Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency.

The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.

Ghrelin ovarian cell expression in patients with polycystic ovary syndrome: an immunohistochemical evaluation.

INTRODUCTION: The influence of ghrelin on different organs has been studied recently, e.g. in the regulation of pituitary hormone release, regulation of energy homeostasis, glucose metabolism and insulin secretion, cell proliferation, and reproductive function. However, the etiology of polycystic ovary syndrome has not been fully explained. The aim of our study was to estimate the presence of ghrelin in polycystic ovaries cells and evaluation of the relationship between ghrelin occurrence and cells proliferation. METHODS: In the present work we have compared ten polycystic ovaries with ovaries without pathology as the control group. We used immunohistochemical method to detect ghrelin. The cells proliferation was evaluated by Ki 67 proliferation index. RESULTS: Ghrelin immunostaining was demonstrated in cytoplasm of ovarian secondary interstitial cells and in atretic corpus luteum. The cell nuclei were ghrelin positive in granulosa, theca layers of follicular cyst in both groups as well as in luteal cells of young corpus luteum in healthy ovaries. Ki 67 immunostaining was observed in granulosa and theca layers of follicular cyst in polycystic and healthy ovaries. CONCLUSIONS: It is possible that local ghrelin expression plays an important role in the direct control of ovarian development and function and ghrelin may participate in patomechanism of PCOS.

[Graves' disease and hyperprolactinemia in a patient with Noonan syndrome neurofibromatosis type 1]. / Maladie de Graves-Basedow et hyperprolactinémie chez une femme atteinte du syndrome de Noonan/neurofibromatose de type 1.

We report the case of a 42-Year-old woman with Recklinghausen disease (neurofibromatosis type 1) and Noonan syndrome who developed Graves' disease. Hyperthyroidism, which had existed for two Years without treatment, led to the discovery of neurofibromatosis type 1. The diagnosis of Graves' disease was confirmed by blood hormone levels, thyroid gland ultrasound, radioisotope scan and thyroid iodine uptake. Additional tests were carried out due to the patient's short stature and the presence of subcutaneous nodules. Hyperprolactinemia, bone defects (bone density testing), and abnormal MRI signals from the optic chiasma were disclosed. The diagnosis of Recklinghausen disease was proven histologically. The possible co-existence of neurofibromatosis type 1 and Noonan syndrome are discussed on the basis of this clinical case.

Elevated ghrelin plasma levels in patients with polycystic ovary syndrome.

Polycystic ovary syndrome is a common endocrine disorder in women. It is associated with hirsuitism, obesity, insulin resistance, abnormality in the growth hormone/insulin-like growth factor I (IGF-1) axis and polycystic ovaries. The etiology of PCOS has not been clarified. Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor. It is mainly secreted by stomach cells but has also been shown to be present in hypothalamus, pituitary, pancreas and gonads. Ghrelin is a regulator of energy homeostasis and GH secretion. The influence of ghrelin on insulin secretion and gonadal function is known. Since ghrelin may play an important role in pathophysiology of PCOS, we studied ghrelin levels in a group of 52 women with PCOS and in 16 women in a control group. Plasma levels of insulin, total testosterone, SHBG, LH, and FSH were also measured. In conclusion, PCOS women have higher ghrelin levels than controls. Ghrelin negatively correlates with BMI and insulin levels in PCOS group. A relation between ghrelin and SHBG was observed. Our data suggest that ghrelin could be the possible link in PCOS etiology.

[Effect of lanreotide on prolactin level in patients with pituitary mixed tumors]. / Influence du lanréotide sur la concentration sérique de prolactine chez les patients atteints de tumeurs somato-lactotropes.

Acromegaly is a disease caused by a pituitary tumor (somatotropinoma) or by ectopic secretion of GH or IGF-1. About 15% of tumors secrete not only GH but PRL as well. Last time a lanreotide and an octreotide (the somatostatine analogues) are useful in the therapy of acromegaly. We observed the influence of the lanreotide on GH and prolactin. We noticed that the lanreotide caused not only serum level reduction of a growth hormone but also prolactine in patients with mixed pituitary tumors.

[Estimation of efficacy of the octreotide LAR administration in the patients with somatotropinoma]. / Ocena skutecznosci stosowania oktreotydu LAR u pacjentów z guzami przysadki typu somatotropinoma.

