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Philippe Chanson

Treatment with somatostatin analogs has now gained a large place in the therapeutic management of acromegaly. In a survey of more than 75 acromegalic patients regularly seen at our Clinical Center we found that 60% were currently being treated with a somatostatin analog (octreotide or lanreotide), either because of surgical and/or radiation failure or contraindication, or while waiting for the effects of radiation therapy. Using stringent biochemical definition of disease control (mean growth hormone (GH) level during an 8-hourly diurnal profile less than 2 μg/l and normal insulin-like growth factor-I (IGF-I) level), 40% of these patients may be considered as 'cured' by medical treatment (P Chanson & Y Le Bouc, unpublished data). These figures, which reflect our routine clinical practice are in accordance with the data in the prospective studies reported in the literature (1–4). However, it is well known that such medical treatment is very expensive (5). In France,

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Philippe Chanson, Charles P. Jedynak, and Paul Czernichow

Abstract. Management of early postneurosurgical diabetes insipidus (DI) requires parenteral vasopressin before intranasal administration of desmopressin-1 desamino-8 D arginine vasopressin (dDAVP) can be initiated. We have evaluated in 15 neurosurgical patients the effect and the tolerance of a 3-day regimen of dDAVP administered im every 12 h. Patients were randomly ascribed to one of 3 treatment groups: 1 μg (N = 6), 2 μg (N = 5) or 4 μg (N = 4) were administered twice daily. dDAVP was effective whatever the dose, and DI was corrected by the 6th h of treatment. Effects were maximal on diuresis and urinary osmolality from the 18th h onwards. The effects were sustained throughout the treatment period. Reversal to pretreatment status occurred 24 h after the last injection. Moreover, 72 h after the last injection, natremia and osmolality reached values significantly below pretherapeutic values. The tolerance was excellent: hyponatremia which occurred in 11 patients, either occasionally or throughout the treatment period, remained mild and never had clinical consequences. In conclusion, before initiation of intranasal dDAVP, a 3-day treatment by 1, 2 or 4 μg of dDAVP injected im twice daily in neurosurgical patients corrected DI. Mild overhydration owing to a positive fluid balance was a side-effect which is also encountered in other therapeutic methods necessitating meticulous control of water intake.

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Mirella Hage, Clément Janot, Sylvie Salenave, Philippe Chanson, and Peter Kamenicky

To gain more insight on the pathogenesis of somatotroph pituitary adenomas, recent studies have focused on a subgroup of patients with acromegaly displaying a paradoxical growth hormone (GH) response during oral glucose tolerance test (OGTT). The paradoxical rise of GH after oral glucose intake occurs in about one third of acromegaly patients and has been pathogenetically linked, by analogy to glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing syndrome, to the ectopic expression of GIP receptor (GIPR) in somatotroph adenoma cells. GIPR-expressing adenomas are negative for activating GNAS gene mutations and display distinct cytogenetic and DNA methylation profiles, highlighting their unique molecular pathogenesis. Acromegaly patients with a paradoxical GH response pattern seem to display higher insulin growth factor-1 (IGF-1) concentrations and harbour smaller adenomas that are more often of the densely granulated phenotype. They seem also to show a better response to somatostatin receptor ligands. In addition, persistent paradoxical GH response after surgery may be a biological marker of the residual disease postoperatively. Targeted therapy to antagonize GIP receptor on GIPR-expressing somatotroph adenomas could be a new treatment approach for acromegaly patients with a paradoxical pattern GH response to OGTT.

