[Management of asymptomatic primary hyperparathyroidism: French Society of Endocrinology expert consensus].
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Bone Diseases↗
Biomedical subjects
A Tabarin
Publications and source records attributed to A Tabarin.
Decreased expression of retinoid nuclear receptor (RAR alpha and RAR gamma) mRNA determined by real-time quantitative RT-PCR in peripheral blood mononuclear cells of hypothyroid patients.
In vivo assessment of the cellular impact of thyroid hormones on target tissues might be of help for physiological studies and to evaluate the consequences of various diseases of the thyroid gland in humans. Given the tenuous relationship between retinoid and tri-iodothyronine (T3) status and that retinoids have also intracellular roles, the aim of this study was to determine the effect of hypothyroidism on the expression of T3 nuclear receptors (TR) and retinoic acid nuclear receptors (RAR, RXR) in human peripheral blood mononuclear cells (PBMC). Using real time RT-PCR, we quantified the relative amount of mRNA of the thyroid (TR alpha and TR beta) and retinoid (RAR alpha, RAR gamma, and RXR alpha) nuclear receptors in PBMC of euthyroid (n = 22) compared with hypothyroid (n = 22) subjects. Classical plasma parameters (free T3 (FT3), free thyroxine (T4) (FT4), thyroid-stimulating hormone (TSH), retinol (ROH), retinol-binding protein (RBP) and transthyretin (TTR)) were also measured. In hypothyroid subjects, the concentration of TSH was elevated, and dramatically low T3 and T4 concentrations were associated with a decrease in the expression of TR beta. Expression of RAR alpha and RAR gamma significantly decreased in hypothyroid versus control subjects, while an increased concentration of ROH was emphasised by hypothyroidism. These results first indicated that primary hypothyroidism induces hypoactivation of the retinoid nuclear pathway in PBMC, which was not predicted by the plasma ROH level. Further investigations will be necessary to evaluate these parameters in very small changes in thyroid hormone production such as mild (subclinical) hypothyroidism.
Base Sequence↗
One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel.
OBJECTIVE: Somatostatin analogue treatment is first-line medical therapy for acromegaly. This study compared the efficacy and tolerability of titrated doses of the long-acting somatostatin analogue preparation lanreotide Autogel with fixed doses and with lanreotide prolonged release (PR) 30 mg microparticles. PATIENTS: Patients entering the initial study had received a diagnosis of active acromegaly within the previous 5 years. DESIGN: This open, comparative, multicentre study was a 1-year extension of a previous trial during which patients with acromegaly had switched from lanreotide PR 30 mg microparticles injected intramuscularly every 7, 10 or 14 days, for at least 3 months, to one of three fixed doses of lanreotide Autogel (120, 90, or 60 mg every 28 days, respectively). In this extension study, patients continued to receive 60, 90, or 120 mg of lanreotide Autogel by deep subcutaneous injection every 28 days for 1 year. Doses could be titrated at entry or after four or eight injections, according to the GH/IGF-I response (dose increased if GH > 2.5 micro g/l, or decreased if GH < 1 micro g/l with normal IGF-I). MEASUREMENTS: Mean +/- SEM GH and IGF-I concentrations were analysed and gallbladder echography performed at weeks 0, 16, 32, and 48. Acromegaly symptoms were recorded monthly and tolerance and side-effects were monitored throughout the study. RESULTS: In total, 130 patients entered this extension phase. After 1 year of treatment with titrated doses of lanreotide Autogel, mean GH (2.4 +/- 0.2 micro g/l) and IGF-I (287 +/- 12 micro g/l) concentrations were significantly lower than with lanreotide microparticles (GH, 2.8 +/- 0.2 micro g/l, P < 0.001; IGF-I, 332 +/- 15 micro g/l, P < 0.01) or with fixed-dose lanreotide Autogel (GH, 3.0 +/- 0.2 micro g/l, P < 0.001; IGF-I, 310 +/- 14 micro g/l, P = 0.02). GH hypersecretion was reduced to </= 2.5 micro g/l in 68% of patients with titrated-dose lanreotide Autogel compared with 49% with microparticles (P < 0.001) and 56% with fixed-dose lanreotide Autogel (P </= 0.005). In the 65 patients who did not require any dose titration, there was no substantial change in serum lanreotide concentration, GH or IGF-I levels over the 12-month study duration. Acromegaly was effectively controlled (GH </= 2.5 micro g/l and normalized IGF-I) in significantly more patients (43%) compared with microparticles (32%; P < 0.05). There was a trend for improved control of acromegalic symptoms with dose titration, whereas the incidence of gastrointestinal symptoms and local tolerance was similar with lanreotide Autogel and lanreotide microparticles. Gallbladder echographies showed new lithiasis in 8% of lanreotide Autogel patients. CONCLUSION: Dose titration of lanreotide Autogel improved GH and IGF-I control in patients with acromegaly beyond that achieved using fixed doses of lanreotide Autogel or lanreotide microparticles. Titrated long-term lanreotide Autogel treatment is well tolerated.
