Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study.

PURPOSE: A large, randomized, double-blind, Phase III core study demonstrated that pasireotide LAR was significantly superior to octreotide LAR at providing GH <2.5 µg/L and normalized IGF-1 after 12 months' treatment in patients with acromegaly. We report the efficacy and safety of pasireotide LAR and octreotide LAR after up to 26 months' treatment. METHODS: Patients with GH <2.5 µg/L and IGF-1 ≤1× ULN at month 12, or patients considered to be experiencing clinical benefit, were eligible to continue receiving their randomized therapy in the extension. Efficacy and safety in the pasireotide LAR and octreotide LAR groups were evaluated for up to 26 months. RESULTS: Overall, 120 patients who completed the core study continued receiving pasireotide LAR (n = 74) or octreotide LAR (n = 46) in the extension. At month 25, biochemical control (GH <2.5 µg/L and normal IGF-1) was achieved by 48.6% (36/74) and 45.7% (21/46) of patients in the pasireotide LAR and octreotide LAR arms [60.8% (45/74) and 52.2% (24/46) when including patients with IGF-1 < LLN], respectively. In total, 74.7% of pasireotide LAR and 71.6% of octreotide LAR patients had tumor volume decrease ≥20% from baseline to month 26. Most AEs were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0% of pasireotide LAR and octreotide LAR patients, respectively. No new safety signals were observed in the extension compared with the core study. CONCLUSIONS: GH and IGF-1 suppression is maintained for up to 25 months during pasireotide LAR treatment. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.

Emerging trends in the diagnosis and treatment of acromegaly in Canada.

OBJECTIVE: To evaluate demographic data and quality of care of patients with acromegaly in Canada and their evolution over time and secondly, to evaluate predictors of co-morbidities and treatment outcomes. DESIGN AND PATIENTS: Retrospective analyses of clinical, biochemical and treatment outcome data of 649 patients with acromegaly (males: 50·7%) followed from 1980 to 2010 (mean 10·2 years, SD 13·7) in eight tertiary care centres from six Canadian provinces. RESULTS: In comparison to 1980-1994, the number of patients referred with acromegaly in the last 15 years was higher with female preponderance (52·8% vs 41·4%, P = 0·01) and an older age at diagnosis (46·4 ± 14 vs 41·3 ± 12 years, P < 0·0001). Diabetes was present in 28%, hypertension in 37% and sleep apnoea in 33% of cases. Pretreatment IGF-1 levels, but not GH levels were significant predictors of diabetes (P = 0·0002) and hypertension (P < 0·0001). Eighty-nine per cent of patients underwent pituitary surgery, 64·5% had medical therapy and 22% received radiotherapy. Radiotherapy was less utilized in the past 15 years (16% vs 45%, P < 0·0001). Multimodal therapy achieved remission or control of acromegaly in 70% of patients. Patients in remission or disease control had lower initial random GH (P = 0·04) and IGF-1 levels (P < 0·0001). Hypopituitarism was present in 23% of patients and cancer in 8·5%. CONCLUSIONS: There was an increase over time of referral for acromegaly management with female predilection. Initial higher IGF-1, but not GH levels, were predictive of co-morbidities and persistent active disease after treatment. Disease remission or control was attained in 70% of patients utilizing multimodal therapy.

Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly.

It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 µg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 µg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.

Oral estroprogestin: an alternative low cost therapy for women with postoperative persistent acromegaly?

Oral estrogens reduce GH-induced IGF-1 production and preliminary studies have shown that adjuvant estroprogestin (EP) therapy with octreotide LAR may control disease activity in some female patients who are partially responsive to octreotide LAR. Our aim was to verify if EP alone or in combination with octreotide LAR can achieve remission of acromegaly in selected cases of patients uncontrolled by surgery. Eleven women with persistent active acromegaly following surgery participated in this unblinded open label pilot study. Their mean age was 49.8 ± 4.3 years. Two patients were drug naïve, two patients had stopped octreotide LAR because of intolerance and seven were treated with octreotide LAR. The patients received either EP (EP pill, 20 µg ethinylestradiol, 100 µg levonorgestrel) alone (4 patients) or added to octreotide LAR (7 patients). Fasting GH, IGF-1, glucose, HDL- and LDL-cholesterol, and triglycerides were measured at baseline and at last visit. MRI was controlled at baseline and at last visit. Duration of estrogen treatment was 3.1 ± 0.5 years. Serum IGF-1 levels were normalized in 8/11 patients (73%). Serum GH concentrations did not change significantly during treatment (11.6 ± 5.6 µg/L prior to EP vs 5.5 ± 1.2 µg/L following EP). In patients treated with EP alone, remission was achieved in 2/4 patients (IGF-1 percentages of the upper limit of normal age-matched range (%ULN): 211 ± 40% before EP compared to 95 ± 15% after EP, P = 0.028). In the seven patients treated by EP added to octreotide LAR, remission was achieved in 6 patients (IGF-1%ULN: 158 ± 9% before EP compared to 86 ± 4% after EP, P = 0.0003). Glucose and cholesterol levels were unchanged by EP treatment (data not shown). MRI did not show any evidence of tumour progression with EP in patients who had a tumour remnant. In conclusion, oral estrogen treatment appears to normalize serum IGF-1 concentrations in over 70% of women with acromegaly uncured by surgery irrespective of their sensitivity to octreotide LAR. We suggest that estrogens may be a temporary cost-effective and safe treatment for women with postoperative persistent acromegaly.