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Philippe Chanson, Anne Dib, André Visot, and Patrick J Derome

Chanson P, Dib A, Visot A, Derome PJ. McCune–Albright syndrome and acromegaly: clinical studies and responses to treatment in five cases. Eur J Endocrinol 1994;131:229–34. ISSN 0804–4643

We report here five new patients with McCune–Albright syndrome and acromegaly. In the five patients studied (three males and two females aged 19–42 years), acromegaly began before the age of 20 years and was recognized after the diagnosis of fibrous dysplasia, which was polyostotic in three cases and monostotic in two. Bone fibrous dysplasia always involved the base of the skull and in four patients prevented surgical removal of the pituitary adenoma, which was visualized easily by magnetic resonance imaging. Serum growth hormone (GH) levels ranged between 20 and 48 μg/l and were not suppressed by an oral glucose load. Thyrotropin-releasing hormone administration produced a paradoxical increase in serum GH levels in all the patients. Four of the five patients had hyperprolactinemia (43–670 μg/l). In the sole patient who could be operated on, a typical adenoma with positive immunostaining for GH was incompletely removed and postoperative radiation therapy failed to cure the acromegaly. In two patients, medical therapy with bromocriptine and/or octreotide was partially or totally ineffective whatever the dose (up to 1.5 mg per day) and duration (2–4 years) of octreotide treatment.

Philippe Chanson, Service d'Endocrinologie et Maladies de la Reproduction, Hôpital Bicêtre, F94275 Le Kremlin-Bicêtre, France

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Lise Duranteau, Philippe Chanson, Joelle Blumberg-Tick, Guy Thomas, Sylvie Brailly, Jean Lubetzki, Gilbert Schaison, and Philippe Bouchard

We investigated the potential pituitary origin of gonadal insufficiency in hemochromatosis. Gonadotropin secretion was studied in seven patients with hemochromatosis and hypogonadism, before and after chronic pulsatile GnRH therapy. Pulsatile LH secretion was studied before (sampling every 10 min for 6 h) and after 15-30 days of chronic pulsatile GnRH therapy (10-12 μg per pulse). Prior to GnRH therapy, all the patients had low serum testosterone, FSH and LH levels. LH secretion was non-pulsatile in four patients, while a single pulse was detected in the remaining three. Chronic pulsatile GnRH administration did not increase serum testosterone levels; similarly, serum LH levels remained low: neither pulse frequency nor pulse amplitude was modified. We conclude that hypogonadism in hemochromatosis is due to pituitary lesions.

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Michèle Le Dafniet, Anne-Marie Brandi, Michèle Kujas, Philippe Chanson, and Françoise Peillon

Le Dafniet M, Brandi A-M, Kujas M, Chanson P, Peillon F. Thyrotropin-releasing hormone (TRH) binding sites and thyrotropin response to TRH are regulated by thyroid hormones in human thyrotropic adenomas. Eur J Endocrinol 1994:130:559–64. ISSN 0804–4643

In order to see whether, in thyrotropic adenomas with thyrotoxicosis, plasma thyroid hormones regulate the thyrotropin-releasing hormone (TRH) binding sites and the thyrotropin (TSH) response to TRH, we investigated: the presence of TRH binding sites in two cases of thyrotropic adenomas associated with hyperthyroidism and in one case of thyrotropic adenoma secondary to thyroid failure; and the in vitro effect, in a perifusion system, of triiodothyronine (T3) on the response of TSH to TRH in three cases of TSH-secreting adenomas associated with hyperthyroidism. The TRH binding sites were absent in the adenomas associated with high levels of circulating thyroid hormones, whereas they were present in the adenoma secondary to primary thyroid failure (K4 =47 nmol/l, Bmax = 40 nmol/ kg membrane proteins). In vitro, the three adenomas spontaneously released TSH in the perifusion medium (1.49 ±0.06 (mean ± sem), 7.25±0.12 and 16.73±0.36 mIU·−1·106 cells−1·2 min−1) and exhibited an ample TSH response to 10−7 mol/l TRH pulses. In two cases, tumoral secretion of fragments was compared with those of fragments maintained since the time of surgical removal in the presence of 10−8 mol/l T3. The TSH responses to TRH were abolished in the presence of T3 in these two cases. We conclude that thyrotropic adenomas associated with hyperthyroidism are still controlled in vivo by T3. In particular, T3 regulates the TSH response to TRH, probably via a down-regulation of the TRH binding sites.

