Puberty: Physiology and Abnormalities, 1st ed. 2016

3. Hormonal Changes in Childhood and Puberty

Rodolfo A. Rey Stella M. Campo María Gabriela Ropelato  and Ignacio Bergadá 


Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET-FEI-División de Endocirnología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, Buenos Aires, C1425EFD, Argentina

Rodolfo A. Rey (Corresponding author)


Stella M. Campo


María Gabriela Ropelato


Ignacio Bergadá





The functional ontogeny of the hypothalamic-pituitary-gonadal axis has particular features that distinguish it from most organs and systems characterized by functional differentiation in early fetal life and complete maturation reached by birth or infancy. Conversely, the gonadal axis displays an incomplete development in utero and during early postnatal life, followed by a functional quiescence of part of the axis during childhood and full maturation during puberty. Although this ontogeny seems to reflect exclusively the changes in the activity of the hypothalamic-gonadotrope axis, a careful look into gonadal developmental physiology uncovers local distinctive features that are also involved in the resulting ontogeny of the reproductive system. In this chapter, we will address the latest understanding on the regulation of the gonadal axis in males and females during development. We will particularly focus on the concept that childhood is not a period of complete quiescence of the gonads and on the differences observed in gonadal function between the early postnatal activation period—which many authors call “mini-puberty”—and canonical puberty. Finally, we will briefly discuss the changes observed in other hormonal axes, which are also related to growth and development.

Hormonal Changes in the Male Reproductive Axis

Fetal Life

Initial functional differentiation of endocrine testicular cell populations is independent of pituitary gonadotropins (reviewed in ref [1]). Sertoli and germ cells aggregate to form the seminiferous cords during the seventh fetal week, whereas mesenchymal cells differentiate into Leydig cells in the interstitial tissue in the eighth week. Sertoli cells secrete anti-Müllerian hormone (AMH) , responsible for the regression of the Müllerian ducts, i.e., the anlagen of the uterus, fallopian tubes, and upper vagina, and Leydig cells secrete androgens and insulin-like factor 3 (INSL3) . Androgens drive fetal virilization of the genitalia and, together with INSL3, are required for testis descent to the scrotum.

In the first trimester, the predominant gonadotropin is human chorionic gonadotropin (hCG) secreted by the placenta. The hypothalamic nuclei that secrete gonadotropin-releasing hormone (GnRH) and the pituitary gonadotrope differentiate later: luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are secreted into the bloodstream from the 17th fetal week (reviewed in [2]). Gonadotropin levels decrease in the third trimester [3], probably due to the negative feedback exerted by placental estrogens.

Placental hCG and pituitary LH induce androgen secretion in Leydig cells. Testosterone levels are high, reaching adult levels, between the 10th and 20th fetal weeks, and decrease during the third trimester (reviewed in [2]).

Basal AMH production is independent of gonadotropins throughout life; however, FSH increases testicular AMH secretion by stimulating Sertoli cell multiplication and upregulating AMH expression in each Sertoli cell [4]. FSH also induces inhibin B secretion by Sertoli cells; inhibin B exerts a negative feedback on FSH.

Birth and Infancy

The circulating levels of gonadotropins and testicular hormones are low at birth (Table 3.1) [57]. During the first week of life, gonadotropins increase [6]; in the male, LH levels are higher than FSH (Fig. 3.1). The LH surge drives testosterone and INSL3 secretion. Importantly, for testosterone measurement, serum samples must be extracted to avoid interferences that artificially overestimate results in the first 2 weeks of life [6]. Peak levels of LH, testosterone, and INSL3 are reached during the third month [79]; thereafter, they decrease to very low or undetectable from approximately 6 months of age until the onset of puberty (Fig. 3.1).

