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Original Studies |
Department of Clinical Biochemistry, Division of Endocrinology (K.K., F.B., D.K.), and Department of Pediatrics (K.K., N.A., J.W.), University of Bonn, Bonn, Germany; Department of Pediatrics, University of Zurich (M.Z.), Zurich, Switzerland; Department of Pediatrics, University of Lubeck (O.H.), Lubeck, Germany; and Department of Pediatrics, University of Heidelberg (M.B.), Heidelberg, Germany
Address all correspondence and requests for reprints to: Dr. Kirsten Kubini, Department of Clinical Biochemistry, Division of Endocrinology, and the Department of Pediatrics, University of Bonn, Bonn, Germany.
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Abstract |
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Introduction |
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Subjects and Methods |
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We studied 54 males ranging in age from 1 month to 16.8 yr.
Karyotypes were 46,XY (n = 48); 45,X0/46,XY (n = 3);
47,XXY/45,X0 (n = 1); and 46,XX (n = 2). The patients had
been referred to the Departments of Pediatrics and Divisions of
Endocrinology at the Universities of Zurich (Switzerland), Bonn,
Heidelberg, Lubeck, and Cologne (Germany) for hormonal evaluation of
gonadal function, including a hCG stimulation test. The patients were
divided into 3 subgroups depending on their clinical presentation
(Table 1
): group I, patients with normal
phallus but nonpalpable testes or suspicious testicular function
(n = 21); group II, patients with anomaly of the phallus but
palpable testes (n = 16); and group III, patients with anomaly of
the phallus and nonpalpable testes (n = 17). The final
diagnoses of 42 patients after work-up are shown in Table 1. In 4
patients the parents refused further evaluation. All patients were
clinically prepubertal, and testicular volume, if palpable, was less
than 3 mL.
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The basal blood samples were obtained in the morning, followed by a single im injection of 5000 IE hCG/m2 body surface area. Seventy-two hours later, a second sample was taken. Plasma was stored at -20 to -80 C until analysis.
Testosterone, inhibin B, FSH, and LH were measured before hCG
administration; testosterone and inhibin B were measured after hCG
administration. An increment in plasma testosterone (
testosterone)
of more than 0.8 ng/mL or an absolute level greater than 0.9 ng/mL
after hCG treatment were considered to indicate the presence of
functioning testicular tissue and were defined as normal (21).
Hormonal assays
Serum inhibin B was measured in duplicate by a previously
described (13) enzyme-linked immunoabsorbent assay
(Serotec, Kidlington, UK) using two different antibodies
directed against distinct epitopes on the 
- and ß-subunits. The
detection limit was 15 pg/mL; the inter- and intraassay coefficients of
variation were 14.2% and 4.6%, respectively. Reference values (median
and 5th-95th percentile) for inhibin B are based on 143 healthy,
prepubertal German boys (our unpublished data) and are
comparable to the data reported by Andersson et al. (10, 11). Testosterone, FSH, and LH were measured by a commercially
available enzyme immunoassay (Roche Molecular Biochemicals, Mannheim, Germany). The detection limits were:
testosterone, 0.02 ng/mL; FSH, 0.1 U/L; and LH, 0.1 U/L.
Statistical analysis
The changes in testosterone before and after hCG treatment were
compared using the Wilcoxon test. The testosterone increment after hCG
was expressed as testosterone, Spearman rank correlation
coefficients were calculated between testosterone and basal inhibin
B, basal FSH, and basal LH. Inhibin B levels before and after hCG
administration were compared by paired t test, as they were
normally distributed (Kolmogorow-Smirnov test). Inhibin B levels below
the detection limit were set at 15 pg/mL.
Each individual inhibin B level was assigned to an age-dependent subgroup (subgroup 1, 0–6 months; subgroup 2, 6 months to 2 yr; subgroup 3, 2 yr until puberty), and individual inhibin B SD scores according to these subgroups were calculated.
All statistical analyses were performed using SPSS, Inc., software (SPSS, Inc., Chicago, IL), version 7.5 for Windows.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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testosterone) correlated strongly (r = 0.84; P <
0.0001; Fig. 1). The median testosterone
increase was 1.26 ng/mL (range, 0.00–13.2). Inhibin B before hCG
(median, 95 pg/mL; range, 10–703) and after hCG (106 pg/mL; 10–600)
did not differ significantly.
