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Original Studies |
Department of Growth and Reproduction, Rigshopitalet (A.-M.A., N.E.S.), and the Department of Biostatistics, Panum Institute (J.H.P.), Copenhagen, Denmark; and the Departments of Pediatrics (J.T., A.-M.H., T.S., O.S.) and Physiology, University of Turku, Turku, Finland (J.T., A.-M.H.)
Address all correspondence and requests for reprints to: Anna-Maria Andersson, M.Sc., Ph.D., Department of Growth and Reproduction, Rigshospitalet, GR 5064, 9-Blegdamsvej, DK-2100 Copenhagen, Denmark. E-mail: rh01788{at}rh.dk
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Introduction |
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-subunit linked to
either a ßA-subunit (inhibin A) or a
ßB-subunit (inhibin B). Immunoassays for inhibin have
until recently suffered from cross-reaction with inactive monomeric
precursor forms present in plasma and from lack of discrimination
between inhibin A and inhibin B (6). Using a nonspecific inhibin assay,
it has been suggested that inhibin levels are increased in humans
during the first year of life (7). By the use of newly developed
immunoassays that are specific for either the bioactive inhibin A or
the inhibin B form (8), it has recently been demonstrated that it is
inhibin B that is the principal inhibin form in men and in women during
the follicular phase, whereas inhibin A is mainly present in the luteal
phase of the female menstrual cycle and is absent in men (8, 9). In
adult men, serum levels of inhibin B seem to be a promising marker of
Sertoli cell function (10, 11). The aim of the present study was to
evaluate secretion of the biologically active form, inhibin B, during
the first 2 yr of life in healthy boys and girls. In addition, serum
levels of FSH, LH, and testosterone (boys) were studied longitudinally
in the same group of children. |
Materials and Methods |
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The first blood sample was taken from umbilical vessels at birth. Thereafter, single blood samples were taken randomly between 0900–1500 h at 3-months intervals up to 2 yr of age. After centrifugation, sera were frozen and stored at -20 to -70 C.
Serum inhibin B was measured in duplicate in a double antibody
enzyme-immunometric assay using a monoclonal antibody raised against
the inhibin ßB-subunit in combination with a labeled
antibody raised against the inhibin -subunit, as previously
described (8). This assay was recently used in our laboratory to
measure levels of serum inhibin B in pubertal and adolescent boys (13).
The detection limit was 18 pg/mL, and the intra- and interassay
coefficients of variation were 15% and 18%, respectively.
Serum FSH and LH were measured by time-resolved immunofluorometric assay (Delfia, Wallac, Finland) with detection limits of 0.06 and 0.05 U/L, respectively. Intra- and interassay coefficients of variation were below 8% in both FSH and LH assays. The assay for LH measurements had a small (<1.5%) cross-reactivity with hCG. Considering the high levels of placenta-derived hCG in maternal and cord blood, this assay was thus unsuitable for LH measurements in cord blood. Testosterone was measured by RIA (Coat-a-Count, Diagnostic Products Corp., Los Angeles, CA) with a detection limit of 0.23 nmol/L and intra- and interassay coefficients of variation below 10%. The testosterone assay had a low cross-reaction to other steroids, including estradiol, estrone, and androstenedione. This cross-reaction was at the level of 0.01–2%, which normally would not significantly affect the results. However, the high levels of placenta-derived steroid that are present in maternal and cord blood render the assay unsuitable for measurements in cord blood and during the first few weeks of life (14). (Due to the limited amount of sera, FSH, LH, and testosterone levels were the results of a single measurement.)
