Summary
Puberty is a critical phase of development during which complex physiological and psychological changes result in the immature child attaining reproductive capacity. The timing of the onset of puberty is related to ethnicity, health, nutrition, environmental and inherited factors. Healthy girls enter puberty between the ages of 8 and 13 years.
3.1 Background
Puberty is a critical phase of development during which complex physiological and psychological changes result in the immature child attaining reproductive capacity. The timing of the onset of puberty is related to ethnicity, health, nutrition, environmental and inherited factors. Healthy girls enter puberty between the ages of 8 and 13 years.
In recent years data reporting a younger age at the onset of puberty have been the focus of considerable discussion, and there is still some controversy regarding the age at which the onset of puberty should be considered to be premature. Since the beginning of the twentieth century, a fall in the age at menarche is well documented in European and North American populations. The National Health Examination and National Health and Nutrition Examination from North America reported that the percentage of black girls experiencing menarche before the age of 11 years increased from 4.6% to 12.2% between 1959 and 2008 and for white girls from 2.6% to 6.3%. At the beginning of the century, the most affluent girls experienced menarche at an earlier age than their peers living in poverty, while in more recent years this association has reversed, with white girls living in poverty experiencing an earlier menarche than their affluent peers, although this observation is not reported in other ethnic groups.
While the age at menarche can be accurately documented in prospective studies, data reporting the earlier features of puberty may be less robust. In 1997 a North American study of 17,000 girls reported that 48% of black girls and 15% of white girls had either breast development or pubic hair or both by the age of 8 years. These observations led to a recommendation that the age at which a girl should be investigated for precocious puberty should be lowered from 8 to 7 years for white girls and to 6 years for black girls. However, more recent publications suggest that important pathology may be missed in girls presenting between the ages of six and eight who are not investigated. For now it seems wise to carefully assess all girls aged less than 8 years at the onset of puberty.
3.2 Physical Changes of Puberty
The first outward sign of puberty is usually breast development, described as thelarche. Oestrogens stimulate fat deposition in the breast and stromal and ductal tissue growth. Growth hormone and prolactin also promote ductal growth, while progesterone enables lobular growth and alveolar budding. The distinction of simple adipose tissue from true glandular breast tissue can be difficult in overweight and obese girls, and in these patients assessment of the speed of growth, ultrasound appearances of the uterus and ovaries, and skeletal maturity by ‘bone age’ X-ray may be required to ascertain a girl’s stage of development.
The onset of breast development is accompanied by a rapid acceleration in the speed of growth. Pubic and axillary hair growth (pubarche) usually follows the start of the pubertal growth spurt, although is the first feature of puberty in approximately 15% of normal girls, particularly those of black ethnicity.
Menarche (the first menstrual bleed) occurs approximately 2–2.5 years after the first signs of puberty, and may be preceded by physiological leukorrhoea, a physiological vaginal discharge resulting from oestrogen stimulation of the vaginal mucosa. Menstrual cycles are typically anovulatory for the first year to 18 months, and during this period bleeding may be heavy and irregular.
The Tanner system describes the stages of breast and pubic hair development during normal puberty. This scoring system allows objective assessment of the stage of pubertal development and change over time. Details are given in Table 3.1.
| Breast | Pubic hair |
|---|---|
| Stage 1: No palpable glandular breast tissue | Stage 1: No hair |
| Stage 2: Palpable breast bud beneath the areola | Stage 2: Fine, downy hair growth |
| Stage 3: Breast tissue palpable beyond the areola, breast has a smooth contour with no areolar development | Stage 3: Sparse, coarse terminal hair |
| Stage 4: Areola development with elevation above the contour of the breast | Stage 4: Terminal hair that extends across the pubic region |
| Stage 5: Areolar and breast contour are confluent, areola is hyperpigmented with papillae development and nipple protrusion | Stage 5: Terminal hair extends beyond the inguinal crease and onto the thigh |
3.2.1 Uterine Development
Ultrasound examination is a valuable tool in the assessment of pubertal development.
