Showing papers in "Journal of Endocrinological Investigation in 2000"
TL;DR: An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin exerted a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.
Abstract: An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin. It has been demonstrated that Ghrelin specifically stimulates GH secretion from rat pituitary cells in culture as well as in rats in vivo. In this preliminary study, in 4 normal adults [age (mean+/-SE): 28.6+/-3.5 yr; body mass index (BMI): 22.3+/-2.1 kg/m2] we administered 1.0 microg/kg Ghrelin or GHRH-29 to compare their GH-releasing activities in humans. In all subjects Ghrelin induced a prompt, marked and long-lasting increase in circulating GH levels (peak: 107.9+/-26.1 microg/l; AUC: 6503.1+/-1632.7 microg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3+/-4.5 microg/l; AUC: 1517.5+/-338.4 microg/l/h). In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.
394 citations
TL;DR: The data demonstrate that at least in male patients with IDDM, osteopenia is the consequence of a lowered bone formation with a predominance of bone resorption over formation.
Abstract: The objective was to evaluate the prevalence and severity of osteopenia in patients with uncomplicated insulin-dependent diabetes mellitus (IDDM) and to obtain more information on the pathophysiology of diabetic osteopenia. In 35 patients with uncomplicated IDDM (21 men and 14 women; age 37.6+/-9.9 yr; duration of disease 8.5+/-3.5 years) bone mineral density was measured by dual energy X-ray absorptiometry (DEXA). In addition, markers of bone formation [plasma insulin-like growth factor I (IGF-I), serum alkaline phosphatase (ALP), serum bone alkaline phosphatase (BAP) and serum osteocalcin] and bone resorption [urinary excretion of calcium and of the cross-linked N-telopeptide of type 1 collagen, both corrected for the excretion of creatinine] were measured in the diabetic patients and in 33 healthy controls, matched for sex, age, height, weight and body mass index (BMI). In 67% of the diabetic men and 57% of the diabetic women osteopenia of the femoral neck and/or the lumbar spine (T-value < or = -1 SD) was present. Fourteen percent of the male patients, but none of the female patients, met the criteria for osteoporosis (T-value < or = -2.5 SD). In the whole group of diabetic patients the mean plasma IGF-I level tended to be lower (p<0.10) as compared to that in the controls. In the diabetic patients with femoral neck osteopenia, the mean plasma IGF-I level was significantly lower (p<0.05) than in those without osteopenia at this site. There were no differences in the mean serum ALP, BAP and osteocalcin levels between the diabetic patients and the controls, nor between the diabetic patients with and without femoral neck osteopenia. Considering only the male diabetic patients, significantly lower mean plasma IGF-I (-26%), serum ALP (-24%) and serum osteocalcin (-38%) levels were present in the patients with femoral neck osteopenia than in those without osteopenia at this site, suggesting lowered bone formation. The bone resorption markers were similar in all (sub)groups of diabetic patients and not different between diabetic patients and controls. Bone mineral density (BMD) did not correlate with plasma levels of glycosylated hemoglobin (HbA1c). BMD values were not related to any of the bone resorption or formation markers, except for plasma IGF-I both in the femoral neck (r=+0.38, p=0.026) and the lumbar spine (r=+0.34, p=0.043). Our data demonstrate that at least in male patients with IDDM, osteopenia is the consequence of a lowered bone formation with a predominance of bone resorption over formation.
302 citations
TL;DR: In this article, the efficiency of vitamin D synthesis in 48 premenopausal women (14-44 years) in relation to three different types of dressing in summer was investigated, and the results indicated that sun exposure of skin areas of hands and face may partially provide vitamin D, but may not be enough to eliminate vitamin D deficiency.
Abstract: Vitamin D is an essential steroid involved in bone metabolism, cell growth, differentiation, and regulation of the minerals in the body. The main sources of this vital vitamin are adequate diet and photosynthesis in the skin. The aim of this study was to investigate the efficiency of vitamin D synthesis in 48 premenopausal women (14-44 years) in relation to three different types of dressing in summer. Women in the first group (Group I) dressed in a style which exposed the usual areas of the skin to sunlight; women in the second group (Group II wore traditional clothing with the skin of the hands and face uncovered, while the third group (Group III) dressed in traditional Islamic style, covering the whole body including hands and face. Serum 25OHD levels of Group I, Group II, and Group III were 56+/-41.3 nmol/l, 31.9+/-24.4 nmol/l, 9+/-5.7 nmol/l, respectively (Group I vs Group III, p 0.05). Vitamin D levels were low in 44 percent of the Group I and 60% of the Group II, which suggested that sun exposure of skin areas of hands and face may partially provide vitamin D synthesis, but may not be enough to eliminate vitamin D deficiency. All the patients in group III had vitamin D levels below normal. This study emphasizes the necessity of vitamin D fortification of food even in a sunny country where some people may not be exposed to sunlight because of inappropriate clothing or an indoor-life.
250 citations
TL;DR: A truncated c-kit product, tr-kit, is specifically expressed in post-meiotic stages of spermatogenesis, and is accumulated in mature spermatozoa, suggesting that it might play a role in the final function of the gametes, fertilization.
