REVIEW

published: 23 July 2018

doi: 10.3389/fendo.2018.00410

Up-To-Date Review About

Minipuberty and Overview on
Hypothalamic-Pituitary-Gonadal Axis
Activation in Fetal and Neonatal Life
Lucia Lanciotti, Marta Cofini, Alberto Leonardi, Laura Penta and Susanna Esposito*

Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Perugia, Italy

Minipuberty consists of activation of the hypothalamic-pituitary-gonadal (HPG) axis

during the neonatal period, resulting in high gonadotropin and sex steroid levels, and
occurs mainly in the first 3–6 months of life in both sexes. The rise in the levels of these
hormones allows for the maturation of the sexual organs. In boys, the peak testosterone
Edited by: level is associated with penile and testicular growth and the proliferation of gonadic
Valentino Cherubini, cells. In girls, the oestradiol levels stimulate breast tissue, but exhibit considerable
Azienda Ospedaliero Universitaria
Ospedali Riuniti, Italy fluctuations that probably reflect the cycles of maturation and atrophy of the ovarian
Reviewed by: follicles. Minipuberty allows for the development of the genital organs and creates the
Stefano Zucchini, basis for future fertility, but further studies are necessary to understand its exact role,
Policlinico S. Orsola Malpighi, Italy
especially in girls. Nevertheless, no scientific study has yet elucidated how the HPG axis
Jarmo Jääskeläinen,
Kuopio University Hospital, Finland turns itself off and remains dormant until puberty. Additional future studies may identify
Marco Bonomi, clinical implications of minipuberty in selected cohorts of patients, such as premature and
Istituto Auxologico Italiano (IRCCS),
Italy small for gestational age infants. Finally, minipuberty provides a fundamental 6-month
*Correspondence: window of the possibility of making early diagnoses in patients with suspected sexual
Susanna Esposito reproductive disorders to enable the prompt initiation of treatment rather than delaying
susanna.esposito@unimi.it
treatment until pubertal failure.
Specialty section: Keywords: gonadotropin, hypothalamic-pituitary-gonadal, minipuberty, oestradiol, testosterone
This article was submitted to
Pediatric Endocrinology,
a section of the journal INTRODUCTION
Frontiers in Endocrinology

Received: 22 April 2018 Puberty is the period of life in which a child develops secondary sexual characteristics and
Accepted: 02 July 2018 reproductive function. Puberty requires activation of the hypothalamic-pituitary-gonadal (HPG)
Published: 23 July 2018 axis, resulting in secretion of hypothalamic gonadotropin-releasing hormone (GnRH), which in
Citation: turn stimulates secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by
Lanciotti L, Cofini M, Leonardi A, the pituitary gland and the consequent maturation of gametogenesis as well as secretion of gonadal
Penta L and Esposito S (2018) hormones. Before the onset of puberty, the HPG axis is temporary activated in two other periods
Up-To-Date Review About
of life, i.e., in the midgestational fetus and in the newborn. In recent years, many studies in the
Minipuberty and Overview on
Hypothalamic-Pituitary-Gonadal Axis
literature have referred to this latter period as minipuberty.
Activation in Fetal and Neonatal Life. Minipuberty was first described in the 1970s (1, 2), but its role is still not well understood. The
Front. Endocrinol. 9:410. aim of this review is to analyse the impact and the clinical role of minipuberty. PubMed was used
doi: 10.3389/fendo.2018.00410 to search for all relevant studies published over the last 25 years using the key words “minipuberty,”

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Lanciotti et al. Implications of Minipuberty

