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Original Studies |
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo (V.N.B., M.C.B., M.B.F.K., A.C.L., I.J.P.A., B.B.M.), SP-01060–970 Sao Paulo; and the Departamento de Endocrinologia, Faculdade Federal de Medicina do Triângulo Mineiro, Uberaba (M.F.B., A.C.P.T., B.H.J.), MG-38025 440 Minas Gerais, Brazil
Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Hospital das Clínicas, Disciplina de Endocrinologia, Caixa Postal 3671, Sao Paulo, SP-01060–970, Brazil. E-mail: beremen{at}usp.br
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, new methodologies have been applied to commercial LH and FSH assays. Because of their improved sensitivity, basal gonadotropin levels determined by these assays may provide a better discrimination among the various forms of precocious puberty and thus eliminate the need to perform a GnRH stimulation test. In this study, we used commercial fluorometric AutoDELFIA assays (Wallac Oy, Turku, Finland) to measure basal LH, FSH, testosterone, and estradiol levels as well as GnRH-stimulated concentrations of LH and FSH in normal subjects at various stages of puberty and also in patients with precocious puberty. After analyzing our normative data, we evaluated the diagnostic value of these hormones in distinguishing among the various causes of precocious puberty.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The research protocol was approved by the ethical committees of Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo and Faculdade Federal de Medicina do Triângulo Mineiro, Uberaba (Minas Gerais, Brazil). Written consent to participate in this study was obtained from the subjects or their parents.
Two hundred and seventy-seven Brazilian normal subjects (162 males, aged 2–37 yr, and 115 females, aged 2–37 yr) volunteered for this study. None had a history of chronic illness or use of any medication. All had height and weight within 2 SD from the mean for age and sex and a normal physical examination. Pubertal development was evaluated by two endocrinologists according to Tanner’s criteria (breast staging in females and testicular size in males) (13, 14). Subjects up to age 18 yr were grouped according to sex and Tanner’s criteria (T1 through T5). Older individuals were considered adults and grouped only according to sex.
Seventy-seven patients (13 boys, aged 1.2–9.8 yr, and 64 girls, aged 0.9–8.8 yr) with precocious puberty were recruited for this study. Their height was -1.0 to +6.5 SD from the mean for age and sex in boys and -1.7 to +4.2 SD in girls. Bone age according to the method of Greulich and Pyle (15) ranged from 2.3–13.6 ys in boys and from 2.3–13.6 yr in girls. Testicular size varied from T1 to T4 in boys, and breast development varied from T2 to T5 in girls. Only 11 girls had had menarche. Patients were classified as having GDPP or other causes of precocious puberty based on clinical and auxological data, nuclear magnetic resonance of the hypothalamic-pituitary region, pelvic and adrenal ultrasounds, involution or no progression of secondary sexual characteristics, and suppression of LH, FSH, and testosterone or estradiol levels during GnRH analog therapy. In particular, this classification did not take into consideration the results of a GnRH stimulation test. Based on these criteria, 58 (7 boys and 51 girls) treated patients had GDPP (48 idiopathic, 6 hypothalamic hamartomas, 1 meningomyelocele, 1 neurofibromatosis with central nervous system glioma, 1 case secondary to an excised adrenal tumor and 1 case secondary to previous exogenous androgen exposure). Ten patients (5 boys and 5 girls) had GIPP: 2 familial male gonadotropin-independent precocious puberty, 1 hCG-producing hypothalamic dysgerminoma, 1 testicular tumor, 1 congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency, 1 steroidal cell ovarian tumor, and 4 McCune-Albright syndrome. The other 9 patients (1 boy and 8 girls) had isolated forms of precocious puberty: 6 with idiopathic isolated premature pubarche (1 boy and 5 girls) and 3 girls with idiopathic isolated premature telarche.
