Laura Lucaccioni1*
Viola Trevisani2
Alessandra Boncompagni3
Lucia Marrozzini2
Alberto Berardi3
Lorenzo Iughetti1,2- 1Pediatric Unit, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
- 2Department of Medical and Surgical Sciences of the Mothers, Children and Adults, Post Graduate School of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy
- 3Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
Hypothalamic-pituitary-gonadal (HPG) axis activation occurs three times in life: the first is during fetal life, and has a crucial role in sex determination, the second time is during the first postnatal months of life, and the third is with the onset of puberty. These windows of activation recall the three windows of the “Developmental Origin of Health and Disease” (DOHaD) paradigm and may play a substantial role in several aspects of human development, such as growth, behavior, and neurodevelopment. From the second trimester of pregnancy there is a peak in gonadotropin levels, followed by a decrease toward term and complete suppression at birth. This is due to the negative feedback of placental estrogens. Studies have shown that in this prenatal HPG axis activation, gonadotropin levels display a sex-related pattern which plays a crucial role in sex differentiation of internal and external genitalia. Soon after birth, there is a new increase in LH, FSH, and sex hormone concentrations, both in males and females, due to HPG re-activation. This postnatal activation is known as “minipuberty.” The HPG axis activity in infancy demonstrates a pulsatile pattern with hormone levels similar to those of true puberty. We review the studies on the changes of these hormones in infancy and their influence on several aspects of future development, from linear growth to fertility and neurobehavior.
Introduction
During embryogenesis, the pituitary gland begins synthesizing both Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) at around 9 weeks of gestation (1). LH and FSH can be detected in fetal blood from 12 to 14 weeks (2, 3) and start to be GnRH-dependent after 31–32 weeks (4, 5).
Prenatal modulation of the HPG axis activity is also due to placental hormone production. In fact, the structure of hCG is an analog of LH and may bind to the LH receptor, with similar biological effects on gonadal tissues (2, 6). Moreover, the placenta produces Estrogens (E) and Progesterone (P), that rise during the third trimester. This has a negative effect on gonadotropin levels and results in a drop in LH and FSH in cord blood at birth in healthy infants of both sexes (6–8).
After birth, the removal of placental hormones from the neonate's circulation results in a lack of negative feedback on the GnRH pulse generator and reactivation of the HPG axis. This postnatal activation that starts in the first few days of life is known as “minipuberty” (9).
Studies on healthy term neonates indicate that the rise of LH and FSH begins at around 1 week of age. It achieves a peak, reaching the pubertal range, between 1 and 3 months of life and then declines toward the age of 6 months (6–8, 10–13). These postnatal hormonal changes have different trends in boys and girls. Particularly in males, it seems to be related to the development and maturation of the reproductive system. Furthermore, the impact of gonadotropins and sex-steroid hormones during this first period of life has been studied and relates to many different aspects of infant growth and behavior (14).
The aim of this review is to summarize the current understanding on minipuberty and its role as a temporary window of opportunity for diagnosis and possible treatment in babies with disorders of sex development (DSD). Moreover, we would like to highlight the extent of what happens (or not) during minipuberty in terms of hormonal changes and trends which may influence future neurobehavior.
Infants Born at Term
Males: In male neonates, both LH and FSH levels peak between 1 and 3 months of age and then gradually decrease to prepubertal levels at around 6-9 months (9, 12, 14). The LH peak is higher than the FSH level. Testosterone (T) starts to increase 1 week following the LH rise and declines to prepubertal values by 6 months of age (11, 12, 15). T levels, both in cord blood and in serum during the first postnatal months, are higher in boys than in girls (11–13, 15–17).
The number of Leydig cells in both testes increases considerably until the third month of life, which correlates with the T trend and then gradually decreases due to an apoptosis process (18, 19). Sertoli cells also grow during the first postnatal months under the stimulation of FSH (20) but, without the expression of androgen receptors (AR) during infancy, they do not complete their maturation and spermatogenesis does not occur (21). This leads to an increase of testicular volume during the first months after birth, which then gradually decreases until the second year of life due to the halt in cell proliferation, the reduction of AMH production, and the formation of the blood-testicular barrier (22, 23).