Table 3.1

Reproductive axis hormone levels (median and 3rd and 97th percentiles) in boys from birth to puberty (Tanner stages G1 to G5)


Tanner stage




Inhibin B (pg/mL)






1–3 daysa


0.13 (0–1.10)

0.20 (0–3.97)

48 (18–148)

1.66 (0.62–5.13)

217 (62–444)

328 (140–819)

46 (20–115)

7–14 daysa


3.50 (0.08–9.57)

1.75 (0.33–6.90)

71 (17–325)

2.46 (0.59–11.27)

297 (95–625)

411 (119–877)

58 (17–123)

20–30 daysa


2.60 (0.51–5.90)

1.40 (0.54–2.50)

113 (43–508)

3.92 (1.49–17.61)

309 (203–540)

588 (324–1197)

82 (45–168)

1–6 monthsb


0.29 (0.10–2.92)

0.50 (0.15–2.19)

193 (18–355)

6.69 (0.62–12.31)

421 (320–640)

697 (421–1470)

98 (59–206)

6 months–1.9 yearsb


0.10 (0.10–0.35)

0.56 (0.30–1.26)

10 (10–10)

0.35 (0.35–0.35)

240 (80–609)

1132 (684–2329)

159 (96–326)

2.0–8.9 yearsb


0.10 (0.10–0.18)

0.75 (0.24–1.70)

10 (10–10)

0.35 (0.35–0.35)

179 (78–389)

684 (236–1831)

96 (33–256)

9–18 yearsb


0.10 (0.10–2.78)

1.70 (0.58–2.54)

10 (10–108)

0.35 (0.35–3.74)

95 (43–282)

714 (257–1371)

100 (36–192)



0.80 (0.12–2.76)

2.08 (1.20–4.08)

12 (10–182)

0.42 (0.35–6.31)

156 (67–227)

295 (69–1017)

41 (10–142)



2.43 (0.67–4.65)

2.96 (1.43–7.44)

182 (12–368)

6.31 (0.42–12.76)

201 (91–371)

71 (30–423)

10 (4–59)



3.03 (1.44–5.03)

3.55 (2.05–7.94)

392 (187–664)

13.59 (6.48–23.02)

154 (115–271)

65 (33–164)

9 (5–23)



2.90 (1.34–6.31)

2.55 (1.14–6.99)

438 (114–682)

15.19 (3.95–23.65)

174 (110–278)

82 (38–195)

11 (5–27)

aData from [6]

bData from [10]


Fig. 3.1

Schematic representation of the ontogeny of pituitary-testicular serum hormone levels from birth to puberty (Tanner stages G1 to G5) and its relationship to androgen receptor (AR) expression in Sertoli cells and testicular histology. At 3 months (A), Leydig cells of the interstitial tissue secrete testosterone, but percentage of Sertoli cells positive for AR is extremely low or null; consequently, AMH production is not inhibited by testosterone, and spermatogenesis does not progress into meiosis. At 8 years (B), more almost 100 % of Sertoli cells express the AR, but the interstitial tissue does not have mature Leydig cells and testosterone is low; therefore, Sertoli cells remain immature, AMH is high, and no meiosis occurs. At late puberty (C), Leydig cells produce high testosterone levels, which provoke the maturation of AR-positive Sertoli cells, reflected in the inhibition of AMH and also in the development of full spermatogenesis. Gn - gonadotropins (Adapted from Rey RA, Musse M, Venara M, Chemes HE. Ontogeny of the androgen receptor expression in the fetal and postnatal testis: its relevance on Sertoli cell maturation and the onset of adult spermatogenesis. Microsc Res Tech 2009; 72: 787–95. With permission from John Wiley & Sons, Inc.)

AMH and inhibin B levels also increase progressively through infancy (Table 3.1) [61012]. In the first months of life, the surge may be linked to FSH-dependent Sertoli cell proliferation [13]. AMH and inhibin B are useful biomarkers of FSH action [14], as seen in neonates with congenital central hypogonadism [15].

This postnatal activation of the hypothalamic-pituitary-gonadal axis has been called “mini-puberty” and is reflected in subtle clinical changes in the male: Sertoli cell proliferation results in a minor increase in testicular volume, which can only be detected by ultrasonography (reviewed in [16]), and Leydig cell androgen production has a trophic effect on the genitalia. Interestingly, the high androgen levels observed during fetal life and the postnatal period are not capable of inducing Sertoli cell maturation and full spermatogenesis, as they do during puberty (see below). The lack of androgen effect on the seminiferous cords may be explained by the fact that the androgen receptor is not expressed in Sertoli cells in the first year of life (Fig. 3.1) [17]. Actually, when the axis activation abnormally continues beyond the age of 1 year, persistently elevated testosterone results in signs of seminiferous tubule maturation like those observed during canonical puberty, e.g., AMH downregulation and inhibin B increase [18].

