High variability in baseline urinary free cortisol values in patients with Cushing's disease.

OBJECTIVE: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data. DESIGN: Observational study (enrolment phase of Phase III study). METHODS: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks. RESULTS: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism. CONCLUSIONS: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.

A systematic review of craniospinal irradiation for leptomeningeal disease: past, present, and future.

PURPOSE: Leptomeningeal disease (LMD) is a rare but deadly complication of cancer in which the disease spreads to the cerebrospinal fluid and seeds the meninges of the central nervous system (CNS). Craniospinal irradiation (CSI) involves treatment of the entire CNS subarachnoid space and is occasionally used as a last-resort palliative therapy for LMD. METHODS: This review examined literature describing the role of CSI for LMD from solid and hematologic malignancies in adults. A search for studies published until September 1, 2020 was conducted using PubMed database. RESULTS: A total of 262 unique articles were identified. Thirteen studies were included for analysis in which a total of 275 patients were treated with CSI for LMD. Median age at time of irradiation was 43 years, and most patients had KPS score of 70 and higher. The most common cancers resulting in LMD were acute lymphocytic leukemia, breast cancer, and acute myelogenous leukemia. Median CSI dose was 30 Gy and 18% of patients were treated with proton radiation. 52% of patients had stable-to-improved neurologic symptoms. Median overall survival for the entire cohort was 5.3 months. Patients treated with marrow-sparing proton radiation had median OS of 8 months. The most common treatment toxicities were hematologic and gastrointestinal events. CONCLUSIONS: Despite advances in systemic and radiation therapies, LMD remains a devastating end-stage complication of some malignancies. Treatment-related toxicities can be a significant barrier to CSI delivery. In select patients with LMD, marrow-sparing proton CSI may provide safer palliation of symptoms and prolong survival.

In vivo response to growth hormone-releasing peptide-6 in adrenocorticotropin-dependent Cushing's syndrome by lung carcinoid tumor is associated with growth hormone secretagogue receptor type 1a mRNA expression.

GH secretagogues (GHS) have been used for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) since 1997 due to their ability to increase ACTH and cortisol levels in Cushing's disease. The aim of this study was to correlate ACTH response to GH-releasing peptide-6 (GHRP-6) in vivo with GH secretagogue receptor type 1a (GHSR-1a) mRNA expression in a patient with lung carcinoid tumor. The patient was a 26-yr-old male with diagnosis of ACTH-dependent CS. He presented negative responses to human CRH and desmopressin tests; yet, a significant increase in ACTH after the GHRP-6 test was observed. Sellar magnetic resonance imaging (MRI) showed slight posterior hypointensity, but bilateral petrosal sinus sampling did not show central gradient. Computed tomography (CT) and MRI of thorax/abdomen/cervical were negative and 111In-pentetreotide scintigraphy depicted abnormal uptake on the right lung. The patient was submitted to right thoracotomy for exeresis of lung nodule and hilar lymph node which were characterized as atypical lung carcinoid tumor and he presented clinical and laboratorial remission after surgery. GHSR-1a mRNA expression was studied with real-time quantitative PCR and tumor data were compared with fragments of normal lung and pituitary. There was a higher GHSR-1a expression in the lung carcinoid tumor as compared with normal tissues. The ACTH response to GHRP-6 in a patient with ectopic ACTH production by a lung carcinoid tumor was associated with GHSR-1a expression in the tumor tissue, suggesting an association between GHSR-1a mRNA overexpression and the in vivo response to GHS.

Long-term treatment of Cushing's disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial.