Abstract: The tyrosine-kinase receptor c-kit and its ligand, stem cell factor (SCF), are essential for the maintenance of primordial germ cells (PGCs) in both sexes. However, c-kit and a post-meiotic-specific alternative c-kit gene product play important roles also during post-natal stages of spermatogenesis. In the adult testis, the c-kit receptor is re-expressed in differentiating spermatogonia, but not in spermatogonial stem cells, whereas SCF is expressed by Sertoli cells under FSH stimulation. SCF stimulates DNA synthesis in type A spermatogonia cultured in vitro, and injection of anti-c-kit antibodies blocks their proliferation in vivo. A point mutation in the c-kit gene, which impairs SCF-mediated activation of phosphatidylinositol 3-kinase, does not cause any significant reduction in PGCs number during embryonic development, nor in spermatogonial stem cell populations. However males are completely sterile due to a block in the initial stages of spermatogenesis, associated to abolishment of DNA-synthesis in differentiating A1-A4 spermatogonia. With the onset of meiosis c-kit expression ceases, but a truncated c-kit product, tr-kit, is specifically expressed in post-meiotic stages of spermatogenesis, and is accumulated in mature spermatozoa. Microinjection of tr-kit into mouse eggs causes their parthenogenetic activation, suggesting that it might play a role in the final function of the gametes, fertilization.
161 citations
TL;DR: Determining the physiologic influences that modulate GnRH secretion, the prime initiator of reproductive function in the human, is fundamental not only to the understanding of the rare condition of congenital idiopathic hypogonadotropic hypogOnadism (IHH), but also common disorders such as constitutional delay of puberty and hypothalamic amenorrhea.
Abstract: Determining the physiologic influences that modulate GnRH secretion, the prime initiator of reproductive function in the human, is fundamental not only to our understanding of the rare condition of congenital idiopathic hypogonadotropic hypogonadism (IHH), but also common disorders such as constitutional delay of puberty and hypothalamic amenorrhea. IHH is characterized by low levels of sex steroids and gonadotropins, normal findings on radiographic imaging of the hypothalamic-pituitary regions, and normal baseline and reserve testing of the remainder of the hypothalamic-pituitary axes. Failure of the normal pattern of episodic GnRH secretion results in delay of puberty and infertility. IHH is characterized by rich clinical and genetic heterogeneity, variable modes of inheritance, and association with other anomalies. To date, 4 genes have been identified as causes of IHH in the human; KAL [the gene for X-linked Kallmann syndrome (IHH and anosmia)], DAX1 [the gene for X-linked adrenal hypoplasia congenita (IHH and adrenal insufficiency)], GNRHR (the GnRH receptor), and PC1 (the gene for prohormone convertase 1, causing a syndrome of IHH and defects in prohormone processing). As these mutations account for less than 20% of all IHH cases, discovery of additional gene mutations will continue to advance our understanding of this intriguing syndrome.
108 citations
TL;DR: The present data could support a role for activin A in human endocrine pancreas in modulating insulin response to different glucose concentrations and could support the idea that women with gestational diabetes have higher serum Activin A levels than healthy pregnant women at the same gestational age.
Abstract: Activin A is a dimeric glycoprotein showing a high sequence homology with transforming growth factor-beta (TGF-beta) and playing autocrine/paracrine actions in reproductive tissues. However, since the synthesis of activin is ubiquitous it may have a role in regulating cell growth and differentiation in several tissues. Previous studies showed that activin A is expressed by insulin-positive B cells of human pancreatic islets, and women with gestational diabetes have higher serum activin A levels than healthy pregnant women at the same gestational age. The present study aimed to evaluate the effect of activin A on insulin secretion from cultured human pancreatic islets. With this purpose human pancreatic islets were incubated with varying concentrations of activin A (0.1 to 10.0 nM). In absence of glucose, activin A did not modify insulin secretion at the different concentrations used. In absence of activin A, 8.3 mM and 16.7 mM glucose significantly increased insulin secretion, with a dose-dependent pattern. In presence of a non stimulatory concentration of glucose (3.3 mM), activin A significantly increased insulin secretion starting from low concentration (0.1 nM). Furthermore, the addition of activin A to 8.3 mM and 16.7 mM glucose induced an additional effect of the dose-dependent glucose-mediated insulin secretion (p<0.001). The present data could support a role for activin A in human endocrine pancreas in modulating insulin response to different glucose concentrations.
100 citations
TL;DR: The data suggest that the thrombophilic state present in patients with active Cushing’s syndrome is related to an enhanced metabolic function of endothelial cells; this in turn may be caused by an heightened production of thrombin with secondary hyperfibrinolysis.
