Clinical features and therapeutic outcomes of patients with acromegaly: single-center experience.

The aim of this study was to review the outcome of acromegaly treatment, as well as co-morbidity and mortality in a series of patients with acromegaly attending a single center in the last 10 yr. In that period, 53 patients were treated for acromegaly. Transsphenoidal operation was applied as the first-line therapy in 94.3% of patients and it led to disease remission in 59.2% of them. The remission criteria included a nadir GH<1 µg/l after glucose load, and normal age-related IGF-I levels. The remission rate after transsphenoidal surgery was significantly higher in the group of patients with microadenoma (76.9%), than in the group of patients with macroadenoma (52.8%). Patients with invasive tumors had remission rate of 16.7% after transsphenoidal surgery. There were no perioperative deaths. As the second-line treatment somatostatin analogues, radiotherapy, and dopaminergic agonists were used. Hypertension and diabetes were the most frequent co-morbidities in the group of patients. After successful treatment, 30% of patients with diabetes or impaired glucose tolerance had significant improvement of glycemic control. Transsphenoidal surgery is the appropriate firstline therapy in patients with somatotropinoma. Medical and radio-therapy should be reserved as the second-line therapy after surgery failure.

Decreased peak bone mass is associated with a 3-bp deletion/insertion of the CYP19 intron 4 polymorphism: preliminary data from the GOOS study.

Finding that estrogen plays an important role in bone homeostasis in men prompted research on relationship of polymorphism at the CYP19 gene and the bone mass. Therefore, influence of 3-bp deletion/insertion polymorphism of CYP19 (TTTA)7 allele on the peak bone mass attainment in males was studied. Fifty-eight unrelated male participants, aged 21-35, were selected depending on the presence of (TTTA)7 (no.=19) or (TTTA)7-3 (no.=39) alleles from the initial cohort of 92 young males. Heterozygotes (TTTA)7/(TTTA)7-3 (no.=13) were not included in the analysis. Serum levels of estradiol, free testosterone, 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, and beta-crosslaps were measured. Bone mass was measured by DXA at the hip and at the spine. (TTTA)7-3 allele was associated with significantly lower femoral neck bone mineral density (BMD) (p=0.02). Logistic regression model indicated strong association of (TTTA)7-3 allele with low BMD in the range of osteopenia/osteoporosis (p=0.014, odds ratio 12.36, confidence intervals 1.65-92.46). In the present study association of 3-bp deletion polymorphism of the (TTTA)7 allele with decreased peak bone mass in males is reported for the first time. However, further studies are necessary to elucidate the functional relevance of this polymorphism.

Clinical and morphological features of undifferentiated monomorphous GH/TSH-secreting pituitary adenoma.

A 41-year-old male presented with progressive visual defects, acromegaly and hyperthyroidism. After clinical evaluation a giant GH/TSH-secreting pituitary adenoma was diagnosed. Administration of the somatostatin analog octreotide at doses of 150 microg s.c. per day inhibited the secretion of both GH and TSH. A three-week treatment with octreotide prior to surgery led to slight visual improvement and CT scan showed some new necrotic areas within the tumor mass. Transcranial surgery was performed. By immunohistochemical analyses of the adenoma tissue GH, prolactin and beta-chorionic gonadotropin were detected; TSH was negative. Electron microscopy revealed an undifferentiated, monomorphous adenoma with morphological features of an acidophil stem cell adenoma such as the presence of misplaced exocytoses, fibrous bodies and mitochondrial gigantism. However, the tumor cells contained small secretory granules (up to 250 nm) accumulated along the cell membrane characteristic of thyrotrope cells. Furthermore, some adenoma cells were fusiform with long cytoplasmic processes resembling thyrotropes. Two months after the operation CT scan revealed a large residual tumor. Serum GH and TSH levels had increased again and the TSH level was even higher than before the treatment. The patient died suddenly, most probably of lethal arrhythmia. Specimens of the adenoma tissue obtained at autopsy confirmed the previous findings with the exception of positive immunostaining for TSH which was found in less than 1% of the adenoma cells. This undifferentiated, monomorphous GH/TSH-secreting pituitary adenoma represents an entity that is unusual both in its ultrastructural features and clinical manifestations suggesting a cytogenesis from an early, undifferentiated stem cell.

