Reversal of Isolated Hypogonadotropic Hypogonadism [IHH]: Long-Term Integrity of Hypothalamo-Pituitary-Testicular Axis is Dependent on Intermittent Androgen Exposure
Reversal of gonadotropin-deficiency occurs in up to 10% of IHH males, unrelated to whether initial presentation was with absent or partial/arrested puberty. Like Hypothalamic Amenorrhoea [HA], it is associated with similar genetic variants to those found in classical IHH.
However, it remains unclear whether robust Gonadotropin Releasing-Hormone [GnRH] neurosecretory-integrity is retained long-term, or whether this reversal is “fragile” and these men remain predisposed to resume IHH under unfavourable environmental conditions. The senior author of this report has maintained contact with two of the five Kallmann’s Syndrome [KS] men from his original publication, both of whom remain reproductively intact to this day.
However, Raivio’s group recently described two unrelated men harbouring biallelic GNRHR mutations whose IHH reversed in their mid-20s, but then relapsed at ages 61 and 31 years, respectively.
Researchers report two patients with atypical Kallmann’s syndrome who initially appeared to ‘recover’ normal gonadotropin-secretion, consistent with reversal, but subsequently evidenced the requirement for periodic, albeit infrequent, exposure to intramuscular testosterone undecanoate 1g depot in order to maintain long-term GnRH neurosecretory axis integrity.
In both cases, the injection-interval was more than double the accepted duration of action. This regime sufficed to alleviate symptoms, and maintain physiological haematocrit, serum testosterone (T) and gonadotrophin levels. These observations highlight the plasticity of neuroendocrine control of GnRH secretion.
Integrity of the gonadotropic axis was restored in both cases for periods of a year or more following single doses of TU. The mechanism for this is unclear, but might relate to androgen-driven up-regulation of genes involved in neuroendocrine regulation of GnRH secretion.
Santhakumar A, Balasubramaniam R, Miller M, Quinton R. Reversal of Isolated Hypogonadotropic Hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure. Clinical Endocrinology. Reversal of Isolated Hypogonadotropic Hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure - Santhakumar - Clinical Endocrinology - Wiley Online Library
Kallmann syndrome (KS) is defined by the association of congenital anosmia with isolated hypogonadotropic hypogonadism (IHH) resulting from deficiency of GnRH (gonadotropin releasing-hormone). KS patients typically require exposure to physiologic levels of gonadal steroids to achieve and maintain sexual maturation, peak bone mass and optimal muscle health. IHH was considered to be a lifelong form of GnRH deficiency until, over the past 15 years, three other non-classical reproductive disease variants were identified: adult-onset idiopathic HH (Nachtigall, et al., 1997), reversal-of-IHH/KS in adulthood (Quinton, et al., 1999; Raivio, et al., 2007) and genetically-predisposed hypothalamic amenorrhoea (HA) (Caronia, et al., 2011).
Reversal of gonadotropin-deficiency occurs in up to 10% of IHH males, unrelated to whether initial presentation was with absent or partial/arrested puberty. Like Hypothalamic Amenorrhoea [HA], it is associated with similar genetic variants to those found in classical IHH.
However, it remains unclear whether robust Gonadotropin Releasing-Hormone [GnRH] neurosecretory-integrity is retained long-term, or whether this reversal is “fragile” and these men remain predisposed to resume IHH under unfavourable environmental conditions. The senior author of this report has maintained contact with two of the five Kallmann’s Syndrome [KS] men from his original publication, both of whom remain reproductively intact to this day.
However, Raivio’s group recently described two unrelated men harbouring biallelic GNRHR mutations whose IHH reversed in their mid-20s, but then relapsed at ages 61 and 31 years, respectively.
Researchers report two patients with atypical Kallmann’s syndrome who initially appeared to ‘recover’ normal gonadotropin-secretion, consistent with reversal, but subsequently evidenced the requirement for periodic, albeit infrequent, exposure to intramuscular testosterone undecanoate 1g depot in order to maintain long-term GnRH neurosecretory axis integrity.
In both cases, the injection-interval was more than double the accepted duration of action. This regime sufficed to alleviate symptoms, and maintain physiological haematocrit, serum testosterone (T) and gonadotrophin levels. These observations highlight the plasticity of neuroendocrine control of GnRH secretion.
Integrity of the gonadotropic axis was restored in both cases for periods of a year or more following single doses of TU. The mechanism for this is unclear, but might relate to androgen-driven up-regulation of genes involved in neuroendocrine regulation of GnRH secretion.
Santhakumar A, Balasubramaniam R, Miller M, Quinton R. Reversal of Isolated Hypogonadotropic Hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure. Clinical Endocrinology. Reversal of Isolated Hypogonadotropic Hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure - Santhakumar - Clinical Endocrinology - Wiley Online Library
Kallmann syndrome (KS) is defined by the association of congenital anosmia with isolated hypogonadotropic hypogonadism (IHH) resulting from deficiency of GnRH (gonadotropin releasing-hormone). KS patients typically require exposure to physiologic levels of gonadal steroids to achieve and maintain sexual maturation, peak bone mass and optimal muscle health. IHH was considered to be a lifelong form of GnRH deficiency until, over the past 15 years, three other non-classical reproductive disease variants were identified: adult-onset idiopathic HH (Nachtigall, et al., 1997), reversal-of-IHH/KS in adulthood (Quinton, et al., 1999; Raivio, et al., 2007) and genetically-predisposed hypothalamic amenorrhoea (HA) (Caronia, et al., 2011).
