonal and metabolic response to ARG. Our findings also show that ARG stimulates IGFBP-1 despite marked increase in insulin secretion; this escape from the negative relationship linking insulin and IGFBP- 1 would likely reflect the ARG-induced glucagon increase.

Rapid decrease in adrenal responsiveness to ACTH stimulation after successful pituitary surgery in patients with Cushing's disease.

OBJECTIVE: The aim of this study was to investigate the effects of transsphenoidal surgery (TS) on the adrenal sensitivity to ACTH (adrenocorticotropin) stimulation in patients with Cushing's disease (CD). METHODS: We measured the cortisol response to 1 µg synthetic ACTH (1-24) 6 days after pituitary surgery in 45 patients with CD. Mean follow-up period was 56·5 months (SE 4·7). RESULTS: In 24 of 28 patients in sustained remission after pituitary surgery, peak cortisol concentrations below 774 nm (28·0 µg/dl) were recorded after stimulation with 1 µg synthetic ACTH (86%). Two patients with recurrent disease after initial remission (late relapse) also showed ACTH-stimulated peak cortisol levels below 774 nM. Fourteen of 15 patients with persistent CD after surgery (early failure) showed absolute peak cortisol levels >774 nm in response to ACTH stimulation. CONCLUSION: Patients in remission after pituitary surgery for CD showed a rapid decrease of adrenal responsiveness to exogenous ACTH stimulation. This phenomenon may be explained by ACTH-receptor down-regulation in the adrenal cortex after complete removal of the pituitary corticotroph adenoma. In our study, the postoperative low-dose ACTH stimulation test had a sensitivity of 93% and a specificity of 87% in predicting immediate remission of CD after pituitary surgery.

Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients.

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.