Young J.,University Paris - Sud |
Young J.,Institute National Of La Santeet Of La Recherche Medicale Unite 693 |
Bouligand J.,University Paris - Sud |
Bouligand J.,Institute National Of La Santeet Of La Recherche Medicale Unite 693 |
And 16 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010
Context: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. Objective: The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. Results: We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patientsweobserved a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. Conclusion: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans. Copyright © 2010 by The Endocrine Society.
Munier M.,Institute National Of La Santeet Of La Recherche Medicale Unite 693 |
Munier M.,University Paris - Sud |
Meduri G.,Institute National Of La Santeet Of La Recherche Medicale Unite 693 |
Meduri G.,Institute Federatif Of Recherche 93 |
And 8 more authors.
Endocrinology | Year: 2010
Mineralocorticoid receptor (MR) plays a critical role in brain function. However, the regulatory mechanisms controlling neuronal MR expression that constitutes a key element of the hormonal response are currently unknown. Two alternative P1 and P2 promoters drive human MR gene transcription. To examine promoter activities and their regulation during neuronal differentiation and in mature neurons, we generated stably transfected recombinant murine embryonic stem cell (ES) lines, namely P1-GFP and P2-GFP, in which each promoter drove the expression of the reporter gene green fluorescent protein (GFP). An optimized protocol, using embryoid bodies and retinoic acid, permitted us to obtain a reproducible neuronal differentiation as revealed by the decrease in phosphatase alkaline activity, the concomitant appearance of morphological changes (neurites), and the increase in the expression of neuronal markers (nestin, β-tubulin III, and microtubule-associated protein-2) as demonstrated by immunocytochemistry and quantitative PCR. Using these cell-based models, we showed that MR expression increased by 5-fold during neuronal differentiation, MR being preferentially if not exclusively expressed in mature neurons. Although the P2 promoter was always weaker than the P1 promoter during neuronal differentiation, their activities increased by 7- and 5-fold, respectively, and correlated with MR expression. Finally, although progesterone and dexamethasone were ineffective, aldosterone stimulated both P1 and P2 activity and MR expression, an effect that was abrogated by knockdown of MR by small interfering RNA. In conclusion, we provide evidence for a tight transcriptional control of MR expression during neuronal differentiation. Given the neuroprotective and antiapoptotic role proposed for MR, the neuronal differentiation of ES cell lines opens potential therapeutic perspectives in neurological and psychiatric diseases. Copyright © 2010 by The Endocrine Society.
Maione L.,University Paris - Sud |
Maione L.,Institute National Of La Santeet Of La Recherche Medicale Unite 693 |
Maione L.,University of Naples Federico II |
Benadjaoud S.,Service de Neuroradiologie |
And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013
Context: Kallmannsyndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. Objective: The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. Patients: Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n=15) and controls (n=30) of similar age. Design and Methods: We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. Results: OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. Conclusions: KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life. Copyright © 2013 by The Endocrine Society.