“mini-puberty,” “HPG axis,” “gonadotropins,” and “sexual (16). Indeed, mutations of the LH/CG receptor can cause the
hormones,” combined with “fetal life,” “newborn,” absence of virilization and feminization of the external genitalia
“preterm,” “small for gestational age,” “growth,” “congenital (17). Thus, the fetal testicular T is secreted first under the
hypogonadotropic hypogonadism,” “Turner syndrome,” control of placental hCG, and only after the 9th WG, T secretion
“Klinefelter syndrome” and “CAIS”. Additional sources were comes under the control of pituitary LH. A clear increase in
found from the references of the publications that were obtained T concentration occurs between 8 and 11 WG and reaches a
from the search. The data obtained from studies published maximum between 11 and 14 WG. The peak level (40–580 ng/dL)
between 1973 and 2017 are included in this review, and the most is similar to the adult value (14), whereas T levels in the fetal testes
recent research is dated March 2017. can reach ∼1.9–2.1 ng/mg of tissue (16). After the 20th WG, T
decreases toward term (8, 14). The fetal testicles also express FSH
receptors that probably control Sertoli cell proliferation, although
HYPOTHALAMIC-PITUITARY-GONADAL only few studies exist regarding the effects of FSH (18–20). Anti-
(HPG) AXIS ACTIVATION IN FETAL LIFE mullerian hormone (AMH) that is produced by the Sertoli cells
in the fetal testes causes the regression of the mullerian ducts,
During embryogenesis, neurons that produce GnRH develop which prevents the formation of internal feminine genitalia. T
from the epithelium of the medial olfactory pit and move to favors the development of male urogenital structures from the
the fetal hypothalamus by migrating along nerve fibers (3). This wolffian duct, such as the vas deferens, epididymis, and seminal
process occurs at ∼40 days of gestation (4). Simultaneously, the vesicles, while the formation of the prostate, penis and scrotum is
pituitary gland develops and begins synthesizing both LH and due to the active metabolite of T (dihydrotestosterone).
FSH at 9 weeks of gestation (WG) (5), although the hormones In female fetuses, the lack of AMH allows the mullerian
appear in the fetal blood by 12–14 WG (6). Kisspeptin and ducts to develop into the fallopian tubes, uterus and upper part
KISS1R are factors that are involved in the regulation of fetal of the vagina (21). The development of the primordial follicle
GnRH neuron activity. However, serum LH and FSH levels are in the fetal ovaries begins before 13 WG, but the follicles are
independent of GnRH and kisspeptin at midgestation, but they more rapidly created after 14–15 WG. The pool of primordial
become GnRH-induced after 30–31 WG (7). follicles is ∼100,000 at 15 WG and then rapidly increases to
The gonadotropin levels peak at midgestation in both the reach a higher number at 34 WG (680,000). Subsequently,
pituitary gland and the serum and subsequently decrease toward the pool remains stable, at least until 8 months after birth
birth and are suppressed at term (8, 9). This pattern is probably (22). This pool, which represents the foundation of female
caused by the gradual increase in the production of placental fertility, is formed when estrogen levels are high in the fetal
estrogens toward the end of gestation (10) that suppresses the circulation. However, the majority of estrogen production during
activity of the fetal HPG axis. fetal life is due to the placenta, and ovarian production can be
Additionally, female fetuses produce higher LH and FSH considered irrelevant. Additionally, the roles of FSH and LH
levels than male fetuses (6, 11). Indeed, Debieve et al. (12) in ovarian development during pregnancy are not completely
measured LH and FSH at midpregnancy (the group had median understood. It seems that normal development occurs until the
ages of 23.8 WG for the females and 22.6 WG for the males) 34th WG even in anencephalic fetuses. In contrast, during the
and at term (median ages: 39.2 WG for the females and 38.9 last part of gestation, a marked difference can be found; in
WG for the males). Both gonadotropins were present in the anencephalic fetuses small and growing antral follicles cannot be
first group and exhibited a clear difference between the females observed as they can in normal fetuses (23), which suggests that
and males; the girls exhibited much higher levels (33.0 ± 23.2 hypothalamic stimulation is necessary to ensure physiological
vs. 4.4 ± 3.3 mIU/mL for LH and 54.4 ± 27.7 vs. 0.77 ± ovarian development after the 7th month of gestation.
0.49 mIU/mL for FSH). In contrast, in the term female fetuses,
both LH and FSH were undetectable, and only very low FSH
levels were observed in the term male fetuses. The midpregnancy MINIPUBERTY AND ITS IMPLICATIONS IN
gonadotropin peak coincides with the first ovarian follicle or HEALTHY INFANTS
seminiferous tubule maturation. The difference between genders
is probably caused by the negative feedback that results from the At delivery, in healthy infants the LH and FSH levels are low in
higher concentrations of fetal testicular hormones (6, 13, 14). the cord blood in both sexes (24) due to the inhibitory effect of the
Another marked difference between the sexes is that the LH high levels of placental estrogens. In boys, the LH level increases
levels overcome the FSH levels in male fetuses (15), whereas the by ∼10-fold in the few minutes after delivery, and this increase is
opposite situation occurs in females. followed by a concomitant rise in the T levels that lasts for ∼12 h
During fetal life, the masculinization of genitalia depends on (25, 26). In girls, this increase does not occur.
the production of testosterone (T) by the Leydig cells of the In the first few days after birth, the fall in circulating
fetal testicles and on its action on target organs. During the placentally produced steroids causes a progressive lack of
first trimester of gestation, placental human chorio-gonadotropin negative feedback on the neonatal GnRH pulse generator. In
(hCG) induces the differentiation of testicular mesenchymal this manner, the activity of the HPG axis is reinitiated, and
cells into Leydig cells and stimulates T production through the gonadotropin levels begin rising between days 6 and 10 after birth
activation of the LH/CG receptors expressed on their surfaces (27, 28). In infant boys, the serum LH level reaches the pubertal

