Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose

Abstract

Context 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 humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. Objective The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. Methods 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. Results 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 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. Conclusions 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.

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…More recently, Delaney and colleagues specifically evaluated the co-occurrence of CHH and arhinia, providing evidence that most patients exhibited clinical and/or biochemical signs of GnRH deficiency. However, a small portion of female patients had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis [192]. These findings, together with previous studies in arhinic mice [15], indicate that the main olfactory system may not be necessary for the migration of GnRH neurons.…”

Discovery of the Retinol STRA6 Receptor as a Novel Binding Receptor for SARS-CoV-2 in COVID-19: In Silico Research.

“…It acts via distinct receptors, G-protein coupled receptor (GnRH) found in gonadotropes to induce production of the gonadotropin hormones, follicle and luteinizing -stimulating hormones (FSH), (LH) (85). a study found that congenital anosmia (loss of smell) is frequently linked with GnRH deficiency in human patients, leading to the widely held belief that GnRH neurons rely on olfactory structures to reach the brain, but this suggestion has yet to be proven (86).…”

Recent advances in understanding and managing Kallmann syndrome

“…The role of alterations of olfactory/vomeronasal patterning on defective GnRH neuron migration and olfactory dysfunction is still not well clarified 17 – 19 . However, relatively normal reproductive functions, or a late-onset hypogonadism, have been described in sporadic patients with congenital olfactory agenesis with anosmia 20 , 21 ; moreover, data from eugonadal patients with arrhinia show that human GnRH neurons may not entirely depend upon olfactory structures for their normal migration and function 22 . Studies on animal models unravelling the common origin of olfactory cells and a subpopulation of GnRH neurons from the neural crest 23 , an embryonic region that gives rise to the peripheral nervous system, bone, and melanocytes, may provide an additional interpretation of the syndromic association of hypogonadism and anosmia.…”