Endocrinologically, the first signal for puberty is given by the adrenals (adrenarche). The onset of DHEA-S production from the adrenal zona reticularis leads to the phenomenon of adrenarche.

During infancy and early childhood, adrenal androgens (androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulphate) are secreted in small amounts. Their secretion increases gradually with age. This increase in androgen levels is responsible for the appearance of body odour, pubic hair and axillary hair. Therefore, pubic hair develops independently of the activation of the hypothalamic-pituitary-gonadal pathways.

Adrenarche is marked by the growth of the zona reticularis [8] and a parallel increase in the adrenal androgen levels. This phenomenon is only seen in the human beings and in some old world primates, such as the chimpanzee [9]. Plasma concentrations of the adrenal androgens increase, whereas those of cortisol remain stable, suggesting that factors other than corticotropin are involved. Hormones postulated for this role are the yet undefined androgen-stimulating factor, Corticotrophin Releasing Hormone (CRH) and more recently hormones related to body mass, such as insulin and leptin [10–13]. Although the temporal relation between adrenarche and the onset of puberty suggests that adrenal androgens might have a regulatory influence on the timing of puberty, it is now accepted that the two events are independent processes.

Two types of GnRH neurons have been identified to date, GnRH neuron I and II. GnRH neurons II have no known function in humans and are not involved in reproductive function, as inferred from Kallmann’s syndrome patients in whom GnRH neurons I only are affected. GnRH neurons I originate in the embryonic period and exhibit an endogenous secretion very early in development. After birth, their activity is “turned-off” by the low circulating levels of androgens/oestrogens released by the gonads, by means of a negative feedback mechanism. At puberty, the reactivation of this “gonadostat” is independent of the effect exerted by the steroids and is related to a reduced sensitivity to their action [14–17].

The second candidate is TTF-1 (thyroid transcriptional factor-1), another homeobox gene. After birth, it remains expressed in selected neuronal and glial population of the hypothalamus. At the onset of puberty, TTF-1 enhances GnRH and erbB2 and KiSS-1 gene transcription but inhibits preproenkephalin promoter activity [19].

The third candidate is EAP-1, earlier known as C14ORF4. Like TTF-1, EAP-1 transactivates the promoter of genes involved in facilitating the advent of puberty while suppressing the expression of genes inhibitory to the pubertal process. Knocking down hypothalamic EAP-1 expression causes delayed puberty and disrupted oestrous cyclicity, both in rats and monkeys [20, 21].

The KiSS-1/GPR54 system has been recognized recently as the director of central functional network and peripheral signals. Genetic, physiological and clinical data strongly indicate that the KiSS-1/GPR system is an essential gatekeeper of GnRH function, and not just one more element in the cascade of signals controlling the gonadotropic axis. It allows the integration of central and peripheral inputs and plays therefore a decisive role in the control of reproductive function [29].

Both in rats and in primates, a marked increase in KiSS-1 and GPR54 mRNA levels coincide with the onset of puberty [24, 30]. Moreover, the sensitivity of GnRH system to kisspeptin is dramatically enhanced in adult versus juvenile mice [42]. Thus, the developmental activation of the GnRH axis by KiSS-1 at puberty reflects a dual phenomenon involving, not only the increase of kisspeptin tone, but also the enhancement of its efficiency to activate GnRH neurons, probably through post-transcriptional changes in GPR54 signalling [31].

Hypothalamic KiSS-1 system also plays an essential role in relaying the negative feedback input of sex steroids onto GnRH neurons. In male and female rats, bilateral gonadectomy evoked a consistent increase in KiSS-1 mRNA at the hypothalamus. Recent studies added further elements to the role of kisspeptin in the feedback control of gonadotropins by showing that negative regulation of hypothalamic KiSS-1 gene expression by oestrogen appears to be restricted to the nucleus arcuatus (Arc), known to be pivotal for negative feedback of sex steroids. In contrast, at the anteroventral periventricular nucleus (AVPN), KiSS-1 mRNA decreased after gonadectomy and increased after sex steroid replacement [32, 33]. AVPN is involved in mediating the positive feedback effects of oestrogen upon GnRH and LH surges. Therefore, via positive regulation of GnRH secretion, KiSS-1 neurons might be involved also in generation of the pre-ovulatory gonadotropin surge.

