Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)
Author:
Bonomi Marco12, Vezzoli Valeria2, Krausz Csilla3, Guizzardi Fabiana2, Vezzani Silvia456, Simoni Manuela456, Bassi Ivan2, Duminuco Paolo2, Di Iorgi Natascia7, Giavoli Claudia18, Pizzocaro Alessandro9, Russo Gianni10, Moro Mirella2, Fatti Letizia2, Ferlin Alberto11, Mazzanti Laura12, Zatelli Maria Chiara13, Cannavò Salvo14, Isidori Andrea M15, Pincelli Angela Ida16, Prodam Flavia17, Mancini Antonio18, Limone Paolo19, Tanda Maria Laura20, Gaudino Rossella21, Salerno Mariacarolina22, Francesca Pregnolato23, Maghnie Mohamad7, Maggi Mario3, Persani Luca12, _ _, _ _, Aimaretti G, Altobelli M, Ambrosio M R, Andrioli M, Angeletti G, Arecco F, Arnaldi G, Arosio M, Balsamo A, Baldassarri M, Bartalena L, Bazzoni N, Beccaria L, Beck-Peccoz P, Bellastella G, Bellizzi M, Benedicenti F, Bernasconi S, Bizzarri C, Bona G, Bonadonna S, Borretta G, Boschetti M, Brunani A, Brunelli V, Buzi F, Cacciatore C, Cangiano B, Cappa M, Casalone R, Cassio A, Cavarzere P, Cherubini V, Ciampani T, Cicognani D, Cignarelli A, Cisternino M, Colombo P, Corbetta S, Corciulo N, Corona G, Cozzi R, Crivellaro C, Dalle Mule I, Danesi L, D’Elia A V, degli Uberti E, De Leo S, Della Valle E, De Marchi M, Di Iorgi N, Di Mambro A, Fabbri A, Foresta C, Forti G, Franceschi A R, Garolla A, Ghezzi M, Giacomozzi C, Giusti M, Grosso E, Guabello G, Guarneri M P, Grugni G, Isidori A M, Lanfranco F, Lania A, Lanzi R, Larizza L, Lenzi A, Loche S, Loli P, Lombardi V, Maggio M C, Mandrile G, Manieri C, Mantovani G, Marelli S, Marzullo M, Mencarelli M A, Migone N, Motta G, Neri G, Padova G, Parenti G, Pasquino B, Pia A, Piantanida E, Pignatti E, Pilotta A, Pivetta B, Pollazzon M, Pontecorvi A, Porcelli P, Pozzan G B, Pozzobon G, Radetti G, Razzore P, Rocchetti L, Roncoroni R, Rossi G, Sala E, Salvatoni A, Salvini F, Secco A, Segni M, Selice R, Sgaramella P, Sileo F, Sinisi A A, Sirchia F, Spada A, Tresoldi A, Vigneri R, Weber G, Zucchini S
Affiliation:
1. 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy 2. 2IRCCS Istituto Auxologico Italiano, Division of Endocrine and Metabolic Diseases & Laboratory of Endocrine and Metabolic Research, Milan, Italy 3. 3Department of Biomedical, Experimental and Clinical Sciences ‘Mario Serio’, University of Florence, Florence, Italy 4. 4Department of Biomedical, Metabolic and Neural Sciences, Unit of Endocrinology, University of Modena and Reggio Emilia, Modena, Italy 5. 5Department of Medicine, Endocrinology, Metabolism and Geriatrics, Azienda USL of Modena, Modena, Italy 6. 6Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy 7. 7Department of Pediatrics, IRCCS Giannina Gaslini, University of Genoa, Genoa, Italy 8. 8Endocrinology and Metabolic Diseases Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy 9. 9Endocrinology Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy 10. 10Department of Pediatrics, IRCCS San Raffaele Hospital, Milan, Italy 11. 11Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy 12. 12Department of Medical and Surgical Sciences, Alma Mater Studiourm, University of Bologna, Bologna, Italy 13. 13Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy 14. 14Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Messina, Messina, Italy 15. 15Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy 16. 16Division of Internal Medicine, Endocrinology and Diabetology Unit, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy 17. 17Department of Health Sciences, University of Eastern Piedmont, Novara, Italy 18. 18Operative Unit of Endocrinology, Catholic University of the Sacred Heart, Rome, Italy 19. 19Endocrinology, Diabetes and Metabolic Disease Unit, A.O. Ordine Mauriziano di Torino, Torino, Italy 20. 20Dipartimento di Medicina Clinica e Sperimentale, Università dell’Insubria sede di Varese, Varese, Italy 21. 21Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy 22. 22Department of Translational Medical Sciences, University of Naples ‘Federico II’, Naples, Italy 23. 23IRCCS Istituto Auxologico Italiano, Experimental Laboratory of Immunological and Rheumatologic Researches, Milan, Italy
Abstract
Objective
Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.
Design
Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.
Methods
We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).
Results
90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.
Conclusions
Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism
Cited by
75 articles.
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