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Puberty is a major event in the life of every adolescent. Normal timing and progression reflect the overall general health of the individual. Variations in timing and progression can represent normal variants. Awareness of these normal variants can relieve undue anxiety on the part of the parents and adolescent.
Puberty is a dynamic period of development marked by rapid changes in body size, shape, and composition, all of which are sexually dimorphic. The onset of puberty corresponds to a skeletal (biological) age of ≈11 y in girls and 13 y in boys. On average, girls enter and complete each stage of puberty earlier than do boys. The timing and tempo of puberty vary widely, even among healthy children1. Figures 1-5.
The timing of puberty is the final result of the interplay between strong genetic determinants and a large number of regulators, which include different endogenous factors and environmental signals, from nutrient availability to photic cues2. The hypothalamic-pituitary-gonadal (HPG) axis undergoes an active phase during fetal and neonatal development and then enters a resting phase that lasts for the rest of childhood till puberty. Puberty begins with re-activation of the HPG system3. This process requires the interactive participation of both glial and neuronal regulatory circuitries that serve to control the secretion of gonadotropin-releasing hormone (GnRH) neurons. The secretory activity of GnRH neurons is triggered by several trans-synaptic inputs of both inhibitory and excitatory nature. The decreased release of inhibitory neurotransmitters such as gamma amino butyric acid and the opiod peptides as well as the increased release of excitatory neurotransmitters such as excitatory amino acids, transforming growth factor alpha (TGFα), insulin-like growth factor-1, and the kisspeptins are capable of initiating the cascade of events leading to increased GnRH secretion at puberty4. The glial component is predominantly facilitatory, and exerted by growth factors that directly or indirectly stimulate GnRH secretion5.
For many years, the prepubertal quiescent period was considered to occur due to a high sensitivity of GnRH neurons (gonadostat) to the very low levels of sex steroids and to intrinsic inhibitory mechanisms within CNS that exert a blockade to hypothalamic GnRH secretion. According to the “gonadostat” theory, the low levels of testosterone/estradiol released by the prepubertal testes/ovaries exert negative feedback effects that inhibit GnRH secretion. The major inhibitory factor for GnRH release before puberty, at least in primates, appears to be γ-aminobutyric acid (GABA); the reduction in tonic GABA inhibition results in increase in the release of neurotransmitters, such as glutamate, which is followed by increase in pubertal GnRH release6. In view of recent evidence that demonstrated that estradiol is essential for the emergence of kisspeptin expression in GnRH neurons in the prepubertal period, it was proposed that the gradual development of an estradiol-kisspeptin positive feedback relationship provides a GnRH neuron amplification mechanism that is used to facilitate the emergence of pulsatile gonadotropin secretion necessary for puberty onset7.
Puberty is also associated with an independent physiologic event, adrenarche, or adrenal activation that typically occurs between six and eight years of age in both genders8. However, when applying highly sensitive methods for the analysis of 24 h urinary androgen metabolite excretion; results clearly indicate that adrenarche is a continuous developmental process, starting with a detectable increase in the excretion of DHEA and related androgenic steroids at least as early as three years of age9.
Variations in Timing
Although researchers disagree about whether children are entering and/or progressing through puberty earlier today than in the mid-1900s, some recent analyses of US cross-sectional data concluded that girls are reaching puberty earlier over this time span, as measured by age at breast development stage, pubic hair development stage, and/or age of menarche. Conversely, other studies concluded that there is no compelling evidence of an earlier age of menarche when comparing data collected in the 1950s and 1960s with data collected between 1988 and 1994. Furthermore, for breast and pubic hair development, studies cannot be adequately compared or the degree of change is not significant10. Far fewer studies of puberty timing in boys are available, but 2 studies suggested that male puberty timing is occurring earlier11,12.