New strong evidence indicates that hypothalamic KiSS-1 may participate also in delivering information regarding the nutritional status of the organism to GnRH- neurons. Kiss-1 may therefore contribute to the link between energy stores and fertility [34, 35]. It has been shown that the permissive actions of leptin on the reproductive axis are mediated through modulation of GnRH secretion. Because GnRH neurons do not express leptin receptors, [35] kiss peptins might explain badly understood metabolic processes, signalled onto GnRH neurons via peripheral hormones such as leptin. However, several key aspects of the physiology of this system still remain open [36].

In conclusion, KiSS-1 system is an essential downstream element in the negative and (probably) positive feedback loops controlling gonadotropin secretion [37]. In addition, it may participate in the signalling to GnRH neurons of peripheral inputs from hormones such as leptin [38].

On the other hand, there might be a direct peripheral negative effect of leptin on gonadal function through inhibition of the steroidogenic enzymes [39, 40].

In humans and animals, leptin blood concentrations rise with the onset of puberty. In adolescents of both sexes, the gradual rise in serum leptin levels before puberty together with a decline in circulating levels of soluble leptin receptor suggest that these changes may serve as one of the signals to the central nervous system that metabolic conditions are adequate to support pubertal development and trigger puberty [41].

No gender differences were detected in the relationship between leptin serum levels and fat mass in pre-pubertal and early pubertal subjects. In contrast, at Tanner stages IV and V, the serum hormone concentrations decrease in males and increase in females. In addition, a significant negative correlation between circulating concentrations of testosterone and leptin was described in males only [38].

Finally, it has been shown that normal leptin levels are necessary for the maintenance of menstrual cycles and normal reproductive function in adolescents of both sexes.

In conclusion, leptin seems to exert a positive central effect on the hypothalamic-pituitary-gonadal axis and a negative peripheral one on the gonads. Leptin might signal that the metabolic conditions are adequate to support pubertal development and trigger puberty.

Inhibin, a heterodimeric glycoprotein, belongs to the TGF-b super family produced by ovarian granulosa cells. It is composed of an alpha and one or two beta subunits. These form two different products, inhibin A and B, respectively. FSH stimulates the synthesis and secretion of inhibins by the gonads, which in turn are involved in the feedback regulation of FSH secretion. In girls, inhibin A concentrations increase between stage 2 and 3 of puberty, remain constant throughout stages 4 and 5, and correlate positively with bone age, inhibin B and oestradiol serum levels [45, 46]. Inhibin B blood concentrations increase further similarly to inhibin A levels, reaching a plateau at 12–18 years. They correlate with oestradiol [45, 46] and FSH serum levels [48].

Blood concentrations of follistatin decrease slightly from stage 1–4 and 5 of puberty in girls [46]. Blood levels of activin A were shown to remain unmodified from stage 1–3 of puberty in females [48].

In conclusion, at puberty the concentrations of the two negative regulators of FSH secretion, inhibin and follistatin, change in opposite directions [46], whereas the blood levels of a positive regulator, activin A, increase, at least in females. All together, these alterations in serum concentrations of FSH-regulatory peptides lead to an increase in FSH secretion.

Puberty is the period of life that leads to adulthood through complicated and sometimes painful physiological and psychological changes. Delayed puberty may have a dramatic impact on the mental and social development of an adolescent.

In the literature, different definitions for “delayed puberty” can be found.

The classical endocrinological definition and the current paediatric definition are identical for girls, but slightly different for boys:

Delayed puberty is a rare condition, occurring in only approximately 2.5 % of the population. [1, 2, 42, 55]. The relative incidence of the different forms of hypogonadism in delayed puberty is shown on Table 11.1. In the series of Reindollar et al. [58], hypogonadotropic hypogonadism is found in 31 %, hypergonadotropic hypogonadism in 43 % and eugonadotropic hypogonadism leading to primary amenorrhea in presence of partial or complete development of secondary sex characteristics in 26 %.

There are no guidelines indicating when in the absence of pubertal signs an investigation should be started. Following both definitions listed above, in girls, a first evaluation should be done not later than at the age of 13.

Important is empathetic counselling to counteract the mostly deep anxiety due to the fact of being different from other girls at the same age. The child and the parents have to be fully and accurately informed and reassured that an underlying pathological process is rare and that the delay of the onset of puberty is mostly due to a benign, often familiar, deviation from the normal time course.

