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Perspectives and Editorials |
Sato I, Yoshikawa A, Shimizu K, Ishiwari A, Mukai T,
Iwamoto T. Urinary prostate-specific antigen is a noninvasive indicator of
sexual development in male children. J Androl. 2007
;28: 155
–157
| Received for publication September 26, 2006; accepted for publication September 27, 2006. |
PSA, first identified 25 years ago, was originally thought to be highly tissue-specific to the prostate and has had clinical relevance primarily as a tumor biomarker for surveillance of adenocarcinoma of the prostate (Wang et al, 1979; Diamandis and Yu, 1995). With the advent of more sensitive immunoassays, additional tissues such as periurethral and perianal glands, endometrium, breast cancers, and tumors of other organ systems were recognized to produce PSA, albeit at much lower levels (Diamandis and Yu, 1995; Balk et al, 2003). Consequently, other clinical applications for PSA determination have been explored. One group investigated the possibility that PSA could serve to delineate fetal sex in amniotic fluid but found no difference in concentrations between males and females (Wolff et al, 1999). As a biomarker of pubertal onset, serum PSA is relatively insensitive compared to other measures such as early morning testosterone, the free androgen index (testosterone/SHBG), and ICMA LH (Wu et al, 1993; Neely et al, 1995; Kim et al, 1999). While mean PSA values increase at successive stages of pubertal maturation, PSA concentrations remain undetectable in 30%–70% of boys in stage 2 of genital development, and mean values increase significantly only at mid-puberty (stage 3) (Viera et al, 1994; Kim et al, 1999). Moreover, despite showing positive correlation with androgen and LH values, PSA measurements exhibit substantial overlap among individual boys at different pubertal stages (Viera et al, 1994; Kim et al, 1999).
Sato and colleagues have undertaken the daunting task of evaluating the applicability of urinary prostate-specific antigen (PSA) determination as a biochemical correlate of male sexual maturation. They compare urinary PSA activity with chronological age and pubertal development using the SMITEST PSA card (Seratec Diagnostica, Gottingen, Germany) and extend these observations using an immunochromatographic membrane method to investigate longitudinal changes in urinary PSA measurements in neonates. Given that PSA is androgen-regulated and that serum values have been shown to increase with pubertal maturation, it is not surprising that the authors report that urinary PSA is undetectable in prepubertal boys between 4 months and 9 years of age and detectable in all boys at pubertal stage 3 and above. Urinary PSA was also detectable in 32% of boys between ages 10 and 12 in whom pubertal staging was not described; thus, the sensitivity of this urine assay compared to the assays used in published studies of serum PSA in pubertal children cannot be assessed. Nevertheless, as with the serum assays, there appears to be overlap in urinary PSA activity across chronological ages and pubertal stages; thus, urinary PSA determination does not provide improved prediction of pubertal onset or staging. These studies, however, were conducted on spot urines obtained between 9:30 AM and 12 PM. It is conceivable that the results might have improved sensitivity and specificity if pooled urine collections had been used, since early puberty is marked by diurnal variability in LH and FSH pulses and testosterone secretion.
In the second part of this study, the authors measure urinary testosterone and PSA in spot urines collected weekly from birth to 18 weeks of age in 6 infants. These serial measurements reveal a random and unpredictable fluctuating pattern of PSA secretion. The intermittent peaks in urinary PSA occur between 4–14 weeks of age, a time interval that corresponds to the well-documented neonatal activation of the HPG axis (Forest et al, 1979; Berger et al, 1991). Unfortunately, the normally observed rise in androgen secretion is not consistently found in weekly spot urines from birth until 18 weeks, a finding that is contradictory to published data describing higher serum testosterone concentrations at birth and at 2–4 months of age during the neonatal "mini-puberty" (Forest et al, 1979; Courbier et al, 1990; Berger et al, 1991). These discordant data reinforce that only a small fraction of circulating free or bound testosterone is secreted in urine as testosterone conjugates. Most of it is metabolized to ketosteroids and other metabolites that are undetectable on testosterone RIAs, rendering urinary testosterone determination highly inaccurate for evaluating androgen production. The reliance upon urinary testosterone concentrations to assess androgen production is a significant technical flaw of this study that impedes the authors' ability to adequately evaluate the correlation between PSA and androgen production in neonates.