Acromegaly↗
Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study.
BACKGROUND: Incidentally discovered adrenal tumours are frequently associated with subclinical autonomous cortisol hypersecretion of unknown origin. Aberrant hormone receptors have been observed in case reports of overt Cushing's syndrome. The question arises as to whether such receptors may be present in the functioning adrenal incidentaloma, which is common and might be a subclinical stage of Cushing's syndrome. PATIENTS AND METHODS: Twenty-one consecutive patients with a unilateral incidentaloma, the biochemical features of subclinical cortisol hypersecretion and/or the scintigraphic features of an autonomously functioning adrenal adenoma were investigated for plasma cortisol responses to various stimuli: upright posture, meal, combined hypothalamic-hormones, the vasopressin analogue terlipressin, glucagon, angiotensin II, the serotonin 5-HT4 agonist cisapride, and ACTH. Six normal controls were similarly investigated. All subjects were studied during 8 mg per day dexamethasone in order to avoid any ACTH-dependent variation of plasma cortisol. RESULTS: The most constant responses in adrenal incidentalomas were observed after stimulation by terlipressin (18/20 patients, 28-415% cortisol increase) and cisapride (17/21 patients, 25-364% cortisol increase). Eighteen out of 21 patients responded to several stimuli (cortisol increase >or= 25%), and all responded to at least one stimulus other than ACTH, while such responses were absent in the controls. Plasma ACTH remained suppressed in all subjects throughout the study. CONCLUSIONS: Aberrant membrane receptors detected by in vivo stimulation tests appear to be common in autonomously functioning unilateral adrenocortical adenomas. These receptors may be involved in the modulation of cortisol secretion in adrenal incidentaloma, with potential therapeutic consequences for the control of subclinical cortisol hypersecretion.
Adenoma↗
The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.
OBJECTIVE: Our aim was to report the recent changes in diagnosis and management of TSH-secreting pituitary adenomas. METHODS: We retrieved 43 consecutive patients with TSH-secreting pituitary tumors (23 male and 20 female) among 4400 pituitary adenomas followed between 1976 and 2001 in six Belgian and French centers. RESULTS: TSH was elevated in 18/43 and alpha subunit in 13/32 patients. In patients with intact thyroid (n=30), mean free tri-iodothyronine was 13.1 pmol/l (range 3.5-23) and mean free thyroxine was 38.4 pmol/l (range 10.2-62.7). Hyperprolactinemia and acromegaly were associated in 9/43 and 8/43 cases. The number of associated hypersecretions was higher in macroadenomas than in microadenomas (Chi square = 11.2, P<0.01). Two women had sporadic multiple endocrine neoplasia type 1-associated syndrome. The proportion of microadenomas versus macroadenomas was 1/11 (period 1974-1986) and 8/32 (period 1987-2001). Bilateral petrosal sinus sampling, (111)In-pentreotide scintigraphy and ((11)C)-l-methionine positron emission tomography scan confirmed diagnosis in four questionable microadenomas. Macroadenomas with extrasellar extension (31 cases) had a tendency to be medially located. Medical treatment with somatostatin analogs was initiated as first-line treatment in 26 patients. TSH levels were reduced by more than 50% in 23/26 cases. A tumoral shrinkage of more than 20% was observed in 5/13 cases. Surgery was performed in 36 patients. After 1 year, 21 of them (58.3%) met the criteria of surgical favorable outcome. Pituitary radiotherapy (n=8) and somatostatin analogs allowed normalization in cases not cured by surgery. CONCLUSION: Ultrasensitive methods for TSH measurement led to an earlier recognition of TSH-secreting pituitary tumors. In this series, we observed that TSH-secreting pituitary tumors are today more frequently found at the stage of microadenomas, medially located, without associated hypersecretions and needing new exploration methods as compared with older series. This changing spectrum in the presentation of TSH-secreting pituitary tumors and the excellent response to somatostatin analogs has been accompanied by an improvement in the prognosis of the disease.