Key Points

·               In the first week after birth, serum levels of gonadotropins and testicular hormones are low.

·               Testosterone levels in serum samples should be performed after steroid extraction in the first 2 weeks of life.

·               Until the age of 3–6 months, basal gonadotropin levels are useful markers of pituitary function, testosterone and INSL3 reflect Leydig cell activity, and AMH and inhibin B are indicative of Sertoli cell function.


After the third to sixth months of life in the male, gonadotropins, testosterone, and INSL3 are very low in serum (Fig. 3.1 and Table 3.1). Therefore, the assessment of Leydig cell function during childhood through testosterone or INSL3 determinations requires stimulation with exogenous hCG administration (reviewed in [9]). The decrease in gonadotrope activity during childhood—reflected in low LH and FSH circulating levels—does not seem to be dependent on a negative feedback by testicular factors, since it also occurs in anorchid boys [19].

Classically, childhood has been described as a quiescent period of the gonadal axis, on the basis of low gonadotropin and testosterone serum levels. However, Sertoli cells remain active: they secrete high levels of AMH, a typical marker of the prepubertal testis, and inhibin B (Fig. 3.1). Serum AMH and inhibin B are useful biomarkers to study testicular function during the inadequately called prepubertal “pause” of the reproductive axis.

Key Points

·               During childhood, basal serum gonadotropins, testosterone, and INSL3 are very low or undetectable with routine methods in normal boys, so they are not useful markers of the pituitary-Leydig cell axis unless stimulation tests are used.

·               Basal serum AMH and inhibin B are high and should be used as primary biomarkers of testicular function.


From a clinical standpoint, puberty refers to the period of life spanning 3–5 years characterized by the development of secondary sexual characteristics and the progressive acquisition of the reproductive capacity. In the male, the clinical landmark of pubertal onset is gonadarche, i.e., when testicular volume attains 4 ml (Fig. 3.2). However, it is clear that the physiology of puberty begins somewhat earlier, with a progressive increase in gonadotropin pulse amplitude and frequency (reviewed in [20]). Gonadarche occurs at a mean age of 11.5 years in boys [21]; when it occurs before the age of 9, puberty is considered to be precocious, while it is considered as delayed puberty when gonadarche occurs between 14 and 18 years of age.


Fig. 3.2

Schematic representation of the pubertal events in the pituitary-testicular axis. The first events are clinically undetectable: when the boy is in Tanner stage 1, gonadotropin levels increase, FSH provokes Sertoli cell proliferation, and LH induces Leydig cell maturation. After some time, the increase in Sertoli cell number is reflected in testicular volume (TV) progression to 4 ml, the clinical milestone of pubertal onset. During Tanner stage 2, intratesticular testosterone concentration increases and provokes Sertoli cell maturation, reflected in downregulation of AMH, increase of inhibin B, and onset of adult spermatogenesis; testicular volume further increases. In Tanner stage 3, the increase in serum testosterone becomes evident, and secondary sex characteristics start developing. During Tanner stages 4 and 5, full testicular volume and secondary sex characteristics are attained

At the onset of puberty, the increase in FSH secretion by the gonadotrope induces the proliferation of immature Sertoli cells and boosts testicular volume from 2 to 4 ml, clinically reflected in Tanner stage 2. LH drives the maturation of Leydig cells, which provokes a progressive increase in androgen concentration within the testis resulting in Sertoli cell maturation (reviewed in [22]). Consequently, Sertoli cell proliferation stops, AMH production declines [1012], and inhibin B secretion rises [2324], as seen in Tanner stages 2–3 (Table 3.1). The increase in serum testosterone levels is a later event, occurring in Tanner stages 3–5 [25], when testicular volume is above 10 ml. Androgens are aromatized to estrogens, and breast development (“gynecomastia”) occurs in more than half of normal boys during mid- to late puberty. This physiological event usually reverses spontaneously . Steroid hormones are essential for the occurrence of peak height velocity in Tanner stages 3–4. INSL3 secretion also increases during puberty but becomes gonadotropin independent once adult Leydig cells become fully differentiated (reviewed in [9]).