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Lanciotti et al. Implications of Minipuberty

range by 1 week of age, the peak is detected between the 2nd and Additionally, in prepubertal boys, Sertoli cells secrete inhibin
10th weeks of life, and the level then decreases to the prepubertal B, which represents a marker of Sertoli cell function. This
range by 4–6 months (27–30) (Figure 1). Female infants have hormone, which is already present in the cord blood, increases
lower peak LH values, but the pattern is similar (Figure 2) (27– soon after birth, peaks at 3–6 months of age, reaches greater
29). In contrast, the FSH levels are higher in females than in values then those observed in adults (mean +/– SD: 378 +/– 23
males and peaking between 1 week and 3 months. Subsequently, pg/mL), and remains elevated until at least the age of 15 months
in males, the FSH values gradually decrease to the prepubertal (28, 32, 41).
range within 4 months of age, whereas in females, these values Minipuberty has been associated with physiological gonadal
remain elevated until to 3–4 years of age (27, 29, 31). development processes, such as penile and testicular growth
Table 1 summarizes sex differences and the patterns of basal and the proliferation of gonadic cells. Cortes et al. (42) found
LH/FSH in the first month of life. In male neonates, the that penile length is positively correlated with serum T and
pattern of T secretion is similar to that of LH secretion: T increases from birth (mean +/– SD, 3.49 +/– 0.4 cm) to 3 years
is low in the cord blood, gradually increases to peak at 1–3 of age with the highest growth velocity occurring from birth to 3
months and then declines to prepubertal values by 6–9 months months (1 mm/month). In contrast, testicular volume increases
of age (2, 27, 28, 30, 32). Similarly, the number of Leydig significantly in the first 5–6 months of life, from 0.27 to 0.44
cells in the testicular tissue increases considerably until the cm3 , and the volume subsequently decreases to 0.31 cm3 at ∼9
third month and then gradually decreases due to apoptosis of months (43). This pattern is positively correlated with FSH levels
the fetal Leydig cells (33–36). Sertoli cells also develop in the (30), which is probably due to the proliferation of Sertoli cells
first months after birth under the stimulation of FSH (37), in the seminiferous tubules (37). Additionally, Hadziselimovic
but they do not express androgen receptors during infancy, et al. proposed that germ cells can differentiate into adult (Ad)
and therefore spermatogenesis does not occur (38). These cells spermatogonia due to the transient activation of the HPG axis
secrete AMH in male neonates: the highest levels are observed during the first months of life (44).
at 3 months, and the levels subsequently decline and remain Thus, the first months of life are fundamental for the
at relatively stable levels throughout childhood until puberty development of the male reproductive organs. In contrast, it is
at which point AMH progressively decline to the adult level not completely clear whether these months are also important
of 3–4% of the infant level (39). The absence of androgen for the reproductive functions of girls. At birth, oestradiol levels
receptors explains why AMH levels remain elevated in the are high in the cord blood of both sexes. Umbilical cord estrogen
presence of the high T levels during early infancy (38, 40). concentrations depend on gestational age, the mode of delivery,

FIGURE 1 | Patterns of fetal and postnatal luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T) secretion in males.

FIGURE 2 | Patterns of fetal and postnatal luteinizing hormone (LH), follicle stimulating hormone (FSH) and oestradiol secretion in females.

