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- McCune-Albright Syndrome: A Detailed Pathological And Genetic Analysis of Disease Effects in an Adult Patient. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Jul 25.:jc20141291.
Context: McCune Albright syndrome (MAS) is a clinical association of endocrine and non-endocrine anomalies caused by post-zygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular and adrenal disease. Other rarer disease related features are emerging. Objective: To study pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and non classically affected tissues. Design: A comprehensive autopsy and genetic analysis Setting: Tertiary referral University Hospital Patients: Adult male patient with MAS and severe disease burden including gigantism Intervention(s): Clinical, hormonal and radiographic studies; gross and microscopic pathology analyses, conventional PCR and droplet digital PCR analyses of affected and non affected tissues Main Outcome Measure: Pathological findings, presence of GNAS1 mutations Results: The patient was diagnosed with MAS syndrome at six years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism and hyperparathyroidism were diagnosed throughout adult period. The patient died at the age of 39 from pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS mutation distributed across many endocrine and non-endocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism, and hyperplasia of the thymus and endocrine pancreas. Conclusions: This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1 related pathology across a wide range of affected organs.
- Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy. [JOURNAL ARTICLE]
- Andrologia 2014 Jul 25.
Male-to-female transsexual persons use oestrogens + antiandrogens to adapt their physical bodies to the female sex. Doses are usually somewhat higher than those used by hypogonadal women receiving oestrogen replacement. Particularly in cases of self-adminstration of cross-sex hormones, doses may be very high. Oestrogens are powerful stimulators of synthesis and release of prolactin and serum prolactin levels are usually somewhat increased following oestrogen treatment. Prolactinomas have been reported in male-to-female transsexual persons, both after use of high and conventional doses of oestrogens but remain rare events. We report two new cases of prolactinomas in male-to-female transsexual persons, one in a 41-year-old subject who had used nonsupervised high-dose oestrogen treatment since the age of 23 years and another one in a 42 year old who had initiated oestrogen treatment at the age of 17 years. Their serum prolactin levels were strongly increased, and the diagnosis of a pituitary tumour was confirmed by imaging techniques. Both cases responded well to treatment with cabergoline treatment whereupon serum prolactin normalised. Our two cases are added to the three cases of prolactinomas in the literature in persons who had used supraphysiological doses of oestrogens.
- Burkitt's lymphoma presenting with hypopituitarism: a case report and review of literature. [Journal Article]
- Endocrinol Diabetes Metab Case Rep 2014.:140029.
Hypopituitarism is a rare presentation of Burkitt's lymphoma (BL). The purpose of this report is to present a case of BL presenting with panhypopituitarism and to review other case reports of lymphoma presenting with pituitary dysfunction to highlight the distinguishing features of these cases from other benign aetiologies of pituitary dysfunction such as non-functioning pituitary adenomas. We reviewed a total of 11 cases of lymphoma presenting with pituitary dysfunction published from 1998 to 2013 including the present case. The demographics, clinical presentations, laboratory features, radiological findings, histological diagnosis, treatment administered and outcomes were described. Of the total number of patients, 45.5% of the cases had diffuse large B-cell lymphoma while 27.3% had BL. Anterior pituitary dysfunction was more common than posterior pituitary dysfunction at presentation. The other common associated presenting symptoms were painful ophthalmoplegia, cranial nerve palsies and constitutional symptoms. Hypothalamic-pituitary abnormalities were often demonstrated radiologically to be associated with cavernous sinus and/or stalk involvement. All patients who completed immunochemotherapy responded haematologically. Pituitary dysfunction also improved in most cases although the recovery tended to be partial. In conclusion, a high index of suspicion of underlying malignancy, such as lymphoma, should be present in patients presenting with acute pituitary dysfunction associated with painful ophthalmoplegia, rapidly evolving neurological features, radiological features atypical of a pituitary adenoma and constitutional symptoms. An early diagnosis is essential as prompt initiation of definitive therapy will induce disease remission and recovery of pituitary dysfunction.Hypopituitarism may be the presenting symptom of lymphoma in the absence of associated overt symptoms or signs of a haematological malignancy resulting in delay in diagnosis and institution of treatment.Pituitary dysfunction due to tumour infiltration has a greater tendency to involve the posterior pituitary and infundibulum resulting in diabetes insipidus and hyperprolactinaemia compared with a non-functioning pituitary adenoma.The common associated symptoms of hypopituitarism due to lymphoma infiltration of the hypothalamic-pituitary system include painful ophthalmoplegia, cranial nerve palsies and constitutional symptoms.Radiological abnormalities of the hypothalamic-pituitary region are usually present and often associated with cavernous sinus or stalk involvement.With early institution of definitive treatment, both haematological response and improvement of pituitary dysfunction are expected although the reversal of hypopituitarism tends to be partial and delayed.A high index of suspicion of underlying malignancy such as lymphoma should be present in patients presenting with acute pituitary dysfunction associated with painful ophthalmoplegia, radiological features atypical of pituitary adenomas and constitutional symptoms to enable early diagnosis and prompt initiation of definitive therapy.
