{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:03:00Z","timestamp":1792141380451,"version":"4.4.0"},"reference-count":44,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,1,1]]},"abstract":"<jats:p>We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting from a novel homozygous inactivating mutation of the CYP19 (P450arom) gene. At first observation, continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient presented also a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. The analysis of the effects induced by the successive treatment with high doses of testosterone, alendronate, and estradiol allows further insight into the roles of androgens and estrogens on several metabolic functions. High doses of testosterone treatment resulted in a severe imbalance in the estradiol to testosterone ratio together with the occurrence of insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of two carotid plaques. Furthermore, the study confirms previous data concerning the key role of estrogens on male bone maturation, at least in part, and regulation of gonadotropin secretion. The biopsy of the testis showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. Thus, a possible role of estrogen in male reproductive function is suggested but without revealing a direct cause-effect relationship.<\/jats:p><jats:p>Data from this case provide new insights into the role of estrogens in glucose, lipid, and liver metabolism in men. This new case of aromatase deficiency confirms previous data on bone maturation and mineralization, and it reveals a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.<\/jats:p>","DOI":"10.1210\/jc.2003-030313","type":"journal-article","created":{"date-parts":[[2004,1,10]],"date-time":"2004-01-10T01:32:57Z","timestamp":1073698377000},"page":"61-70","source":"Crossref","is-referenced-by-count":274,"title":["Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol Treatment"],"prefix":"10.1210","volume":"89","author":[{"given":"Laura","family":"Maffei","sequence":"first","affiliation":[{"name":"Consultorios Asociados de Endocrinologia (L.M., G.T.), 1425 Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Murata","sequence":"additional","affiliation":[{"name":"Prince Henry\u2019s Institute of Medical Research (Y.M., C.D.C., E.R.S.), Victoria 3168 Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Rochira","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chair of Endocrinology (V.R., C.C.), University of Modena and Reggio Emilia, 41100 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Tubert","sequence":"additional","affiliation":[{"name":"Consultorios Asociados de Endocrinologia (L.M., G.T.), 1425 Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Aranda","sequence":"additional","affiliation":[{"name":"Tomografia Computada Buenos Aires-TCBA (C.A., M.V.), 1425 Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Tomografia Computada Buenos Aires-TCBA (C.A., M.V.), 1425 Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Clyne","sequence":"additional","affiliation":[{"name":"Prince Henry\u2019s Institute of Medical Research (Y.M., C.D.C., E.R.S.), Victoria 3168 Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Davis","sequence":"additional","affiliation":[{"name":"Jean Hailes Foundation (S.D.), Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan R.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Prince Henry\u2019s Institute of Medical Research (Y.M., C.D.C., E.R.S.), Victoria 3168 Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Carani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chair of Endocrinology (V.R., C.C.), University of Modena and Reggio Emilia, 41100 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071615523445500_R1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1359\/jbmr.2000.15.3.507","article-title":"Bone has a sexually dimorphic response to aromatase deficiency.","volume":"15","author":"Oz","year":"2000","journal-title":"J Bone Miner Res"},{"key":"2020071615523445500_R2","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1210\/edrv.20.3.0370","article-title":"Estrogen receptor null mice: what we learned and where will they lead us?","volume":"20","author":"Couse","year":"1999","journal-title":"Endocr Rev"},{"key":"2020071615523445500_R3","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1056\/NEJM199410203311604","article-title":"Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.","volume":"331","author":"Smith","year":"1994","journal-title":"N Engl J Med"},{"key":"2020071615523445500_R4","first-page":"3689","article-title":"Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.","volume":"80","author":"Morishima","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1056\/NEJM199707103370204","article-title":"Effect of testosterone and estradiol in a man with aromatase deficiency.","volume":"337","author":"Carani","year":"1997","journal-title":"N Engl J Med"},{"key":"2020071615523445500_R6","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1056\/NEJM199808273390905","article-title":"Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency.","volume":"339","author":"Bilezikian","year":"1998","journal-title":"N Engl J Med"},{"key":"2020071615523445500_R7","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1210\/jcem.85.5.6583","article-title":"Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters.","volume":"85","author":"Rochira","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R8","doi-asserted-by":"crossref","first-page":"5476","DOI":"10.1210\/jc.2002-020498","article-title":"Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene.","volume":"87","author":"Herrmann","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1530\/eje.0.1400111","article-title":"Oestrogen deficiency in men: where are we today?","volume":"140","author":"Faustini-Fustini","year":"1999","journal-title":"Eur J Endocrinol"},{"key":"2020071615523445500_R10","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1172\/JCI10942","article-title":"Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men.","volume":"106","author":"Falahati-Nini","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071615523445500_R11","doi-asserted-by":"crossref","first-page":"951","DOI":"10.7326\/0003-4819-133-12-200012190-00010","article-title":"Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study.","volume":"133","author":"Amin","year":"2000","journal-title":"Ann Intern Med"},{"key":"2020071615523445500_R12","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1046\/j.1365-2265.2002.01428.x","article-title":"Oestrogen, bones and men: when testosterone just isn\u2019t enough.","volume":"56","author":"Khosla","year":"2002","journal-title":"Clin Endocrinol"},{"key":"2020071615523445500_R13","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1210\/jcem.87.6.8556","article-title":"Pituitary function in a man with congenital aromatase deficiency: effect of different doses of transdermal E2 on basal and stimulated pituitary hormones.","volume":"87","author":"Rochira","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R14","first-page":"2370","article-title":"Estrogen suppression in males: metabolic effects.","volume":"85","author":"Mauras","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R15","first-page":"3027","article-title":"Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback.","volume":"85","author":"Hayes","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R16","first-page":"1739","article-title":"Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood.","volume":"82","author":"Mullis","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R17","doi-asserted-by":"crossref","first-page":"8948","DOI":"10.1073\/pnas.85.23.8948","article-title":"Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells.","volume":"85","author":"Corbin","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071615523445500_R18","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1210\/jcem-53-2-412","article-title":"Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture.","volume":"53","author":"Ackerman","year":"1981","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R19","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.1073\/pnas.121180498","article-title":"Effects