Germ cells undergo the complete spermatogenic process, leading to sperm production (Fig. 3.1) and to the overt increase in testis volume to 15–25 ml in Tanner stages 4–5 (Fig. 3.2) (reviewed in [22]). FSH and spermatogenesis are essential for inhibin B production, which in turn acts as a negative feedback regulator of pituitary FSH [26]. Therefore, in puberty and adulthood, inhibin B is an extremely informative biomarker of testicular function, since it reflects the whole pubertal maturation process, i.e., FSH and testosterone action on Sertoli cells and spermatogenesis.

It is noteworthy that gonadotropin and androgen levels are equally high during fetal life, the postnatal activation (or “mini-puberty”), and puberty, but clinical signs of seminiferous tubule maturation—like AMH downregulation and complete spermatogenesis leading to testis enlargement—only occur during pubertal development. As mentioned before, the ontogeny of the androgen receptor in Sertoli cells seems to be the underlying explanation: in the human, androgen receptor expression appears faintly in few Sertoli cells by the end of the first year. A progressive increase occurs between 2 and 8 years, and by the age of puberty, all Sertoli cells are strongly positive for the androgen receptor (reviewed in [22]).

Key Points

·               In the initial steps of puberty, serum LH and FSH increase by pulses.

·               Serum AMH decreases and inhibin B increases, reflecting Sertoli cell maturation induced by intratesticular androgens, before serum testosterone increases.

·               Serum inhibin B is an excellent biomarker of androgen and FSH action on spermatogenesis.

Hormonal Changes in the Female Reproductive Axis

Fetal Life

The development of the ovary takes longer than that of the testis in fetal life, and it does not occur in the absence of germ cells. Another sexual dimorphism is that oogonia enter meiosis during fetal life, whereas male germ cells only initiate meiosis at puberty. Primary oocytes become surrounded by flattened follicular cells to form primordial follicles, which represent the quiescent follicle ovary reserve. Progressively, flattened cells change to cubic (granulosa) cells, resulting in the formation of primary follicles at around 20 weeks of fetal life. By the 26th week, primary follicles have grown and produce low amounts of AMH [27], which have no effects on Müllerian derivatives because the AMH receptor is no longer expressed. Follicular maturation proceeds to the small antral stage during the last stages of intrauterine life. At this moment, the first meiotic division reaches diplotene stage and becomes arrested until puberty. Estrogen production by the ovary during fetal life is minimal, as compared to high estrogen production by the placenta. Ovarian development up to the seventh month of fetal life occurs independently of fetal gonadotropins [28]. Indeed, follicular development until the small antral stage is mostly gonadotropin independent. During the first half of gestation, female fetuses have higher serum LH and FSH levels than male fetuses. This sex difference has been explained by the absence of a negative feedback. LH and FSH levels decrease toward the end of gestation and are low at term due to high circulating estrogen levels [3].

Birth and Infancy

At birth, gonadotropin levels are low in girls (Table 3.2). Placental hormones are cleared from the newborn circulation during the first postnatal days [5]. By the end of the first week [6], FSH and LH levels start to increase and peak between the first and sixth months [27]. A sexual dimorphism in gonadal inhibin production is evident in the newborn. This dimorphism starts during fetal development, when the inhibin α-subunit is not expressed in the fetal ovaries [29], and is reflected at birth, when inhibins A and B are undetectable in females (Table 3.2). Serum levels of inhibins A and B increase during the first weeks of life [6].

Table 3.2

Reproductive axis hormone levels (median and 3rd and 97th percentiles) in girls from birth to puberty (Tanner stages B1 to B5)


Tanner stage



E2 (pg/mL)

Inhibin Ba (pg/mL)




2–7 days


0.13 (0.10–1.0)

0.51 (0.19–17.5)

65 (27–94)

Non detectable

6 (ND–25)

0.8 (ND–3.5)

7–30 days


0.45 (0.10–1.8)

6.7 (0.30–20.7)

42 (27–55)

Not available

12 (ND-64)

1.6 (ND–8.9)

1–6 months


0.30 (0.10–0.50)

4.8 (3.5–9.0)

40 (10–60)

48 ± 8.5

15 (4.5–29.5)

2.1 (0.6–4.1)

6 months–2 years


0.17 (0.10–0.30)

3.2 (0.57–7.5)

25 (10–40)

17.5 ± 1.6

8 (3.0–18.9)

1.1 (0.4–2.6)

2–8 years


0.10 (0.10–0.30)

