Roles and Responsibilities
Consultant Endocrinologist, Newcastle upon Tyne Hospitals NHS Foundation Trust
Founder Member & Vice Chair of COST Action BM1105 (Neuroendocrine Control of Reproduction). This is an EU-funded, international consortium of physicians and scientists studying hypogonadotropic hypogonadism, which is characterised by delayed or absent puberty and infertility. This condition results from GnRH deficiency and is frequently associated with a lack of sense of smell (called Kallmann syndrome). This 4 year project, funded by COST (European Cooperation in Science & Technology), aims to build a collaborative network that is actively seeking to involve patients, in order to translate scientific discoveries into improved patient care. www.gnrhnetwork.eu
Isolated hypogonadotrophic hypogonadism (IHH) is a genetically heterogeneous condition resulting from deficiency (or less commonly resistance to the action) of hypothalamic gonadotrophin-releasing hormone (GnRH). It affects around 1-in-4000 males together with a smaller proportion of females.
Affected individuals typically fail to enter puberty and are infertile without specialist endocrine care. Around 50% of IHH patients exhibit one or more congenital non-reproductive defects, most commonly lack a sense of smell (anosmia -defining Kallmann syndrome), but also including mirror movements, absence of a kidney, deafness, cleft lip/palate and dental or digit anomalies.
Although IHH is a relatively rare and non-lethal disease, it constitutes a crucial experiment-of-nature with the potential to provide important insights into the developmental biology of human reproduction and, to some extent, also of the skeleton and nervous system.
A novel clinical observation first made by our group, subsequently investigated in greater detail as part of an international collaboration, has been that up to 10% of IHH men undergo spontaneous maturation of the gonadotroph axis in later life, such that they become independent of testosterone replacement and can exhibit normal fertility. This phenomenon of IHH-with-Reversal seems to require a period of exposure to exogenous androgens and evidences a greater-than-anticipated plasticity in the neuroendocrine control of the human reproductive axis.
The genetics of IHH remains only partly elucidated. We we have contributed substantially to the international consortium investigating this (www.cost.eu/domains_actions/bmbs/Actions/BM1105) and also helped indentify the condition as being oligogenic, rather than monogenic-Mendelian in origin. We have shown that monoallelic IHH-associated sequence variants, at least one of which has been traced back to a common ancestor living in the New Stone Age, occur at low frequency in normal humans, but that women with weight/stress-related hypothalamic amenorrhoea (HA) are relatively enriched with these variants. Thus HA, hitherto perceived to be an entirely environmentally-induced condition resulting from mismatch between energy intake and expenditure, is now more accurately defined as resulting from genetic-environmental interaction. Moreover, the longevity of at least one disease-associated variant in the human genome suggests some kind of paradoxical heterozygote advantage under defined conditions.
We maintain a very close relationship with the international web-based IHH patient support group (www.kalmanns.org). Patients and their families are able to stay in touch with research progress and get prompt clinical advice. They, in turn, have been extremely helpful to us by volunteering to participate in genetic research.