Academic literature on the topic 'Gonades – Physiopathologie'

To investigate the function of the hypothalamic-hypophyseal-gonadal axis in testicular germ cell tumors, we evaluated gonadotropin responses to gonadotropin-releasing hormone (GnRH) in 12 untreated patients with testicular cancer (5 seminomas and 7 non-seminomas). GnRH was given i.v. at a dose of 100 μg as a bolus, and venous blood samples were collected at 0, 20, 60, and 120 min. As controls, 14 healthy males were studied. Basal levels of testosterone, estradiol and prolactin were also detected in each patient. Hormonal serum concentrations were measured by the radioimmunoassay. Mean basal testosterone, estradiol and prolactin levels were not significantly different from those of controls. Patients had a lower FSH and LH peak after GnRH than controls, without, however, any significant difference. As regards histology, nonseminoma patients lacked an FSH response to GnRH and had statistically lower mean peak levels than controls. Moreover, non-seminoma patients had statistically lower mean peak values of LH after GnRH than controls. These data show that patients with testicular germ cell tumor, and more particularly those with non-seminomas, have an altered function of the hypothalamic-hypophyseal-gonadal axis, which is already present prior to therapy. Further studies, particularly in stage I patients treated only with orchiectomy, should be performed to confirm and better define the Physiopathologic significance of the altered hypothalamic-hypophyseal-gonadal axis in testicular cancer and to clarify the alteration of fertility, which is frequently present before treatment.

Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.

AbstractObjectivesThe objective of this review was to characterize the use of biomarkers of male hypogonadism in childhood and adolescence.ContentsThe hypothalamic-pituitary-gonadal (HPG) axis is active during fetal life and over the first months of postnatal life. The pituitary gland secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH), whereas the testes induce Leydig cells to produce testosterone and insulin-like factor 3 (INSL), and drive Sertoli cells to secrete anti-Müllerian hormone (AMH) and inhibin B. During childhood, serum levels of gonadotropins, testosterone and insulin-like 3 (INSL3) decline to undetectable levels, whereas levels of AMH and inhibin B remain high. During puberty, the production of gonadotropins, testosterone, and INSL3 is reactivated, inhibin B increases, and AMH decreases as a sign of Sertoli cell maturation.Summary and outlookBased on our knowledge of the developmental physiology of the HPG axis, these biomarkers can be used in clinical practice to interpret the physiopathology of hypogonadism. Additionally, these markers can have diagnostic value in different forms of hypogonadism that may appear during childhood and adolescence.

La stérilité affecte à l’heure actuelle près de 15-20 % des couples et sa prévalence est en progression depuis quatre à cinq décennies. Cette progression évolue parallèlement à la prévalence de l’épidémie d’obésité et de syndrome métabolique dans le monde. De multiples arguments physiologiques et épidémiologiques chez l’Homme soutiennent l’hypothèse de l’influence de l’homéostasie des lipides sur la fonction gonadique. En particulier, le cholestérol est un facteur clef dans la régulation de la stéroïdogenèse et de la gamétogenèse. Bien que les atteintes gonadiques semblent multifactorielles, les mécanismes moléculaires restent méconnus dans la majorité des cas. Les Liver X receptors (LXRα et β) sont des récepteurs nucléaires activés par les oxystérols. Ce sont classiquement des régulateurs du métabolisme lipidique. Plusieurs études ont démontré l’importance de ces récepteurs dans la physiologie des gonades. Ce travail identifie les rôles multiples des LXRs dans le maintien de la fertilité masculine et féminine, et décrit l’effet de l’homéostasie du cholestérol sur la maturation des cellules germinales dans le testicule et l’ovaire. Ce travail se concentre sur l’analyse comparative d’une lignée de souris ré-exprimant LXRβ (Lxrαϐ-/-:AMHLxrϐ) sous contrôle de promoteur d’AMH humain (expression spécifique dans les cellules de Sertoli dans le testicule et les cellules de granulosa dans l’ovaire) sur un fond génétique de souris Lxrαϐ-/-. L’absence d’un isoforme d LXR aboutit à des défauts spécifiques dans un type cellulaire du testicule. Néanmoins, le dysfonctionnement d’un type cellulaire est compensé. En effet, de multiples défauts sont nécessaires pour aboutir à la stérilité. LXR dans les cellules de granulosa est critique pour la maturation et la survie des ovocytes, l’ovulation, et par conséquence pour la fertilité. Ainsi, LXRβ est une cible potentielle pour réguler la fertilité féminine et la prévention de syndrome d’hyperstimulation ovarienne. Nos résultats ouvrent des perspectives pour des nouvelles cibles diagnostiques et pronostiques dans la fertilité
Sterility affects 15 % of French population and its prevalence is propagating since four or five decades. Many human physiological and epidemiological arguments support the impact of lipid homeostasis on the gonads; indeed, cholesterol is a key regulator of steroidogenesis and gametogenesis. Nevertheless, the molecular mechanisms remain hidden. Liver X receptors alpha and beta (LXRα and β) belong to the superfamily of nuclear receptors and are activated upon binding to oxysterols. LXRs are mainly implicated in cholesterol homeostasis. Increasing bulk of literature identified these non-steroid nuclear receptors as major regulators of the gonad physiology. This work uncovers previously unidentified putative roles of LXRs and ability of cholecterol excess to alter male and female germ cell maturation. Herein, we analyse a new mouse strain (Lxrαϐ-/-:AMHLxrϐ) re-expressing LXRβ under control of AMH promoter (specific to Sertoli in testis and granulosa cells in ovary) in a background of Lxrαϐ-/- mouse. Our results identify LXRs as primordial to maintain male and female fertility. They have pleotropic « non-classical » roles ranging from lipid homeostasis to the regulation of germ cell maturation and bi-directional control of steroid synthesis. If the cellular defects in the absence of LXRs within the testis are significant, they are generally compensated and consequently, single cell compartment is tolerated. Unlike the testis, LXRβ in the granulosa cells is « the regulator » of multiple mechanisms essential for follicle maturation, ovocyte survival and for controlled ovulation. LXRβ is therefore a potnetial target to regulate female fertility and to prevent ovarian hyperstimulation syndrome. Our results open the perspectives for the identification of new diagnostic and/or prognostic markers in both male and female fertility

