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Cynthia Ramiandrasoa, Frédéric Castinetti, Isabelle Raingeard, Patrick Fenichel, Olivier Chabre, Thierry Brue and Blandine Courbière

Background

Little is known about Sheehan's syndrome (SS), even though it is believed that its incidence is low. The aims of this study were to determine the clinical features and diagnostic delay of SS and to ascertain whether early signs could have allowed earlier diagnosis.

Subjects and methods

All patients with SS diagnosed in reference units in the southeast of France between 1980 and 2011 were recruited for this study. Data on obstetrical history, clinical symptoms suggestive of hypopituitarism, early signs, hormone analysis, and magnetic resonance imaging were collected.

Results

Of the 40 women found to have SS, 39 were studied. Mean delay in the diagnosis of SS was 9±9.7 years. We found that four of the 35 assessable patients were diagnosed with agalactia, 16 of the 29 assessable ones with amenorrhea, 19 of the 39 with hypothyroidism, eight with acute adrenal insufficiency, and 15 with asthenia. Among the patients for whom there was a diagnostic delay of more than 1 year (n=28), seven had headaches during the postpartum period, all assessable patients had agalactia, six of the 22 assessable ones had amenorrhea, seven of 28 had hypothyroidism, and 12 of 28 had asthenia.

Conclusion

Most signs of SS are aspecific and classical signs such as agalactia and amenorrhea are often difficult to detect, which can explain the long diagnostic delay. We suggest that all women failing to lactate after postpartum hemorrhage (PPH) should be evaluated by measuring prolactin levels and women with signs such as amenorrhea and asthenia, even several years after PPH, should undergo a blood test including assessment of thyroxine, TSH, 0800 h ACTH–cortisol, and IGF1 levels.

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Anne-Laure Borel, Robert Boizel, Patrice Faure, Geneviève Barbe, Jean Boutonnat, Nathalie Sturm, Daniel Seigneurin, Ivan Bricault, Jean-Pierre Caravel, Philippe Chaffanjon and Olivier Chabre

Objective

Measurement of thyroglobulin in the washout of lymph node (LN) fine needle aspirates is recommended in the follow-up of patients with differentiated thyroid cancer (DTC). The significance of low fine needle aspirates thyroglobin (FNATg) levels remains a question, which we addressed.

Method

Prospective study comparing FNATg with FNA cytology. Exploration of 34 DTC patients (53 cervical LNs), 26 non-thyroidectomized patients with a thyroid-unrelated cervical mass (negative controls) and 13 with 21 thyroid nodules (positive controls). The 12 DTC patients (19 LNs) with a malignant FNA cytology and/or high FNATg level received LN surgery (11 patients) or I131-iodine treatment (1 patient) and the outcome measure was pathological or scintigraphic evidence of DTC LN metastasis.

Results

All 26 negative controls showed FNATg <1 ng/FNA and all 21 positive controls showed high levels of FNATg (127–210 000 ng/FNA, median 38 000). Among DTC patients in 25 LNs with a benign FNA cytology, FNATg was undetectable in 24 and low in 1 (6 ng/FNA); in 19 LNs with a malignant FNA cytology, FNATg was high in 17 (80–140 000 ng/FNA, median 7174 ng/FNA) and low in 2 (6.6 and 7.1 ng/FNA), which proved to be low Tg immunostaining oncocytic DTC metastasis; in 9 LNs with a non-informative cytology, FNATg was undetectable in 8 but 11 825 ng/FNA in 1, which proved a DTC metastasis. Measurement of FNA albumin demonstrated that contamination of FNA by serum proteins was negligible.

Conclusion

Low FNATg levels can indicate a DTC metastasis. It cannot be related to clinically relevant levels of serum Tg.

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Marie-Laure Kottler, Yen-Yin Chou, Olivier Chabre, Nicolas Richard, Camille Polge, Sylvie Brailly-Tabard, Philippe Chanson, Anne Guiochon-Mantel, Ilpo Huhtaniemi and Jacques Young

Context

Mutations of the FSH β gene, causing in women isolated FSH deficiency and hypogonadism, are very rare and only a few have been described.

Objective

To describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSH β, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation.

Patient

A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency.

Methods and results

Sequencing of the FSH β gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSH β cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the α -subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHβ protein could not be detected in western blot.

In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas anti-Mullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels.

Conclusion

A novel FSH β mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.

