Roles and Responsibilities
Consultant Endocrinologist, Newcastle upon Tyne Hospitals NHS Foundation Trust
Idiopathic hypogonadotrophic hypogonadism (IHH)
Idiopathic 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 lack a sense of smell. Other associations include mirror movements, absence of a kidney, deafness, cleft lip/palate and dental 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, and subsequently investigated in greater detail as part of the same transatlantic 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 reversal” seems to require a period of exposure to exogenous androgens and evidenced greater than anticipated plasticity in the neuroendocrine control of the human reproductive axis.
The genetics of IHH remains only partly elucidated and we have contributed substantially to the international consortium investigating this by means of a candidate gene approach. We also maintain a very close relationship with the international web-based IHH patient support group, with mutually beneficial results. Patients and their families are able to stay in touch with research progress and they, in turn, have been extremely helpful to us by volunteering to participate in genetic research. Our group recently co-authored the first published account of IHH resulting from heterozygous mutations in two separate genes (FGFR1 and NELF). We hypothesise that the guidance molecule encoded by the NELF gene exerts a significant modulatory role in establishing a mature gonadotrophic axis.
We have recently established an immortalised human GnRH-secreting neuroblast cell line (TERFB4) in culture that, following transfection with a GnRH-luciferase reporter plasmid, we hope will provide an important vehicle for modelling genetic and environmental influences on GnRH secretion.
Katie MacArthur BSc
Simon Pearce MD FRCP
Professor of Endocrinology, Honorary Consultant Physician