Testosterone Partially Ameliorates Metabolic Profile and Erectile Responsiveness to PDE5 Inhibitors in an Animal Model of Male Metabolic Syndrome
Sandra Filippi PhD
University of Florence Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction— Departments of Pharmacology and Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorLinda Vignozzi MD, PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorAnnamaria Morelli PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorAravinda K. Chavalmane PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorErica Sarchielli PhD
University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
Search for more papers by this authorBenedetta Fibbi MD, PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorFarid Saad MD
Bayer Schering Pharma AG—Scientific Affairs Men's Healthcare, Berlin, Germany;
Search for more papers by this authorPeter Sandner MD
Bayer Schering Pharma AG—Global Drug Discovery, Wuppertal, Germany;
Search for more papers by this authorPeggy Ruggiano MD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorGabriella B. Vannelli MD
University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
Search for more papers by this authorEdoardo Mannucci MD
University of Florence—Diabetes Section Geriatric Unit, Department of Critical Care, Florence, Italy;
Search for more papers by this authorCorresponding Author
Mario Maggi MD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari delle Malattie della Riproduzione), Milan, Italy
Mario Maggi, MD, Clinical Physiopathology, Andrology Unit, University of Florence, Viale Pieraccini, 6 Florence 50139, Italy. Tel: 39 0554271415; Fax: 39 0554271413; E-mail: [email protected]Search for more papers by this authorSandra Filippi PhD
University of Florence Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction— Departments of Pharmacology and Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorLinda Vignozzi MD, PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorAnnamaria Morelli PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorAravinda K. Chavalmane PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorErica Sarchielli PhD
University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
Search for more papers by this authorBenedetta Fibbi MD, PhD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorFarid Saad MD
Bayer Schering Pharma AG—Scientific Affairs Men's Healthcare, Berlin, Germany;
Search for more papers by this authorPeter Sandner MD
Bayer Schering Pharma AG—Global Drug Discovery, Wuppertal, Germany;
Search for more papers by this authorPeggy Ruggiano MD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
Search for more papers by this authorGabriella B. Vannelli MD
University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
Search for more papers by this authorEdoardo Mannucci MD
University of Florence—Diabetes Section Geriatric Unit, Department of Critical Care, Florence, Italy;
Search for more papers by this authorCorresponding Author
Mario Maggi MD
University of Florence—Andrology Unit Department of Clinical Physiopathology, Florence, Italy;
CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari delle Malattie della Riproduzione), Milan, Italy
Mario Maggi, MD, Clinical Physiopathology, Andrology Unit, University of Florence, Viale Pieraccini, 6 Florence 50139, Italy. Tel: 39 0554271415; Fax: 39 0554271413; E-mail: [email protected]Search for more papers by this authorS. Filippi and L. Vignozzi equally contributed.
ABSTRACT
Introduction. Metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors (hyperglycemia, hypertension, dyslipidemia, visceral fat accumulation) that is also associated with hypogonadism and erectile dysfunction (ED).
Aim. To clarify the relationships among MetS, hypogonadism, and ED, we developed an animal model of MetS.
Methods. Male rabbits fed a high-fat diet (HFD), with or without testosterone (T) supplementation, were compared with control rabbits (fed a standard chow) and with rabbits made hypogonadal by a single injection of a long-acting GnRH-analog, triptorelin.
Main Outcome Measures. Evaluation of metabolic disturbances (plasma glucose, cholesterol, triglycerides, testosterone, LH, FSH level, glucose tolerance, mean arterial pressure, visceral fat accumulation), and corpora cavernosa (CC) relaxant capacity (in vitro contractility study) in HFD animals as compared with control, GnRH analog-treated rabbits, and T-supplemented HFD rabbits.
Results. HFD rabbits showed all the features of MetS. HFD induced hypogonadotropic hypogonadism is characterized by a reduction of plasma T, FSH, LH levels, testis and seminal vesicles weight, and testicular steroidogenic enzymes. Such a phenotype is similar to that induced by triptorelin administration. A reduced GnRH immunopositivity in hypothalamus suggests a central origin of HFD-related hypogonadism. HFD also induced penile alterations, as demonstrated by a reduction of acetylcholine-and electrical field stimulation-induced CC relaxation, hyper-responsiveness to the NO donor, SNP, and unresponsiveness to PDE5 inhibitors. Similar penile alterations were observed in triptorelin treated rabbit. In HFD, as well as in triptorelin treated rabbits, PDE5 and eNOS mRNA expression quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were significantly decreased. T administration prevented almost all penile alterations observed in HFD rabbits. T treatment dramatically reduced HFD-induced visceral obesity, partially ameliorating also the metabolic profile.
Conclusion. We have developed an animal model of MetS associated with hypogonadotropic hypogonadism and penile alterations including unresponsiveness to PDE5 inhibitors. T supplementation was able to partially revert HFD-induced phenotype. Filippi S, Vignozzi L, Morelli A, Chavalmane AK, Sarchielli E, Fibbi B, Saad F, Sandner P, Ruggiano P, Vannelli GB, Mannucci E, and Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 Inhibitors in an animal model of male metabolic syndrome. J Sex Med 2009;6:3274–3288.
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