Mini Review Article

HOR MONE Horm Res Paediatr 2020;93:76–84 Received: November 5, 2019

RESEARCH I N DOI: 10.1159/000508329 Accepted: April 30, 2020
Published online: June 29, 2020
PÆDIATRIC S

Minipuberty: Why Does it Happen?

Marianne Becker a Volker Hesse b
   

a Pediatric
Endocrinology and Diabetology (DECCP), Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg;
b DEUZWEG
German Center for Growth, Development and Health Promotion in Childhood and Adolescence, Berlin,
Germany

Keywords Introduction
Minipuberty · Testosterone · Estradiol · Gonadotropin ·
Hypothalamic-pituitary-gonadal axis Puberty is the physical maturation of a child’s body
into an adult body which is capable of sexual reproduc-
tion. This maturation is induced by an activation of the
Abstract hypothalamic-pituitary-gonadal (HPG) axis which
Minipuberty describes the transient sex-specific activation causes a gender-specific elevation in the gonadotrop-
of the hypothalamic-pituitary-gonadal (HPG) axis during ic hormones (luteinizing hormone [LH] and follicle-
the first 6 months of life in boys and during the first 2 years stimulating hormone [FSH]) and sex steroid hormones
in girls. It leads to a rise of luteinizing hormone, follicle-stim- (testosterone in males and estradiol in females). Clas-
ulating hormone, estradiol, and testosterone. The existence sical (canonical) puberty occurs in adolescence, but the
of minipuberty has been known for > 40 years, but we still HPG axis is activated prior to this, once in utero and
do not fully understand why it takes place. Current thinking once in the first months of life. The first 2 activations
suggests that it is an essential imprinting period for different of the HPG axis neither induce physical pubertal
body functions. Firstly, minipuberty plays an important role changes (no change in Tanner stage) nor result in the
in genital organ development; testosterone influences pe- capacity for reproduction. But the HPG axis activa-
nile growth, the number of Sertoli cells, and spermatogen- tions in utero and during the first months of life do
esis. Secondly, it seems to influence the infant’s body com- induce a gender-specific elevation in sex hormones;
position; testosterone likely has an imprinting effect on BMI they could, therefore, be described as “endocrine pu-
and body weight of boys and growth velocity in the first 6 berties.” Hence, humans experience 3 “endocrine pu-
months of life. Thirdly, it affects cognitive functions; testos- berties” [1] throughout life (Table 1; Fig. 1, 2). This re-
terone has an impact on language organization in the infant view focuses on the second transient endocrine puber-
brain and estradiol affects laryngeal sound production and ty, also called “minipuberty.” We address the issue of
baby babbling. There are inconsistent findings concerning why humans experience 3 endocrine puberties and not
the impact of minipuberty on sex-specific playing behavior. just 1. We examine which changes are induced by mi-
Minipuberty is an interesting field of research, and further nipuberty and its functions.
studies in this area will teach us more about this exciting
period of human development. © 2020 S. Karger AG, Basel

© 2020 S. Karger AG, Basel Dr. Marianne Becker

Pediatric Endocrinology and Diabetology (DECCP)
Centre Hospitalier de Luxembourg
karger@[Link]
4, rue Ernest Barblé, LU–1210 Luxembourg (Luxembourg)
[Link]/hrp [Link] @ [Link]
 Testosterone, ng/dL
LH, U/L
FSH, U/L

600 10

500 9
Testosterone, ng/dL

400 8

FSH, U/L
LH, U/L
300 7

200 6

100 5

0 0
12 22 Birth 1 2 3 4 5 6 8 10 12 14 16 18 20
Weeks of gestation Age, months Age, years

Fig. 1. Pattern of LH, FSH, and testosterone during the 3 endocrine puberties in boys.

