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.

Trial registration: ClinicalTrials.gov NCT01511588 NCT00383656 NCT00392756.

Keywords: GnRH; Kallmann; arhinia.

© Published by Oxford University Press on behalf of the Endocrine Society 2020.

Figures

Figure 1.

Initial neuroendocrine evaluation in a female patient with arhinia (No. 11) at age 16 years (before hormone replacement therapy) demonstrating undetectable gonadotropins but normal cortisol, prolactin, and growth hormone (GH) secretion, including normal sleep augmentation of GH. Estradiol was undetectable (

Figure 2.

Axial (1, 4), sagittal (2, 5), and coronal (3, 6) cone-beam computed tomography sections depicting the maxillofacial region in a, healthy control individual (left) and, patient with arhinia (right). Note the multiple olfactory foramina (arrows) on the surface of the cribriform plate in the control patient, whereas the cribriform plate, as well as the surrounding paranasal sinuses, are completely ossified in the patient with arhinia. a, ethmoid sinus; b, frontal sinus; c, crista galli; d, sphenoid sinus.

Figure 3.

Hormonal responses to long-term gonadotropin-releasing hormone (GnRH) administration in a male arhinia patient (No. 4). GnRH was initially administered at a physiological dose (25 ng/kg/bolus subcutaneously) but was increased to pharmacologic doses as high as 800 ng/kg/bolus over the course of 1 year (see inset, upper left) in an attempt to overcome testicular resistance as manifested by hypergonadotropism with low testosterone and inhibin B levels. The patient’s data points are indicated by black circles and black lines. Horizontal dashed lines indicate the upper and lower limits of hormone levels in healthy adult men (41). The gray shaded area denotes the 95% CI of hormone levels in patients with congenital GnRH deficiency who responded in a typical fashion to GnRH with normalization of luteinizing hormone, follicle-stimulating hormone, and testosterone levels accompanied by mature sperm production (29). To convert testosterone (ng/dL) to nmol/L, multiply by 0.0347. To convert inhibin B (pg/mL) to ng/L, multiply by 1.0.

Figure 4.

Frequent sampling study in patient No. 11 on day 6 of a physiological gonadotropin-releasing hormone (GnRH) regimen (75 ng/kg/bolus administered intravenously every 90 minutes for the first 7 days; then every 60 minutes until ovulation). Note normal luteinizing hormone and follicle-stimulating hormone levels and the presence of LH pulses (gray arrowheads) after 4 of 5 GnRH boluses (black arrowheads and vertical black lines). A pelvic ultrasound performed the same day demonstrated a maximum follicle diameter of 8 mm and an early proliferative (6 mm) endometrium.