Reversal of isolated hypogonadotropic hypogonadism

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pituitary–testicular axis in two men is dependent on intermittent ... In both cases, the injection interval ... to establishing a 3–4 month injection interval, but subsequent planned ... burgeoning alcohol dependency (to this day unresolved). He was.

Clinical Endocrinology (2013)


Reversal of isolated hypogonadotropic hypogonadism: long-term integrity of hypothalamo– pituitary–testicular axis in two men is dependent on intermittent androgen exposure Kallmann syndrome (KS) is defined by the association of congenital anosmia with isolated hypogonadotropic hypogonadism (IHH) resulting from deficiency of gonadotrophin-releasing hormone (GnRH). 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 nonclassical reproductive disease variants were identified as follows: adult-onset idiopathic IHH,1 reversal of IHH/KS in adulthood2,3 and genetically predisposed hypothalamic amenorrhoea (HA).4 Reversal of gonadotrophin deficiency occurs in up to 10% of IHH males, unrelated to whether initial presentation was with absent or partial/arrested puberty. Like HA, it is associated with similar genetic variants to those found in classical IHH.3 However, it remains unclear whether robust 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 KS men from his original publication,2 both of whom remain reproductively intact to this day. However, Raivio’s group recently described two unrelated men harbouring biallelic GNRHR mutations (R262Q/R262Q and R139H/R262Q, respectively) whose IHH reversed in their mid-20s, but then relapsed at ages 61 and 31 years, respectively.5 We report two patients with atypical Kallmann’s syndrome who initially appeared to ‘recover’ normal gonadotrophin secretion, consistent with reversal, but subsequently evidenced the requirement for periodic albeit infrequent, exposure to intramuscular testosterone undecanoate 1 g depot (TU, Nebidoâ; Bayer AG, Leverkusen, Berlin) 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.

Case 1 He originally presented to a urology clinic with sexual dysfunction aged 532 years and found to be hypogonadal. He was simply started on testosterone replacement, and no investigations were performed into its aetiology. He was, however, referred to a clinical geneticist who noted a history of congenital © 2013 John Wiley & Sons Ltd

anosmia and referred him on to our unit, where he was first seen 18 months after his initial presentation. He reported normal puberty, with no history of cryptorchidism, or any evident secondary cause of gonadotrophin deficiency (e.g. systemic disease or prescribed opiates) and had conceived two children in his late 20s. He exhibited anosmia and marked segmental disproportion, but no other nonreproductive defect. Testicular volumes were 15 ml (normal range 12–25 ml); Tanner staging G5 PH5 AH3. Biochemistry confirmed IHH, MRI demonstrated hypoplastic olfactory sulci and DEXA scan showed spinal osteoporosis. There was no family history or pubertal delay, anosmia or any other relevant nonreproductive defect. Adult-onset IHH/atypical KS seemed to be the ‘best fit’ clinical diagnosis, and he was started on Testogelâ, resulting in improvements in all parameters including bone mineral density (BMD). However, 2 years later, reassessment off therapy showed complete reversal of IHH (Table 1a). During the two subsequent years off therapy, haematocrit, serum testosterone (T) and gonadotrophins all progressively decreased, with loss of BMD. He was started on TU, with a view to establishing a 3–4 month injection interval, but subsequent planned injections had to be serially postponed due to persistently normal T and gonadotrophin levels. We eventually determined that an injection interval of 8 months easily sufficient to maintain normal haematocrit, serum T and LH pulsatility (Appendix S1) at preinjection ‘trough’.

Case 2 He first presented to our unit with absent puberty (G2 PH2 AH1) and IHH having just turned 18. There was no history of microphallus or cryptorchidism, and his four older brothers had all undergone normal puberty. He received 4 months treatment with human chorionic gonadotrophin (hCG 1500 IU thrice weekly by subcutaneous injection) with good clinical response. Six months after completing his course of hCG, he had almost completed puberty (G4 PH4 AH2), appeared to exhibit normal gonadotroph function, and so was discharged from follow-up on no therapy with a presumptive diagnosis of resolved constitutional delay. Ten years later, he presented to a psychiatry-led sexual dysfunction clinic with erectile dysfunction, sparse body hair and a burgeoning alcohol dependency (to this day unresolved). He was then referred back to our unit and noted to have incomplete puberty (G5 PH4 AH2, Testes 10–12 ml) and mild gynaecomastia. Biochemistry once more confirmed IHH, and he was restarted on TE, which he received intermittently over the next 10 years, during which period, he became lost to follow-up. At the age of 40 years, he presented for the third time, having stopped TE 6 months previously. He gave a history of tiredness, 1


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