Michèle Le Dafniet, Unité INSERM 223, Faculté de Médecine, Pitié-Salpêtrière, 105 Boulevard de l'Hôpital, 75013 Paris, France

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Roger Abs, Frank Nobels, Johan Verhelst, Philippe Chanson, Charles Mahler, Bob Corthouts, Pierre Blockx, and Albert Beckers

We aimed to investigate the dynamics of adrenocorticotropin (ACTH) and cortisol secretion in pituitary-dependent Cushing's syndrome with bilateral macronodular adrenal hyperplasia presenting as a single adrenal macronodule, and to determine the imaging characteristics of this syndrome. Three female patients were studied. Plasma ACTH and serum cortisol secretion were studied by determining their rhythmicity and pulsatility and their responses to the administration of ovine corticotropin-releasing factor, thyrotropin-releasing hormone, metyrapone, tetracosactrin, insulin and dexamethasone. Techniques used to localize the anatomical lesion were bilateral simultaneous inferior petrosal sinus sampling, magnetic resonance examination of the pituitary, computed tomography (CT) scanning and [75Se]cholesterol scintigraphy of the adrenal glands. Plasma ACTH and serum cortisol levels were measured using a commercial radioimmunoassay and an immunoradiometric assay. The ACTH and cortisol pulse number and amplitude were calculated using established computer software. In all three patients ACTH and cortisol secretory dynamics fulfilled the requirements for diagnosis of pituitary-dependent Cushing's syndrome. A close relationship between ACTH and cortisol pulses also favored a pituitary dependency. Study of the amplitude of cortisol pulses classified two patients in the group of hypopulsatile Cushing's disease. Adrenal CT scanning demonstrated the presence of a large single nodule. [75Se]Cholesterol scintigraphy showed bilateral radionuclide uptake, although mostly localized over the adrenal nodule. All patients underwent successful trans-sphenoidal hypophysectomy. Over a period of 1 year, a slow shrinkage of the adrenal nodule was observed in two patients, while no change in volume was observed in one patient. Demonstration of an adrenal macronodule on CT scanning in patients with Cushing's syndrome is in itself insufficient to allow the diagnosis of hypercorticism due to a unilateral adrenal adenoma. Additional dynamic endocrine testing, inferior petrosal sinus sampling and imaging techniques such as [75Se]cholesterol scintigraphy remain necessary to reach a correct diagnosis.

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Philippe Chanson, Alexandre Dormoy, and Olaf M Dekkers

Surgery is the treatment of choice for non-functioning pituitary macroadenomas (NFPAs). In cases of postoperative remnant growth or tumor recurrence, radiotherapy (RT) can be considered. The role of RT in the postoperative management of NFPAs is still debated. The main arguments against routine use of RT are the lack of randomized controlled trials, the use of clinically irrelevant endpoints in most studies on RT, the benign character of the condition, the potential for side effects of RT, and the option to apply RT at a later stage. However, because of its excellent efficacy in inhibiting tumor growth, reducing tumor volume and improving any existing visual defects, and as its side effects seem to be limited compared to the benefits provided, RT keeps a place in the management of NFPAs when a tumor remnant persists, particularly if it is invasive and displays high proliferation markers, if surveillance shows a relevant increase in tumor volume or if the tumor is close to the optic chiasm. The size of the remnant, its vicinity with the optic pathways, and the potential risk to healthy surrounding tissues need to be considered when deciding on an RT procedure.

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Emmanuelle Kuhn, Alexandra A Weinreich, N R Biermasz, Jens Otto L. Jorgensen, and Philippe Chanson

Abstract

Context: Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis, and surveillance is generally limited as symptomatic growth is considered very rare.

Case Descriptions: We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and microprolactinomas) complicated by apoplexy during pregnancy.

Conclusion: During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

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Jean-Benoît Corcuff, Jacques Young, Pauline Masquefa-Giraud, Philippe Chanson, Eric Baudin, and Antoine Tabarin

Context

Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described.

Objective

To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism.

Design

Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN).

Patients and settings

A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals.

Intervention

Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities).

Main outcome

Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition.

Results

After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.

Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal.

Conclusion

Metyrapone–ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.