Acromegaly↗
[Therapeutic strategies in somatotroph adenomas with extrasellar extension: role of the medical approach, a consensus study of the French Acromegaly Registry].
UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.
Acromegaly↗
[Bone mineral density and biological markers of bone repair in patients with adrenal incidentaloma: effect of subclinical hypercortisolism].
PURPOSE: Some adrenal incidentalomas produce cortisol in mild excess ('subclinical' Cushing's adenomas) and can potentially induce osteopenia. Their diagnosis is usually based on exclusive tumour uptake on adrenal scintigraphy using 131I-6 beta-methyl-iodo-19-norcholesterol and on inadequate cortisol response to dexamethasone (DXM) suppression tests. The aims of the present study were to evaluate bone mineral density (BMD) and metabolic markers of bone turnover in patients with incidentalomas and to test the effect of mild hypercortisolism on bone parameters. METHODS: Thirty-five patients (13 men, 22 postmenopausal women, 49-76 years) with unilateral incidentaloma were studied. BMD was measured by dual X-ray absorptiometry. Two biochemical markers of bone formation, serum osteocalcin (BGP) and bone alkaline phosphatase (bALP), and two markers of bone resorption, urinary free deoxypyridinoline (D-Pyr) and urinary carboxy-telopeptide of bone type 1 collagen (CTX), were measured by radioimmunoassay. D-Pyr and CTX were corrected for creatinine excretion. RESULTS: Median values of lumbar and femoral T-score were -1.125 and -0.920, respectively, whereas corresponding Z-score values where normal (0.105 and 0.120, respectively). Thirty-nine percent of patients had low serum BGP values and 3% had low bALP values; 16% showed elevated D-Pyr/creatinine values and 23% increased CTX/creatinine values. Patients both with suppression of the contralateral adrenal on scintigraphy and with an inadequate cortisol response to 1 mg DXM (> 50 nmol/L) (n = 14) presented a lower femoral T-score (P < 0.02) and, to a lesser extent, a lower femoral Z-score (P = 0.11) than other patients (n = 21). The proportion of increased values of CTX/creatinine (42% versus 11%, P = 0.08) also tended to be higher in the first than in the second group of patients. These two groups of patients were similar in terms of age, but tumour size was larger (P < 0.04) and plasma ACTH value was lower (P < 0.02) in patients with scintigraphic and endocrine abnormalities. CONCLUSION: Subclinical hypercortisolism defined on the basis of scintigraphic and hormonal criteria seems to contribute to bone loss in patients with adrenal incidentaloma. As other possible side effects of mild hypercortisolism, these findings have to be taken into account in the therapeutic management of these patients.
Adrenal Gland Neoplasms↗
A novel thyroid hormone receptor-beta mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes.
Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.
Adult↗
Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma.
OBJECTIVE: To audit the performances of the analytes used in the diagnosis of pheochromocytoma and to present a graphical guideline to help the diagnosis. DESIGN: A 5 year retrospective study. SETTINGS: Laboratory and departments of a university hospital. PARTICIPANTS: In-patients, suspected of bearing a pheochromocytoma, were investigated for urinary metanephrines and catecholamines (photometric method) and vanillylmandelic acid, fractionated catecholamines and metanephrines [high pressure liquid chromatography (HPLC) coupled to electrochemical detection (ED)] urinary excretion. MAIN OUTCOME: Patients with a pheochromocytoma (24 out of 2003 patients) were diagnosed by the combination of normetanephrine and metanephrine determination. RESULTS: All analytes but dopamine were significantly elevated in patients with a pheochromocytoma. The area under the receiver operating characteristics (ROC) curves were the highest for total metanephrines, normetanephrine and metanephrine determinations. Because of analytical interferences in the metanephrines determination, the normetanephrine and metanephrine performed better. It is noteworthy that all pheochromocytomas had either normetanephrine or metanephrine levels above their respective optimal threshold (sensitivity 100%). The best optimal threshold performance was reached by the mean of three daily samples. Total or fractionated catecholamines or vanillylmandelic acid were less accurate tools. CONCLUSION: Amongst urinary tests, the combined use of HPLC/ED determination of normetanephrine and metanephrine seems the most effective screening strategy for the diagnosis of pheochromocytoma. The older total metanephrine photometric assay is grieved by analytical interferences.
