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University of Helsinki, Hospital for Children and Adolescents, and the Program for Developmental and Reproductive Biology, Biomedicum Helsinki, FIN-00029 Hus, Finland
Address all correspondence and requests for reprints to: Dr. Sanna Wickman, University of Helsinki, Hospital for Children and Adolescents, FIN-00029 Helsinki, Finland. E-mail: sanna.wickman{at}helsinki.fi
Abstract
In early pubertal boys, E concentrations are very low. We studied the role and site of action of endogenous E in the regulation of gonadotropin secretion in early and midpubertal boys by inhibiting the action of E with a potent and specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were referred to us because of suspicion of delayed puberty were included in the study. The boys were in either early or midpuberty, and they composed 3 groups: 10 boys did not receive any treatment, 12 boys received T alone, and 13 boys received T and letrozole.
In the untreated group during the 5-month follow-up, no changes were observed in 17ß-E2, T, basal gonadotropin, or inhibin B concentrations or in the GnRH-induced gonadotropin responses. In the T-treated group during the 5-month treatment, the T concentration increased by 55% (P < 0.05), and the 17ß-E2 concentration increased by 130% (P < 0.02). Concurrently, basal gonadotropin concentrations were suppressed, but the GnRH-induced gonadotropin responses and the inhibin B concentration remained unchanged. In the T- plus letrozole-treated group during the 5-month treatment, an increase in T concentration of 606% was observed (P < 0.001), but the 17ß-E2 concentration remained unchanged. The changes in the 17ß-E2 concentration within 5 months in the untreated and the T- plus letrozole-treated groups were different (P < 0.02), indicating significant inhibition of endogenous E synthesis during letrozole treatment. During the T plus letrozole treatment, basal gonadotropin concentration, the GnRH-induced LH response, and inhibin B concentration increased, and the GnRH-induced FSH response did not change significantly. Serum nocturnal gonadotropin pulses were determined in 5 boys treated with T and in 5 boys treated with T plus letrozole. In the T- plus letrozole-treated group, the nocturnal LH pulse amplitude increased, and the LH pulse frequency and interpulse interval remained unchanged.
In conclusion, in early and midpubertal boys, suppression of the action of E by the P450 aromatase inhibitor increased LH concentration, LH pulse amplitude, and the GnRH-induced LH response, which indicates that in boys during early and midpuberty, endogenous E regulates LH secretion at the site of the pituitary.
THE ESSENTIAL ROLE of E in the regulation
of gonadotropin secretion in adult men was confirmed in three different
reports of cases in which the action of E was blocked by inactivating
mutations in the genes for the ER
(1) or for the enzyme
P-450 aromatase (2, 3, 4). In all of these men, gonadotropin
concentrations were elevated (1, 2, 3, 4), and they decreased
with E therapy in the men with P-450 aromatase gene mutations (3, 4). The site of action of endogenous E in the
hypothalamic-pituitary unit in adult men was recently clarified in a
study in which the effects of suppression of E2 by the P450
aromatase inhibitor, anastrozole, in normal men were compared with the
effects in men with idiopathic hypogonadotropic hypogonadism (IHH), who
lack endogenous hypothalamic GnRH secretion and whose pituitary-gonadal
system had been normalized by long-term pulsatile GnRH therapy
(5). In this study in both normal men and men with IHH,
gonadotropin concentrations increased when the action of E was
suppressed, but despite similar changes in sex steroid concentrations,
the increase was greater in the normal men than in the men with IHH.
These observations demonstrated that in adult men gonadotropin
secretion is regulated by endogenous E at the sites of both pituitary
and hypothalamus.
