Publications by authors named "Frédérique Albarel"

24 Publications

  • Page 1 of 1

The risks of medical treatment of prolactinoma.

Ann Endocrinol (Paris) 2021 Feb 26;82(1):15-19. Epub 2020 Dec 26.

Service d'endocrinologie, hôpital de la Conception, 147, boulevard Baille, 13005 Marseille, France; Aix Marseille université, centre de références maladies rares HYPO, Assistance Publique-Hôpitaux de Marseille, Marseille, France.

First-line treatment of prolactinoma is usually medical, based on dopamine agonists receptors, mainly cabergoline. The classical side-effects of cabergoline (low blood pressure and nausea) have been well known since it was first introduced. Other side-effects, however, are more controversial or simply less frequent, but need to be considered during monitoring. This review will focus on these side-effects: cardiac valvular fibrosis, pleural, pericardial and retroperitoneal fibrosis, addictive/compulsive behaviors, and risks secondary to significantly decreased tumor volume. We will also describe how such side-effects should be monitored and managed. In our opinion, the low prevalence of these side-effects should not cast doubt on the role of cabergoline in the therapeutic algorithm of prolactinoma.
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February 2021

Women's perceptions of femininity after craniopharyngioma: a qualitative study.

Clin Endocrinol (Oxf) 2021 May 9;94(5):880-887. Epub 2020 Dec 9.

Department of Gynecology-Obstetric and Reproductive Medicine, AP-HM, Hôpital La Conception-Hôpital Nord, Marseille, France.

Background: Previous quantitative studies have shown a reduced quality of life in patients treated for craniopharyngioma (CP). However, few have assessed their sexual quality of life and other issues related to patient intimacy have not yet been addressed. Standardized questionnaires limit the approach to sexuality and the exploration of patient experiences. A qualitative study, which allows in-depth analysis, may represent an interesting approach to explore intimacy in women with a history of CP.

Objective: To assess the impact of a CP history on femininity and relationships in women.

Design And Patients: A qualitative study with semi-structured interviews was conducted with 15 adult women treated for CP during childhood, adolescence or at childbearing age up to 40 years of age. Interviews were audio recorded, anonymized and transcribed literally. Data analysis was carried out with an inductive approach according to the grounded theory method.

Results: Three main themes were identified: (a) apparent changes leading to altered self-perception that may impact on femininity and generate lower self-esteem; (b) managing the hidden disabilities of the disease inducing a need for permanent control; and (c) building parenthood and couple relationships: coping with sexual dysfunction and infertility.

Conclusions: Our study highlighted alterations in self-perception and femininity due to body change and disability resulting from CP treatment, impacting both couple and social relationships. Interviewing women who underwent CP surgery at different ages highlighted specific needs and different expectations of medical professionals which emphasize the importance of offering both global and personalized care.
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May 2021

Germinal defects of SDHx genes in patients with isolated pituitary adenoma.

Eur J Endocrinol 2020 Oct;183(4):369-379

Aix Marseille Univ, APHM, INSERM, MMG, Hospital La Conception, Laboratory of Molecular Biology, Marseille, France.

Background: The '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.

Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.

Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome.

Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.

Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.
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October 2020

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

Eur J Endocrinol 2020 Aug;183(2):221-231

Assistance Publique Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

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.

Conclusions: 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.
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August 2020

Fluctuation analysis of postoperative secretory status in patients operated for acromegaly.

Ann Endocrinol (Paris) 2020 Feb 19;81(1):11-17. Epub 2019 Dec 19.

Neurosurgery department, CHU Timone, Aix-Marseille university, AP-HM, Marseille, France; Inserm, MMG, Aix-Marseille university, Marseille, France.

Objective: The aim of this study was to describe endocrinological outcome in patients operated on for acromegaly.

Methods: A retrospective study included 167 patients. Patients were assessed in the early postoperative period (EPP), at 3 months (M3), at 1 year (Y1), and then annually. They were classified as grade I (IGF-1 level normal-for-age and positive GH response on oral glucose tolerance test [nadir <0.4ng/L]); grade II (discordant); or grade III or IV (acromegaly, controlled or uncontrolled under medical therapy, respectively).