- A meta-analysis of prevalence estimates and moderators of low bone mass in people with schizophrenia. [JOURNAL ARTICLE]
- Acta Psychiatr Scand 2014 Jul 10.
To assess the prevalence and moderators of low bone mass, osteopenia and osteoporosis in schizophrenia patients.Major electronic databases were searched from inception till December 2013 for studies reporting the prevalence of low bone mass (osteopenia + osteoporosis = primary outcome), osteopenia or osteoporosis in schizophrenia patients. Two independent authors completed methodological appraisal and extracted data. A random effects meta-analysis was utilized.Nineteen studies were included (n = 3038 with schizophrenia; 59.2% male; age 24.5-58.9 years). The overall prevalence of low bone mass was 51.7% (95% CI = 43.1-60.3%); 40.0% (CI = 34.7-45.4%) had osteopenia and 13.2% (CI = 7.8-21.6%) had osteoporosis. Compared with controls, schizophrenia patients had significantly increased risk of low bone mass (OR = 1.9, CI = 1.30-2.77, P < 0.001, n = 1872) and osteoporosis (OR = 2.86, CI = 1.27-6.42, P = 0.01, n = 1824), but not osteopenia (OR = 1.33, CI = 0.934-1.90, P = 0.1, n = 1862). In an exploratory regression analysis, older age (P = 0.004) moderated low bone mass, while older age (P < 0.0001) and male sex (P < 0.0001) moderated osteoporosis. The subgroup analyses demonstrated high heterogeneity, but low bone mass was less prevalent in North America (35.5%, CI = 26.6-45.2%) than Europe (53.6%, CI = 38.0-68.5%) and Asia (58.4%, CI = 48.4-67.7%), and in mixed in-/out-patients (32.9%, CI = 49.6-70.1%) vs. in-patients (60.3%, CI = 49.6-70.1%).Reduced bone mass (especially osteoporosis) is significantly more common in people with schizophrenia than controls.
- Hyperprolactinaemia and psychotropics: endocrine effects and treatment. [Journal Article]
- Br J Hosp Med (Lond) 2014 May; 75(5):264-7.
Hyperprolactinaemia is a common endocrine abnormality. Causes are multifactorial. Medication use contributes a considerable amount, with psychotropics often implicated, although underlying hypothalamic-pituitary pathology can co-exist. This article discusses the management of hyperprolactinaemia during psychotropic use.
- Bone turnover markers in medicamentous and physiological hyperprolactinemia in female rats. [Journal Article]
- Vojnosanit Pregl 2014 Jun; 71(6):559-64.
There is a lack of data on the effects of prolactin on calcium metabolism and bone turnover in hyperprolactinemia of various origins. The aim of this study was to compare the influence of medicamentous and physiological hyperprolactinemia on bone turnover in female rats.Experimental animals (18 weeks old, Wistar female rats) were divided as follows: the group P - 9 rats, 3 weeks pregnant; the group M3-10 rats that were intramuscularly administrated sulpirid (10 mg/kg) twice daily for 3 weeks, the group M6 - 10 rats that were intramuscularly administrated with sulpirid (10 mg/kg) twice daily for 6 weeks, and age matched nulliparous rats as the control group: 10 rats, 18-week-old (C1) and 7 rats, 24 weeks old (C2). Laboratory investigations included serum ionized calcium and phosphorus, urinary calcium and phosphorous excretion, osteocalcin and serum procollagen type 1 N-terminal propeptide (P1NP).Experimental animals in the group P compared to the control group, displayed lower mean serum ionized calcium (0.5 +/- 0.2 vs 1.12 +/- 0.04 mmol/L; p < 0.001); higher mean serum phosphorus (2.42 +/- 0.46 vs 2.05 +/- 0.2 mmol/L; p < 0.05); increased urinary calcium (3.90 +/- 0.46 vs 3.05 +/- 0.58; p < 0.01) and significantly increased P1NP (489.22 +/- 46.77 vs 361.9 +/- 53.01 pg/mL; p < 0.001). Experimental animals in the group M3 had significantly decreased P1NP, compared to the contol group. Prolongated medicamentous hyperprolactinemia (the group M6) induced increased serum ionized calcium (1.21 +/- 0.03 vs 1.15 +/- 0.02 mmol/L; p < 0.001); decreased serum phosphorus (1.70 +/- 0.13 vs 1.89 +/- 0.32 mmol/L; p < 0.001); decreased osteocalcin and P1NP.Physiological hyperprolactinemia does not have such harmful effect on bone metabolism as medicamentous hyperprolactinemia. Chronic medicamentous hyperprolactinemia produces lower serum levels of bone formation markers. Assessment of bone turnover markers in prolongated medicamentous hyperprolactinemia provides an opportunity for earlier diagnosis of bone metabolism disturbances and should be considered as mandatory.
