Why don't corticotroph tumors always produce Cushing's disease?

OBJECTIVE: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. DESIGN: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. METHODS: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. RESULTS: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. CONCLUSIONS: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications.

CONTEXT: Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood. OBJECTIVE: The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD. DESIGN: A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed. RESULTS: Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas. CONCLUSIONS: The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

Self-limited acute hepatotoxicity caused by pegvisomant.

We present a case of acute severe hepatitis in a patient with acromegaly receiving combination therapy with somatostatin analogs and pegvisomant. Hepatitis resolved completely 18 weeks after diagnosis of hypertransaminasemia without discontinuation of therapy and with a close clinical and biochemical follow-up. In this case, despite the severity of the hepatitis, therapy could be continued as hypertransaminasemia was gradually decreasing after the maximum peak. We also review the literature on toxic hepatitis associated to pegvisomant therapy analyzing the etiology, clinical predisposing factors and natural evolution.

[Surgical treatment of primary hyperparathyroidism in pregnancy]. / Tratamiento quirúrgico del hiperparatiroidismo primario en el embarazo.

Primary hyperparathyroidism during pregnancy is a pathological entity with an unknown incidence that presents certain physiological, therapeutic and prognostic characteristics leading to greater difficulty in diagnosis and a high risk of complications. We present the case of a 16-week pregnant woman who presented with asymptomatic hypercalcemia secondary to a solitary parathyroid adenoma. Since conservative measures produced no improvement, surgery was performed in the second trimester of pregnancy, with satisfactory pre- and postnatal results. Surgery in the second trimester constitutes a safe alternative to conservative treatment.

Primary hyperparathyroidism in pregnancy.

Gestational primary hyperparathyroidism presents with features which, from a physiological and prognostic viewpoint, entail great difficulty in diagnosis and a high risk of complications. These complications occur at rates of 67% and 80% in the mother and fetus, respectively, and can be reduced by up to four times by means of prompt application of effective therapeutic measures. We report a case involving a pregnant woman in the 16th week of gestation who presented with asymptomatic hypercalcemia secondary to a solitary parathyroid adenoma. When the patient did not improve after conservative therapeutic measures, it was decided to employ surgical treatment in the second trimester of pregnancy. The surgery was successful, and the follow-up period was without complications for the mother and neonate. We therefore agree with the growing evidence that surgery in the second trimester of pregnancy constitutes a safe and effective alternative to conservative treatment.

[Patients in treatment for malnutrition in primary care, study of 500 real patients]. / Pacientes en tratamiento por desnutrición en atención primaria, estudio sobre 500 pacientes reales.

OBJECTIVE: The worsening of the nutritional status of certain segments of the population has led to frequent situations of chronic undernourishment even in the healthy population. There are very few data available on the prevalence and causes of malnutrition in Primary Health Care. The present study attempts to provide measurable information, obtained at random from the doctors involved in the country's Primary Health Care, on the characteristics of the undernourished patients, the cause of the undernourishment, the diagnostic means used, the treatment applied and the progress of the patients regularly treated in Primary Health Care facilities. MATERIALS AND METHOD: A sample of 1,819 doctors in Primary Health Care were surveyed to know their opinions on the nutritional status of their patients. They were asked to complete a "Patient Record" for the first patient to enter their office suffering from undernourishment. A total of 505 Patient Records were received from the different Primary Health Care doctors taking part in the study throughout Spain. RESULTS: Of the patients included, 10% were aged less than 10, while 46.7% were between 16 and 65 years of age and 44.2% were over 65. The main diagnosis in these patients was varied, with cancer patients (22.6%) and anorexics, including anorexia nerviosa and other non-oncological causes, (16.4%) the most common. As for the tests used for diagnosing undernourishment, those most frequently applied were physical examination (61%) and biochemical tests (56.4%). The risk factor most commonly found in these patients was old age/senility (21%). Nutritional support (55.8%) and dietary recommendations (45.3%) were the therapies most often applied. Only 47% of patients correctly implemented their treatment according to the doctors in Primary Health Care and the prognosis was as follows: 31% were expected to improve, 20% to worsen and 44% of cases would remain stable. CONCLUSIONS: From this study, it is concluded that most undernourished patients in Primary Health Care are there due to a severe pathology or because of age; that anthropometric and biochemical methods are used for diagnosis purposes although the clinical interview is of basic importance; that a large proportion of patients require some type of nutritional supplements; and finally that, according to the doctors, the expectations of improvement in the nutritional status of these patients are not good.

[Patients at risk for malnutrition in primary care. Social and health study]. / Pacientes en riesgo de desnutrición en asistencia primaria. Estudio sociosanitario.

GOALS: The worsening nutritional condition of certain population segments is an ever more frequent situation. Malnutrition also has considerable consequences, both in healthy individuals and in patients, leading to an increase in morbidity/mortality among the general population. The purpose of the present study is to learn the opinion of doctors in primary health care about the frequency of patients at risk of malnutrition attending their clinics; the most common forms of diagnostic technique used, the groups of population and situations that show the greatest risk of malnutrition as well as the therapeutic actions undertaken. MATERIALS AND METHODS: The present study effected 1819 opinion polls of primary health care doctors, distributed in proportion to the provincial distribution of doctors throughout Spain. With a margin of error of +/- 2.3% and a confidence interval of 95.5% (K-2). RESULTS: Of the patients seen in primary health care centres, 11% are at risk of malnutrition and approximately 61% of the total are detected at the medical clinic. The situations with the greatest risk are advanced age (71%), marginalized population (drug abusers, alcoholics) (56%), anorexia (50%), patients with mental disorders (42%), oncological pathologies (41%) and prolonged confinement in bed (39%). The therapeutic attitudes considered most appropriate by primary health care practitioners are a greater attention to diets and the use of nutritional supports in cases of established malnutrition. CONCLUSIONS: The present study reflects a high incidence of malnutrition risk among patients attending primary health care clinics (11%); and highlights the importance, from the point of view of preventive medicine, of improving nutritional education among professionals, as well as the availability of simple therapeutic actions and support measures that might help to avoid larger-scale problems with a large social and financial cost.

Pheochromocytoma in a pregnant woman with multiple endocrine neoplasia type 2a.

Pheochromocytoma is a rare cause of hypertension. Its coexistence with pregnancy is exceptional and laparoscopic removal has rarely been reported. We describe the case of a 34-year-old woman with multiple endocrine neoplasia type 2a (MEN 2a) with adrenal pheochromocytoma diagnosed in the 6th week of pregnancy. After pretreatment with phenoxybenzamine, a successful transperitoneal laparoscopic adrenalectomy was performed in the twentieth week of gestation. The management of pheochromocytoma in pregnancy and the indications for laparoscopic surgery in pregnant patients are discussed.