[Tests of adrenal gland and ovarian function in the hyperandrogenemia syndrome]. / Testovi funkcije nadbubrezne zlijezde i jajnika u sindromu hiperandrogenemije.

Androgen production in women is under the influence of pituitary hormones on ovaries and adrenal glands, or they originate from peripheral conversion of androgen precursor. Each of the three principal compartments of androgen production has a serum specific marker that may be clinically helpful. Serum testosterone signifies ovarian production, dehydroepiandrosterone sulfate (DHA-S) is an adrenal marker, and serum 3 alpha-diol glucuronide reflects androgen action in the peripheral compartment. Many physiologic and pathologic states affect transport proteins and enzyme systems which modulate androgenic activity. This fact makes the determination of mechanism and origin of hyperandrogenemia more difficult, as well as the choice of therapy. In the syndrome of hyperandrogenemia, the primary place of the disorder is determined by the tests of adrenal cortex and ovary functions. The correct response of androgens in dexamethasone test is manifested by free testosterone suppression to < 0.028 nmol/L, and by DHA-S and plasma cortisol suppression under the reference values. In the complex and controversial syndrome of hyperandrogenemia, the nafarelin test is used after insufficient free testosterone suppression in dexamethasone test. The significant diagnostic criterion is the rise of 17-hydroxyprogesterone (17-OHP) over 7 nmol/L, which aligns a great number of idiopathic hyperandrogenemias in the group of polycystic ovary syndrome. A good correlation was found between the rise of 17-OHP in nafarelin test and the suppression of free testosterone in dexamethasone test. This finding supports the conception that both tests determine the ovary function and that their sensitivity and specificity for ovary hyperandrogenemia is comparable.

[The role of the TRS-Glucotest apparatus in self-monitoring by patients with diabetes mellitus]. / Uloga TRS-Glukotest aparata u samokontroli bolesnika sa secernom bolesti.

Successful treatment of diabetes mellitus requires a reliable control of glycaemia where self-monitoring with reflectometer plays a significant role. TRS-glucotest reflectometer (TRS, Zagreb), the result of our experts' efforts, makes it possible for diabetic patients to perform self-monitoring. According to our research TRS-glucotest reflectometer shows lower blood glucose levels for more than 20%, especially in 3.8-11.5 mmol/L range of glucose concentration, that is in the range most often expected in patients with diabetes got under control. A considerable dispersion of the results got by measuring glucose levels with reflectometer doesn't offer the possibility to correct the obtained values. Our results suggest that TRS-glucotest reflectometer should be improved so that reliable control of glycaemia can be made what is especially important in patients with intensive conventional insulin treatment.

[Low-renin hypertension and inherited mineralocorticoid diseases]. / Niskoreninska hipertenzija i nasljedne bolesti mineralokortikoida.

Liddle's syndrome, apparent mineralocorticoid excess (AME) and glucocorticoid remediable aldosteronism (GRA) are inherited diseases characterized by hypertension and low plasma renin activity. Constitutive activation of distal renal epithelial sodium channel (Liddle's syndrome), defect in 11 beta-hydroxysteroid dehydrogenase activity (AME) and unequal crossing over, fusing regulatory sequences of 11 beta-hydroxylase gene to coding sequences of aldosterone synthase gene and forming a new chimeric gene (GRA), cause apparent or real mineralocorticoid excess. This diseases are often being unrecognized and classified as essential hypertension, especially in patients with normal serum potassium level. Family history of hypertension and characteristic serum and urine++ steroid profile direct us to diagnosis, and genetic analysis will confirm it.

[Importance of the CRH (corticotropin releasing hormone) test in the differential diagnosis of Cushing's syndrome]. / Vrijednost CRH-testa u diferencijalnoj dijagnozi Cushingova sindroma.

In the group of 13 patients with Cushing's syndrome (CS) CRH test was performed by sampling the blood from peripheral vein and in eight patients also after inferior petrosal sinus catheterization (IPSC) to resolve the disease etiology. In the group of patients with Cushing's disease (CD, n = 11), which was proven by surgery and adenoma immunohistochemistry, 10/11 had in CRH test the significant increase of cortisol and ACTH in the peripheral blood. Among two patients with ectopic ACTH syndrome one had the significant increase of both hormones in CRH test. After IPSC the ratio of ACTH in the petrosal sinus and in the peripheral vein was significant in 4/8 patients before, and in 6/8 after CRH administration. The intersinus gradient was significant in 3/8 patients before, and in 4/8 after CRH test. According to our results we can conclude that the determination of ACTH in the blood from peripheral veins after CRH administration is a very sensitive method for differential diagnosis of CS, while the results after IPSC were less sensitive in our conditions than those described in the literature.