Chez les mammifères, le développement testiculaire des gonades XY est initié par les facteurs de transcription SRY/SOX9 qui promeuvent la différenciation des cellules de Sertoli. Chez l’embryon XX, la signalisation RSPO1/WNT/beta-catenin contrôle la différenciation des cellules de la granulosa et le développement ovarien. De fait, les souris XY n’exprimant pas Sox9 (KO) développent des ovaires et les souris XX n’exprimant pas Rspo1(KO) développent des ovotestis, constitués d’une partie testiculaire et une ovarienne. Leur formation est due à la différenciation précoce de cellules de granulosa et la reprogrammation d’une partie d’entre elles, en cellules de Sertoli. Chez les souris XX Rspo1 KO, SRY n’est pas nécessaire au développement testiculaire.De plus, les gonades des souris XX et XY présentant une double inactivation des gènes Rspo1 et Sox9 (Double Knockout/DKO) montrent une différenciation testiculaire partielle et complète respectivement, avec un développement d’ovotestis chez les individus XX DKO et un développement de testicules hypoplasiques chez les souris XY DKO. SOX9 et/ou SRY ne sont donc pas nécessaires à la différenciation testiculaire dans ce contexte, suggérant l’implication d’autres facteurs.L’objectif de ma thèse est de tester l’hypothèse selon laquelle SOX8, un facteur de transcription de la même famille que SOX9, pourrait induire le développement testiculaire chez les souris XX et XY DKO Rspo1 Sox9. Afin d’établir l’existence d’une compensation entre ces gènes SOX, nous avons analysé leur expression et le développement des gonades chez la souris DKO pour les gènes Rspo1 et Sox8 ou Sox9. Nous avons ensuite étudié les souris mutantes simultanément pour les gènes Rspo1, Sox8 et Sox9 (triple knockout/TKO). Notre hypothèse est qu’une perte d’expression des gènes Sox8 et Sox9 chez les souris TKO empêche la reprogrammation des cellules de la granulosa en Sertoli et par conséquent le développement testiculaire. Nous avons donc analysé la morphologie des gonades, les caractères sexuels secondaires, ainsi que l’organisation des gonades avec les différentes populations cellulaires qui les constituent par histologie et immuno-marquages à différents stades : à 17.5 jours de développement embryonnaire (E17.5) où la reprogrammation de cellules de granulosa en Sertoli commence dans la souris XX Rspo1 KO; chez les souris juvéniles au jour 10 (P10) où le développement somatique est achevé; et chez les souris adultes 40 jours après la naissance (P40).Nos résultats montrent que SOX8 et SOX9 sont exprimés de manière indépendante dans les gonades des souris XY and XX DKO Rspo1 Sox9 et DKO Rspo1 Sox8 à E17.5 et à P10. De plus, les souris XY et XX DKO Rspo1 Sox8 développent des testicules et des ovotestis indiquant que la perte d’un seul facteur SOX n’altère pas la formation des testicules, comme dans les souris XY et XX DKO Rspo1 Sox9. Cependant, chez les souris XX et XY TKO, la reprogrammation des granulosa en Sertoli à E17.5 et le développement testiculaire postnatal ne sont plus observés, démontrant que SOX8 peut compenser la perte de SOX9. De plus, les gonades des souris XY et XX TKO sont des ovaires atrophiques, indiquant que la différenciation ovarienne peut s’opérer.En résumé, nous avons analysé l’étiologie du développement physiopathologique des gonades chez les souris ayant une perte de fonction de RSPO1. Bien que SOX8 ne soit pas nécessaire à la différenciation testiculaire chez la souris, il peut promouvoir le développement testiculaire en l’absence de SRY et SOX9 en raison de sa redondance fonctionnelle avec SOX9. Chez l’Homme, dans les cas cliniques d’ambiguïtés sexuelles avec différenciation testiculaire, qui ne sont pas expliqués par le défaut d’expression de SRY ou SOX9, SOX8 pourrait ainsi être un facteur causatif