BACKGROUND: Treating hypercortisolism in patients with Cushing's disease after failed surgery often requires chronic medication, underlining the need for therapies with favourable long-term efficacy and safety profiles. METHODS: In a randomised, double-blind study, 162 adult patients with persistent/recurrent or de novo Cushing's disease received pasireotide. Patients with mean urinary free cortisol at/below the upper limit of normal or clinical benefit at month 12 could continue receiving pasireotide during an open-ended, open-label phase, the outcomes of which are described herein. RESULTS: Sixteen patients received 5 years of pasireotide treatment. Among these, median (95% confidence interval) percentage change from baseline in mean urinary free cortisol was -82.6% (-89.0, -41.9) and -81.8% (-89.8, -67.4) at months 12 and 60. Eleven patients had mean urinary free cortisol ≤ upper limit of normal at month 60. Improvements in clinical signs were sustained during long-term treatment. The safety profile of pasireotide at 5 years was similar to that reported after 12 months. Fifteen of 16 patients experienced a hyperglycaemia-related adverse event; glycated haemoglobin levels were stable between months 6 and 60. Adverse events related to hyperglycaemia, bradycardia, gallbladder/biliary tract, and liver safety were most likely to first occur by month 6; adverse event severity did not tend to worsen over time. CONCLUSIONS: This represents the longest prospective trial of a medical therapy for Cushing's disease to date. A subset of patients treated with pasireotide maintained biochemical and clinical improvements for 5 years, with no new safety signals emerging. These data support the use of pasireotide as an effective long-term therapy for some patients with Cushing's disease.

Growth hormone pulsatility in active and cured acromegalic subjects.

GH secretion in normal subjects is periodic, with pulses prevailing during sleep. During the day (basal secretion), GH levels are, in general, undetectable. We studied GH secretion by cluster analysis, collecting samples every 20 min for 24 h in 44 subjects: 11 patients with active acromegaly; 16 "cured" acromegalics, and 17 normal subjects. The purpose of this study was to compare GH secretion between patients with active acromegaly and "cured" patients and between "cured" acromegalic patients and normal controls. The number of pulses detected through the 24-h GH profile was not different between acromegalic patients regardless of disease activity (17.5 +/- 4.4 vs. 15.0 +/- 6.0, respectively), but was different when active acromegalic patients and normal controls were compared (8.1 +/- 1.0; P < 0.05) and when cured acromegalic patients and normal controls were compared (P < 0.05). The GH pulsatile secretion/total GH secretion ratio was higher in normal controls than in acromegalic patients regardless of disease activity. We concluded that 1) the increases in GH pulsatility in active and cured acromegalic patients are similar, but most of the 24-h GH secretion is nonpulsatile; 2) half of the GH secretion in normal subjects occurs during pulses; 3) cured acromegalic patients, even those with normal GH and insulin-like growth factor I levels, do not recover a normal GH secretory pattern.

Resistance to vasopressin action on the kidney in patients with Cushing's disease.

OBJECTIVE: To assess the plasma levels and action of arginine vasopressin (AVP) in patients with Cushing's disease. There are many reports that patients with Addison's disease have increased AVP levels associated with hyponatraemia and hypoosmolality, but none on the dynamics of secretion of this neurohormone during osmolality-based stimulation in patients with chronic hypercortisolism. DESIGN AND SUBJECTS: The plasma AVP concentration and the urinary and plasma osmolality after a 7.5-h water deprivation test (WDT) were evaluated in 13 patients with Cushing's disease and 15 normal (control) individuals. In patients with Cushing's disease we also assessed the urinary osmolality in response to 10 micrograms i.v. desmopressin (DDAVP) administered at the end of the WDT. RESULTS: At the end of the WDT, urinary osmolality was significantly lower in patients with Cushing's disease (511.5 +/- 148.5 mOsm/l) than in the normal subjects (981.1 +/- 107.1 mOsm/l, P < 0.001), whereas plasma osmolality did not differ between the two groups. Consequently, the urine/plasma osmolality ratio (Uosm/Posm) was lower in patients with Cushing's disease than in normal individuals (1.8 +/- 0.5 compared with 3.4 +/- 0.4, P < 0.001). The AVP concentration also was greater (7.3 +/- 3.1 pmol/l) in those with Cushing's disease than in the controls (3.9 +/- 2.3 pmol/l, P < 0.005). After administration of DDAVP to the hypercortisolaemic patients, the urinary osmolality attained (718.0 +/- 200.0 mOsm/l) was still lower than that in the normal group at the end of WDT (P < 0.005). CONCLUSIONS: Patients with Cushing's disease presented higher AVP levels and smaller Uosm/Posm ratios than normal subjects. After DDAVP, the patients with Cushing's disease were unable to concentrate the urine adequately. These data suggest that the kidney shows resistance to the action of both endogenous and exogenous AVP in patients with Cushing's disease.

Somatotrophic and corticotrophic function outcome after transesphenoidal surgery in patients with sellar tumors and pre-operative endocrine deficits.