Adolescent↗
ACTH silent adenoma shrinking under cabergoline.
OBJECTIVES: The authors present a case report that proposes the use of cabergoline treatment in silent ACTH adenoma, an unusual member of the heterogeneous group of the so-called clinically non-functioning pituitary adenomas. DESIGN: Following the clinical and radiological improvement of a recurrent silent ACTH adenoma in a 77-year-old patient treated with cabergoline (0.5 mg every 2 days for 2 years), in vitro studies of the original tumor were performed. METHODS: The original tumor from the patient was studied by in situ hybridization and dopamine D2 receptor autoradiography. It was compared with four macroprolactinomas and two macroadenomas from patients with Cushing's disease. RESULTS: The D2 receptor mRNA signal of the reported case was intense and of the same order of magnitude as that observed in control prolactinomas. Dopamine D2 receptor autoradiography was twice that of control corticotroph adenomas and was close to that observed in prolactinomas. CONCLUSIONS: This is the first description of an in vivo shrinkage of an ACTH silent adenoma under cabergoline. We demonstrate in vitro, the presence of D2 receptors in the primitive tumor in concentrations similar to those found in control prolactinomas. These results suggest that therapeutic trials with cabergoline might be undertaken in recurring cases of ACTH silent tumors and more generally, non-functioning pituitary adenomas.
Adenoma↗
Decreased pituitary sensitivity to glucocorticoids in endurance-trained men.
OBJECTIVE: Muscular exercise induces hypothalamo-pituitary-adrenal (HPA) axis activation and when regularly repeated, as in endurance training, leads to HPA axis adaptation. To assess whether non-professional endurance-trained (ET) men with a substantial training load and no clinical or biological features of HPA axis overactivity can present subtle alterations of HPA axis sensitivity to glucocorticoid negative feedback, nine ET men were subjected to HPA axis testing using the dexamethasone-corticotrophin-releasing hormone (CRH) test. DESIGN: Nine endurance-trained men and eight healthy age-matched sedentary men were studied. Morning plasma cortisol and 24 h urinary free cortisol (UFC) were determined and a low dose dexamethasone suppression test (LDDST) was performed followed by CRH stimulation (dexamethasone-CRH test). RESULTS: After a day without physical exercise, at 0800 h, plasma ACTH and cortisol concentrations, and the 24 h UFC and UFC/urinary creatinine (UC) ratio were similar in ET and sedentary men. By contrast, clear differences between the groups were seen in cortisol and ACTH responses to the dexamethasone-CRH test. In eight ET subjects, after LDDST, basal ACTH and cortisol levels were similar to those of sedentary men, whereas one ET subject displayed a poor suppression of cortisol level (131 nmol/l). After injection of CRH, however, three of nine ET men's cortisol levels were not suppressed by dexamethasone but instead displayed significant CRH-induced increase (peak cortisol: 88, 125 and 362 nmol/l). No sedentary subject exhibited any increase in cortisol levels. CONCLUSION: Three of nine ET men with a mean maximum rate of O2 uptake (VO2, max) of 61 ml/kg per min, running 50-70 km per week, were resistant to glucocorticoid suppression during the combined dexamethasone-CRH test.
Adult↗
Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas.