All these hormonal changes during the first months of life have a great impact on the urogenital system. This involves not only the testes but also the development and growth of the penis, prostate, and scrotal hair. In fact, the postnatal T surge within the first three months has been associated with penile growth in infancy (24). The increase in androgens has been associated with cutaneous manifestations, such as sebaceous gland hypertrophy and acne (25). There is also a link with the development of transient isolated scrotal hair between 3 and 6 months of life with a spontaneous disappearance within the first year of life (26).
Females: In female infants, FSH levels are higher than LH, following a different trend than in males. FSH shows the same gonadotropin peak as in males at 1–3 months of age but can remain elevated up to 3–4 years of life. In contrast, LH levels decrease at the same age as in boys (9, 12, 27).
E levels at birth are high, with similar values in the cord blood of both sexes (28), followed by a gradual decrease during the first days of life and a new increase after the first week only in girls.
E remains high until 6 months with fluctuating levels, probably related to the FSH trend, and decreases toward 2 years of life (29–31). The mammary glands and uterus are certainly E target tissues but evidence of minipuberty effects is not univocal. At birth, most full-term babies of both sexes have palpable breast tissue (32) that probably results from placental E effect. In the following months, breast tissue in females remains larger and persists longer due to HPG axis activity and its consequent E production (30). In contrast, uterine length increases in utero but, after birth, there is a steady decrease from day 7 toward the third month, after which the volume remains stable until the second year (30).
With little evidence from few studies, the biological role of minipuberty in girls is still controversial and partially unknown.
Babies born small for gestational age (SGA): The HPG axis activation in SGA infants born at term is not well defined and its short-term and long-term effects on growth and development are still controversial. Studies on SGA females found higher postnatal FSH levels compared with neonates born appropriate for gestational age (AGA). This different pattern of secretion in SGA females was also associated with reduced uterine and ovarian size that persisted into young adulthood (33, 34). Moreover, Anti Mullerian Hormone (AMH) levels have been reported to be higher in SGA girls at 2–3 months of life, suggesting possible altered follicular development (35).
In contrast with these findings, other studies have reported higher E in SGA females after the administration of a GnRH stimulation test, although the reported basal levels were not significantly different (35).
In male SGA term neonates, HPG axis activation has been linked both to lower (36) and higher (34) FSH and T (37) levels, with uncertain effects in adult life (38).
Further studies are necessary to clarify the pattern of minipuberty in SGA male and female infants, along with the clinical implications. It is important to bear in mind that SGA neonates are at increased risk of metabolic and endocrinological disorders. These include reduced insulin sensitivity and increased adrenal hyperandrogenism, with consequent precocious pubarche and reduced ovulation rate (39).
Preterm Infants
Little is known about the influence of prematurity on HPG axis activity and its effects. Fewer studies have investigated this pattern longitudinally in preterm (PT) babies compared with those born full-term (FT). Preterm birth does not seem to influence the postnatal HPG axis activation, as gonadotropin levels begin to rise after birth (whenever that is, as fetal-placental interruption) with the same timing as in FT infants.
Moreover, this hormonal surge might be even stronger and more prolonged than in FT infants (40, 41). However, these data are not univocal (40–42) in either the amplitude or the duration between different sexes. Immaturity of the hypothalamic feedback has been suggested as a possible mechanism for this strong and prolonged activation, although its biological significance is still not completely understood.
