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Review
. 2022 Nov 8;23(22):13695.
doi: 10.3390/ijms232213695.

Deciphering the Roles & Regulation of Estradiol Signaling during Female Mini-Puberty: Insights from Mouse Models

Marie M Devillers  1 , Sakina Mhaouty-Kodja  2 , Céline J Guigon  1
Affiliations
Review

Deciphering the Roles & Regulation of Estradiol Signaling during Female Mini-Puberty: Insights from Mouse Models

Marie M Devillers et al. Int J Mol Sci. .

Abstract

Mini-puberty of infancy is a short developmental phase occurring in humans and other mammals after birth. In females, it corresponds to transient and robust activation of the hypothalamo-pituitary-ovarian (HPO) axis revealed by high levels of gonadotropin hormones, follicular growth, and increased estradiol production by the ovary. The roles of estradiol signaling during this intriguing developmental phase are not yet well known, but accumulating data support the idea that it aids in the implementation of reproductive function. This review aims to provide in-depth information on HPO activity during this particular developmental phase in several mammal species, including humans, and to propose emerging hypotheses on the putative effect of estradiol signaling on the development and function of organs involved in female reproduction.

Keywords: GnRH; estradiol; estradiol receptor; hypothalamus; mini-puberty; ovary.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of the gonadotrope axis at different periods of life in the mouse. FSH (green line) and LH (blue line) are detected in the last part of gestation, induced by GnRH stimulation. The high levels of maternal estrogens (dotted pink line) may not exert negative feedback at this time on FSH and LH synthesis and secretion due to high levels of α-fetoprotein (AFP) produced by the fetal liver. After birth, maternal estradiol wanes from pup serum, and this may lead to the loss of estradiol negative feedback and to the dramatic rise in gonadotropin levels observed at the time of mini-puberty. Additional ovarian factors may contribute to this rise (see the text). The gonadotropin surge contributes to increased estradiol production by the ovary at mini-puberty (continuous pink line). After that, the decrease in AFP after birth, and the maturation of inhibin negative feedback, may contribute to the observed fall in gonadotropin levels, remaining low up to puberty. During reproductive life, gonadotropin levels are regulated by both estradiol negative and positive feedback. Estradiol negative feedback in aged mice is attenuated, thereby increasing gonadotropin levels. Note that the levels of hormones shown during the different periods are given on an indicative basis since no studies encompass all these periods. See references in the text. The figure was prepared with the help of Mr. Le Ciclé, using BioRender, under Academic License terms.
Figure 2
Figure 2
Significant changes in reproductive hormone levels during prepubertal life in the mouse. (A) The different stages of the prepubertal period in the mouse. The chronological axis displays the neonatal, infantile, and juvenile periods in this species. Mini-puberty takes place within the infantile period. (B) Gonadotropin and estradiol levels in prepubertal and adult female mice at different stages of the estrous cycle were determined by Luminex assay and GC/MS-MS, respectively, as published by our group in [29], including the additional age of 27 dpn analyzed at the same time as the other ages using the same methods. Hormonal levels of the infantile period are shown as blue bars.
Figure 3
Figure 3
Different categories of follicles are present in the prepubertal ovary in mammals. The prepubertal ovary is endowed with growing follicles up to the antral stage, and unlike the adult ovary during reproductive life, it does not display large healthy follicles of the size of preovulatory follicles despite high gonadotropin levels during mini-puberty.
Figure 4
Figure 4
Particular characteristics of the first follicular waves in rodents. The first growing follicles are located in the central region of the ovary, delimited by dotted grey lines. Although most are destined to follicular atresia before puberty, a subset is ovulated at puberty and the very beginning of reproductive life [64,65]. The first follicular waves would be responsible for ovarian endocrine activity throughout prepubertal life [64]. During mini-puberty, immature follicles at the preantral/early antral stage show some functional characteristics of preovulatory follicles, such as Cyp19a1 and Lhcgr expression in granulosa cells [29]. Scale bars: 100 μm.
Figure 5
Figure 5
Proposed hypothesis on the dialogue between the ovary and the hypothalamo-pituitary system at mini-puberty. Estradiol produced by the first follicular waves may exert a negative feedback loop on the hypothalamus to restrain gonadotropin synthesis and secretion; however, the high levels of AFP may still limit its action. In contrast, we hypothesize that AMH produced by the subsequent follicular waves may up-regulate FSH synthesis by the pituitary and possibly LH and FSH levels by acting on GnRH neurons in the hypothalamus. See references in the text.
Figure 6
Figure 6
Possible roles of mini-pubertal estradiol on different organs related to reproduction. This hormone could play a pleiotropic role in the body by regulating the development and differentiation of several target tissues, including the hypothalamic system driving GnRH pulsatility, several brain areas contributing to sexual and maternal behaviors (amygdala, olfactory system, hypothalamus), the mammary gland and the uterus. See references in the text.
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