1 Department of Pediatrics, Division of Endocrinology, University of Michigan, Ann Arbor, MI 48109-0646, 2 Department of Pediatrics, Division of Endocrinology, University of Chicago, Pritzker School of Medicine, Chicago, IL 60637-1470 USA and 3 Institute of Reproduction and Development, Monash University, Clayton, Victoria, 3168 Australia
4 To whom correspondence should be addressed at: D1205 MPB, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0718, USA. Email: cmfoster{at}umich.edu
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Abstract |
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Key words: FSH/gonadal peptides/inhibin/puberty
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Introduction |
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FSH secretion is under the complex regulation of GnRH, which controls episodic release and is also released constitutively under the positive stimulation of the activin family of FSH-regulatory peptides (for reviews see Farnworth, 1995; Padmanabhan and Sharma, 2001
). The activins are peptides in the transforming growth factor-
(TGF-
) family that are produced in gonadal, pituitary and extragonadal tissues (Ying, 1988
). Although there are several known activin forms, serum assays have only been developed for activin-A and activin-AB. Only activin-A has been detected in human serum at concentrations above assay sensitivity (Knight et al., 1996
; Evans et al., 1997
). Human activin-A concentrations may vary in the menstrual cycle and perhaps with ageing, but have not been reported to fluctuate with pubertal maturation (Muttukrishna et al., 1996
; Foster et al., 2000
; Luisi et al., 2001
). Inhibins, also members of the TGF-
family, are produced principally in the gonads and act to depress FSH secretion (Ying, 1988
; Bilezikjian et al., 1994
; Kishi et al., 1999
). Two forms of inhibin, inhibin-A and -B, are produced in the ovary, while the testis produces only inhibin-B (Roberts et al., 1993
; Anawalt et al., 1996
; Hayes et al., 1998
). Serum inhibin-A concentrations, produced from dominant follicles (Roberts et al., 1993
), are at pubertal concentrations in girls during the 3 months after birth and then decline to low concentrations until late puberty (Bergadá et al., 1999
; Foster et al., 2000
; Sehested et al., 2000
; Raivio and Dunkel, 2002
). Serum inhibin-B concentrations are produced from Sertoli cells in boys and small antral follicles in girls (Roberts et al., 1993
). Serum inhibin-B concentrations are at pubertal levels for up to 3 months after birth in boys and girls (Bergadá et al., 1999
). Inhibin-B concentrations then decline to low levels in girls until the time of puberty (Bergadá et al., 1999
; Foster et al., 2000
; Sehested et al., 2000
). Inhibin-B concentrations are much greater in boys than in girls throughout childhood and exhibit a further increase in boys at the time of puberty (Andersson et al., 1997
).
FSH is also regulated by follistatin, a monomeric peptide that binds activin and prevents activin binding to its receptor, thereby inhibiting FSH secretion (Robertson, 1992; de Winter et al., 1996
; Phillips and de Kretser, 1998
). Processing of mRNA results in at least two forms of follistatin, a 315 kDa amino acid (aa) peptide and a 288 kDa aa (Robertson, 1992
; Phillips and de Kretser, 1998
). Follistatins are made in the gonads, pituitary and extra-gonadal tissues (Robertson, 1992
; Phillips and de Kretser, 1998
). Serum concentrations of total follistatin decline in late puberty in girls (Foster et al., 2000
), raising the possibility that activin could be more available as puberty progresses. Follistatin concentrations have not been studied extensively in boys.
