ESPE Yearbook of Paediatric Endocrinology

J Neurosci. 2020 Dec 2;40(49):9455–9466. 10.1523/JNEUROSCI.2069-20.2020. PMID: 33158965 https://www.jneurosci.org/content/40/49/9455.long

In brief: These authors used two transgenic mouse models to assess the direct action of estrogens and androgens on GHRH neurons to control growth, pubertal development and reproductive physiology.

Growth hormone (GH) release is critical for normal progression of sexual maturation. Women with GH deficiency show impaired sexual maturation and/or fertility (1). However, the existence of a steroid-sensitive neuronal population involved in this crosstalk between growth and puberty remains mysterious. GH secretion is regulated by two neuronal populations located in the hypothalamus. One population releases somatostatin and has an inhibitory action on GH secretion and the other synthesizes GH-releasing hormone (GHRH) which is stimulatory. Hypothalamic GHRH neurons express estrogen receptor α (ERα) (2) but no detectable levels of androgen receptor (AR) (3). GH stimulates sex steroid synthesis and follicle development by increasing ovarian sensitivity to gonadotropins. However, the existence of a feedback by gonadal steroids onto GHRH neurons to control GH secretion during puberty was still unknown.

To address this issue, the authors generated two transgenic mouse models which harboured a deletion of ERα or AR in GHRH cells. They showed the crucial role of ERα in GHRH neurons, as its deletion disrupts growth in both sexes and pubertal progression in females. By contrast, deletion of AR in GHRH cells causes only a delay in female pubertal completion without impacting growth. As hypophysiotropic GHRH neurons are mostly located in the arcuate nucleus, the authors investigated the potential crosstalk between GHRH and Kiss1 neurons. Using dual-reporter genes and developmental analysis of GHRH and Kiss1 expression, they showed that a subset of GHRH/ERα neurons appear to shift phenotype to become Kiss1/ERα neurons in adult females. In contrast, GHRH and Kiss1 did not colocalize in male mice. This observation could explain the sex difference in GH release pattern and in gonadal steroid control of growth and puberty. In summary, this study provides new insights on the direct action of estrogen on growth and puberty. GHRH/Kiss1 neurons appear to play a role in the crosstalk between the somatotropic and gonadotropic axes during female puberty.

Reference: 1. de Boer JA, Schoemaker J, van der Veen EA (1997) Impaired reproductive function in women treated for growth hormone deficiency during childhood. Clin Endocrinol (Oxf) 46:681–6892. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I (2001) Estrogen receptor (ER)alpha, but not ERbeta, gene is expressed in growth hormone-releasing hormone neurons of the male rat hypothalamus. Endocrinology 142:538–5433. Fodor M, Oudejans CB, Delemarre-van de Waal HA (2001) Absence of androgen receptor in the growth hormone releasing hormone-containing neurones in the rat mediobasal hypothalamus. J Neuroendocrinol 13:724–727.