- The influence of hyperprolactinemia on coagulation parameters in females with prolactinomas. [Journal Article, Research Support, Non-U.S. Gov't]
- Srp Arh Celok Lek 2014 May-Jun; 142(5-6):314-9.
Currently there is little information on the effects of prolactin (PRL) on the coagulation and fibrinolytic systems.The aim of this study was to evaluate the effects of hypeprolactinemia on the parameters of the hemostatic system and activation of the coagulation system.We studied PRL levels, body mass index (BMI), values of activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), D-dimer level, von Willebrand factor antigen (vWFAg) and fibrinogen in 15 young female patients with microprolactinomas before and after therapy and in 15 healthy female controls.As expected, pretreatment PRL levels were significantly higher in patients than in controls (140.90 +/- 42.87 vs. 12.53 +/- 4.05 ng/ml; p < 0.001). PT, although still in the normal range, was prolonged in patients with hyperprolactinemia as compared to the control group (13.53 +/- 1.39 vs. 12.65 +/- 0.53 s; p = 0.03) and normalized after therapy (12.69 +/- 0.65 vs. 12.65 +/- 0.53 s; p = 0.88). TT, although in normal range, was significantly shorter in the hypeprolactinemic patients than in the controls (14.34 +/- 4.52 vs. 17.21 +/- 1.35 s; p < 0.025) and after treatment remained significantly shorter than in the controls (15.17 +/- 1.55 vs. 17.21 +/- 1.35 s; p < 0.0001). D-dimer values before treatment in the patients with hyperproplactinemia were above the normal range (239.47 +/- 107.93 vs. 131.27 +/- 50.64 ng/ml, p = 0.002) and decreased to normal values after therapy (239.47 +/- 107.93 vs. 146.60 +/- 39.15 ng/ml; p < 0.001). D-dimer levels correlated with PRL (r = 0.30) and the change in serum D-dimer values significantly correlated with the change in PRL levels during therapy (r = 0.62). aPTT, vWFAg and fibrinogen were similar in patients and controls.In our study, increased thrombin generation that resulted in elevated D-dimer levels may be one of the contributing factors to the prethrombotic state in patients with hyperprolactinemia.
- Synthes Skull Base Surgery Award 113 Long-term Follow-up of Male Patients with Prolactinomas: Is Bone Densitometry Necessary? [JOURNAL ARTICLE]
- Neurosurgery 2014 Aug.:196.
Male patients with prolactinoma commonly present with macroadenoma and a history of long-standing hypogonadism. Data regarding the effect of hypogonadism on bone health in these patients are scarce. The present study compared the long-term results of male patients with prolactinomas treated primarily either surgically or medically.This retrospective study evaluated the records of 44 male patients with proven prolactinoma. Clinical and biochemical characteristics, as well as tumor size, were assessed at baseline and first and last follow-up.The mean age at diagnosis was 47 ± 15 years. Mean body mass index (BMI) at diagnosis was 28.7 ± 4.5 kg/m. Median prolactin levels were 1979 μg/L (interquartile range [IQR] 768.4 5368), and MRI scan showed macro- or microadenoma in 82% and 18%, respectively. Pathological bone density was revealed in 25% of patients. Therapeutic strategy included primary operation in 34% and dopamine agonists in 66% of these patients. The average long-term follow-up was 81.4 ± 62.6 months. Mean body mass index tended to decrease, from 28.7 ± 4.5 to 28.0 ± 4.4 kg/m (P = .36). Median prolactin concentration decreased significantly to 13.8 μg/L (6.2 29.4) (IQR; P < .0001), and was within normal range in 73% of patients. Hyperprolactinaemia was controlled in 66% in the medically treated group vs 93% in the surgically treated group (P = .07). Control of hyperprolactinaemia required dopamine agonist therapy in 47% of patients with primary surgical therapy, compared to 90% of patients with primary medical therapy (P = .003). Fifty-five percent of all patients required testosterone therapy. Biphosphonate and/or vitamin D and calcium were prescribed in 29% of all patients, with no significant difference according to the therapeutic strategy (ie, primary surgery vs primary medical therapy; P = .16).Based on our results, bone densitometry in male patients with prolactinoma can be recommended. The present data support the discussion about the need for pituitary surgery as primary treatment in selected male patients aside from the classical indication (ie, intolerance of dopamine agonists and non-responder).