Hypotheses to explain the proposed recent population-level changes in puberty timing from the mid-1900s to the present time are controversial. One prominent hypothesis is that exposure to endocrine disrupting chemicals (EDCs) cause an earlier age of puberty. EDCs are a class of chemicals that interfere with steroid hormone activity via a variety of modes of action, at a number of levels, and puberty timing has been identified as a sensitive marker of response to EDC exposure. Male and female puberty timing end points are especially sensitive to in utero or peripubertal exposure to certain EDCs, particularly estrogens and antiandrogens10.
Records from several northern European countries, particularly Norway, Denmark, and Finland, document that the age of menarche, a convenient marker for the timing of puberty in girls, decreased from ≈16 to 17 years during the 19th century to ≈13 years by the middle of the 20th century. It has been widely assumed that improved health and nutrition associated with the coming of the Industrial Revolution were responsible for most if not all of that decline in the mean age of menarche. Evidence has accumulated that point to a major influence of body fat on the timing of puberty, at least in girls. The well-documented epidemic of obesity in American children provides a plausible explanation for the decreasing age in both the age of onset of breast development and the age of menarche13. However, it is theoretically possible that earlier breast development in obese girls is the consequence of an increase in estrogen production from expanded adipocytes not from the activation of the HPG axis, and therefore not representing a genuine puberty onset. The lack of conclusive data showing parallel advances of the age at menarche in obese and non-obese girls favours this argument, suggesting a temporal dissociation between the initial signs of thelarche and the completion of pubertal maturation with the first menstrual cycle (menarche)14.
One reason that data on obesity and the timing of puberty in boys may be limited is that because there is no easily defined pubertal event, such as menarche, in boys, so it is simply more difficult to study this relationship13.
Catch-up growth in children can be associated with early puberty following foetal or combined foetal-postnatal under nutrition. However, early puberty does not seem to occur following catch-up growth after isolated postnatal undernutrition15.
Benign variants of normal pubertal development
Adolescents and younger children with benign variants of normal pubertal development—such as premature adrenarche or thelarche, early normal puberty, and constitutional delay—are common in pediatric practice16.
Adrenarche refers to the developmental maturation of the adrenal gland, observed only in the human, chimpanzee and gorilla. At adrenarche, the innermost layer of the human adrenal cortex, the zona reticularis (ZR), starts to produce increasing amounts of DHEA and its sulphate ester DHEAS. The term ‘adrenarche’ was coined by Fuller Albright and Nathan Talbot in the 1940s when they linked the developmental rise in adrenal androgens to the appearance of pubic and axillary hair, which they called ‘sexual hair’. Soon thereafter, Lawson Wilkins’ group described a group of girls who developed pubic and axillary hair before the age of 8 years, a condition they termed ‘premature pubarche’ (PP). They considered PP a benign constitutional variant with no impact on later life if ‘adrenal tumours’ or ‘adrenal hyperplasia’ were excluded as underlying causes. Idiopathic premature adrenarche (IPA) has been traditionally considered to be an extreme variation of the normal. However, a number of studies in children with early onset androgen excess provide increasing evidence for the notion that IPA in girls may precede the development of polycystic ovary syndrome (PCOS)9.
A recently proposed definition of PA is the concurrent presence of adrenal androgen levels increased above the age- and sex-specific reference range and clinical signs of an increase in androgen action, such as adult-type body odour, oily hair and skin and/or PP, occurring before the age of 8 years in girls and 9 years in boys9.
