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Review

Decoding Mini-Puberty and Its Clinical Significance: A Narrative Review

by
Anastasios Serbis
1,2,
Chrysoula Kosmeri
2,
Natalia Atzemoglou
1,
Katerina-Marina Lampropoulou
3,
Lida-Eleni Giaprou
1,
Dimitrios Rallis
1,3 and
Vasileios Giapros
1,3,*
1
Faculty of Medicine, School of Health Sciences, University of Ioannina, 45500 Ioannina, Greece
2
Department of Pediatrics, University Hospital of Ioannina, 45500 Ioannina, Greece
3
Neonatal Intensive Care Unit, University Hospital of Ioannina, 45500 Ioannina, Greece
*
Author to whom correspondence should be addressed.
Endocrines 2025, 6(2), 28; https://doi.org/10.3390/endocrines6020028
Submission received: 2 January 2025 / Revised: 27 February 2025 / Accepted: 6 May 2025 / Published: 9 June 2025
(This article belongs to the Section Pediatric Endocrinology and Growth Disorders)
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Abstract

:
Mini-puberty refers to the transient activation of the hypothalamic–pituitary–gonadal (HPG) axis during early infancy, lasting up to six months in boys and 12–24 months in girls. This phase represents the second activation of the HPG axis, following its initial activation during the second half of fetal life. At birth, the removal of the suppressive effect of placental estrogens on the HPG axis prompts a rise in both gonadotropins and sex steroid hormones, resulting in distinct clinical and laboratory markers of mini-puberty. While the clinical significance of mini-puberty remains partially understood, emerging evidence underscores its essential role in several aspects of human growth and development. In boys, testosterone influences penile growth, increases Sertoli cell numbers in the testes, and lays the foundation for future spermatogenesis. In girls, the increase in estradiol levels promotes follicular maturation and stimulates breast and uterine growth. Beyond the gonadal effects, mini-puberty appears to impact body composition, affecting body weight and promoting accelerated growth. Additionally, it may affect early psychosomatic and neural maturation, playing a role in several key aspects of the infantile brain. This narrative review examines recent findings on the physiology of the activation of the HPG axis before and after birth along with its significance in various aspects of human growth and development. In addition, mini-puberty-unique features in specific groups, such as preterm and small-for-gestational-age infants, are presented.

1. Introduction

Throughout the human lifespan, the hypothalamic–pituitary–gonadal (HPG) axis is activated on three distinct occasions: first during fetal development, again in the early postnatal months, during the so-called mini-puberty, and finally at the onset of puberty. The significance of fetal HPG axis activation is partially understood but seems to play a role in genital development, especially in males, as evidenced by the genital underdevelopment seen at birth in patients with congenital hypogonadism [1,2].
The second activation of the HPG axis, occurring in the first few months after birth, has attracted increasing attention in recent years as a focus of scientific research [3,4]. In males, mini-puberty involves a surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a peak in testosterone levels between 1 and 3 months of age. Indeed, testosterone levels reach 100–400 ng/dL (3.5–13.9 nmol/L) which are comparable to early–mid pubertal levels. This testosterone surge contributes to testicular growth, penile development, and the establishment of the Sertoli and Leydig cell populations, which are vital for future spermatogenesis and fertility. In females, mini-puberty is marked by fluctuating levels, mainly of estradiol, which stimulate transient ovarian activity and the formation of antral follicles. However, the exact role of these hormonal changes in female infants remains unclear [5].
Emerging research suggests that the postnatal HPG axis activation may have broader implications beyond reproductive development. For example, it has been implicated as an important factor affecting linear growth and body composition [6]. In both sexes, the hormonal surges during mini-puberty influence neurodevelopment by shaping sex-specific brain structures and neural circuits that affect cognitive and behavioral outcomes [7]. Additionally, the mini-puberty phase may provide a unique window for diagnosing and addressing disorders of sexual development or hormonal dysfunction, while small-for-gestational-age (SGA) and premature infants show some unique hormonal patterns during their mini-puberty [5].
This review examines the activation of the HPG axis during fetal life, delves into its postnatal activation, and summarizes the current knowledge of hormonal changes in the pituitary and gonads. It also highlights the physiological effects of these hormones on target tissues, emphasizing their importance in early development and potential clinical applications, and delineates the unique features of mini-puberty in SGA and premature infants.

2. Hypothalamic–Pituitary–Gonadal Axis Activation During Fetal Life

As early as 40 days after conception, the ∼10,000 neurons that will be responsible for gonadotropin-releasing hormone (GnRH) production appear in the olfactory placode of the developing nose and rapidly migrate, using the olfactory nerve as scaffolding, into the brain along two main migratory pathways (dorsal and ventral). It is noteworthy, not only that the number of GnRH immunoreactive neurons in humans is significantly higher than previously thought, but also that GnRH cells migrate into several extrahypothalamic brain regions in addition to the hypothalamus [8]. GnRH production in the fetal hypothalamus is detected at around 15 weeks of gestation [9,10]. By the end of the first trimester, GnRH neurons have established a complex interconnection both with the gonadotropin-producing neurons of the pituitary and with a wide range of local neuronal networks [11]. This enables them to receive various central and peripheral inputs [12]. In addition, evidence from experimental animal studies suggests that GnRH pulsatile secretion as well as other important functions of GnRH neurons are under the control of the so-called Kisspeptin-Neurokinin B-Dynorphin (KNDy) neuronal network [13,14]. Evidence for KNDy neurons’ role in humans exists but is currently less robust than in other species and has been challenged [15]. For example, it has been shown that mutations in genes encoding neurokinin B or its receptor have been linked to hypogonadotropic hypogonadism [16]. In addition, putative KNDy neurons have been identified in the infundibular nucleus of women [17], but kisspeptin neurons of young men may not coexpress dynorphin [18]. The exact time at which the interconnection between GnRH neurons and the KNDy system is established and the importance of such a connection in humans remains to be elucidated [19]. It is noteworthy that GnRH neurons themselves lack estrogen receptor alpha (ER-alpha). Τhe placenta-produced estrogen suppression of GnRH and gonadotropin production that occurs near birth has been shown to be mediated through the KNDy system [20,21].
At the pituitary level, the gonadotropins LH and FSH can already be detected in the fetal developing pituitary at 9 weeks [22] and in the fetal circulation by 12–14 weeks of gestation [23]. At some point during intrauterine life, gonadotropin secretion becomes fully regulated by the hypothalamic GnRH, but when exactly this happens is unknown. The portal vascular system is present by the end of the first trimester but seems to fully mature much later. A study on anencephalic fetuses that have a functional pituitary but no hypothalamus showed that gonadotropic cells are present up to 18 weeks of gestation, and then gradually involute to disappear by the 32nd week [24]. Another study showed that LH and FSH production is independent of GnRH and kisspeptin levels until mid-gestation and become GnRH-induced after the 30th–31st weeks [25]. These observations suggest that GnRH is essential for gonadotropic cell function from almost mid-gestation onwards. Gonadotropin levels in fetal circulation peak around the 30th week of gestation and gradually decrease until birth, most probably due to the increasing levels of estrogen produced by the placenta which suppresses the fetal HPG axis [26].
Gonadotropin levels differ between the two sexes. During the first half of intrauterine life, female fetuses have higher levels of LH and FSH, both if measured as pituitary content or as serum levels. This difference is mainly attributed to the higher levels of testicular hormones in the male fetal circulation exerting negative feedback on the hypothalamus and pituitary [27]. Another difference is the higher concentration of LH compared to FSH in male fetuses, while the opposite is true for female fetuses [28]. Human chorionic gonadotropin (hCG), which is secreted by the placenta, is also involved in the fetal HPG axis regulation. hCG is structurally and functionally similar to LH, with which it shares a common cellular receptor [29]. hCG levels in the fetus rise during the first trimester, peaking at 8–12 weeks of gestation, and then decrease at a slow rate, remaining quite high until the end of gestation [27].
At the gonad level, the gonadal sex of the fetus is undifferentiated up to the 6th week of gestation. In 46,XY fetuses, the SRY gene on the Y chromosome interacts with a complex network of other genes to activate the testis pathway [30,31]. In this case, placental hCG acts on the testicular mesenchymal cells, transforming them into Leydig cells, which secrete testosterone and anti-Mullerian hormone (AMH) as early as the 8th week of gestation. Testosterone is transformed to its more potent metabolite dihydrotestosterone via the action of the enzyme 5-α reductase, leading to the formation of the prostate, penis, and scrotum. AMH, on the other hand, is important for the regression of Mullerian ducts, thus averting uterus and fallopian tube formation. Between the 10th and 20th week of gestation, testosterone levels peak in the male fetal circulation, reaching almost adult values (40–580 ng/dL) [22]. It should be noted that testosterone production in the fetal testes is regulated initially by the placental hCG and only after the 9th week of gestation does it come under the control of the fetal pituitary LH production. After the 20th week of gestation, testosterone gradually decreases toward term [32]. Regarding pituitary FSH, it seems that it plays a role in Sertoli cell proliferation, since fetal testes have been shown to express FSH receptors, but the relevant literature is scarce [32,33].
In 46,XX fetuses, the absence of the SRY gene, together with the activation of some recently discovered genes, direct toward female gonadal sex [30,31]. The absence of AMH leads to the persistence of Mullerian ducts and the formation of the uterus, the fallopian tubes, and the upper one-third of the vagina. Primordial follicles in the fetal ovaries first appear around the 14th week of gestation [34]. Around the 20th week of gestation, the first primary follicles appear and gradually progress to the antral stage during the third trimester [34,35]. The number of follicles starts to increase around the 14th–15th up until the 34th week of gestation, and then it remains stable [36]. Concerning folliculogenesis during fetal life, the role of fetal estrogens and gonadotropins is not completely understood. Fetal estrogen production seems to play little or no role in follicle maturation, since the largest amount of estrogen during fetal life comes from the placenta. In addition, studies in anencephalic female fetuses have shown that fetal gonadotropins are important in the development of growing antral follicles only after the 34th week of gestation and not before [37]. More studies are needed to identify the importance of fetal LH, FSH, and estrogen production in developing fetal ovaries.