Results regarding sex steroid-mediated regulation of gonadotropin secretion in adult men may not be applicable to boys, because before the onset of puberty gonadotropin secretion is primarily under control mechanisms mediated by the central nervous system, whereas during puberty changes occur in the relative roles of the central nervous system- and sex steroid-mediated inhibition of gonadotropin secretion. In early and midpubertal boys, T administration has been shown to decrease LH concentrations, and LH pulse frequency, but to have no effect on LH pulse amplitude or GnRH-induced LH release, indicating that T affects the hypothalamic GnRH pulse generator (6). In adult men, in contrast, T administration has been demonstrated to decrease LH concentration, LH pulse amplitude, and the GnRH-induced LH response and to have no effect on LH pulse frequency, suggesting that the pituitary is the site of action for T (7). Thus, it appears that during puberty the sensitivity of the hypothalamus to sex steroid-mediated inhibition decreases and, in contrast, the sensitivity of the pituitary increases.
When E2 concentrations in early and midpubertal boys were increased to the adult male range by E2 infusion, LH concentration and LH pulse frequency decreased, but neither LH pulse amplitude nor the exogenous GnRH-induced LH response changed (8). These results indicate that in early and midpubertal boys the hypothalamic-pituitary system is responsive to exogenous E, and that supraphysiological concentrations of E act at the site of the hypothalamus. However, the role of a significantly lower endogenous E concentration (9) in the control of gonadotropin secretion in boys during early and midpuberty has not been resolved.
In this study we clarified the role and a site of action of endogenous E in the regulation of gonadotropin secretion in boys during early and midpuberty by inhibiting E synthesis with a potent and specific P450 aromatase inhibitor, letrozole.
Subjects and Methods
Subjects
A total of 35 boys were recruited for the study. The boys were referred to the Hospital for Children and Adolescents, University of Helsinki, for evaluation of delayed puberty and/or short stature. Diagnosis of constitutional delay of puberty was defined as a Tanner genital or pubic hair stage observed at an age older than the mean + 2 SD for healthy Finnish boys (10) or a testis volume of less than 4 ml after 13.5 yr of age. At entry, none of the boys had had any pubertal increase in growth velocity. Neither medical history, clinical examination, nor routine laboratory tests revealed any signs of chronic illnesses to account for the delayed puberty in any of the boys. In some boys, T concentration and testis volume at the start of the follow-up indicated that they were already at midpuberty. In these boys puberty might have advanced spontaneously in a short time without any treatment. However, we believe that it was justified to treat these boys because none of the boys had yet had a pubertal increase in growth velocity, and in such circumstances it is difficult to predict the onset of the pubertal growth spurt and the rate of progression of puberty. Furthermore, all treated boys wanted medical intervention. None of the boys had received any previous sex hormone treatment. Two boys were receiving inhaled corticosteroid treatment for asthma.
Protocol
Informed written consent was obtained from the patient and his guardian. The protocol was approved by the ethical committee of the Hospital for Children and Adolescents and the National Agency for Medicines.
The boys were divided into 3 groups. Ten boys with a mean age of
15.0 ± 0.2 yr (range, 14.4–16.8 yr) decided to wait for
spontaneous progression of puberty without medical intervention and
thus composed the untreated group. Twenty-five boys with a mean age of
15.2 ± 0.2 yr (range, 13.5–16.5 yr) desired medical intervention
and received one of the 2 treatments. The boys in the T-treated group
(12 boys) received T enanthate (Testoviron-Depot-250, Schering AG, Berlin, Germany; 1 mg/kg, im, every 4 wk, six times). The T-
plus-letrozole-treated group (13 boys) received T
enanthate (as above) and, in addition, an aromatase inhibitor,
letrozole (Femar, Novartis AG, Stein, Switzerland;
purchased from the hospital pharmacy; 2.5 mg, orally, once a day for 12
months). Letrozole (CGS 20267) is a novel, specific, and
potent fourth generation nonsteroidal aromatase inhibitor that inhibits
the conversion of T to 17ß-E2 and that of
4-androstenedione to estrone. It is mostly
metabolized in the liver, and letrozole, and its
metabolites are mainly excreted via the kidneys. The plasma terminal
elimination half-life is approximately 2 d. Steady state plasma
concentrations are reached within 2–6 wk with a dose of 2.5 mg, once a
day. Letrozole is currently indicated as a treatment for
metastatic breast cancer. It has been shown to be well tolerated, and
it has no other pharmacological effect in vivo
(11, 12, 13, 14, 15, 16). The metabolic and hormonal effects of a
comparably potent aromatase inhibitor, anastrozole, in late pubertal
boys and adult men (aged 14–22 yr) have been studied previously
(17). To our knowledge, our study is the first in which a
potent, fourth generation aromatase inhibitor has been used in children
or early or midpubertal adolescents. The rationale for giving the boys
this new P450 aromatase inhibitor was our hypothesis that this
treatment, which inhibits E action, would help the boys to achieve
their genetic height potential. The results of the double blind,
placebo-controlled part of this study, which included 23 of these 25
treated boys, have been published previously (18). Eight
boys in the untreated group, 11 boys in the T-treated group, and 13
boys in the T- plus letrozole-treated group completed the
5-month follow-up; 8, 11, and 10, respectively, completed the 12-month
follow-up; and 7, 10, and 10, respectively, completed the 18-month
follow-up. One boy in the T- plus letrozole-treated group
was considered noncompliant, and therefore his results were excluded
from the analyses.