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Results |
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The individual levels of inhibin B, FSH, LH, and testosterone in
boys are plotted longitudinally in Fig. 1
, a–d, and the mean values of inhibin
B, FSH, LH, and testosterone at each age are plotted in Fig. 2. Table 1
shows the median and range for the four hormones within each age group;
for comparison, the reference ranges in prepubertal children and adult
men are also presented. In term cord blood, inhibin B levels (mean
± SE, 154 ± 15 pg/mL) were slightly above or in the
high range of levels observed in 5- to 10-yr-old boys, whereas FSH
levels (0.73 ± 0.14 IU/L) were comparable to those observed later
in childhood. LH and testosterone levels were not determined in cord
blood due to cross-reactivity with placenta-derived hormones in the
assays for LH and testosterone. Serum levels of inhibin B, FSH, LH, and
testosterone were all elevated at 3 months of age. Serum inhibin B
levels (mean ± SE, 378 ± 23 pg/mL) were
elevated to well above adult levels, whereas FSH and LH levels
(1.78 ± 0.14 and 1.71 ± 0.50 IU/L, respectively) were
elevated into the low adult range, and testosterone levels (4.41
± 0.68 nmol/L) were below adult levels. Serum levels of FSH, LH, and
testosterone decreased in the following 3–6 months. Serum levels of
testosterone were undetectable from 6 months of age, whereas serum
levels of FSH and LH (0.67 ± 0.17 and 0.1 ± 0.03 IU/L,
respectively) were decreased to the range observed later in childhood
at 9 months of age. In 12 of 15 boys, the individual maximum level of
serum inhibin B was observed at 3 months of age, with declining levels
in the following months. In the remaining three boys, the individual
maximum level of serum inhibin B was observed at 6 months of age.
Although serum inhibin B levels decreased from 3 (or 6) months of age,
they remained elevated even after the levels of the other three
hormones had decreased to within the range observed later in childhood.
In the majority of the boys (n = 10), there was a change in the
slope of the declining values around 15–18 months of age, with a
slower subsequent fall in inhibin B levels, whereas the decrease was
even more in the remaining boys. At 24 months of age, serum levels of
inhibin B (124 ± 11 pg/mL) were either above (n = 2) or in
the high range (n = 13) for 5- to 10-yr-old boys. No significant
correlation between individual levels of inhibin B and FSH was observed
at any of the ages studied.
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The individual levels of inhibin B, FSH, and LH in girls are
plotted longitudinally in Fig. 3, a–c,
and the mean values for inhibin B, FSH, LH, and testosterone at each
age are plotted in Fig. 4. The hormonal
patterns were generally more complex in girls than in boys. In girls,
levels of inhibin B in cord blood were undetectable in all measured
samples (n = 11), and FSH levels were either undetectable (n
= 3) or in the range observed later in prepubertal childhood (n =
6; mean ± SE, 0.17 ± 0.09 IU/L). At 3 months of
age, three girls had inhibin B levels that were elevated (157 ±
34 pg/mL), but to a lesser degree than in boys, four girls had low but
detectable inhibin levels (38 ± 5 pg/mL), and four had
undetectable levels (three samples missing at this age). At 6 and 9
months of age, there was still high interindividual variation in the
levels of inhibin B in girls, although inhibin B was detectable in most
samples. From 12 months of age onward, levels of inhibin B were either
undetectable or low (37 ± 2 pg/mL). At 3 months of age, serum FSH
levels increased to a mean of 2.67 ± 1.91 IU/L, corresponding to
the high range of FSH levels observed later in childhood in girls. FSH
levels remained in this range in all subsequent samples, with some
individual variation (see Fig. 3b). Serum LH levels were generally
undetectable or very low in all samples from 3–24 months of age,
corresponding to levels observed later in childhood. However, at 3
months of age, one girl diverged from the general FSH/LH pattern. This
girl had a serum FSH level of 24.0 IU/L and a LH level of 1.0 IU/L at
this age. Inhibin B and estradiol (not shown) levels in the same sample
were undetectable. In subsequent samples this girl did not diverge from
the general hormonal pattern observed in infant girls. There was no
significant correlation between individual levels of inhibin B and FSH
in girls at any age, although a nonsignificant negative trend was
apparent.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Boys