3. Mini-Puberty in Males

Mini-puberty refers to the second activation of the hypothalamic–pituitary–gonadal (HPG) axis which occurs within the first few weeks of life in both boys and girls. Nevertheless, its duration and hormonal patterns differ significantly between the two sexes. In males, LH and FSH levels rise early, stimulating testosterone production, with a peak around 1–3 months but decline by 4–6 months as the HPG axis becomes quiescent. In females, gonadotropin and estradiol levels are higher and remain elevated for a longer period, sometimes persisting up to 12–24 months [38]. Mini-puberty was initially described in boys by Forest et al. in 1973 [39]. It begins immediately after birth with the cessation of placental estrogens’ inhibitory effect on fetal pituitary secretion of FSH and LH (Figure 1). This triggers a rapid rise in testosterone within minutes, peaking at 2 to 3 h after delivery, followed by a decrease within the next 6 to 12 h [40]. Subsequently, all hormones in the HPG axis decline in both sexes for approximately one week and then they start increasing again [41,42]. More specifically, LH levels rise during the second week of life, peaking between weeks 2 and 10, leading to increased testosterone production by Leydig cells [43]. Testosterone levels reach concentrations similar to those in adults at 2 to 3 months, then decrease, returning to low levels by 6 months of age [44]. Notably, testosterone levels during mini-puberty exhibit significant variability [42] but, in any case, seem to play an important role in the continued development of the male external genitalia, particularly of the penis [45]. Furthermore, it has been shown that androgen synthesis during this phase is mainly the result of the backdoor pathway, as metabolites of the Δ4 rather than the Δ5 lyase pathway of steroidogenesis are mainly found in the urine of male infants [46]. As a response to LH surges, Leydig cells produce insulin-like factor 3 (INSL3) with concentrations peaking around one month of age. It has been shown that this peptide is important for testicular descent and for the final placement of the testicles in the scrotum [47].
On the other hand, FSH starts rising after the first week of life, peaks at 10 to 15 days, and gradually declines after three months of life variability [42]. This FSH surge acts upon immature Sertoli cells and germ cells, driving their mitotic proliferation and the development of seminiferous tubules [48,49]. In addition to increasing in number, Sertoli cells support the maturation of gonocytes into spermatogonial stem cells. This increase in cellular proliferation leads to a transient increase in testicular volume, peaking around 4 to 6 months of age, and reaching an increase of up to 40% compared to birth size [42]. This whole activation of the testes seems to be important for future reproductive capacity of the individuals since Sertoli and germ cells play a crucial role in post-pubertal spermatogenesis [42]. Nevertheless, androgen receptors in Sertoli cells start being expressed after one year of age with a gradual increase up to 4 to 5 years of age [50]. This precludes meiotic activity and therefore spermatogenesis in Sertoli cells during mini-puberty, despite the intratesticular testosterone rise [51]. Sertoli cell stimulation by FSH leads to the production of increasing amounts of AMH and inhibin B, with serum concentrations of these peptides peaking around four months and remaining elevated during the early childhood years [41,52].

4. Mini-Puberty in Females

Similarly to males, in females, estradiol levels are elevated in the cord blood at birth but drop rapidly during the first days of life [53]. After the first week of life, estradiol levels begin to rise in girls and remain higher than in boys over the following months [54]. This increase is the result of ovarian stimulation by pituitary gonadotropins and coincides with ovarian follicular development [54,55]. Indeed, it has been shown that estradiol intraovarian concentration is higher during the first 6 months of life [56], and large ovarian follicles are more common during the first 6 to 12 months of life [57]. Parallel to estrogen increase, peptides produced by the granulosa cells, such as AMH and inhibin B, also increase during the mini-puberty gonadotropin surge [44,54]. In contrast to testosterone levels in boys which peak between 1 and 3 months and gradually decline by 6 months, estradiol levels in girls fluctuate, likely due to the cyclic maturation and regression of ovarian follicles [54] (Figure 2). After the first year, estradiol levels start to decline but they never reach the nadir that is observed in boys during childhood when measured with ultrasensitive methods [58].
Regarding estrogen-sensitive tissues, placental estrogens stimulate breast tissue, leading to its presence in most full-term infants [59]. At birth, mammary gland size does not differ between the two sexes, but during infancy, girls display larger mammary glands than boys, probably due to endogenous estrogen stimulation of the breast tissue [54,59,60]. Regarding the uterus, its growth is stimulated prenatally, with rapid size reduction occurring in the months following birth due to the withdrawal of high placental estrogen effect [54,61]. As explained in more detail in the following chapter, premature girls show reduced size of the mammary glands and uterus at birth compared to full-term girls because they miss the peak late intrauterine estrogen exposure [54]. After birth, endogenous estrogen production leads to a more pronounced effect on breast and uterine growth in such girls [54].
The significance of increased reproductive hormones during mini-puberty is well established for male genital development and future fertility. In females, the primordial follicular pool formation occurs before birth and is not affected throughout much of mini-puberty [36]. Estrogen-sensitive organs such as the mammary glands and the uterus increase in size during mini-puberty in female infants as a response to the activation of the HPG axis and estrogen production by the developing ovarian follicles [54,62]. Further, studies on female mouse models suggest that during mini-puberty, gonadotropins are critical for early follicular development and may play additional roles, such as influencing sexual and maternal behaviors, and establishing coordinated GnRH pulsatility [62]. In addition, recent evidence suggests that the nitric oxide (NO) signaling pathway in hypothalamic neurons is essential for regulating the release of GnRH both in female and male humans and mice, and neuronal nitric oxide synthase deficiency can further lead to anosmia, hearing loss, and intellectual disability [63,64]. Despite these data, mini-puberty impact on female gonadal function and fertility remains incompletely understood.

