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Gonadotropin-Releasing Hormone Immunoreactivity in the Nasal Epithelia of Adults with Kallmann’s Syndrome and Isolated Hypogonadotropic Hypogonadism and in the Early Midtrimester Human Fetus

Division of Endocrinology (R.Q., W.H., P.-M.G.B.) and Department of Anatomy (W.H., C.T.), Royal Free Hospital School of Medicine, University College London; the Department of Otorhinolaryngology, Royal Free Hospital (W.G., R.E.Q.); the Department of Endocrinology, St. Bartholomew’s Hospital, and the Royal London School of Medicine and Dentistry (G.M.B.), London, United Kingdom

Address all correspondence and requests for reprints to: Dr. P.-M. G. Bouloux, Department of Endocrinology, Royal Free Hospital, Pond Street, London, United Kingdom NW3 2QG. E-mail pmb{at}rfhsm.ac.uk

GnRH-secreting neurons are known to originate in the epithelium of the medial olfactory placode, whence they migrate along the axons of the terminal nerve via the forebrain and into the hypothalamus. Synaptic contact between the developing olfactory bulbs and fascicles of the vomeronasal, terminal, and olfactory nerves does not occur in Kallmann’s syndrome. Consequently, there is migration arrest of GnRH cells and partial or complete failure of formation of the olfactory bulbs, resulting in severe olfactory deficit and hypogonadotropic hypogonadism.

In the present study, using an immunofluorescent, double immunostaining technique and confocal laser scanning microscopy, we observed GnRH-immunoreactive neurons in the hypothalamus of a 14-week-old human fetus. However, migration of GnRH neurons was not complete, and indeed, such cells were seen to be migrating along terminal nerve fascicles beneath the cribriform plate in a 16-week-old fetus. The same immunofluorescent technique demonstrated the presence of GnRH cells in biopsies of nasal mucosa obtained from three adults with Kallmann’s syndrome, one normosmic subject with hypogonadotropic hypogonadism, and a eugonadal male cadaver. These findings are consistent with two different interpretations: the nasal GnRH neurons may be vestigial, representing cells that failed to migrate during embryogenesis; alternatively, they may have been generated de novo later in life, a possibility consistent with the recognized plasticity of human postnatal olfactory neuroepithelium. They also reveal that subjects with the normosmic (i.e. non-Kallmann’s) form of GnRH deficiency are able to synthesize immunologically recognizable GnRH, implying that failure of GnRH synthesis is not responsible for this type of hypogonadotropic hypogonadism.

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