Sexual Differentiation and Development: II Puberty
Delayed puberty is one of the most common referrals to paediatric and adult endocrine clinics. It is defined as absence of breast development in a girl by 13.5 years or failure of testicular growth to >4 ml by 14 years in a boy. Constitutional delay of puberty is by far the most common diagnosis in boys, accounting for around 80% of cases, whereas in girls delayed puberty is more likely to reflect serious underlying pathology. Clinical assessment of boys with delayed puberty should be aimed towards identifying patients with individual underlying pathology. If constitutional delay is confirmed then treatment is conservative to observe any spontaneous development over 6–8 months. If no pubertal change is evident then treatment with low-dose testosterone will induce hypothalamic–pituitary activity and trigger the onset of puberty. In girls with delayed puberty and primary amenorrhoea a specific cause is more usually found. Clinical examination will establish signs of Turner syndrome and subsequent investigations must include karyotype analysis. Treatment is specific for the underlying cause.
Puberty describes a series of events associated with a growth spurt and culminating in the acquisition of sexual maturity and reproductive function. The phenotypic changes of puberty follow a set pattern (Fig. 24a). Any deviation from the ‘consonance’ of puberty suggests an underlying abnormality. The timing of puberty is influenced by genetic factors and, critically, by body weight and composition. Over the last century, in the Western world, the age of onset of puberty has become earlier, in association with an increase in final height. In boys, puberty begins with the attainment of testicular volumes of 4 ml but the growth spurt occurs late in puberty and is predicted by a testicular volume of 10 ml. Conversely, in girls growth is an early pubertal event occurring with the onset of breast development.
Growth and puberty. Increases in gonadal steroid production at puberty stimulate the production of growth hormone. GH is secreted in a pulsatile fashion at night and there is an increase in the amplitude of GH pulses during normal puberty, although not their frequency. Increased GH secretion is reflected in the pubertal growth spurt which forms a crucial part of the maturational processes during adolescence. Absence or delay in the growth spurt usually indicates lack of consonance of puberty and requires investigation.
Adrenarche. Adrenal androgen secretion increases before puberty, at about age 6–8 years, and is associated with the onset of the development of axillary and pubic hair and apocrine sweat glands and, usually, a small increase in height velocity.
Endocrine regulation of puberty
The hypothalamic–pituitary–gonadal axis is active in fetal life with high gonadotrophin concentrations seen in the first half of gestation followed by reduced levels in the second half, thought to be due to a developing negative feedback system by gonadal steroids. In the immediate postnatal period gonadotrophin levels are high, related to the withdrawal of placental steroids and alterations to the negative feedback equilibrium. Gonadotrophin levels subsequently fall and remain low throughout early childhood, although detectable LH pulses can be identified as early as 6 years.
The onset of puberty is marked by a rise in LH secretion, which occurs firstly as nocturnal pulses. This occurs several years before the onset of phenotypic puberty and is in response to increased GnRH secretion and enhanced responsiveness of the pituitary gonadotrophs to the GnRH stimulus. Evidence for pulsatile LH secretion can be seen in ovarian ultrasound scans of normal prepubertal girls which show multiple ovarian follicles distributed throughout the ovary, an appearance typical of pulsatile LH input (Fig. 24b).
The factors that regulate the onset of LH secretion at the start of puberty remain to be fully elucidated but a number of neu- rotransmitters and other endocrine, paracrine and autocrine factors have been identified that modify the hypothalamic–pituitary–gonadal axis at this time. It has been recognized for some time that body weight and body composition affect the onset of puberty and the hormone leptin, derived from peripheral adipose tissue, plays a major role in signalling changes in body composition to the hypothalamus.
LH secretion gradually increases with the establishment of regular LH pulses occurring every 90 minutes during both night and day. LH secretion results in the production of gonadal steroids and the onset of secondary sexual characteristics. Increasing gonadal steroid concentrations regulate the GnRH pulse generator, establishing the mature diurnal variation and feedback systems seen in both sexes. In girls, estrogen levels rise dramatically in the year before menarche, establishing the positive feedback needed to induce a preovulatory LH surge. In boys, the regular LH pulses result in peak testosterone concentrations in the early mornings (Fig. 24c).
Gonadal development in childhood and puberty
In males, there is a rise in testosterone production between the ages of 2 and 4 months associated with Leydig cell multiplica- tion but after that the testes remain relatively inactive until the onset of puberty. Testicular size increases from around the age of 10 years, reflecting increased gonadotrophin secretion and growth of seminiferous tubules.
In females, the elevated gonadotrophin levels seen after birth decline by the age of 2–3 years and remain low throughout childhood. The rise in gonadotrophin secretion seen by the age of 6 is associated with the development of antral follicles in the ovary and a rise in estrogen concentration. The commencement of sex hormone production and release during puberty is accompanied by gonadal and accessory sex organ growth and function. The end of puberty is marked by the menarche with the onset of regular ovulatory cycles.