5. Mini-Puberty in Premature and Small-for-Gestational-Age Infants

Mini-puberty is profoundly different in preterm infants compared to that of full-term infants. Several studies have shown that premature boys and girls born between 28 and 32 weeks of gestation experience a higher and more prolonged postnatal LH and FSH increase [65,66]. More specifically, in preterm boys, LH, FSH, and testosterone levels reach significantly higher concentrations than those observed in full-term boys at 1 to 3 months of age [65,67]. This exaggerated mini-puberty results in faster testicular and penile growth in preterm boys compared to their full-term counterparts [67]. Regarding preterm girls, they also display an accentuated HPG axis activity, with FSH levels rising more sharply, peaking at approximately 32 weeks of corrected age and persisting for a longer duration compared to full-term girls [55,65]. Early FSH increase to levels up to 300 times those observed in term girls leads to a transient ovarian stimulation, with several follicles progressing to the antral phase and producing increased amounts of AMH [55].
When the infant is extremely premature, the normal prenatal and postnatal regulation of the HPG axis can be significantly affected and the normal negative feedback loops are very immature. Several cases of extremely premature girls born between 25 and 30 weeks of gestation have been described as having the so-called preterm ovarian hyperstimulation syndrome. First described in 1985 by Sedin et al. [68], this condition is characterized by breast enlargement, swelling of the external genitalia (clitoris, and both labia majora and minora), and vaginal bleeding, along with increased levels of gonadotropins and estradiol and the presence of ovarian cysts [69,70,71]. Interestingly, this syndrome usually self-resolves, while data on its long-term effects on reproductive function are scarce and inconsistent [72].
In SGA boys, birth weight significantly influences the hormonal dynamics of mini-puberty, affecting both the duration of HPG axis activation and testosterone levels. More specifically, Boncompagni et al. [73] have recently shown that male infants born SGA exhibit reduced testosterone levels during mini-puberty compared to their appropriate-for-gestational-age (AGA) peers. Pepe et al. showed that in SGA boys, testosterone levels at 3 months were higher in those born preterm compared to those born term [74]. Both these and earlier studies [75] have shown higher gonadotropin levels in blood and in urine and prolonged HPG axis activation, potentially as a compensatory mechanism. The attenuated testosterone surge in SGA males during mini-puberty could impact the development of male reproductive organs and future fertility potential [76], but the relevant literature is scarce and often contradictory, and therefore further research is needed [77,78,79,80]. Regarding SGA girls, higher serum levels of FSH compared to AGA girls have been identified, along with higher estradiol concentrations at 6 months of age which are negatively correlated with gestational age and weight gain [74]. The heightened gonadotropin and estradiol levels in SGA females during mini-puberty could influence early ovarian follicular development, pubertal tempo, and timing, as well as future reproductive function, but the relevant literature is scarce [81,82,83].

6. Mini-Puberty, Early Linear Growth, and Body Composition

Linear growth has been shown to differ between boys and girls during the first year of life. Indeed, male infants grow in length more rapidly than girls, especially during the first 6 months of life, leading to an average difference of 2,6 cm per year. A study by Kiviranta et al. [6] compared the linear growth of 18,570 healthy boys and girls during their first year of life. In 84 of them, growth velocity was compared with repeated measurements of urinary testosterone, estradiol, and serum IGF-I during the first 6 months. Growth velocity showed a strong positive correlation with testosterone levels in both sexes. Testosterone was higher in boys compared to girls between 7 days and 6 months of age, coinciding with the higher growth velocity in boys observed from birth to 6 months. Further, the highest difference in growth velocity between boys and girls was observed during the first month of life (corresponding to 4.1 cm per year), coinciding with the postnatal testosterone surge in boys. Interestingly, no significant differences in IGF-I levels between the two sexes and no association between IGF-I levels and growth velocity were identified. On the contrary, in a more recent study by Boncompagni et al. [73], no significant correlation between urinary testosterone and growth velocity was found, even if the lack of a postnatal peak of testosterone translated into a slower catch-up growth in full-term SGA neonates. Sex steroid hormones play a well-established role in linear growth during puberty. However, the limited number of studies, their conflicting findings, and the complex interplay of hormonal, nutritional, and genetic factors in early growth prevent a definitive association between mini-puberty and linear growth in infancy.
Regarding body composition, females typically exhibit a lower proportion of lean mass (muscle) and a higher proportion of fat mass compared to males, with gonadal steroids believed to play a central role in this difference. It is not totally clear if this sexual dimorphism in body composition is already present at birth, since the relevant data are conflicting. Some studies suggest that such differences between sexes are already observable at birth, with variations in the HPG axis activation during mid-gestation being responsible [84,85]. On the contrary, other studies have identified no such differences [86,87]. During the first months after birth, it is possible that testosterone level variations play a role in further shaping sex-related body composition differences. For example, in a recent study by Davis et al. [88], total mass, fat-free mass, and percent fat mass were measured by air displacement plethysmography in a large, diverse group of healthy term infants from various ethnic backgrounds. Measurements were performed once between the first and the third days of life and again at five months, and differences between the two sexes were recorded at both time points. Males were found to have greater total mass and fat-free mass but lower percent fat mass compared to females. Between the two time points, fat-free mass increased more in males, with a resultant average difference of 410 g at 5 months of age. On the opposite, females showed a relatively higher increase in percent fat mass.