Results: Taking all patients with all grades, 35% changed grades between EPP and M3, 26% between M3 and Y1 and 9% after Y1. In grade I, respectively 22%, 15% and 2% of patients changed grades between EPP and M3, between M3 and Y1, and after Y1, compared to 31%, 6% and 6% in grade IV. Respectively 57%, 67%, and 47% of grade II patients changed grades between EPP and M3, between M3 and Y1, and after Y1; between EPP or M3 and last follow-up (>1 year), respectively 74% and 75% of grade II patients changed grades. Knosp category, resection quality and abnormal GH response (vs. abnormal IGF-1) significantly impacted grade II patients' outcome.

Conclusions: Whereas outcome in grades I and III-IV seems to be determined by 1 year, grade II discordant patients' outcome remains uncertain even after 1 year.
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February 2020

Surgical indications for pituitary tumors during pregnancy: a literature review.

Pituitary 2020 Apr;23(2):189-199

Neurosurgery Department, Aix-Marseille Univ, APHM, CHU Timone, La Timone Hospital, 264 rue Saint-Pierre, 13005, Marseille, France.

Purpose: Surgical indications for pituitary tumors during pregnancy are rare, and are derived from a balance between expected benefits, particularly for maternal benefits, and anesthetic/surgical risks.

Methods: A literature review was performed to define the optimal surgical indications for pituitary adenomas (PA) and other pituitary tumors during pregnancy.

Results: Main benefits are expected in case of critical visual impairment and/or life-threatening endocrine disturbances. Multidisciplinary patient management is systematically required although nonobstetric surgery presents a reasonable risk during pregnancy. The risks of congenital malformation during the first trimester and those of premature birth during the third trimester make the second trimester the optimal period for surgery. In prolactin-secreting, nonsecreting, GH- and TSH-secreting PAs, transsphenoidal surgery (TS) is recommended in cases involving severe visual impairment, characterized by severe visual field deficit, visual acuity impairment, and abnormal optical coherence tomography findings, and when no other medical alternatives are possible and/or sufficient. Uncontrolled and severe Cushing's disease (CD) during pregnancy increases both maternal and fetal morbimortality, thus justifying TS or sometimes dopamine agonist therapy as a safer alternative. Finally, metyrapone, ketoconazole, or bilateral adrenalectomy could be recommended in certain cases after the failure of medical therapies and/or TS. Surgery is also required for suprasellar meningiomas, craniopharyngiomas, and pituitary cysts in the case of severe visual deficit.

Conclusion: Surgical indications for pituitary tumors are rare during pregnancy; therefore, surgery should be avoided when possible. Further, the second trimester should be considered as the optimal surgical period. Severe visual disturbance and uncontrolled CD are the main surgical indications during pregnancy.
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April 2020

MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis.

Eur J Endocrinol 2019 Sep;181(3):R107-R118

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France.

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.
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September 2019

Functioning gonadotroph adenoma with severe ovarian hyperstimulation syndrome: A new emergency in pituitary adenoma surgery? Surgical considerations and literature review.

Ann Endocrinol (Paris) 2019 Apr 7;80(2):122-127. Epub 2019 Feb 7.

Department of neurosurgery, hôpital La Timone, Assistance publique-Hôpitaux de Marseille (AP-HM), Marseille, France; Aix-Marseille université, institut national de la santé et de la recherche médicale (Inserm), U1251, Marseille medical genetics (MMG), Marseille, France.

The authors reported 2 cases of functioning gonadotroph pituitary adenoma (FGPA) revealed by an ovarian hyperstimulation syndrome (OHSS) in young women. In the first case, OHSS was observed after GnRH analog injection. Pelvic echography revealed multiple voluminous ovarian cysts. Dopamine agonist posology failed in estradiol hypersecretion control, which necessitated endoscopic endonasal transsphenoidal surgery. The patient experienced improvement in pelvic pain as estradiol hypersecretion decreased during the first few postoperative days. Outcome was favorable, and her menstrual cycle was normal after two months. The second case was a young girl with spontaneous pelvic pain and elevated plasma FSH and estradiol levels. FGPA was confirmed on cerebral MRI. Dopamine agonists were introduced, and surgical removal of the pituitary tumor was scheduled for 7 days later. In the meantime, the patient was admitted and underwent surgery for bilateral adnexal torsion related to OHSS. The pituitary tumor was removed one week later. Outcome was favorable, and estradiol and FSH plasma levels were normal after 3 months. The ovarian cysts were no longer visible on echography after 3 months. Given the lack of efficacy of the current standard medical therapy, surgical removal of pituitary adenomas is the reference treatment for FGPA. The authors suggest that severe OHSS related to FGPA should be considered as a relative surgical emergency and that surgery should not be unduly delayed, given the unpredictable risk of adnexal torsion, particularly in case of voluminous ovarian cysts. The authors performed a literature review on this topic.
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April 2019

Daily life, needs and expectations of patients with acromegaly in France: An on-line survey.