Study protocol
Blood was obtained from all subjects for basal serum measurements of LH, FSH, and testosterone in boys and estradiol in girls. A GnRH stimulation test was performed in 112 normal subjects (66 males and 46 females) and in 77 patients (13 boys and 64 girls) with precocious puberty. In T4 and T5 normal adolescents and adult women, the test was performed in the early follicular phase of the menstrual cycle. In each test, 100 µg GnRH (Relisorm, Serono, Mexico) were administered iv at time zero, and blood samples were drawn at 15 min before and at 0, 15, 30, 45, and 60 min after GnRH administration for serum LH and FSH measurements.
Gonadotropin assays
All samples were measured in duplicate. Serum LH and FSH concentrations were determined by commercial, solid phase, two-site fluoroimmunometric assays (FIA; AutoDELFIA hLH Spec and AutoDELFIA hFSH, Wallac Oy, Turku, Finland), based on the direct sandwich technique (16, 17). The assays were standardized with the WHO Second International Standard human pituitary LH 80/552 and WHO Second International Standard human pituitary FSH 78/549.
Serum testosterone and estradiol concentrations were measured by commercial solid phase FIAs (AutoDELFIA Testosterone and AutoDELFIA Estradiol, Wallac Oy), using polyclonal antibodies and standards calibrated by gravimetric and spectrophotometric methods. Only 200 normal subjects (131 males and 69 females), 34 girls with GDPP, 2 boys and 4 girls with GIPP, and 1 boy and 8 girls with isolated forms of precocious puberty had serum testosterone or estradiol measured by FIAs. In the remaining subjects and patients, these hormones were determined by conventional RIA and were not included in the analysis.
The working range of the assays was established by the precision profile, which is a plot of intraassay variation vs. concentration in the samples. The working range, as defined by the interval in which the intraassay variation was 8% or less, varied from 0.6–250 IU/L for LH, 1–256 IU/L for FSH, 14–1440 ng/dL for testosterone, and 13.6–4086 pg/mL for estradiol. Because of this, the minimal detectable concentration (MDC) was set at 0.6 IU/L for LH, 1 IU/L for FSH, 14 ng/dL for testosterone, and 13.6 pg/mL for estradiol. This was confirmed by measuring 50 samples with serum levels below these MDC values, which showed unacceptably high intra- and interassay variations (12–60%). The interassay variation, as defined by repeated measurements of serum controls run in different assays, was less than 10% for all hormones.
Statistical analysis
All data are expressed as the mean ± SD and range. Comparison among the various groups of normal subjects was performed using nonparametric tests (Kruskal-Wallis followed by multiple comparison procedures according to Dunn’s method), as our variables did not have a normal distribution. Correlation between variables was performed using Spearman’s analysis. Differences were considered significant if P < 0.05. For the purposes of statistical analysis, values falling below the MDC for each hormone were taken as the MDC. The cut-off limit to distinguish between prepubertal and pubertal subjects was defined by the 95th percentile of the normal prepubertal group calculated for each hormone under basal and stimulated conditions. Gonadotropin levels exceeding these cut-off limits in patients with precocious puberty indicated central activation of the HPG axis and thus were considered positive tests for GDPP.
The diagnostic value of basal and stimulated gonadotropin levels to distinguish GDPP from other forms of precocious puberty was determined by calculating the sensitivity, specificity, and positive and negative predicted values (18). The sensitivity indicates the proportion of patients with GDPP who had a positive test (ratio of true positive cases to the sum of true positive and false negative cases). The specificity indicates the proportion of patients with precocious puberty other than GDPP who had a negative test (ratio of true negative cases to the sum of true negative and false positive cases). The positive predicted value indicates the probability of a patient with a positive test to have GDPP (ratio of true positive cases to the sum of true positive and false positive cases). The negative predicted value indicates the probability of a patient with a negative test to have precocious puberty other than GDPP (ratio of true negative cases to the sum of true negative and false negative cases).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Basal LH, FSH, testosterone, and estradiol levels rose slowly with
progression of puberty in normal males and females, yielding
significant differences among the various groups (Tables 1
and 2).