The prepubertal uterus is cylindrical in shape and has a volume (uterine length x anteroposterior depth) of 0.8–1.6 mL. The endometrium is not visualised until the age of 7–8 years.
During puberty the uterus descends into the pelvis and increases in size. A uterine length of 4 cm has been recommended as the stage at which the uterus is considered to be pubertal. Uterine artery Doppler ultrasound can also be helpful in confirming the onset of puberty. In the prepubertal girl, the systolic waveform is narrow without positive diastolic flow. With the onset of puberty, the systolic wave broadens and positive diastolic flow is observed.
Oestrogen stimulates growth of the fundus to greater degree than the cervix, and the cylindrical immature uterus attains the mature, adult pear-shaped configuration. The fundus to cervical ratio increases from 1:1 in the prepubertal girl to 2:1 to 3:1, by the completion of puberty. The mature uterus measures 5–8 cm in length and 1.6–3.5 cm in anteroposterior depth.
The endometrium increases in thickness during puberty and menarche is imminent once it reaches 6–8 mm. The endometrium then undergoes cyclical changes once the menstrual cycle is established.
3.2.2 Ovarian Development
Ovaries increase in size during childhood, but remain relatively homogeneous in appearance with few follicles. By late childhood, ovaries have increased in volume from <1 cm3 in girls aged less than 6 years to measure 1.2–2.3 cm3 in volume.
With the onset of puberty, the ovaries descend deeper in to the pelvis. Gonadotropins stimulate follicular growth and oestrogen secretion and the ovaries increase in volume and become multi-follicular in appearance. The premenarchal ovary measures 2–4 cm3 in volume. By late puberty, the presence of large, stimulated follicles may distort the ovary, making measurements of ovarian volume unreliable, but suggested normal ranges are ovarian length 2.5–5 cm, width 1.5–3 cm and depth 0.6–1.5 cm.
Mean ovarian dimensions during late childhood and adolescence are given in Table 3.2.
Table 3.2 Mean ovarian volumes in late childhood and adolescence
| Chronological age | Mean volume (cm³) | Standard deviation (cm³) |
|---|---|---|
| 8 years | 1.1 | 0.5 |
| 9 years | 2.0 | 0.8 |
| 10 years | 2.2 | 0.7 |
| 11 years | 2.5 | 1.3 |
| 12 years | 3.8 | 1.4 |
| 13 years | 4.2 | 2.3 |
| Postpubertal | 9.8 | 0.6 |
Note. From Orsini LF, Salardi S, Pilu G, Bovicelli L, Cacciari E. Pelvic organs in premenarcheal girls: real-time ultrasonography. Radiology. 1984;153(1):113–6.
3.2.3 Pubertal Growth and Changes in Body Composition
The pubertal growth spurt peaks approximately 6 months before menarche. Following menarche, girls gain a further 5–7.5 cm in height, achieving their near adult height 12–18 months after menarche. At its peak, girls grow with a height velocity of approximately 9 cm/yr. Initially bones increase in length, then in width, and finally bone mineral content and bone mineral density. Peak bone mineralisation lags behind peak bone growth by approximately 1 year, and during this period girls may be at increased risk of fracture. Bone mineral content continues to increase into the third decade of life. A number of studies have examined relationships between age of menarche, bone mineral density, fracture risk and risk of osteoporosis in later life. Collectively, these data report that later age at menarche is a risk factor for impaired bone health, but the mechanisms underlying this are yet to be determined.
During puberty, girls acquire fat mass at a rate of approximately 1 kg/yr, and by completion of puberty fat mass accounts for 25% of the body mass. In contrast, accrual of fat-free mass plateaus from approximately 12 years of age. Fat is deposited on the hips and thighs, and as puberty progresses, the waist:hip ratio falls.