Abstract: Patients with active Cushing’s syndrome have an increased thrombotic tendency. We chose to reassess the mechanism underlying the thrombophilic state associated with this clinical condition using sensitive markers of coagulation and fibrinolysis activation in 17 patients with active disease. The results were compared with those obtained in 12 Cushing’s patients successfully treated by surgery and in 20 normal individuals. The general pattern of results in patients with active disease was the finding of increased levels of von Willebrand factor (VWF: Ag), a marker of enhanced metabolic function of endothelial cells (VWF:Ag 181±42 vs 110±43, p<0.001 in normal subjects), accompanied by signs of heightened thrombin and plasmin generation, expressed by high levels of thrombin-antithrombin (TAT 5.59±3.6 vs 3.06±0.92 ng/ml in controls, p<0.01) and plasmin-antiplasmin complexes (PAP 407±176 vs 245±67 ng/ml in controls, p<0.01). VWF:Ag and TAT values were significantly higher in hypertensive than in normotensive patients with active disease (205±40 vs 155±26 U/dl, p<0.05 and 7.49±3.7 vs 3.45±1.8, p<0.01, respectively). Plasma levels of plasminogen activator inhibitor type 1 were higher, though not to a statistically significant extent, in patients with active disease compared to controls (12.8±12.3 vs 5.6±7.4 IU/ml, NS) and positively correlated with body mass index (r=0.66, p<0.01). After surgical control of Cushing’s syndrome, there was a partial or complete reversal of the abnormalities to values similar to those found in normal individuals. Our data suggest that the thrombophilic state present in patients with active Cushing’s syndrome is related to an enhanced metabolic function of endothelial cells; this in turn may be caused by an heightened production of thrombin with secondary hyperfibrinolysis. Primary prophylaxis with anticoagulants is recommended in these patients when they are exposed to a thrombophilic condition such as surgery.
85 citations
TL;DR: The relative frequency of SAS in a group of patients with acromegaly was 75%.
Abstract: The prevalence of sleep apnea syndrome (SAS) in acromegaly is high. Consequences of SAS are serious and are associated with increased morbidity and mortality. The aim of this study was to assess the relative frequency and predictive factors for SAS in a group of patients with acromegaly (n=55). The presence of SAS was evaluated using the Polymesam device. Hormonal and clinical examination consisted of assessment of growth hormone, insulin-like growth factor I plasma levels, body mass index (BMI), neck circumference, age, sex, treatment modes of acromegaly and ear, nose and throat (ENT) examination. The relative frequency of SAS in our group of patients with acromegaly was 75%. Independent predictors of SAS were: increased activity of acromegaly, higher age and neck circumference. No association between SAS and BMI and ENT findings was observed. The role of gender was controversial.
84 citations
TL;DR: Comparison and intervention studies must be planned to evaluate the best therapeutical approaches to control abnormalities of glucose and lipid metabolism and to assess the possibility to further increase graft and patient survival by appropriate treatment of diabetes and hyperlipidemia.
Abstract: The introduction of cyclosporin and, more recently, tacrolimus in the immunosuppression of transplanted patients has lead to prolonged graft survival and increased patients' life expectancy. It has been therefore possible to evaluate the effects of long-term treatment with these drugs and metabolic alterations in patients on cyclosporin or tacrolimus have been reported by several authors. In particular, the use of these drugs is associated with abnormalities of glucose and lipid metabolism. Post-transplant diabetes is more common with tacrolimus, probably due to more marked effects on the pancreatic beta-cells, whereas increased levels of cholesterol and triglycerides are more frequently associated with cyclosporin treatment, even though, in this latter case, steroid treatment seems to play a major role. Comparison and intervention studies must be planned to evaluate the best therapeutical approaches to control these abnormalities and to assess the possibility to further increase graft and patient survival by appropriate treatment of diabetes and hyperlipidemia.
78 citations
TL;DR: The first case in literature of cutaneous spread of parathyroid carcinoma after FNAC is described, which suggests the use of FNAC should be carefully assessed in the presence of suspect parathyro carcinoma, because this could cause a possible diffusion of a parathyrod carcinoma along the needle tract.
Abstract: Background: Ultrasound-guided fine needle aspiration cytology (FNAC) of suspect parathyroid adenomas is sometimes used for the diagnosis of primary hyperparathyroidism (PHPT). FNAC complications are rare or mild. We describe the first case in literature of cutaneous spread of parathyroid carcinoma after FNAC. Case: A woman underwent a neck ultrasound which revealed a solid hypoechogenic nodule of 1.5 cm at the level of the inferior pole of the right thyroid. In the same time a FNAC of the nodule was performed. Cytology showed no atypical cells. Successively PHPT was diagnosed and a few weeks later the patient had a subcutaneous lump in the same area of FNAC. The patient underwent surgery and histology of the specimen showed a differentiated parathyroid carcinoma. The postoperative course was regular and calcium and parathormone resulted normal. Conclusion: The use of FNAC should be carefully assessed in the presence of suspect parathyroid carcinoma, because this could cause a possible diffusion of a parathyroid carcinoma along the needle tract.
77 citations
TL;DR: Biochemical data indicate that, in particular during spermiogenesis, the general activity of the ubiquitin system is high, which most likely is related to the high requirement for massive breakdown of cytoplasmatic and nuclear proteins during this last phase of spermatogenesis.