Testis volume (19), and serum basal 17ß-E2, T, LH, FSH,
and inhibin B concentrations were determined at the start of treatment
and at 5 months (
7 d after the sixth T injection), 12 months, and 18
months of treatment; all of the basal venous blood samples were drawn
between 0730–1015 h. At the start of treatment and at 5 and 12 months
GnRH (Relefact Hoechst Marion Roussel, Deutschland GmbH, Frankfurt,
Germany; 3.5 µg/kg, iv; maximum, 100 µg) was administered, and LH
concentrations were measured from samples obtained at 0 (before), 20,
30, and 60 min after administration of GnRH, and FSH concentrations
were measured from samples obtained at 0 (before), 30, 60, and 90 min
after administration of GnRH in all 35 boys. The GnRH-induced
gonadotropin response was defined as the difference between the basal
and GnRH-induced peak gonadotropin concentrations. Nocturnal
gonadotropin pulses were studied at the start of treatment and at 5
months in five boys treated with T alone and in five boys treated with
T plus letrozole (Table 1
).
For determination of nocturnal gonadotropin pulses, an indwelling iv
cannula was inserted approximately 1 h before the beginning of
sampling. Sleep was monitored visually by trained nursing personnel.
Serum LH and FSH concentrations were determined every 15 min. Boy 3
fell asleep at 0310 h before treatment; the other boys fell asleep
before midnight. The last sample from patient 10 at 5 months was taken
at 0610 h.
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Serum LH and FSH concentrations were measured singletons by time-resolved immunofluorometric assays (Wallac, Inc., Turku, Finland) (21) The sensitivity of the assay for LH and FSH was 0.05 IU/liter, as defined by the mean + 2 SD of 20 (LH) or 96 (FSH) replicates of a zero sample. The interassay coefficient of variation (CV) for LH was 3.2% at a concentration of 1.96 IU/liter, 4.6% at a concentration of 17.51 IU/liter, and 3.7% at a concentration of 53.95 IU/liter, and the interassay CVs for FSH were 2.6% (6.63 IU/liter), 2.7% (13.17 IU/liter), and 3.3% (35.14 IU/liter). The intraassay CV was calculated by measuring 12 or 36 replicates at 3 different concentrations of LH and FSH. The intraassay CV for LH was 4.08% at a concentration of 0.35 IU/liter (n = 36), 1.96% at a concentration of 2.98 IU/liter (n = 36), and 1.57% at a concentration of 8.71 IU/liter (n = 12). The intraassay CVs for FSH were 4.36% (0.25 IU/liter; n = 36), 1.76% (2.94 IU/liter; n = 36), and 1.56% (6.66 IU/liter; n = 12). These results were used for calculating the assay SD coefficients for the pulse analysis program. LH concentrations less than 0.1 IU/liter were treated as 0.1 IU/liter.
