Early-Onset Central Diabetes Insipidus due to Compound Heterozygosity for AVP Mutations.

BACKGROUND: Genetic cases of isolated central diabetes insipidus are rare, are mostly due to dominant AVP mutations and have a delayed onset of symptoms. Only 3 consanguineous pedigrees with a recessive form have been published. CASE REPORT: A boy with a negative family history presented polyuria and failure to thrive in the first months of life and was diagnosed with central diabetes insipidus. Magnetic resonance imaging showed a normal posterior pituitary signal. A molecular genetic analysis of the AVP gene showed that he had inherited a previously reported mutation from his Lebanese father and a novel A>G transition in the splice acceptor site of intron 1 (IVS1-2A>G) from his French-Canadian mother. Replacement therapy resulted in the immediate disappearance of symptoms and in weight gain. CONCLUSIONS: The early polyuria in recessive central diabetes insipidus contrasts with the delayed presentation in patients with monoallelic AVP mutations. This diagnosis needs to be considered in infants with very early onset of polyuria-polydipsia and no brain malformation, even if there is no consanguinity and regardless of whether the posterior pituitary is visible or not on imaging. In addition to informing family counseling, making a molecular diagnosis eliminates the need for repeated imaging studies.

Pasireotide monotherapy in Cushing's disease: a single-centre experience with 5-year extension of phase III Trial.

PURPOSE: A recent phase III randomized controlled trial (NCT00434148) showed efficacy of pasireotide in the treatment of patients with Cushing's disease (CD). Patients were invited to participate in an extension phase of the protocol and a subgroup had a sustained response. We report the experience with 4 patients in our center of which 2 full responders have completed 5.5 and 4.25 years of treatment with disease control. METHODS: The trial protocol was described previously. The extension phase consisted of 3-monthly visits with clinical, biochemical, and imaging evaluation and investigator-driven pasireotide titration. Research charts were retrospectively analyzed. RESULTS: Four patients with persistent CD following pituitary surgery completed the first 6 months of the trial and 3 continued in the next 6 month open-label phase. Two patients with baseline urinary free cortisol (UFC) 5.3-6.7 times the upper limit of normal had a rapid sustained response to pasireotide and entered the extension phase after 12 months. They remain in clinical and biochemical disease remission and 1 patient now only requires 300 µg daily of pasireotide. All 4 patients developed glucose intolerance; however, the two patients in the extension phase were eventually able to discontinue all diabetes pharmacotherapy. Adverse events included second degree atrioventicular block type 1 without QT prolongation in a patient with pre-existing sinus bradycardia, and symptomatic cholelithiasis requiring cholecystectomy in a second patient. CONCLUSIONS: Pasireotide therapy can provide normalization of UFC and of clinical symptoms and signs of CD during up to 5 years of follow-up. This study demonstrates the possible recuperation of normoglycemia after continued use of pasireotide and control of underlying hypercortisolemia. Longer-term monitoring for potential adverse events related to continued use of pasireotide is indicated.

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.

The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling.

The anterior and intermediate lobes of the pituitary gland derive from the surface ectoderm. They provide a simple system to assess mechanisms of developmental identity established by tissue determinants. Each lobe contains a lineage expressing the hormone precursor pro-opiomelanocortin (POMC): the corticotropes and melanotropes. The T-box transcription factor Tpit controls terminal differentiation of both lineages. We now report on the unique role of Pax7 as a selector of intermediate lobe and melanotrope identity. Inactivation of the Pax7 gene results in loss of melanotrope gene expression and derepression of corticotrope genes. Pax7 acts by remodeling chromatin and allowing Tpit binding to a new subset of enhancers for activation of melanotrope-specific genes. Thus, the selector function of Pax7 is exerted through pioneer transcription factor activity. Genome-wide, the Pax7 pioneer activity is preferentially associated with composite binding sites that include paired and homeodomain motifs. Pax7 expression is conserved in human and dog melanotropes and defines two subtypes of pituitary adenomas causing Cushing's disease. In summary, expression of Pax7 provides a unique tissue identity to the pituitary intermediate lobe that alters Tpit-driven differentiation through pioneer and classical transcription factor activities.

Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis.

Cushing's disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27(Kip1) expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27(Kip1) knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27(Kip1) loss-of-function act cooperatively on pituitary adenoma development.

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.

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.

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.

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.

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.