Ann Endocrinol (Paris) 2019 Apr 25;80(2):110-116. Epub 2018 Sep 25.

Service d'endocrinologie, diabète-nutrition, CHU de Reims, 51092 Reims cedex, France.

Acromegaly can impair quality of life, but impact on patients' daily life, needs and expectations have been poorly explored.

Objectives: To better understand the impact of acromegaly on patients' daily life, and evaluate their needs and expectations.

Patients And Methods: An on-line questionnaire survey of acromegaly patient and relative community members was conducted on the Carenity website.

Results: Twenty-five patients and 3 relatives, with a mean age of 48.9 years, responded. Diagnosis of acromegaly was recent (60% within 10 years). Signs at diagnosis were mainly clinical (fatigue, headache) and physical changes (acral enlargement). Reported complications comprised morphological changes (93%), bone and joint symptoms (75%) and metabolic disorders (75%). Pain and fatigue impacted the daily life of 61% and 54% patients, respectively. Acromegaly had strong impact on mood (79%), leisure (75%) and social life (71%). Patients mostly got information from specialized websites (71%), their endocrinologist (61%) and patient associations (54%). The information sought was patient testimony (82%), practical advice (64%), and information on clinical trials (61%) and treatments (50%). Patients wished to have patient-physician discussion groups (25%), and better knowledge of acromegaly on the part of those they were in contact with (25%).

Conclusion: Acromegaly has a major impact on patients' daily life and mood. Patients wished their disease to be better known, and advocated setting up discussion groups. This study should encourage acromegaly education programs to adapt the services and information that are needed by acromegalic patients.
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April 2019

Expert opinion on pituitary complications in immunotherapy.

Ann Endocrinol (Paris) 2018 Oct 25;79(5):562-568. Epub 2018 Jul 25.

Service d'Endocrinologie, CHRU de Lille, Hopital Huriez, 59037 Lille cedex, France.

Hypophysitis is a frequent toxic endocrine side-effect of immunotherapy. Prevalence is higher with anti-CTLA-4 antibodies (4-20%) or in association with PD-1 inhibitors (8%). Diagnosis is presumptive, based on poorly specific clinical symptoms (usually, headache and asthenia) and/or hyponatremia and/or at least one pituitary deficit and/or abnormal imaging. Visual disorder or polyuropolydipsic syndrome are exceptional. In decreasing order of frequency, deficits are thyrotropic (86-100%), gonadotropic (85-100%) or corticotropic (50-73%); somatotropin deficit or abnormal prolactin level are rarer. Pituitary MRI in acute phase shows variable moderate increase in pituitary volume, ruling out differential diagnoses, especially pituitary metastasis. Treatment of corticotropin deficiency requires systematic emergency replacement therapy, with the usual modalities, while treatment of other deficits depends on clinical status and progression. Thyrotropin and gonadotropin deficits usually recover, but corticotropin deficiency persists over the long term, requiring education and specialized endocrinologic follow-up. Onset of hypophysitis does not contraindicate continuation of immunotherapy and does not usually require high dose synthetic glucocorticoids.
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October 2018

Increased Risk of Persistent Glucose Disorders After Control of Acromegaly.

J Endocr Soc 2017 Dec 24;1(12):1531-1539. Epub 2017 Nov 24.

Aix-Marseille Université, Centre National de la Recherche Scientifique, CRN2M Unité Mixte de Recherche 7286 and Assistance Publique-Hopitaux de Marseille, Department of Endocrinology, La Conception Hospital, National Reference Center for Rare Pituitary Diseases, 13005 Marseille, France.

Purpose: Combining surgery and medical treatments allows the control of growth hormone hypersecretion in 80% of cases. Our objective was to determine the rate of acromegaly comorbidities once hypersecretion of growth hormone is controlled.

Methods: Our retrospective monocentric study was based on 130 patients followed on a regular basis, with acromegaly controlled by medical treatments or cured by surgery or radiation technique. Our main outcome measures were the prevalence of major metabolic complications of acromegaly (diabetes, hypertension, low-density lipoprotein cholesterol, triglycerides) at diagnosis and last follow-up in comparison with French epidemiological data.