Serum 17ß-E2 concentrations were determined by a modified RIA using the coated tube technology (Spectria E2, Orion Diagnostica, Espoo, Finland) after diethyl ether extraction (700 µl serum plus 5 ml diethyl ether) (22). The detection limit of the assay was 6 pmol/liter. Serum 17ß-E2 concentrations below the detection limit were treated as 6.0 pmol/liter. Serum T concentrations were determined by RIA after separation of the steroid fractions on a Lipidx-5000 microcolumn (Packard-Becker, B.V. Chemical Operations, Groningen, The Netherlands) (23). The inter- and intraassay CVs for T were 15% at a concentration of 15.6 nmol/liter. Serum inhibin B concentrations were determined by ELISA (Serotec, Oxford, UK).
Pulse analysis
The nocturnal serum LH and FSH concentrations from each individual at a given time point were analyzed in the same assay. LH and FSH pulses were analyzed by a computerized pulse analysis program, Munro (Zaristow Software, East Lothian, Scotland). The program identifies secretory peaks by height and duration from a smoothed baseline, using the assay SD as a scale factor. Munro is an adaptation of the Pulsar Program developed by Merriam and Wachter (24). The only essential difference is in the calculation of the baseline; in the Munro program, the baseline is generated by linear interpolation between the nadirs, followed by smoothing, using a moving average. The remaining stages of the Munro algorithm are identical with the Pulsar program. As the baseline in the Munro program is calculated from the nadirs rather than from the moving average of the data, this program can process data containing pulses with variable widths and amplitudes. This is considered essential in the analysis of FSH pulses, which are wider than LH pulses.
The cut-off parameters G1–5 of the Munro program for LH were set at 3.98, 2.4, 1.68, 1.24, and 0.93, and those for FSH were set at 10.0, 2.4, 1.68, 1.24, and 0.93 times the intraassay SD as criteria for accepting peaks 1, 2, 3, 4, and 5 points wide, respectively. The smoothing time, a window used to calculate the moving average, was set at 135 min, i.e. 9 data points wide for both LH and FSH. With these settings, the program did not detect any peaks when 33 consecutive samples from plasma pools with LH concentrations of approximately 0.35 and 3.0 IU/liter and with FSH concentrations of approximately 0.25 and 2.9 IU/liter were assayed. Thus, use of a special program for minimizing false positive error in pulse detection (25) was not deemed necessary. Missing values comprised approximately 0.6% of the total samples and were left blank. The interpulse interval was defined as the time interval between consecutive peaks.
Statistical analysis
All values are expressed as the mean ± SEM. Analyses were conducted with the SPSS statistical software for Windows, release 8.0.2 (SPSS, Inc., Chicago, IL). Paired t test or the Wilcoxon matched pairs signed rank-sum test were used for analyses of the changes within groups during the follow-up. For analysis of serial measurements, the summary measures, the differences from the start, were calculated for each subject, and these values were treated as raw data for the appropriate statistical analysis. One-way ANOVA, unpaired t test, Kruskal-Wallis nonparametric ANOVA, or Mann-Whitney U tests were used as appropriate. The Pearson correlation coefficient was used to investigate the relationships between the inhibin B and FSH concentrations. All statistical tests were two-sided. P < 0.05 was considered statistically significant.
Results
There were no significant differences among the three groups at the start of the follow-up in chronological age; testis volume; serum 17ß-E2, T, inhibin B, or basal gonadotropin concentrations; or GnRH-induced gonadotropin responses. In the series of patients who underwent gonadotropin pulse analysis, no difference in any of the variables mentioned above was observed between the T-treated and the T- plus letrozole-treated groups.
Safety
The concentrations of total cholesterol, low and high density lipoprotein cholesterol, triglycerides, transaminases, the leukocyte count, and the bone density were determined during the follow-up. In these safety parameters, no changes sufficient to indicate discontinuation of the treatment were observed in any of the boys. Letrozole was well tolerated; no side-effects were observed.
