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Familial Hyperestrogenism in Both Sexes: Clinical, Hormonal, and Molecular Studies of Two Siblings

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Divisão de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (R.M.M., C.J.L., M.Y.N., A.E.C.B., A.C.L., B.B.M.), 01065-970 São Paulo, Brasil; and Department of Molecular Genetics, University of Texas Southwestern Medical Center (R.M.M., D.W.R.), Dallas, Texas 75390

Address all correspondence and requests for reprints to: Dr. Regina M. Martin, Divisão de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Avenue Dr. Enéas de Carvalho Aguiar, 155 2°andar, Bloco 6, CEP 05403900, 01065-970 São Paulo, Brasil. E-mail: reginamm{at}usp.br.

Familial hyperestrogenism is a rare clinical condition of unknown etiology in which patients present excessive androgen to estrogen conversion. Excessive aromatization is primarily ascribed to abnormalities in the CYP19. Mice that lack steroid 5-reductase type 1 also exhibit hyperestrogenism due to an increased availability of androgen precursors. Here we studied two adult siblings, born to unrelated parents, who presented clinical and hormonal evidence of estrogen excess. The man was treated with topical dihydrotestosterone, which promoted adequate virilization. The woman was treated with anastrazole, a potent aromatase inhibitor, with normalization of menstrual cycles. Genetic linkage to the steroid 5-reductase type 1 gene (SRD5A1) was ruled out in this family. A similar analysis did not rule out linkage to CYP19, although no mutation was identified in the coding region of this gene. Aromatase mRNA was at least 10-fold more abundant in the female patient’s skin fibroblasts vs. the control. Southern analysis of genomic DNA did not reveal rearrangements or amplification of the coding region of CYP19. We conclude that the phenotype of familial hyperestrogenism includes prepubertal gynecomastia, hypogonadism, and short stature in men, and precocious thelarche, macromastia, enlarged uterus, and menstrual irregularities in women. Topical dihydrotestosterone is an efficient alternative treatment in men with hyperestrogenism; in addition, second generation aromatase inhibitors are useful in both sexes.

This work was supported by Grants 98/00195-4 and 98/05227-1 (to R.M.M.) and Grants 97/07170-4 and 00/113362-0 (to C.J.L.) from Fundação de Amparo à Pesquisa do Estado de São Paulo, NIH Grant HD-38127 (to D.W.R.), and Grant 301246/95-5 from Conselho Nacional de Pesquisa (to B.B.M.).

Abbreviations: ⁴A, Androstenedione; AES, aromatase excess syndrome; DHT, dihydrotestosterone; E₁, estrone; E₂, estradiol; E₃, estriol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; T, testosterone.

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