Sixteen patients with sellar tumors that were treated surgically and who had pre-operative somatotrophic and corticotrophic function deficits were submitted to pre- and early post-operative insulin tolerance tests (ITTs). Seven patients had non-functioning adenomas, 5 had prolactinomas, 3 had craniopharyngioma and 1 had cordoma of the clivus. All patients had macro-tumors and none received radiotherapy within the studied period. Seven patients had GH, 4 had cortisol and 5 had both GH/cortisol function pre-operative deficit. Five patients with isolated GH, 4 with isolated cortisol and 3 with both GH/cortisol deficiencies showed a postoperative functional recovery. New cortisol secretion deficits were observed in 2 patients postoperatively and both required long-term steroid replacement. These data suggest that preoperative endocrine deficits may be reversible after surgical decompression of the sellar region and that new endocrine deficits are rarely seen after surgery. All such patients should be tested postoperatively from an endocrinological point of view to reevaluate the need for replacement therapies.

[Subclinical apoplexy in pituitary tumors]. / Apoplexia subclínica em tumores pituitários.

Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopletic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.

[Identical twins discordant for Cushing's disease: case report[]. / Gêmeas idênticas discordantes para a doença de Cushing. Relato de caso.

Cushing's disease is rare in children and its occurrence in identical twins is extremely rare. This paper reports on identical twins discordant for Cushing's disease. One of them first presented with a cushingoid phenotype by the age of 10. Her evaluation showed an increased urinary free-cortisol and serum ACTH. Her pattern in the dexametazone suppression tests was compatible with Cushing's disease. MRI disclosed a pituitary macroadenoma which was removed by the transesphenoidal approach. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells. The patient went into clinical and laboratorial remission after surgery. She re-started to grow after the disappearance of the Cushing's phenotype but she is still shorter than her healthy sister. The latter remains disease-free 4 years after her sister's diagnosis. This represents the third such case reported in the literature. Our findings suggest that acquired factors may be responsible for the genesis of Cushing's disease.

[Pituitary apoplexy followed by endocrine remission. Report of two cases]. / Apoplexia pituitária seguida de remissão endócrina. Relato de dois casos.

Pituitary apoplexy is rare and endocrine remission in patients with apopletic secreting pituitary adenomas is even rarer. This study reports on two patients with pituitary macroadenomas (one with Cushing's disease and the other with acromegaly) in whom endocrine remission occurred after apoplexy. The first patient had Cushing's disease and had an ictus of headache and vomiting after which she started a progressive remission of hypercortisolism. A post-apoplexy MRI disclosed persistence of a sellar and supra-sellar mass. She was submitted to transesphenoidal surgery. An hypertensive hemorrhagic cyst was found with no tumor. The second patient had acromegaly. While performing a LHRH-stimulation test he had an ictus of headache, vomiting, no visual loss and appearance of diabetes insipidus. A CT scan disclosed an intrasellar hematoma. Despite the size of the tumor and since there was no visual impairment, this patient was followed up without surgery. Imaging follow-up showed a progressive shrinkage and disappearance of the mass, which was corroborated by endocrine remission. A high rate of recurrence is reported in such patients in the literature. Both patients are being currently followed-up on a long-term basis.

[Preservation of gonadotrophic function and pregnancy in Sheehan's syndrome: a case report and review of the literature]. / Preservação da função gonadotrófica e gravidez na síndrome de Sheehan: relato de um caso e revisão de literatura.

Pregnancy occurring in patient with Sheehan's syndrome is seldom described. It depends on the preservation of LH and FSH secretion after the pituitary apoplexy event. PURPOSE--To report a patient with Sheehan's syndrome who became pregnant twice after the pituitary apoplexy episode and to discuss the maintenance of gonadotrophic function. METHOD--Clinical aspects are described and the pituitary reserve evaluation was performed as well as a computerized tomography and a magnetic resonance imaging of the brain. RESULTS--Gonadotrophic and thyrotrophic function were preserved and the neuroradiologic evaluation disclosed an empty sella turcica preservation of the posterior lobe of the hypophysis. CONCLUSION--A patient with Sheehan's syndrome is reported in whom the LH and FSH pituitary secretion was preserved allowing normal pregnancy twice after the pituitary apoplexy.