Results: As expected, controlling hypersecretion significantly improved the metabolic complications of acromegaly. However, the proportion of patients having at least one metabolic complication of acromegaly at last follow-up (mean, 72 months after remission) was 27% for altered glucose tolerance or diabetes, 39% for hypertension, 34.3% for hypercholesterolemia, and 13.3% for hypertriglyceridemia. Interestingly, our data showed that diabetes was the only comorbidity different with a higher prevalence in patients in remission versus a general population of a similar median age (21.6% vs 6.9%, respectively).

Conclusions: The follow-up of glucose disorders needs to be maintained on a long-term basis in patients controlled for acromegaly.
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December 2017

Successful IVF pregnancy despite inadequate ovarian steroidogenesis due to congenital lipoid adrenal hyperplasia (CLAH): a case report.

Hum Reprod 2016 11 3;31(11):2609-2612. Epub 2016 Oct 3.

Aix-Marseille Université, CNRS, CRN2M UMR 7286, 13344 cedex 15, Marseille, France

Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty.
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November 2016

Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study.

Hum Reprod 2016 06 19;31(6):1363-74. Epub 2016 Apr 19.

Univ Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France INSERM Unité Mixte de Recherche 1185, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre F-94276, France Service de Génétique Moléculaire, Pharmacogénétique, et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

Study Question: What is the exact prevalence of Kisspeptin Receptor (KISS1R) mutations in the population of patients with normosmic congenital hypogonadotrophic hypogonadism (nCHH) by comparison with other genes, involved in gonadotrophin-releasing hormone (GnRH) release or action?

Summary Answer: KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases and were less prevalent than GnRH Receptor (GNRHR) mutations.

What Is Known Already: The respective prevalence of each of the genetic causes of nCHH is unclear. Large series of patients are very rare and suffer from heterogeneity of the population of CHH studied.

Study Design, Size, Duration: Patients with nCHH were consecutively enrolled in a single French referral centre and were gradually tested for KISS1R between January 2006 and April 2015.

Participants/materials, Setting, Methods: A total of 603 patients with nCHH (399 men and 204 women) were diagnosed at the Bicêtre Hospital and underwent KISS1R analysis. The GNRHR, tachykinin receptor 3 (TACR3), gonadotrophin-releasing hormone 1 (GNRH1), tachykinin 3 (TAC3) and KISS1 genes were also sequenced. Functional characterization of KISS1R mutations included a study of signal transduction using a reporter gene (serum response element-luciferase (SRE-Luc) involved in the mitogen-activated protein (MAP) kinase pathway.

Main Results And The Role Of Chance: We detected 15 KISS1R variants (10 novel), in 12 of the 603 patients (2.0%, 95% CI [0.9-3.1]. KISS1R mutations were less prevalent than GNRHR (4.7%) and TACR3 (2.6%) mutations but more prevalent than GNRH1 (1.5%), TAC3 (1.0%) and KISS1 (0%) mutations. KISS1R mutants were present in the biallelic state in 8 of the 12 patients concerned. Among 5 men with biallelic KISS1R mutations, 4 had either micropenis or cryptorchidism. In vitro analysis of the 5 new variants present in the biallelic state (C95W, Y103*, C115W, P176R and A287E) showed a loss of function.

Limitations, Reasons For Caution: The prevalence of TACR3, GNRH1, TAC3 and KISS1 mutations was calculated from a smaller number of nCHH patients than KISS1R and GNRHR. This should prompt caution concerning the reported prevalence of mutations in these four genes.

Wider Implications Of The Findings: We show that KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases. Together, the genes analysed here were mutated in fewer than 15% of patients, suggesting a role of other genes in nCHH. The presence of cryptorchidism and/or micropenis in the majority of men with biallelic KISS1R mutations strongly suggests that this gene is essential for prenatal GnRH secretion.

Study Funding, Competing Interests: This work was supported in part by grants from Paris-Sud University (Bonus Qualité Recherche, and Attractivité grants) to J.B., French Ministry of Health, Hospital Clinical Research Program on Rare Diseases. Assistance Publique Hôpitaux de Paris, Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO) to J.Y. C.P. was supported by student fellowships 'Année Recherche' from Agence Régionale de Santé Provence Alpes Côtes d'Azur. The authors have nothing to disclose.
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June 2016

Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome.

Hum Reprod 2016 Apr 13;31(4):782-8. Epub 2016 Feb 13.

