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Free access

Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France

Jacques Young, Jérôme Bertherat, Marie Christine Vantyghem, Olivier Chabre, Salima Senoussi, Rita Chadarevian, Frédéric Castinetti, and the Compassionalte use Programme

Objective

Ketoconazole (KTZ) is one of few available treatments for Cushing’s syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ.

Design

An observational prospective French cohort study (Compassionate Use Programme (CUP)).

Methods

Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury.

Results

Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes.

Conclusions

These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.

Free access

Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas

Laure Cazabat, Rossella Libè, Karine Perlemoine, Fernande René-Corail, Nelly Burnichon, Anne-Paule Gimenez-Roqueplo, Laurence Dupasquier-Fediaevsky, Xavier Bertagna, Eric Clauser, Philippe Chanson, Jérôme Bertherat, and Marie-Laure Raffin-Sanson

Objective: Germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have recently been described in three families with GH or prolactin-secreting tumors, as well as in a few patients with apparently sporadic somatotropinomas. The aim of the study was to determine the prevalence of AIP mutations in a large cohort of patients with apparently sporadic GH-secreting tumors.

Design: One hundred and fifty-four patients were included in a prospective cohort designed to study the genetic predisposition to GH-secreting tumors together with 270 controls.

Methods: In all these subjects, the entire coding sequence of the AIP gene was screened for germline mutations.

Results: AIP mutations were detected in 5 out of 154 patients (3%): nonsense mutations in exon 4 (p.Lys201X; n = 2) and in exon 6 (p.Arg304X), one deletion in exon 3 (c.404delA; pHis135LeufsX21), and one mutation affecting the splice acceptor site of exon 4 (c.469-2 A > G). The five patients with an AIP mutation were significantly younger (mean age ± S.D.: 25 ± 10 vs 43 ± 14 years, P = 0.005) and three of them presented with gigantism. One missense mutation (p.Arg304Gln) was found in a single patient that was absent in all controls.

Conclusions: Germline mutations of the AIP gene were found in a small proportion of patients with sporadic pituitary somatotropinomas. This study shows that age and gigantism are simple clinical features which can help to select patients for mutation screening. It also supports the role of AIP in pituitary tumorigenesis.

Free access

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study

Bertrand Baussart, Chiara Villa, Anne Jouinot, Marie-Laure Raffin-Sanson, Luc Foubert, Laure Cazabat, Michèle Bernier, Fideline Bonnet, Anthony Dohan, Jerome Bertherat, Guillaume Assié, and Stephan Gaillard

Objective

Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment.

Design

Follow-up of a cohort of consecutive patients treated by surgery.

Methods

Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan–Meier representation. A cox regression model was used to predict remission.

Results

Median follow-up was 18.2 months (range: 2.8–155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33–41.8) after surgery. From Kaplan–Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6–96.4%) and 81% (95% CI: 71.2–92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty.

Conclusions

In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

Restricted access

Corticotroph tumor progression speed after adrenalectomy

Laura Bessiène, Sandrine Moutel, Marine Lataud, Anne Jouinot, Fidéline Bonnet-Serrano, Jean Guibourdenche, Chiara Villa, Bertrand Baussart, Stephan Gaillard, Maxime Barat, Anthony Dohan, Xavier Bertagna, Bertrand Dousset, Jérôme Bertherat, and Guillaume Assié

Objectives

After bilateral adrenalectomy in Cushing’s disease, corticotroph tumor progression occurs in one-third to half of patients. However, progression speed is variable, ranging from slow to rapid. The aim was to explore corticotroph progression speed, its consequences and its risk factors.

Design

A retrospective single-center observational study.

Methods

In total,103 patients with Cushing’s disease who underwent bilateral adrenalectomy between 1990 and 2020 were included. Clinical, biological, histological and MRI features were collected. Median duration of follow-up after bilateral adrenalectomy was 9.31 years.

Results

In total,44 patients progressed (43%). Corticotroph tumor progression speed ranged from 1 to 40.7 mm per year. Progression speed was not different before and after bilateral adrenalectomy (P  = 0.29). In univariate analyses, predictive factors for rapid corticotroph tumor progression included the severity of Cushing’s disease before adrenalectomy as the cause of adrenalectomy, high ACTH in the year following adrenalectomy and high Ki67 immunopositivity in the tumor. During follow-up, early morning ACTH absolute variation was associated with corticotroph tumor progression speed (P-value = 0.001). ACTH measurement after dynamic testing did not improve this association.

Conclusion

After adrenalectomy, corticotroph progression speed is highly variable and manageable with MRI and ACTH surveillance. Progression speed does not seem related to bilateral adrenalectomy but rather to intrinsic properties of highly proliferative and secreting tumors.

Open access

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Hanna Nowotny, Uta Neumann, Véronique Tardy-Guidollet, S Faisal Ahmed, Federico Baronio, Tadej Battelino, Jérôme Bertherat, Oliver Blankenstein, Marco Bonomi, Claire Bouvattier, Aude Brac de la Perrière, Sara Brucker, Marco Cappa, Philippe Chanson, Hedi L Claahsen-van der Grinten, Annamaria Colao, Martine Cools, Justin H Davies, Helmut-Günther Dörr, Wiebke K Fenske, Ezio Ghigo, Roberta Giordano, Claus H Gravholt, Angela Huebner, Eystein Sverre Husebye, Rebecca Igbokwe, Anders Juul, Florian W Kiefer, Juliane Léger, Rita Menassa, Gesine Meyer, Vassos Neocleous, Leonidas A Phylactou, Julia Rohayem, Gianni Russo, Carla Scaroni, Philippe Touraine, Nicole Unger, Jarmila Vojtková, Diego Yeste, Svetlana Lajic, and Nicole Reisch

Objective

To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design and methods

A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results

Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4–5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions

This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

Restricted access

Differences in the spectrum of steroidogenic enzyme inhibition between Osilodrostat and Metyrapone in ACTH-dependent Cushing syndrome patients

Fidéline Bonnet-Serrano, Jonathan Poirier, Anna Vaczlavik, Christelle Laguillier-Morizot, Benoît Blanchet, Stéphanie Baron, Laurence Guignat, Laura Bessiene, Léopoldine Bricaire, Lionel Groussin, Guillaume Assié, Jean Guibourdenche, and Jérôme Bertherat

Introduction

Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome (CS).

Methods

Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS).

Results

Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2–688.4) and 14.9 (2.5–54.3) nmol/L, respectively) than in patients treated with Osilodrostat (10.3 (0.5–71.9) and 4.0 (0.3–13.3) nmol/L) (P = 0.0009 and P = 0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 (0.93–4.82) nmol/L vs 1.31(0.13–5.09) nmol/L, P = 0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were significantly decreased in Osilodrostat group (P < 0.0001).

Conclusion

In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat.

Free access

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma

Lucie Allard, Frédérique Albarel, Jérôme Bertherat, Philippe Jean Caron, Christine Cortet, Carine Courtillot, Brigitte Delemer, Christel Jublanc, Dominique Maiter, Marie Laure Nunes, Gerald Raverot, Julie Sarfati, Sylvie Salenave, Emmanuelle Corruble, Walid Choucha, and Philippe Chanson

Context

In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective

Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design

This was a multicenter (France and Belgium) retrospective study.

Patients

Eighteen patients treated with antipsychotics were included.

Results

Under DA, median PRL levels decreased from 1247 (117–81 132) to 42 (4–573) ng/mL (P = 0.008), from 3850 (449–38 000) to 141 (60–6000) ng/mL (P = 0.037) and from 1664 (94–9400) to 1215 (48–5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0–57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusion

Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.