Individual hormonal levels varied widely in each pubertal stage in both
sexes, but the largest overlap occurred when T1 and T2 groups were
compared. The cut-off limits to distinguish between prepubertal and
pubertal levels were determined based on basal measurements obtained
from 100 normal T1 subjects (Tables 1 and 2). In boys, these limits
were 0.6 IU/L for LH (n = 60) and 19 ng/dL for testosterone
(n = 56), whereas in girls, they were 0.6 IU/L for LH (n =
40) and 13.6 pg/mL for estradiol (n = 25). Hormonal levels below
these cut-off limits, however, occurred in a significant proportion of
T2 subjects, but less so in the more advanced stages of puberty. Taking
all normal pubertal subjects together, prepubertal levels were seen in
14.7% (15 of 102) of males and 24% (18 of 75) of females in the case
of LH, in 39.2% (40 of 102) of males and 69.3% (52 of 75) of females
in the case of FSH, and in 10.6% (8 of 75) of females in the case of
estradiol. In contrast, testosterone levels of 19 ng/dL or less were
found in 27% (7 of 26) of T2 boys, but not in the more advanced stages
of puberty. In adults, no overlap was seen when LH, testosterone, and
estradiol levels were compared with those in the normal prepubertal
group. With respect to FSH, basal levels overlapped more substantially
than LH among the various pubertal groups in both sexes, not allowing
the definition of a cut-off limit for this hormone.
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13.6 pg/mL) in 41.2% (20 of 34) of these patients. Unfortunately,
testosterone levels were measured by RIA (144 ± 110 ng/dL; range,
34–275) and not FIA in boys with GDPP, and thus were not included in
this study.
In patients with precocious puberty other than GDPP,
i.e. GIPP and isolated forms (Table 3), basal LH was consistently at
prepubertal levels (0.6 IU/L). Only two boys and four girls with GIPP
had serum concentrations of testosterone (467 ± 107 ng/dL; range,
392–543) and estradiol (67 ± 61 pg/mL; range, 14–133) measured
by FIA; all had levels above the cut-off limits of 19 ng/dL and 13.6
pg/mL, respectively. In contrast, all patients with isolated premature
pubarche or telarche (one boy and eight girls) had testosterone or
estradiol levels below these cut-off limits.
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In normal males and females, mean peak LH levels rose steadily
with progression of puberty, yielding significant differences among the
various groups (Table 4). The cut-off
limits to distinguish between prepubertal and pubertal LH
responsiveness to GnRH stimulation were determined based on
LH-stimulated levels obtained from 27 normal T1 subjects. These limits
were 9.6 IU/L in boys (n = 16) and 6.9 IU/L in girls (n =
11). In the normal pubertal group, LH levels below these limits were
seen in 8% (4 of 50) of males and 20% (7 of 35) of females, occurring
only in T2 subjects.
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In patients with precocious puberty, peak LH levels above 9.6 IU/L in boys and above 6.9 IU/L in girls were considered a pubertal response to GnRH stimulation, pointing to the diagnosis of GDPP. According to these criteria, the sensitivity of peak LH for the latter diagnosis in boys was 100% (7 of 7), specificity was 100% (5 of 5), positive predicted value was 100% (8 of 8), and negative predicted value was 100% (5 of 5). In girls, the sensitivity of peak LH levels for the diagnosis of GDPP was 92.2% (47 of 51), specificity was 100% (13 of 13), positive predicted value was 100% (47 of 47), and negative predicted value was 76.5% (13 of 17).