In studies using less specific assays for inhibin that comeasure inhibin forms that are not biologically active, it has previously been demonstrated that inhibin levels are elevated in parallel with FSH and LH during the first months of life in both humans (7) and primates (15). The significance of this early postnatal elevation in immunoreactive inhibin levels is emphasized by our results, which show that this elevation in human male infants most likely represents a genuine elevation in inhibin bioactivity conferred by the inhibin B form. In contrast, it was recently shown that serum levels of inhibin B in 1- to 2-month-old male rhesus monkeys are at the same level as in juvenile monkeys, using the same specific inhibin B assay as that used in our study (16, 17). This result indicates that inhibin B levels in male rhesus monkeys, in contrast to those in humans, do not exhibit an early postnatal peak followed by a decrease to a lower level later in childhood. Nevertheless, FSH, LH, testosterone, and nonspecific inhibin levels all follow this pattern during this neonatal period in both humans and rhesus monkeys. As inhibin B seems to be a marker of Sertoli cell function, this difference in neonatal levels of inhibin B may reflect differences in Sertoli cell maturation between the two species. In humans, the total number of Sertoli cells increases 5- to 6-fold during the first year of life (18, 19), whereas in primates the mitotic activity of Sertoli cells seems to be limited during this period (20). A second period of postnatal Sertoli cell proliferation occurs around puberty in both humans (18) and primates (20), when the pituitary-gonadal axis is (re)activated, suggesting that activation of this axis may be important for Sertoli cell proliferation (21). As the number of Sertoli cells is believed to be a determinant of spermatogenic potential, adverse effects on Sertoli cell proliferation may be expected to result in impaired sperm output in adulthood. In adult men with hypogonadotropic hypogonadism, basal inhibin B levels have been shown to correlate to prior endogenous gonadotropin stimulation, but not to prior postpubertal exogenous gonadotropin stimulation (22). Furthermore, baseline inhibin levels in these patients seemed to predict the spermatogenic response to gonadotropin treatment (23). It has been suggested that there may be a developmental window during which gonadotropin stimulation of the testis is critical to Sertoli cell function later in life (22). Lack of gonadotropin stimulation in men with congenital or early onset of hypogonadotropic hypogonadism may limit the number or development of Sertoli cells during these developmental periods and thereby limit inhibin B secretion. The neonatal period of endocrine activity of the hypothalamic-pituitary-gonadal axis is possibly such an important developmental window, although fetal, childhood, or early pubertal gonadotropin secretion may also play a role. Thus, treatment of prepubertal hypogonadotropic hypogonadal boys with recombinant human FSH stimulated the production of inhibin B, which presumably reflected an increased Sertoli cell function, and induced growth of the testes (21). Similarly, induced precocious puberty in rhesus monkeys was associated with marked proliferation of Sertoli cells (20). Interestingly, reversible blocking of the pituitary-gonadal axis during the first 4 months of life in monkeys resulted in lower sperm counts in treated animals than in control animals, indicating that the normal activation of the pituitary-gonadal axis during this period also in primates may be important for subsequent spermatogenesis (24).
Sertoli cells are, however, not the only testicular cell type that increases in number during and shortly after the early postnatal activation of the hypothalamic-pituitary-gonadal axis. A quantitative study of cell numbers in testes obtained at autopsy showed that the total number of germ cells in boys increased until 100 days of age, with a successive decrease in germ cell number in boys older than 100 days (25). Likewise, a pronounced rise in the number of fetal Leydig cells has been shown to take place during the third month after birth, followed by a rapid decrease (26). Furthermore, Leydig cells at this age are larger than those found in the preceding or following weeks. This transient Leydig cell development is presumably stimulated by the elevated LH levels observed at this age and is most likely responsible for the transient elevated testosterone levels. This elevation in testosterone levels has been suggested to be involved both in testicular changes, such as the increase in germ cell number (25), and in sexual differentiation of the central nervous system (27).
