Dihydrotestosterone and Leptin Regulate Gonadotropin-Releasing Hormone (GnRH) Expression and Secretion in Human GnRH-Secreting Neuroblasts |
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| Authors: | Annamaria Morelli Benedetta Fibbi Mirca Marini Enrico Silvestrini Giulia De Vita Aravinda K. Chavalmane Linda Vignozzi Sandra Filippi Gianni Forti Gabriella B. Vannelli Mario Maggi |
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| Affiliation: | 4. Endocrinology Units, Department of Clinical Physiopathology, University of Florence, Florence, Italy;2. Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy;3. Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, University of Florence, Florence, Italy;1. Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”University of FlorenceFlorenceItaly;2. Unit of EndocrinologyDepartment of Biomedical, Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly;3. Dipartimento di Medicina Clinica e ChirurgiaSezione di EndocrinologiaUniversità Federico II di NapoliNaplesItaly;4. Unit of Endocrinology and DiabetologyDepartment of Internal MedicineOspedale M. BufaliniCesenaItaly;5. Ospedale BellariaIRCCS, Istituto delle Scienze Neurologiche di BolognaBolognaItaly;6. Endocrine UnitDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”University of FlorenceFlorenceItaly;7. Endocrinology UnitMedical DepartmentMaggiore-Bellaria HospitalBolognaItaly;1. Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy;2. Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Experimental and Clinical Biomedical Sciences, NEUROFARBA, University of Florence, Florence, Italy;3. Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;4. Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy;5. Mass Spectrometry Centre (CISM), University of Florence, Florence, Italy |
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| Abstract: | IntroductionThe reversal of hypogonadotropic hypogonadism (HH), occurring after discontinuation of testosterone therapy in adolescents with delayed puberty and in a small percentage of adults with congenital HH, suggests a role for androgens in favoring a spontaneous recovery of reproductive function.AimWe investigated the effect of androgens and leptin on gonadotropin-releasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts (FNC-B4).MethodsQuantitative real-time polymerase chain reaction RT-PCR for mRNA expression and radioimmunoassay for GnRH secretion were used. Immunohistochemical studies assessed GnRH protein expression. FNC-B4 migration was analyzed with multiwell Boyden chamber technique.Main Outcome MeasuresEffects of the non-aromatizable androgen dihydrotestosterone (DHT) and leptin in FNC-B4 were tested after 24 and 48 hours.ResultsExposure to increasing concentrations of DHT after 24 hours significantly stimulated GnRH mRNA in FNC-B4. This effect was still present after prolonged exposure (48 hours). Similarly, treatment with leptin significantly induced GnRH mRNA after 24 hours, but not at 48 hours. Interestingly, mRNA for leptin receptors (LEPR) was significantly reduced after 48 hours of leptin, while, at this time point, it was stimulated by DHT. Coincubation for 48 hours with leptin and DHT maintained the stimulatory effect on both GnRH and LEPR mRNA, suggesting that DHT could stabilize the leptin effect by preventing downregulation of LEPR. Similar results were obtained for GnRH protein expression analysis. Moreover, both DHT and leptin increased GnRH release into the culture medium. We also found that DHT or leptin treatment significantly increased FNC-B4 basal migration. As we previously found that GnRH stimulates FNC-B4 migration, we hypothesized that this effect could be mediated by DHT- and leptin-induced GnRH release. Accordingly, the GnRH antagonist cetrorelix inhibited DHT- and leptin-induced migration.ConclusionOur results suggest that androgens (adequate hormonal status) could have a positive effect on GnRH neuronal activity by synergizing with leptin (adequate energy status) in the regulatory mechanisms required for reproductive and sexual fitness. Morelli A, Fibbi B, Marini M, Silvestrini E, De Vita G, Chavalmane AK, Vignozzi L, Filippi S, Forti G, Vannelli GB, and Maggi M. Dihydrotestosterone and leptin regulate gonadotropin-releasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts. J Sex Med 2009;6:397–407. |
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