2.2 (0.57–4.6)

10 (10–16)

38.0 ± 8.4

10.9 (1.9–39.2)

1.5 (0.3–5.5)

8–18 years


0.50 (0.10–1.6)

2.8 (0.78–4.8)

25 (10–60)

39 ± 8.3

19.9 (4.7–60.1)

2.8 (0.7–8.4)



1.2 (0.30–5.3)

4.6 (1.1–7.3)

34 (11–71)

60.6 ± 6.1



2.97 (0.41–8.5)

5.4 (2.1–8.6)

42 (20–77)

133.5 ± 14.3


B4 and B5b

4.97 (1.2–8.7)

5.4 (1.3–10.8)

68 (30–166)

66.9 ± 6.4

aValues are expressed as mean ± SEM

bAt early follicular phase

ND - non detectable.

The postnatal gonadotropin surge induces ovarian follicular development and increase of ovarian granulosa cell products, estradiol, inhibin B, and AMH. During the first 2 years, FSH secretion predominates in girls and induces maturation of ovarian follicles; thus, large follicles and measurable estradiol concentrations might be observed [227]. Estradiol levels fluctuate—probably reflecting maturation and atresia of ovarian follicles—and then decrease during the second year of life.

Key Points

·               At birth, inhibin B and AMH are undetectable in serum. In the first week after birth, gonadotropins and estradiol are low.

·               Serum levels of FSH, LH, AMH, and inhibin B increase during the first weeks of life.

·               During the first 2 years of age, FSH concentration is higher than LH.

·               Serum AMH and inhibin B are useful markers of ovarian function, particularly when highly sensitive estradiol assays are not available.


At the end of the 2nd year of life, a gradual dampening of GnRH secretion activity starts in girls, leading to its relative quiescence during childhood because of steroid-independent (predominant) and steroid-dependent inhibitory mechanisms [2]. Consequently, FSH, LH, and estradiol secretion are low (Table 3.2). FSH secretion is predominant (about 10–50 times higher than LH), largely higher than in boys [3031]. This gender dimorphism may be due to the lower inhibin B production by the ovary [11]. Serum LH and estradiol levels are hardly detectable in girls, even using ultrasensitive assays [3032]. The presence of measurable serum levels of inhibin B and AMH in females during childhood reflects functionally active gonads. However, the absence of inhibin A suggests that the follicles present in the ovary have not reached an advanced stage of antral development. During childhood, serum FSH levels are insufficient to sustain full follicular development, and a large number of small developing follicles become atretic.

Key Points

·               FSH concentration is measurable and LH is very low or undetectable LH. FSH response is predominant to stimulation tests with GnRH or with GnRH agonists.

·               AMH and inhibin B reflect functionally active gonads and are markers of the ovarian reserve.


Like in boys, in girls gonadarche follows a prior increase in the amplitude of GnRH pulses and—consequently—of LH and FSH secretion, taking place initially at night and then, as puberty advances, throughout the day. The clinical onset of puberty or gonadarche in girls is marked by breast development (“thelarche”), which occurs at a mean age of 9.7 years [21]. When thelarche occurs before the age of 8, puberty is considered as precocious.

Progressive increases in LH, FSH, and estradiol serum levels are observed all throughout puberty (Table 3.2). Serum LH concentrations increase 10- to 50-fold as compared to childhood, while FSH concentrations increase two- to threefold. As a result, the serum LH/FSH ratio is approximately 1 at Tanner stages 4 and 5. Also, the onset of puberty is characterized by an increased serum LH response to GnRH or GnRH agonists [33].

From pubertal onset, the “initial recruitment” of primordial follicles to reach the small antral stage—which is gonadotropin independent—is followed by a tonic follicular growth phase stimulated by FSH and finally by a “cyclic recruitment” of the follicle that will be ovulated during each menstrual cycle .

Levels of inhibin B increase through pubertal Tanner stages 2 and 3, possibly reflecting its production by small antral follicles in response to gonadotropin stimulation. Inhibin B levels attained at Tanner stage 3 are higher than those observed in adult women. AMH levels do not change considerably, although the peak seems to be reached peripubertally [3435]. It has been proposed that this stage of pubertal development may represent a period of consistently high ovarian follicular activity before the development of the adult menstrual cycle, with ovulation and a luteal phase [36]. The progressive and sustained increment of inhibin B serum levels throughout pubertal development would be the signal that the pituitary gland receives to initiate a full functioning negative feedback mechanism between inhibin and FSH.