7. Mini-Puberty and Neurodevelopment

Mini-puberty has been shown to influence the organization and function of the brain in a sex-specific manner. First, testosterone surge in male infants is critical for the masculinization of the brain. More specifically, it shapes the hypothalamic structures involved in regulating reproductive behaviors, including the establishment of GnRH pulsatility [3,89]. In addition, it contributes to differences in gray and white matter distribution and cortical thickness which are later reflected in specifically male or female cognitive and behavioral patterns [7,90]. Further, sex steroid hormones during mini-puberty influence cognitive and behavioral outcomes by shaping neural circuits involved in learning, memory, and social behaviors. For example, testosterone levels have been linked to social cognitive abilities, such as face processing and empathy, particularly in boys [91]. In girls, estradiol fluctuations during mini-puberty may influence the early development of emotional regulation and social bonding circuits [92]. Another important role of sex hormones during mini-puberty is the facilitation of neural network organization in a period coinciding of heightened brain plasticity. Indeed, it has been shown that testosterone and estradiol enhance synaptogenesis, dendritic growth, and myelination during mini-puberty, processes critical for efficient neural communication [62,89].
Beyond the critical role of sex steroids, other hormones of the HPG axis have been implicated in early neuronal maturation. Notably, GnRH functions not only as a controller of axis activation but also as a key neuromodulator influencing brain development and cognition [93]. As already described, GnRH neurons are scattered and project beyond the hypothalamus to regions such as the hippocampus, the amygdala, and the prefrontal cortex [94,95]. GnRH pulses seem to influence neurogenesis, synaptic plasticity, and cognitive function. Defects in GnRH neuron migration and development such as the ones occurring in Kallmann syndrome have been shown to be associated with cognitive deficits and neurodevelopmental defects [96]. It is noteworthy that in a recent study by Manfredi-Lozano et al. [97], it was shown that restoring physiological GnRH levels abolishes olfactory and cognitive defects in a Down syndrome mouse model (Ts65Dn), while pulsatile GnRH therapy improves cognition and brain connectivity in adult Down syndrome patients. These results suggest that GnRH neuronal activity during mini-puberty could play a crucial role in early neurodevelopment. Closely intertwined with the GnRH system, the NO signaling pathway serves as a key neuromodulator, fine-tuning neuronal differentiation and synaptic function. Disruption of neuronal NO synthase (NOS1) activity has been linked to hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice [64], suggesting that this system may play a crucial role as early as during mini-puberty in shaping brain development [89].

8. Diagnosing Mini-Puberty Abnormalities

The evaluation of infants with potential mini-puberty alterations requires precise diagnostic approaches and is not always straightforward. Baseline hormone measurements (such as LH, FSH and testosterone in males, estradiol in females) are informative, but they are not routinely performed in all infants, and they may not always capture subtle dysfunctions of the HPG axis during this period. The GnRH stimulation test, commonly employed in assessing conditions like precocious puberty or hypogonadism [98], has been considered for evaluating mini-puberty [99]. However, its utility in neonates and infants is debated since the lack of standardized reference ranges for stimulated LH and FSH levels in this age group and the invasiveness of the procedure limit its routine application. Therefore, a comprehensive clinical evaluation for signs of defective mini-puberty (such as maldescended testes or micropenis in male infants), especially in high-risk cases followed by baseline hormonal assessment and, when appropriate, dynamic testing, is recommended to accurately diagnose and understand deviations in mini-puberty [38].

9. Conclusions

It is well established that during mid-gestation, the HPG axis of the fetus becomes increasingly active but is gradually suppressed as birth approaches due to the inhibitory effects of placental hormones on the fetal hypothalamus. At birth, with the removal of this suppression, the HPG axis is reactivated. This reactivation leads to a testosterone surge in males, peaking between 1 and 3 months of age, while in females, estradiol levels show fluctuations until around 6 months, with a gradual decrease afterwards. Mini-puberty plays a vital role in the maturation of the genital organs and seems to create the conditions needed for future fertility. However, its precise significance, particularly in females, remains unclear and requires further investigation. Similarly, the mechanisms through which the HPG axis becomes quiescent after mini-puberty and remains inactive until puberty are not yet fully understood. Finally, mini-puberty offers a critical window to explore potential clinical implications, particularly for specific patient groups such as preterm or small-for-gestational-age infants. Further studies are needed to clarify the clinical significance and the potential implications of mini-puberty alterations in such specific populations.

Author Contributions

Conceptualization, A.S. and V.G.; methodology, A.S., D.R. and C.K.; investigation, K.-M.L., N.A. and L.-E.G.; resources, K.-M.L., N.A. and L.-E.G.; writing—original draft preparation, A.S. and C.K.; writing—review and editing, V.G. and D.R.; supervision, A.S. and V.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not available.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AMHAnti-Mullerian hormone
HPGHypothalamic–pituitary–gonadal
FSHFollicle-stimulating hormone
LHLuteinizing hormone
SGASmall for gestational age
GnRHGonadotropin-releasing hormone
KNDyKisspeptin-Neurokinin B-Dynorphin
hCGHuman chorionic gonadotropin