Guidelines for the prevention, detection and therapy of vitamin d deficiency in adults

It is estimated that over one billion of people around the globe have low serum values of vitamin D, therefore, we can consider vitamin D deficiency as a pandemic and public health problem. Geographic position of Croatia, especially the continental part of the country, is a risk factor for the development of deficiency of vitamin D in the population. The aim of these guidelines is to provide the clinicians with easy and comprehensive tool for prevention, detection and therapy of vitamin D deficienney in healthy population and various groups of patients. They were made as a result of collaboration of clinicians of different backgrounds who are dealing with patients at risk of vitamin D deficiency. These guidelines are evi- dence-based, according to GRADE-system (Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendation. The main conclusions address the recommended serum vitamin D values in the population which should be between 75 and 125 nmol/L and defining recommended preven- tive and therapeutic dosages of vitamin D in order to reach the adequate levels of serum vitamin

Calcaneus ultrasound in males: normative data in the Croatian population (ECUM study).

Limited number of dual X-ray absorptiometry (DXA) devices in Croatia makes this diagnostic technique unavailable to the majority of the population. Quantitative ultrasound (QUS) of the calcaneus could be an alternative tool for assessing fracture risk. However, age-specific normative data should be obtained before using the QUS in everyday clinical practice. The aim of our Epidemiology of Calcaneus Ultrasound in Males (ECUM) study is to establish the normative QUS data in a healthy sample of Croatian males. A total of 1002 male participants, aged 20-99, recruited in different Croatian counties, were included in the study. In each subject broadband ultrasound attenuation (BUA), speed of sound (SOS) and quantitative ultrasound index (QUI) of the left calcaneus were measured using the Sahara ultrasound device (Hologic). The coefficients of variation were 2.85 for BUA, 0.37 for SOS and 2.49 for QUI. Significant declining with age was found for all three parameters, BUA (p<0.001), SOS (p<0.001) and QUI (p<0.001), with respective r values 0.14, 0.27 and 0.23. The peak SOS (1,562.8+/-28.5 m/sec) and QUI (103.6+/-16.5) values were observed in the third decade, whereas the peak BUA value (86.2+/-19.2 db/MHz) was observed in the fourth decade. A subgroup of 103 participants, aged 20-29, was used to estimate young adult mean and SD for QUI and calculate the T-scores. Using the World Health Organization diagnostic criteria the rates of osteoporosis (T-score<-2.5) in the males aged 50 and older was 5.8%. However, when we used the cut-off value of the T-score<-1.8, as previously suggested, prevalence of osteoporosis in Croatian males >50 yr was 16.2%. Although further studies might improve our understanding of the QUS role in the fracture prediction, we hope that the results presented here will improve the clinical management of osteoporosis in males.

Some aspects of adrenocortical stress response following stroke.

Stress response measured as the cortisol secretion rate as well as urinary 17 oxogenic steroid (17 OGS) and 17 oxosteroid (17 OS) excretion was investigated in a group of 28 patients with stroke (11 with hypertensive intracerebral hemorrhage and 17 with ischemic cerebrovascular insult). Significantly higher cortisol secretion values were found in the group of patients who died (p less than 0.01). Similarly, the first day urinary 17 OGS excretion pointed to the greater adrenocortical response in patients who died (p less than 0.05). Urinary 17 OS excretion was normal or below normal in the majority of patients and no difference was found between either male or female patients who survived or died. Our findings indicate that adrenocortical changes which maximize the production of cortisol are operative soon after the onset of stroke. The cortisol secretion rate appeared to be a good indicator of the severity of the stress caused by stroke and may be useful in predicting the prognosis of the illness.

Measurement of salivary insulin-like growth factor-I in acromegaly: comparison with serum insulin-like growth factor-I and growth hormone concentrations.