Assessment of the speed of growth can be helpful in determining the onset of puberty, particularly in overweight and obese girls in whom the distinction of simple adiposity from true breast tissue may be difficult. A girl’s target height can be calculated from the formula
and the 98th confidence interval, described as the ‘target height range’, rests 8 cm above and below the girl’s target height. Overweight and obese girls tend to have a height at the upper limit, or just above the upper limit of the centile predicted from the midparental height range, but grow with a height velocity that is appropriate for their age. Girls in whom puberty is early grow more quickly than their peers during the prepubertal years, and tall stature is then enhanced with the early onset of the pubertal growth spurt, resulting in a height which is above the centile predicted from the target range. In contrast, those girls in whom puberty is delayed are likely to have a height below the lower limit of the target height range.
3.3 Endocrine Changes of Puberty
3.3.1 Adrenarche
Adrenarche is the first endocrine feature of puberty, and describes maturation of the androgen-producing pathways in the adrenal resulting in an increase in the androgen precursors dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S). However, as these hormones have only weak androgenic activity the period of adrenarche is generally clinically silent.
The mechanisms regulating the onset of adrenarche are largely unknown. Adrenocorticotrophic hormone (ACTH) is required as adrenarche does not proceed in patients with ACTH deficiency and those with ACTH resistance.
3.3.2 Gonadarche
The term gonadarche refers to the period during which the hypothalamic–pituitary–ovarian pathway is reactivated. Although temporally related to adrenarche, this is a distinct endocrine event.
At birth the hypothalamic–pituitary–ovarian pathway is well developed. Oestrogen levels are high, and gonadotropins are low until the end of the first week of life when gonadotropin secretion escapes inhibition from placental hormones. Secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH) then increase. Serum FSH peaks at 3–6 months of age, declines from the age of 12 months and is unmeasurable using conventional assays by the age of 2 years. The rise in LH is more modest, and stimulates oestrogen secretion from ovarian follicles for the first 2–4 months of life. During early childhood the activity of this hormone pathway is down-regulated, and it remains quiescent until the onset of puberty.
Gonadarche is initiated when factors inhibiting activity of the hypothalamic–pituitary–ovarian pathway are lifted, and permissive factors enable reactivation of the pathway.
During childhood, gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus is inhibited by gamma amino butyric acid (GABA). A role of makorin ring finger protein 3 (MKRN3) in the suppression of puberty during childhood has been implicated from observations that MKRN3 levels fall in the prepubertal years, and are inversely related to gonadotropin levels once puberty is established. Furthermore, loss of function mutations in the gene encoding the MKRN3 are reported in both familial and idiopathic precocious puberty.
To date, two molecules have been identified that appear to have an important, permissive role in the initiation of puberty. Kisspeptin is secreted from neurones in the arcuate nucleus of the hypothalamus, and the onset of puberty is marked by a rise in kisspeptin secretion. As kisspeptin secretion increases, the amplitude and frequency of GnRH pulses is amplified initially during nighttime hours, and as puberty progresses, during daytime hours also. GnRH stimulates the synthesis and release of LH and FSH from the anterior pituitary. In early puberty, FSH concentrations exceed LH but as puberty progresses and the amplitude of GnRH pulses increases, LH secretion becomes dominant.
Neurokinin B stimulates kisspeptin release, while dynorphin inhibits release. Mutations in the genes that encode kisspeptin, the neurokinin B pre-hormone TAC3, and its receptor TAC3 R are reported in patients with hypogonadotropic hypogonadism and delayed puberty.
Leptin, a hormone secreted by adipocytes, also stimulates kisspeptin secretion. A critical role for leptin in the initiation of puberty has been suggested from observations that leptin-deficient girls do not enter puberty until the administration of recombinant leptin, which restores gonadotropin pulsatility and induces puberty. Leptin concentrations reflect total body fat, and this pathway may have a role in the aetiology of the earlier puberty observed in obese and overweight girls.
LH and FSH work in concert to stimulate the synthesis and secretion of oestrogen from the ovary. In early puberty secretion of LH and FSH is restricted to the sleeping hours, and oestrogen concentrations are highest in the morning, but as puberty progresses this diurnal pattern of hormone secretion is lost.