Nevertheless, the observed elevations in urinary PSA are probably a consequence of androgen action. These data suggest that androgens are able to stimulate PSA production by androgen-responsive tissues in infants and that the increased secretion of PSA does not persist when androgens decline, as both urinary and serum PSA have been found to be unmeasurable in older infants and prepubertal children. As noted by the authors, it is unclear whether the week-to-week variability in urinary PSA values reflects technological problems related to sampling methodology, that is, using spot versus pooled urine collections, or whether it is caused by true physiologic fluctuations in PSA production despite sustained elevations in testosterone concentrations during this time period.
These data suggest potential clinical applications for PSA determination in children with disorders of the reproductive system. Although serial urine monitoring to identify sporadic peaks is impractical, if PSA is shown to be consistently elevated in pooled urine specimens in parallel with elevations in serum androgens, urinary PSA determination may serve as a less invasive means of assessing neonatal testicular function than obtaining blood specimens for serum androgens. Moreover, as a biochemical marker of androgen action, PSA could be measured in conjunction with SHBG to test for androgen sensitivity in children with suspected androgen insensitivity syndrome. Similarly, in children with other disorders of sex development who are inadequately virilized, PSA determination might be helpful as a biochemical measure of androgen secretion and action.
The authors make the intriguing observation of higher urinary testosterone but lower urinary PSA concentrations in preterm compared to full-term infants, which raises provocative speculations regarding physiologic differences in reproductive function of preterm and term neonates. Despite the twofold to threefold higher urinary testosterone values, urinary PSA, presumably an androgen-responsive gene, in the preterm infants is 60% lower than in full-term infants. This discrepancy in the data is puzzling. The higher urinary testosterone concentrations in premature infants are consistent with a published study showing higher mean serum testosterone concentrations in premature infants (Tapanainen et al, 1981). If so, is there a difference in PSA responsiveness to androgens in preterm infants, or is exposure to androgens during the third trimester critical for complete development of the prostate? Alternatively, are the urinary testosterone concentrations in preterm infants misleadingly elevated compared to serum androgens because of methodological concerns or because of biologic differences in testosterone metabolism or secretion in preterm versus term infants? This study not only enhances our understanding of PSA secretion in infants and children but also stimulates thought-provoking questions regarding the physiology of PSA and its relationship to androgens in infants that will require further study.
References
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Diamandis EP, Yu H. New biological functions of prostate-specific
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Forest MG, Sizonenko PC, Cathiard AM, Bertrand J. Hypophysogonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy. J Clin Invest. 1974; 3: 819 –828.
Kim MR, Gupta MK, Travers SH, Rogers DG, Van Lente F, Faiman C. Serum prostate specific antigen, sex hormone binding globulin and free androgen index as markers of pubertal development in boys. Clin Endocrinol. 1999;50: 203 –210.[CrossRef][Medline]
Neely EK, Hintz RL, Wilson DM, Lee PA, Gautier T, Argente J, Stene M. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr. 1995;127: 40 –46.[CrossRef][Medline]
Tapanainen J, Koivisto M, Vihko R, Huhtaniemi I. Enhanced activity of the pituitary-gonadal axis in premature human infants. J Clin Endocrinol Metab. 1981;52: 235 –238.[Abstract]
Vieira JG, Nishida SK, Pereira AB, Arraes RF, Verreschi IT. Serum levels of prostate-specific antigen in normal boys throughout puberty. J Clin Endocrinol Metab. 1994; 78: 1185 –1187.[Abstract]
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Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ. Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys. J Clin Endocrinol Metab. 1993; 76: 26 –31.[Abstract]
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  M. M. Lee Editorial Commentary J Androl, January 1, 2007; 28(1): 155 - 157. [Full Text] [PDF]
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