Carine Courtillot

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure

OBJECTIVE Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis. DESIGN AND METHODS We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center. RESULTS Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turners syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1. CONCLUSION A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.

Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors

There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile146→Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlRI146L), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlRI146L in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future.

Benign Breast Diseases

Benign breast diseases have always been neglected in comparison to cancer, despite the fact that there are many more patients with such diseases than patients presenting to a breast clinic for cancer. Like normal breast tissues, benign breast diseases are under a complex system of controls by both systemic hormonal and local factors. In this review, we attempt to present an overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of these disorders.

Normal spermatogenesis in a man with mutant luteinizing hormone.

Men with mutations in LHB, the gene encoding the beta subunit of luteinizing hormone (LHB), have azoospermia with absent or few fetal Leydig cells. We report a mutation in LHB in a man and his sister. The man presented with absence of virilization, undetectable luteinizing hormone, and a low serum testosterone level. He had complete spermatogenesis with a normal sperm count. The mutant luteinizing hormone had a low level of partial activity in vitro. We concluded that the residual luteinizing hormone activity, resulting in the expression of steroidogenic enzymes in few mature Leydig cells producing small amounts of intratesticular testosterone (20.2 ng per gram), was sufficient for complete and quantitatively normal spermatogenesis.

Cardiovascular findings and management in Turner syndrome: insights from a French cohort

OBJECTIVE Congenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults. DESIGN/METHODS We recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300). RESULTS Informative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0-60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th-75th percentiles: 15-30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7-30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m(2) in 39% of the cohort. CONCLUSION Our study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.

Quand et comment traiter une hyperprolactinémie

Points essentials • L’hyperprolactinemie a un retentissement sur l’axe gonadotrope. • L’amenorrhee, les troubles du cycle et la galactorrhee predominent chez la femme, tandis que, chez l’homme, du fait de la frequence de macroadenomes a prolactine, les troubles de la libido ou en rapport avec le volume tumoral au niveau hypophysaire sont souvent au premier plan. • Le dosage radio-immunologique rend aise le diagnostic des hyperprolactinemies. • Il est necessaire d’eliminer les causes secondaires, en particulier medicamenteuses, d’hyperprolactinemie avant de poursuivre les explorations a la recherche d’une tumeur hypophysaire par IRM. • Le traitement de premiere intention des adenomes a prolactine repose sur l’utilisation d’agonistes dopaminergiques, en particulier de la cabergoline, du fait de leur tres bonne efficacite et des risques de recidive apres chirurgie. • Pour une patiente ayant un desir de grossesse, il faut continuer l’agoniste dopaminergique pendant la grossesse en cas de macroadenome mais l’arreter en cas de microadenome. • Le traitement des hyperprolactinemies induites par les traitements antipsychotiques necessiterait une evaluation plus poussee.

Vulvar Lichen Sclerosus Is Very Frequent in Women With Turner Syndrome

Department of Endocrinology and Reproductive Medicine (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France; Center of Rare Gynecologic Diseases (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Paris, 75103, France; and Center of Rare Endocrine Growth Diseases (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Paris, 75103, France

Hypogonadism as a Reversible Cause of Torsades de Pointes in Men

Long QT intervals corrected for rate (QTc) >480 to 500 milliseconds predispose to the polymorphic ventricular tachycardia torsades de pointes (TdP).1 Because QTc is shorter and TdP is less frequent in men than in women and because testosterone shortens ventricular repolarization, we examined the effect of hypogonadism and androgen deprivation therapy (ADT) on QTc and TdP risk.2 We prospectively evaluated testosterone and related plasma levels in each man seen with TdP (n=7) over 19 months at a single university hospital (Hopital Pitie-Salpetriere, Paris, France, Commission nationale de l’informatique et des libertes No. 1491960v0, patients’ informed consent obtained). We then analyzed the European pharmacovigilance database (up to June 2017, URL: https://clinicaltrials.gov, Unique identifier: NCT03193138) searching for QTc/TdP adverse drug reactions ( Medical Dictionary for Regulatory Activities terms: long-QT syndrome [LQT], ECG QT-prolonged, and TdP) associated with ADT, and we performed a cross-sectional analysis of the association between the International Classification of Diseases revisions 9 and 10 codes for LQT/TdP and hypogonadism in 1.1 million men in a US electronic health record cohort (up to November 2017, Vanderbilt University Medical Center, Institutional Review Board approval no. 171796).3 Hypogonadism was diagnosed in 7 of 7 cases of TdP (Table). After correction of low testosterone …

Fécondité chez les femmes ayant une sclérose en plaques

La sclerose en plaques (SEP) touche preferentiellement les femmes en âge de procreer, et les femmes atteintes de cette maladie ont moins d’enfants que la population generale. La question d’une possible baisse de la fertilite chez ces femmes n’est pas resolue, et peu d’etudes se sont interessees a la question. Les quelques donnees disponibles indiquent que le delai necessaire pour concevoir et le taux de fausses couches spontanees sont, chez ces femmes, similaires a ceux de la population generale. Il est neanmoins possible que la fertilite soit diminuee chez les femmes atteintes de SEP, notamment en rapport avec une diminution de la reserve ovarienne ou les traitements utilises. D’autres facteurs peuvent expliquer la fecondite plus basse de ces femmes, comme la dysfonction sexuelle ou, surtout, le choix de ne pas avoir d’enfant une fois la maladie declaree. Nous allons ici passer en revue les differents elements connus concernant la fertilite et la fecondite des femmes atteintes de SEP.

Erratum à l’article « Un programme d’éducation thérapeutique centré sur la transition des patients, avec endocrinopathie chronique, entre les services d’endocrinologie pédiatrique et adulte » [Presse Med. 45 (5) (2016) e119–e129]

La Presse Medicale - In Press.Proof corrected by the author Available online since jeudi 28 juillet 2016