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Lanciotti et al. Implications of Minipuberty

TABLE 1 | Luteinizing hormone (LH) and follicle stimulating hormone (FSH) values MINIPUBERTY IN PREMATURE INFANTS
(means ± SD) in neonates.
AND IN THOSE SMALL FOR GESTATIONAL
Age LH in males LH in females FSH in males FSH in females AGE (SGA)
(days)
Postnatal HPG axis activation also occurs in premature infants
1–5 0.39 ± 0.48 0.48 ± 0.66 0.96 ± 0.60 2.00 ± 1.37
and is even stronger and more prolonged in time than in
6–10 2.31 ± 2.29 0.45 ± 0.33 2.91 ± 4.38 2.44 ± 2.52
full-term infants (53, 54). Kuiri-Hanninen et al. (30) recently
11–15 3.55 ± 2.84 1.58 ± 1.28 3.71 ± 2.69 8.16 ± 4.27 compared full-term (FT) and preterm (PT) males by measuring
16–20 4.13 ± 2.76 1.03 ± 1.39 2.63 ± 1.45 1.62 ± 1.05 urinary gonadotropins and T in serial urine samples and
21–25 2.86 ± 1.51 0.46 ± 0.25 2.50 ± 1.51 7.07 ± 5.92 comparing the results with testicular and penile growth. The
26–28 2.22 ± 2.37 2.75 ± 2.39 2.25 ± 0.81 9.74 ± 9.89 trends of LH and T secretion are similar among the groups, but
Values of LH and FSH are in mIU/mL.
the levels are significantly higher in PT than in FT males when
Adapted from Schmidt and Schwarz HP (27). measured at 7 and 30 days of age. These levels then decline in
both groups, but a significant difference can still be observed at
month 6. Additionally, a positive association between the level
pregnancy complications, and twinning, but not on infant sex of HPG axis activation and the grade of prematurity has been
(45). In a study conducted by Troisi et al. (46), the mean found, and PT males have been associated with faster penile
oestradiol values measured in cord blood were found to be and testicular growth after birth, which suggests that HPG axis
11,941 pg/ml in females and 12,782 pg/ml in males, and the activation plays a role in completing genital development.
difference between gender was not significant. During the first In PT females, the FSH and LH values are higher than
postnatal days, oestradiol levels gradually decrease, but after 1 those in FT girls (55) and exhibit a more elevated and more
week of age, they increase in girls only and remain high in prolonged peak; these patterns might reflect the expression of
the subsequent period (47–49) until at least the 6th month of the immaturity of a negative feedback system in the HPG axis of
life. Similar observations were made by Bidlingmaier et al. (50), PT girls. The greater levels of FSH in PT females are probably
who found the higher oestradiol concentration in the ovaries due to a delay in ovarian folliculogenesis; the ovaries are still
of 1- to 6-month-old girls compared with those at the end of immature and do not seem to be able to produce sufficient
the first year in postmortem samples. At 3 months of age, the estrogens that may inhibit gonadotropin secretion. Additionally,
median serum oestradiol level in girls is 30.0 pmol/L (range the FSH peak is followed by transient ovarian stimulation (which
< 18–100) (47). However, individual oestradiol levels in girls reaches a maximum at ∼4 weeks of age) that results in the
exhibit considerable fluctuation in the first months of life, which presence of antral follicles on ultrasonography and increases in
may reflect the cycles of maturation and atrophy of the ovarian the levels of granulosa cell–derived AMH and oestradiol (31),
follicles. Indeed Kuiri-Hanninen et al. (31) reported increased which are higher in the serum of PT than FT girls (49). Estrogen
numbers of antral follicles on ovarian ultrasonography in infant receptor alpha is expressed in the fetal mammary glands from
girls, and this fact corresponds to parallel elevations of oestradiol ∼30 weeks of gestation (56), which might explain the absence of
(48, 49) and AMH levels (31, 51). Indeed, in infant girls, there breast development in PT infants. However, in these girls, there
is a marked rise of AMH levels at 3 months of age (15 pmol/L; is a stronger association between the postnatal oestradiol surge
4.5–29.5 pmol/L) compared with the levels found in cord blood and the growth of the mammary gland diameter and uterine
(2 pmol/L; 2–15.5 pmol/L) and at 1 year of age (51). This fact length (48).
may demonstrate the postnatal proliferation of granulosa cells, A possible clinical consequence of this intensive stimulation
which produce AMH, and the contemporary development of the on the genital organs that occurs in premature infants is ovarian
ovarian follicles, which probably occurs in response to the parallel hyperstimulation syndrome. First described in 1985 by Sedin
FSH surge (31, 51). et al. (57) in 4 very preterm neonates, ovarian hyperstimulation
The mammary glands and the uterus are also certainly syndrome is characterized by oedema of the vulva, solitary or
estrogen target tissues in the fetus and in newborn. At birth, most multiple cysts in the ovaries on ultrasonography, breast growth,
full term babies of both sexes have palpable breast tissue (52) occasional vaginal bleeding and high serum gonadotropin
that probably results from in-uterus stimulation from placental and oestradiol levels. This syndrome is probably the extreme
estrogens. However, in the following months, the breast tissue consequence of the immaturity of the negative feedback
in females remains larger and persists longer (52). In boys, mechanisms that act on the HPG axis, and this absence of
the mammary gland diameter gradually decreases until the 6th feedback results in hyperstimulation of the target organs. Several
month, whereas in full-term girls, it remains large, reflecting the cases have been reported in the literature (58–62), and all cases
activity of endogenous estrogens (48). In contrast, the uterine indicate that it is a self-limiting disease that does not require
length increases primarily during pregnancy due to the hormones treatment if there are no complications, but follow-up until
that cross the placental barrier, and after birth, it is longest at day clinical resolution is necessary.
7 in full-term babies and then steadily decreases toward the third Infants born small for gestational age (SGA) are at risk of
month and remains fairly unchanged until the second year (48). developing metabolic and endocrinological disorders (63). It is
Therefore, the role of minipuberty in girls is still controversial well known that SGA children are at greater risk of type 2 diabetes
and partially unknown. and cardiovascular diseases, expecially those with high catch up

