Journal Article

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

da Silva Dalben, Gisele, Kaindl, Angela, Hall, Janet E, Almpani, Konstantinia, Seminara, Stephanie B, Jacobsen, Christina M, Tonello, Cristiano, Morioka, Kosuke, Salnikov, Kathryn B, Balasubramanian, Ravikumar, Prasad, Rameshwar, Garcia, Jose Elias, Henkind, Jennifer, Law, Jennifer R, Noukelak, Germaine Y, Russell, Bianca E, Clements, Scott, Volochayev, Rita, Zechi-Ceide, Roseli M, Prada, Rolando, Williamson, Kathleen A, Perez, Orlando, Reigstad, Hallvard M, Crowley, William F, Dwyer, Andrew A, Mondal, Uttam K, Cho, Chie-Hee, Rauch, Anita, Kokitsu-Nakata, Nancy M, Chalmers, Laura, Kim, Susan, Inoue, Kaoru, Mizota, Michiyo, Graham, John M, DiOrio, Nicole P, Capri, Yline, Meader, Brooke, Steindl, Katharina, Arora, Gazal, Plummer, Lacey, Shaw, Natalie D, Lin, Angela E, Delaney, Angela, Buitrago, Tatiana Pineda, Lee, Janice, Vendramini-Pittoli, Siulan

2020

Overview

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.

• Publisher: Oxford University Press,Copyright Oxford University Press
• Subject: Abnormalities, Multiple - genetics / Abnormalities, Multiple - metabolism / Abnormalities, Multiple - pathology / Abnormalities, Multiple - physiopathology / Adolescent / Adult / Aged / Anosmia / Axons / Breast / Child / Child, Preschool / Clinical / Cohort Studies / Craniofacial abnormalities / Diagnosis / Embryology / Female / Follicle Stimulating Hormone - blood / Gonadotropin releasing hormone / Gonadotropin-Releasing Hormone - deficiency / Gonadotropin-Releasing Hormone - metabolism / Gonadotropins / Gonads - abnormalities / Gonads - pathology / Health aspects / Humans / Hypogonadism - genetics / Hypogonadism - metabolism / Hypogonadism - pathology / Hypogonadism - physiopathology / Hypothalamus / Infant / Luteinizing hormone / Luteinizing Hormone - blood / Male / Medical records / Menstruation / Middle Aged / Neurogenesis - physiology / Neurons / Neurons - metabolism / Neurons - physiology / Nose / Nose - abnormalities / Olfaction disorders / Olfaction Disorders - congenital / Olfaction Disorders - genetics / Olfaction Disorders - metabolism / Olfaction Disorders - physiopathology / Olfactory Pathways - metabolism / Olfactory Pathways - pathology / Olfactory system / Ontogeny / Organ Size / Patients / Phenotypes / Phenotyping / Physiological aspects / Pituitary / Pituitary (anterior) / Young Adult