In most recommendations, a precise diagnostic evaluation is recommended in girls with persisting absence of the onset of puberty at the age of 14.5 years (mean + 3 standard deviations). However, a further evaluation is recommended earlier if a girl without onset of puberty starts to suffer because she becomes socially isolated among her classmates because of her physical retardation. Therefore, acceleration of puberty has to be taken into account for the decision when to start clinical evaluation in absence of pubertal signs.

In conclusion, investigation has to be started earlier than it has been recommended 20 years ago. It depends on the psychosocial pressure exerted on a child by the pubertal development of the pair group of schoolmates and friends.

Figure 11.5 presents a simplified flow chart of the assessment of delayed female puberty. It describes schematically the process for the investigation of adolescent girls presenting with lack of spontaneous pubertal development. Shaded boxes show the major differential diagnoses of constitutional delay of growth and puberty, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism. However, no clinical algorithm can fully meet the requirements of all individual cases. Thus, adapted clinical decision–making is important at each stage.

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in girls with 30 % of cases, as it is in boys [66]. CDGP is defined as a delay of growth occurring in otherwise healthy adolescents with stature reduced for chronological age, but generally appropriate for bone age and stage of pubertal development, both of which are usually delayed. It is more frequent in boys than in girls with a 10:1 ratio and is the most common cause of delayed puberty (80–90 %).

In most cases delayed puberty is not due to any underlying pathology, but instead represents an extreme end of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and maturation [66]. The characteristically retarded linear growth occurs during the early years of life and is followed by regular growth paralleling the normal growth curve throughout the rest of prepubertal years. Pubertal growth spurt is attenuated and occurs after the usual expected time. In girls, exclusive maternal inheritance seems to be the major mode of inheritance whereas for boys the mode of inheritance is almost equally maternal, paternal or bilineal [52]. The majority of cases (70–80 %) are familial. Sedlmyer & Palmert classified family histories of pubertal timing among primary relatives in 95 of 122 of the CD and in 25 of 45 of the functional hypogonadotropic hypogonadism (FHH) cases. Analysis revealed at least a tendency to pubertal delay in 77 % of the CDGP and in 64 % of the FHH families and a diagnosis of delay in 38 % of the CDGP and 44 % of the FHH families. Both parents contributed to the positive family histories. The rates of positive family histories among the CDPD and FHH groups were approximately twice those seen among the other subjects in our case series [66]. Bone mineral density can be compromised by the low serum steroid concentrations measured [67, 68]. Specifically, the attainment of peak bone mass may be impaired, although recent data do not indicate significant changes in volumetric bone mineral density in young men with previous CDGP compared with appropriate controls [69].

The sleep-related increase in LH concentrations that characterizes the onset of puberty, is normally present in CDGP children. As a consequence of inadequate production of gonadal steroids, acute provocative tests may show a GH response wrongly consistent with partial GH deficiency [70]. Pre-treatment with oestrogens in girls results as expected in the normalization of the GH responses. The LH response to the LH-RH analogue leuprolide acetate is intermediate between that of hypogonadal patients and normal pubertal children, and is therefore useful in differentiating CDGP from hypogonadotropic hypogonadism. Recently, a critical appraisal of available diagnostic tests has been published [59].

Supportive care is essential. Although no specific treatment is required, the psychosocial problems faced by CDGP children may force physicians to substitute [55, 64, 71]. In girls, oestrogen therapy is recommended only after statural considerations have been carefully taken into account. Ethinylestradiol should be avoided. The administration of oestrogen, even in small amounts, leads to progressive skeletal maturation, and ultimately to epiphyseal fusion. The use of anabolic steroids or growth hormone to stimulate growth is highly controversial [72–75] and is not recommended in most reviews [66].

The inheritance patter of CDGP has been recently analysed by Winter et al. [52]. In girls, exclusive maternal inheritance seems to be the major mode of inheritance.

Table 11.1 lists the most important causes of delayed puberty other than constitutional delay of puberty and growth. These causes are usually grouped in four categories:

The characteristic endocrine pattern for hypothalamic hypogonadotropic, hypophyseal hypogonadotropic and hypergonadotropic hypogonadism is presented on Fig. 11.6.