Regulation of Gonadal Steroid Production
Gonadotropin releasing hormone (GnRH) is secreted from the hypothalamus in a pulsatile fashion. A complex neuroendocrine regulatory mechanism involving multiple stimulatory and inhibitory inputs contributes to GnRH secretion. GnRH secretion in prepubertal children as measured by LH concentration is characterized by low and irregular pulses occurring every 3– 4 hours, and serum concentrations of LH and FSH are low. As the child approaches puberty, both the amplitude and frequency of GnRH pulses increase during the night- time hours, with pulse frequency approximating once per hour and returning to base line by morning (Figure1). This phenomenon leads to a diurnal variation in testosterone secretion in boys and to a lesser extent, oestradiol concentrations in girls. As puberty progresses, the changes in GnRH pulses extend to the daytime hours, stabilizing at a period of every 90– 120 minutes, with corresponding increases in afternoon concentrations of sex steroids. However, the diurnal variation in testosterone remains noticeable in adult men throughout the lifespan. Changes in GnRH pulse frequency alter relative production of FSH and LH, with slower pulsatility increasing FSH production. In adult women, pulse frequency varies over the menstrual cycle, ranging from every 60– 100 minutes.
Fig1. LH and testosterone secretion in a boy in the early stages of pubertal maturation demonstrating increased testosterone concentration and LH pulse amplitude and frequency during sleep, with decreases in both amplitude and frequency in the morning. Reproduced with permission from Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, et al. Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest. 1974 Sep;54(3):609– 18. Copyright © 1974 The American Society for Clinical Investigation.
An interesting phenomenon is the transient activation of GnRH, gonadotropin, and sex steroid secretion that occurs in the first few months of life, termed the ‘minipuberty of infancy’. In boys, testosterone concentrations fall in the first weeks after birth. By 4 weeks of age, however, testosterone levels rise and peak in boys at 7.2 ± 2.3 nmol/ L at about 1– 3 months of age, approximating levels seen in early- mid puberty. By 5– 6 months of age, testosterone concentrations fall and reach otherwise normal prepubertal ranges in the second half of the first year. In girls, oestradiol levels do not have an obvious peak but fluctuate over time, decreasing by 6– 12 months of age. Gonadotropin levels in boys are sufficient to cause increases in testicular volume, and testosterone concentrations are high enough to cause penile growth and acne. In girls, oestradiol levels during the minipuberty contribute to breast bud and uterine growth.
As puberty approaches, increases in GnRH pulsatility can be measured in both boys and girls as subtle increases in LH levels years before the clinical onset of puberty. These increases have been detected in serum as well as in urine. As clinically apparent changes occur with pubertal maturation, concentrations of sex steroids increase concurrently and eventually reach adult levels.
Gonadal Peptide Hormones
In addition to the sex steroids testosterone and oestradiol, other important products of the testes and ovaries are the peptide hormones inhibin and anti- Müllerian hormone (AMH). Both are products of the Sertoli cells of the testes and the ovarian granulosa cells. Inhibin exists in two major isoforms, inhibin B and inhibin A, with inhibin B produced primarily during the follicular phase and inhibin A during the luteal phase. Inhibin secretion is stimulated by FSH and functions in both males and females as part of a negative feedback loop to suppress pituitary release of FSH. Anti- Müllerian hormone plays an important role in the development of the male internal genitalia in the early weeks of gestation. In the adult ovary, AMH appears to decrease the growth of primordial follicles. Measurement of AMH has clinical utility as a reflection of the number of primordial ovarian follicles and possibly in the assessment of polycystic ovary syndrome.
Serum concentrations of AMH and the inhibins change between infancy and adulthood. In boys, AMH concentrations are high at birth and gradually decline during prepubertal life, with levels averaging 90– 100 ng/ ml at age 7– 10 years. At the onset of puberty, concentrations fall rapidly to reach levels similar to those seen in females. In girls, AMH concentrations are low at birth and remain modest in comparison to males. Levels increase slightly around the time of puberty, but average 2– 3 ng/ ml in adolescent girls /
By contrast, concentrations of inhibin B gradually rise during the prepubertal years. Several investigators have studied this relationship of the rise in inhibin B to the clinical manifestations of puberty. In a prospective, longitudinal study of a small number of boys and girls, Crofton et al. found progressive increases in inhibin B from genital Tanner stages 1 through 3 in boys and in creases in both inhibin A and B between breast Tanner stages 1 and 4 in girls. In a series of much larger cross sectional studies of data derived from NHANES III, Lee and colleagues found a gradual increase of inhibin B in both boys and girls through late childhood and into early adolescence, with the majority of prepubertal girls having levels below the limit of detection. On a population basis in girls, inhibin B was modestly useful for predicting the onset of puberty as established on clinical grounds, with an optimal cut- point on receiver operating characteristic (ROC) analysis of 17.9 pg/ ml, but relatively high false positive and negative rates. However, in boys the degree of interindividual variation rendered inhibin B alone unhelpful to establish the onset of puberty.
Growth Hormone/ Insulin- like Growth Factor- 1 (IGF- 1)
A hallmark of puberty is acceleration of height velocity, often called the pubertal growth spurt. Growth hormone is released in a pulsatile fashion, with more than 75% of daily release occurring at night. The most reliable pulse of growth hormone secretion occurs 45– 90 minutes after the onset of the first cycle of deep sleep, with a variable number of lesser pulses through the night. With the onset of puberty and the rise in oestradiol and testosterone con centrations, the amount of growth hormone released increases by a factor of approximately three. Serum concentrations of IGF- 1 increase by a similar amount. In addition to directly stimulating growth hormone secretion, aromatizable androgens potentiate the effect of growth hormone on IGF- 1 release. Additionally, growth hormone has a direct effect on ovarian granulosa cells to increase steroidogenesis, and IGF- 1 acts to increase ovarian FSH receptors. With progression of puberty, oestrogen concentrations rise in both sexes, ultimately resulting in maturation of the epiphyseal growth plates and cessation of linear growth. The higher concentration and earlier secretion of oestrogens in girls appears to account for the earlier occurrence of the pubertal growth spurt and the shorter average adult height in girls vs. boys.
