Secondary vs. primary pituitary xanthogranulomas: which yellow is more mellow?

Pituitary xanthogranulomatomas (XG) are a rare pathological entity caused by accumulation of lipid laden macrophages and reactive granuloma formation usually triggered by cystic fluid leakage or hemorrhage. Our aim was to compare clinical characteristics and presenting features of patients with secondary etiology of XG and those with no identifiable founding lesion (primary -"pure" XG) in order to gain new insights into this rare pituitary pathology. In a retrospective review of 714 patients operated for sellar masses, at tertiary center, we identified 16 (2.24%) with histologically confirmed diagnosis of pituitary XG over the period of 7 years (2015-2021). Patients were further analyzed according to XG etiology: "pure"- XG (n = 8) with no identifiable founding lesion were compared to those with histological elements of pituitary tumor or cyst - secondary XG (n = 8). We identified 16 patients (11 male), mean age 44.8 ± 22.3 years, diagnosed with pituitary XG. Secondary forms were associated with Ratke's cleft cyst (RCC, n = 2) and pituitary adenoma (PA, n = 6). The most common presenting features in both groups were hypopituitarism (75%), headache (68.5%) and visual disturbances (37.5%). Predominance of male sex was noted (males 68.75%, females 31.25%), especially in patients with primary forms. Patients with primary pituitary XG were all males (p = 0.0256) and more frequently affected by panhypopituitarism (87.5% vs. 25%, p = 0.0406) compared to patients with secondary causes. Hyperprolactinemia was noted in pituitary tumor group with secondary etiology only (p = 0.0769). Majority of lesions were solid on magnetic resonance imaging - MRI (81.25%). Distinct clinical phenotype was observed dependent on the etiology of XG.

The sellar region as presenting theater for hematologic malignancies-A 17-year single-center experience.

Hematological neoplastic mass lesions of the sellar region are rare. We identified five cases of hematological malignancy with first presentation in the sellar region from our departmental database of 1,405 patients (0.36%) with sellar lesions diagnosed over the 17-year period (2005-2021). All patients were females (mean age 55.2 ± 3.4 years). One patient had multiple myeloma (MM), one patient had acute myeloid leukemia (AML), while three other patients had lymphoma (intravascular lymphoma (IVL, n = 1) or non-Hodgkin's lymphoma (NHL, n = 2). Most patients presented with ophthalmoplegia, and one patient with diabetes insipidus (DI), with short duration of symptoms (median 30 days). All patients had an elevated erythrocyte sedimentation rate and altered blood count, while patients with lymphoma had elevated lactate dehydrogenase (LDH). Sellar mass was demonstrated in three patients while the patient with IVL had an empty sella and in the AML patient posterior lobe T1W hyperintensity was lost. Two patients (IVL and NHL) presented with multiple anterior pituitary deficiencies and one patient (AML) had DI. All patients were treated with chemotherapy. Two patients responded well to treatment (one had reversed hypopituitarism), while three patients died. Differential diagnosis of sellar-parasellar pathology should include suspicion of hematological malignancy, particularly in patients with short duration of nonspecific symptoms, neurological signs (ophthalmoplegia), blood count alterations and LDH elevation, pituitary dysfunction and imaging features atypical for pituitary adenoma. Early diagnosis is crucial for timely initiation of hematological treatment aimed at inducing disease remission and partial or full recovery of pituitary function.

Hypopituitarism in five PROP1 mutation siblings: long-lasting natural course and the effects of growth hormone replacement introduction in middle adulthood.