The temporal changes in the serum concentrations of the FSH-regulatory peptides seem to be associated with changes in serum FSH concentration. Raivio et al. (2000) demonstrated that early pubertal boys exhibit an inverse relationship between baseline inhibin-B concentrations and peak FSH levels after GnRH stimulation, but the role of the other FSH-regulatory proteins in children has not been investigated. In puberty, FSH responses to GnRH may be regulated, not only by inhibins, but also by changes in other FSH-regulatory proteins. Gonadal maturation may be required before gonadal feedback of FSH-regulatory peptides can occur in response to FSH stimulation. As FSH secretion is controlled by the combined effects of the activins, inhibins, follistatins and sex steroids as well as GnRH, understanding the changes in gonadal production of FSH-regulatory peptides in the basal state and under GnRH-induced FSH stimulation should provide insights into the role of the gonad in FSH regulation during development. We hypothesized that the prepubertal and pubertal ovary and the pubertal testis would respond to FSH stimulation with changes in FSH-regulatory protein concentrations confirming the presence of a prepubertal feedback loop between FSH and FSH-regulatory peptides in boys and girls. To test this hypothesis, we increased FSH secretion in children by administering the GnRH agonist analogue, leuprolide acetate, and followed the changes in gonadotrophins, FSH-regulatory peptides and sex steroids over 24 h.
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Materials and methods |
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Of the 11 boys (Table II), six were referred for short stature. Four of these six boys had delayed adolescence, one of these six boys had isolated growth hormone deficiency and, in one, no diagnosis was made. Two boys had delayed adolescence without short stature. Two boys had precocious puberty with advancement of bone age. One of these boys had late onset congenital adrenal hyperplasia and developed central puberty after suppression of his adrenal steroids. The final boy had early pubic hair growth without significant elevation of adrenal androgens. One boy had a prior orchidopexy for undescended testes. His phallus and gonad length were at the 10th percentile. Since his gonadotrophins, inhibin-B and activin-A concentrations were comparable with those of the other boys studied, his data were included in the analysis.
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Assays
Serum LH, FSH and testosterone were determined using Delfia® immunofluorometric assay kits (Wallac, Gaithersburg, MD) with assay sensitivities of 0.05 IU/l for LH and FSH and 0.1 nmol/l for testosterone. The intra- and inter-assay coefficients of variation (CVs) were 3.1 and 6.1% for LH, 3.9 and 4.8% for FSH, and 5.1 and 9.5% for testosterone. Estradiol, determined by radioimmunoassay kits (Diagnostic Products Corporation, Los Angeles, CA), had an assay sensitivity of 18pmol/l, and intra- and inter-assay CVs of 5 and 9%, respectively.
Activin-A, inhibin-A and inhibin-B were determined using two-site enzyme-linked immunosorbent assays (ELISAs; Serotec, Raleigh, NC). The assay sensitivities were 0.2 ng/ml for activin-A, 8 pg/ml for inhibin-A and 15 pg/ml for inhibin-B. The intra- and inter-assay CVs were 6 and 16% for activin-A, 6 and 13% for inhibin-A, and 10 and 16% for inhibin-B.
Follistatin 288 was determined using a two-site ELISA, as described previously (Evans et al., 1998), with an assay sensitivity of 9.75 pg/ml. The intra- and inter-assay CVs were 12 and 16%, respectively. This assay cross-reacts by 10% with follistatin 315. Total follistatin concentrations were determined using a heterologous radioimmunoassay described previously (O'Connor et al, 1999
), which employs dissociating reagents to remove the interference of bound activin. The rabbit polyclonal antiserum was raised against 35 kDa bovine follistatin, and human recombinant (hr)-follistatin 288 was used as both tracer and standard. Cross-reactivity is 100% for hr-follistatin 288 and 33% for hr-follistatin 315. The assay sensitivity was 1.7 ng/ml, and the intra- and inter-assay CVs were 6.7 and 4.8%, respectively.
