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- Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function. [JOURNAL ARTICLE]
- Pituitary 2014 Aug 22.
Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis.HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function.Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived.All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 μg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 μg) ACTH stimulation consistent with central adrenal insufficiency.STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.
- Hypothalamic pituitary dysfunction amongst nasopharyngeal cancer survivors. [JOURNAL ARTICLE]
- Pituitary 2014 Aug 19.
Radiation fields for nasopharyngeal cancer (NPC) include the base of skull, which places the hypothalamus and pituitary at risk of damage. We aimed to establish the prevalence, pattern and severity of hypothalamic pituitary (HP) dysfunction amongst NPC survivors.We studied 50 patients (31 males) with mean age 57 ± 12.2 years who had treatment for NPC between 3 and 21 years (median 8 years) without pre-existing HP disorder from other causes. All patients had a baseline cortisol, fT4, TSH, LH, FSH, oestradiol/testosterone, prolactin and renal function. All patients underwent dynamic testing with insulin tolerance test to assess the somatotroph and corticotroph axes. Baseline blood measurements were used to assess thyrotroph, gonadotroph and lactotroph function.Hypopituitarism was present in 82 % of patients, 30 % single axis, 28 % two axes, 18 % three axes and 6 % four axes deficiencies. Somatotroph deficiency was most common (78 %) while corticotroph, gonadotroph and thyrotroph deficiencies were noted in 40 % (4 complete/16 partial), 22 and 4 % of the patients respectively. Hyperprolactinaemia was present in 30 % of patients. The development of HP dysfunction was significantly associated with the time elapsed from irradiation, OR 2.5 (1.2, 5.3), p = 0.02, for every 2 years post treatment. The use of concurrent chemo-irradiation (CCRT) compared to those who had radiotherapy alone was also significantly associated with HP dysfunction, OR 14.5 (2.4, 87.7), p < 0.01.Despite low awareness and detection rates, HP dysfunction post-NPC irradiation is common. Use of CCRT may augment time related pituitary damage. As these endocrinopathies result in significant morbidity and mortality we recommend periodic assessment of pituitary function amongst NPC survivors.
- A pitfall in diagnosing Cushing's disease: ectopic ACTH-producing pituitary adenoma in the sphenoid sinus. [JOURNAL ARTICLE]
- Pituitary 2014 Aug 17.
To show a rare case of Cushing's disease and possible cause of failed transsphenoidal surgery.We report on a 50-year-old woman suffering from ACTH-dependent Cushing's syndrome. Endocrinological work-up including low-dose/high-dose dexamethasone test (Liddle-test) and CRH test were clearly compatible with pituitary origin. Although an MRI showed no pituitary tumor, CRH-stimulated petrosal sinus sampling revealed a significant central-peripheral gradient in ACTH concentrations, rendering Cushing's disease very likely. The patient underwent transsphenoidal surgery with negative exploration of the pituitary gland. After intraoperative re-evaluation of the preoperative MRI, a "polyp" at the bottom of the sphenoid sinus was identified. The intraoperative microscopic aspect as well as instantaneous sections and cytology of a biopsy confirmed an adenoma, which was then removed. Histological analysis demonstrated an ACTH-producing pituitary adenoma adjacent to respiratory mucous membrane consisting of ciliated epithelium with submucous connective tissue. Postoperatively, ACTH concentrations were decreased and intermittent hydrocortisone substitution treatment was initiated. At the 3-month follow up, Cushing's stigmata were found to be alleviated and the hydrocortisone dosage could be reduced.Ectopic pituitary adenoma tissue causing Cushing's disease is extremely rare but a potential cause for surgical failure or re-evaluation.
- Evaluation of survivin splice variants in pituitary tumors. [JOURNAL ARTICLE]
- Pituitary 2014 Aug 9.
Survivin is an apoptosis inhibitor, expressed in almost all types of human malignancies, but rarely in differentiated normal tissues. Recently, survivin gene splice variants with different anti-apoptotic activities have been reported. The current study was undertaken to examine the expression of survivin and its splice variants ∆Ex3 and 2β in pituitary tumors, and to correlate the amount of particular transcripts with clinical staging in pituitary adenomas. Quantitative detection of survivin and its splice variants ∆Ex3 and 2β transcripts in non-cancerous pituitary tissues (n = 12) and different types of pituitary tumor (n = 50).Samples were collected from 50 pituitary tumors including 26 non-functional tumors, 21 GH-secreting tumors, 2 PRL-secreting tumors and 1 ACTH-secreting tumor. 12 normal pituitary glands received after autopsy served as a control of the study. 29 thyroid cancers tissues were used as a positive control. The RT-qPCR with TaqMan hydrolysis probes were used to determine the expression of analyzed splice variants of survivin.The obtained data showed that both survivin and its splice variants were expressed in different types of pituitary adenoma as well as in normal pituitary tissue. However, the level of its expression was similar in all studied cases. Patient age negatively correlated with tumor invasiveness. Moreover, our study showed a tendency for negative correlation between patient age and tumor diameter.No significant differences between survivin and its splice variants ∆Ex3 and 2β expression in pituitary tumors and in normal pituitary glands as well as in invasive and in non-invasive tumors were found, suggesting that survivin does not play a significant role in pituitary tumorigenesis.
- 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. [JOURNAL ARTICLE]
- Pituitary 2014 Aug 8.
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.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.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.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.
- A cautionary note on generic depot octreotide. [JOURNAL ARTICLE]
- Pituitary 2014 Jul 27.
- Extracapsular en bloc resection in pituitary adenoma surgery. [JOURNAL ARTICLE]
- Pituitary 2014 Jul 27.