Serum 17ß-E2, T, inhibin B, and basal gonadotropin concentrations and GnRH-induced gonadotropin responses
Serum 17ß-E2, T, inhibin B, and basal gonadotropin
concentrations in the 33 boys who were included in this study group
have been published previously (18). At the start and at 5
months of treatment, the study data include 2 boys in the T- plus
letrozole-treated group (patients 9 and 10 in Table 1
) who
were not included in the previous study.
In the untreated group, during follow-up for 5 months, no change was
observed in the T concentration (10.3 ± 3.3 nmol/liter at the
start and 12.8 ± 3.6 nmol/liter at 5 months of treatment) or the
17ß-E2 concentration (15.3 ± 3.1 pmol/liter at the start and
21.1 ± 6.2 pmol/liter at 5 months of treatment; P
= 0.07). The basal gonadotropin concentrations and the GnRH-induced
gonadotropin responses remained unchanged (Fig. 1). No change was seen in the
inhibin B concentration (P = 0.054).
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), and the FSH concentration by 70%
(P < 0.01; Fig. 1). Despite the decrease in basal
gonadotropin concentrations, the GnRH-induced LH and FSH responses and
also the inhibin B concentration remained unchanged (Fig. 1).
In the T- plus letrozole-treated group during treatment
for 5 months, an increase of 606% in T concentration from 8.5 ±
3.0 to 60.0 ± 11.4 nmol/liter was observed (P <
0.001); the increase in the T concentration within 5 months was higher
than that in the group treated with T alone (P <
0.01). The 17ß-E2 concentration was 12.5 ± 2.6 pmol/liter at
the start of treatment and 9.8 ± 1.1 pmol/liter at 5 months
(P = 0.2), indicating that letrozole
inhibited the increase in 17ß-E2 concentration associated with T
administration. Between the untreated and the T- plus
letrozole-treated groups, the changes in 17ß-E2
concentration during 5 months were different (P <
0.02), indicating functional inhibition of endogenous E synthesis
during letrozole treatment. In the T- plus
letrozole-treated group, despite very high serum T
concentrations, the basal LH concentration increased by 208%
(P < 0.001; Fig. 1), and the basal FSH concentration
increased by 167% (P < 0.001; Fig. 1). The
GnRH-induced LH response increased by 73% (P < 0.001;
Fig. 1), but the GnRH-induced FSH response did not change significantly
(P = 0.08; Fig. 1). The inhibin B concentration
increased by 24% (P < 0.05). At 12 months in the T-
plus letrozole-treated group, when the boys were treated
with letrozole alone, the T concentration remained high;
the 17ß-E2 concentration remained low; the basal gonadotropin
concentrations, GnRH-induced LH response, and inhibin B concentration
were elevated; and the GnRH-induced FSH response remained
unchanged.
Eighteen months from the start of the follow-up and 6 months after discontinuation of all treatments, the T, 17ß-E2, basal gonadotropin, and inhibin B concentrations were similar in all three groups (18).
Serum nocturnal gonadotropin pulses
Clinical characteristics and the serum 17ß-E2 and T
concentrations of the 10 boys who underwent gonadotropin pulse analysis
are shown in Table 1. Before the treatment, the pattern of nocturnal
gonadotropin secretion in all of the boys was characteristic for early
and midpubertal boys; nocturnal elevation in gonadotropin
concentrations was seen (Figs. 2 and 3). Both LH and FSH concentrations
were lower from 2200–0145 h than from 0200–0600 h in all boys. During
the 5 months of treatment in the group treated with T alone, nocturnal
LH concentrations decreased in four of the five boys, and the FSH
concentrations decreased in all of the boys. In three of the boys who
were treated with T alone, LH concentrations decreased to or below the
detection limit; therefore, no pulses could be determined. In contrast,
in two boys who were also treated with T alone, gonadotropin pulses and
nocturnal increases in concentrations were observed during the
treatment. In the T- plus letrozole-treated group, the
nocturnal LH and FSH concentrations increased in all of the boys during
the treatment. Gonadotropin pulses and the diurnal profile of
gonadotropin secretion were also observed during the T plus
letrozole treatment. In the T- plus
letrozole-treated group, the mean LH pulse amplitude,
calculated from all of the LH pulse amplitudes detected, increased
during the treatment (P < 0.02; Fig. 4); no significant changes were seen in
the FSH pulse amplitude (Fig. 4), gonadotropin pulse frequencies (Fig. 4), or interpulse intervals. In the group treated with T alone, the
changes in the pulse variables, referred to above, were not calculated
because during the treatment no pulses could be determined in three
boys with very low gonadotropin concentrations.