Table 1. The 3 endocrine puberties during human development (according to Hesse [1])

Time period First description

1. Intrauterine weeks 10–24 of gestation Grumbach and Kaplan [3], 1974;

Reyes et al. [6], 1974
2. Postnatal 1–6 months Forest et al. [10], 1973
3. Classic (canonical) puberty girls: onset at 8–13 years
boys: onset at 9–14 years
variable duration of 3.5–4.5 years

Hormonal Analysis review, for each study, we will indicate the applied sam-
pling method, so as to enable the reader to make the best
Studies targeting minipuberty are based on hormone possible assessment of the data presented.
measurements in different matrices (the blood, saliva,
and urine) and at different time points. Further studies
are needed to evaluate the reliability of hormone-sam- A Short Description of the First Endocrine Puberty
pling methods in the saliva and urine. Recent data show
that direct immunoassays overestimate testosterone con- The first transient pubertal period takes place in utero
centrations, especially in female newborns, and that mea- [3] between the 10th and 24th gestational week. Levels of
surement by liquid chromatography-tandem mass spec- LH and FSH (measured by radioimmunoassay [RIA])
trometry (LC-MS/MS) is more reliable [2]. Hence, sam- peak at midgestation and progressively decline thereafter,
pling material and analytical method should be taken into until being completely suppressed at birth [4] by the ris-
account when evaluating studies on minipuberty. In this ing concentration of placental estrogen [5].

Minipuberty: Why Does it Happen? Horm Res Paediatr 2020;93:76–84 77

DOI: 10.1159/000508329
 Estrogen, pg/mL
LH, U/L
FSH, U/L

LH

Oestrogen

FSH
4,000

3,000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 27 60
Cycle, days

50
logarithmic scale

2,000
Estradiol, pg/mL

FSH, U/L
LH, U/L
40
1,000
30
100
20

10
10

0 0
12 22 Birth 1 2 3 4 5 6 8 10 12 14 16 18 20
Weeks of gestation Age, months Age, years

Fig. 2. Pattern of LH, FSH, and estradiol during the 3 endocrine puberties in girls.

In the male fetus, testosterone secretion (measured by the current research on minipuberty, focusing on its in-
RIA) peaks in the first trimester of pregnancy between the fluence upon: (1) the development of genital organs and
11th and 14th gestational week [6] (Fig. 1). Fetal testos- fertility, (2) somatic development, (3) cognitive develop-
terone is essential for normal genital development. The ment, and (4) behavior.
anogenital distance seems to be a marker of intrauterine
androgen exposure [7]. Fetal testosterone also influences Hormonal Changes during Minipuberty
sexually dimorphic brain development [8]. The rise of gonadotropins (LH and FSH) observed in
In the female fetus, the rise of gonadotropins in utero minipuberty stimulates testosterone production in the
is observed as well, but the estradiol production is pre- testicles in boys and estradiol production in the ovaries in
dominantly of placental origin. The estradiol peak occurs girls (Fig. 1, 2).
in the third trimester of pregnancy (Fig. 2). After birth, in the absence of placental steroids sup-
Corbier et al. [9] describe a sharp but short rise of tes- pressing the HPG axis, the HPG axis becomes progres-
tosterone (gas chromatography [GC]/MS) in male new- sively active again. Gonadotropin levels (RIA) rise ap-
borns, but no such rise was observed in girls. proximately 1 week postnatally [11].
LH levels (RIA) are higher in boys than in girls, peak-
ing between the 2nd and 10th week of life and declining
Minipuberty thereafter to prepubertal levels by the age of 4–6 months
[11–13]. FSH levels (RIA) are higher in girls than in boys
The second endocrine puberty takes places at the age during minipuberty [11–13] and stay elevated until the
of 1–6 months. This is the second transient activation of age of 3–4 years in girls, but not in boys (in whom a de-
the HPG axis. Minipuberty was first described by Forest cline to prepubertal values occurs by the age of 6 months)
et al. [10] in 1973. Since then, the elevation of hormones [12].
at minipuberty has been well characterized, and an in- In boys, LH stimulates testosterone production, so
creasing number of studies have been published in an at- the level of testosterone increases (RIA), peaking in the
tempt to understand this phenomenon. Here, we review 2nd–3rd month of life [13, 14]. During this time, the