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Lanciotti et al. Implications of Minipuberty

growth. In fact, the fetus in nutritional deficiency constantly GH becomes predominant during infancy until the period of
replans his metabolism to slow growth with relative resistance puberty, when the rise of levels of sexual hormones results in
to insulin, IGF-1 and GH, that persists in childhood and adult the growth spurt, which is essential for final growth and bone
life too (64). Besides, lower insulin sensitivity has been also maturation.
associated to an increased incidence of adrenal and ovarian Recently, new studies have described an association between
hyperandrogenism, clinically evident as precocious pubarche and minipuberty and growth, particularly in males. Indeed, sex
reduced ovulation rate (65). steroids and gonadotropic hormones in the first 5 months of
In females, being SGA has been associated with reduced life seem to influence somatic development in boys during the
uterine and ovary size (66), whereas, in males, SGA has following 6 years. Becker et al. (71) conducted a prospective
been linked to infertility and reduced testicular volume and T study of 35 healthy infants (17 males) and reported that the
concentrations in adult life (67). Minipuberty in SGA infants is surge in T during the first months of life has an influence on
still not well defined, and the data reported in the literature are human somatic and adipose tissue development in childhood.
controversial. Recently, Nagai et al. (68) conducted a longitudinal Indeed, boys exhibit faster increases in weight and BMI at the
study and reported lower FSH and T, as well as higher LH age of 8 weeks than do girls. At this age, the median T level has
concentrations, in SGA infants compared with appropriate for been found to be 7.37 nmol/L, which corresponds to pubertal
gestational age (AGA) infants. In contrast, in previous studies, male values. Subsequently, other trials have been conducted with
elevated serum FSH concentrations have been detected in SGA greater numbers of participants. Kiviranta et al. (72) studied 84
infant girls and boys (69); similarly, higher T levels have been healthy neonates (45 of which were males). The linear growth
found in SGA than in AGA boys (70). Further studies are velocity was significantly faster from birth to 6 months of age
necessary to definitely clarify the patterns of minipuberty in SGA in boys than in girls, and the greatest growth velocity difference,
infants and their clinical implications. i.e., 4.1 cm per year, was observed at 1 month of age, which is
simultaneous with the peak of the postnatal gonadal activation,
MINIPUBERTY AND GROWTH especially in terms of T level.

