Abstract
Puberty is a process in which a child’s body matures into an adult body capable of sexual reproduction and involves physiologic, somatic, and constitutional changes associated with further development of the internal and external genitalia and secondary sex characteristics. On average, girls begin the process at the age of 10–11 and end puberty at around 15–17, while boys begin at around the ages of 11–12 and end at around 16–17. Puberty which starts earlier than average is known as precocious puberty and puberty which starts later than usual is known as delayed puberty. The onset of puberty is the consequence of a complex sequence of maturation in the central nervous system (CNS) that is not fully understood. A critical body mass is required before the CNS begins to activate puberty [1]. Two autonomous but associated processes, controlled by different mechanisms, but strictly linked temporally, are involved in the amplified secretion of sex steroids in the peripubertal and pubertal period.
Puberty is a process in which a child’s body matures into an adult body capable of sexual reproduction and involves physiologic, somatic, and constitutional changes associated with further development of the internal and external genitalia and secondary sex characteristics. On average, girls begin the process at the age of 10–11 and end puberty at around 15–17, while boys begin at around the ages of 11–12 and end at around 16–17. Puberty which starts earlier than average is known as precocious puberty and puberty which starts later than usual is known as delayed puberty. The onset of puberty is the consequence of a complex sequence of maturation in the central nervous system (CNS) that is not fully understood. A critical body mass is required before the CNS begins to activate puberty [1]. Two autonomous but associated processes, controlled by different mechanisms, but strictly linked temporally, are involved in the amplified secretion of sex steroids in the peripubertal and pubertal period. One process has been designated “adrenarche,” and involves an increase in adrenal androgen secretion [2], and the second event, “gonadarche,” involves the pubertal activation of the hypothalamic–pituitary gonadotropin–gonadal apparatus [3]. These two events and their role in puberty shall be measured separately.
Adrenal System (“Adrenarche”)
Social behavior (childhood experience) is related to the adrenal axis, which produces cortisol and dehydroepiandrosterone (DHEA) and its sulfate (DHES). Increases in the production of DHEA/DHES by the adrenal gland begin around the age of 8 and continue until the mid-20s [4], thereby roughly bracketing the progression of pubertal development from ages 10 to 18. The increase in DHEA/DHES production in males appears to extend some 5 years beyond that in females [4], suggesting important sex differences in the onset of reproduction potential.
DHEA/DHES is the most shared hormone in the human body and is well known for its key role as a precursor for estrogen production during fetal development [5] and for its rise during maturation [6]. DHEA/DHES is a neurosteroid, and is produced in the brain as well as in the adrenal gland [7]. DHEA/DHES binds to neurotransmitter gamma-aminobutyric acid type (GABAA) receptors, acting as an antagonist [8], and presumably impacting neural mechanisms. In peripheral tissues, DHEA/DHES is converted to estrogen and testosterone [9], and may thereby also elicit effects, such as bone and muscle growth, through testosterone and estrogen receptors in systems other than the brain [10]. Premature adrenarche has been revealed to have effects on both cognition and psychosocial development [11–12].
Hypothalamic–Pituitary System (“Gonadarche”)
Reproductive maturation involves maturation of the hypothalamic–pituitary–gonadal axis (Figure 2.1). The hypothalamic neurons mature in accordance with a genetic (familial) pattern. In mammals, activation of gonadotropin-releasing hormone (GnRH) neurons is the key event gating the onset of puberty. However, the mechanisms that trigger GnRH secretion at puberty remain one of the enigmas of modern science.
Figure 2.1 Hypothalamic–pituitary–gonadal axis. ARC, arcuate nuclei; AVPV, anteroventral periventricular nuclei; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone.
Kisspeptin stimulates GnRH secretion by a direct effect on GnRH neurons, which express the kisspeptin receptor, GPR54. Kisspeptin expression is upregulated in the anteroventral periventricular nuclei (AVPV) and downregulated in the arcuate nuclei (ARC) of the hypothalamus by sex steroids. Compared with male, the female AVPV contains a much higher number of kisspeptin neurons, which are critical for the luteinizing hormone (LH) surge under estradiol regulation. Expression of Kiss1 in the ARC appears to be involved in the negative feedback regulation of GnRH/LH by sex steroids and induces slow pulses of GnRH, which activate follicle-stimulating hormone (FSH) pulses. The expression of Kiss1 mRNA in the ARC is inhibited by estradiol, progesterone, and testosterone. These same hormones induce Kiss1 mRNA expression in the AVPV, where kisspeptin neurons are thought to be involved in the positive feedback regulation of GnRH/LH [13]. GnRH neurons also integrate information from the body through hormones such as neuropeptide Y and adiponectin.
Migration of GnRH-secreting neurons from the nasal olfactory epithelium to the basal hypothalamus occurs during embryogenesis. KAL1 (on X chromosome) is involved in the migration of the GnRH neurons, with mutations of KAL1 responsible for 30–70% of Kallmann syndrome cases [14]. Kallmann syndrome, a familial disorder characterized in 1944, is manifested by failure of the hypothalamus to produce and release GnRH, which results in a complete lack of FSH and LH (hypogonadotropic hypogonadism). Other developmental anomalies, i.e., craniofacial distortion, harelip, cleft palate, and cryptorchidism, are also frequently associated with it. Inheritance of the disorder appears to be autosomal recessive, dominant with incomplete expressivity, or X-linked associated with partial deletion of the short arm of the X chromosome.
GnRH is released from the medial basal hypothalamus in a pulsatile pattern, approximately every 70–90 minutes [15], and its half-life is 2–5 minutes. GnRH contributes to the release of both LH and FSH from the anterior part of the pituitary. GnRH binds to its receptor on pituitary cells within 1 minute of release and activates the G protein (phospholipase C and ERK pathways); the GnRH receptor then undergoes desensitization in 5 minutes and becomes active again within 30 minutes [16]. FSH is the first gonadotropin to rise at puberty, in response to low-frequency GnRH pulses in the ARC; small changes in LH levels are seen in parallel. FSH levels begin to increase at the age of ~7–8 years in females and 9–11 years in males; however, LH does not begin to rise until the age of 9–12 years [17]. With the acceleration of GnRH pulse frequency, FSH and LH reach adult levels (Figure 2.2). GnRH release is regulated by feedback signals from testosterone, inhibin, activin, estrogen, progesterone, and others. Low levels of estrogen have little effect on LH secretion, but inhibit FSH secretion. High levels of estrogen induce the LH surge at female midcycle, and high steady levels of estrogen lead to sustained elevated LH secretion [18]. Low levels of progesterone, acting at the level of the pituitary gland, enhance the LH response to GnRH and are responsible for the FSH surge at midcycle. High levels of progesterone inhibit the pituitary secretion of gonadotropins by inhibiting GnRH pulses at the level of the hypothalamus [18]. Corticotropin-releasing hormone (CRH), secreted during stress, as well as opiates, downregulate GnRH secretion [19].