Twenty years after the first description of combined hypopituitarism (CPHD) caused by PROP1 mutations, the phenotype of affected subjects is still challenging for clinicians. These patients suffer from pituitary hormone deficits ranging from IGHD to panhypopituitarism. ACTH deficiency usually develops later in life. Pituitary size is variable. PROP1 mutation is the most frequent in familial congenital hypopituitarism (CH). Reports on initiation of hormonal replacement including growth hormone (GH) in adults with CH are scarce. We identified 5 adult siblings with CPHD due to PROP1 mutation (301-302delAG), aged 36-51 years (4 females), never treated for hormone deficiencies. They presented with short stature (SD from - 3.7 to - 4.7), infantile sexual characteristic, moderate abdominal obesity and low bone mineral density in 3 of them. Complete hypopituituitarism was confirmed in three siblings, while two remaining demonstrated GH, TSH, FSH and LH deficiencies. Required hormonal replacement including rhGH was initiated in all patients. After several months necessity for hydrocortisone replacement developed in all patients. After 2 years of continual replacement therapy, BMD and body composition (measured by DXA-dual X-ray absorptiometry) improved in all subjects, most prominently in two younger females and the male sibling. Besides rhGH therapy, these three patients have received sex hormones contributing to the favorable effect. The male sibling was diagnosed with brain glioblastoma two years following complete hormonal replacement. This report provides important experience regarding hormonal replacement, particularly rhGH treatment, in adults with long-term untreated CH. Beneficial effect of such therapy are widely acknowledged, yet these subjects could be susceptible to certain risks of hormonal treatment initiated in adulthood. Careful and continual clinical follow-up is thus strongly advised.

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens-An Insight From Translational Studies.

Estrogen signaling plays an important role in pituitary development and function. In sensitive rat or mice strains of both sexes, estrogen treatments promote lactotropic cell proliferation and induce the formation of pituitary adenomas (dominantly prolactin or growth-hormone-secreting ones). In male patients receiving estrogen, treatment does not necessarily result in pituitary hyperplasia, hyperprolactinemia or adenoma development. In this review, we comprehensively analyze the mechanisms of estrogen action upon their application in male animal models comparing it with available data in human subjects. Sex-specific molecular targets of estrogen action in lactotropic (PRL) cells are highlighted in the context of their proliferative and secretory activity. In addition, putative effects of estradiol on the cellular/tumor microenvironment and the contribution of postnatal pituitary progenitor/stem cells and transdifferentiation processes to prolactinoma development have been analyzed. Finally, estrogen-induced morphological and hormone-secreting changes in pituitary thyrotropic (TSH) and adrenocorticotropic (ACTH) cells are discussed, as well as the putative role of the thyroid and/or glucocorticoid hormones in prolactinoma development, based on the current scarce literature.

Single center study of 53 consecutive patients with pituitary stalk lesions.

BACKGROUND: The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk's (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis. AIM: To present the various causes of PSL-their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology. METHOD: A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32 ± 4.2 years (range 6-67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010-2018. RESULTS: Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown. CONCLUSION: Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.

Combined Administration of Ghrelin and Corticotropin-Releasing Hormone in the Diagnosis of Cushing's Disease.

BACKGROUND/AIMS: Exaggerated adrenocorticotropic hormone (ACTH) and cortisol responses to ghrelin in Cushing's disease (CD) have previously been reported, similarly to responses to corticotropin-releasing hormone (CRH). We assessed the ability of ghrelin to enhance ACTH and cortisol responses when added to CRH stimulation in CD patients. METHODS: In 21 CD patients (18 females, 3 males; age 49.8 ± 10.2 years; BMI 29.8 ± 0.8) and 8 healthy subjects (7 females, 1 male; age 40.6 ± 5.3 years; BMI 29.9 ± 1.2), we administered (1) ghrelin 100 µg i.v. bolus, (2) CRH 100 µg i.v. bolus, and (3) ghrelin + CRH combination. ACTH and cortisol were analyzed by commercially available kits from samples taken at 0, 15, 30, 45, 60, 90 and 120 min. ACTH and cortisol responses were calculated as peak and area under the curve (AUC0-120 min). RESULTS: ACTH and cortisol at baseline and stimulated with ghrelin and/or CRH (peak and AUC0-120 min) were significantly higher in CD patients compared to controls (p < 0.01). ACTH and cortisol responses to ghrelin or CRH were similar in CD patients. Combined ghrelin + CRH administration in CD patients produced the highest ACTH response (peak and AUC0-120 min) compared to ghrelin or CRH alone (p < 0.01). Cortisol responses after ghrelin + CRH were uncoupled with ACTH responses and similar to the response to ghrelin or CRH alone in both groups. ACTH and cortisol responses, during all three tests, were similar in CD patients with micro- or macroadenomas. CONCLUSION: Ghrelin administration causes exaggerated ACTH and cortisol responses in CD patients compared to healthy controls. In combination with CRH, it additionally enhances ACTH secretion without further additive effect on cortisol output.