No correlation was observed between inhibin B and FSH in boys. Experimental studies in monkeys suggest that mechanisms that regulate the hormonal interactions between the pituitary and the gonad are established in the newborn primate. GnRH antagonist treatment, which blocks FSH and LH release, results in severely suppressed testosterone (28) and inhibin B (16) levels in infant male rhesus monkeys, indicating that testosterone and inhibin B production and secretion at this age, as in the adult male, are stimulated by gonadotropins. However, in our study, inhibin B levels, although slowly decreasing, remained above or in the high range of inhibin B levels observed later in childhood even a year after gonadotropins had reached low childhood levels. This indicates that inhibin B production, once activated by gonadotropin stimulation, can continue autonomously or under the influence of other unknown factors for a period. The negative gonadal feedback mechanisms seem also to be operating in the neonate, as gonadectomy of newborn male and female rhesus monkeys results in dramatically elevated gonadotropin levels (29, 30). Both gonadal steroids and inhibin B are likely gonadal feedback regulators of gonadotropin secretion. This closed feedback loop of the pituitary-gonadal axis is presumably also established in the human newborn. For example, we have observed highly elevated FSH levels in a 3-month-old boy with gonadal dysfunction, reflected in undetectable serum inhibin B levels (unpublished observation). The failure of these pituitary-gonadal interactions to be reflected in a significant correlation between serum inhibin B and FSH levels may be explained by the dramatic hormonal changes occurring during a relatively short period. Even within a given age group, e.g. 3–6 months, the activity of the pituitary-gonadal axis may be increasing in some individuals and may be on the decline in others. Thus, individual hormone levels at a given age may reflect different stages of hormonal interaction. Alternatively, additional regulatory factors that interact with the pituitary-gonadal axis may be operating in the newborn. Thus, unknown nongonadal factors seem to be responsible for the subsequent hiatus in gonadotropin secretion later in childhood (31).
Girls
Little is known about the physiological significance of the early postnatal activation of the hypothalamic-pituitarygonadal hormone axis in girls, and to our knowledge, no studies of GnRH antagonist treatment during the neonatal period in female primates have been presented.
In the normal immature ovary, ovulation does not occur, but different stages of follicular maturation are frequently observed during childhood (32). There seems to be a definite increase in follicle maturation with age. However, the most rapid increase takes place during the first 4 months of postnatal life, concurrent with activation of the pituitary-gonadal axis (32). In a study of prepubertal ovaries obtained at autopsy, the incidence of polycystic ovaries in girls was shown to peak around the age of 4 months, presumably as a result of the increased gonadotropin stimulation (32). In contrast, an ultrasonic study indicated that the incidence of polycystic ovaries did not change during the first 2 yr of life, although the incidence of cystic ovaries with macrocyst was much higher in the first, than in the second, year of life (33). Furthermore, inhibin activity and estradiol levels in follicular fluid tend to be elevated at 0–2 months of age and decrease thereafter (34). In our study, one girl had dramatically elevated FSH and LH levels at the age of 3 months. In the same sample, inhibin B and estradiol were undetectable, a finding that might indicate gonadal dysfunction in this girl. However, in subsequent samples from this girl, FSH and LH were at levels similar to those in the other girls, as was inhibin B. Furthermore, no other clinical data suggested that this girl was endocrinologically abnormal. An alternative explanation for the apparently deviant hormone pattern of this girl at the age of 3 months could be that girls at this age have brief episodes of gonadotropin peaks. Thus, this apparently deviant hormone pattern might be perfectly normal, although it was not observed in the other girls due to the sampling frequency. Gonadotropin levels in the same range as that in this girl have previously been measured in serum from girls under the age of 1 yr (7). Along the same lines, it may be speculated that the large interindividual variation in inhibin B levels at the age of 3–9 months may reflect large intraindividual variation, perhaps in a pseudocyclic pattern. However, a sampling frequency of 3 months clearly only offers a crude indication of the hormonal changes that take place during the first year of life, and more detailed studies of hormone levels in infant girls are needed to further elucidate these issues.
In conclusion, the first 1–2 yr of life, in particular the first few months, are characterized by high gonadal endocrine activity, including a supraadult secretion of inhibin B in boys. This early hormonal activation seems to be important for sexual development and may be potentially vulnerable to endocrine interference, e.g. from suspected impact of environmental factors (35).