- Idiopathic (constitutional) premature adrenarche
- Congenital adrenal hyperplasia
- 21-Hydroxylase deficiency
- 11β-Hydroxylase deficiency
- 3β-Hydroxysteroid dehydrogenase deficiency
- Cushing disease
- Glucocorticoid resistance (due to inactivating glucocorticoid receptor (GR) mutations)
- Apparent cortisone reductase deficiency (due to inactivating hexose-6-phosphate dehydrogenase (H6PD) mutations)
- Apparent DHEA sulfotransferase deficiency (due to inactivating PAPS synthase type 2 (PAPSS2) mutations)
- Autonomous endogenous or exogenous androgen excess
- Virilising tumours originating from adrenals or gonads
- Exogenous testosterone treatment
The term ‘‘premature thelarche’’ (PT) refers to isolated breast development before age 8 in girls, without any other signs of sexual maturation. Of all premature puberty disorders in girls, PT is the most common. The incidence is highest in the first year of life, falling in the second, third, and fourth years, and slightly increasing after the fifth year. Some consider that this increase might represent an ‘‘intermediate’’ entity, between isolated PT and central precocious puberty (PP), (also ‘‘thelarche variant,’’ ‘‘atypical PT’’) characterized by older age at onset, which some authors believe may progress to PP17.
Most term newborns have breast tissue, which has been attributed to pregnancy hormone stimulation, with regression of breast tissue occurring at 3 months of age in both genders. Subsequent studies have demonstrated that breast tissue in infants persists beyond 3 months and is physiological, most likely due to secretion of gonadotropins and estrogens in infancy. Classic isolated premature thelarche in most patients occurs after documented regression of the neonatal breast nodule, although in 30-40% breast tissue is present from birth. Persistence of breast tissue after 10 months of age has traditionally been accepted as one criterion for classic premature thelarche, although 6 months has been the accepted cut-off in some studies. In healthy children palpable breast tissue was still present in 45.2% of male and 61.6% of female visits after 10 months of age. At age 18 months, 5% of girls had a breast size unit greater than 2.88 cm2 and 5% of boys had a breast size unit greater than 1.00 cm2 18.
The possible progression of PT to PP has not been well established. Some studies found that girls with PT had normal puberty and did not progress to PP. Age of menarche has been reported as correlated with maternal age at menarche or somewhat earlier, but still within the normal range. Other studies showed that PT may progress to PP at a variable rate, from 10% to 18.4%. Girls with thelarche could progress into precocious puberty irrespective of their age of presentation17.
The pathophysiology of premature thelarche is still unknown. PT has been postulated to result from transient partial activation of the hypothalamic-pituitary-gonadal axis with excessive secretion of follicle-stimulating hormone (FSH), increased breast sensitivity to estradiol, transient estradiol secretion by an ovarian cyst, increased estrogen production from precursors of adrenal origin, and increased dietary estrogen, including soy-based formula17.
Cyclic vaginal bleeding in the absence of other signs of secondary sexual development was described in 4 girls by Heller et al19 and given the name premature menarche. Premature menarche is a transient disorder although the duration of premature bleeding may be several years. Normal pubertal development with resumption of menstruation occurs at an appropriate age and has no effect on the subsequent fertility of the patient. It does not appear to result in any limitation of the final height of the patient20.
Gonadotropin pulsatile secretion in girls with premature menarche showed luteinizing hormone (LH) pulses with low amplitude and a pubertal pattern of frequency whereas follicle-stimulating hormone (FSH) increased without demonstrable episodic secretion. Luteinizing hormone-releasing hormone (LHRH) tests demonstrated that FSH responses are greater than the LH responses, as in prepuberty. Estradiol levels were augmented above the normal prepubertal range21.
Constitutional Delay of Growth and Puberty
An adolescent who is falling off the growth curve will prove to be healthy but have a constitutional delay of growth and puberty. These late bloomers typically move to a lower height centile sometime before the age of 3 years, and then remain on the same height centile throughout most of their childhood. At around 12 to 14 years of age for boys (10 to 12 years for girls), which is the typical period of concern, they again cross downward to a lower height centile, due to the delayed onset of their pubertal growth spurt relative to their peers16.
Puberty is a sensitive phase of physical, mental, and social development for both girls and boys. A thorough acquaintance with the normal course of puberty is necessary. Any deviation from it, though it will be viewed with great anxiety by the young patient, can represent either a normal or pathological variant of pubertal development. The physician should be able to provide the young patient with accurate information and see him or her through the process of puberty in a reassuring manner3.
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