Long-term outcome of idiopathic hypogonadotropic hypogonadism

Abstract

This review focuses on the presentation, treatment and long-term outcomes of men with idiopathic hypogonadotropic hypogonadism (IHH). The traditional view that IHH is a simple monogenic disorder has now been revised, with some cases having an oliogenic basis involving mutations in more than one locus in each affected individual. The majority of IHH men respond well to induction of spermatogenesis with gonadotropins or pulsatile gonadotropin-releasing hormone. Favourable prognostic factors include larger testicular size, prior gonadotropin therapy, no previous androgen therapy, absence of cryptorchidism and pretreatment inhibin B levels more than 60 pg/ml. Genetic factors influence response to therapy and patients with KAL1 mutations tend to have less favourable outcomes as they may have defects in multiple levels of the hypothalamic-pituitary-gonadal axis.Androgen replacement is warranted in all IHH patients after usual chronological age of puberty, and poor treatment compliance is associated with lower bone mineral density and higher fat mass. However, 10% of patients display sustained reversal so a brief treatment interruption should be considered. IHH is a heterogeneous disorder. The complex genetics and interaction with environmental factors likely underlie the variable expressivity of the reproductive and nonreproductive phenotypes. The demonstration of reversibility, the impact of inadequate testosterone replacement and the good response to induction of spermatogenesis confirm the need for specialist care and long-term follow-up.