Pediatric Endocrine Division Duke University Medical Center Durham, North Carolina 27710
Address all correspondence and requests for reprints to: Dr. Mary M. Lee, Duke University Medical Center, Pediatric Endocrine Division, 308 Bell Building, Box 3080, Durham, North Carolina 27710. E-mail: Lee00140{at}mc.duke.edu.
The relative quiescence of the hypothalamic-pituitary-gonadal (HPG) axis before puberty poses a challenge to clinical evaluation of the reproductive system in prepubertal children. During childhood, barring early infancy and puberty, the pituitary gonadotropes are exceptionally sensitive to negative feedback from low doses of sex steroids, and the HPG axis is under tonic central inhibition (1, 2, 3). Parturition appears to trigger a brief surge of LH in male neonates that stimulates a transitory rise in testosterone concentrations for about 12 h (4). The secretion of testosterone then rapidly declines, and serum values are indistinguishable from those in females by 24 h of age. The decline in placental and gonadal steroids after birth eliminates sex steroid-mediated inhibition of gonadotropin secretion, leading to activation of the HPG axis at 12 wk of age (5, 6, 7, 8). With the loss of negative feedback, the increased secretion of FSH and LH stimulates the production of gonadal steroids in a sex-specific profile for several months. Subsequently, the reproductive axis is again tonically suppressed until puberty, with males and females exhibiting differential sensitivity to sex steroid inhibition (1, 2, 3). The postnatal surge of reproductive hormones, termed the "minipuberty" of infancy, confirms that the various components of the reproductive system are functional in the newborn, although the HPG axis undergoes further subtle maturational changes before the onset of pubertal maturation.
During the transient activation of the HPG axis in infants, FSH and LH are secreted at pubertal concentrations in both males and females, but the amplitude and duration of the increased gonadotropin secretion differ (6, 8, 9). In males, random FSH and LH values start to rise at 1 wk of age, are maximal at 12 months, then decline by 6 months to the prepubertal range (6, 8, 9). The concentrations of the gonadal hormones, testosterone and inhibin B, parallel this pattern (5, 7, 9, 10, 11, 12). Testosterone concentrations reach a peak at 13 months of age, then decline to prepubertal values by 6 months, whereas inhibin B concentrations surpass adult values during early infancy and exhibit a more gradual decline.
Although the hormonal profile during the postnatal surge in reproductive hormones has been well characterized in male infants, analogous studies in females have been hampered by extensive individual variability in hormonal concentrations, and the greater frequency of values falling below the threshold of detection for the assays. Nevertheless, a similar activation of the HPG axis has been unequivocally demonstrated in female infants. In comparison to males, the concentrations of LH increase to a comparable or minimally lower range, whereas those of FSH are 5- to 10-fold higher (6, 7, 8, 13). Moreover, the increased secretion of FSH persists for a longer duration; scattered values during the second year of life remain elevated above the prepubertal range. Inhibin B concentrations are elevated during early infancy and gradually decline to a prepubertal nadir by 12 months of age (9, 12, 14, 15). However, for a number of individual samples, particularly those from older infants, the gonadotropin and inhibin values are below the lower limits of detection. Inadequate assay sensitivity has been especially problematic for estradiol measurements. Most studies have been unable to discern elevations in mean serum estradiol, despite sporadic values that are elevated to the midfollicular range at 26 months of age (5, 9, 12) and evidence of increased estradiol production and follicular activity in gonadal pathology specimens (16, 17). Consequently, limited data are available for compiling reference normative values of these reproductive hormones for female infants.
In this issue of JCEM, Chellakooty et al. (18) report the concentrations of a number of reproductive hormones in a large cohort of healthy female infants and analyze the effect of parameters such as birth weight and gestational age on the expression of these hormones. The authors obtained blood samples from 473 female infants at a corrected gestational age of 3 months to correspond with the established peak of the postnatal surge of gonadotropins and sex steroids. In addition to including a large number of infants to minimize the variability introduced by interindividual differences, the authors have the advantage of systematically measuring a constellation of related hormones in the same subjects. The normative data reported in this paper will be particularly useful to clinicians and clinical researchers because the authors have used several of the newer generation assays with increased sensitivity that are either commercially available or comparable to those used clinically.
The results of Chellakooty et al. (18) confirm that female infants have a pubertal increase in secretion of gonadotropins and gonadal hormones but reveal a tremendous interindividual variability in concentrations of these hormones. In contrast to earlier studies, estradiol and inhibin B were measurable in 85% of their subjects, and FSH and SHBG in all. LH was below the detection limit in 41% of the infants, despite using the sensitive Delfia fluoroimmunoassay. The authors provide several useful tables that depict the median, 2.5th, and 97.5th percentiles for FSH, LH, inhibins A and B, estradiol, and SHBG in term appropriate-for-gestational-age infants, as well as in infants grouped according to gestational age and weight for gestational age. These data highlight the complexity of reproductive hormone secretion in females and reinforce the difficulty of using random hormone values to characterize the profile of hormones secreted in a pulsatile pattern.
Chellakooty et al. (18) have started to explore the effects of intrauterine growth and fetal maturation on the reproductive hormones. They report higher inhibin B and estradiol concentrations in premature compared with term infants. On multiple linear regression analysis, serum estradiol and inhibin B both correlate inversely with gestational age, and serum estradiol and SHBG correlate inversely with body weight at 3 months of age. The authors note that these data indicate that ovarian hormones are elevated in premature infants for a longer duration after delivery than term infants, but they have no insights or speculations on the physiological relevance of this finding. Whether the premature ovary is more responsive to gonadotropins or whether these findings reflect the relative immaturity of the HPG axis with a temporal shift in its postnatal activation is unknown. Perhaps these subtle differences in endocrine function of the infant ovary are predictive of potential functional disturbances of the reproductive system at sexual maturity, as speculated by Ibanez et al. (19). In contrast to the recent report of higher FSH concentrations in small-for-gestational-age (SGA) infants (19), Chellakooty et al. (18) find no difference in the concentrations of the reproductive hormones between SGA, appropriate-for-gestational-age, and large-for-gestational-age infants. These seemingly contradictory findings must be interpreted with care, however, in light of the small numbers of SGA infants in each study and the wide fluctuations observed in individual hormone values. The establishment of normative reference data in a large number of infants reduces the vagaries imposed by the pulsatile nature of gonadotropin secretion and the interindividual variability in hormone profiles.
Will a better understanding of the reproductive endocrine profile of female infants enable these tests to be used clinically to evaluate future reproductive function and fertility? Can this information lead to insights on the regulation of the reproductive axis in infants? What is the physiological significance of the postnatal surge of reproductive hormones, and what accounts for the differences in gonadotropin profiles and sensitivity to sex steroid inhibition between males and females? Specific focused studies to address these and other questions regarding female reproductive function can be designed and interpreted with these reference data in mind.
Footnotes
Abbreviations: HPG, hypothalamic-pituitary-gonadal; SGA, small-for-gestational-age.
Received June 16, 2003.
Accepted June 16, 2003.
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