Key Points

·               Serum LH concentrations rise at puberty to levels 10–50 times higher than prepubertal levels, while FSH concentrations increase 2–3 times during puberty.

·               A rise in serum inhibin B levels during puberty may reflect follicle development induced by FSH in early puberty.

·               The increment of inhibin B throughout pubertal development initiates full functioning negative feedback between this peptide and FSH.

·               AMH reaches its peak levels peripubertally.

Menstrual Cycle

The first menstrual bleeding is known as menarche and occurs between 1.5 and 3 years after thelarche (reviewed in [37]). Gonadotropins , follicular development, and ovarian steroids and inhibins exhibit a well-defined cyclic pattern during menstrual cycles. During the early postmenarcheal years, menstrual cycles can range from 21 to 45 days, and anovulatory cycles are predominant [38]. Regular menstrual cycles are attained 3–5 years post-menarche. The menstrual cycle is divided into a “follicular phase” (first day of bleeding until ovulation) followed by a “luteal phase.” As each menstrual cycle begins, FSH concentrations rise over LH concentrations, and consequently, multiple small antral follicles are recruited to begin preovulatory development. By cycle day 8, one follicle becomes selected to ovulate due to its increased responsiveness to FSH and LH, while the remainder follicles become atretic. The dominant follicle reaches more than 10 mm in diameter and increasingly synthesizes estradiol. Later, at the end of follicular phase, it grows up to 20 mm in diameter. This follicle, known as Graafian follicle, produces a sharp increase in serum levels of estradiol that becomes sufficient to produce a positive feedback on pituitary LH secretion. This results in the mid-cycle LH surge, which in turn provokes ovulation [3940]. After ovulation, during the luteal phase, the remaining granulosa cells that are not released with the oocyte become luteinized and combine with the newly formed theca lutein cells and surrounding stroma in the ovary to form the corpus luteum, a transient endocrine organ that predominantly secretes progesterone. The high levels of estradiol and progesterone attained at mid-luteal phase slow GnRH pulse frequency [41], which results in a predominance of FSH secretion initiating the next cycle of follicular development.

Serum AMH shows only minimal—clinically irrelevant—variations during the spontaneous menstrual cycle, since it reflects the small follicle ovarian reserve [42]. Inhibin B increases primarily during the follicular phase, while inhibin A predominates in the luteal phase. Inhibin B is produced at early stages of follicular development, whereas inhibin A is preferentially secreted by more differentiated follicular and luteinized cells [43]. The high-molecular-weight precursor of the inhibin α-subunit is present in circulation during the follicular phase as well as during the luteal phase.

Key Points

·               Menstrual cycles are irregular and frequently anovulatory in the first 2 years after menarche.

·               Gonadotropins, estrogens, and progesterone show a typical cyclic variation.

·               AMH barely changes throughout the cycle, whereas inhibin B is higher during the follicular phase and inhibin A during the luteal phase.

Hormonal Changes in Other Axes

The Adrenal Axis

The ontogeny of the adrenal cortex shows major differences between fetal and postnatal steroidogenic activity. During fetal life, the so-called fetal zone of the cortex occupies approximately 80 % of the gland. Steroid synthesis is predominantly represented by pregnenolone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) in the fetal zone. The outer zone is responsible for cortisol production under the influence of fetal adrenocorticotropic hormone (ACTH) from the eighth week and aldosterone. However, the fetal adrenal gland has little 3β-hydroxysteroid dehydrogenase activity. The placenta is rich in this enzyme, catalyzing the conversion of pregnenolone to progesterone, which is used by the fetus in the biosynthesis of aldosterone and cortisol, thus closing the adrenal fetal-placental circuit.

After birth and during the first months of life, a significant regression (approximately 50 %) of the adrenal gland occurs concomitantly with a marked decrease in the production of DHEA. Serum concentrations of cortisol vary widely in neonates with low levels close to the detection limit of the assay [44]. The circadian rhythm of cortisol appears to be installed by the end of the first year of life, although a wide interindividual variability exists [45]. Between the first and fifth years of life, serum concentrations of androstenedione and DHEAS remain very low.