- Within-drug benefit-risk evaluation of olanzapine long-acting injection at one and two years of treatment. [JOURNAL ARTICLE]
- Int J Methods Psychiatr Res 2014 Jul 3.
We sought to evaluate the within-drug benefit-risk of olanzapine long-acting injection (LAI) using both quantitative and qualitative methods. Subjects included 1192 adult patients with schizophrenia or schizoaffective disorder who participated in clinical trials with the opportunity for at least two years of continuous treatment with olanzapine LAI (45-405 mg every two to four weeks). Using the Benefit Risk Action Team (BRAT) framework, we evaluated frequency versus duration of benefits and risks commonly observed with atypical antipsychotics. We then used the Transparent Uniform Risk/Benefit Overview (TURBO) method, which weighs the drug's two most medically serious and/or frequent adverse events versus its primary benefit (effectiveness) and an ancillary benefit. The most frequent events among all patients were remaining free of relapse (91.4% for an average of 306 days at one year, 88.4% for 546 days at two years) and symptomatic remission (81.7% for an average of 239 days at one year, 84.1% for 438 days at two years). One- and two-year incidence of ≥7% weight gain was 33.3% and 41.7%. Incidences for sexual dysfunction, hyperprolactinemia, and post-injection delirium/sedation syndrome (PDSS) were <2%. TURBO ratings unanimously selected PDSS and weight gain as key risks and resulted in an average score in the acceptable benefit-risk balance range. Copyright © 2014 John Wiley & Sons, Ltd.
- Efficacy and safety of aripiprazole in Chinese Han schizophrenia subjects: A randomized, double-blind, active parallel-controlled, multicenter clinical trial. [JOURNAL ARTICLE]
- Schizophr Res 2014 Jun 30.
Antipsychotics, such as aripiprazole and risperidone, are often used to treat individuals with schizophrenia. The efficacy as well as safety of aripiprazole in Western populations has been described. The objective of this study is to investigate the efficacy, safety, and tolerability of aripiprazole and risperidone in Chinese Han schizophrenia subjects in mainland China.The 6-week, double-blind, randomized, parallel study was conducted in 5 medical centers in mainland China from November 2007 to March 2011. A total of 279 subjects with a primary DSM-IV diagnosis of schizophrenia were randomly assigned (with a randomization ratio of 1:1) to aripiprazole (n=139) or risperidone (n=140). Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative and general psychopathology subscale scores, and Clinical Global Impressions-Severity of Illness (CGI-S), and Improvement scale scores. Extrapyramidal symptoms (EPS), weight gain, serum prolactin level, QTc interval, and self-reported adverse events were also assessed as measures of safety and tolerability.Both the aripiprazole and risperidone groups showed statistically significant improvement of PANSS total, positive, negative, general psychopathology subscale scores, and CGI-S scores from baseline to the endpoint (all p<0.01). Significant improvement was noted in the first week for both treatment groups. There were no significant differences in efficacy measurements between the two treatment groups. Mean change of PANSS total scores from baseline to the endpoint was -26.8±18.1 for aripiprazole and -30.0±17.7 for risperidone, (p=0.1475). The responder rate was 71% (n=99) and 76% (n=107) for aripiprazole and risperidone, respectively, (p=0.323). The incidences of EPS were similar in the aripiprazole (25%, n=35) and risperidone groups (24%, n=34), respectively (p=0.757). No clinically meaningful effects on QTc interval, QRS duration, or PR interval were observed in either treatment groups. However, the incidence of clinically significant weight gain (p=0.0118) and hyperprolactinemia (p<0.001) in the aripiprazole group was significantly lower than in the risperidone group.The study demonstrated that aripiprazole, as well as risperidone, had rapid and persistent efficacy for psychotic symptoms from the first week of therapy. There may be poor efficacy for aripiprazole compared with risperidone for overall improvement, but there were no significant differences in this study. Aripiprazole showed good tolerability with less weight gain and hyperprolactinemia compared with risperidone. The overall efficacy and safety of aripiprazole in Chinese Han schizophrenia subjects were similar to that reported in Western populations.