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At the start of the follow-up, inverse relationships between
inhibin B concentrations and GnRH-induced FSH responses were seen
within all of the groups (Fig. 5); no
correlations were observed between inhibin B and basal FSH
concentrations within the groups. At 5 months, during the treatment
with T alone, or during the treatment with T plus
letrozole, the correlations between inhibin B
concentrations and GnRH-induced FSH responses disappeared (Fig. 5). At
12 months in the T-treated group (after discontinuation of T
treatment), the correlation reappeared (r = -0.7;
P < 0.02; Fig. 5), and in the T- plus
letrozole-treated group, during treatment with
letrozole alone, a correlation was seen that almost
reached statistical significance (r = -0.6; P =
0.088; Fig. 5). At 18 months when data from all of the boys were
pooled, a negative correlation was observed between inhibin B and basal
FSH concentrations (r = -0.6; P < 0.01).
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In this study the action of endogenous E was suppressed in early and midpubertal boys by the P450 aromatase inhibitor letrozole. We have previously demonstrated that during letrozole treatment, LH and FSH concentrations increased concomitantly with the increase in T concentration (18). These findings demonstrated that the negative feedback between endogenous E and gonadotropin secretion established in adult men (1, 2, 3, 4, 5) is already operative from early puberty onward.
In early and midpubertal boys E2 (8) and T (6, 26) administration have been shown to decrease LH concentrations, but to have no effect on the GnRH-induced LH response. Moreover, both T and E2 have been demonstrated to decrease the LH pulse frequency, but to have no effect on the LH pulse amplitude in early and midpubertal boys (6, 8). These findings suggest that, in boys during early and midpuberty, sex steroids act at the site of the hypothalamus. This is in accord with our observation that, during the T treatment, the basal gonadotropin concentrations decreased, but the GnRH-induced gonadotropin responses remained unchanged. Moreover, our results suggest that these effects of T were mediated through E, because, despite very high T concentrations during the treatment with T plus the P450 aromatase inhibitor letrozole, the gonadotropin concentrations increased. However, when the action of endogenous E was suppressed by the T plus letrozole treatment, the LH pulse amplitude and the GnRH-induced LH response increased, but the LH pulse frequency, which is assumed to reflect the frequency of hypothalamic GnRH secretion (27, 28), did not change. These observations suggest that low concentrations of endogenous E in early and midpubertal boys may not influence the GnRH pulse generator, and that in boys during early and midpuberty, the site of action of E is the pituitary. The discrepancy concerning the site of action of E in the hypothalamic-pituitary unit between our study and a previous study reporting a primarily hypothalamic site of action (8) is unclear. One possibility is that supraphysiological concentrations of E and endogenous E act on gonadotropin secretion differently. In the previous studies (6, 8, 26) as well as in our study, supraphysiological sex steroid concentrations were attained in the group treated with T alone by exogenous administration. In contrast, in the group treated with T plus letrozole, we demonstrated the effects of suppression of low, early pubertal concentrations of E. However, in adult men, endogenous E has been clearly demonstrated to act at the site of the hypothalamus (5), and the fact that we did not find any change in pulse frequency during the T plus letrozole treatment may also have been due to our study group being relatively small. Whether endogenous E in boys during early and midpuberty also acts at the site of the hypothalamus in addition to the pituitary control of gonadotropin secretion will have to be clarified by future studies with larger patient groups and longer periods of blood sampling.