References

  1. Grinspon, R.P.; Bergadá, I.; Rey, R.A. Male Hypogonadism and Disorders of Sex Development. Front. Endocrinol. 2020, 11, 211. [Google Scholar] [CrossRef]
  2. Sheng, J.A.; Bales, N.J.; Myers, S.A.; Bautista, A.I.; Roueinfar, M.; Hale, T.M.; Handa, R.J. The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions. Front. Behav. Neurosci. 2020, 14, 601939. [Google Scholar] [CrossRef]
  3. Kuiri-Hänninen, T.; Sankilampi, U.; Dunkel, L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: Minipuberty. Horm. Res. Paediatr. 2014, 82, 73–80. [Google Scholar] [CrossRef]
  4. Becker, M.; Hesse, V. Minipuberty: Why Does it Happen? Horm. Res. Paediatr. 2020, 93, 76–84. [Google Scholar] [CrossRef]
  5. Lanciotti, L.; Cofini, M.; Leonardi, A.; Penta, L.; Esposito, S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front. Endocrinol. 2018, 9, 410. [Google Scholar] [CrossRef]
  6. Kiviranta, P.; Kuiri-Hänninen, T.; Saari, A.; Lamidi, M.L.; Dunkel, L.; Sankilampi, U. Transient Postnatal Gonadal Activation and Growth Velocity in Infancy. Pediatrics 2016, 138, e20153561. [Google Scholar] [CrossRef]
  7. Hines, M.; Spencer, D.; Kung, K.T.; Browne, W.V.; Constantinescu, M.; Noorderhaven, R.M. The early postnatal period, mini-puberty, provides a window on the role of testosterone in human neurobehavioural development. Curr. Opin. Neurobiol. 2016, 38, 69–73. [Google Scholar] [CrossRef]
  8. Casoni, F.; Malone, S.A.; Belle, M.; Luzzati, F.; Collier, F.; Allet, C.; Hrabovszky, E.; Rasika, S.; Prevot, V.; Chédotal, A.; et al. Development of the neurons controlling fertility in humans: New insights from 3D imaging and transparent fetal brains. Development 2016, 143, 3969–3981. [Google Scholar] [CrossRef]
  9. Balasubramanian, R.; Dwyer, A.; Seminara, S.B.; Pitteloud, N.; Kaiser, U.B.; Crowley, W.F., Jr. Human GnRH deficiency: A unique disease model to unravel the ontogeny of GnRH neurons. Neuroendocrinology 2010, 92, 81–99. [Google Scholar] [CrossRef]
  10. Schwanzel-Fukuda, M.; Crossin, K.L.; Pfaff, D.W.; Bouloux, P.M.; Hardelin, J.P.; Petit, C. Migration of luteinizing hormone-releasing hormone (LHRH) neurons in early human embryos. J. Comp. Neurol. 1996, 366, 547–557. [Google Scholar] [CrossRef]
  11. Hrabovszky, E.; Molnár, C.S.; Nagy, R.; Vida, B.; Borsay, B.; Rácz, K.; Herczeg, L.; Watanabe, M.; Kalló, I.; Liposits, Z. Glutamatergic and GABAergic innervation of human gonadotropin-releasing hormone-I neurons. Endocrinology 2012, 153, 2766–2776. [Google Scholar] [CrossRef]
  12. Maeda, K.; Ohkura, S.; Uenoyama, Y.; Wakabayashi, Y.; Oka, Y.; Tsukamura, H.; Okamura, H. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. 2010, 1364, 103–115. [Google Scholar] [CrossRef]
  13. Uenoyama, Y.; Nagae, M.; Tsuchida, H.; Inoue, N.; Tsukamura, H. Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction. Front. Endocrinol. 2021, 12, 724632. [Google Scholar] [CrossRef]
  14. Velasco, I.; Franssen, D.; Daza-Dueñas, S.; Skrapits, K.; Takács, S.; Torres, E.; Rodríguez-Vazquez, E.; Ruiz-Cruz, M.; León, S.; Kukoricza, K.; et al. Dissecting the KNDy hypothesis: KNDy neuron-derived kisspeptins are dispensable for puberty but essential for preserved female fertility and gonadotropin pulsatility. Metabolism 2023, 144, 155556. [Google Scholar] [CrossRef]
  15. Mills, E.G.; Dhillo, W.S. Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health. J. Neuroendocrinol. 2022, 34, e13201. [Google Scholar] [CrossRef]
  16. Topaloglu, A.K.; Reimann, F.; Guclu, M.; Yalin, A.S.; Kotan, L.D.; Porter, K.M.; Serin, A.; Mungan, N.O.; Cook, J.R.; Imamoglu, S.; et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat. Genet. 2009, 41, 354–358. [Google Scholar] [CrossRef]
  17. Rometo, A.M.; Rance, N.E. Changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women. J. Neuroendocrinol. 2008, 20, 1376–1381. [Google Scholar] [CrossRef]
  18. Hrabovszky, E.; Sipos, M.T.; Molnár, C.S.; Ciofi, P.; Borsay, B.; Gergely, P.; Herczeg, L.; Bloom, S.R.; Ghatei, M.A.; Dhillo, W.S.; et al. Low degree of overlap between kisspeptin, neurokinin B, and dynorphin immunoreactivities in the infundibular nucleus of young male human subjects challenges the KNDy neuron concept. Endocrinology 2012, 153, 4978–4989. [Google Scholar] [CrossRef]
  19. Beltramo, M.; Dardente, H.; Cayla, X.; Caraty, A. Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin. Mol. Cell. Endocrinol. 2014, 382, 387–399. [Google Scholar] [CrossRef]
  20. Tena-Sempere, M. Hypothalamic KiSS-1: The missing link in gonadotropin feedback control? Endocrinology 2005, 146, 3683–3685. [Google Scholar] [CrossRef]
  21. Mittelman-Smith, M.A.; Williams, H.; Krajewski-Hall, S.J.; Lai, J.; Ciofi, P.; McMullen, N.T.; Rance, N.E. Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 2012, 153, 2800–2812. [Google Scholar] [CrossRef]
  22. Clements, J.A.; Reyes, F.I.; Winter, J.S.; Faiman, C. Studies on human sexual development. III. Fetal pituitary and serum, and amniotic fluid concentrations of LH, CG, and FSH. J. Clin. Endocrinol. Metab. 1976, 42, 9–19. [Google Scholar] [CrossRef]
  23. Schwanzel-Fukuda, M.; Pfaff, D.W. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989, 338, 161–164. [Google Scholar] [CrossRef]
  24. Pilavdzic, D.; Kovacs, K.; Asa, S.L. Pituitary morphology in anencephalic human fetuses. Neuroendocrinology 1997, 65, 164–172. [Google Scholar] [CrossRef]
  25. Guimiot, F.; Chevrier, L.; Dreux, S.; Chevenne, D.; Caraty, A.; Delezoide, A.L.; de Roux, N. Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. J. Clin. Endocrinol. Metab. 2012, 97, E2221–E2229. [Google Scholar] [CrossRef]
  26. Massa, G.; de Zegher, F.; Vanderschueren-Lodeweyckx, M. Serum levels of immunoreactive inhibin, FSH, and LH in human infants at preterm and term birth. Biol. Neonate 1992, 61, 150–155. [Google Scholar] [CrossRef]
  27. Takagi, S.; Yoshida, T.; Tsubata, K.; Ozaki, H.; Fujii, T.K.; Nomura, Y.; Sawada, M. Sex differences in fetal gonadotropins and androgens. J. Steroid Biochem. 1977, 8, 609–620. [Google Scholar] [CrossRef]
  28. Debieve, F.; Beerlandt, S.; Hubinont, C.; Thomas, K. Gonadotropins, prolactin, inhibin A, inhibin B, and activin A in human fetal serum from midpregnancy and term pregnancy. J. Clin. Endocrinol. Metab. 2000, 85, 270–274. [Google Scholar] [CrossRef]
  29. Casarini, L.; Santi, D.; Brigante, G.; Simoni, M. Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG. Endocr. Rev. 2018, 39, 549–592. [Google Scholar] [CrossRef]