A pituitary pseudocapsule often contains tumor tissue and should be removed for radical resection. It can be used as a surgical plane for more radical resection of the tumor in many cases of pituitary adenomas. We evaluated the advantages and disadvantages of extracapsular en bloc capsulectomy.From 1992 until 2011, 1,089 treated patients were grouped according to the resection technique: en bloc capsulectomy, fragmented capsulectomy, or piecemeal resection. Their surgical and endocrinological outcomes and complications were evaluated.Extracapsular tumor resection was performed in 263 patients; en bloc capsulectomy in 94 patients and fragmented capsulectomy in 169, whereas piecemeal resection was performed in 826. Extracapsular resection was performed more frequently in prolactin- and thyroid-stimulating hormone-secreting tumors. Total resection was more frequently achieved in extracapsular resection and its chance was 100 % when tumors were removed in an en bloc fashion. For the functioning pituitary adenomas, endocrinological remission was achieved in all patients whose tumors were removed in an en bloc fashion and there was no recurrence. Postoperative cerebrospinal fluid (CSF) rhinorrhea developed in 4.2 and 2.7 % in the extracapsular resection group and the piecemeal resection groups, respectively. The chance of postoperative aggravation of pituitary function was not statistically different between groups.Extracapsular resection is critical for radical tumor resection and endocrinological remission. The removal of a pseudocapsule does not increase the risk of postoperative hypopituitarism nor postoperative CSF rhinorrhea.
- Giant prolactinomas: clinical manifestations and outcomes of 16 Arab cases. [JOURNAL ARTICLE]
- Pituitary 2014 Jul 26.
The management of giant prolactinomas remains a major challenge, despite dopamine agonists being the first line of treatment, owing to its efficacy to normalize prolactin levels and reduce tumor volume. The aim of this study is to characterize the therapeutic aspects, manifestations and outcomes of 16 cases of giant prolactinomas admitted at a single tertiary center in Riyadh, Saudi Arabia.Retrospective data collection involving 16 Saudi patients diagnosed with giant prolactinoma at the Pituitary Clinic in King Fahad Medical City, Riyadh, Saudi Arabia between January 2006 and July 2012.A total of 16 patients (ten males; six females) with age of diagnosis between 21 and 55 years (mean 34.9 years) were included in the analysis. The most common presenting features include headache, visual defects and sexual dysfunction. Baseline mean serum prolactin level were extremely high for both sexes which eventually decreased by as much as 97 % after cabergoline treatment. Serum prolactin concentrations completely normalized in six patients and significantly decreased in five patients 3-5 times that of normal range. Tumor volume also decreased by an average of 86 % for males and 87 % for females. Two patients had no tumor size change with cabergoline and required surgery.Findings indicate that cabergoline provides dramatic clinical improvements with excellent safety profile. Cabergoline should therefore be considered as the primary therapy for giant prolactinomas.
- The role of colonoscopic screening in acromegaly revisited: review of current literature and practice guidelines. [JOURNAL ARTICLE]
- Pituitary 2014 Jul 23.
Acromegaly is a chronic, debilitating and disfiguring condition with a significantly increased morbidity and mortality due to cardiovascular, as well as respiratory complications. Patients with acromegaly are usually diagnosed at the age of 40, however, the duration of symptoms can vary from 5 to 10 years before the formal diagnosis is confirmed. Recent advances in the field of acromegaly have improved survival significantly. A strong association between acromegaly and premalignant colonic lesions and colon cancer has been highlighted. Furthermore, patients with acromegaly have a greater lifetime risk of malignant transformation and a far worse overall prognosis from colorectal cancer, which is now considered a major disease related complication.A comprehensive search strategy was applied for the Medline/PubMed electronic database from its inception until April 2014. We considered all human research articles published in English, not classified as case report, editorial, comment, letter, or news.Specific recommendations for large bowel endoscopic screening in patients with acromegaly have been proposed. In this comprehensive review we discuss the current state of knowledge and evidence on colonoscopic screening in patients with acromegaly illustrated by a case of aggressive colorectal cancer presenting late in a young woman with difficult to control acromegaly.
- Gamma knife radiosurgery for Cushing's disease and Nelson's syndrome. [JOURNAL ARTICLE]
- Pituitary 2014 Jul 10.
This paper presents our 18 years of experience in treating ACTH secreting adenomas (Cushing's disease and Nelson's syndrome) using the Leksell gamma knife (LGK) irradiation.Twenty-six patients with Cushing's disease were followed-up after LGK irradiation for 48-216 months (median 78 months). Seventeen patients had undergone previous surgery, in nine patients LGK irradiation was the primary therapy. Furthermore, 14 patients with Nelson's syndrome were followed-up for 30-204 months (median 144 months).LGK treatment resulted in hormonal normalization in 80.7 % of patients with Cushing's disease. Time to normalization was 6-54 months (median 30 months). The volume of the adenoma decreased in 92.3 % (in 30.7 % disappeared completely). There was no recurrence of the disease. In all 14 patients with Nelson's syndrome ACTH levels decreased (in two patients fully normalized) their ACTH levels. When checked up 5-10 years after irradiation regrowth of the adenoma was only detected in one patient (9.1 %), in 27.3 % adenoma volume remained unchanged, in 45.4 % adenoma volume decreased and in 18.2 % adenoma completely disappeared. Hypopituitarism did not develop in any patient where the critical dose to the pituitary and distal infundibulum was respected.LGK radiation represents an effective and well-tolerated option for the treatment of patients with Cushing's disease after unsuccessful surgery and may be valuable even as a primary treatment in patients who are not suitable for, or refuse, surgery. In the case of Nelson's syndrome it is possible to impede tumorous growth and control the size of the adenoma in almost all patients.