Abstract: The ubiquitin system is involved in numerous cellular processes, regulating the amounts and/or activities of specific proteins through posttranslational coupling with ubiquitin or ubiquitin-like proteins In spermatogenesis, there appears to be a special requirement for certain components of the ubiquitin system, as exemplified in human and mouse by mutation of USP9Y and HR6B, respectively Both genes encode proteins which take part in the ubiquitin system and are ubiquitously expressed, but their mutation generates no apparent phenotype other than male infertility Different phases of mammalian spermatogenesis probably require different specialized activities of the ubiquitin system It is anticipated that ubiquitination activities similar to those required during mitotic cell cycle regulation will play some role in control of the meiotic divisions In spermatocytes, there is an intricate link among DNA repair, the ubiquitin system, and regulation of meiotic chromatin structure, as indicated by the co-localization of proteins involved in these processes on meiotic recombination complexes HR6B and its nearly identical homolog HR6A are multiple function proteins, with ubiquitin-conjugating activity and essential roles in post-replication DNA repair HR6B, possibly together with the ubiquitin-ligating enzyme mRAD1 8Sc, is most likely involved in chromatin re-organization during the meiotic and post-meiotic phases of spermatogenesis Biochemical data indicate that, in particular during spermiogenesis, the general activity of the ubiquitin system is high, which most likely is related to the high requirement for massive breakdown of cytoplasmatic and nuclear proteins during this last phase of spermatogenesis
TL;DR: In this article, the mean child rate of all the 29 diagnosed adult Finnish males with classical 21-hydroxylase deficiency (21-OHD) was calculated and compared with the mean of the whole Finnish male population with equal age distribution.
Abstract: Though appropriate glucocorticoid substitution therapy should abolish both cortisol deficiency and adrenal androgen excess in patients with 21-hydroxylase deficiency (21-OHD), the long-term outcome is not always satisfactory. There are several reports on low adult height in both male and female patients, and impaired fertility has been reported in females with 21-OHD. There are only few reports on gonadal function of adult male patients with 21 -OHD. In this study, we calculated the child rate of all the 29 diagnosed adult Finnish males with classical 21-OHD and compared it with the mean child rate of the whole Finnish male population with equal age distribution. Sixteen males with 21-OHD and their age-matched healthy controls were further examined in a cross-sectional study. Auxology and pituitary gonadal axis were examined in both patients and controls. Testicular ultrasonography of the patients was also performed. The mean child rate of the 29 males with 21-OHD was 0.07 which was significantly lower (p<0.001) than that in the Finnish male population of the same age (0.34). In the cross-sectional study, males with 21-OHD had serum testosterone, inhibin B, LH and FSH concentrations comparable to those of healthy controls and reference values. Serum DHEA-S concentrations were remarkably low, even in the undersubstituted males with 21-OHD (p<0.001, compared with the healthy controls). In the patient group, serum inhibin B concentration did not correlate with serum FSH concentration. Adrenal rest tumors of the testicles were found in two undersubstituted males with 21-OHD. In conclusion, our study suggests normal pituitary and gonadal function but reduced child rate in adult males with 21-OHD. This might be explained by suboptimal psychosocial adaptation to the chronic disease. However, the patients in this study were young and the final child rate may become essentially higher.
TL;DR: It is suggested that adolescents with diabetes have similar serum levels of DHEA-S, SHBG, DHT and 3αdiol G as healthy subjects at all stages of puberty, however, there are significant differences in serum testosterone and free testosterone levels in adolescents with Diabetes when compared to healthy, sex- and pubertal stage-matched controls in late puberty.
Abstract: Delayed sexual maturation is still frequently seen in adolescents with type 1 diabetes. A close relationship between insulin and androgen metabolism has been found in a number of studies. Our study was designed to investigate whether or not abnormalities in androgen secretion could play a role in the onset of sexual maturation in adolescents with type 1 diabetes. We have asked whether or not there was a correlation between daily insulin dosage, duration of diabetes, metabolic control, age, pubertal stage, and body mass index (BMI) versus serum androgen concentrations. Basal total and free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha diol-G) plasma concentrations were measured in 36 pubertal boys and 31 pubertal girls with type 1 diabetes and in 59 sex- and pubertal stage-matched control subjects without diabetes. Significantly higher serum total testosterone (p<0.01) and free testosterone (p<0.05) levels were found in females and males with type 1 diabetes than in controls at pubertal stage 5. DHEA-S, SHBG, DHT and 3alpha diol G concentrations in patients with diabetes were not significantly different from those in controls. There was no correlation between daily insulin requirements and serum androgen levels. These data suggest that adolescents with diabetes have similar serum levels of DHEA-S, SHBG, DHT and 3alpha diol G as healthy subjects at all stages of puberty. However, there are significant differences in serum testosterone and free testosterone levels in adolescents with diabetes when compared to healthy, sex- and pubertal stage-matched controls in late puberty. We hypothesize that the increased testosterone levels in patients with diabetes could relate to reduced fertility in females, disorders of sexual maturation and an increased risk for cardiovascular complications later in life.
TL;DR: Patients with PWS show clear reduction of IGF-I levels as well as of the somatotroph responsiveness to provocative stimuli independently of body weight excess, which strengthens the hypothesis that PWS syndrome is frequently connoted by GH insufficiency.