OBJECTIVE: Biochemistry and I-6beta-iodomethyl norcholesterol scintigraphy (IMS) have both been used to assess cortisol secretion by adrenocortical incidentalomas. However, which biochemical abnormalities indicate subclinical corticoid excess is still debatable whilst IMS is expensive and cumbersome. The aim of the study was to evaluate prospectively patients with adrenal incidentalomas using both IMS and biochemical methods to examine whether the IMS pattern is associated with biochemical abnormalities and, if this is so, to find a biochemical parameter that could be used as a screening test to identify a subset of patients on whom IMS could subsequently be performed. METHODS: Thirty-one patients with benign cortical adenomas were recruited from 43 consecutive patients with adrenal incidentalomas. All 31 patients underwent IMS and measurement of (i) 0800 h serum cortisol, ACTH, dehydroepiandrosterone and 17-hydroxyprogesterone; (ii) midnight serum cortisol; (iii) 2400 h excretion of urinary free cortisol; (iv) cortisol after the overnight 1 mg dexamethasone (DEX) suppression test; (v) cortisol after an i.v. 4 mg DEX test; (vi) determination of the diurnal variation in serum cortisol. RESULTS: Sixty-one per cent of patients displayed unilateral uptake during IMS and 39% showed bilateral uptake. Patients with unilateral uptake exhibited significantly lower ACTH concentrations (P=0.0005), higher midnight cortisol concentrations (P=0.02), disrupted diurnal variation of serum cortisol (P=0.02) and higher cortisol concentrations after DEX suppression tests (P=0.01). Cortisol concentrations following the two DEX suppression tests correlated closely (r=0.80, P=0.0001). The i.v. 4 mg DEX test was clearly more sensitive for the diagnosis of unilateral uptake than the overnight 1 mg DEX test (76 vs 52%). Using various thresholds of cortisol concentration following the overnight 1 mg DEX test, it was found that the sensitivity of the test could be improved to 100% if the threshold was set at 60 nmol/l rather than the classical value of 138 nmol/l. All patients but one with post-test serum cortisol concentrations above 60 nmol/l as against none of patients with cortisol below 60 nmol/l exhibited at least one associated biochemical abnormality indicating subclinical glucocorticoid excess. CONCLUSION: In adrenocortical incidentalomas, unilateral uptake during IMS suggests subclinically excessive and/or autonomous cortisol secretion. A cortisol concentration above 60 nmol/l following the overnight 1 mg DEX test is highly correlated with unilateral uptake and is associated with biochemical abnormalities indicating subclinical glucocorticoid excess. Our results favour the use of the 1 mg overnight DEX test with revised criteria of interpretation as a screening test for subclinical hypercortisolism among patients with adrenocortical incidentalomas.
Adenoma↗
Congenital adrenal hypoplasia and DAX-1 gene mutations.
DAX-1 is a member of the orphan nuclear hormone receptor family. Its mutations cause X-linked adrenal hypoplasia congenita, a disease characterized by adrenal insufficiency due to impaired organogenesis of the adrenal cortex and hypogonadotrophic hypogonadism. We review herein the pathologic and clinical features of the disease and describe some recent advances in the clinical expression of X-linked adrenal hypoplasia congenita.
Adrenal Insufficiency↗
A randomized study comparing blood glucose control and risk of severe hypoglycemia achieved by non-programmable versus programmable external insulin pumps.
OBJECTIVE: To compare a non-programmable and a programmable insulin external pump using regular insulin on glycemic stability, the risk of severe hypoglycemia and metabolic control in type 1 diabetic patients. MATERIAL AND METHODS: Ten type 1 diabetic patients were involved in a randomized, crossover study comparing two periods of 3 months with continuous subcutaneous insulin infusion (CSII) either with a non-programmable insulin pump or a programmable insulin pump. Comparisons were made among mean blood glucose values before and after meals, at bedtime and at 2: 00 a.m.; the risk of severe hypoglycemia assessed by the low blood glucose index (LBGI); and HbA1c. RESULTS: Mean average blood glucose (BG) measurements were significantly lower with the programmable in comparison with the non-programmable insulin pump (respectively 157+/-78 vs. 165+/-79, p=0.034). While postprandial values for BG were not different between the two pumps, the use of the programmable pump resulted in a significant decrease in mean preprandial BG levels (140+/-68 vs. 150+/-73 mg/dl p=0.039). Conversely mean BG level was lower at 2 a.m. with the non-prgrammable pump (125+/-81 vs. 134 +/-93 mg/dl, p=0.02) but with a higher incidence of hypoglycemia. Mean LBGI was comparable with the two pumps (3.1+/-8.6 vs. 2.8+/-6.9, p=0.1). There was a 0.2% decrease in HbA1c during the programmable pump period that did not reach statistical significance (p=0.37). CONCLUSIONS: The present study suggests that programmable external insulin pumps, although more complex and more expensive than non-programmable insulin pumps, significantly reduce fasting glycemia during the day without increasing the risk of severe hypoglycemia and are safer during the night.