Our results may also be important from a clinical point of view. Identification and delimitation of the developmental periods receptive to gonadotropin stimulation should lead to improved endocrine management of patients with congenital or early onset of gonadal failure. Identification of inadequate activation of the hypothalamic-pituitary-gonadal axis during the neonatal period may provide clues about developmental deficiencies that otherwise only become apparent around puberty or later in life. Furthermore, in some cases (e.g. in gonadotropin deficiency) identification of inadequate infant activation of the hypothalamic-pituitary-gonadal axis might enable the initiation of treatment at the most responsive periods in development.
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Acknowledgments |
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Footnotes |
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Received September 26, 1997.
Revised October 27, 1997.
Accepted November 7, 1997.
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concentrations in infant, prepubertal, and
adult male rhesus monkeys (Macaca mulatta) and in juvenile
males during premature initiation of puberty with pulsatile
gonadotropin-releasing hormone treatment. Endocrinology. 123:250–256.
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M. Chellakooty, I. M. Schmidt, A. M. Haavisto, K. A. Boisen, I. N. Damgaard, C. Mau, J. H. Petersen, A. Juul, N. E. Skakkebaek, and K. M. Main Inhibin A, Inhibin B, Follicle-Stimulating Hormone, Luteinizing Hormone, Estradiol, and Sex Hormone-Binding Globulin Levels in 473 Healthy Infant Girls J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3515 - 3520. [Abstract] [Full Text] [PDF]
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T. Raivio, J. Toppari, M. Kaleva, H. Virtanen, A.-M. Haavisto, L. Dunkel, and O. A. Janne Serum Androgen Bioactivity in Cryptorchid and Noncryptorchid Boys during the Postnatal Reproductive Hormone Surge J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2597 - 2599. [Abstract] [Full Text] [PDF]
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E. B. Berensztein, M. I. Sciara, M. A. Rivarola, and A. Belgorosky Apoptosis and Proliferation of Human Testicular Somatic and Germ Cells during Prepuberty: High Rate of Testicular Growth in Newborns Mediated by Decreased Apoptosis J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5113 - 5118. [Abstract] [Full Text] [PDF]
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R. M. Sharpe, B. Martin, K. Morris, I. Greig, C. McKinnell, A. S. McNeilly, and M. Walker Infant feeding with soy formula milk: effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity Hum. Reprod., July 1, 2002; 17(7): 1692 - 1703. [Abstract] [Full Text] [PDF]
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L. Ibanez, C. Valls, M. Cols, A. Ferrer, M. V. Marcos, and F. de Zegher Hypersecretion of FSH in Infant Boys and Girls Born Small for Gestational Age J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1986 - 1988. [Abstract] [Full Text] [PDF]
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C.J.H. Kelnar, C. McKinnell, M. Walker, K.D. Morris, W.H.B. Wallace, P.T.K. Saunders, H.M. Fraser, and R.M. Sharpe Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy? Hum. Reprod., May 1, 2002; 17(5): 1367 - 1378. [Abstract] [Full Text] [PDF]
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H.-P. E. Larsen, J. Thorup, L. T. Skovgaard, D. Cortes, and A. G. Byskov Long-term cultures of testicular biopsies from boys with cryptorchidism: effect of FSH and LH on the number of germ cells Hum. Reprod., February 1, 2002; 17(2): 383 - 389. [Abstract] [Full Text] [PDF]
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C. A. Quigley The Postnatal Gonadotropin and Sex Steroid Surge--Insights from the Androgen Insensitivity Syndrome J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 24 - 28. [Abstract] [Full Text] [PDF]
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 E. Terasawa and D. L. Fernandez Neurobiological Mechanisms of the Onset of Puberty in Primates Endocr. Rev., February 1, 2001; 22(1): 111 - 151. [Abstract] [Full Text]