From the age of 5–6 years, adrenarche occurs featuring a progressive increase in the secretion of androstenedione and DHEA . Although they are metabolites with weak androgen activity, in some cases they are responsible for some degrees of clinical manifestation such as body odor, pimples on the face, axillary hair, and/or pubic hair of different magnitude. Usually these manifestations are observed from the age of 7 years in girls and 8 years in boys. The physiological mechanisms of adrenarche have not been well characterized yet, but the potential mechanisms could be ACTH dependent [46].

Basal and ACTH-stimulated levels of DHEA and DHEAS increase throughout puberty, with slightly higher DHEA levels in females in late puberty and higher DHEAS levels in males after puberty. Overall circulating adrenal androgens increase more than tenfold from the onset of adrenarche to peak adult values, around the third decade of life, and thereafter decline progressively. Cortisol secretion and the diurnal rhythm show no changes.

The Growth Axis

Growth hormone (GH)/insulin-like growth factor (IGF) axis is the main responsible for linear growth in humans. The role that each hormone plays in growth varies according to the ontogeny of human growth and development from fetal life to the end of puberty.

Size at birth is the result of multifactorial factors that include environmental, maternal, placental, and fetal factors. Although GH is known to be produced from the end of the first trimester of fetal life and its circulating concentrations reach very high levels by midgestation, the direct action of GH on fetal growth is limited. Probably IGF-I and IGF-II are the most important factors involved in fetal growth regulation. Both increase progressively in fetal circulation until the end of gestation when they drop abruptly. At term the serum concentrations of IGF-I are directly related to birth weight [47]. Circulating insulin-like growth factor-binding protein 3 (IGFBP3) is present in very low concentrations from midgestation suggesting a negligible role comparing to its postnatal role in the maintenance of the binary and ternary complex with IGF-I and the acid labile subunit (ALS). On the contrary, insulin-like growth factor-binding protein 1 (IGFBP1) levels appear to be an indicator of fetal nutrition [47].

Markedly elevated GH values associated to low IGF-I levels are found during the first weeks of life in full-term and preterm neonates. GH secretory pattern is pulsatile governed by neuroendocrine mechanisms [48]. High serum concentrations of GH levels may be due to the lack of negative feedback from low levels of circulating IGF-I and yet to other underdeveloped inhibitory mechanisms [49].

By the end of the first month of life, a progressive maturation of the regulatory mechanisms of GH secretion occurs. Somatostatin and GH-releasing hormone (GHRH), as well as other neuropeptides, lead to the characteristic basal and stimulated serum concentrations of GH during infancy and childhood [50]. GH release occurs over short intervals known as the ultradian rhythms and circadian rhythms that occur during 24 h. Ultradian rhythm of GH is every 20 min with maximum of spontaneous release during the night [51]. Amplitude and frequency of pulsatile GH secretory are regulated and influenced by a variety of different influences such as age, pubertal status and nutrition, and wake-sleep states through complex neural and humoral signals.

Close to pubertal onset, the secretion of growth hormone appears to decrease concomitantly with decreasing growth rate, suggesting a transient decrease in growth hormone secretion that recovers after the onset of puberty. Thereafter, marked changes occur. During puberty there are 1.5 times more amplitude pulses of GH due to higher pulse duration and amplitude, and the integrated GH secretion is 2–2.5 times higher in late puberty [52]. This physiological increment in GH secretion is associated with a significant increase in IGF-I and IGFBP-3 serum concentrations , possibly in response to estrogens.

Insulin and Carbohydrate Metabolism

Insulin sensitivity refers to the ability of insulin to stimulate glucose metabolism, while insulin resistance denotes a situation in which an excess of insulin is required to maintain adequate homeostasis of glucose metabolism. During puberty, there is a physiological transient drop in insulin sensitivity of approximately 30 %. Most of it occurs in Tanner stages 3–4, especially in females. Basal insulin increases throughout puberty. Clearly, there is an inverse relationship between fat mass and insulin sensitivity. The drop in the insulin sensitivity is accompanied by an increase in acute insulin response to glucose and a fall in the disposition index of glucose. Interestingly, IGF-I levels rise and drop in a pattern similar to the rise and fall of insulin across the different stages of puberty, suggesting that the GH/IGF-I axis might also contribute to the physiological insulin resistance of puberty.



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