Philippe Chanson

Guidelines for acromegaly management: An update

OBJECTIVE The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

A consensus on criteria for cure of acromegaly

OBJECTIVE The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

CONTEXT AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN This study was an international, multicenter, retrospective case collection/database analysis. SETTING The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Isolated Familial Hypogonadotropic Hypogonadism and a GNRH1 Mutation

We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide-containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.

Germ-Line Mutation Analysis in Patients with Multiple Endocrine Neoplasia Type 1 and Related Disorders

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.

TAC3 and TACR3 Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans

CONTEXT Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. OBJECTIVE The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. RESULTS We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. CONCLUSION Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.

Octreotide Therapy for Thyroid-Stimulating Hormone-Secreting Pituitary Adenomas: A Follow-up of 52 Patients

Table. SI Units, Drug, and Abbreviation Thyroid-stimulating hormone (TSH)-secreting adenomas are rare, constituting fewer than 1% of all pituitary adenomas in large neurosurgical series [1-3]. The inappropriate secretion of TSH by these tumors can result in hyperthyroidism [1-5], but diagnosis may be delayed because symptoms are often attributed to more common causes of thyrotoxicosis. This delay, coupled with the usually aggressive nature of these tumors, allows tumors to become large and invasive. In most cases, surgical removal is incomplete, and, even after additional pituitary irradiation, only about 40% of patients can be cured [1, 6]. The use of dopamine agonists has proved to be generally unsuccessful [1, 4, 5]. Because native somatostatin inhibits TSH secretion in healthy persons [7, 8] and in patients with TSH-secreting adenomas [9], treatment with the long-acting somatostatin analog octreotide has been proposed for such patients. Studies of octreotide in a limited number of patients with TSH-secreting adenomas have shown a favorable effect of this drug on TSH secretion, thyroid function, and, in rare cases, pituitary adenoma size [2,10-36]. To assess the efficacy of octreotide therapy in patients with TSH-secreting adenomas, we reviewed outcomes in 15 new cases and 37 previously reported cases. Methods Patients Twenty-seven men and 25 women who were 16 to 84 years old (median age, 44 years) and had a TSH-secreting adenoma were evaluated. Studies were done at 24 medical centers in nine countries (Appendix). Data were collected from reports published in the English or French language between 1987 and 1991 [2,10-36]. The list of published articles and abstracts of papers presented at various national and international meetings was provided by the Centre de Documentation of Laboratoires Sandoz, Rueil-Malmaison, France. The authors of these studies were asked to provide us, when possible, with follow-up information on their patients [2, 10-36]. In 6 of these patients (patients 30 to 35), available data were too imprecise or incomplete, particularly regarding TSH levels, to allow pertinent evaluation [29-32]. However, some data on these patients were analyzed. Data on 15 additional patients (patients 38 to 52) whose studies were done in various centers (see Appendix) and not previously reported were included in the final analysis. In all patients, the diagnosis of thyrotropinoma had been made on the basis of an inappropriate secretion of TSH (that is, the coexistence of increased serum thyroid hormone levels and an increased or normal [but at least unsuppressed] TSH serum level [3]. In all but 5 patients, who had surgically proven microadenoma, macroadenoma generally associated with suprasellar or laterosellar extension was shown by computed tomographic (CT) scan or magnetic resonance imaging (MRI). Before octreotide therapy, 23 patients had undergone pituitary adenomectomy; 9 of these patients had also had radiotherapy of the pituitary area without resolution of hyperthyroidism. At the time octreotide therapy was initiated, some patients were receiving antithyroid medication because of hyperthyroidism or thyroid hormone replacement because of previous thyroidectomy or radioiodine treatments, and only fragmentary information could be obtained in these cases. In all but 4 of the remaining patients (90%), hyperthyroidism was present before treatment. Basal serum TSH levels were increased (5.2 to 129 mU/L) in 23 of 49 patients and normal (but inappropriately unsuppressed in the presence of high thyroid hormone levels) in the remaining patients. Thirty patients had increased serum levels (1.5 to 311 g/L) of free -subunitthe uncombined subunit of glycoprotein hormones often secreted in excess together with TSH by TSH-secreting adenomas [3]whereas 4 of the 37 patients studied had normal levels. Nine of the patients had mixed growth hormone-TSH-secreting adenoma and also had the classic features of acromegaly. Treatment Regimen The initial dose of octreotide (Sandostatin, Sandoz Pharma, Ltd., Basel, Switzerland) ranged from 50 to 100 g subcutaneously two or three times per day. The dosage was increased according to individual biochemical responses to a maximum level of 500 g three times per day. The median octreotide dose at the final evaluation was 300 g/d. In 25 patients, treatment