The most recent longitudinal data suggest that minipuberty declines at about the same post-term age in term neonates compared with premature infants, suggesting that the HPG activity is regulated in an evolutionarily way (13). In particular, Kuiri-Hanninen et al. (13) used spot urine samples in order to compare gonadotropin and testosterone levels in a small cohort of FT and PT male neonates with a gestational age (GA) between 24.7 and 36.6 weeks. From day 7 to 14 months of age they measured length, weight, penile length, and testicular volume. They simultaneously collected urine samples to detect urinary gonadotropins and testosterone levels until 6 months of age. Their findings revealed higher hormonal levels in PT babies with a positive association between testosterone levels and penile growth, as well as between FSH levels and testicular growth after birth until 5 months of age, when a subsequent decrease occurred. In addition, studies on PT female infants demonstrated higher gonadotropin levels than those in FT girls with a prolonged duration of the peak (43) but a sharp decrease around term age (30). In these PT girls, an amplified postnatal E surge was observed at around three months of corrected age and there was an association with increased growth of the mammary gland and uterine length. Possible clinical consequences of this intensive stimulation in premature females are evidenced by features of the ovarian hyperstimulation syndrome with edema of the vulva, solitary or multiple cysts in the ovaries on ultrasonography, breast growth, and occasional vaginal bleeding (44, 45).
The hormonal differences between boys and girls during minipuberty appear to be fundamental for later sexual differentiation and development. In particular, we think that increasing knowledge on minipuberty in girls may give us key information about the premature thelarche of girls below 2 years of age, and the early puberty that occurs before 8 years of age. In SGA neonates, results are still controversial and more studies are needed to clarify how gonadotrophins and sexual hormones change according to sex. This may be very useful, considering that SGA-born children may go through early puberty and/or precocious isolated pubarche. In preterm babies, we speculated that the prolonged activation of HPG axis may be one of the factors influencing the early re-activation of the HPG axis before puberty age.
Babies With Disorders of Sex Development
The development of internal and external genitalia is a complex balance between gene expression and hormonal influence and an anomaly at each stage can result in 46, XY DSD.
From this point of view, minipuberty can be considered as a window of sensitivity, because it may allow the clinician to come to an early diagnosis and possible treatment opportunity.
Studies on primates testing the effects of a reversible suppression of minipuberty using GnRH agonists or antagonists described lower testis volume and penile length in cases treated compared with controls (46–48). Male infants with congenital central hypogonadism (CHH) were found to have an absence of both fetal and postnatal FSH, LH, and T surges (49). This lack of postnatal FSH secretion seems to be the main reason for impaired germ cell differentiation with later infertility, especially if associated with cryptorchidism (50, 51). As a result, minipuberty may potentially provide a short window of time to make an early diagnosis and for treatment in male neonates that exhibit a micropenis with or without cryptorchidism (52, 53), improving the outcome of orchidopexy, and also reducing the long-term consequences of an absent minipuberty.
On the other hand, the finding of elevated gonadotropins during minipuberty in a 46, XY male neonate with undetectable testosterone levels may suggest congenital anorchism (vanishing testis or testicular regression syndrome). Infants with complete androgen insensitivity syndrome may present with lower-than-normal postnatal LH and T levels, whereas these hormones may be normal or high in cases of partial androgen insensitivity syndrome (54).
We have a unique opportunity to evaluate the spontaneous function of the HPG hormone axis during minipuberty. It is therefore recommended that serum FSH, LH, and testosterone are measured during the first 6 months of life in infants with DSD or suspected CHH. In particular, we would suggest checking for these hormones at seven days of life, and one, three, and, if possible, 6 months of life, to detect the minipuberty trend. The use of the LH/FSH ratio may provide important information in the workup of infants suspected of DSD, especially regarding the sex specific ratio detected in literature (55).
Minipuberty: A Window for Treatment?
Neonates affected by cryptorchidism, micropenis, and CHH must receive timely treatment to optimize genital development. The current recommendation for a micropenis is brief therapy with low-dose testosterone delivered by intramuscular injection or by topical application to induce penile growth. This treatment was also assumed to work for cryptorchidism. However, while exogenous T stimulates penile growth, it does not affect testicular development. In fact, current recommendations advocate surgical correction for undescended testes during the first year of life (56). Nevertheless, there are limitations to this treatment. Small testes augment the risk of testicular trauma and tissue loss during orchidopexy (57), increasing the likelihood of a negative impact on future fertility. Moreover, successful scrotal repositioning of testes does not prevent infertility. However, a normal minipuberty after successful surgery may lead to the presence of Ad spermatogonia (58). The role of Ad spermatogonia is to maintain the supply of stem cells for spermatogenesis. In 178 testicular biopsies after orchidopexy the authors found three groups of high, intermediate, and low risk of infertility depending on the presence of Ad spermatogonia. After puberty, sperm concentrations were analyzed and correlated positively with plasma gonadotropin and testosterone levels. For all these reasons, recreating the hormonal milieu of minipuberty with gonadotrophin treatment could be beneficial for these patients.