[Nephropathic cystinosis: report of 2 cases and review of the literature]. / Cistinose nefropática: relato de 2 casos e revisão da literatura.

We describe two patients with infantile nephropathic cystinosis who presented nephrogenic diabetes insipidus in addition to Fanconi syndrome. After the diagnosis was confirmed by slit-lamp examination that showed crystallization of the cornea and by the presence of cystine crystals in the bone marrow, the patients underwent conservative and supportive treatment including correction of acidosis, replacement of fluid losses and protection from bone demineralization with replacement of phosphorus, calcium and vitamin D. Patient 1 deceased after an episode of bronchopneumonia complicated by profound acidosis. Patient 2 was started on cysteamine which effectively reduce cystine in body tissues and prevents or slows progression of end-organ damage.

Adrenocorticotropin levels do not change during early recovery of transsphenoidal surgery for ACTH-secreting pituitary tumors.

In patients with ACTH-secreting pituitary tumor the peri-tumoral normal corticotrophs were supposed to be suppressed by cronic hypercortisolemia since frequently they develop transient secondary adrenal insufficiency after pituitary tumor resection and during early postoperative days. We evaluated the ACTH dynamics during transsphenoidal surgery in 16 patients with ACTH-secreting pituitary tumors (6 cured by surgery, 8 not cured Cushing's disease patients and 1 cured by surgery and 1 not cured Nelson's syndrome patients) and tested the hypothesis that in these patients, ACTH secretion from the peri-tumoral normal corticotrophs is inhibited and hence removal of the entire tumor should result in subtle postoperative reduction in plasma ACTH. Blood samples for ACTH determination were obtained from 14 Cushing's disease patients immediately before pituitary gland manipulation and 10, 30, 60, 90, 120, 150 and 300 min after pituitary tumor resection and on postoperative day one. In Nelson's syndrome patients the blood sample was obtained only after tumor removal. All patients received intravenous hydrocortisone during surgery and on the first postoperative day. Patients were considered cured by surgery if they presented adrenal insufficiency after hydrocortisone withdrawal. Mechanical pituitary manipulation induced increase in ACTH level. In all 14 Cushing's disease patients (cured and not cured), mean plasma ACTH levels were significantly greater 10 min after pituitary tumor resection (54.4+/-12.8 pmol/l) than in the premanipulation period (ACTH=26.3+/-5.3 pmol/l) (p=0.005). In Cushing's disease patients, the ACTH levels did not change significantly until 300 min after pituitary tumor resection either in those 6 patients cured by surgery (at 10 min after pituitary tumor resection ACTH was 54.4+/-12.8 pmol/l for all 14 Cushing's disease patients and at 300 min after tumor removal ACTH was 39.0+/-12.6 pmol/l for cured and 41.3+/-15.7 pmol/l for not cured Cushing's disease patients). The ACTH level also persisted high until 300 min after complete pituitary tumor resection in one cured patient with Nelson's syndrome. ACTH level does not change in the early recovery period after ACTH-secreting pituitary tumor, even in those cured patients, and probably peri-tumoral normal corticotrophs are not completely suppressed by cronic hypercortisolemia (and acute glucocorticoid administration) when these patients are under intense stress, like transsphenoidal surgery. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfere in the maintenance of high ACTH-levels during the early postoperative period, since ACTH half-life is only 8-15 min. In patients with ACTH-secreting pituitary tumors, the behavior of the human hypothalamic-pituitary-adrenal system during transsphenoidal surgery does not conform to the specifications of a negative feedback mechanism.

Pitfalls in pituitary diagnosis: peculiarities of three cases.

Due to the increasing availability and sensitivity of diagnostic methods, biochemical and imaging abnormalities of pituitary function and anatomy are becoming more frequent. Hyperprolactinaemia was found in three women without any prolactin (PRL) related clinical features. All three patients had normal libido, regular menses with evidence of ovulation, no galactorrhoea, and normal FSH, LH, TSH and free T4 serum levels. Magnetic resonance imaging (MRI) of the sellar region showed images that were compatible with pituitary microadenomas in all three cases. Due to the discordance between laboratory and clinical features, we searched for the presence of PRL aggregates with high molecular weight and low biological activity (macroprolactinaemia). Initially, we screened with a polyethylene glycol precipitation method, and then confirmed the presence of macroprolactinaemia by chromatography. All three cases screened positive for the presence of macroprolactinaemia. MRI alterations, compatible with pituitary microadenomas, may be due to true microincidentalomas, normal anatomical variations or imaging artefacts. In conclusion, we have described the presence of double diagnostic pitfalls that might lead to unnecessary medical or surgical intervention.