78 Horm Res Paediatr 2020;93:76–84 Becker/Hesse

DOI: 10.1159/000508329
testosterone values may reach those of fertile adult men preterm babies is similar to that in full-term babies, but
[13, 14]. Androgen production seems to occur rather via that the HPG axis activation in the former is increased
the backdoor pathway than the classic pathway [15]. Be- and prolonged, resulting in higher sex steroid concentra-
fore the age of 6 months, testosterone levels will be again tions than in the latter.
in the prepubertal range. There is a wide interindividual It is still not clear by which mechanism the activation
variation in testosterone values [13]. A study based on of the HPG axis is silenced after a few months. Minipu-
salivary testosterone measurements concluded that, in berty is a window of opportunity to examine the HPG
contrast to the strong genetic contribution observed in axis. A serum LH and FSH measurement in this period
classical puberty, minipuberty seems to be strongly in- may help to diagnose infants with hypogonadotropic hy-
fluenced by environmental factors. It has been found pogonadism. Later in infancy, the HPG axis is physiolog-
that genetic variants influencing salivary testosterone ically quiescent, so diagnosing hypogonadotropic hypo-
levels (detected by enzyme immunoassay [EIA]) in gonadism at this early stage can help to induce puberty at
males are regulators of reproductive function and cho- the appropriate physiological age. Since the hormonal
lesterol; in females, genes related to estrogen signaling rise is gender-specific during minipuberty, hormone
are more important [16]. Further studies are needed to analyses can help to classify biological sex in infants with
understand the factors contributing to the interindivid- a suspected disorder of sexual development (DSD). The
ual variations in the transient sex hormone surge during observed optimal markers for the prediction of testicular
minipuberty. tissue are anti-Müllerian hormone AMH (by EIA), T (by
In some animal species, a transient activation of the LC-MS/MS), and the LH/FSH ratio (by fluoroimmunoas-
HPG axis in males is observed. In monkeys, a postnatal say [FIA]) [23].
rise of LH and testosterone (RIA) during the first 3
months is seen [17]. A testosterone surge (RIA) is also Minipuberty and Its Influence on Genital Organ
observed in neonatal male rats, male mice, and male foals Development and Fertility
[9]. In general, the transient rise in testosterone in boys or
Estradiol (RIA) rises more in girls than in boys [13, estradiol in girls is not followed by clinically visible phys-
14], with a level of Tanner stage 4 being normal in girls ical changes. Ultrasound evaluation of testicular size may
[18]. The difference between the sexes in the level of es- document a transient (not detectable by palpation) in-
tradiol is, however, less significant than the level of testos- crease in testicular volume during minipuberty [24]. In
terone [13, 14]. A study based on urinary estradiol mea- rare cases, the transient rise of sex hormones can result in
surements (using LC-MS/MS) postulated fluctuations transient clinical visible pubertal signs in otherwise
during minipuberty instead of a rise and subsequent fall healthy infants: vaginal bleeding in girls [25] or palpable
of estradiol concentration; they observed huge intrain­ testicular growth with the development of pubic hair in
dividual differences in serial urinary estradiol measure- boys [26, 27].
ments [19]. Regarding the persisting effects of minipuberty, the
Data on hormonal changes in minipuberty in preterm hormonal surge is of importance for penile growth and
babies are scarce. Reference data based on serum mea- testicular development in boys. Testosterone levels (RIA)
surements in 82 preterm babies for LH and FSH (mea- in minipuberty correlate positively with penile growth
sured by immunochemiluminometric assay [ICMA]) and penile growth velocity [28]. In preterm boys, the ac-
showed higher values for gonadotropins in preterm in- tivation of the HGP axis is increased, with higher (uri-
fants than in full-term infants, and higher LH and FSH nary) LH (TR-IFMA) and testosterone (LC-MS/MS)
values in preterm girls than in preterm boys [20]. This concentrations than in full-term boys, resulting in a sig-
was confirmed by a study based on serial urinary mea- nificantly faster testicular and penile growth [22]. In male
surements (using time-resolved immunofluorometric as- babies suffering from hypogonadotropic hypogonadism,
say [TR-IFMA]) [21]. Data on testosterone and estradiol treatment with subcutaneously administered gonadotro-
values during minipuberty are based only on serial uri- pins postnatally can provide normal penile growth and is
nary measurements (LC-MS/MS), showing a peak for tes- an effective therapy for micropenis in infancy [29], but
tosterone 4 weeks after birth (higher in preterm than in data about the outcome of long-term treatment are miss-
full-term boys [22]) and fluctuating levels of estradiol ing. Only 1 study has evaluated the long-term outcome of
(higher in preterm than in full-term girls [19]). Based on administering subcutaneous FSH in combination with
this evidence, it seems that the onset of minipuberty in intramuscular testosterone in the first months of life (in