Long-term cabergoline therapy is not associated with valvular heart disease in patients with prolactinomas.

Ergot-derived dopamine receptor agonists, especially pergolide and cabergoline, have been associated with an increased risk of valvular heart disease in patients treated for Parkinson's disease. Cabergoline at lower doses than those employed in Parkinson's disease is widely used in patients with prolactinomas, because of its high efficacy and tolerability; however, its safety with regard to cardiac valve disease is unknown. In order to assess the prevalence of cardiac valve regurgitation in patients with prolactinomas treated with long-term cabergoline, we performed a prospective and multicentric study including four university centers in the province of Quebec. A transthoracic echocardiogram was performed in 70 patients with prolactinomas treated with cabergoline for at least 1 year (duration of treatment, 55 +/- 22 months; cumulative dose 282 +/- 271 mg, mean +/- SD) and 70 control subjects matched for age and sex. Valvular regurgitation was graded according to the American Society of Echocardiography recommendations as mild, moderate, or severe. Moderate valvular regurgitation was found in four patients (5.7%) and five control subjects (7.1%) (P = 0.73). No patient had severe valvular regurgitation. There was no correlation between the presence of significant heart-valve regurgitation and cabergoline cumulative dose, duration of cabergoline treatment, prior use of bromocriptine, age, adenoma size, or prolactin levels. Our results show that low doses of cabergoline seem to be a safe treatment of hyperprolactinemic patients. However, in patients with prolonged cabergoline treatment, we suggest that echocardiographic surveillance may be warranted.

A Canadian multi-centre, open-label long-term study of Pegvisomant treatment in refractory acromegaly.

PURPOSE: Acromegaly is a rarely diagnosed condition with potentially serious complications including accelerated heart disease and reduced survival. After a mean interval of nearly 9 years from onset of disease, a significant proportion of patients are diagnosed with invasive adenomas precluding complete surgical resection. Furthermore, strict normalization of the growth hormone (GH) target insulin-like growth factor I (IGF-I) cannot always be achieved by adjunctive medical therapy with somatostatin analogues. Here we report the results of a Canadian multi-centre study open-label, dose-titrated long-term study examining safety and efficacy outcomes of a growth hormone receptor antagonist, pegvisomant in 19 patients with refractory acromegaly. METHODS: Previously pegvisomant-treated and treatment-naïve refractory acromegalic patients at least 18 yr of age were eligible (n=19). Patients received open-label daily subcutaneous injections of pegvisomant adjusted according to IGF-I levels. Safety and IGF-I levels were assessed every 4 to 6 wk. Baseline and follow-up visits at 3-month intervals also included administration of the Signs and Symptoms of Acromegaly Questionnaire. This study is registered with ClinicalTrials.gov, NCT00151437. RESULTS: We show that, in escalating doses, pegvisomant results in age-adjusted normalization of IGF-I in nearly all such patients. This IGF-I normalization occurred early on and was maintained throughout the study period of 27 months (IGF-I standard deviation score (SDS), mean +/- SE: 1.66 +/- 0.36, P=0.0003 vs baseline), with a nadir at 18 months (IGF-I SDS, mean +/- SE: 1.50 +/- 0.38, P=0.0010 vs baseline). IGF-I control was also accompanied by measurable improvements in disease-associated symptoms and without radiographic evidence of pituitary tumour progression. Overall, the safety profile of pegvisomant therapy in this patient population was found to be satisfactory and suitable for a long-term treatment. CONCLUSION: Our findings provide support for the long-term safety and efficacy of the GH receptor antagonist pegvisomant in achieving IGF-I control in patients with refractory acromegaly.