Plurihormonal Pituitary Neuroendocrine Tumours - A Single Centre Experience.

Introduction. Plurihormonal pituitary neuroendocrine tumours (PitNET)/adenomas are pituitary neuroendocrine tumours composed of monomorphous cell populations expressing anterior pituitary transcription factors and/or hormones belonging to more than one cell lineage. Studies dedicated to plurihormonal tumours are rare and quite heterogenous with their results, bearing in mind changes in diagnostic criteria and inconsistent use of antibodies for anterior pituitary transcription factors in the diagnostic immunohistochemical panel. Material and Methods. We retrospectively analysed all patients surgically treated for PitNETs from 2016 to July 2022 in a tertiary healthcare institution. All tumours previously diagnosed PitNETs with the word "plurihormonal" were re-examined and potentially re-classified, according to 2022 WHO classification of endocrine tumours. Results. Among 721 patients surgically treated for PitNET in 5.5 years period, the diagnosis of plurihormonal PitNET was established in 11 tumours (1.3%). All tumours showed diffuse and intensive positivity for anterior pituitary transcription factors PIT1 and SF1. Clinically, all patients presented with acromegaly. Conclusions. Retrospective studies related to newly defined plurihormonal PitNETs with a reassessment of diagnoses are necessary due to their rarity and ambition to investigate their origin and biological behaviour. The fact that the majority of plurihormonal PitNETs are clinically presented with acromegaly and show simultaneous positivity to PIT1 and SF1 transcription factors deserve special attention and need for further research in larger cohorts of these exceptional tumours.

Plasma kisspeptin levels in pregnancies with diabetes and hypertensive disease as a potential marker of placental dysfunction and adverse perinatal outcome.

BACKGROUND: The aim of this study was to prospectively evaluate plasma kisspeptin levels in 129 singleton pregnancies with diabetes [pregestational insulin-dependent diabetes mellitus (type 1) and gestational diabetes (GD)] and hypertensive disease [chronic hypertension (CH), gestational hypertension, and preeclampsia (PE)] as a potential marker of placental dysfunction and adverse perinatal outcome. STUDY DESIGN: Kisspeptin levels were evaluated in the first, second, and third trimesters in patients with type 1 diabetes (16 patients), H (22), and healthy control (25) and in the second and third trimesters in patients with GD (20), gestational hypertension (18), and PE (28). Maternal kisspeptin levels were correlated with pregnancy outcome, parameters of fetoplacental circulation, ultrasound-detected abnormalities of placental morphology, and placental weight at delivery. RESULTS: In pregnancies with type 1 diabetes and H, mean kisspeptin levels were significantly lower compared with the control group (p<0.001 in the first and second trimesters and p<0.05 in the third trimester). Decreased plasma kisspeptin levels in the second and third trimesters were found in patients with GD (p<0.001 in the second and third trimesters) and PE (p<0.001 in the second trimester and p<0.05 in the third trimester). In patients with PE and placental dysfunction, low kisspeptin levels in the third trimester were associated with adverse perinatal outcome. CONCLUSIONS: Our study demonstrates reduced kisspeptin levels in pregnancies with diabetes, H, PE, and placental dysfunction. In patients with PE and placental dysfunction, decreased kisspeptin levels were associated with adverse perinatal outcome. Larger studies are needed to investigate the role of kisspeptin as a potential marker of placental dysfunction and adverse perinatal outcome.

Bone remodeling, bone mass and weight gain in patients with stabilized schizophrenia in real-life conditions treated with long-acting injectable risperidone.