Minipuberty: Why Does it Happen? Horm Res Paediatr 2020;93:76–84 79

DOI: 10.1159/000508329
3 patients) [30]. This study showed no difference in in- been described [42]. Furthermore, in preterm girls, a pos-
hibin β values (as a marker for Sertoli cell function) at a itive correlation between urinary estradiol (LC-MS/MS)
pubertal age between infants that had been treated with and uterine growth as well as mammary gland diameter
gonadotropins at minipuberty and a nontreated control has been observed [19]. There are no data available con-
group. Penile length was not commented on in this study. cerning longer-lasting effects of estradiol concentration
More studies are warranted to evaluate the long-term ef- during minipuberty on fertility or breast and uterine de-
ficacy of this treatment. velopment in adult women.
During minipuberty, an increase in the number of
Sertoli cells [31] and germ cells [32] is observed in the Minipuberty and Its Influence on Somatic
testicles. As Sertoli cells do not express an androgen re- Development
ceptor during infancy, the rise in testosterone during There are studies evaluating the influence of minipu-
minipuberty does not induce spermatogenesis [33]. berty on body composition and growth.
However, the postnatal transient activation of the HPG
axis seems to play an important role in fertility in boys. Body Composition
Several studies in cryptorchidic boys showed an insuf- Hormone concentrations during minipuberty influ-
ficient maturation of gonadocytes into type A-dark ence the somatic development during the first 6 years in
spermatocytes [34]. Even after timely orchidopexy, boys. Testosterone (RIA) and LH (using microparticle
there is a risk of infertility (38% in bilateral cryptorchi- enzyme immunoassay [MEIA]) concentrations during
dism [35]), but an improved fertility index can be ob- minipuberty correlate negatively with body weight and
tained after treatment with gonadotropin-releasing hor- body mass index until the age of 6 years. The level of es-
mone (GnRH) analog during the first year of life prior tradiol (RIA) during minipuberty correlates positively
to orchidopexy [36]. This supports the hypothesis that with the skin-fold thickness during the first 6 years.
cryptorchidism is not the cause of infertility, but rather No such influence has been observed in girls [13]. In
a sign of a disturbed HPG axis. According to this hy- studies on female rats, it has been demonstrated that post-
pothesis, the abnormal HPG axis and ensuing defective natally administered estradiol and testosterone has a pro-
minipuberty influence future infertility. The current Eu- gramming effect on the development of adipose tissue
ropean guideline for urology from 2016 therefore sug- later in life [43, 44].
gests offering treatment with a GnRH analog to boys
with bilateral undescended testes to improve their fertil- Growth
ity outcome [37]. On the other hand, there are studies Data on the influence of minipuberty on growth veloc-
showing a higher rate of germ cell apoptosis in adults ity are conflicting. One study, with 84 participants, re-
after prepubertal human chorionic gonadotropin (hCG) vealed a positive correlation of serial urinary testosterone
treatment for cryptorchidism [38]. As there is a lack of (LC-MS/MS) on growth velocity in the first 6 months in
evidence of long-term efficacy to improve fertility by boys and girls [45]. Another study, based on serial serum
hormonal treatment, the current guideline of the Amer- testosterone measurement in 35 babies, found no correla-
ican Urology Association from 2014 [37] and the con- tion between testosterone concentration (RIA) during
sensus of the Nordic countries from 2007 [39] do not minipuberty and growth velocity at any time point during
recommend hormone therapy. Further studies evaluat- the first 6 years [13]. Whether this difference is due to the
ing adult fertility and the potential side effects after pre- different sampling materials (urinary vs. serum testoster-
operative GnRH therapy during the first year of life are one) or the small sample sizes needs to be elucidated by
therefore urgently required. In animal models, Li et al. further studies.
[40] (using LC-MS/MS) and Chen et al. [41] (using en- In a retrospective study on infants with multiple pitu-
zyme-linked immunosorbent assay [ELISA]) showed itary hormone deficiency (including growth hormone de-
that the postnatal transient testosterone surge influenc- ficiency), growth under early growth hormone substitu-
es gonocyte transformation and testicular function in tion (starting in the first year of life) was improved in
male rats and mice. those not suffering from hypogonadism (but not in those
In girls, there is less evidence to support the influence with hypogonadism, and hence not having a minipuber-
of minipuberty on fertility and development of the genital ty), suggesting a potential impact of minipuberty on
organs, but a positive correlation of the mammary gland growth during the first year of life [46].
diameter and estradiol (RIA) at the age of 3 months has