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K. M. Main, I. M. Schmidt, and N. E. Skakkebæk A Possible Role for Reproductive Hormones in Newborn Boys: Progressive Hypogonadism without the Postnatal Testosterone Peak J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4905 - 4907. [Abstract] [Full Text]
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 P. I A HUGHES How vulnerable is the developing testis to the external environment? Arch. Dis. Child., October 1, 2000; 83(4): 281 - 282. [Full Text] [PDF]
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 R.M. Sharpe, M. Walker, M.R. Millar, N. Atanassova, K. Morris, C. McKinnell, P.T.K. Saunders, and H.M. Fraser Effect of Neonatal Gonadotropin-Releasing Hormone Antagonist Administration on Sertoli Cell Number and Testicular Development in the Marmoset: Comparison with the Rat Biol Reprod, June 1, 2000; 62(6): 1685 - 1693. [Abstract] [Full Text]
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A. Sehested, A. Juul, A. M. Andersson, J. H. Petersen, T. K. Jensen, J. Müller, and N. E. Skakkebaek Serum Inhibin A and Inhibin B in Healthy Prepubertal, Pubertal, and Adolescent Girls and Adult Women: Relation to Age, Stage of Puberty, Menstrual Cycle, Follicle-Stimulating Hormone, Luteinizing Hormone, and Estradiol Levels J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1634 - 1640. [Abstract] [Full Text]
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K. Kubini, M. Zachmann, N. Albers, O. Hiort, M. Bettendorf, J. Wölfle, F. Bidlingmaier, and D. Klingmüller Basal Inhibin B and the Testosterone Response to Human Chorionic Gonadotropin Correlate in Prepubertal Boys J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 134 - 138. [Abstract] [Full Text]
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K L Ng, S F Ahmed, and I A Hughes Pituitary-gonadal axis in male undermasculinisation Arch. Dis. Child., January 1, 2000; 82(1): 54 - 58. [Abstract] [Full Text]
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S. J. Winters and T. M. Plant Partial Characterization of Circulating Inhibin-B and Pro-{alpha}C During Development in the Male Rhesus Monkey Endocrinology, December 1, 1999; 140(12): 5497 - 5504. [Abstract] [Full Text]
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J. Deladoëy, C. Flück, M. Bex, N. Yoshimura, N. Harada, and P. E. Mullis Aromatase Deficiency Caused by a Novel P450arom Gene Mutation: Impact of Absent Estrogen Production on Serum Gonadotropin Concentration in a Boy J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4050 - 4054. [Abstract] [Full Text]
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S. von Eckardstein, M. Simoni, M. Bergmann, G. F. Weinbauer, P. Gassner, A. G. Schepers, and E. Nieschlag Serum Inhibin B in Combination with Serum Follicle-Stimulating Hormone (FSH) Is a More Sensitive Marker Than Serum FSH Alone for Impaired Spermatogenesis in Men, But Cannot Predict the Presence of Sperm in Testicular Tissue Samples J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2496 - 2501. [Abstract] [Full Text]
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E. Carlsen, C. Olsson, J. H. Petersen, A.-M. Andersson, and N. E Skakkebæk Diurnal Rhythm in Serum Levels of Inhibin B in Normal Men: Relation to Testicular Steroids and Gonadotropins J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1664 - 1669. [Abstract] [Full Text]
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S F Ahmed, A Cheng, and I A Hughes Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome Arch. Dis. Child., April 1, 1999; 80(4): 324 - 329. [Abstract] [Full Text]
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K. Steger, R. Rey, F. Louis, S. Kliesch, H.M. Behre, E. Nieschlag, W. Hoepffner, D. Bailey, A. Marks, and M. Bergmann Reversion of the differentiated phenotype and maturation block in Sertoli cells in pathological human testis Hum. Reprod., January 1, 1999; 14(1): 136 - 143. [Abstract] [Full Text] [PDF]
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A.-M. Andersson, J. Müller, and N. E. Skakkebæk Different Roles of Prepubertal and Postpubertal Germ Cells and Sertoli Cells in the Regulation of Serum Inhibin B Levels J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4451 - 4458. [Abstract] [Full Text]
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