  30. Pitetti, J.L.; Calvel, P.; Romero, Y.; Conne, B.; Truong, V.; Papaioannou, M.D.; Schaad, O.; Docquier, M.; Herrera, P.L.; Wilhelm, D.; et al. Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice. PLoS Genet. 2013, 9, e1003160. [Google Scholar] [CrossRef]
  31. O’Rahilly, R. The timing and sequence of events in the development of the human reproductive system during the embryonic period proper. Anat. Embryol. 1983, 166, 247–261. [Google Scholar] [CrossRef] [PubMed]
  32. Reyes, F.I.; Boroditsky, R.S.; Winter, J.S.; Faiman, C. Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. J. Clin. Endocrinol. Metab. 1974, 38, 612–617. [Google Scholar] [CrossRef]
  33. O’Shaughnessy, P.J.; Baker, P.J.; Monteiro, A.; Cassie, S.; Bhattacharya, S.; Fowler, P.A. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J. Clin. Endocrinol. Metab. 2007, 92, 4792–4801. [Google Scholar] [CrossRef] [PubMed]
  34. Kurilo, L.F. Oogenesis in antenatal development in man. Hum. Genet. 1981, 57, 86–92. [Google Scholar] [CrossRef]
  35. Cole, B.; Hensinger, K.; Maciel, G.A.; Chang, R.J.; Erickson, G.F. Human fetal ovary development involves the spatiotemporal expression of p450c17 protein. J. Clin. Endocrinol. Metab. 2006, 91, 3654–3661. [Google Scholar] [CrossRef]
  36. Forabosco, A.; Sforza, C. Establishment of ovarian reserve: A quantitative morphometric study of the developing human ovary. Fertil. Steril. 2007, 88, 675–683. [Google Scholar] [CrossRef]
  37. Baker, T.G.; Scrimgeour, J.B. Development of the gonad in normal and anencephalic human fetuses. J. Reprod. Fertil. 1980, 60, 193–199. [Google Scholar] [CrossRef] [PubMed]
  38. Rohayem, J.; Alexander, E.C.; Heger, S.; Nordenström, A.; Howard, S.R. Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement. Endocr. Rev. 2024, 45, 460–492. [Google Scholar] [CrossRef]
  39. Forest, M.G.; Cathiard, A.M.; Bertrand, J.A. Evidence of testicular activity in early infancy. J. Clin. Endocrinol. Metab. 1973, 37, 148–151. [Google Scholar] [CrossRef]
  40. Corbier, P.; Dehennin, L.; Castanier, M.; Mebazaa, A.; Edwards, D.A.; Roffi, J. Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J. Clin. Endocrinol. Metab. 1990, 71, 1344–1348. [Google Scholar] [CrossRef]
  41. Bergadá, I.; Milani, C.; Bedecarrás, P.; Andreone, L.; Ropelato, M.G.; Gottlieb, S.; Bergadá, C.; Campo, S.; Rey, R.A. Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life. J. Clin. Endocrinol. Metab. 2006, 91, 4092–4098. [Google Scholar] [CrossRef] [PubMed]
  42. Busch, A.S.; Ljubicic, M.L.; Upners, E.N.; Fischer, M.B.; Raket, L.L.; Frederiksen, H.; Albrethsen, J.; Johannsen, T.H.; Hagen, C.P.; Juul, A. Dynamic Changes of Reproductive Hormones in Male Minipuberty: Temporal Dissociation of Leydig and Sertoli Cell Activity. J. Clin. Endocrinol. Metab. 2022, 107, 1560–1568. [Google Scholar] [CrossRef] [PubMed]
  43. Schmidt, H.; Schwarz, H.P. Serum concentrations of LH and FSH in the healthy newborn. Eur. J. Endocrinol. 2000, 143, 213–215. [Google Scholar] [CrossRef]
  44. Andersson, A.M.; Toppari, J.; Haavisto, A.M.; Petersen, J.H.; Simell, T.; Simell, O.; Skakkebaek, N.E. Longitudinal reproductive hormone profiles in infants: Peak of inhibin B levels in infant boys exceeds levels in adult men. J. Clin. Endocrinol. Metab. 1998, 83, 675–681. [Google Scholar] [CrossRef]
  45. Boas, M.; Boisen, K.A.; Virtanen, H.E.; Kaleva, M.; Suomi, A.M.; Schmidt, I.M.; Damgaard, I.N.; Kai, C.M.; Chellakooty, M.; Skakkebaek, N.E.; et al. Postnatal penile length and growth rate correlate to serum testosterone levels: A longitudinal study of 1962 normal boys. Eur. J. Endocrinol. 2006, 154, 125–129. [Google Scholar] [CrossRef]
  46. Dhayat, N.A.; Dick, B.; Frey, B.M.; d’Uscio, C.H.; Vogt, B.; Flück, C.E. Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome. J. Steroid Biochem. Mol. Biol. 2017, 165, 312–322. [Google Scholar] [CrossRef] [PubMed]
  47. Bay, K.; Virtanen, H.E.; Hartung, S.; Ivell, R.; Main, K.M.; Skakkebaek, N.E.; Andersson, A.M.; Toppari, J. Insulin-like factor 3 levels in cord blood and serum from children: Effects of age, postnatal hypothalamic-pituitary-gonadal axis activation, and cryptorchidism. J. Clin. Endocrinol. Metab. 2007, 92, 4020–4027. [Google Scholar] [CrossRef]
  48. Burton, E.; Abeydeera, S.A.; Sarila, G.; Cho, H.J.; Wu, S.; Tien, M.Y.; Hutson, J.; Li, R. The role of gonadotrophins in gonocyte transformation during minipuberty. Pediatr. Surg. Int. 2020, 36, 1379–1385. [Google Scholar] [CrossRef]
  49. Simorangkir, D.R.; Marshall, G.R.; Plant, T.M. Sertoli cell proliferation during prepubertal development in the rhesus monkey (Macaca mulatta) is maximal during infancy when gonadotropin secretion is robust. J. Clin. Endocrinol. Metab. 2003, 88, 4984–4989. [Google Scholar] [CrossRef]
  50. Chemes, H.E.; Rey, R.A.; Nistal, M.; Regadera, J.; Musse, M.; González-Peramato, P.; Serrano, A. Physiological androgen insensitivity of the fetal, neonatal, and early infantile testis is explained by the ontogeny of the androgen receptor expression in Sertoli cells. J. Clin. Endocrinol. Metab. 2008, 93, 4408–4412. [Google Scholar] [CrossRef]
  51. Rey, R.A. Mini-puberty and true puberty: Differences in testicular function. Ann. Endocrinol. 2014, 75, 58–63. [Google Scholar] [CrossRef] [PubMed]
  52. Aksglaede, L.; Sørensen, K.; Boas, M.; Mouritsen, A.; Hagen, C.P.; Jensen, R.B.; Petersen, J.H.; Linneberg, A.; Andersson, A.M.; Main, K.M.; et al. Changes in anti-Müllerian hormone (AMH) throughout the life span: A population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J. Clin. Endocrinol. Metab. 2010, 95, 5357–5364. [Google Scholar] [CrossRef] [PubMed]
  53. Winter, J.S.; Hughes, I.A.; Reyes, F.I.; Faiman, C. Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J. Clin. Endocrinol. Metab. 1976, 42, 679–686. [Google Scholar] [CrossRef] [PubMed]
  54. Kuiri-Hänninen, T.; Haanpää, M.; Turpeinen, U.; Hämäläinen, E.; Seuri, R.; Tyrväinen, E.; Sankilampi, U.; Dunkel, L. Postnatal ovarian activation has effects in estrogen target tissues in infant girls. J. Clin. Endocrinol. Metab. 2013, 98, 4709–4716. [Google Scholar] [CrossRef]
  55. Kuiri-Hänninen, T.; Kallio, S.; Seuri, R.; Tyrväinen, E.; Liakka, A.; Tapanainen, J.; Sankilampi, U.; Dunkel, L. Postnatal developmental changes in the pituitary-ovarian axis in preterm and term infant girls. J. Clin. Endocrinol. Metab. 2011, 96, 3432–3439. [Google Scholar] [CrossRef]
