ABSTRACT Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype – phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.

OBJECTIVE: The ideal dosage of cross-sex hormones remains unknown. The aim of this study was to evaluate the luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin levels after low-dose estrogen therapy with or without cyproterone acetate in transgender women. METHODS: The serum hormone and biochemical profiles of 51 transgender women were evaluated before gonadectomy. Hormone therapy consisted of conjugated equine estrogen alone or combined with cyproterone acetate. The daily dose of conjugated equine estrogen was 0.625 mg in 41 subjects and 1.25 mg in 10 subjects, and the daily dose of cyproterone acetate was 50 mg in 42 subjects and 100 mg in one subject. RESULTS: Estrogen-only therapy reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 731.5 to 18 ng/dL, 6.3 to 1.1 U/L and 9.6 to 1.5 U/L, respectively. Estrogen plus cyproterone acetate reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 750 to 21 ng/dL, 6.8 to 0.6 U/L and 10 to 1.0 U/L, respectively. The serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin in the patients treated with estrogen alone and estrogen plus cyproterone acetate were not significantly different. The group receiving estrogen plus cyproterone acetate had significantly higher levels of gamma-glutamyltransferase than the group receiving estrogen alone. No significant differences in the other biochemical parameters were evident between the patients receiving estrogen alone and estrogen plus cyproterone acetate. CONCLUSION: In our sample of transgender women, lower estrogen doses than those usually prescribed for these subjects were able to adjust the testosterone and estradiol levels to the physiological female range, thus avoiding high estrogen doses and their multiple associated side effects.

Relatamos uma nova mutação no gene GNRHR em um homem com hipogonadismo hipogonadotrófico isolado normósmico (HHIn). A região codificadora do gene GNRHR foi amplificada e sequenciada. Três variantes p.[Asn10Lys;Gln11Lys]; [Tyr283His] foram identificadas no GNRHR em um homem com HHIn esporádico. As três variantes estavam ausentes no grupo controle (130 adultos normais). A segregação familiar mostrou que as variantes previamente descritas p.[Asn10Lys;Gln11Lys] se localizavam no mesmo alelo, em heterozigose composta com a nova variante p.Tyr283His. As mutações p.[Asn10Lys;Gln11Lys] são sabidamente inativadoras. A variante p.Tyr283His afeta um resíduo bem conservado, e a análise in silico sugeriu que essa é uma mutação deletéria. Descrevemos uma mutação inédita no gene GNRHR em um paciente com HHIn nIHH. A ausência da variante no grupo controle, a conservação entre as espécies, a análise in silico e a segregação familiar sugerem que a p.Tyr283His é uma mutação inativadora, identificada em heterozigose composta com as mutações p.[Asn10Lys;Gln11Lys]. Arq Bras Endocrinol Metab. 2012;56(8):540-4

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4

OBJETIVO: Analisar os genes AMH e AMHR2 em indivíduos com síndrome de persistência dos ductos de Müller (SPDM). PACIENTES E MÉTODO: Amostras de DNA genômico de oito pacientes com SPDM foram obtidas de leucócitos de sangue periférico. Sequenciamento direto da região codificadora e das áreas intrônicas próximas aos éxons dos genes AMH e AMHR foi realizado. RESULTADOS: As mutações p.Arg95*, p.Arg123Trp, c.556-2A>G e p.Arg502Leu no gene AMH foram identificadas em cinco pacientes e as mutações p.Gly323Ser e p.Arg407* no gene AMHR2, em dois indivíduos. As análises in silico das mutações c.556-2A>G, p.Arg502Leu e p.Arg407*, não descritas anteriormente na literatura, previram que elas são deletérias e possivelmente a causa da doença. CONCLUSÃO: Uma provável etiologia molecular foi encontrada nos oito pacientes portadores de SPDM avaliados. No gene do AMH foram identificadas quatro mutações e no AMHR2, duas mutações. Três das seis mutações encontradas são mutações novas, c.556-2A>G e p.Arg502Leu no gene AMH; e p.Gly323Ser no AMHR2. Arq Bras Endocrinol Metab. 2012;56(8):473-8

OBJECTIVE: To screen for mutations in AMH and AMHR2 genes in patients with persistent Müllerian duct syndrome (PMDS). PATIENTS AND METHOD: Genomic DNA of eight patients with PMDS was obtained from peripheral blood leukocytes. Directed sequencing of the coding regions and the exon-intron boundaries of AMH and AMHR2 were performed. RESULTS: The AMH mutations p.Arg95*, p.Arg123Trp, c.556-2A>G, and p.Arg502Leu were identified in five patients; and p.Gly323Ser and p.Arg407* in AMHR2 of two individuals. In silico analyses of the novel c.556-2A>G, p.Arg502Leu and p.Arg407* mutations predicted that they were harmful and were possible causes of the disease. CONCLUSION: A likely molecular etiology was found in the eight evaluated patients with PMDS. Four mutations in AMH and two in AMHR2 were identified. Three of them are novel mutations, c.556-2A>G, and p.Arg502Leu in AMH; and p.Gly323Ser in AMHR2. Arq Bras Endocrinol Metab. 2012;56(8):473-8