BACKGROUND: Prolactin-raising antipsychotics, risperidone (antidopaminergic activity), may be associated with low bone mass. On the other hand, risperidone may cause an increase in body weight thought to be favorable for bone. OBJECTIVES: (1) To determine bone remodeling parameters and bone mass in patients with schizophrenia on long-term treatment with long-acting injectable risperidone (LAIR) in naturalistic settings, and (2) to evaluate the change in body weight, metabolic profile and neuroendocrine status in these patients. DESIGN: This was a prospective, cross-sectional study. PATIENTS: Patients included 26 outpatients with controlled schizophrenia in real-life conditions (age 31.3 ± 1.3 years, BMI 28.1 ± 1.0) on long-term maintenance therapy with LAIR for a mean of 18.0 ± 1.6 months (range 6-36) with a mean dose of 38 ± 2 mg. 35 subjects matched for sex, age, BMI and education served as healthy controls. METHODS: Serum osteocalcin, C-terminal telopeptide of type I collagen (CTx), vitamin D, leptin, prolactin, sex steroids, and parathyroid hormone were assessed. Indices of insulin sensitivity and resistance were determined following an oral glucose tolerance test (OGTT). Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN). RESULTS: Mild to moderate hyperprolactinemia (1,000-2,000 mU/l) was associated with asymptomatic hypogonadism. Prolactin values >2,000 mU/l occurred in a few female patients. Hypogonadism leads to a slight increase (upper limit of normal) in bone resorption marker (CTx) in patients with schizophrenia (p = 0.023). As for bone mass, although lower at the spine than in healthy subjects, it did not reach statistical significance (p = 0.094), while at the FN, BMD was not different from healthy subjects. Body weight increased on average 8.7 ± 1.6 kg in more than 50% of patients. Leptin levels adjusted for BMI in females were significantly higher in patients than in healthy female subjects (p = 0.018), while in males there was no difference between the groups (p = 0.833). A high prevalence of low vitamin D levels and more current smokers were found in patients with schizophrenia. As for the metabolic profile during treatment with risperidone, the low Matsuda index of insulin sensitivity (p = 0.039) confirmed insulin resistance in these patients. CONCLUSION: A potential long-term consequence of asymptomatic hypogonadism due to risperidone-induced hyperprolactinemia might cause a slight rise in bone resorption marker (CTx). On the other hand, by increasing body weight, risperidone could have a protective effect on the bone and thus no change in bone mass was recorded when compared with healthy controls.

Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours - an immunohistochemical study.

INTRODUCTION: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray. MATERIAL AND METHODS: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients. RESULTS: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group. CONCLUSIONS: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.

Mapping the journey of transition: a single-center study of 170 childhood-onset GH deficiency patients.

OBJECTIVE: To analyze metabolic parameters, body composition (BC), and bone mineral density (BMD) in childhood-onset GH deficiency (COGHD) patients during the transition period (TP). DESIGN: Single- center, retrospective study was performed on 170 consecutive COGHD patients (age 19.2 ± 2.0 years, range 16-25) transferred after growth completion from two pediatric clinics to the adult endocrine unit. Two separate analyses were performed: (i) cross-sectional analysis of hormonal status, metabolic parameters, BC, and BMD at first evaluation after transfer from pediatrics to the adult department; (ii) longitudinal analysis of BC and BMD dynamics after 3 years of GH replacement therapy (rhGH) in TP. RESULTS: COGHD was of a congenital cause (CONG) in 50.6% subjects, tumor-related (TUMC) in 23.5%, and idiopathic (IDOP) in 25.9%. TUMC patients had increased insulin and lipids levels (P < 0.01) and lower Z score at L-spine (P < 0.05) compared to CONG and IDOP groups. Patients treated with rhGH in childhood demonstrated lower fat mass and increased BMD compared to the rhGH-untreated group (P < 0.01). Three years of rhGH after growth completion resulted in a significant increase in lean body mass (12.1%) and BMD at L-spine (6.9%), parallel with a decrease in FM (5.2%). CONCLUSION: The effect of rhGH in childhood is invaluable for metabolic status, BC, and BMD in transition to adulthood. Tumor-related COGHD subjects are at higher risk for metabolic abnormalities, alteration of body composition, and decreased BMD, compared to those with COGHD of other causes. Continuation of rhGH in transition is important for improving BC and BMD in patients with persistent COGHD.