80 Horm Res Paediatr 2020;93:76–84 Becker/Hesse

DOI: 10.1159/000508329
 Minipuberty and Its Influence on Cognitive Minipuberty and Its Influence on Behavior
Development There are several studies examining the influence of
The hormonal rise during minipuberty affects not minipuberty on behavior. A study based on salivary tes-
only somatic development, but also cognitive develop- tosterone measurement (EIA) in infants (males and fe-
ment. Brain plasticity remains high during minipuberty males aged 3–4.9 months) revealed a correlation between
and the brain continues to develop rapidly throughout testosterone levels and scores on the Distress to Limita-
the early postnatal period [47], making a possible influ- tions scale (based on the Infant Behavior Questionnaire-
ence of minipuberty on brain development conceivable. revised, which was completed by their parents) in the
It is a well-known fact that, on average, girls tend to male infants. Based on this study, it has been hypothe-
acquire linguistic skills earlier and with a greater level of sized that testosterone levels during minipuberty could
complexity than boys [48]. influence emotional regulation in male infants [56]. A
Several studies based on 1 cohort of patients showed further study by this group showed that, in male infants,
associations of gonadotrophic and sex hormone values higher salivary androgen levels predicted a stronger pref-
during minipuberty with speech development. In 4-week- erence for male-typical stimuli at the age of 3–4 months
old babies, recording event-related brain potentials (ERP) [57]. In this study cohort, no significant differences be-
revealed a clear phonological discrimination effect with a tween the sexes in salivary testosterone levels (EIA),
bilateral distribution in girls. In boys, the discrimination which are extremely sex-distinct during this time period
effect was correlated with the testosterone value (RIA) at in the serum (RIA) [13], were observed. This might have
this age. Boys with a high level of testosterone showed no been due to the sampling material that was chosen or the
discrimination effect, but those with a low testosterone delayed sampling time (after the age of 3 months). Based
level showed a left lateralized discrimination effect [49]. on the same cohort, a correlation of the obtained salivary
The level of estradiol (RIA) at the age of 4 weeks has testosterone values (EIA) at the age of 3–4.9 months with
been positively correlated with the melody complexity in- play behavior and eye-contact time at the age of 19 months
dex (MCI) at the age of 4 and 8 weeks. The MCI is an in- was analyzed. It was observed that there was no influence
dex of an infant’s frequency modulation skills and pro- of salivary testosterone levels during minipuberty on gen-
vides melodic primitives for language [50]. The estradiol der-linked play behavior [58] or eye-contact time [59] in
level (RIA) at the age of 4 weeks was also positively cor- young children of either sex.
related to the individual infant’s articulatory skills (by Another study, based on urinary testosterone mea-
means of ART, which is a measure to evaluate the infant’s surement (LC-MS/MS) during the first 6 months of life,
ability to babble) at the age of 5 months. Interestingly, found a correlation to sex-typed behavior (evaluated by
testosterone serum concentration (RIA) at the age of 20 the Preschool Activity Inventory) at the age of 14 months
weeks was negatively correlated with their babbling ca- [60]. This has been supported by a study which used pe-
pacity [51]. The observation that “free estradiol” (SHBG- nile growth during the first 3 months as an indirect mark-
E2) measured at the age of 5 months (RIA) was positively er for testosterone concentrations during minipuberty.
correlated and testosterone (RIA) was negatively corre- This study revealed a significant positive correlation be-
lated with sentence comprehension at the age of 4–5 years tween penile growth during the first 3 months and mas-
could be interpreted as an expression of possible long- culine behavior, and a negative correlation with feminine
term effects [52]. behavior at the age of 3–4 years (assessed using the Pre-
These data are in line with the findings of a study based school Activities Inventory) [61].
on salivary testosterone measurements (EIA). Salivary tes- In studies with Rhesus monkeys, the manipulation of
tosterone at the age of 1–3 months was negatively corre- the postnatal testosterone surge significantly affected pe-
lated to the size of the parent-reported expressive vocabu- nile growth and development but did not affect the ex-
lary in boys and in girls, and mediated the sex difference in pression of sex differences in play and sexual behavior
the expressive vocabulary at 18–30 months of age [53]. [62, 63].
These studies all suggest that sex hormone concentra- A study which evaluated the influence of the first (in
tions during minipuberty may indeed influence language utero) endocrine puberty demonstrated a positive corre-
development up to the age of 5 years. The findings are lation of fetal testosterone (measured in the amniotic flu-
supported by animal studies which show that postnatally id by RIA) and the Quantitative Checklist for Autism in
administered sex hormones influence brain development Toddlers (Q-CHAT) [64]. This raises the question of
and behavior later in life [54, 55]. whether minipuberty (the second endocrine puberty)