In 2002, Main et al. (59) published the first case of CHH and micropenis treated with short-term recombinant human LH and FSH. The outcome of this case was successful; the penile length increased by 50% and the testicular volume almost tripled. Similar results were described in other recent cases (60, 61).
The REMAP study (62) investigated the use of recombinant LH plus FSH preparations in neonates and infants with a micropenis and/or cryptorchidism due to hypogonadotropic hypogonadism. During therapy, all ten patients increased their height velocity: LH levels increased from undetectable to high-normal; FSH reached supranormal levels; and Inibin-b, AMH, and T reached normal levels. Penile length normalized among all children and intriguingly confirms the emerging evidence that testicular descendance is induced by gonadotrophin treatment (61, 63). Furthermore, in this study the therapy may have induced high/normal activation of Sertoli and Leydig cells, restoring testicular endocrine function and improving future fertility.
Vincel et al. (64) analyzed testicular biopsies before and after orchidopexy or hormonal treatment in patients with isolated bilateral cryptorchidism with a high infertility risk. Their results showed how the number of Ad spermatogonia and the number of germ cells per at least 100 tubular cross-sections increased or decreased post-surgery. Indeed, patients who received hormonal treatment showed an important increase in the number of cells and the complete transition of gonocyte and fetal spermatogonia to Ad spermatogonia. These findings support the hypothesis that GnRH induces LH release; LH increases testosterone levels acting directly on Leyding cells, mimicking minipuberty (50, 65).
Finally, studies have focused on the molecular mechanisms that explain the ability of GnRH to rescue fertility. The analysis demonstrates that several IncRNAs involved in epigenetic programming were responsive to GnRH treatment, helping in the preparation of Ad spermatogonial stem cells for commitment to differentiation. In particular, the authors found that DMRTC2, PAX7, BRACHYURY/T, and TERT were associated with defective minipuberty and were responsive to GnRHa (66). Minipuberty may represent a “window of opportunity” to evaluate the HPG axis by measuring basal hormone concentrations with no need for stimulation tests in infants with suspected reproductive disorders. Minipuberty provides a unique opportunity to evaluate the spontaneous function of the HPG axis which is lost thereafter for approximately another 10 years until the HPG axis is reactivated in puberty (67).
Is Our Environment Influencing Minipuberty in Humans and Predisposing Them to DSD?
Endocrine Disruptor Chemicals (EDC) are compounds detectable in every setting of daily life. These chemical compounds are found in a range of products such as those containing pesticides, metals, additives or food contaminants, and personal care products (68). In fact, EDCs are so common that it is almost impossible for individuals to avoid them during everyday activities. These substances may cause adverse health effects, disrupting endocrine function. In particular, they interfere with the endocrine and reproductive systems through nuclear receptors, non-nuclear steroid hormone receptors, non-steroid receptors, orphan receptors, enzymatic pathways, and other mechanisms (69). Children may be exposed both directly and indirectly to ECDs, especially during the three main temporal windows of the DOHaD paradigm and during breastfeeding (70, 71). Concerning breastfed children, Ortega-Garcia et al. detected a linear positive correlation between anogenital distance (AGD) in male infants and the duration of breastfeeding (72). The results of this study, called MALAMA, suggested breastfeeding to be a protective factor against the reduction of the AGD of 2-year-old boys. The authors hypothesized this could be related to early exposure to EDCs through baby formula milk (72).
