ESPE Yearbook of Paediatric Endocrinology

Brief summary: This literature review summarized the recent advances in our understanding of the GnRH system throughout life and its implication in the brain development beyond its conventional role in reproductive control.

During embryonic development GnRH neurons migrate from the olfactory placode to the hypothalamus, where they control the hypothalamus–pituitary–gonadal axis (1,2). But many GnRH neurons migrate to other brain regions, such as the cortex and the hippocampus (1), and exert possible non-reproductive functions.

These authors analysis of reported data on rodent studies resulted in 3 theories:

1) Minipuberty is potentially important for brain development and the maintenance of sensory and cognitive function throughout life (3).

2) The pulsatile pattern of GnRH secretion is potentially important for olfactory perception and cognition (4).

3) GnRH regulates postnatal myelination in the neocortex and may influence adult brain structure and function (4).

Taken together, these findings raise questions about potential long-term side effects of (non-pulsatile) depot GnRH agonist therapy for precocious puberty or transgender children and adults, as well as the effects of downstream hormone replacement to treat congenital hypogonadotropic hypogonadism. It also opens new avenues regarding the potential use of pulsatile GnRH administration to prevent aging-related cognitive decline and learning abilities.

References: 1. Casoni F, Malone SA, Belle M, Luzzati F, Collier F, Allet C, Hrabovszky E, Rasika S, Prevot V, Chédotal A, Giacobini P. Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains. Development. 2016;143(21):3969–3981. 2. Duittoz AH, Forni PE, Giacobini P, Golan M, Mollard P, Negrón AL, Radovick S, Wray S. Development of the gonadotropin-releasing hormone system. J Neuroendocrinol. 2022;34(5):e13087. 3. Chachlaki K, Messina A, Delli V, Leysen V, Maurnyi C, Huber C, Ternier G, Skrapits K, Papadakis G, Shruti S, Kapanidou M, Cheng X, Acierno J, Rademaker J, Rasika S, Quinton R, Niedziela M, L’Allemand D, Pignatelli D, Dirlewander M, Lang-Muritano M, Kempf P, Catteau-Jonard S, Niederländer NJ, Ciofi P, Tena-Sempere M, Garthwaite J, Storme L, Avan P, Hrabovszky E, Carleton A, Santoni F, Giacobini P, Pitteloud N, Prevot V. NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice. Sci Transl Med. 2022; 14(665):eabh2369. 4. Manfredi-Lozano M, Leysen V, Adamo M, Paiva I, Rovera R, Pignat JM, Timzoura FE, Candlish M, Eddarkaoui S, Malone SA, Silva MSB, Trova S, Imbernon M, Decoster L, Cotellessa L, Tena-Sempere M, Claret M, Paoloni-Giacobino A, Plassard D, Paccou E, Vionnet N, Acierno J, Maceski AM, Lutti A, Pfrieger F, Rasika S, Santoni F, Boehm U, Ciofi P, Buée L, Haddjeri N, Boutillier AL, Kuhle J, Messina A, Draganski B, Giacobini P, Pitteloud N, Prevot V. GnRH replacement rescues cognition in Down syndrome. Science. 2022; 377(6610):eabq4515.