was extended beyond 3 months (range, 3 to 61 months; mean, 20 17 months). Evaluation Patients were evaluated at various intervals determined by the protocol of the medical center at which they were treated. Data from the pretherapeutic evaluation were available in 49 patients. The response to the first injection of octreotide (50 or 100 g), although assessed in 40 patients, was provided in 35. Evaluation of TSH levels was done after 1 to 2 weeks of octreotide therapy in 33 patients. Evaluation was done again after 1 month of therapy in 23 patients. In the 25 patients receiving long-term therapy (> 3 months), evaluation was done at 3-month intervals during the first year and thereafter at 6-month intervals. For each evaluation, we attempted to retrieve measurements of serum TSH, free -subunit, and thyroid hormone levels done on blood samples collected in the morning or, when available, hourly during a 3- to 12-hour profile; mean values were used for analysis. Levels of TSH, -subunit and thyroid hormone (generally as free thyroxine, free triiodothyronine, or both) were measured by immunoradiometric assay or radioimmunoassay using commercially available kits at the individual study centers. In consideration of the different assays used, the normal ranges for TSH and free thyroxine levels were set at 0.1 to 5 mU/L and 10 to 20 pmol/L, respectively. Methods of serum free -subunit determination were too heterogeneous to allow within-group comparison. Thus, the individual course of -subunit was assessed according to the normal reference range indicated by the individual medical center. In general, hormonal responses are indicated as a percentage decrease in hormone levels or expressed in terms of whether they returned to within the normal range (as defined by the investigators). Serial anatomic evaluation of the pituitary gland by either CT scan or MRI was available in 26 patients. In 7 patients, the percentage change in tumor volume was calculated. Abdominal ultrasound examinations were done at regular intervals and at the final evaluation in 19 of the 25 patients receiving long-term therapy. Statistical Analysis Statistical analysis was done using a Wilcoxon test for paired data. Results are expressed as mean SD. Results Hormonal Effects The acute response of serum TSH levels to the first injection of octreotide (50 to 100 g) was evaluated in 35 patients (Figure 1). The TSH level decreased in all but 2 of these patients (mean decrease for the whole group, 55.8% 27%), the nadir occurring between 3 and 6 hours after injection. The -subunit level decreased in 15 of the 19 patients assessed (mean decrease, 37.5% 24%). Figure 1. Individual levels of thyroid-stimulating hormone (TSH) and free -subunit during single-dose octreotide studies in patients with TSH-secreting adenomas. Thirty-three patients were evaluated for the short-term effect of octreotide (Figure 2). The mean pretreatment TSH concentration was 14.7 25.9 mU/L. Reduction of TSH levels after 1 to 2 weeks of octreotide therapy (50 or 100 g two or three times daily) was observed in 30 patients (mean decrease for the whole group, 74.1%). Serum TSH levels decreased to a mean level of 3.8 7.4 mU/L (P < 0.01). Among patients whose basal serum TSH levels were supranormal, 88% showed a reduction of more than 50% in the TSH level; in 72%, the TSH level returned to normal. The -subunit levels, assessed in 19 patients, showed a similar pattern, with a mean reduction of 64.3% (24%). In about two thirds of the patients, the TSH response after 1 to 2 weeks was better than after the first dose; this analysis included 5 patients who did not respond to acute injection with a reduction in TSH level of more than 50%. Thyroid hormone levels decreased in all patients and returned to normal in 73% of patients. Patients had similar TSH and thyroid hormone responses to octreotide, regardless of whether they had a pure TSH-secreting adenoma or a mixed growth hormone-TSH-secreting adenoma. After 1 month of treatment, serum TSH (n = 23) and -subunit (n = 11) levels were similar to those seen after 1 week of treatment (data not shown). In 3 patients, despite the lack of normalization of serum TSH levels, thyroid hormone levels returned to normal after 1 week of therapy [10, 17]. The relation between individual dosage and the hormonal response was impossible to assess because of the different octreotide doses used (ranging from 100 to 300 g/d). Although 2 of the patients studied showed persistently suppressed TSH levels, thyroid hormone levels that initially returned to normal demonstrated an escapedefined as the re-increase in serum levels despite increasing dosageearly between weeks 2 and 4 of treatment. This led to the discontinuation of treatment in these two patients. Figure 2. Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) during short-term (1 to 2 weeks) octreotide therapy in patients with TSH-secreting adenomas. Octreotide therapy was continued beyond 3 months (range, 3 to 61 months; mean, 20 17 months) in 25 patients, with daily doses ranging from 100 to 1500 g. Overall, the response to treatment, as assessed by TSH and -subunit levels, was better than or similar to that after short-term treatment. Based on the persistence of normal thyroid hormone levels, efficacy was maintained in 21 of the 25 patients (84%) as long as the treatment was continued. Tachyphylaxisdefined as the necessity to increase doses to maintain normal TSH levelswas observed in 5 of the 21 patients. Thyroid hormone levels did not increase, however, and, in fact, remained normal in 4 of these pati