Neuroendocrine dysfunction in patients recovering from subarachnoid hemorrhage.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a recently identified risk factor for hypopituitarism, particularly growth hormone (GH) and corticotrophins deficiencies. The aim of our study was to identify possible predictor(s) for neuroendocrine dysfunction in SAH survivors. DESIGN: Pituitary function was evaluated in 93 patients (30 males, 63 females), aged 48.0+/-1.1 years (mean+/-SE), and with a Glasgow Outcome Scale score of 4.6+/-0.6 (mean+/-SE) more than one year following SAH. In the acute phase, SAH was complicated by vasospasm (VS) in 18 and by hydrocephalus (HDC) in 9 patients. Baseline serum values of insulin growth factor 1 (IGF-I), cortisol, thyroxine (T4), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in males), estradiol (in females) and prolactin were determined. RESULTS: According to the results of baseline hormonal evaluation, 47 patients (50.5%) had no hormonal abnormalities. Seven patients (7.5%) had multiple pituitary hormone deficiencies: Four patients (4.3%) had two (GH and cortisol), one patient had three (gonadal, adrenal and GH) and two patients had deficiency of all pituitary axes. Thirty-nine patients (42%) had one abnormal axis (13 adrenal, 2 thyroid, 4 gonadal and 20 GH). None of the subjects was treated with desmopressin or exhibited symptomatic polyuria. The VS and HDC during the acute phase of SAH were related to abnormal pituitary status (VS with low IGF-I levels and HDC with low cortisol levels). CONCLUSION: Through a screening procedure, neuroendocrine dysfunction was identified in a substantial number of asymptomatic patients with previous SAH. Cerebral VS and HDC at the time of SAH emerged as risk factors possibly predicting development of pituitary dysfunction. Low basal levels of IGF 1 and cortisol may help in selecting patients requiring further evaluation of pituitary function.

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Familial Cancer Clustering in Patients with Prolactinoma.

People are at higher risk for malignancy as they get older or have a strong family history of cancer. This study aims to collect family history of cancer in a large cohort of patients with pituitary adenomas (PA) in outpatient clinic from years 2005-2017. Overall, 46.6% of 1062 patients with PA had a family member affected with cancer. Breast cancer in family members was reported in 15.3% of patients with prolactinomas which was significantly higher than in families of patients with non-functioning pituitary adenomas (NFPA) (10.0%) or acromegaly (6.8%) (p = 0.004). Lung cancer in family members was reported in 12.1% of patients with prolactinomas, significantly higher than in families of NFPA patients (7.0%, p = 0.049). Colorectal cancer in relatives of patients with PA was reported with any type of PA. Furthermore, patients with a positive family history of malignancy were diagnosed with PA at an earlier age than patients with a negative family history (43.6 ± 15.9 vs 46.0 ± 16.4 years, p = 0.015). Female patients with prolactinoma are more commonly diagnosed before the age of 25 years. Forty-two percent of patients with PA diagnosed before the age of 25 years had a second- and third-degree relative with cancer, significantly higher than patients with PA diagnosed later in life (25.8%, p < 0.001). Breast, lung, and colon cancers in second- and third-degree relatives were reported in significantly higher proportion of patients with PA diagnosed before the age of 25 years, compared with patients with PA diagnosed later in life (breast cancer: 10.9 vs 6.1%, p = 0.033; lung cancer: 10.9 vs 5.8%, p = 0.02; colon cancer: 9.5 vs 4.0%, p = 0.004). These results suggest familial cancer clustering in patients with prolactinoma and young patients with PA (younger than 25 years at diagnosis of PA). In particular, there is a strong association between prolactinoma and family history of breast and lung cancers. Further research of possible shared genetic susceptibility of prolactinoma and breast and lung cancers is needed.

Prostate cancer metastasis and soy isoflavones: a dogfight over a bone.