Université Pierre et Marie Curie, F-75012 Paris, France Service d'Endocrinologie et Maladies de la Reproduction, Centre de référence des Maladies Endocriniennes Rares de la Croissance (CRMERC), Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France

Study Question: What are the prevalence and the outcomes of spontaneous pregnancies (SP) in a large cohort of French women with Turner syndrome (TS)?

Summary Answer: Amongst 480 women with TS, 27 women (5.6%) had a total of 52 SP, with 30 full-term deliveries for 18 women.

What Is Known Already: Primary ovarian insufficiency is a classic feature of TS. So far, few studies have evaluated the rate of SP in these patients.

Study Design, Size, Duration: The French Ministry of Health set up a National Reference Centre for Rare Growth Disorders (CRMERC), including TS. We studied a cohort of adult TS patients from seven endocrine units (Saint-Antoine, Pitié-Salpêtrière, Bicêtre, Lyon, Marseille, Brest, Reims Hospitals) belonging to this centre, between January 1999 and January 2014.

Participants/materials, Setting, Methods: A total of 480 adult patients with TS were included. The patients' clinical characteristics, karyotypes and reproductive histories had been collected, after informed consent, in a web database called CEMARA. Our reference population was issued from a database belonging to the French Health Ministry, collecting pregnancy outcomes in the French general population. In order to find predictive characteristics of SP, TS with spontaneous pregnancies were compared with non-pregnant TS patients from our cohort.

Main Results And The Role Of Chance: There were 27 patients (5.6%) who had a total of 52 SP. The two predictive factors which correlated with occurrence of a SP were spontaneous menarche and mosaic karyotype. The median delay to conception was 6 months (range 0-84). Miscarriage occurred in 16 pregnancies, 30.8% versus 15% in the general French population (P < 0.01). The remaining pregnancy outcomes were legal abortion (n = 2), medical interruption (n = 3), intrauterine fetal death (n = 1) and delivery at term (n = 30). Caesarean section rates were higher than in the general population, respectively 46.7% versus 21% (P < 0.001). Pregnancy-induced hypertensive disorders (PHDs) occurred in four cases (13.3%), including two cases of mild pre-eclampsia (6.7%). Neither aortic root dilatation nor aortic dissection were observed. The median birthweight was 3030 g (range 2020-3460). Two cases of TS were identified in the 17 daughters issued from this cohort.

Limitations, Reasons For Caution: It would have been interesting to evaluate AMH levels and SP occurrence, as a predictive factor. Unfortunately, hormonal measurements were missing for some patients. Prospective studies are necessary to display prognostic values of AMH for SP and thus better target fertility preservation programmes in TS patients.

Wider Implications Of The Findings: This study suggests that pregnancy outcomes in SPs are more favourable than those after oocyte donation in TS patients. However, the risk of fetal chromosomal abnormalities remains high. Our study will be useful in order to give patients with TS, their families, paediatricians and physicians involved in reproduction, better counselling concerning their fertility.

Study Funding/competing Interests: Funding was provided by the Association pour la recherche Claude Bernard, Paris France All authors claim no competing interests.

Trial Registration Number: NA.
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April 2016

Postoperative follow-up of Cushing's disease using cortisol, desmopressin and coupled dexamethasone-desmopressin tests: a head-to-head comparison.

Clin Endocrinol (Oxf) 2015 Aug 20;83(2):216-22. Epub 2015 Mar 20.

Department of Endocrinology, CHU La Timone, APHM and CRN2M-UMR 7286- Faculte de Medecine Secteur Nord, Aix Marseille Université, Marseille, France.

Objective: Predicting the outcome of patients operated on for Cushing's disease (CD) is a challenging task. Our objective was to assess the accuracy of immediate postsurgical plasma cortisol, desmopressin test and the coupled dexamethasone-desmopressin test (CDDT) as predictors of outcome.

Design And Patients: Sixty-seven patients with initial remission and a minimal postsurgical follow-up greater than 18 months were included in this retrospective bicentre study.

Measurements: Follow-up included 3-6 months followed by yearly 24-h urinary-free cortisol, ACTH and cortisol plasmatic levels, a 1-mg overnight dexamethasone suppression test (1-mg DST), desmopressin test and the CDDT. ROC curves were performed to define the optimal threshold of immediate postsurgical cortisol level and 3- to 6-month desmopressin test and CDDT, as predictors of final outcome in comparison with classical biological markers of recurrence.