Growth is influenced by different hormones depending on the

period of life. In fact, in the first years, thyroid hormones play the MINIPUBERTY AND HYPOGONADISM
main role, together with insulin and glucocorticoids. By contrast,
In the last 20 years, studies have been conducted to establish
an association between minipuberty and hypogonadotropic
TABLE 2 | Replacement therapy for hypogonadotropic hypogonadism in the first hypogonadism (HH), especially in males, and have found that
year of life.
the disease is characterized by the absence of the postnatal FSH,
References Year N. cases Hormonal Clinical and LH, and T surge. For this reason, minipuberty provides a short-
therapy hormonal outcome time window of opportunity to make an early diagnosis (41).
At birth, HH can be revealed by a micropenis with or without
Main et al. 2000 3 T ↑ T levels and penis associated cryptorchidism, and male neonates exhibiting these
(80) length
“red flags” should undergo a single serum sample examination
Main et al. 2002 1 rLH and rFSH ↑ inhibin B levels; ↑
to identify congenital gonadotropin deficiency (73, 74). A
(81) testicular volume and
penis length novel study conduced in a large cohort of HH patients, in
Bougnères 2008 2 rLH and rFSH ↑ T, inhibin B and AMH fact, confirmed the importance of identifying male genital
et al. (82) levels; ↑ testicular tract anomalies in prepubertal age, in particular showing that
volume and penis micropenis or cryptorchidism are significantly more represented
length in HH resulting from Kallman syndrome (75). The best period
Stoupa 2017 6 rLH and rFSH ↑ T, inhibin B and AMH for the measurement of the serum concentrations of reproductive
et al. (83) levels; ↑ penis length
hormone is between 4 and 8 weeks of life, but it can be
AMH, anti-mullerian hormone; rFSH, recombinant stimulating hormone; rLH, recombinant practically performed until 6 months of age (73). Besides, a recent
luteinizing hormone; T, testosterone. study suggested that testicular position increases from birth to

TABLE 3 | Minipuberty in Klinefelter syndrome (KS).

References Year N. cases N. controls Age of population Hormonal findings

Lahlou et al. (88) 2004 18 215 0–3 years FSH, LH, inhibin B, and AMH not different between groups; T ↓ in KS
Ross et al. (89) 2005 22 – 1–23 months T ↓ in KS
Aksglaede et al. (90) 2007 10 613 3 months ↑ T, LH and FSH; inhibin B not different between groups
Cabrol et al. (91) 2011 68 215 2–750 days T, LH, inhibin B and AMH not different between groups; normal or ↑ FSH levels in KS

AMH, anti-mullerian hormone; LH, uteinizing hormone; rFSH, recombinant stimulating hormone; T, testosterone.

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Lanciotti et al. Implications of Minipuberty