  56. Bidlingmaier, F.; Strom, T.M.; Dörr, H.G.; Eisenmenger, W.; Knorr, D. Estrone and estradiol concentrations in human ovaries, testes, and adrenals during the first two years of life. J. Clin. Endocrinol. Metab. 1987, 65, 862–867. [Google Scholar] [CrossRef]
  57. Cohen, H.L.; Shapiro, M.A.; Mandel, F.S.; Shapiro, M.L. Normal ovaries in neonates and infants: A sonographic study of 77 patients 1 day to 24 months old. AJR Am. J. Roentgenol. 1993, 160, 583–586. [Google Scholar] [CrossRef]
  58. Courant, F.; Aksglaede, L.; Antignac, J.P.; Monteau, F.; Sorensen, K.; Andersson, A.M.; Skakkebaek, N.E.; Juul, A.; Bizec, B.L. Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method. J. Clin. Endocrinol. Metab. 2010, 95, 82–92. [Google Scholar] [CrossRef]
  59. Jayasinghe, Y.; Cha, R.; Horn-Ommen, J.; O’Brien, P.; Simmons, P.S. Establishment of normative data for the amount of breast tissue present in healthy children up to two years of age. J. Pediatr. Adolesc. Gynecol. 2010, 23, 305–311. [Google Scholar] [CrossRef]
  60. Schmidt, I.M.; Chellakooty, M.; Haavisto, A.M.; Boisen, K.A.; Damgaard, I.N.; Steendahl, U.; Toppari, J.; Skakkebaek, N.E.; Main, K.M. Gender difference in breast tissue size in infancy: Correlation with serum estradiol. Pediatr. Res. 2002, 52, 682–686. [Google Scholar] [CrossRef]
  61. Nguyen, R.H.; Umbach, D.M.; Parad, R.B.; Stroehla, B.; Rogan, W.J.; Estroff, J.A. US assessment of estrogen-responsive organ growth among healthy term infants: Piloting methods for assessing estrogenic activity. Pediatr. Radiol. 2011, 41, 633–642. [Google Scholar] [CrossRef] [PubMed]
  62. Devillers, M.M.; Mhaouty-Kodja, S.; Guigon, C.J. Deciphering the Roles & Regulation of Estradiol Signaling During Female Mini-Puberty: Insights from Mouse Models. Int. J. Mol. Sci. 2022, 23, 13695. [Google Scholar] [CrossRef]
  63. Delli, V.; Dehame, J.; Franssen, D.; Rasika, S.; Parent, A.S.; Prevot, V.; Chachlaki, K. Male minipuberty involves the gonad-independent activation of preoptic nNOS neurons. Free Radic. Biol. Med. 2023, 194, 199–208. [Google Scholar] [CrossRef]
  64. Chachlaki, K.; Messina, A.; Delli, V.; Leysen, V.; Maurnyi, C.; Huber, C.; Ternier, G.; Skrapits, K.; Papadakis, G.; Shruti, S.; et al. NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice. Sci. Transl. Med. 2022, 14, eabh2369. [Google Scholar] [CrossRef] [PubMed]
  65. Tapanainen, J.; Koivisto, M.; Vihko, R.; Huhtaniemi, I. Enhanced activity of the pituitary-gonadal axis in premature human infants. J. Clin. Endocrinol. Metab. 1981, 52, 235–238. [Google Scholar] [CrossRef] [PubMed]
  66. Shinkawa, O.; Furuhashi, N.; Fukaya, T.; Suzuki, M.; Kono, H.; Tachibana, Y. Changes of serum gonadotropin levels and sex differences in premature and mature infant during neonatal life. J. Clin. Endocrinol. Metab. 1983, 56, 1327–1331. [Google Scholar] [CrossRef]
  67. Kuiri-Hänninen, T.; Seuri, R.; Tyrväinen, E.; Turpeinen, U.; Hämäläinen, E.; Stenman, U.H.; Dunkel, L.; Sankilampi, U. Increased activity of the hypothalamic-pituitary-testicular axis in infancy results in increased androgen action in premature boys. J. Clin. Endocrinol. Metab. 2011, 96, 98–105. [Google Scholar] [CrossRef]
  68. Sedin, G.; Bergquist, C.; Lindgren, P.G. Ovarian hyperstimulation syndrome in preterm infants. Pediatr. Res. 1985, 19, 548–552. [Google Scholar] [CrossRef]
  69. Lee, Y.L.; Jamli, F.M. Preterm ovarian hyperstimulation syndrome presenting as clitoromegaly in a premature female infant. Arch. Dis. Child. 2022, 107, 166–167. [Google Scholar] [CrossRef]
  70. Mosallanejad, A.; Tabatabai, S.; Shakiba, M.; Alaei, M.R.; Saneifard, H. A Rare Case of Ovarian Hyperstimulation Syndrome in a Preterm Infant. J. Clin. Diagn. Res. 2016, 10, Sd07–Sd08. [Google Scholar] [CrossRef]
  71. Altuntas, N.; Turkyilmaz, C.; Yuce, O.; Kulali, F.; Hirfanoglu, I.M.; Onal, E.; Ergenekon, E.; Koç, E.; Bideci, A.; Atalay, Y. Preterm ovarian hyperstimulation syndrome presented with vaginal bleeding: A case report. J. Pediatr. Endocrinol. Metab. 2014, 27, 355–358. [Google Scholar] [CrossRef] [PubMed]
  72. Sun, Y.; Chen, C.; Di, T.; Zhu, Y.; Zhu, R.; Chen, S.; Qian, Y. Clinical characteristics of preterm ovarian hyperstimulation syndrome: Seven cases from China and 14 cases from the literature. Gynecol. Endocrinol. 2019, 35, 819–824. [Google Scholar] [CrossRef] [PubMed]
  73. Boncompagni, A.; Pietrella, E.; Passini, E.; Grisolia, C.; Tagliazucchi, M.; Tagliafico, E.; Lugli, L.; Berardi, A.; Iughetti, L.; Lucaccioni, L. Minipuberty in Male Full-term Neonates Appropriate and Small for Gestational Age and in Preterm Babies: Data from a Single Centre. J. Clin. Res. Pediatr. Endocrinol. 2024, 16, 50–59. [Google Scholar] [CrossRef]
  74. Pepe, G.; Calafiore, M.; Velletri, M.R.; Corica, D.; Valenzise, M.; Mondello, I.; Alibrandi, A.; Wasniewska, M.; Aversa, T. Minipuberty in born small for gestational age infants: A case control prospective pilot study. Endocrine 2022, 76, 465–473. [Google Scholar] [CrossRef]
  75. Nagai, S.; Kawai, M.; Myowa-Yamakoshi, M.; Morimoto, T.; Matsukura, T.; Heike, T. Gonadotropin levels in urine during early postnatal period in small for gestational age preterm male infants with fetal growth restriction. J. Perinatol. 2017, 37, 843–847. [Google Scholar] [CrossRef]
  76. Thorsted, A.; Lauridsen, J.; Høyer, B.; Arendt, L.H.; Bech, B.; Toft, G.; Hougaard, K.; Olsen, J.; Bonde, J.P.; Ramlau-Hansen, C. Birth weight for gestational age and the risk of infertility: A Danish cohort study. Hum. Reprod. 2020, 35, 195–202. [Google Scholar] [CrossRef] [PubMed]
  77. Kerkhof, G.F.; Leunissen, R.W.; Willemsen, R.H.; de Jong, F.H.; Stijnen, T.; Hokken-Koelega, A.C. Influence of preterm birth and birth size on gonadal function in young men. J. Clin. Endocrinol. Metab. 2009, 94, 4243–4250. [Google Scholar] [CrossRef]
  78. Boonstra, V.H.; Weber, R.F.; de Jong, F.H.; Hokken-Koelega, A.C. Testis function in prepubertal boys and young men born small for gestational age. Horm. Res. 2008, 70, 357–363. [Google Scholar] [CrossRef]
  79. Jensen, R.B.; Vielwerth, S.; Larsen, T.; Greisen, G.; Veldhuis, J.; Juul, A. Pituitary-gonadal function in adolescent males born appropriate or small for gestational age with or without intrauterine growth restriction. J. Clin. Endocrinol. Metab. 2007, 92, 1353–1357. [Google Scholar] [CrossRef]