Abstract: Basal IGF-I levels and the GH response to at least two among provocative stimuli such as clonidine (CLO, Catapresan, 150 mcg/m2 p.o.), GHRH (1 mcg/kg i.v.)+arginine (ARG, 0.5 g/kg i.v. infusion during 30 min) and GHRH+pyridostigmine (PD, Mestinon cpr 60 mg p.o.) have been evaluated in 43 children with Prader-Willi syndrome (PWS, 17 males and 26 females, age 3-22 yr, 7 normal weight and 36 obese PWS), in 25 normal short children (NC, 17 males and 8 females, 7.7-18.5 yr) and in 24 children with simple obesity (OB, 14 males, 10 females, 7.7-21.5 yr). Both normal weight and obese PWS had mean IGF-I levels lower than those recorded in NC (p<0.001) and OB (p<0.001). The GH responses to GHRH+ARG and GHRH+PD in NC were similar and higher than that to CLO (p<0.001). In PWS the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.001) which, in turn, was higher than that to CLO (p<0.001); these responses in PWS were lower than those in normal children (p<0.02) and similar to those in OB. In normal weight PWS the GH responses to GHRH+ARG and to GHRH+PD were similar and higher than to CLO (p<0.05); however, each provocative stimulus elicited a GH rise lower than that in NC (p<0.05). In obese PWS as well as in OB the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.02) which, in turn, was higher than that to CLO (p<0.001); all GH responses in obese PWS and OB were lower than those in NC (p<0.001) but similar to those in normal weight PWS. In conclusion, patients with PWS show clear reduction of IGF-I levels as well as of the somatotroph responsiveness to provocative stimuli independently of body weight excess. These results strengthen the hypothesis that PWS syndrome is frequently connotated by GH insufficiency.
TL;DR: Investigation of combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with anaplastic thyroid carcinoma, and in some patients multimodality treatment (TT, RT andCHT) is associated with increased survival.
Abstract: The aim of this study was to investigate the role of multimodality treatment in patients with anaplastic thyroid carcinoma. From 1992 to 1999, 39 consecutive patients with a histologically or cytologically proven anaplastic thyroid carcinoma were referred to the Thyroid Center of Padua General Hospital. There were 28 females and 11 males with a median age of 69 years (range 39-88 years). About one-third of patients had a history of preceeding nodular goiter. Two patients had areas of differentiated thyroid carcinoma at histological examination. Local disease was present in 26 patients while distant metastases, mainly to the lung, were present in 22 at diagnosis or quickly developed during the observation period in all the others except one. Thirty-two patients were previously untreated: 9 of them were in good general condition, 1 had limited lung metastases, and the tumor mass was considered resectable by the surgeon. These 9 patients were treated with cisplatin once a week and radiotherapy (RT) 36Gy in 18 fractions over three weeks, followed by total thyroidectomy (TT) and by further chemotherapy (CHT) with adriamycin and bleomycin in 4 patients. Seven patients, 3 with lung metastases at diagnosis, had undergone TT, followed by RT in 5, in another hospital and were subsequently referred to our center due to the presence of distant metastases. Therefore, a total of 16 patients (Group 1) was treated with TT, RT and CHT in various order. Nine patients with distant metastases at diagnosis (Group 2) received CHT; one of them had a disappearance of lung metastases and was then treated by TT and further CHT. Group 3 consisted of 14 elderly patients in poor general conditions; 4 of these received local RT, while the remaining did not receive any treatment. Four complete responses were seen in patients from Group 1, and 1 from Group 2. One patient without distant metastases at diagnosis is alive and free of disease 6 months after TT and adjuvant CHT, and 12 months after diagnosis. Three had long-term survival (14, 24, 27 months) with a disease-free interval of 6-8-10 months. The patient from Group 2 who was treated in a second time by TT is alive without disease after 60 months. Median survival rate was 11 months for Group 1, 5.7 months for Group 2 and 4 months for Group 3. In some patients multimodality treatment (TT, RT and CHT) is associated with increased survival. Nine out of 16 patients, who underwent surgery and complementary treatment, had no local progression. In all but one distant metastases developed, mainly in the lung, during or after post-surgical CHT. The best results were obtained in younger patients with less advanced disease. Early diagnosis is mandatory. Only a few patients responded to CHT, confirming that anaplastic thyroid carcinoma is often resistant to anticancer drugs. Our experience with combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with anaplastic thyroid carcinoma. Preoperative CHT and RT may enhance surgical resectability of the primary tumor.
TL;DR: Two patients with Cushing’s disease who developed thromboembolic complications soon after inferior petrosal sinus sampling are reported.
Abstract: Bilateral inferior petrosal sinus sampling for ACTH with corticotrophin releasing hormone stimulation has become an established test in differentiating pituitary Cushing's disease from Cushing's syndrome due to ectopic ACTH secretion. We report two patients with Cushing's disease who developed thromboembolic complications soon after inferior petrosal sinus sampling. We discuss the possible mechanisms leading to this complication in a syndrome in which thromboembolic complications are well recognized and highlight the need for consideration of prophylactic anticoagulation.
TL;DR: If risperidone therapy must be continued in patients with psychotic disorders, addition of the dopamine agonists bromocriptine or cabergoline may successfully alleviate hyperprolactinemia and the associated manifestations without worsening psychotic symptoms.