Serum markers of cardiovascular risk in patients with acromegaly before and after six months of treatment with octreotide LAR.

Acromegaly is associated with increased morbidity and mortality from cardiovascular disease. Inflammatory markers, such as C-reactive protein and leucocyte count, haemostatic markers, such as fibrinogen and factor VIII and cardiac hypertrophy marker, B-type natriuretic peptide, have emerged as important cardiovascular risk markers in the general population. The objective of this study was to assess the serum levels of conventional, inflammatory, haemostatic markers and NT-pro BNP in mostly non-diabetic normotensive patients with acromegaly, as well as the effect of 6 months of octreotide LAR therapy on these markers. We studied 12 patients with active acromegaly, 12 patients in whom remission of acromegaly had been achieved by surgery and 12 healthy control subjects matched for age, gender and body mass index. At baseline fasting blood was obtained for measurements of GH, IGF-1, glucose, insulin, lipids, lipoprotein (a), C-reactive protein, leucocyte count, fibrinogen, factor VIII and NT-pro BNP. After baseline evaluation, patients with active acromegaly were treated with octreotide LAR for 24 weeks. At 24 weeks, measurements were repeated as on baseline. Insulin resistance index and fibrinogen levels were higher in patients with active acromegaly than patients and subjects in control groups. CRP, leucocyte count, factor VIII and NT-pro BNP were similar in the three groups. Octreotide LAR reduced GH, IGF-1 and insulin resistance index but did not alter levels of CRP and NT-pro BNP.

An unusual association of a sellar gangliocytoma with a prolactinoma.

The simultaneous occurrence of a hypothalamic and sellar gangliocytoma with a pituitary prolactinoma is very rare. The explanation for such an association is not known. We describe the case of a woman who had a coexisting adjacent pituitary prolactinoma and gangliocytoma within the same sellar mass. The tumor cells of the gangliocytoma demonstrated expression of enkephalin, a product of proopiomelanocortin known to be a prolactin secretagogue. We postulate that in this patient there may be a link between gangliocytoma enkephalin and prolactin hypersecretion.

Octreotide LAR for the treatment of acromegaly.

BACKGROUND: Somatostatin analogs previously considered as adjuvant therapy in acromegaly are increasingly used as a first-line therapy in selected cases. OBJECTIVE: To review the octreotide LAR pharmacological and clinical data, and discuss the impact of this agent on current treatment regimens. METHODS: We reviewed PubMed publications since the first use of octreotide LAR in acromegaly, and historical articles related to the discovery and development of this molecule. We chose, for efficacy and safety data, reviews, clinical and randomized controlled trials that included >or=10 patients. RESULTS/CONCLUSION: Octreotide LAR controls acromegaly in approximately 50-60% of patients by inhibiting GH and IGF-I secretion, and by reducing tumor size. This drug is well tolerated in most patients.

The role of diabetes in acromegaly associated neoplasia.

BACKGROUND: The risk and mortality due to cancer in patients with acromegaly have been previously investigated. Although GH/IGF-1 excess provides a probable pathophysiological explanation, the degree of IGF-1 excess and the role in acromegaly-associated neoplasms of diabetes, a common comorbidity in acromegaly with known association with cancer, remains unclear. METHODS: Acromegalic patients treated in three Canadian referral centers (Toronto, Montreal, Edmonton) were included. All available clinical information was recorded including: age, initial and last percentage of the upper limit of normal (%ULN) IGF-1 levels, comorbidities and other neoplasms (benign and malignant). RESULTS: 408 cases were assessed. 185 were women (45.3%), 126 (30.9%) developed extra-pituitary neoplasms: 55 malignant and 71 benign. The most frequent anatomic site was the gastrointestinal tract (46 [11.3%]), followed by head and neck (36 [8.8%]) and multiple locations (14 [3.4%]). 106 (26.0%) cases had diabetes. Initial IGF-1 was significantly higher in men older than 50 (380.15 vs. 284.78, p = 0.001) when compared to men younger than 50. Diabetics showed significantly higher initial IGF-1 (389.38 vs. 285.27, p = 0.009), as did diabetics older than 50 compared with those without diabetes. 45.3% (48/106) of cases with diabetes developed extra-pituitary neoplasms vs. 24.3% (71/292) without diabetes (p = 0.001, OR: 2.576 95%CI 1.615-4.108). 22.6% (24/106) of cases with diabetes developed malignant tumors vs. 9.2% (27/292), (p < 0.001, OR 2.873, 95%CI 1.572-5.250). CONCLUSIONS: These data suggest that acromegalic patients with diabetes are more likely to develop extra-pituitary neoplasms and their initial IGF-1 levels are higher. The contribution of IGF-1 vs. diabetes alone or in combination in the development of extra-pituitary neoplasms warrants further investigation.

Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly.

UNLABELLED: Assessment of postoperative disease activity of acromegaly is a major challenge. The consensus criteria for cure, which are glucose-suppressed GH less than 1 micro g/liter and normal IGF-I levels, might be discrepant, and their respective relationship to acromegaly-related morbidity is not well known. THE AIMS OF OUR STUDY WERE: firstly, to correlate plasma IGF-I with plasma glucose-suppressed GH concentrations; and secondly, to correlate each of these biochemical parameters with morbidity [impaired glucose tolerance (IGT), diabetes, and hypertension] in postoperative patients with acromegaly. Fifty-three patients with long-term follow-up (mean, 12.7 yr; range, 1-30 yr) after transsphenoidal surgery for acromegaly and 20 healthy subjects matched for age, sex, and body mass index were evaluated for plasma glucose [by 75-g oral glucose tolerance test (OGTT)], GH (by immunoradiometric assay), plasma IGF-I (by immunoradiometric assay), and blood pressure (BP) measurements. Remission was defined by a normal IGF-I. We identified 34 acromegalics in remission and 19 with active disease. There was no statistical difference between all three groups for age, sex, BMI, and for fasting and 2-h post-OGTT plasma glucose. The time elapsed since surgery was similar in both groups of acromegalics. The OGTT-GH nadir was less than 1 micro g/liter in 31 patients in remission (91.2%) and in nine patients with active disease (47.4%). Prevalence of IGT was lower in acromegalics in remission (14.7%) in comparison with patients with active disease (47.4%; P = 0.01). Plasma IGF-I and GH nadir cut-off of 0.25 microg/liter were strong predictors of abnormal glucose tolerance (odds ratio, 13.6; confidence interval, 2.5-73.7; P = 0.003). GH nadir cut-off of 1 microg/liter and basal GH of 2.5 microg/liter failed to predict abnormal glucose tolerance. There was no statistical difference for prevalence of hypertension and systolic BP values, but diastolic BP was significantly lower in patients in remission than in those with active disease (P < 0.05). Our observations indicate that the validity of the GH threshold of 1 microg/liter post OGTT might be inadequate as a criterion of biochemical remission of acromegaly and as a marker of associated comorbidities. However, normalized IGF-I concentrations and a lower GH cut-off value less than 0.25 micro g/liter are strongly associated with a lower prevalence of IGT and lower diastolic BP in long-term postoperative acromegaly.

Enhanced lipoprotein lipase secretion and foam cell formation by macrophages of patients with growth hormone deficiency: possible contribution to increased risk of atherogenesis?

GH deficiency is associated with increased prevalence of atherosclerosis, and recent data indicate a proatherogenic role for macrophage lipoprotein lipase (LPL) in the arterial wall. In this pilot study, we determined LPL expression and foam cell formation in monocyte-derived macrophages of 12 control subjects and nine patients with GH deficiency without GH replacement therapy. LPL mRNA levels, mass, and activity were increased in macrophages of patients with GH deficiency. In these subjects, macrophage LPL activity correlated with body mass index and fat mass. Incubation of patient macrophages with IGF-I for 24 h or differentiation of monocytes isolated from GH-deficient patients into macrophages in the presence of this growth factor decreased the amount of LPL mass. Compared with control cells, macrophages derived from GH-deficient patients took up and stored increased amounts of proatherogenic lipoproteins and were more easily converted to foam cells. In the supernatants of these cells, increased levels of free fatty acids and TNFalpha were also documented. These results demonstrate that macrophages of patients with GH deficiency secrete increased amounts of proatherogenic cytokines and are more susceptible to foam cell formation. These alterations may contribute to the increased cardiovascular risk in patients with GH deficiency.

Benefits of gliclazide in the atherosclerotic process: decrease in monocyte adhesion to endothelial cells.