Statistics
Analysis of sex differences was determined in age-matched boys and girls such that only data from those girls with bone ages of 7.9 years or more were compared with the data of the boys. The choice of 7.9 years as a cut-off was based on studies regarding the normal age of onset of pubertal development in girls (Wu et al., 2002). As many as 10% of normal girls have breast development by age 8. Comparisons between girls were made by grouping girls by bone age. Three groups were defined: bone ages 0.93 years (n=5), bone ages 5.57.3 years (n=6) and bone ages
7.9 years (n=7). All hormone values were transformed logarithmically prior to analysis. Multiple comparisons were made by repeated measures of analysis of variance followed by a TukeyKramer test for post hoc significance. Significance was defined as P<0.05. Both the significance within the repeated measures and the post hoc comparisons between values within an analysis are presented. Comparisons of peak, baseline, and percentage change values were performed by one-way analysis of variance followed by Fisher's PLSD. A P-value of <0.05 was considered significant.
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Results |
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Discussion |
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To understand better the relationship between gonadal function and FSH secretion, we determined changes in several FSH-regulatory peptide concentrations after stimulating FSH secretion with the GnRH agonist, leuprolide acetate, using a protocol similar to that described by others (Rosenfield et al., 1989; Garibaldi et al., 1993
) in children with variations in pubertal development. Within 4 h of leuprolide acetate injection, there is a robust release of FSH which is greater in younger than older girls and is inversely correlated with bone age. Within 1620 h of the maximal FSH concentration, inhibin-B concentrations increase in girls, but this is only seen consistently after 4 years of age. This suggests that the infantile ovary is not sufficiently developed to respond with inhibin-B production after FSH stimulation. In the ovary, inhibin-B is produced in antral follicles and the number of antral follicles increases with advancing age in girls. Thus, it is likely that insufficient antral follicles have formed in infants to allow for inhibin-B feedback on pituitary FSH secretion. The fact that GnRH agonist stimulation of FSH is greatest in young girls and declines with advancing age is best explained by an increasing ability of the ovary to produce inhibin-B as it matures throughout childhood. Since FSH stimulates inhibin-B concentrations in girls 5 years of age and older, an inhibin-BFSH feedback loop can exist in girls before the onset of puberty. The majority of our studies were conducted in girls with variant forms of puberty. Many of the girls had precocious thelarche, a condition that is considered a variant of normal (Van Winter et al., 1990
; Lee, 2003
). Such girls usually have normal reproductive axes in adulthood, so it is likely that the hypothalamicpituitarygonadal axis functions in a manner similar to that seen in normal children. We were able to perform a limited study in five completely normal early pubertal girls and were gratified to see a similar, significant, increase in inhibin-B concentrations. In contrast to the girls with variations of pubertal development, inhibin-A concentrations also increased in the normal girls. In our study, approximately half of the boys had constitutional delay of puberty. This is also considered a variant form of puberty and is associated with normal pubertal progression and reproduction despite delay in the timing of puberty (Lee, 2003
). Altogether, our data indicate that the inhibinFSH feedback axis is established before adulthood in both boys, as has been noted previously (Raivio et al., 2000
), and girls.
The sex differences seen in the concentrations of FSH-regulatory peptides are intriguing. Although pubertal-aged boys respond to FSH stimulation with an increase in serum inhibin-B concentrations, the magnitude of the increase is significantly lower than what is seen in girls. Ambient inhibin-B concentrations, however, are much greater in boys than in girls, suggesting that boys have restrained FSH concentrations before and during early puberty, as compared with girls, because of a greater threshold of inhibin negative feedback. Girls begin puberty earlier than do boys, and girls have a 5-fold greater rate of idiopathic precocious puberty than do boys (Grumbach and Styne, 1998). Thus it is conceivable that the earlier timing of puberty in girls is related to the lesser inhibin restraint of constitutive FSH secretion leading to earlier gonadal stimulation of sex steroid secretion and subsequent sex steroid maturation of the hypothalamicpituitary axis. Early sex steroid exposure of the hypothalamicpituitary axis results in central sexual precocity in both boys and girls (Foster et al., 1984
; Pescovitz et al., 1984
).