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testosterone remained very strong (r = 0.77; P <
0.0001). The relationship between individual inhibin B
SD scores and final diagnoses is shown in Fig. 2.
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testosterone The mean inhibin B SD scores were -1.98
and -0.8, respectively (P < 0.0038). In patients with
androgen resistance, inhibin B levels and testosterone were normal
(n = 3) or elevated (n = 4) for age (mean inhibin B
SD score, 1.78; testosterone: median, 6.7
ng/mL; range, 1.3–13.2 ng/mL). Five patients with male
pseudohermaphroditism and known tubular involvement (gonadal
dysgenesis) had inhibin B levels below the fifth percentile (mean
inhibin B SD score, -1.73), but in three of them
the testosterone response to hCG was normal ( testosterone, 1.3,
1.96 and 3.3 ng/mL). Testicular damage (testicular torsion, orchiopexy,
testicular trauma) was invariably followed by inhibin B values below
the fifth percentile and insufficient testosterone (mean inhibin B
SD score, -1.98). Two patients with the XX-male
syndrome had inhibin B and testosterone levels normal for age. In
most patients a clear correlation between inhibin B levels and
testosterone could be demonstrated, but seven children had diverging
results: three patients with gonadal dysgenesis (aged 3 months) had a
normal testosterone response to hCG but inhibin B levels below the
fifth percentile (inhibin B, 86, 86, and 103 pg/mL), one patient with
cryptorchidism had low testosterone (0.53 ng/mL), but inhibin B
levels within the normal range for age (69 pg/mL), and three patients
with LH receptor defect presenting with hypospadias (n = 2) and
ambiguous genitalia (n = 1) had no testosterone increase after
hCG, but inhibin B levels were within the lower normal range for age
(inhibin B SD scores, 71 (-1.05); 62 (-0.75),
and 110 (-0.54) pg/mL; see Table 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our data differ from previous reports in two aspects: 1) although
we found no influence of hCG stimulation or inhibin B levels, earlier
studies in young adults have reported an increment (22, 23); and 2)
although we found very low inhibin B levels in cases with anorchia or
testicular dysgenesis, earlier reports found no differences in
comparison with normal boys (24). These discrepancies are most likely
due to the previously used, less specific and sensitive inhibin assays
cross-reacting with free -subunits (25).
Whereas basal inhibin B thus can be used as a general marker of testicular presence and function in boys with absent, insufficient, or normal tubular tissue, the situation may be different in patients with some specific conditions. In our five patients with testicular dysgenesis basal inhibin B levels were low, whereas the testosterone response to hCG was normal in three of them, suggesting that tubular function is more severely affected than Leydig cell function. On the other hand, in patients with defects of testosterone biosynthesis, Leydig cell aplasia, or LH receptor defect, one would expect normal inhibin B levels, whereas the testosterone response to hCG would be absent or low. This was indeed the case in three patients with LH receptor defect.
It remains unclear why some prepubertal patients with androgen resistance have elevated inhibin B levels in the absence of elevated peripheral FSH. A similar finding of increased levels of anti-Mullerian hormone in patients with androgen insensitivity was reported by Rey et al. (12), suggesting an increased production of peptide hormones by Sertoli cells in these patients. As a possible explanation, androgen resistance may lead to a higher daily production rate of FSH (not reflected by basal FSH levels) due to the resistance of the gonadotropins to testosterone feedback and thus to an increase in circulating inhibin B. Alternatively, the insufficient paracrine action of testosterone on Sertoli cells (26, 27) may directly lead to an unphysiological high inhibin B production rate.
In conclusion, our data demonstrate that inhibin B is a reliable indicator of the presence and absence of testes in infants and prepubertal boys. Particularly in cryptorchid boys, a single inhibin B determination may predict Sertoli and Leydig cell function, thus obviating further hormonal studies. Furthermore, inhibin B levels add a valuable tool to the differential diagnosis of sexual ambiguity, yielding low levels in global testicular disorders and normal or elevated levels in specific disorders concerning androgen biosynthesis or action.
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Acknowledgments |
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Footnotes |
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Received March 25, 1999.
Revised September 29, 1999.
Accepted October 11, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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4-androstendione in normal
newborns: evidence for testicular activity at birth. J Clin
Endocrinol Metab. 41:977–980.[Abstract]
subunit in human serum:
implications for radioimmunoassay. J Clin Endocrinol Metab. 70:1208–1212.[Abstract]
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