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Luigi Maione, Thierry Brue, Albert Beckers, Brigitte Delemer, Patrick Petrossians, Françoise Borson-Chazot, Olivier Chabre, Patrick François, Jérôme Bertherat, Christine Cortet-Rudelli, Philippe Chanson and for the French Acromegaly Registry Group

Context

Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries.

Design

The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012.

Results

Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94–1.87) in men and 1.24 (0.77–1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70–1.42). Most deaths were due to cancer.

Conclusions

The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

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Hélène Lasolle, Christine Cortet, Fréderic Castinetti, Lucie Cloix, Philippe Caron, Brigitte Delemer, Rachel Desailloud, Christel Jublanc, Christine Lebrun-Frenay, Jean-Louis Sadoul, Luc Taillandier, Marie Batisse-Lignier, Fabrice Bonnet, Nathalie Bourcigaux, Damien Bresson, Olivier Chabre, Philippe Chanson, Cyril Garcia, Magalie Haissaguerre, Yves Reznik, Sophie Borot, Chiara Villa, Alexandre Vasiljevic, Stephan Gaillard, Emmanuel Jouanneau, Guillaume Assié and Gérald Raverot

Objectives

Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.

Design

Multicenter retrospective study by members of the French Society of Endocrinology.

Methods

Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.

Results

The median treatment duration was 6.5 cycles (range 2–24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0–72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0–57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.

Discussion

Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Free access

Thomas Cuny, Morgane Pertuit, Mona Sahnoun-Fathallah, Adrian Daly, Gianluca Occhi, Marie Françoise Odou, Antoine Tabarin, Marie Laure Nunes, Brigitte Delemer, Vincent Rohmer, Rachel Desailloud, Véronique Kerlan, Olivier Chabre, Jean-Louis Sadoul, Muriel Cogne, Philippe Caron, Christine Cortet-Rudelli, Anne Lienhardt, Isabelle Raingeard, Anne-Marie Guedj, Thierry Brue, Albert Beckers, Georges Weryha, Alain Enjalbert and Anne Barlier

Context

Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population.

Objective

We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions.

Design

The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions.

Patients and settings

One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study.

Results

Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients.

Conclusion

Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

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Elena Valassi, Alicia Santos, Maria Yaneva, Miklós Tóth, Christian J Strasburger, Philippe Chanson, John A H Wass, Olivier Chabre, Marija Pfeifer, Richard A Feelders, Stylianos Tsagarakis, Peter J Trainer, Holger Franz, Kathrin Zopf, Sabina Zacharieva, Steven W J Lamberts, Antoine Tabarin and Susan M Webb

Objective

The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).

Design and methods

Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).

Results

Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups.

Conclusions

The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

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Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Antoine Tabarin, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, John A H Wass, Peter J Trainer and for the ERCUSYN Study Group

Objective

To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing’s syndrome (ERCUSYN), and to examine if their use differs from the current guidelines.

Patients and methods

We analyzed data on the diagnostic tests performed in 1341 patients with Cushing’s syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS).

Results

Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years (P < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years (P < 0.05). Of the additional tests, late-night serum cortisol (LSeC) was measured in 62% and 48-h 2 mg/day low-dose dexamethasone suppression test (LDDST) in 33% of cases. ACTH was performed in 78% of patients. LSeC and overnight 1 mg DST supported the diagnosis of both PIT-CS and ADR-CS more frequently than UFC (P < 0.05).

Conclusions

Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

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Maria A Tichomirowa, Anne Barlier, Adrian F Daly, Marie-Lise Jaffrain-Rea, Cristina Ronchi, Maria Yaneva, Jonathan D Urban, Patrick Petrossians, Atanaska Elenkova, Antoine Tabarin, Rachel Desailloud, Dominique Maiter, Thomas Schürmeyer, Renato Cozzi, Marily Theodoropoulou, Caroline Sievers, Ignacio Bernabeu, Luciana A Naves, Olivier Chabre, Carmen Fajardo Montañana, Vaclav Hana, Georges Halaby, Brigitte Delemer, José Ignacio Labarta Aizpún, Emmanuel Sonnet, Ángel Ferrandez Longás, Marie-Thérèse Hagelstein, Philippe Caron, Günter K Stalla, Vincent Bours, Sabina Zacharieva, Anna Spada, Thierry Brue and Albert Beckers

Background

Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.

Methods

We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.

Results

Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.

Conclusion

Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Free access

Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, Peter J Trainer, John A H Wass, Antoine Tabarin and for the ERCUSYN Study Group

Background

Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial.

Objective

(1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS).

Patients and methods

1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS).

Results

Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups.

Conclusions

PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.