Peak LH was at prepubertal levels in all patients with GIPP and in all
patients with isolated forms of precocious puberty (Table 3
). Six of 10
patients (3 boys and 3 girls) with GIPP had completely suppressed LH
and FSH responses to GnRH stimulation in association with higher
testosterone or estradiol concentrations.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To distinguish more precisely between prepubertal and pubertal levels of the various hormones, it was important to first define the MDC of our assays, as prepubertal levels are expected to be low, in many cases approaching the sensitivity of the method. In our study, the MDC was calculated with the aid of the precision profile and was defined as the lowest level that could be measured with an intraassay variation of 8% or less. This approach was chosen instead of the traditional method of determining the dose corresponding to the mean and -2 SD of several replicates of the zero standard, because, as indicated by Taylor et al., the latter method frequently underestimates the MDC (22).
The cut-off limits to distinguish between prepubertal and pubertal levels of LH were defined by the 95th percentile of the normal prepubertal population (18). This percentile was chosen because our aim was to establish a test with high specificity, i.e. a test that, when positive, would indicate central activation of the HPG axis with a high degree of confidence. Such high specificity would not be obtained if the limits were set at a lower percentile, although this could improve the sensitivity of the test.
Cut-off limits for serum LH in our study were set at 0.6 IU/L for both sexes under basal conditions and at 9.6 IU/L in boys and 6.9 IU/L in girls after GnRH stimulation. Thus, basal LH levels of 0.6 IU/L or less were considered prepubertal, whereas levels of 0.7 or more were taken as pubertal. However, considering that the limit of 0.6 IU/L falls at the lower end of the standard curve where the intraassay variation approaches 8%, such levels may not be distinguished precisely from 0.7 IU/L. Therefore, whenever basal LH is between 0.6–0.7 IU/L, we recommend repeating the measurement in another basal sample or even performing a GnRH stimulation test. Peak LH levels exceeding the cut-off limits of 9.6 IU/L in boys and 6.9 IU/L in girls would then indicate central activation of the HPG axis, which, in patients with precocious puberty, would favor the diagnosis of GDPP.
In our normal population, basal LH levels of 0.6 IU/L or less were frequently found in T2 subjects and were also found in some T3 through T5 adolescents of both sexes. These findings are in agreement with previous studies using immunoradiometric assay (IRMA) and immunochemiluminometric assay (ICMA) (7, 21) and indicate that there is significant overlap of basal LH levels in the various stages of puberty, mainly in T1 and T2 subjects, regardless of the method used to measure LH. Thus, despite their improved sensitivity, new assays for LH determination do not distinguish clearly between basal prepubertal and pubertal levels of this hormone. A better discrimination was obtained in our study when LH levels were measured after GnRH stimulation. This is particularly true in subjects with Tanner stage 3 or more advanced stages of puberty, who consistently had peak LH exceeding the cut-off limits of 9.6 or 6.9 IU/L. However, peak LH levels still overlapped significantly in T1 and T2 subjects, with 33% of T2 boys and 70% of T2 girls displaying peak LH below these limits. Thus, in contrast with basal values that overlapped in all stages of puberty, peak LH levels measured by AutoDELFIA kits overlapped only in early puberty and allowed a better definition of central activation of the HPG axis.
In our patient population, basal LH levels of 0.6 IU/L or less occurred in all patients with GIPP and isolated forms of precocious puberty, but also in 28.5% of boys and 37.2% of girls with GDPP. Thus, whenever basal LH falls below the cut-off limit of 0.6 IU/L, no information is provided that could help in the differential diagnosis of the various forms of precocious puberty. In contrast, basal LH levels above 0.6 IU/L strongly suggest the presence of GDPP, as all of our patients with such levels had this disease. In those patients with basal LH levels of 0.6 IU/L or less, the diagnosis of GDPP was more precisely established by performing a GnRH stimulation test. All boys (2 of 2) and 79% (15 of 19) of girls with GDPP who exhibited basal LH levels of 0.6 IU/L or less had peak LH exceeding the cut-off limits of 9.6 and 6.9 IU/L, respectively. Four girls with GDPP had both basal LH levels of 0.6 IU/L or less and peak LH levels of 6.9 IU/L or less, indicating once again that values falling below these limits do not exclude the diagnosis of GDPP. Several hypotheses may be proposed to explain the prepubertal LH response to GnRH stimulation seen in these 4 patients. First, Garibaldi et al. demonstrated that girls with GDPP in the early phase of the disease may have clinically relevant estradiol production in the face of low LH secretion, suggesting that endocrine or paracrine factors other than gonadotropins may play a role in this event (23). Alternatively, the test could have been performed in the luteal phase, when progesterone levels are high and may thus interfere with gonadotropin secretion (24, 25). Although progesterone measurements are not available for these girls, the fact that estradiol levels were low (<13.6–38.0 pg/mL) on the day of the test and that these patients did not have menstrual periods make this hypothesis unlikely.