  80. Meng, F.; Yao, M.; Li, S.; Tian, A.; Zhang, C.; Luo, X. The impact of impaired intrauterine growth on male fertility: A systematic review and meta-analysis. Andrology 2024, 12, 1651–1660. [Google Scholar] [CrossRef]
  81. Verkauskiene, R.; Petraitiene, I.; Albertsson Wikland, K. Puberty in children born small for gestational age. Horm. Res. Paediatr. 2013, 80, 69–77. [Google Scholar] [CrossRef] [PubMed]
  82. Meas, T.; Deghmoun, S.; Lévy-Marchal, C.; Bouyer, J. Fertility is not altered in young adults born small for gestational age. Hum. Reprod. 2010, 25, 2354–2359. [Google Scholar] [CrossRef] [PubMed]
  83. Lorthe, E.; Benhammou, V.; Marchand-Martin, L.; Pierrat, V.; Lebeaux, C.; Durox, M.; Goffinet, F.; Kaminski, M.; Ancel, P.Y. Cohort Profile: The Etude Epidémiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort. Int. J. Epidemiol. 2021, 50, 1428–1429m. [Google Scholar] [CrossRef]
  84. Fields, D.A.; Gilchrist, J.M.; Catalano, P.M.; Giannì, M.L.; Roggero, P.M.; Mosca, F. Longitudinal body composition data in exclusively breast-fed infants: A multicenter study. Obesity 2011, 19, 1887–1891. [Google Scholar] [CrossRef]
  85. Fomon, S.J.; Nelson, S.E. Body composition of the male and female reference infants. Annu. Rev. Nutr. 2002, 22, 1–17. [Google Scholar] [CrossRef]
  86. Andersen, G.S.; Girma, T.; Wells, J.C.; Kæstel, P.; Leventi, M.; Hother, A.L.; Michaelsen, K.F.; Friis, H. Body composition from birth to 6 mo of age in Ethiopian infants: Reference data obtained by air-displacement plethysmography. Am. J. Clin. Nutr. 2013, 98, 885–894. [Google Scholar] [CrossRef]
  87. Jain, V.; Kurpad, A.V.; Kumar, B.; Devi, S.; Sreenivas, V.; Paul, V.K. Body composition of term healthy Indian newborns. Eur. J. Clin. Nutr. 2016, 70, 488–493. [Google Scholar] [CrossRef] [PubMed]
  88. Davis, S.M.; Kaar, J.L.; Ringham, B.M.; Hockett, C.W.; Glueck, D.H.; Dabelea, D. Sex differences in infant body composition emerge in the first 5 months of life. J. Pediatr. Endocrinol. Metab. 2019, 32, 1235–1239. [Google Scholar] [CrossRef]
  89. Chachlaki, K.; Le Duc, K.; Storme, L.; Prevot, V. Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics. J. Neuroendocrinol. 2024, 36, e13387. [Google Scholar] [CrossRef]
  90. Kung, K.T.; Browne, W.V.; Constantinescu, M.; Noorderhaven, R.M.; Hines, M. Early postnatal testosterone predicts sex-related differences in early expressive vocabulary. Psychoneuroendocrinology 2016, 68, 111–116. [Google Scholar] [CrossRef]
  91. Lombardo, M.V.; Ashwin, E.; Auyeung, B.; Chakrabarti, B.; Taylor, K.; Hackett, G.; Bullmore, E.T.; Baron-Cohen, S. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J. Neurosci. 2012, 32, 674–680. [Google Scholar] [CrossRef] [PubMed]
  92. Hines, M.; Constantinescu, M.; Spencer, D. Early androgen exposure and human gender development. Biol. Sex. Differ. 2015, 6, 3. [Google Scholar] [CrossRef]
  93. Prévot, V.; Tena-Sempere, M.; Pitteloud, N. New Horizons: Gonadotropin-Releasing Hormone and Cognition. J. Clin. Endocrinol. Metab. 2023, 108, 2747–2758. [Google Scholar] [CrossRef]
  94. Roa, J.; Tena-Sempere, M. Unique Features of a Unique Cell: The Wonder World of GnRH Neurons. Endocrinology 2018, 159, 3895–3896. [Google Scholar] [CrossRef]
  95. Campbell, R.E.; Coolen, L.M.; Hoffman, G.E.; Hrabovszky, E. Highlights of neuroanatomical discoveries of the mammalian gonadotropin-releasing hormone system. J. Neuroendocrinol. 2022, 34, e13115. [Google Scholar] [CrossRef] [PubMed]
  96. Kałużna, M.; Budny, B.; Rabijewski, M.; Kałużny, J.; Dubiel, A.; Trofimiuk-Müldner, M.; Wrotkowska, E.; Hubalewska-Dydejczyk, A.; Ruchała, M.; Ziemnicka, K. Defects in GnRH Neuron Migration/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome. Genes 2021, 12, 868. [Google Scholar] [CrossRef]
  97. Manfredi-Lozano, M.; Leysen, V.; Adamo, M.; Paiva, I.; Rovera, R.; Pignat, J.M.; Timzoura, F.E.; Candlish, M.; Eddarkaoui, S.; Malone, S.A.; et al. GnRH replacement rescues cognition in Down syndrome. Science 2022, 377, eabq4515. [Google Scholar] [CrossRef] [PubMed]
  98. Ab Rahim, S.N.; Omar, J.; Tuan Ismail, T.S. Gonadotropin-releasing hormone stimulation test and diagnostic cutoff in precocious puberty: A mini review. Ann. Pediatr. Endocrinol. Metab. 2020, 25, 152–155. [Google Scholar] [CrossRef]
  99. Starzyk, J.; Wójcik, M.; Wojtyś, J.; Tomasik, P.; Mitkowska, Z.; Pietrzyk, J.J. Ovarian hyperstimulation syndrome in newborns--a case presentation and literature review. Horm. Res. 2009, 71, 60–64. [Google Scholar] [CrossRef]
Endocrines 06 00028 g001
Figure 1. Schematic representation of LH, FSH, and testosterone changes during fetal and early infantile life in healthy boys. FSH: follicle-stimulating hormone, LH: luteinizing hormone.
Figure 1. Schematic representation of LH, FSH, and testosterone changes during fetal and early infantile life in healthy boys. FSH: follicle-stimulating hormone, LH: luteinizing hormone.
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Figure 2. Schematic representation of LH, FSH, and estradiol changes during fetal and early infantile life in healthy girls. FSH: follicle-stimulating hormone, LH: luteinizing hormone.
Figure 2. Schematic representation of LH, FSH, and estradiol changes during fetal and early infantile life in healthy girls. FSH: follicle-stimulating hormone, LH: luteinizing hormone.
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Serbis, A.; Kosmeri, C.; Atzemoglou, N.; Lampropoulou, K.-M.; Giaprou, L.-E.; Rallis, D.; Giapros, V. Decoding Mini-Puberty and Its Clinical Significance: A Narrative Review. Endocrines 2025, 6, 28. https://doi.org/10.3390/endocrines6020028

AMA Style

Serbis A, Kosmeri C, Atzemoglou N, Lampropoulou K-M, Giaprou L-E, Rallis D, Giapros V. Decoding Mini-Puberty and Its Clinical Significance: A Narrative Review. Endocrines. 2025; 6(2):28. https://doi.org/10.3390/endocrines6020028

Chicago/Turabian Style

Serbis, Anastasios, Chrysoula Kosmeri, Natalia Atzemoglou, Katerina-Marina Lampropoulou, Lida-Eleni Giaprou, Dimitrios Rallis, and Vasileios Giapros. 2025. "Decoding Mini-Puberty and Its Clinical Significance: A Narrative Review" Endocrines 6, no. 2: 28. https://doi.org/10.3390/endocrines6020028

APA Style

Serbis, A., Kosmeri, C., Atzemoglou, N., Lampropoulou, K.-M., Giaprou, L.-E., Rallis, D., & Giapros, V. (2025). Decoding Mini-Puberty and Its Clinical Significance: A Narrative Review. Endocrines, 6(2), 28. https://doi.org/10.3390/endocrines6020028

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