Minipuberty: Why Does it Happen? Horm Res Paediatr 2020;93:76–84 81

DOI: 10.1159/000508329
possibly influences autism spectrum disorder (ASD). composition. Furthermore, there is evidence suggesting a
Only a few studies have been conducted in this field. Sal- potential impact of minipuberty on language develop-
ivary testosterone levels (EIA), measured in 84 infants at ment in both sexes. Inconsistent data exist concerning the
3–4.9 months of life, revealed that higher postnatal testos- influence of minipuberty on behavior.
terone concentrations in early infancy were predictive of Many studies are based on salivary or urinary hor-
higher scores on the ASD scale and lower verbalization at mone analysis, for which a validation is still missing. LC-
the age of 18 months [65]. Conflicting data were reported MS/MS measurements are more reliable than direct im-
in another study, also based on salivary testosterone mea- munoassays [2]. It is therefore important to take the sam-
surements (EIA) in 35 participants at the age of 3–4 pling material and analytical method into account when
months; the results suggested no relationship between evaluating studies concerning minipuberty.
testosterone and scores of the Q-CHAT in 18–24 months Minipuberty is an interesting field of research and fur-
old children [66]. ther studies will teach us more about this exciting period
A more recent study has reevaluated whether salivary of human development.
testosterone values (EIA) obtained at the age of 1–3
months (the sample timing corresponding better to the
testosterone peak during minipuberty) correlated with Acknowledgement
the Q-CHAT score at the age of 18–30 months in 87 ba-
bies. In this study, no correlations of testosterone values We are grateful to Prof. Carine de Beaufort and Mr. Sean Sap-
and Q-CHAT scores were found in boys or girls [67]. cariu, PhD, for critical review of the manuscript, and Mrs. Maële
Dahin for her assistance with the graphs.
Most likely, testosterone values during minipuberty are
not associated with an increase in autistic traits, but fur-
ther studies are needed to clarify this issue. The intra-
uterine effects of testosterone seem to be of more impor- Disclosure Statement
tance for autism development than the postnatal effects
The authors have no conflicts of interest to declare.
[64].
So far there is no clear evidence of an influence of sex
hormone concentrations during minipuberty on sex-typ-
Funding Sources
ical behavior. More studies are needed to address this
question. The authors did not receive any funding.

Conclusion Author Contributions

Minipuberty is the second physiological transient ac- Both authors designed this review. M.B. drafted the manuscript
and V.H. revised it critically. Both authors approved the final ver-
tivation of the HPG axis occurring in healthy infants at
sion to be published and agree to be accountable for all aspects of
the age of 1–6 months. It plays an important role in the the work in ensuring that questions related to the accuracy or in-
development of the genital organs and fertility in males tegrity of any part of the work are appropriately investigated and
and seems to influence the development of their body resolved.

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