3 months of age and decreases thereafter, overlapping with the and high-normal serum T levels in KS infants, as well as evidence
period of minipuberty. Therefore, testicular distance to pubic of subtle Sertoli cell dysfunction with low-normal inhibin B
bone may be a useful biomarker of postnatal testicular function, levels. This situation may predict the postpubertal resistance of
both for Leyding and Sertoli cell activity (76). Sertoli cells to FSH action in subjects with KS in adult life (91).
Hadziselimovic et al. identified impaired minipuberty as the Table 3 summarizes studies on minipuberty in KS.
main reason for cryptorchidism-induced infertility (77). Indeed, Finally, androgen receptors also play an important role in
the lack of secretion of LH and T in the perinatal period prevents HPG axis activity. Indeed, infants with complete androgen
the differentiation of germ cells, which results in infertility after insensitivity who present with a mutation in the androgen
puberty (78). receptor do not exhibit the physiological peaks in LH and
Furthermore, the importance of minipuberty has been consequently T during minipuberty, whereas neonates with
highlighted by evidence that orchiopexy alone does not necessary partial androgen insensitivity exhibit high-normal levels of
improve fertility in cryptorchid males, whereas in 6-month-olds, postnatal T and LH (92).
long targeted therapy with LH-Rh analogs following successful
surgery results in the normalization of the sperm parameters in CONCLUSIONS
adult life (79). Table 2 presents case reports and descriptions of
small trials of patients with HH who were treated during the first The HPG axis is physiologically activated in the fetus during
year of life with recombinant human LH and FSH or with T in midgestation and gradually turns off toward term due to
attempts to imitate physiological minipuberty. In all cases, the the negative feedback of placental hormones on the fetal
effects were beneficial. The substitutive therapy with T resulted hypothalamus. At birth, when the restriction is removed, the
in a marked increase in T level and penile length, whereas HPG axis reactivates, which results in a T peak in males between
recombinant gonadotropin administration caused increase not months 1 and 3; by contrast, the oestradiol levels in females
only in T level, but also in LH, FSH, as well as inhibin B and fluctuate until 6 months of age. Minipuberty allows for the
AMH. This hormonal pattern results both in the increase of development of the genital organs and creates the basis for future
penile length and testicular volume and in fertility potential fertility, but further studies are necessary to understand its exact
later in life. The administration of gonadotropins is safe, role, especially in girls. Nevertheless, no scientific study has yet
well tolerated and effective. Finally, new evidences suggest elucidated how the HPG axis turns itself off and remains dormant
also the possibility of treatment with a gonadotropin-releasing until puberty. Additional future studies may identify clinical
hormone agonist, which induces gonocytes to differentiate implications of minipuberty in selected cohorts of patients,
into Ad spermatogonia and rescues fertility (84). As regards such as premature and small for gestational age infants. Finally,
hypergonadotropic hypogonadism, one of the most frequent minipuberty provides a fundamental 6-month window of the
causes is Turner syndrome (TS). In these patients, perinatal possibility of making early diagnoses in patients with suspected
FSH secretion is similar to that in healthy girls (85), however, sexual reproductive disorders to enable the prompt initiation of
during infancy, the pattern of FSH secretion is strictly related to treatment rather than delaying treatment until pubertal failure.
karyotype. Young girls with monosomy TS exhibit a persistent
elevation of FSH up to 6 years, whereas those with 45,X/46,XX AUTHOR CONTRIBUTIONS
mosaicism have only minimally elevated FSH values, which
suggests the presence of feedback effects on the HPG axis due to LL drafted the manuscript. MC and AL performed the literature
retained ovarian function (86, 87). review. LP supervised the project. SE revised the manuscript and
Contrasting data can be found in the literature about males made substantial scientific contributions.
with Klinefelter syndrome (KS). Lahlou et al. (88) found that,
in their cohort of KS patients 0–3 years old, the FSH, LH, and FUNDING
inhibin B levels were similar to those in healthy controls with the
exception of T, which exhibited a physiological increase during This review was partially supported by the World Association
the first trimester, but always remained at a lower level thereafter for Infectious Diseases and Immunological Disorders (grant n.
when compared with controls. Similarly, Ross et al. underlined WAidid2017_06). WAidid has no role in literature analysis and
that the neonatal surge in T is attenuated in the KS population manuscript preparation, but only gave an unrestricted grant for
(89). In contrast, Aksglaede et al. (90) found elevated LH levels covering expenses.

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86. Fechner PY, Davenport ML, Qualy RL, Ross JL, Gunther DF, et al. Toddler Conflict of Interest Statement: The authors declare that the research was
Turner Study Group. Differences in follicle-stimulating hormone secretion conducted in the absence of any commercial or financial relationships that could
between 45,X monosomy Turner syndrome and 45,X/46,XX mosaicism be construed as a potential conflict of interest.
are evident at an early age. J Clin Endocrinol Metab. (2006) 91:4896–902.
doi: 10.1210/jc.2006-1157 Copyright © 2018 Lanciotti, Cofini, Leonardi, Penta and Esposito. This is an open-
87. Chrysis D, Spiliotis BE, Stene M, Cacciari E, Davenport ML. Gonadotropin access article distributed under the terms of the Creative Commons Attribution
secretion in girls with Turner syndrome measured by an ultrasensitive License (CC BY). The use, distribution or reproduction in other forums is permitted,
immunochemiluminometric assay. Horm Res. (2006) 65:261–6. provided the original author(s) and the copyright owner(s) are credited and that the
doi: 10.1159/000092516 original publication in this journal is cited, in accordance with accepted academic
88. Lahlou N, Fennoy I, Carel J-C, Roger M. Inhibin B and anti-müllerian practice. No use, distribution or reproduction is permitted which does not comply
hormone, but not testosterone levels, are normal in infants with nonmosaic with these terms.

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