FSH stimulation of the gonads in boys and girls is not associated with a change in activin-A concentration. This may be due to the fact that the prepubertal and pubertal gonadal production of activin-A is insensitive to FSH stimulation, or that gonadal-derived activin-A changes are masked by the extra-gonadal production of activin-A. Our previous observations, however, indicate that, at least in girls, follistatin concentrations decrease with the progression of puberty (Foster et al., 2000), suggesting that more free activin-A may be available to stimulate pituitary activin-A receptors. The similarity of follistatin 288 concentrations between boys and girls also allows for the possibility that girls could have higher free activin-A concentrations than boys, permitting greater stimulation of pituitary FSH and further accounting for sex differences between boys and girls.
Total follistatin concentrations were measured in 10 subjects at two time points. Although the results did not achieve significance, the fact that nine of 10 children had a decline in total follistatin concentrations suggests that acute stimulation by GnRH agonist may decrease production of total follistatin. In rats, fast frequency GnRH pulses are associated with an increase in follistatin mRNA (Kirk et al., 1994), suggesting that increased GnRH exposure could increase follistatin secretion. Whether the change in mRNA expression translates into changes in protein is not known. In our previous cross-sectional study of FSH-regulatory peptides in girls and women (Foster et al., 2000
), total follistatin declined significantly between girls in early puberty and women in the follicular phase of the menstrual cycle. Girls with early puberty have fast frequency GnRH secretion only for 36 h at night and women in the follicular phase of the menstrual cycle have fast frequency GnRH secretion during the day with some slowing at night. Additional studies will be required to determine whether changes in serum concentration of total follistatin can be seen in boys across puberty and whether these changes have a physiological significance in either gender.
Direct comparisons of the concentrations of inhibin-B in boys and girls have not been performed in previous studies, but the available data support our observation that inhibin-B concentrations are much greater in boys than in girls. Manasco et al. (1997) demonstrated that total inhibin concentrations in boys exceeded those of girls throughout puberty. Companion papers by Crofton et al. (2002a
,b
) also suggest that girls have lower concentrations of inhibin-B than do boys, even though statistical comparisons were not made in these studies. The greater concentrations of inhibin-B in boys are likely to account for the lower baseline and blunted stimulated FSH concentrations we have observed in boys compared with girls.
It is of interest that activin-A concentrations were significantly greater in girls than boys in our study. This differs from previous studies which found no sex differences in activin-A in males and females during puberty (Luisi et al., 2001) or in adulthood (Loria et al., 1998
). The reason for this discrepancy in findings is unclear, but could relate to the timing of serum sampling. Our comparisons were made at a uniform time of day, since we have noted previously that there may be diurnal variation in serum activin A concentrations (Foster et al., 1999
). This variation may have masked the ability to detect sexual dimorphism in prior studies. The developing adrenal gland may also release activin-A into the circulation (Spencer et al., 1992
) and might contribute to sexual dimorphism in activin-A concentrations. The fact that sexual dimorphism in activin-A concentrations exists in boys and girls is consistent with the possibility that circulating activin-A could stimulate the pituitary to produce the observed sexual dimorphism in FSH concentrations between boys and girls.
In summary, our results indicate that GnRH agonist-stimulated FSH concentrations are greatest in infant girls and decline steadily with age. GnRH agonist-stimulated FSH can increase inhibin B concentrations in mid childhood and in early puberty, but not in infant girls. The fact that stimulated inhibin-B concentrations are low in infancy but readily measurable in mid childhood, varying in the opposite direction to stimulated FSH concentrations, suggests that inhibin B production from the ovary in developing girls may serve a feedback regulatory role in FSH secretion. Further, the demonstration of sexual dimorphism of activin-A and inhibin-B concentrations in boys and girls also supports the role of these FSH-regulatory peptides in the prepubertal control of FSH secretion.
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Acknowledgements |
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References |
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Submitted on March 1, 2004; resubmitted on July 5, 2004; accepted on August 18, 2004.
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