Acromegaly is caused by excessive secretion of growth hormone by a hypophyseal adenoma type of somatotropinoma. IGF-I is formed in the liver and mediates most biological actions of GH. Treatment of adenomas, which secrete GH, involves pharmacotherapy followed by surgery. Modern pharmacotherapy leaning is based on somatostatin analogues (factor restrictive secretion GH): octreotide, octreotide LAR and lanreotide. The aim of our study was estimation of efficiency of octreotide LAR in the patients with somatotropinoma prepared to neurosurgery intervention. We examined 16 patients (10 of women and 6 men) with the features of active acromegaly. In all cases the increased concentration of HGH and IGF-I were observed. The presence of pituitary adenoma in all patients was confirmed by MRI. The patients were treated with octreotide LAR monthly in dose 20 mg and 30 mg respectively. Before and after application of somatostatin analogues the concentration HGH, IGF-I, PRL in serum were marked. The concentration of GH before octreotide LAR therapy in all patients increased remarkable and ranged from 15.6 to 78.6 ng/ml, mean: 31.20 +/- 16.84 (norm: 0-10 ng/ml), also, in all cases the serum IGF-I level was increased and ranged from 451 to 1107.6 ng/ml, mean: 801.75 +/- 207.82 (norm: 100-400 ng/ml). The prolactin concentration ranged from 7.4 to 49.9 ng/ml, mean: 22.8 +/- 13.7 (norm: 2-20 ng/ml) and in 8 (50%) cases the increased of PRL concentration in serum was observed. After the administration of octreotide LAR the level of: GH [mean: 12.99 +/- 17.16 ng/ml (p < 0.001)], of IGF-I [mean 422.8 +/- 229 ng ml (p < 0.01)] statistical important decreased and prolactin in 8 with increased concentration [mean: 12.45 +/- 5.57 (p < 0.01)] were observed. Long acting somatostatin analogues--octreotide LAR is particular efficient in lowering of growth hormone and IGF-I in patients with somatotropinoma and shows efficiency in normalization of increased prolactin concentration. Because of extreme effectiveness of octreotide LAR, it should be used the routine treatment at the patients suffering from active acromegaly and preparing to neurosurgical treatment.

Short-term pre-surgical treatment with somatostatin analogues, octreotide and lanreotide, in acromegaly.

Eighteen patients with symptoms of active acromegaly were treated with somatostatin analogues for 4 weeks before surgery. Both before and after the treatment, levels of growth hormone (GH), prolactin (PRL), insulin growth factor -I (IGF-I), luteotropin (LH), folliculostimulin (FSH) and subunit alpha of glycoprotein hormones were estimated. Glucose tolerance test, magnetic resonance imaging (MRI) examination, sight acuity and field of vision tests were also performed. The same tests were performed on ten control patients with clinically and biochemically active acromegaly, subjected to surgery but not treated with somatostatin analogues. In six patients treated with somatostatin analogues GH levels decreased significantly to less than 5 ng/ml and in two patients remained elevated while in 10 patients GH level decreased and ranged from 6.1 to 42.9 ng/ml. In 13 patients we observed a decrease in IGF-I to normal levels (<400 ng/dl) and in 3 patients we noted a decrease to levels slightly higher than normal. There was also a slight decrease in alpha subunit concentration. In the glucose inhibition test 4 patients demonstrated normalized GH levels. In patients with elevated PRL and TSH levels, treatment with somatostatin analogues induced their decrease. No changes were observed in levels of LH and FSH. After therapy MRI examination disclosed a decrease in tumor volume in two patients (by 20 and 25%, respectively) and no changes in tumor size in 16 patients. The two patients with a decreased tumor volume also showed normalized glucose tolerance tests. All patients manifested an improved clinical condition. Neurosurgeons disclosed a decreased tumor consistency which greatly facilitated surgical procedure. Our studies documented favourable effects of somatostatin analogues on the assayed hormone levels, and on the general condition of the patients as well as on the course of the surgical procedure itself.

[Investigations on the pathogenesis of primary varicose veins]. / Badania nad patogeneza pierwotnych zylaków konczyn dolnych.

The data from the clinical course and epidemiology of primary varicose veins of lower limb suggest that sex hormones can directly influence the development of the disease through their intracellular receptor localised in cells of venous wall. The purpose of this study was to determine the stereometric differences in the structure of healthy and varicose veins of lower limb and to determine the presence and localisation of oestrogen and progesterone receptors in the cells of vein. The segments of greater saphenous vein obtained from the 8 women operated for varicose vein were used for the study. The segments of the greater saphenous vein obtained from 8 women that underwent femoro-popliteal venous bypass procedure were used as control group. The vein samples for stereometric analysis were preserved in Buin's solution, embedded in paraffin and then evaluated with automatic analyser MagiCal. To determine the presence of oestrogen and progesterone receptors the immunohistochemic analysis LAB with monoclonal antibodies produced by DAKO was used. The decreased smooth muscle fraction in venous wall, thickening of adventitia, the change of the smooth muscle cells to stroma cells ratio in the muscular layer of venous wall and change of muscular layer to adventitia ratio were observed in varicose veins in comparison with control group. The oestrogen receptors were found in the nuclei of the smooth muscle cells and endothelium. The progesterone receptors were localised in nuclei of smooth muscle cells and cells of subendothelial layer. It seems that quantitative analysis of sex hormones receptor in the venous wall could be useful in the determination of patients with increased risk of the development of primary varicose veins.

[Radioimmunologic methods for determining cortisol binding globulin-CBG in human serum]. / Radioimmunologiczna metoda oznaczania transkortyny (Cortisol Binding Globulin-CBG) w surowicy ludzkiej.

The authors described double antibodies radioimmunoassay of human cortisol binding globulin serum level in support of previous isolated and purified trancortin and anti-transcortin antibodies produced by rabbit immunization. Antigen was iodinated by chloraminet method and purification on Ultragel AcA 54 column. Standard curve had specific Bx/Box100%. Using described method investigation of transcortin globulin serum level is precise and repetitive.