Atherosclerotic cardiovascular disease is the leading cause of premature death in patients with diabetes. Atherosclerosis is a chronic immune-mediated disease, the initiation, progression, and destabilization of which is driven and regulated by inflammatory cells. One critical event in the initiation of this vascular inflammatory disease is the adhesion of leukocytes to the activated endothelium and their migration into the vessel wall. These processes are mediated by the upregulation of adhesion molecules on endothelial cells (ECs) and an increased expression in the vascular wall of chemotactic factors to leukocytes. Monocyte binding to ECs is increased in diabetes. One major determinant of this alteration could be oxidative stress. Given the free-radical scavenging activity of gliclazide, we determined the ex vivo and in vitro effects of this drug on human monocyte binding to ECs and the molecular mechanisms involved in this effect. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes normalizes the levels of plasma lipid peroxides and monocyte adhesion in these subjects. Gliclazide (10 microg/mL) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to ECs in vitro. The inhibitory effect of this drug on AGE-induced monocyte adhesion involves a reduction in EC adhesion molecule expression and inhibition of nuclear factor kappaB (NF-kappaB) activation. In addition, gliclazide inhibits oxLDL-induced monocyte adhesion to cultured human aortic vascular smooth muscle cells (HASMCs) in vitro and reduces the production of monocyte chemotactic protein-1 (MCP-1) by these cells. Taken collectively, these results show that gliclazide, at concentrations in the therapeutic range, inhibits ex vivo and in vitro monocyte adhesiveness to vascular cells. By doing so, this drug could reduce monocyte recruitment into the vessel wall and thereby contribute to attenuating the sustained inflammatory process that occurs in the atherosclerotic plaque. These findings suggest that treatment of diabetic patients with this drug may prevent or retard the development of vasculopathies associated with diabetes.

Monocyte adhesion in diabetic angiopathy: effects of free-radical scavenging.

Increased interaction of monocytes with vascular cells is linked to the development and progression of atherosclerosis in patients with diabetes. One major determinant of increased monocyte binding to vascular cells could be oxidative stress. Given the free-radical scavenging properties of gliclazide, we evaluated the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells and smooth muscle cells (SMCs). Short-term administration of gliclazide to patients with type 2 diabetes decreases plasma lipid peroxides and lowers the enhanced adhesion of diabetic monocytes to cultured endothelial cells observed before gliclazide treatment. Gliclazide (10 microg/ml) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to cultured endothelial cells. The suppressive effect of gliclazide on AGE-induced monocyte adhesion to endothelium involves a reduction of cell adhesion molecule mRNA and protein expression and an inhibition of NF-kappaB activation. Gliclazide also inhibits oxLDL-induced monocyte adhesion to cultured human aortic smooth muscle cells (HASMCs). Furthermore, treatment of HASMCs with gliclazide results in a marked decrease in oxLDL-induced monocyte chemoattractant protein-1 expression, both at the gene and protein levels. These results suggest that gliclazide, at concentrations in the therapeutic range (5-10 microg/ml), by its ability to decrease monocyte-vascular cell interactions could reduce monocyte accumulation in the atherosclerotic plaque and thereby contribute to attenuate the sustained inflammatory process that occurs in the vessel wall. These findings suggest that treatment of diabetic patients with gliclazide may prevent or retard the development of vascular disturbances associated with diabetes.

Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with acromegaly: a randomized, multicenter, open-label, phase I study.

Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long-acting-release (LAR) formulation of pasireotide may offer advantages over the subcutaneous formulation. This randomized, open-label, Phase I study evaluated the safety, PK, and PD of pasireotide LAR 20, 40, or 60 mg/month in patients with acromegaly. Safety assessments and blood samples for PK and PD were taken at designated time points. Thirty-five patients were randomized and completed the study. Steady-state pasireotide concentrations were achieved following three monthly injections. Trough pasireotide concentrations (ng/mL) 28 days after each injection were: 2.48, 4.16, and 3.10 (20 mg group); 6.42, 6.62, and 7.12 (40 mg group); and 9.51, 11.7, and 13.0 (60 mg group). At study end, 51% and 57% of patients achieved GH levels ≤2.5 µg/L and IGF-1 levels below ULN, respectively. Compared with baseline, fasting blood glucose and HbA1c levels increased, whereas fasting blood insulin levels decreased. Acromegaly symptoms were generally improved. Adverse events were mostly gastrointestinal and mild/moderate. Pasireotide LAR was generally well tolerated. Steady-state PK was achieved after three monthly doses; exposures were approximately dose proportional. Control of GH, IGF-1, and symptoms improved, suggesting that pasireotide LAR may be an effective treatment for acromegaly.

Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review.

OBJECTIVE: To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole. METHODS: We present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options. RESULTS: A 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. CONCLUSION: Clinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir.

