Abstract: The present invention relates to the pulsatile administration of the gonadotropin-releasing hormone (GnRH) for the treatment of food intake related disorder related disorder such as obesity (overeating) and anorexia (undereating). The inventors demonstrated that a population of mutant mice expressing BoNT/B in GnRH neurons (Gnrh::cre;iBot overweight), in which the GnRH release is inhibited, did not only fail to reach puberty onset and showed hypogonadotropic hypogonadism, but also developed overweight and hyperleptinemia. Unexpectedly, they found that the increase in body weight in mutant mice persisted in adulthood despite a significant decrease in food intake. Using a mouse model of obesity inventors observed an altered pattern of pulsatile LH secretion and that the frequency of LH pulses is inversely correlated to body weight and adiposity demonstrating that the heavier the animals were getting the more the GnRH/LH pulsatile pattern was altered.

Abstract: In the present invention, inventors provide compelling evidence showing that PCOS neuroendocrine reproductive and metabolic dysfunctions are transmitted in PAMH mice for at least three generations. Inventors employed genome-wide methylated DNA immunoprecipitation (MeDIP) analysis to characterize methylated genes in ovaries from control and PAMH mice of the third generation, the first unexposed transgenerational offspring, together with transcriptome analysis in these tissues. Inventors identified many genes with altered transcriptome expression in ovarian tissues of PCOS-animals and they show that several key molecules associated to the PCOS phenotype are epigenetically regulated through DNA hypomethylation. Inventors report that several differentially methylated signatures found in the ovaries of PCOS-like mice are also present in blood samples from women with PCOS and from daughters born to women with PCOS.

Abstract: The present invention relates to the field of therapeutic treatment of polycystic ovary syndrome (PCOS). Polycystic ovary syndrome, PCOS, is the most common female reproductive disorder against which no therapeutic solution is available, beyond changes in the lifestyle. The inventors have now shown by using in vivo preclinical models, that individuals affected with PCOS have an abnormal elevated production of GnRH and that this elevated production of GnRH was transmitted to their offspring that also develop PCOS. Further, by examining AMH levels in a cohort of pregnant PCOS and control women, the inventors have found that AMH concentrations are significantly higher in PCOS women as compared to healthy women during the second trimester of gestation. These unexpected findings has allowed conceiving both prevention and treatment therapeutic strategies based on the administration of GnRH antagonists.

Abstract: The present invention pertains to novel therapeutic ways for treating cognitive disorders associated with olfactory dysfunction. By using a mouse model of Down syndrome (DS—Ts65Dn mice), the present inventors have demonstrated that GnRH insufficiency is involved in the age-dependent acquisition of cognitive decline in DS and that pulsatile GnRH treatment allows reversing olfactory- and cognitive-associated impairments in DS. The present inventors have further demonstrated that GnRH insufficiency is involved in the pathological pathways of cognitive disorders in which the cognitive decline is associated with olfactory dysfunction, and, accordingly, that pulsatile GnRH administration can be used for the treatment of cognitive disorders associated with olfactory dysfunction. Accordingly, the present invention pertains to the use of GnRH for the treatment of cognitive disorders, said GnRH being administered by pulsatile administration.