Prostate cancer is a complex, progressive, bone-tropic disease, which is usually associated with skeletal issues, poor mobility and a fatal outcome when it reaches the metastatic phase. Soy isoflavones, steroid-like compounds from soy-based food/dietary supplements, have been found to decrease the risk of prostate cancer in frequent consumers. Herein, we present a systematization of the data on soy isoflavone effects at different stages of metastatic prostate cancer progression, with a particular interest in the context of bone-related molecular events. Specifically, soy isoflavones have been determined to downregulate the prostate cancer cell androgen receptors, reverse the epithelial to mesenchymal transition of these cells, decrease the expressions of prostate-specific antigen, matrix metalloproteinase and serine proteinase, and reduce the superficial membrane fluidity in prostate cancer cells. In addition, soy isoflavones suppress the angiogenesis that follows prostate cancer growth, obstruct prostate cancer cells adhesion to the vascular endothelium and their extravasation in the area of future bone lesions, improve the general bone morphofunctional status, have a beneficial effect on prostate cancer metastasis-caused osteolytic/osteoblastic lesions and possibly affect the pre-metastatic niche formation. The observed, multilevel antimetastatic properties of soy isoflavones imply that they should be considered as promising components of combined therapeutic approaches to advanced prostate cancer.

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

BACKGROUND: Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. SUBJECTS AND METHODS: Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP. RESULTS: Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. CONCLUSIONS: Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

Intracerebral hemorrhage as a first sign of pheochromocytoma: case report and review of the literature.

Pheochromocytomas and sympathetic paragangliomas are rare catecholamine-secreting tumours that represent very rare causes of intracerebral haemorrhage in the young, with only a few cases reported. A 32-year-old man presented to our emergency department because of sudden onset of severe headache. He had a six-month history of paroxysmal headache, palpitations, and sweating. During examination he became somnolent and developed left-sided hemiplegia. A computed tomographic (CT) scan of the brain showed a right temporoparietal haematoma. He was admitted to the Clinic for Neurosurgery and the haematoma was evacuated. The patient was comatose, on assisted respiration, with frequent hypertensive crises. An examination for possible secondary causes of hypertension was undertaken. Plasma metanephrine value was elevated (414 pg/mL, reference values < 90 pg/mL). Abdominal CT scans revealed a large mass (6 cm) in the right adrenal gland. After adequate control of the hypertension was achieved with nonselectivealpha- and beta-adrenergic blockers the tumour was excised. The histopathologic findings confirmed the diagnosis of pheochromocytoma. The genetic analysis demonstrated a duplication in exon 1 of the VHL gene. We reported a rare, potentially fatal complication of pheochromocytoma - an intracerebral haemorrhage. This case and review of similar rare cases in the literature illustrate the importance of early recognition of the characteristic symptoms of catecholamine excess in young patients with hypertension.

High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome.

CONTEXT: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported. OBJECTIVE: The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors. SUBJECTS AND METHODS: In 60 adults (aged 35.8+/-1.3 yr) who recovered from HFRS 3.7 +/- 0.5 yr ago (median 2 yr), assessment of serum T(4), free T(4), TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests. RESULTS: Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60). CONCLUSION: A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.

Metabolic Syndrome in Hypopituitarism.

Prevalence of metabolic syndrome (MetS) and mortality rates from cardiovascular causes are increased in patients with hypopituitarism. Features of obesity, visceral adiposity, dyslipidemia, insulin resistance, and hypertension are common in these patients. Unreplaced growth hormone (GH) deficiency and inadequate replacement of other hormone insufficiencies may be responsible for the adverse body composition and metabolic profile associated with hypopituitarism. Recently, fatty liver disease was added to this unfavorable metabolic phenotype. Long-term treatment with low-dose GH replacement is considered safe and advantageous for metabolic profile and normalization of cardiovascular mortality rates in hypopituitary patients. Positive influence of optimal balance in replacement of other pituitary hormone deficiencies with doses of hydrocortisone (<20 mg/day), weight-adjusted T4 doses, and transdermal estrogen in women is also very important. Active screening and treatment of all cardiometabolic risk factors and comorbidities may further improve outcomes in patients with hypopituitarism.

Clinical case seminar: Familial intracranial germinoma.

BACKGROUND: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor recurrence. CONCLUSION: To the best of our knowledge so far, only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside of Japan. They are treated successfully with GH therapy in adult period. < /p > < p >.