Moreover, EDCs may interfere with HPG activation (73), both during fetal life or immediately after birth, throughout minipuberty. EDCs during minipuberty in males could impair testicular descent (74). Focusing on some of the most analyzed compounds in this research area, several studies have demonstrated that Bisphenol A (BPA) has an anti-androgen function, decreasing testosterone levels, an event that impacts sex differentiation during fetal life and modifies the AGD length (75, 76). In particular, Sun et al. showed how maternal exposure to BPA was associated with shortened AGD in boys at 12 months of age, highlighting a gender specific effect (77). Another family of EDCs influencing minipuberty are phthalates. Maternal exposure to phthalates during pregnancy showed a reduced T level in males at minipuberty and, because of the antiandrogenic effect of these compounds, the testosterone-luteinizing hormone ratio (T/LH) is also lower in the same period (78). This is probably due to compensated Leydig cell function, requiring higher levels of LH to maintain the necessary level of T for embryo differentiation. It was demonstrated in animal models that phthalates can inhibit Insl3 production and consequently modify the gubernaculum growth necessary for the testes' transabdominal descent (79, 80). However, the effects of these compounds on Insl3 and T in the human testes were less attenuated than in rodents. Table 1 summarizes the most recent studies on the effect of EDC on HPG axis during minipuberty in humans. The impact of EDCs is not limited to the postnatal period. Indeed, alongside this phase there are two more windows of development: fetal and puberty. In these phases, cells are promptly proliferating, and epigenetic changes are more likely to occur (81). All this may lead to additional effects in later stages of life including delayed or precocious puberty (82–85), small testes and high levels of follicle-stimulating hormone (FSH) (86, 87), polycystic ovary syndrome (88), and breast cancer (89).
Table 1. Possible effects in humans of the main EDCs on minipuberty and long-term consequences (68–89).
Our environment plays a crucial role in developmental programming. The influence of EDCs on minipuberty may predispose an individual to undescended testis, AGD modifications, or reduction of T surge. We should always keep an eye on the appearance of the external genitalia in neonates and on the possible maternal exposure to phthalates and BPA through a specific interview.
How Minipuberty Influences Linear Growth During the First 6 Months of Life
During minipuberty, the transient HPG axis activation results in a sex steroid surge. Some studies have indicated a higher growth velocity and a faster increase in weight (and lean body mass) associated with somatic changes in boys when compared with girls during the first 6 months of life (90–93). Based on these results, studies have tested the hypothesis of an association with minipuberty, particularly with the peak of testosterone production. Kiviranta et al. (94) evaluated the precise timing and the magnitude of this sexual dimorphism in growth among a large cohort of full-term healthy boys and girls during the first years of life. In a smaller sample of healthy neonates, serial measurements of urinary and blood hormones were assessed. Results from this study demonstrated that linear growth was significantly faster in boys than in girls, especially when comparing the first three months of age. Interestingly, this observation occurred simultaneously with the peak of postnatal gonadal activation and the authors found a positive correlation between T levels and growth velocity in both sexes, elucidating a possible novel biological role of minipuberty as an engine of growth velocity during the first months of life. Differences in sex hormones during minipuberty between boys and girls are important for the sex differentiation in linear growth and body composition, with males having a higher growth velocity and accumulating more lean mass compared to females.