Abstract: Risperidone is a novel antipsychotic agent that blocks both dopaminergic and serotonergic receptors. In several reports, clinically significant hyperprolactinemia has been reported in patients on this agent. However, the optimal management of risperidone-induced hyperprolactinemia has not been clarified. We reviewed the records of 5 patients with psychotic disorders who were evaluated for risperidone-induced hyperprolactinemia. There were 4 females and 1 male patient, aged 30–45 yr. All patients had significant hyperprolactinemia, with prolactin (PRL) levels ranging from 65.5 to 209 μg/l. All but 1 of these patients had manifestations of hypogonadism. In these 4 patients, risperidone therapy was continued and the dopamine agonists bromocriptine or cabergoline were added. In 3 out of 4 patients, such additional therapy reduced the PRL level and alleviated hypogonadism. None of the patients treated with these agents had a worsening of psychosis. We conclude that risperidone can cause clinically significant hyperprolactinemia in patients treated with this drug. If risperidone therapy must be continued in such patients, addition of the dopamine agonists bromocriptine or cabergoline may successfully alleviate hyperprolactinemia and the associated manifestations without worsening psychotic symptoms.
TL;DR: For the time being the molecular analysis of microdeletions of the Y chromosome is indicated in infertile patients with sperm concentration lt;5x106/ml and in men undergoing assisted reproduction techniques, since the genetic defect and, most probably, the related infertility problem will be transmitted to the sons.
Abstract: Molecular analysis of Y-chromosomal microdeletions is routinely performed in the work-up of male infertility, in order to establish a diagnosis and for genetic counseling of the couple, since such microdeletions are transmitted to the male offspring. The review of published data shows that microdeletions are relatively common in patients with azoospermia or severe oligozoospermia, with wide variations in the reported deletion frequency depending mainly on the selection criteria. In general, patients with proximal deletions, involving the AZFa and/or the AZFb region show severe defects of spermatogenesis with a high prevalence of Sertoli cell only syndrome, while deletions of the distal AZFb and of the AZFc region can be compatible with residual spermatogenesis. Microdeletions have been only sporadically found in normozoospermic patients. For the time being the molecular analysis of microdeletions of the Y chromosome is indicated in infertile patients with sperm concentration <5 x 10(6)/ml and in men undergoing assisted reproduction techniques, since the genetic defect and, most probably, the related infertility problem will be transmitted to the sons.
TL;DR: This review concentrates on the clear cases where knocking out a gene in mice has caused male infertility and thus comes near to proving that the gene plays a role in the development of sperm.
Abstract: This review concentrates on the clear cases where knocking out a gene in mice has caused male infertility and thus comes near to proving that the gene plays a role in the development of sperm. Knockout mice have been created with primary defects at every stage of spermatogenesis thus creating a framework for decoding the genetic hierarchy that causes male germ cell differentiation. As well as defining essential genes in vivo experiments have defined promoter and untranslated sequences responsible for the expression of proteins at all the spermatogenic stages. In conclusion knockout mice remain the ultimate test of spermatogenic hypotheses as well as providing detailed information about this complex process.
TL;DR: The AZFa region on the Y-chromosome long arm has been recently assembled in a complete sequence map contained in a contig and shown to span more than 1 Mb, and the phenotype of patients with deletion of both USP9Y and DBY seem to be invariably azoospermia with a testicular histology of Sertoli cell-only.
Abstract: The AZFa region on the Y-chromosome long arm has been recently assembled in a complete sequence map contained in a contig and shown to span more than 1 Mb. It contains three genes, USP9Y, DBY and UTY, but only the former two can be at present considered candidate genes for the infertile phenotype associated with deletion of this interval. These genes have X-homologues and are expressed in many tissues, even if DBY has a shorter transcript expressed in the testis only, strengthening its role in spermatogenesis. Only few patients with gene-specific deletion have been reported and a clear genotype-phenotype relation is still lacking. While deletions or even smaller mutations in USP9Y seem to be associated with a testicular phenotype of severe hypospermatogenesis, patients with deletions of DBY may present both Sertoli cell-only syndrome and severe hypospermatogenesis. On the contrary, the phenotype of patients with deletion of both USP9Y and DBY seem to be invariably azoospermia with a testicular histology of Sertoli cell-only.
TL;DR: Interestingly, in male germ cells, CREM is not phosphorylated but associates with ACT, a member of the LIM-only class of proteins that has intrinsic transcriptional activity, suggesting that CREM can bypass the classical requirement for phosphorylation and association with CBP.
Abstract: In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. The CREB and CREM transcription factors are activated by phosphorylation of a key serine residue by kinase stimulated by cyclic AMP, calcium, growth factors and stress signals. Phosphorylation allows recruitment of CBP (CREB Binding Protein), a large co-activator that contacts the general transcriptional machinery. The CREM gene plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. CREM is highly expressed in postmeiotic cells upon a striking developmental switch regulated by the pituitary hormone FSH. CREM-mutant mice generated by homologous recombination reveal that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent while there is a significant increase in apoptotic germ cells. Mutant male mice completely lack spermatozoa, a phenotype reminiscent of cases of human infertility. Interestingly, in male germ cells, CREM is not phosphorylated but associates with ACT, a member of the LIM-only class of proteins that has intrinsic transcriptional activity. Thus, in some circumstance, CREM can bypass the classical requirement for phosphorylation and association with CBP.
TL;DR: Issues are debated in this article including CF mutations in non-CBAVD forms of male infertility, and the potentially misleading role of CF genetic analysis when used to rule out other possible causes of infertility in azoospermic men.
