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Hipogonadismo hipogonadotrófico : causas, terapêutica e potencial de reversibilidade
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O correto desenvolvimento e coordenação do eixo hipotálamo- hipófise-gónadas (HHG) é essencial à fertilidade. O hipogonadismo hipogonadotrófico (HH) é uma doença rara em que existe uma perturbação do eixo por desregulação da libertação ou ação de GnRH, provocando uma falha no atingimento da puberdade e subsequente infertilidade. Quando à síndrome anterior se associam sintomas de anósmia ou hiposmia é diagnóstico de Síndrome de Kallmann (KS).
A lista de genes que têm sido implicados na patogénese molecular do HH congénito tem vindo a aumentar. Estes codificam neuropéptidos e proteínas envolvidas no desenvolvimento e migração dos neurónios GnRH, bem como pontos chave na transmissão de sinal ao longo do eixo. É proposto um modelo de oligogenidade no qual as diversas mutações em vez de contribuírem para um fenótipo mais grave, originassem fenótipos de penetrância variável. Entre os principais genes identificados estão ANOS1, FGFR-1/FGF8, PROKR2/PROK2, KISS1R e TAC3/TACR3.
O tratamento destes doentes deve ser direcionado conforme a fase da vida do indivíduo e conforme o desejo de procriar. Na adolescência é essencial induzir a puberdade a fim de evitar complicações não exclusivas do sistema reprodutivo, na ausência de hormonas esteróides sexuais. Na idade adulta a fertilidade é induzida pela estimulação do eixo reprodutor, com pulsos de GnRH ou tratamento com gonadotrofinas.
O aumento do número de casos reportados com reversibilidade de HH anteriormente documentado veio desafiar o dogma anterior de que esta condição seria permanente. A reversibilidade ocorre em ambos os sexos e parece ser mais frequente do que se previa anteriormente, ocorrendo em cerca de 10 a 15% dos casos, tendo sido documentados casos de deficiência grave de GnRH que abrigam mutações em loci de HH conhecidos. A reversibilidade desta condição sublinha a plasticidade do sistema neuroendócrino e sugere que seja necessária mais investigação.
The correct development and coordination of the hypothalamic-pituitary-gonadal (HHG) axis is essential to fertility. Hypogonadotrophic hypogonadism (HH) is a rare disease where exists a disturbance of the axis by deregulation of the release or action of GnRH, causing a failure to reach puberty and subsequent infertility. When the previous syndrome is associated with symptoms of anosmia or hyposmia is diagnostic of Kallmann syndrome (KS). The list of genes that have been implicated in the molecular pathogenesis of congenital HH has been increasing. These encode neuropeptides and proteins involved in the development and migration of GnRH neurons, and some key points in signal transmission along the axis. An oligogenetic model is proposed where the various mutations, instead of contributing to a more severe phenotype, contributed to variable penetrance phenotypes. Among the major genes identified are ANOS1, FGFR-1 / FGF8, PROKR2 / PROK2, KISS1R and TAC3 / TACR3. The treatment of these patients should be directed according to the stage of life of the individual and according to the desire to procreate. In adolescence it is essential to induce puberty in order to avoid non-exclusive complications of the reproductive system in the absence of sex steroid hormones. In adulthood, fertility is induced by stimulation of the reproductive axis, with GnRH pulses or treatment with gonadotrophins. The increased number of reported cases with reversibility of HH previously documented challenged the previous dogma that this condition would be permanent. Reversibility occurs in both sexes and appears to be more frequent than previously predicted, occurring in about 10 to 15% of cases, with cases of severe GnRH deficiency harboring mutations in known HH loci being documented. The reversibility of this condition underlines the plasticity of the neuroendocrine system and suggests that more research is needed.
The correct development and coordination of the hypothalamic-pituitary-gonadal (HHG) axis is essential to fertility. Hypogonadotrophic hypogonadism (HH) is a rare disease where exists a disturbance of the axis by deregulation of the release or action of GnRH, causing a failure to reach puberty and subsequent infertility. When the previous syndrome is associated with symptoms of anosmia or hyposmia is diagnostic of Kallmann syndrome (KS). The list of genes that have been implicated in the molecular pathogenesis of congenital HH has been increasing. These encode neuropeptides and proteins involved in the development and migration of GnRH neurons, and some key points in signal transmission along the axis. An oligogenetic model is proposed where the various mutations, instead of contributing to a more severe phenotype, contributed to variable penetrance phenotypes. Among the major genes identified are ANOS1, FGFR-1 / FGF8, PROKR2 / PROK2, KISS1R and TAC3 / TACR3. The treatment of these patients should be directed according to the stage of life of the individual and according to the desire to procreate. In adolescence it is essential to induce puberty in order to avoid non-exclusive complications of the reproductive system in the absence of sex steroid hormones. In adulthood, fertility is induced by stimulation of the reproductive axis, with GnRH pulses or treatment with gonadotrophins. The increased number of reported cases with reversibility of HH previously documented challenged the previous dogma that this condition would be permanent. Reversibility occurs in both sexes and appears to be more frequent than previously predicted, occurring in about 10 to 15% of cases, with cases of severe GnRH deficiency harboring mutations in known HH loci being documented. The reversibility of this condition underlines the plasticity of the neuroendocrine system and suggests that more research is needed.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2018
Palavras-chave
Hipogonadismo hipogonadotrófico Síndrome de Kallmann Gonadotrofinas Eixo hipotálamo-hipófise-gónadas Tratamento de infertilidade Indução da puberdade