A study of patients with Nelson's syndrome.

OBJECTIVE: The prevalence of Nelson's syndrome has varied greatly, at least in part because of the variability of the diagnostic criteria employed by different authors. We define Nelson's syndrome as the presence of an enlarging pituitary tumour associated with elevated fasting plasma ACTH levels and hyperpigmentation in patients with Cushing's disease after bilateral adrenalectomy. We have compared patients with Cushing's disease who developed Nelson's syndrome after bilateral adrenalectomy with those who did not. Our objective was to find differences between the two groups which might predict the development of Nelson's syndrome. PATIENTS AND METHODS: We have reviewed the records of 30 patients with Cushing's disease after adrenalectomy, and divided them into two groups; I: 14 who developed Nelson's syndrome and II, 16 who did not. The two groups of patients were compared in their clinical, laboratory and imaging data as well as in the therapeutic procedures that preceded the adrenalectomy. RESULTS: The comparison between the two groups of patients demonstrated a highly significant difference in relation to the development of cutaneous hyperpigmentation (100% in group I and 19% in group II) and neuro-ophthalmological symptoms (21% in group I and 0% in group II) after adrenalectomy. There were no significant differences in laboratory data before adrenalectomy. After adrenalectomy, plasma ACTH levels increased significantly in the patients of both groups, but to much higher levels in those who developed Nelson's syndrome. Plasma ACTH concentrations above 154 pmol/l occurred only in the subjects with Nelson's syndrome. Before adrenalectomy, a pituitary tumour was more frequent in the patients who developed Nelson's syndrome (55% vs. 33% at transsphenoidal pituitary exploration). Pituitary surgery and irradiation were undertaken before adrenalectomy in approximately equal numbers of patients in each group. DISCUSSION: The prevalence of Nelson's syndrome was 47% in our series of 30 patients with Cushing's disease after bilateral adrenalectomy. No clinical or laboratory data before adrenalectomy predicted the development of the syndrome. The value of prophylactic pituitary irradiation could not be evaluated from our clinical material. However, after adrenalectomy, the presence of hyperpigmentation and ACTH levels above 154 pmol/l had positive predictive value for the development of Nelson's syndrome. In this situation magnetic resonance imaging (MRI) of the pituitary is mandatory and, if no tumour is detected, MRI should be repeated at intervals.

Pulsatile release and circadian rhythms of thyrotropin and prolactin in children with growth hormone deficiency.

We have measured mean concentrations and have appraised the pulsatile nature of thyrotropin (TSH) and prolactin (PRL) release in children with classical GH deficiency (GHD; n = 4) and neurosecretory GH dysfunction (NSD; n = 4) and have compared the results with those obtained in children with constitutional delay (control; n = 4). Blood samples were obtained at 20-min intervals for 24 h. Pulse analysis of TSH and PRL was undertaken using the Cluster pulse detection algorithm. Circadian rhythmicity of TSH and PRL was assessed using cosinor analysis. The mean 24-h concentration of GH in the control subjects was significantly higher than that obtained in the GHD and NSD groups. With regard to TSH, the mean serum concentration in the GHD and NSD group were higher than that of the control subjects. This augmentation reflects TSH pulses of large amplitude and area, and a higher interpulse valley mean rather than a difference in peak number or peak duration. No differences in mean PRL concentration or characteristics of PRL pulses were found between the control and GHD and NSD subjects. When the 24 h data sets were divided into day (0800-2000 h) and night (2000-0800 h), the mean nighttime TSH concentration was higher than the daytime concentration in the control, GHD, and NSD groups. Although there were no day versus night differences in TSH pulse frequency in either group, peak amplitude, area, and interpulse valley means were increased during the night in the control group, and peak area, duration, and amplitude mean in the NSD group. The nighttime mean PRL concentrations in the control, GHD, and NSD subjects were higher than those found during the day. This increase was accounted for by increases in PRL peak amplitude, area in the control group, and peak area, amplitude, and interpulse valley mean in the GHD and NSD groups. Cosinor analysis of the 24-h TSH and PRL data revealed clear circadian rhythmicity in all groups of subjects. These data suggest that GHD and NSD are associated with an increase in pulsatile TSH secretion due to an increase in pulse amplitude and interpulse valley mean.