Adult↗
[Hyperadrenocorticism in the adult. Etiology, diagnosis].
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Adrenal Glands↗
A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism.
Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.
Adrenal Glands↗
Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide.
Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free alpha-subunit, fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (+/- SEM) plasma lanreotide levels reached 1.11 +/- 0.43 and 1.69 +/- 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 +/- 0.32 to 1.89 +/-0.27 mU/L (P < 0.01), with parallel significant changes in free alpha-subunit. During the same period, plasma fT4 and fT3 levels decreased from 37.9 +/- 2.9 to 19.7 +/- 2.3 pmol/L (P < 0.01) and from 14.6 +/- 1.1 to 8.3 +/- 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.
Adenoma↗
Variable growth hormone profiles following withdrawal of long-term 30mg slow-release lanreotide treatment in acromegalic patients: clinical implications.
OBJECTIVE: Intramuscular injections of 30mg slow-release (SR) lanreotide (every 10 to 14 days) are an effective treatment in acromegalic patients. Because of an ongoing need to assess the efficacy and the tolerance of a new formulation of a depot preparation of lanreotide, we have evaluated prospectively GH profiles following withdrawal of 30mg slow-release lanreotide in a cohort of acromegalic patients. PATIENTS: Fifty-one acromegalic patients, controlled during long-term 30mg SR lanreotide treatment (GH: 1.44 +/- 0.64 microgram/l, IGF-I: 316 +/- 145ng/ml) (mean +/- s.d.), were studied following the withdrawal of the drug. MEASUREMENTS: Mean GH (half-hour samples, 0800-1200h), IGF-I and lanreotide levels were evaluated 14, 28, and 42 days following the last 30mg SR lanreotide injection. RESULTS: Mean GH levels remained below 2.5 microgram/l in 32 patients (group 1) twenty-eight days following SR lanreotide withdrawal. In these patients, mean GH and IGF-I levels had increased from 1.2 +/- 0.6 to 1.7 +/- 0.5 microgram/l (P < 0001), and from 283 +/- 138 to 359 +/- 168ng/ml (P < 0.001) respectively. In the 19 other patients (group 2), mean GH concentrations had risen above 2.5 microgram/l at 28 days following SR lanreotide withdrawal. Mean GH and IGF-I levels had increased from 1.9 +/- 0.4 to 5.1 +/- 2.8 microgram/l (P < 0.001), and from 371 +/- 143 to 568 +/- 206ng/ml (P < 0.001) respectively. Patients of groups 1 and 2 were comparable with regard to age, sex, tumoral status, mean GH levels before somatostatin analogue treatment, and previous treatments such as radiotherapy and duration of somatostatin analogue therapy, but 75% of group 1 patients underwent surgery compared with 37% of group 2 patients (P < 0.01). Twenty-eight days following SR lanreotide withdrawal, mean lanreotide levels in group 1 and group 2 had decreased from 1.6 +/- 0.7 to 0.6 +/- 0.3ng/ml (P < 0.001), and from 2.7 +/- 2.0 to 0.7 +/- 0.7ng/ml (P < 0.001) respectively. A negative correlation was observed between the lanreotide levels and GH and IGF-I concentrations in the two groups of patients, but the inhibition of GH/IGF-I concentrations by lanreotide levels was higher in group 1 patients than in those of group 2. Six patients of group 1 were treated with 30mg SR lanreotide injected at monthly intervals. During monthly follow-up, mean GH levels increased above 2.5 microgram/l in 2 patients. After 12 months follow-up, mean GH and IGF-I levels from 4 other patients were similar to those obtained with previous therapeutic sequence (i.e. intramuscular injections every 14 days). CONCLUSION: The degree of responsiveness to lanreotide and the duration of somatotroph suppression following lanreotide withdrawal are variable in acromegalic patients controlled during long-term 30mg SR lanreotide treatment. In patients displaying high sensitivity to lanreotide, the interval between i.m. 30mg SR lanreotide injections can be increased to one month, thus reducing the cost of the therapy, without altering its efficacy upon GH/IGF-I control.
Acromegaly↗