Temozolomide Treatment in Aggressive Pituitary Tumors and Pituitary Carcinomas: A French Multicenter Experience

CONTEXT To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. OBJECTIVES The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. PATIENTS Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. DESIGN MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. RESULTS Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. CONCLUSION Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status.

Cardiac Effects of Growth Hormone in Adults With Growth Hormone Deficiency A Meta-Analysis

Background—Growth hormone (GH) treatment may improve morphological and functional cardiac parameters in adults with GH deficiency (GHD). However, clinical trials reported to date involved few patients and yielded variable effects. Methods and Results—We systematically reviewed blinded, placebo-controlled, randomized clinical trials of GH treatment in adults with GHD and open studies in patients with GHD before and after GH treatment, evaluating the effects of GH on cardiac parameters assessed by echocardiography. Sixteen trials (9 blinded and 7 open), involving a total of 468 patients, were identified in 3 bibliographic databases. GH dosage, duration of treatment, and study populations varied among the studies. We conducted a combined analysis of effects on left ventricular mass (LVM), interventricular septum thickness (IVS), left ventricular posterior wall (LVPW), left ventricular end-systolic (LVESD) and diastolic (LVEDD) diameters, stroke volume, E/A ratio, isovolumic relaxation time (IRT), and fractional shortening. Overall effect size was used to evaluate significance, and weighted mean difference between GH and control was given to appreciate size of the effect. GH treatment was associated with a significant increase in LVM: +10.8 (SD: 9.3) g (P =0.02); IVS: +0.28 (0.38) mm (P <0.001), LVPW: 0.98 (0.22) mm (P =0.05), LVEDD: +1.34 (1.13) mm (P <0.001), and stroke volume: +10.3 (8.7) mL (P <0.001). A trend toward a difference in fractional shortening was observed: +1.1 (1.1)% (P =0.06). Overall effect sizes were not significant for LVESD, E/A, and IRT. Conclusions—GH treatment is associated with a significant positive effect on LVM, IVS, LVPW, LVEDD, and stroke volume, as assessed by echocardiography, in adults with GHD.