Inhibin A and inhibin B are produced by the ovary in response to gonadotropin stimulation. Inhibins have an important role in the negative feedback loop, and suppress FSH secretion. In girls with primary ovarian failure, FSH concentrations rise from late childhood.
An increase in inhibin B secretion can be detected before the clinical onset of puberty is evident, which may reflect early ovarian follicular development. In contrast, concentrations of inhibin A, which is thought to be secreted by the corpus luteum, increase later in puberty as an ovulatory menstrual cycle is established.
3.3.3 The Growth Hormone: Insulin-like Growth Factor-I Pathway during Puberty
The growth hormone insulin-like growth factor-I (IGF-I) axis is a classic feedback loop, with growth hormone secretion from the anterior pituitary stimulating the synthesis of IGF-I in a range of peripheral tissues including the liver, which releases IGF-I into the circulation which in turn suppresses growth hormone synthesis and release.
During puberty, the sensitivity of this negative feedback loop is altered. In response to rising oestrogen concentrations, growth hormone is secreted in nocturnal pulses of increased frequency and amplitude, and IGF-I concentrations rise. The mechanisms by which the sensitivity of the negative feedback loop is altered, allowing rising growth hormone concentrations in the face of high IGF-I concentrations, is unknown. During adolescence, IGF-I concentrations reach acromegalic levels, before falling again as growth nears completion approximately 18 months after menarche.
In addition to promoting bone growth, IGF-I also acts on the ovary, working synergistically with gonadotropins to increase sex steroid production, and puberty is typically delayed in girls with growth hormone deficiency.
3.4 Precocious Puberty
Puberty is considered to be precocious in girls aged less than 8 years of age and early in girls aged between 8 and 9 years of age. Girls may present with discordant puberty, with premature pubic hair growth and other features of androgen exposure (premature adrenarche), or isolated vaginal bleeding as the first signs of puberty, or concordant puberty with premature breast development.
Precocious puberty can be further classified according to the state of maturity of the hypothalamic–pituitary pathway. Premature activation of the hypothalamic–pituitary–gonadal pathways is described as ‘true’, ‘central’ or ‘gonadotropin-dependent’ precocious puberty, while puberty resulting from oestrogen or androgen exposure which is not regulated by this pathway is described as ‘pseudo’, ‘peripheral’ or ‘gonadotropin-independent precocious’ puberty. In this chapter the phrases central precocious puberty (CPP) and peripheral precocious puberty (PPP) will be used.
3.4.1 Premature Adrenarche
The term premature adrenarche is used to describe a group of girls in whom there is clinical evidence of androgen exposure below the age of 8 years. Adult body odour is often reported first, followed by greasy hair and skin and finally pubic and axillary hair growth. Girls are often tall at presentation and skeletal maturity is modestly advanced.
The presence of clitoromegaly, a clinical sign of exposure to high levels of androgens, makes a diagnosis of premature adrenarche extremely unlikely. Extreme tall stature and more than 2 years’ advance in skeletal maturity are also unusual.
American studies report the highest prevalence of exaggerated adrenarche in African American girls, with white Caucasian girls being affected least frequently. An association between low birth weight and premature adrenarche has been reported in some studies, but not others. Obese and overweight girls are affected more commonly than slim girls, possibly due to enhanced conversion of DHEA and DHEAS to the more potent androgen testosterone in peripheral fat tissue. Other proposed endocrine mediators include IGF-I, insulin and leptin. Genetic factors are also likely to be important, and twin studies report a heritability of 58% for adrenal androgen excretion rates.
Premature adrenarche has been traditionally considered to be a benign variant of puberty, but data from a number of different populations suggest that premature adrenarche may be associated with metabolic syndrome and polycystic ovary syndrome in later life. To date the evidence that premature adrenarche is associated with long-term health disadvantage is inconclusive, and further longitudinal studies are required.
Premature adrenarche is a diagnosis of exclusion. The differential diagnosis is given in Table 3.3.