How Minipuberty Modulates Neurobehavioral Development
As for sexual development, the human brain is also shaped by a combination of genetic, epigenetic, environmental, and hormonal exposure. Sex steroid hormones are among one of the strongest biological factors influencing neural and behavioral development. Over the past two decades, there has been a growing interest in understanding how sex determination and sexual hormones may affect structural and functional brain development (95, 96). The cellular and molecular mechanisms induced by T (converted to estradiol in the brain) are multifaceted and include neurogenesis, cellular differentiation, axon guidance, synaptic pruning, apoptosis, and phagocytosis. Several studies on mammalian brains, including humans, have demonstrated that early androgen exposure has an influence on sex differences in juvenile behavior (54, 96, 97). Indeed, manipulating androgens prenatally in non-human primates alters brain regions and behaviors (98). Many studies have been performed in girls prenatally exposed to high levels of androgens because of congenital adrenal hyperplasia (CAH) where there is strong evidence of male typical play behavior, suggesting a similar hormonal influence on human brain development (98–104). This influence of androgen levels on the brain has been identified not only among affected girls but also in the general population. Fetal T measured from amniotic fluid positively correlates with male typical play in preschool girls and boys assessed with a standardized questionnaire (105). This prenatal period of HPG axis activation is therefore critical for the sexual differentiation that drives the different organization in circuitry and neuroanatomy between the male and female brain. The early postnatal surge of gonadotropins and T in boys during minipuberty can potentially provide a window of opportunity in understanding the effects of sex steroid hormones on human gender development (106). Emerging evidence suggests that T levels during minipuberty have an influence not only on male genitalia and reproductive function but also on later gender-typical behavior. Indeed, minipuberty occurs during a period of huge and rapid brain development in terms of volume, cortical thickness, surface, and cortical network development (107–109). Lamminmäki et al. (110) found a positive correlation between T levels in FT infants from day 7 to 6 months and future sex-typed behavior at 14 months of life. In this study, the Pre-School Activities Inventory (PSAI) (111, 112) playroom was used during an observation of toy choices. In boys, T levels correlated significantly with PSAI scores and playing with trains. Conversely, playing with dolls was significantly correlated with a negative trend. In addition, Pasterski et al. (113) used AGD at birth and penile growth from birth to 3 months of age to estimate prenatal and postnatal androgen exposure. They re-evaluated children included in the study at 3 to 4 years of age using the PSAI suggesting that T levels in both periods, prenatal and postnatal, are independent contributors to later gender-related behavior. Language development is another area of investigation of a possible correlation with early postnatal HPG axis activation. Results based on small samples suggest a correlation between T levels and a different expressive vocabulary in boys and girls (114, 115). We have summarized some of the clearest studies of the last decade in Table 2 in order to better understand the influence of hormonal changes happening during minipuberty on sex-related behavior. All these emerging results may support a role for the imprinting of T during early infancy in human neurobehavioral sexual differentiation, although its effects are still largely unknown in both the short and long-term.
Table 2. Main studies on minipuberty and neurobehavior.
Conclusion
Although further studies are needed, pre- and postnatal activation of the HPG axis could be considered an important window of prediction on how each newborn will grow and develop. Measurement of LH, FSH, and testosterone at 7 days, one and three months, and, when possible, six months, may help the clinician to better understand how minipuberty develops in different neonates. This will give us important information once the baby approaches puberty or when he or she shows impaired linear growth. Moreover, minipuberty must be considered a fundamental moment for possible therapeutic intervention in DSD. Therapeutic interventions may be able to change the natural history of some DSD or, at least, to improve prognosis in terms of fertility and quality of life.
Author Contributions
LL, VT, ABo, and LM analyzed the existing literature and wrote the draft of the review. ABe and LI critically reviewed the manuscript. All authors read and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: minipuberty, neurobehavior, neonate, gonadotrophins, hypothalamic-pituitary-gonadal axis, hypogonadism
Citation: Lucaccioni L, Trevisani V, Boncompagni A, Marrozzini L, Berardi A and Iughetti L (2021) Minipuberty: Looking Back to Understand Moving Forward. Front. Pediatr. 8:612235. doi: 10.3389/fped.2020.612235
Received: 30 September 2020; Accepted: 14 December 2020;
Published: 18 January 2021.
Edited by:
Amanda Lesley Ogilvy-Stuart, Cambridge University Hospitals NHS Foundation Trust, United KingdomReviewed by:
Sasha Howard, Queen Mary University of London, United KingdomAlan David Rogol, University of Virginia, United States
Copyright © 2021 Lucaccioni, Trevisani, Boncompagni, Marrozzini, Berardi and Iughetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Laura Lucaccioni, bGF1cmEubHVjYWNjaW9uaSYjeDAwMDQwO3VuaW1vcmUuaXQ=