In humans and mice, testicular development in XY gonads involves SRY/SOX9 signaling to promote Sertoli cell differentiation and their formation as testis chords. For ovarian development in XX gonads, RSPO1/WNT/beta-catenin signaling is the main pathway for granulosa cell differentiation and their subsequent assembly into follicles. Indeed, XY Sox9 mutant mice develop ovaries, and XX Rspo1 mutant mice develop ovo-testes, a gonad containing a testicular and an ovarian part. In XX Rspo1 mutant mice, ovo-testicular development involves precocious differentiation of some granulosa cells and their and reprogramming as Sertoli cells. Thus, these single mutant studies demonstrated that SOX9 and RSPO1 are required for testicular and ovarian development respectively, and that SRY is dispensable for testicular development in XX Rspo1 mice. Interestingly, gonad development in XY and XX Rspo1 Sox9 double knockout (DKO) mice has challenged the requirement of SOX9 for testicular development. In XX Rspo1 single mutants, it was assumed that Sertoli cell differentiation was SOX9-dependent, but co-inactivation of Sox9 in DKO mice does not impair the ovo-testicular phenotype. For XY Sox9 single mutant mice developing ovaries, co-inactivation of Rspo1 in XY DKO mice rescues the sex reversal, though the testes are hypo-plastic. Thus, in XY and XX Rspo1 Sox9 DKO mice, SOX9 and/or SRY are dispensable for testicular differentiation, indicating that an alternate testis factor exists. For my research project, we hypothesized that a SOX9-related transcription factor, SOX8, acts redundantly for testicular development in XY and XX Rspo1 Sox9 DKO mice. Thus, to first establish redundancy among the SOX factors, we first analyzed their expression in Rspo1 mutant mice lacking Sox8 or Sox9, and then generated and analyzed gonad development in XY and XX Rspo1 Sox8 DKO mice. Then to test our hypothesis, we studied Rspo1 Sox8 Sox9 triple knockout (TKO) mice. We predicted that a loss of both Sox genes in TKO mice would prevent granulosa cell reprogramming as Sertoli cells and subsequent testicular development. To characterize gonad development and their effects in DKO and TKO mice, we performed analyses in embryonic day 17.5 (E17.5) mice, when granulosa-to-Sertoli cell reprogramming begins in XX Rspo1 single mutants; in juvenile post-natal day 10 (P10) mice, when gonad fate is set; and in young adult P40 mice. We examined a variety of parameters including gonad morphology and secondary sex characteristics, as well as gonad organization and cell population by histological and immunostaining analyses. We report that SOX8 and SOX9 are expressed independently in XY and XX Rspo1 Sox9 DKO and Rspo1 Sox8 DKO gonads in embryonic and juvenile mice. Next, XY and XX Rspo1 Sox8 DKO mice developed testes and ovo-testes, indicating that loss of one SOX factor does not impair testicular differentiation, as in XY and XX Rspo1 Sox9 DKO mice. In XY and XX Rspo1 Sox8 Sox9 TKO mice, granulosa-to-Sertoli cell reprogramming was impaired at E17.5 and post-natal gonads lacked testicular development. Thus, SOX8 can compensate for the loss of SOX9 in Rspo1 Sox9 DKO mice. In addition, gonads in XY and XX TKO mice developed as atrophied ovaries, indicating that ovarian fate is partially maintained.In total, we investigated the etiology of pathophysiological testicular development in RSPO1 loss-of-function mice. Remarkably, though SOX8 is dispensable for male sex determination in mice, it can promote testicular differentiation in the absence of SRY and SOX9 because of functional redundancy with SOX9. Thus, in human cases of sex reversal where testicular development cannot be explained by misexpression of SRY or SOX9, SOX8 could be a causative factor

Spinal cord injury (SCI) is an important pathology leading to possibly fatal consequences. The most common repercussions are those affecting motor and sensitivity skills. SCI-damage occurs in its first phase—as a result of the lesion mechanism (contusion, compression, transection, and primary lesion). After this primary damage, there is a second phase with further deleterious effects on neural degeneration and tissue restoration. At the moment, several investigation groups are working on developing therapeutic strategies to induce neuroprotection. This chapter pretends to introduce the reader to a wide range of these therapies, particularly those with promising results and tested in preclinical and clinical studies. In the first section, physiopathology of SCI will be addressed. Afterwards, the chapter will review neuroprotective strategies such as cyclooxygenase, calpain, and apoptosis inhibitors. Finally, the effect of immunophilin ligands, neural-derived peptides, antioxidants, hypoglycemic agent, gonadal hormones, Na channel blockers, and transplant of cultured cells will also be reviewed.