[Synthesis and characteristics of anti-CBG antibodies (anti-transcortin)]. / Wytwarzanie i charakterystyka przeciwcial anty-CBG (przeciw transkortynie).

We used corticosteroid binding globulin purified by chromatography on the Sepharose column for immunisation of the rabbits. We analysed serum by rocket immunoelectrophoresis and cross immunoelectrophoresis. The titre of the serum was estimated by reaction with 125 I-labelled transcortin (corticosteroid binding globulin). The results of our studies indicate that own serum is valuable and can be use for radioimmunoassay of the CBG in the serum.

[Isolation and purification of transcortin (cortisol binding globulin--CBG) using two-step chromatography]. / Izolacja i oczyszczanie transcortyny globuliny wiazacej kortyzol--(CBG)--za pomoca dwustopniowej chromatografii.

The isolation of cortisol and progesterone binding globulin (CBG) from pregnant women serum was performed using affinity and hydrophobic chromatography. The purity and specificity of isolated transcortin was tested by agarose gel electrophoresis using racket and cross immunoelectrophoresis and specific CBG antibodies. High purity and immunoreactivity of the isolated globulin destitute of other proteins contamination, were obtained.

Carcinoma of prostate in men aged fifty and under: therapeutic options.

We made a retrospective study of 20 men, aged fifty or under, with adenocarcinoma of the prostate to evaluate presenting symptoms, stage, grade, and therapeutic results. Sixty-five percent were found to have extracapsular spread of disease (Stage C or D). The therapy used was one or a combination of three types: radical prostatectomy, radiation therapy, and hormonal manipulation. Five of 6 patients with Stage B disease and 3 of 6 patients with Stage C disease were treated with radiation therapy. The other Stages B and C patients underwent radical prostatectomy. In all 5 of Stage B patients receiving radiation, therapy failed; the mean time to tumor recurrence was 3.2 years. Two of 3 patients with Stage C disease died of metastatic disease within three years of receiving radiation. The 4 patients (Stages B and C) who underwent radical prostatectomy are free of disease. There was a statistically higher failure rate among the radiation therapy patients with Stages B and C disease than among the surgical patients (X2 = 8.4, p less than 0.1).

[Glycoprotein hormone alpha subunit as a marker of pituitary adenoma]. / Podjednostka alfa hormonów glikoproteinowych jako znacznik gruczolaków przysadki.

Blood serum FSH, LH, prolactin and testosterone as well as urinary excretion of 17KS and 17-OHCS were determined in 8 patients with chromophobe pituitary adenomas treated by transphenoidal microsurgical removal or craniotomy with or without subsequent telecobalt therapy. It was found te disease tends to recur in the majority of patients despite the type of therapy. Recurrence is accompanied by gonadotropins hyposecretion, increase in prolactin secretion, secretory disorders in the gonads and adrenals; an increase in prolactin secretion is proportional to the intensity of the compression symptoms. Bromocriptine in a daily doses ranging from 5.0 to 7.5 mg decreases prolactin levels in the recurrent chromophobe pituitary adenomas and does not affect their proliferation.

[Changes in serum levels of glycoprotein hormone alpha subunits in patients with alphoma-type pituitary tumors during LHRH and TRH stimulation tests]. / Zmiany stezenia podjednostki alfa hormonów glikoproteidowych w surowicy chorych z guzami przysadki typu "alfoma" w przebiegu testów stymulacji LH-RH + TRH.

A group of 21 patients with the alphoma-type pituitary tumors was studied. In 9 cases the tumor was associated with acromegaly. Alpha subunit concentration was determined in all the patients and in control subjects in the course of dynamic tests consisting in simultaneous intravenous administration of 200 micrograms TRH and 100 micrograms LH-RH. In basal conditions the concentration of alpha subunit in patients with the alphoma-type tumors ranged between 2.1 and 30 micrograms/l (mean 7.5 +/- 6.6 micrograms/l), and in controls the respective values ranged between 0.2 and 1.6 micrograms/l (mean 0.78 +/- 0.36 micrograms/l). In the course of the LH-RH + TRH test there was an increase in the alpha subunit level both in the patients with alphoma associated with acromegaly and in the remaining cases of alphoma. Statistical analysis of the results obtained for the whole group of patients revealed a significant linear correlation between the alpha unit concentration 20, 30, 60 and 90 minutes following stimulation with the neurohormones and that before stimulation. For 9 patients with the acromegaly-associated tumors a statistically significant increase in the alpha subunit concentration was noted only at the 90-th minute of the stimulation test, while for the remaining 12 patients with alphoma an increase was statistically significant for the whole time of the duration of the test. In healthy subjects the concentration of alpha subunit never exceeded the limits of the normal values in the course of the LH-RH + TRH stimulation test.

Regression of pulmonary metastases from renal carcinoma.

This article describes a patient who had a nephrectomy and hormone therapy for renal carcinoma. There was roentgenographic evidence of pulmonary metastases at the time of surgery. He was alive and showed no clinical or roentgenographic evidence of pulmonary metastases six and one-half years after treatment.