Comparison of our results with those published by Garibaldi et al. (7) using LH IRMAs reveals a similar cut-off limit of 0.5 IU/L for basal LH in both sexes and a similar sensitivity of 67% in establishing the diagnosis of GDPP. This sensitivity dropped to 27% when the same investigators used RIA measurements and a cut-off limit of 3.7 IU/L for basal LH. In contrast, Neely et al. (26) reported a sensitivity of 94% when using LH ICMAs and a cut-off limit of 0.1 IU/L for basal LH in both sexes. Thus, whenever serum LH is measured with kits designed with monoclonal antibodies and sandwich configuration, the sensitivity of basal LH in establishing the diagnosis of GDPP is improved, probably because of the lower MDC associated with these assays. With respect to the GnRH stimulation test, cut-off limits for peak LH levels were set previously at 15 IU/L in girls and 25 IU/L in boys for RIA measurements (2), and at 5.0 IU/L for ICMA determinations (21, 26). A limit of 10 IU/L for boys and 6 IU/L for girls was proposed for peak LH measured by immunofluorometric assay in a previous study, but the researchers did not present data to support these values (2). In contrast with basal LH values, there are no available data on the sensitivity and specificity of peak LH levels after GnRH stimulation to be compared with our data.
In our study, serum levels of FSH, testosterone, and estradiol were also evaluated in an attempt to establish cut-off limits to distinguish between prepubertal and pubertal levels of these hormones. As demonstrated previously with RIA, IRMA, and ICMA, serum FSH measured by immunofluorimetric assay under basal and stimulated conditions overlapped substantially in prepubertal and pubertal subjects and did not allow a good discrimination between these two populations (3, 4, 5, 8, 9, 10, 21). However, 6 of 10 patients with GIPP had fully suppressed FSH as well as LH levels under basal and GnRH-stimulated conditions. As this pattern of response was only seen in our study in patients with GIPP, a completely suppressed gonadotropin response to GnRH, including both LH and FSH, points to the diagnosis of this disease. In respect to testosterone, basal levels exceeded the prepubertal cut-off limit in all boys with GDPP/GIPP, but fell below this threshold in 1 patient with isolated premature pubarche, suggesting that this hormone could be of some help in distinguishing the latter condition from GDPP/GIPP. Basal estradiol levels were not useful to separate isolated premature pubarche or telarche from GDPP, as 41.2% (14 of 32) girls with GDPP had estradiol concentrations below the cut-off limit of 13.6 pg/mL, which are similar to values found in isolated forms of precocious puberty.
In summary, we report in this study basal and GnRH-stimulated levels of LH, FSH, testosterone, and estradiol measured by AutoDELFIA kits (Wallac Oy) in normal subjects throughout the various stages of puberty and also in patients with precocious puberty. Our results demonstrate that basal LH levels above 0.6 IU/L in patients with precocious puberty favor the diagnosis of GDPP with a high degree of confidence. However, basal LH levels of 0.6 IU/L or less may occur in any of the various forms of precocious puberty, indicating the need to perform a GnRH stimulation test.
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Acknowledgments |
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Footnotes |
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Received February 24, 1999.
Revised June 2, 1999.
Accepted June 21, 1999.
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References |
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