MRI of congenital pituitary insufficiency.

We compared 1.5 T magnetic resonance (MR) image findings in 193 patients with congenital pituitary insufficiency. One hundred and thirty nine of the MR studies were obtained in patients who had isolated growth hormone deficiency (GHD). Other fifty-four patients had multiple pituitary hormone deficiency (MPHD). On MR images, normal anterior and posterior lobes of the pituitary gland can be clearly differentiated because the posterior lobe has a characteristic high intensity on T1-weighted images. In fifty-four patients, the high-intensity of the posterior lobe was not seen, but a similar high signal intensity was observed at the proximal stump in fifty-one patients. This high-intensity area is the newly formed ectopic posterior lobe, which also secrets anti-diuretic hormone just as the posterior lobe would. MR imaging can demonstrate the transection of the pituitary stalk and the formation of the ectopic lobe, revealing to be a usefull diagnostic tool in the definition of the type of alteration in growth defects of endocrine origin.

Growth hormone axis in cushing's syndrome.

All levels of the growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor (IGF) and IGF binding protein (IGFBP) axis are influenced by chronic hypercortisolism. Thus, there is a blunted response to GHRH alone or together with other stimuli associated with a marked suppression of endogenous GH secretion but accompanied by normal GHBP, normal to low IGF-1 and GHBPs 1 and 3 with the correspondent 41.5 and 38.5-kD molecular forms of the latter presenting values similar to normal. These findings may suggest enhanced GH sensitivity with normal or increased IGF-1 bioavailability to the correspondent tissue receptors. In conclusion, the glucocorticoid (GC)-induced target tissue resistance can neither be attributed to the suppression of the GH axis nor to changes in circulating GHBPs 1 and 3. However, it may be related either to the described 12-to-20-kD inhibitor(s) which antagonizes postbinding IGF-1 bioactivity (gene expression) and/or by the downmodulation of activator protein-1 (Fos/Jun) activity by the GC-GC receptor complex.

Effect of glycemic control on growth hormone and IGFBP-1 secretion in patients with type I diabetes mellitus.

Growth hormone (GH) secretion disorders have been reported in poorly controlled type I diabetes mellitus patients. Our work was aimed to evaluate GH secretion in 9 type I young diabetes mellitus patients as well as the low molecular weight IGF-binding protein secretion (IGFBP-1) in 5 of them. The patients did not show any signs of malnutrition or neurovascular complications, neither were they on any medication except for insulin. The study protocol included blood samples collection during a 24-h period for measurement of glucose, glycated hemoglobin, GH IGF-I and IGFBP-1 levels under two situations: on poor glycemic control and after 2-3 months on better control through systematic diet, low in carbohydrates and increase in insulin dosage. GH secretion data were analyzed by Cluster algorithm for pulsatility parameters; for rhythm assessment Cosinor method was used. The first study (poor control) reported significant increase of GH maximal and incremental amplitude and duration pulse values, when compared to the second study (better control). Mean 24-h secretion values as well mean GH for interpulse intervals (valleys) decreased, although not statistically significant. The fraction of pulsatile GH/24 h GH did not change significantly with better glycemic control. No changes in pulse frequency were observed. Mean IGF-I concentrations were significantly higher when patients were on better glycemic control. An ultradian variation for GH secretion was noticed in the first study (poor control) and a circadian variation in the second one (better control). IGFBP-1 analysis showed significant decrease of the mean 24-h values under better glycemic control. Linear regression analysis demonstrated a correlation between IGFBP-1 levels and fasting glucose levels. A circadian variation was present in IGFBP-1 secretion, irrespective of glycemic control. Therefore, we concluded that for type I diabetic patients: 1. GH secretion is increased on poor control, through maximal, incremental amplitude and pulse duration values; 2. IGFBP-1 values were significantly reduced and IGF-1 levels significantly higher after better glycemic control; 4. GH ultradian secretion is reported on poor control, and circadian on the better one, 5. IGFBP-1 circadian secretion occurred irrespective of glycemic control.