of estrogen on growth plate senescence and epiphyseal fusion.","volume":"98","author":"Weise","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071615523445500_R20","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1056\/NEJM200008313430902","article-title":"Alendronate for the treatment of osteoporosis in men.","volume":"343","author":"Orwoll","year":"2000","journal-title":"N Engl J Med"},{"key":"2020071615523445500_R21","first-page":"4677","article-title":"Estrogen: consequences and implications of human mutations in synthesis and action.","volume":"84","author":"Grumbach","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R22","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1210\/jcem.86.5.7562","article-title":"Editorial: the role of combination treatment for osteoporosis.","volume":"86","author":"Recker","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R23","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0303-7207(02)00092-8","article-title":"Congenital estrogen deficiency in men: a new syndrome with different phenotypes; clinical and therapeutic implications in men.","volume":"193","author":"Rochira","year":"2002","journal-title":"Mol Cell Endocrinol"},{"key":"2020071615523445500_R24","first-page":"53","article-title":"Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion.","volume":"86","author":"Hayes","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R25","first-page":"243","volume-title":"Kottler ML Clinical findings in an adult man with a novel mutation in the aromatase gene","author":"Pura","year":"2003"},{"key":"2020071615523445500_R26","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1530\/eje.0.1460075","article-title":"Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH.","volume":"146","author":"Main","year":"2002","journal-title":"Eur J Endocrinol"},{"key":"2020071615523445500_R27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/j.1939-4640.1996.tb01756.x","article-title":"Morphometric study of the gubernaculum in male estrogen receptor mutant mice.","volume":"17","author":"Donaldson","year":"1996","journal-title":"J Androl"},{"key":"2020071615523445500_R28","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1210\/jcem.87.1.8172","article-title":"The effects of varying doses of T on Insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.","volume":"87","author":"Singh","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R29","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1677\/joe.0.1760237","article-title":"Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency.","volume":"176","author":"Takeda","year":"2003","journal-title":"J Endocrinol"},{"key":"2020071615523445500_R30","doi-asserted-by":"crossref","first-page":"12735","DOI":"10.1073\/pnas.97.23.12735","article-title":"Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity.","volume":"97","author":"Jones","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071615523445500_R31","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0002-9343(99)00271-5","article-title":"Association of nonalcoholic fatty liver disease with insulin resistance.","volume":"107","author":"Marchesini","year":"1999","journal-title":"Am J Med"},{"key":"2020071615523445500_R32","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/0026-0495(94)90170-8","article-title":"Serum testosterone level is the major determinant of the male-female differences in serum levels of high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol.","volume":"43","author":"Asscheman","year":"1994","journal-title":"Metabolism"},{"key":"2020071615523445500_R33","first-page":"3367","article-title":"Suppression of endogenous testosterone in young men increases serum levels of high density lipoprotein subclass lipoprotein A-I and lipoprotein(a).","volume":"82","author":"Eckardstein","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R34","doi-asserted-by":"crossref","first-page":"3774","DOI":"10.1161\/01.CIR.96.10.3774","article-title":"Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man.","volume":"96","author":"Sudhir","year":"1997","journal-title":"Circulation"},{"key":"2020071615523445500_R35","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/S0140-6736(05)63022-X","article-title":"Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene.","volume":"349","author":"Sudhir","year":"1997","journal-title":"Lancet"},{"key":"2020071615523445500_R36","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1210\/jcem.87.3.8354","article-title":"Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women.","volume":"87","author":"Christian","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R37","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1210\/jcem.84.10.5954","article-title":"Cardiovascular actions of estrogens in men.","volume":"84","author":"Sudhir","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R38","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJM199906103402306","article-title":"The protective effects of estrogen on the cardiovascular system.","volume":"340","author":"Mendelsohn","year":"1999","journal-title":"N Engl J Med"},{"key":"2020071615523445500_R39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0303-7207(01)00420-8","article-title":"Estrogens and health in males.","volume":"178","author":"Lombardi","year":"2001","journal-title":"Mol Cell Endocrinol"},{"key":"2020071615523445500_R40","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1210\/jcem.83.7.4945","article-title":"A novel, nongenomic action of estrogen on the cardiovascular system.","volume":"83","author":"Komesaroff","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615523445500_R41","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1172\/JCI9575","article-title":"Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice.","volume":"105","author":"Nemoto","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071615523445500_R42","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1046\/j.1365-2265.2001.01321.x","article-title":"Hormone replacement therapy may improve hepatic function in women with Turner\u2019s syndrome.","volume":"55","author":"Elsheikh","year":"2001","journal-title":"Clin Endocrinol"},{"key":"2020071615523445500_R43","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/S0022-5347(01)69099-2","article-title":"Aromatase inhibitors for male infertility.","volume":"167","author":"Raman","year":"2002","journal-title":"J Urol"},{"key":"2020071615523445500_R44","first-page":"1299","article-title":"Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients.","volume":"7","author":"Murata","year":"2000","journal-title":"Oncol Rep"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/89\/1\/61\/10741889\/jcem0061.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/89\/1\/61\/10741889\/jcem0061.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T21:54:49Z","timestamp":1705010089000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/89\/1\/61\/2840171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,1,1]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2004,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2003-030313","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,1,1]]}}}