Metabolic glucose status and pituitary pathology portend therapeutic outcomes in acromegaly.

INTRODUCTION: Acromegaly is frequently associated with impaired glucose tolerance and/or diabetes. To evaluate the relationship between glucose metabolism and acromegaly disease, we evaluated 269 consecutive patients from two referral centres. METHODS: Clinical presentation, pituitary tumor size and invasiveness, and pituitary pathology were captured in a dedicated database. RESULTS: 131 women and 138 men with a mean age of 53.8 years were included. Of these, 201 (74.7%) presented with a macroadenoma and 18 (6.7%) with a microadenoma. Radiographic invasion was present in 91 cases (33.8%). Mean tumor diameter was 1.86 cm (0.2-4.6). Pituitary histopathologic findings revealed pure GH-producing somatotroph adenomas (SA) in 147 patients, prolactin-production by mixed lactotroph (LA) and SA or mammosomatotroph adenoma (MSA) in 46 [22.4%], acidophil stem cell adenoma in 6 [2.9%], and other diagnoses in 6 [2.9%]. Medical treatment included octreotide in 96 [36.9%] and in combination with pegvisomant or dopamine agonists in 63 [24.2%]. Nearly 80% of patients achieved IGF-1 normalization. Importantly, patients with pure somatotroph adenomas were significantly more likely to present with abnormal glucose metabolism [48.7%] than those with mixed adenomas [9.7%] [p<0.001] independent of GH/IGF-1 levels or tumor invasiveness. Abnormal glucose metabolism and pituitary pathology also remained linked following IGF-1 normalization. Moreover patients with pure SA and abnormal glucose metabolism were significantly (p<0.001) less likely to achieve disease remission despite the same therapeutic strategies. Conversely, patients with mixed adenomas were more likely (OR: 2.766 (95% CI: 1.490-5.136) to achieve disease remission. CONCLUSIONS: Patients with pure somatotroph adenomas are more likely than those with mixed adenomas to exhibit abnormal glucose metabolism.

Apoplexy of a microprolactinoma during pregnancy: case report and review of literature.

OBJECTIVE: To report a rare case of apoplexy in a microprolactinoma during pregnancy. METHODS: We present the initial clinical manifestations, laboratory results, radiologic findings, and management in a patient who had pituitary apoplexy during early pregnancy. The pertinent literature and management options are also reviewed. RESULTS: A 37-year-old woman with a history of a microprolactinoma presented during the 16th week of her first pregnancy with a sudden onset of severe headache, nausea, vomiting, and blurred vision. Magnetic resonance imaging showed a sellar heterogeneous mass with suprasellar extension and contact with the optic chiasm, compatible with adenoma apoplexy. The patient's visual fields were normal. Conservative management was followed by rapid clinical improvement and a notable regression of the sellar mass after 5 weeks of cabergoline therapy. Uneventful pregnancy resulted in the delivery of a healthy baby. Repeated magnetic resonance imaging was performed 1 week after delivery and showed resolution of the microadenoma. At 3 months after delivery, the patient had recovered regular menses and had sustained normal prolactin levels without treatment. CONCLUSION: This case illustrates a rare occurrence of apoplexy in a microprolactinoma during pregnancy, which was managed conservatively and led to a complete regression of the pituitary tumor.

Cabergoline therapy for prolactinomas: is valvular heart disease a real safety concern?

Dopamine agonists (DAs) are the first-line therapy for the treatment of hyperprolactinemia, with cabergoline, an ergot-derived selective D(2)-receptor agonist, being the preferred and most widely used drug. Recent studies reported cardiac valve regurgitations in patients with Parkinson's disease treated with high doses of DA, raising concerns about the safety of cabergoline in patients with hyperprolactinemia. To date, seven case-control studies have examined the potential association between cardiac valvular abnormalities and cabergoline therapy in patients with hyperprolactinemia. Overall, a total of 463 patients exposed to low doses of cabergoline (mean cumulative doses: 204-443 mg) for a mean duration of 45-79 months have been included in these studies. Patients in all the studies were asymptomatic without clinical signs of cardiac disease. Six studies did not show any association between cabergoline therapy and clinically relevant valvular regurgitation, whereas one study found an increased rate of moderate tricuspid regurgitation. In this report, we review and discuss the results of these studies and emphasize the limitations of the methodology used in the published literature. The clinical significance of the present findings has yet to be confirmed by future larger prospective studies with rigorous echocardiographic protocols and prolonged duration of follow-up.