Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose.

The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in man led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.To determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet three had spontaneous breast development and two women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to two GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male.Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with, but may not depend on, olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.