Clinical Endocrinology (2008) 69, 93–98 doi: 10.1111/j.1365-2265.2007.03160.x © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Ltd 93 ORIGINAL ARTICLE Blackwell Publishing Ltd Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole Madson Queiroz Almeida*, Vinicius Nahime Brito*, Thereza Selma S. Lins†, Gil Guerra-Junior‡, Margaret de Castro§, Sonir Roberto Antonini§, Ivo Jorge Prado Arnhold*, Berenice Bilharinho Mendonca* and Ana Claudia Latronico* *Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42 da Disciplina de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, †Serviço de Endocrinologia Pediátrica, Instituto Materno Infantil, Recife, Brazil, ‡Serviço de Endocrinologia Pediátrica, Universidade de Campinas, Campinas, Brazil and §Serviço de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Ribeirão Preto, Brazil Summary Background Familial male-limited precocious puberty (FMPP) or testotoxicosis is a rare gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the LH receptor. Several clinical therapeutic approaches have been reported for this disorder, but with a paucity of long-term outcome data. Objective To evaluate the long-term treatment of testotoxicosis with cyproterone acetate or ketoconazole. Design A multicentric retrospective clinical study. Patients Ten boys from eight unrelated Brazilian families who carried known LH-receptor activating mutations were treated with 70 mg/m 2 cyproterone acetate (n = 5) or 10 mg/kg ketoconazole (n = 5) for a mean period of 5 and 8 years, respectively. Measurements Chronological and bone ages, bone age/chronological age ratio, target height (TH) range, adult height, basal and GnRH- stimulated gonadotrophin levels and basal testosterone levels were assessed. Results Growth velocity decreased significantly during treatment with cyproterone acetate or ketoconazole when compared to pretreatment value in each group (P < 0·05). Bone age/chronological age ratio decreased significantly after cyproterone acetate or ketoconazole therapy. Basal testosterone levels were significantly lower in patients undergoing ketoconazole compared to cyproterone acetate treatment [0·6 ± 0·3 nmol/l (42 ± 21 ng/dl) vs. 5·6 ± 4·0 nmol/l (392 ± 280 ng/dl); P < 0·05], as expected. Secondary gonadotrophin-dependent precocious puberty occurred at a similar frequency (40%) in both groups. Five patients have attained adult height and two patients have already reached 90% of their adult height. Two of them achieved their TH range and one patient, for whom TH was not available, had an adult height of 0·3 SDS. Four boys (two in each group) did not attain their TH range. Conclusion Long-term treatment with cyproterone acetate or ketoconazole resulted in similar outcomes without important side-effects in boys with testotoxicosis. However, both therapies showed limited efficacy in attaining normal adult height. (Received 25 October 2007; returned for revision 13 November 2007; finally revised 8 December 2007; accepted 10 December 2007) Introduction Familial male-limited precocious puberty (FMPP), also known as testotoxicosis, is a rare dominant form of gonadotrophin-independent precocious puberty caused by constitutively activating mutations of the human LH choriogonadotrophin receptor (LHCGR). 1 This disorder usually presents by age 1– 4 years with signs of puberty, rapid virilization, growth acceleration and skeletal advancement with elevated testosterone levels, despite prepubertal levels of LH. 2–4 Different clinical therapeutic approaches have been used for this disorder. 5–9 Cyproterone acetate, which antagonizes androgen action at the receptor level, represents a valuable therapeutic option for FMPP. 5,6 It was found that cyproterone acetate also induces suppression of the pituitary gonadotrophin secretion in patients with gonadotrophin-dependent precocious puberty. 10–12 The main adverse effects related to this drug were occasional fatigue due to partial adrenal insufficiency and gynaecomastia. 12 In 1996, Itoh et al. 5 described a boy with testotoxicosis successfully treated with cyproterone acetate. However, this treatment did not decrease pubertal and bone age progression in two other cases. 6 Testosterone aromatization to oestrogen was postulated as the potential cause of Correspondence: Madson Q. Almeida, Laboratório de Hormônios e Genética Molecular/LIM 42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 155, 2° andar Bloco 6, 05403-900, São Paulo, SP, Brazil. Tel.: +55 11 30697512; Fax: +55 11 30697519; E-mail: madsonalmeida@gmail.com