Abstract: Congenital bilateral absence of the vas deferens (CBAVD) is a relatively frequent cause of male infertility accounting for 1-2% of cases of male sterility and at least 6% of cases of obstructive azoospermia. In the last decade a genetic basis for CBAVD has been provided by its association with cystic fibrosis (CF) and nowadays CBAVD is in most cases considered to be a mild or incomplete form of CF disease. Many individuals with CBAVD show usually mild CF-compatible clinical manifestations, but the long-term prognosis could possibly not be as innocuous as it presently looks: more data will be available through medium or long-term follow-up studies. Once a correct diagnosis of CBAVD has been formulated and if the couple is planning a pregnancy by artificial reproductive technology, it is crucial to test both the affected male and his partner for CFTR mutations. Such testing has a number of complex implications and should always be performed together with genetic counselling. Other issues are debated in this article including CF mutations in non-CBAVD forms of male infertility, and the potentially misleading role of CF genetic analysis when used to rule out other possible causes of infertility in azoospermic men.
TL;DR: The X-linked androgen receptor (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men, showing that defects in the AR gene lead to the production of dysfunctional receptor protein in up to 10% of males with abnormally low sperm production and male infertility.
Abstract: Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by sex chromosomes. To determine the contribution of genetic aberrations to male infertility, the X-linked androgen receptor (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men. Genetic screening of over 400 patients and controls showed that defects in the AR gene lead to the production of dysfunctional receptor protein in up to 10% of males with abnormally low sperm production and male infertility. The dozens of mutations and polymorphisms uncovered were associated with subtly reduced intrinsic AR activity, and are of two main categories: polymorphic changes in length of a trinucleotide CAG tract in the N-terminal transactivation domain, and missense mutations in the C-terminal ligand-binding domain. These polymorphisms and mutations are associated with reduced AR function due to defective intermolecular protein-protein interactions with coactivator molecules. Genetic screening for AR mutations and polymorphism should be offered to severely oligospermic and azoospermic patients. These traits can be transmitted to progeny, and counseling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy.
TL;DR: The analysis of genetically altered mice which lack either PTHrP or the PTH/PTH rP receptor, as well as of transgenic mice in which the mutant receptor is targeted to the growth plate, has provided a molecular explanation for the severe skeletal abnormalities seen in JMC.
Abstract: JMC is a rare autosomal dominant form of short limb dwarfism characterized by asymptomatic hypercalcemia and skeletal deformities, despite low PTH and PTHrP levels. This rare disorder is likely to be caused by activating mutations in the PTH/PTHrP receptor leading to ligand-independent cAMP accumulation. The analysis of genetically altered mice which lack either PTHrP or the PTH/PTHrP receptor, as well as of transgenic mice in which the mutant receptor is targeted to the growth plate, has provided a molecular explanation for the severe skeletal abnormalities seen in JMC. In addition, the study of this rare human disorder has further elucidated the fundamental role played by the PTH/PTHrP receptor in mediating both the paracrine/autocrine actions of PTHrP in growth plate development and bone elongation, as well as the endocrine actions of PTH. The insight gained from the study of this human disease model is likely to continue to provide an important tool to define the cellular and molecular mechanisms that mediate the biological roles of the PTH, PTHrP and their receptor.
TL;DR: The findings confirm the high incidence of chromosomal anomalies among infertile males, highlight the relevance in male infertility of quantitative/positional modifications of the constitutive heterochromatin, and underline the relevance of cooperation between andrologists and cytogenetists prior to every kind of assisted reproduction.
Abstract: Reduced male fertility can be caused by genetic factors affecting gamete formation or function; in particular, chromosome abnormalities are a possible cause of male subfertility as shown by their higher frequency in infertile men than in the general male population. Meiotic studies in a number of these males have shown spermatogenesis breakdown, often related to alterations in the process of chromosome synapsis. Indeed, any condition that can interfere with X-Y bivalent formation and X-chromosome inactivation is critical to the meiotic process; furthermore, asynapsed regions may themselves represent a signal for the meiotic checkpoint that eliminates spermatocytes with synaptic errors. We performed cytogenetic, hormonal and seminal studies in 333 infertile patients selected because azoospermic, severely oligozoospermic or normozoospermic with failure to fertilize the partner's oocytes in an in vitro fertilization (IVF) program. Our findings: 1) confirm the high incidence of chromosomal anomalies among infertile males; 2) highlight the relevance in male infertility of quantitative/positional modifications of the constitutive heterochromatin; and 3) underline the relevance of cooperation between andrologists and cytogenetists prior to every kind of assisted reproduction, above all prior to intracytoplasmic sperm injection, in which selective hurdles eliminating abnormal germ cells are bypassed.
TL;DR: Findings imply that important pre-mRNA processing pathways might be disrupted in the germ cells of AZFb men, and this work has focused on the RBMY genes, among the oldest genes on the mammalian Y chromosome.
Abstract: Microdeletions of the AZFb region of the human Y chromosome usually result in severe consequences for spermatogenesis. AZFb contains at least four kinds of genes/gene families. These include a number of RBMY genes, which are clustered in the AZFb deletion interval. They are amongst the oldest genes on the mammalian Y chromosome, and are related to the gene encoding hnRNPG (RBMX) on the X chromosome. A retroposon-derived version of these genes is found on chromosome 11 that might replace the function of these genes during meiosis, during which time the X and Y chromosomes are transcriptionally inactivated. Each of these genes encodes proteins with an RNA binding motif, and interacts with more ubiquitously expressed proteins involved in pre-mRNA splice site selection. These findings imply that important pre-mRNA processing pathways might be disrupted in the germ cells of AZFb men.
