Endocrine Abstracts (2009) 20 S3.4

Reversible hypogonadotropic hypogonadism

Nelly Pitteloud


Harvard Medical School, Boston, USA.


Puberty is a complex biologic process inducing sexual development and fertility. Puberty is initiated by the secretion of pulsatile gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. Severe anomalies in GnRH secretion or action may lead to idiopathic hypogonadotropic hypogonadism (IHH), a disorder where patients failed to go through puberty. While IHH was previously thought to require lifelong treatment, we hypothesized that activation of the hypothalamic–pituitary–gonadal (HPG) axis could occur in adulthood with the appropriate stimulus. Retrospective and prospective studies in a large cohort of male IHH (Kallmann syndrome (KS) and normosmic IHH) demonstrate reversal of HH in approximately 10% of cases. Those patients exhibited sustained adult serum T levels after hormonal treatment was discontinued. Mutations in FGFR1, PROKR2, GNRHR were identified in several cases of reversal.

In conclusion: 1) Sustained reversal of IHH occurs in about 10% of patients with KS or nIHH; 2) Genetic defects leading to IHH can be overcome, likely by environmental stimuli such as exposure to sex steroids; 3) Although the mechanism of reversal remains unclear, it may involve plasticity of the GnRH neurons in adulthood; and 4) IHH patients should undergo brief discontinuation of hormonal treatment to assess for reversal.

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