Results: Eleven patients presented recurrence. The patient's median follow-up was 52 months (range, 18-180). As early predictors of outcome, immediate postsurgical plasma cortisol level <35 nmol/l predicted the lack of recurrence with 93% negative predictive value (NPV), whereas predictive positive value (PPV) was 25%. During the follow-up, the CDDT was more precise than the desmopressin test in predicting the lack of recurrence (100% NPV) when performed in the first 3 years after surgery. Positivity of the CDDT was defined based on ROC curves by ACTH and cortisol increments >50%. The CDDT was highly reproducible, as the same response was observed every year in 91% of the patients.

Conclusions: Adding the CDDT the first 3 years after surgery to immediate postsurgical cortisol evaluation should allow obtaining an optimal follow-up management of patients operated for Cushing's disease.
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August 2015

An observational study on adrenal insufficiency in a French tertiary centre: Real life versus theory.

Ann Endocrinol (Paris) 2015 Feb 21;76(1):1-8. Epub 2015 Jan 21.

Service d'endocrinologie, centre de référence DEFHY, hôpital de la Timone, Aix-Marseille université, rue Saint-Pierre, 13005 Marseille, France.

Background: Patients suffering from adrenal insufficiency, whether primary (PAI) or secondary (SAI) have an increased mortality risk and increased morbidity. There are no guidelines on hydrocortisone replacement therapy and little is known on patients' management in current practice. We described patients' profiles and treatment in a tertiary referral centre.

Methods: Data were collected retrospectively from medical charts. PAI and SAI patients were described and compared.

Results: Two hundred and one patients (79 PAI+122 SAI) were included. They had a mean duration of disease of 11.2years. Main causes of PAI were autoimmune diseases (31%) and adrenalectomy (26%). SAI was caused primarily by pituitary tumors (61%) and irradiation (20%). Mean dose of daily hydrocortisone (HC) was 27.5 and 19.9mg/day in PAI and SAI patients respectively, with a majority of patients dividing the dose into 2 intakes (46.8 and 72.2% in PAI and SAI groups, respectively). SAI patients exhibited more cardiovascular risk factors than PAI patients. The HC daily dose was slightly higher in patients with dyslipidemia (in both PAI and SAI groups) and in those with high blood pressure (in the SAI group only). One third of patients were out of work, due to unemployment, sick leaves, or disability.

Conclusions: The management of AI is far from standardized, and individual tailorization is difficult with currently available means of treatment. Under- and overdose of hydrocortisone likely leads to complications, and altered quality of life reflected by a high rate of "out of work" patients.
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February 2015

Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma.

Eur J Endocrinol 2015 Feb 21;172(2):195-204. Epub 2014 Nov 21.

Assistance Publique - Hôpitaux de Marseille (AP-HM)Hôpital Timone, Service d'Endocrinologie et Centre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversitéCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversitéAssistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hôpitaux de Marseille (AP-HM)Hôpital Timone, Service d'Endocrinologie et Centre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversitéCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversitéAssistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France

Objective: Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up.

Design And Patients: Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille.

Methods: Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.

Results: Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients.

Conclusion: Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.
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February 2015

A monocentric experience of growth hormone replacement therapy in adult patients.

Ann Endocrinol (Paris) 2014 Jul 2;75(3):176-83. Epub 2014 Jul 2.

Aix-Marseille université, CNRS, CRN2M UMR 7286, 13344 Marseille cedex 15, France; Service d'endocrinologie, diabète et maladies métaboliques, centre de référence des maladies rares d'origine hypophysaire DEFHY, hôpital Timone, AP-HM, 13385 Marseille cedex 15, France.

Objectives: To describe the results of growth hormone (GH) therapy in adult GH-deficient patients treated in a tertiary referral center, with a focus on quality of life and adherence.

Patients And Methods: Retrospective study of patients followed over a total period of 11 years. Quality of life (QOL) was assessed by the QOL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) score and adherence to treatment was measured by a specific questionnaire. Clinical, biological, body composition and bone mineralization parameters were also analyzed.

Results: Data from 81 patients were analyzed. After a median treatment duration of 7 years, 2/3 of patients reported improved QOL (mean decrease of AGHDA score of 3.0 points, P<0.001). A trend towards more frequent improvement was observed in middle-aged patients, women, childhood-onset GHD, and in patients with initially more impaired QOL. More than 60% of the patients reported continuing treatment without interruption. Seventy percent declared good adherence (≤2 missed injections/month). A majority reported enhanced well-being. Additionally, we observed a mean weight increase of 2 kg, while fat mass, waist/hip circumference ratio and lipids were unchanged. Bone mineral density was significantly increased at lumbar spine and femoral neck.