TL;DR: The experimental and human evidence of the effects of occupational and environmental chemical agents on hypothalamus-pituitary unit, pineal gland, parathyroid and calcium metabolism and adrenal glands is reviewed.
Abstract: In the last few years great concern has arisen from the description of adverse endocrine effects of several occupational and environmental chemical agents on human and/or wildlife health. Such agents may exert their effects directly, specifically binding to hormone receptors, and/or indirectly, by altering the structure of endocrine glands and/or synthesis, release, transport, metabolism or action of endogenous hormones. Many studies have been focused on the outcomes of the exposure to those chemicals mimicking estrogenic or androgenic actions. Nonetheless, the disruption of other hormonal pathways is not negligible. This paper reviews the experimental and human evidence of the effects of occupational and environmental chemical agents on hypothalamus-pituitary unit, pineal gland, parathyroid and calcium metabolism and adrenal glands.
TL;DR: The present review is focused on the clinical implication of RET gene mutations in thyroid cancer patients, and finds that family members at-risk of hereditary MTC may be screened by genetic analysis, to distinguish those carrying or not-carrying the mutation.
Abstract: Different forms of RET mutations are found in papillary and medullary thyroid carcinomas. Rearrangements with other genes (RET/PTC oncogene) play a causative role in a significant proportion of papillary thyroid carcinomas. In this case, several factors influence the frequency and the type of RET/PTC, such as exposure to radiation, age and histological variant of the papillary tumor. On the other hand, the presence of the mutation does not seem to influence the biological behavior of the tumor or its response to conventional treatment modalities. In the setting of medullary thyroid cancer, germline RET point-mutations are implicated in the pathogenesis of virtually all hereditary forms and somatic point-mutations in nearly half of the sporadic forms. The clinical impact of this finding is that family members at-risk of hereditary MTC may be screened by genetic analysis, to distinguish those carrying or not-carrying the mutation. The last can be reassured on their status and relieved from further follow-up. Those with the mutation may be treated at a pre-clinical stage of the disease or even before the disease is started. The present review is focused on the clinical implication of RET gene mutations in thyroid cancer patients.
TL;DR: The case of a 39-yearold woman with oncogenic osteomalacia caused by osteosarcoma of the right scapula which was unrecognized for several years and subsequently developed tertiary hyperparathyroidism after treatment with oral phosphate and Vitamin D is reported.
Abstract: Oncogenic osteomalacia is a rare paraneoplastic syndrome. It is characterized by bone pain, muscle weakness, gait disturbance, fractures and skeletal deformities. Hypophosphatemia, diminished renal phosphate reabsorption, decreased 1,25 dihydroxy Vitamin D and elevated alkaline phosphatase are the biochemical hallmarks of this disorder. Most tumors are of mesenchymal origin. We report the case of a 39-year-old woman with oncogenic osteomalacia caused by osteosarcoma of the right scapula which was unrecognized for several years. She subsequently developed tertiary hyperparathyroidism after treatment with oral phosphate and Vitamin D. This case illustrates that oncogenic osteomalacia may persist for many years before the tumor is discovered. This is because the tumors are frequently very small and are in obscure locations. The uniqueness of this case is the coexistence of hyperparathyroidism and oncogenic osteomalacia. Five other cases have been reported up to date. All patients had received phosphate supplement, ranging from 10 to 14 years prior to their diagnosis. Interestingly, our patient was on the treatment for only 2 years. The proposed mechanism is that exogenous phosphate stimulates parathyroid activity through sequestration of calcium.
TL;DR: Data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1β and cortisol secretion is deranged in anorexia nervosa.
Abstract: A hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in anorexia nervosa (AN), together with some immunological abnormalities, involving citokine — and particularly Tumor Necrosis-Factor-α (TNF-α) — production by polymorphonuclear cells. The ability of pro-inflammatory cytokines to activate the HPA axis is well known; however, there are no data demonstrating an interdependence between immunological and endocrine response in AN. To investigate the presence of a correlation between immune response and pituitary-adrenal function, plasma ACTH and serum cortisol concentrations were measured in 13 AN patients and in the same number of controls. TNF-α and interleukin (IL)-1β production by ex-vivo unstimulated and LPS-stimulated peripheral mononuclear cells was also assessed. Circulating cortisol concentrations were higher (p<0.01) in AN (156.7±45.1 μg/l, mean±SD) than in controls (105.9±25.7 μg/l). Unstimulated IL-1β release in supernatants of mononuclear cell cultures was slightly but not significantly higher in AN than in controls, while TNF-α release was similar in the two groups. A positive correlation was found between IL-1β concentrations in unstimulated culture supranatants and serum cortisol levels in AN (r=0.782, p=0.002), while in normal subjects there was a trend toward a negative correlation; a slight positive correlation, while not significant, between IL-1β and plasma ACTH, as well as between TNF-α and serum cortisol was also found in AN. These data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1β and cortisol secretion is deranged in AN.