The aim of this study was to establish the concentration of insulin-like growth factor-I (IGF-I) in saliva of acromegalic patients, and to compare it with the basal levels of serum IGF-I and growth hormone. IGF-I was determined in extracted serum or neat saliva by a disequilibrium RIA using antibodies and iodinated ligand from Amersham and WHO 87/518 as standard. The detection limit of the assay was 0.5 microgram/l, and the intra- and interassay coefficients of variations were 7.9% and 15% respectively. Our study included 13 healthy adult individuals and 17 acromegalics. Compared with healthy adult subjects, acromegalics had significantly higher salivary IGF-I concentrations (mean +/- SEM 5.4 +/- 2.64 vs. 10.5 + -5.69 micrograms/l; p < 0.01), as well as serum IGF-I (176 +/- 42.9 vs. 520 +/- 98.8 micrograms/l; p < 0.0001) and somatotropin levels (1.2 +/- 1.02 vs. 15.4 +/- 9.89 micrograms/l; p < 0.0001). However, 47.1% patients (8 out of 17) with active acromegaly had salivary IGF-I concentrations within the normal range. Serum IGF-I and somatotropin concentrations were found to follow more closely the disease activity after adenomectomy, compared with the concentrations of salivary IGF-I. These results suggest that the IGF-I levels in serum and saliva are somatotropin-dependent. According to our results, measurement of IGF-I in saliva cannot be considered as an additional measure for evaluation of the disease activity in acromegaly, being less reliable than the determination of IGF-I and somatotropin in serum.

Massive osteolysis in a girl with agenesis of thyroid C cells.

A rare case of massive osteolysis affecting the pelvis of a young girl is presented. The clinical, radiographic, and histopathological features are described in detail. Septicemia complicated the clinical course and the patient eventually died. Histopathological examination of the pelvic lesion revealed massive osteolysis characterized by prominent osteoclastic activity with extensive bone resorption. A thorough post-mortem histological examination of the thyroid gland showed no C cells. This is an interesting observation, since it is known that thyroid C cells are the primary source of calcitonin. Since the main biological effect of calcitonin is to inhibit osteoclastic bone resorption, there is a possibility that massive osteolysis in our case could have been related to the lack of this hormone. There is a clear need for further investigation regarding the role of thyroid C cells and calcitonin in this puzzling disease.

Effects of ritanserin, a novel serotonin-S2 receptor antagonist, on the secretion of pituitary hormones in normal humans.

The availability of a new potent and selective serotonin-S2 antagonist, ritanserin (RIT), encouraged us to further investigate the effect of serotonin on the basal secretion of anterior pituitary hormones in normal humans. Administered in a single 30-mg dose to group 1 consisting of 10 normal women, RIT failed to affect the baseline LH, FSH, GH or TSH levels. In group 2 consisting of 20 normal subjects (ten males and ten females), the same dose of RIT decreased in parallel both ACTH and cortisol levels but only at 180 min. Group 3 consisting of 8 normal men was studied on three separate occasions seven days apart: each subject received graded doses of 10 mg, 20 mg and 30 mg RIT. The mean baseline PRL concentration at 180 min as well as the net integrated area under the hormone curve (nAUC) decreased only after the highest dose, while the baseline cortisol concentrations at 180 min as well as the corresponding nAUC values displayed a clear dose-dependent response. The findings indicated the serotonin-S2 receptors to be only partially involved in the basal secretion of ACTH in normal humans.

Effects of ritanserin, a specific serotonin-S2 receptor antagonist, on the release of anterior pituitary hormones during insulin-induced hypoglycemia in normal humans.

The role of serotonin in the insulin hypoglycemia (IH) stimulated secretion of prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH) and cortisol (F) was studied in a group of 12 normal subjects during the control period after placebo and a consecutive six-day treatment with 20 mg ritanserin (RIT) per day. RIT failed to affect the baseline levels of all the four hormones as well as the PRL response to IH (p > 0.5). The serum GH response to IH was moderately diminished after RIT, the reduction of integrated trapezoidal area under hormone curves (nAUC) being 50.7% +/- 6.9% (p < 0.005). Furthermore, RIT was found to slightly decrease the plasma ACTH response to IH, the reduction of nAUC being 36.3% +/- 2.6% (p < 0.005). Decrease in the corresponding plasma F response to IH was accompanied by 29.1% +/- 2.4% reduction of nAUC (p < 0.005). According to our results, serotonin-S2 receptors appeared to be moderately involved in IH-induced release of GH, but slightly in that of ACTH, leaving unaffected that of PRL.