Conclusion: Our study confirmed a sustained improvement in quality of life and showed that majority of patients were still on GH treatment after a median duration of 7 years.
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July 2014

Hormonal therapy is associated with better self-esteem, mood, and quality of life in transsexuals.

J Nerv Ment Dis 2013 Nov;201(11):996-1000

*Department of Psychiatry, Sainte-Marguerite University Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, France; †EA 3279 Research Unit, University Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, France; ‡Department of Psychiatry, La Colombière University Hospital, Montpellier, France; §Department of Psychiatry, Pasteur University Hospital, Nice, France; and ∥Department of Endocrinology, Timone University Hospital, Marseille, France.

Few studies have assessed the role of cross-sex hormones on psychological outcomes during the period of hormonal therapy preceding sex reassignment surgery in transsexuals. The objective of this study was to assess the relationship between hormonal therapy, self-esteem, depression, quality of life (QoL), and global functioning. This study incorporated a cross-sectional design. The inclusion criteria were diagnosis of gender identity disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) and inclusion in a standardized sex reassignment procedure. The outcome measures were self-esteem (Social Self-Esteem Inventory), mood (Beck Depression Inventory), QoL (Subjective Quality of Life Analysis), and global functioning (Global Assessment of Functioning). Sixty-seven consecutive individuals agreed to participate. Seventy-three percent received hormonal therapy. Hormonal therapy was an independent factor in greater self-esteem, less severe depression symptoms, and greater "psychological-like" dimensions of QoL. These findings should provide pertinent information for health care providers who consider this period as a crucial part of the global sex reassignment procedure.
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November 2013

R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

PLoS One 2013 25;8(7):e69616. Epub 2013 Jul 25.

Université Paris-Sud, Faculté de Médecine Paris-Sud Unité mixte de Recherche en Santé 693, Le Kremlin Bicetre, France.

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.
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March 2014

Outcome of multimodal therapy in operated acromegalic patients, a study in 115 patients.

Clin Endocrinol (Oxf) 2013 Feb;78(2):263-70

Aix-Marseille Université, CNRS, Hôpital Timone, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY, 264 rue Saint Pierre, Marseille Cedex 15, France.

Introduction: Given the new therapeutic options in acromegaly, it seemed important to evaluate the outcome of operated acromegalic patients today.

Objective: To analyse the characteristics and short- and long-term surgical outcome of patients who underwent transsphenoidal surgery for a growth hormone (GH)-secreting adenoma in our centre and to determine predictive factors of remission.

Design And Patients: This retrospective 10-year study included 115 newly diagnosed acromegalic patients operated on at Timone University Hospital, Marseille, France, between 1997 and 2007.

Measurements: Initial and long-term outcomes were evaluated using stringent and current remission criteria, associating GH nadir after oral glucose tolerance test <0·4 μg/l and normal insulin-like growth factor-1 (IGF-1) at 3 months, and a normal IGF-1 at the end of follow-up (52·4 ± 36·8 months, median 41 months, range 6·7-135·4 months, n = 99).

Results: At the end of follow-up, 90·9% of patients had controlled disease. Overall, 49·5% of patients were in long-term remission after surgery alone, and only 2·0% of patients experienced recurrent disease. Multivariate predictors of 3-month remission included mean GH at diagnosis (P = 0·033), tumour invasion (P = 0·013) and surgeon report of incomplete or uncertain macroscopic resection (P = 0·003 and P = 0·047, respectively). Multivariate predictors at diagnosis of long-term remission included mean GH level (P = 0·048), adenoma size (P = 0·007) and absence of pituitary deficit (P = 0·026).

Conclusions: In long-term follow-up after surgery of acromegaly, half of the patients achieved remission after surgery alone and more than 90% had their disease controlled. With stringent 3-month remission criteria, recurrence was rare.
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February 2013

From nodule to differentiated thyroid carcinoma: contributions of molecular analysis in 2012.

Ann Endocrinol (Paris) 2012 Jun 13;73(3):155-64. Epub 2012 Apr 13.

Department of Endocrinology, centre de référence des maladies rares d'origine hypophysaire, Aix-Marseille université, Assistance publique-Hôpitaux de Marseille (AP-HM), 13385 Marseille cedex 05, France.

