Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol Treatment
Laura Maffei,
Yoko Murata,
Vincenzo Rochira,
Gloria Tubert,
Claudio Aranda,
Marcela Vazquez,
Colin D. Clyne,
Susan Davis,
Evan R. Simpson and
Cesare Carani
Consultorios Asociados de Endocrinologia (L.M., G.T.), 1425 Buenos Aires, Argentina; Tomografia Computada Buenos Aires-TCBA (C.A., M.V.), 1425 Buenos Aires, Argentina; Department of Internal Medicine, Chair of Endocrinology (V.R., C.C.), University of Modena and Reggio Emilia, 41100 Modena, Italy; Jean Hailes Foundation (S.D.), Clayton, Australia; and Prince Henry’s Institute of Medical Research (Y.M., C.D.C., E.R.S.), Victoria 3168 Clayton, Australia
Address all correspondence and requests for reprints to: Professor Cesare Carani, Chair of Endocrinology, Department of Internal Medicine, University of Modena and Reggio, Emilia, Policlinico Via del Pozzo, 71, 41100 Modena Italy. E-mail: carani.cesare{at}unimo.it.
We present the fourth case of an adult man (29 yr old) affectedby aromatase deficiency resulting from a novel homozygous inactivatingmutation of the CYP19 (P450arom) gene. At first observation,continuing linear growth, eunuchoid body proportions, diffusebone pain, and bilateral cryptorchidism were observed. The patientpresented also a complex dysmetabolic syndrome characterizedby insulin resistance, diabetes mellitus type 2, acanthosisnigricans, liver steatohepatitis, and signs of precocious atherogenesis.The analysis of the effects induced by the successive treatmentwith high doses of testosterone, alendronate, and estradiolallows further insight into the roles of androgens and estrogenson several metabolic functions. High doses of testosterone treatmentresulted in a severe imbalance in the estradiol to testosteroneratio together with the occurrence of insulin resistance anddiabetes mellitus type 2. Estrogen treatment resulted in animprovement of acanthosis nigricans, insulin resistance, andliver steatohepatitis, coupled with a better glycemic controland the disappearance of two carotid plaques. Furthermore, thestudy confirms previous data concerning the key role of estrogenson male bone maturation, at least in part, and regulation ofgonadotropin secretion. The biopsy of the testis showed a patternof total germ cell depletion that might be due to the concomitantpresence of bilateral cryptorchidism. Thus, a possible roleof estrogen in male reproductive function is suggested but withoutrevealing a direct cause-effect relationship.
Data from this case provide new insights into the role of estrogensin glucose, lipid, and liver metabolism in men. This new caseof aromatase deficiency confirms previous data on bone maturationand mineralization, and it reveals a high risk for the precociousdevelopment of cardiovascular disease in young aromatase-deficientmen.
This work was supported by United States Public Health ServiceGrant R-37AG08174-14 from the National Institute on Aging andby Ministero dell’Università e della Ricerca Scientifica(fondi 60%).
Abbreviations: ArKO, Aromatase knockout; BMD, bone mineral density;BMI, body mass index; GOT, glutamic oxaloacetic transaminase;GPT, glutamic pyruvic transaminase; -GT, -glutamyl-transferase;HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein;LDL, low-density lipoprotein; NASH, nonalcoholic steatohepatitis.
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-GT, 