Today there is a better understanding of the events involved in the initiation and progression of thyroid cancer. It is indeed now known that BRAF and RAS mutations and RET/PTC and PAX8/PPARγ rearrangements account for the majority of molecular alterations detected in differentiated thyroid cancers. Abnormal regulation of microRNAs (miRNAs) is also a promising way of research. The diagnostic utility and prognostic value of detecting these molecular events has been analyzed in several recent studies. BRAF mutation analysis improves the performance of fine-needle aspiration diagnosis by increasing specificity in "indeterminate" cytologies and sensitivity in false negatives. Testing for a "panel of mutations" (BRAF, RAS, RET/PTC and PAX8/PPARγ) improves the performance, detecting papillary carcinomas with non-classic histology. The specificity of these analyzes is excellent but their sensitivity is still insufficient. In the future, specific miRNAs expression profiles in thyroid carcinoma and identification of new mutations might provide interesting information. Several studies have found that BRAF mutations are associated with a more aggressive tumor behavior, a higher risk of recurrence and treatment failure. With regard to the other mutations and rearrangements, current data are conflicting and it seems premature to draw practical conclusions applicable in routine practice. Lastly, targeted therapy with tyrosine kinase inhibitors, based on our understanding of the molecular mechanisms of thyroid oncogenesis, has shown promise in metastatic, progressive, and radioactive iodine-refractory differentiated thyroid carcinomas.
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June 2012

Is hormonal therapy associated with better quality of life in transsexuals? A cross-sectional study.

J Sex Med 2012 Feb 6;9(2):531-41. Epub 2011 Dec 6.

Department of Psychiatry, Sainte-Marguerite University Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France.

Introduction: Although the impact of sex reassignment surgery on the self-reported outcomes of transsexuals has been largely described, the data available regarding the impact of hormone therapy on the daily lives of these individuals are scarce.

Aims: The objectives of this study were to assess the relationship between hormonal therapy and the self-reported quality of life (QoL) in transsexuals while taking into account the key confounding factors and to compare the QoL levels between transsexuals who have, vs. those who have not, undergone cross-sex hormone therapy as well as between transsexuals and the general population (French age- and sex-matched controls).

Methods: This study incorporated a cross-sectional design that was conducted in three psychiatric departments of public university teaching hospitals in France. The inclusion criteria were as follows: 18 years or older, diagnosis of gender identity disorder (302.85) according to the Diagnostic and Statistical Manual, fourth edition text revision (DSM-IV TR), inclusion in a standardized sex reassignment procedure following the agreement of a multidisciplinary team, and pre-sex reassignment surgery.

Main Outcome Measure: QoL was assessed using the Short Form 36 (SF-36).

Results: The mean age of the total sample was 34.7 years, and the sex ratio was 1:1. Forty-four (72.1%) of the participants received hormonal therapy. Hormonal therapy and depression were independent predictive factors of the SF-36 mental composite score. Hormonal therapy was significantly associated with a higher QoL, while depression was significantly associated with a lower QoL. Transsexuals' QoL, independently of hormonal status, did not differ from the French age- and sex-matched controls except for two subscales of the SF-36 questionnaire: role physical (lower scores in transsexuals) and general health (lower scores in controls).

Conclusion: The present study suggests a positive effect of hormone therapy on transsexuals' QoL after accounting for confounding factors. These results will be useful for healthcare providers of transgender persons but should be confirmed with larger samples using a prospective study design.
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February 2012

Congenital pituitary hormone deficiencies: role of LHX3/LHX4 genes.

Expert Rev Endocrinol Metab 2008 Nov;3(6):751-760

c Centre de Recherche en neurobiologie et neurophysiologie de Marseille (CRN2M), UMR6231, Faculté de Médecine Nord, Centre National de la Recherche Scientifique, Université de la Méditerranée and Centre de Référence des déficits hypophysaires, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille, 13385 Marseille, France.

LHX3 and LHX4 are LIM domain transcription factors involved in the early steps of pituitary organogenesis. They are necessary for the proper differentiation of Rathke's pouch that gives rise to the anterior pituitary lobe. Mutations of these transcription factors are involved in congenital hypopituitarism: to date, nine mutations of LHX3 have been reported, responsible for variable pituitary hormone deficiencies and extrapituitary manifestations, including limited neck rotation. By contrast, only five LHX4 mutations have been reported, responsible for variable hormone deficiencies, and pituitary/intracranial abnormalities. Future investigations will aim to better understand human pituitary organogenesis and to shed light on the interspecies differences in the roles of these transcription factors.
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November 2008