Although both LH and FSH concentrations increased during letrozole treatment, differences were observed between LH and FSH in the changes in GnRH-induced responses and in the pulse amplitudes. These differences may be accounted for by the negative feedback effect of inhibin B on FSH secretion, as inhibin B has been demonstrated to regulate FSH secretion in males from early puberty onward (29, 30). In our study correlations between inhibin B concentrations and GnRH-induced FSH responses were demonstrated before treatment in all three groups; the correlation was not observed in either of the treatment groups at 5 months either during the treatment with T alone or during the treatment with T plus letrozole. Interestingly, at 12 months during the treatment with letrozole alone, when the majority of the boys were at midpuberty, the negative correlation between inhibin B concentrations and GnRH-induced FSH responses almost reached statistical significance even though T concentrations were elevated and concentrations of E2 were suppressed. These findings suggest that during puberty the importance of sex steroids in the regulation of FSH secretion diminishes, whereas the role of inhibin B increases. The increasing importance of inhibin B in the regulation of FSH secretion in males during puberty is also supported by the findings that the negative relationship between inhibin B and the basal FSH concentrations does not begin until midpuberty (30, 31). However, further studies with larger patient groups are needed to confirm the relative roles of sex steroids and inhibin B in the regulation of FSH secretion during puberty.
The nocturnal augmentation of gonadotropin secretion, which is characteristic for early and midpubertal boys (32, 33), was demonstrated during the T plus letrozole treatment. Thus, the suppression of the action of E does not affect the diurnal profile of gonadotropin secretion, nor does the considerable increase in the concentrations of androgens. This observation is in accord with previous findings of a diurnal rhythm in gonadotropin secretion in children with gonadal dysgenesis (34, 35). These findings indicate that the circadian rhythm of gonadotropin secretion is regulated by mechanisms mediated by the central nervous system.
Our observations of profoundly suppressed LH concentrations and the disappearance of LH pulses during T treatment in three boys are in agreement with the findings of a previous study (26). The reason why in two boys gonadotropin concentrations were not profoundly suppressed during T treatment is unclear. One explanation might be that the variation in the sensitivity of the hypothalamic-pituitary system to sex steroids, which has been demonstrated to occur in adult men (36), already exists during early and midpuberty.
In this study we suppressed the action of endogenous E in early and midpubertal boys with the P450 aromatase inhibitor letrozole and demonstrated that low physiological concentrations of endogenous E already regulate LH and FSH secretion in boys during early and midpuberty. Moreover, our results indicate that in boys during early and midpuberty, endogenous E-mediated regulation of LH secretion occurs at the site of the pituitary.
Acknowledgments
We gratefully acknowledge the help of Carina Ankarberg-Lindgren and Ensio Norjavaara, Göteborg Pediatric Growth Research Center, Göteborg University (Göteborg, Sweden), for performing the 17ß-E2 assays, and of Ilkka Sipilä, Hospital for Children and Adolescents (Helsinki, Finland), for help with determination of bone ages.
Footnotes
This work was supported by the Foundation for Pediatric Research (Helsinki, Finland).
Abbreviations: CV, Coefficient of variation; IHH, idiopathic hypogonadotropic hypogonadism.
Received December 21, 2000.
Accepted June 26, 2001.
References
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A.-S. Parent, G. Teilmann, A. Juul, N. E. Skakkebaek, J. Toppari, and J.-P. Bourguignon The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration Endocr. Rev., October 1, 2003; 24(5): 668 - 693. [Abstract] [Full Text] [PDF]
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S. Wickman, E. Kajantie, and L. Dunkel Effects of Suppression of Estrogen Action by the P450 Aromatase Inhibitor Letrozole on Bone Mineral Density and Bone Turnover in Pubertal Boys J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3785 - 3793. [Abstract] [Full Text] [PDF]
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J. G. Hreinsson, M. Otala, M. Fridstrom, B. Borgstrom, C. Rasmussen, M. Lundqvist, T. Tuuri, N. Simberg, M. Mikkola, L. Dunkel, et al. Follicles Are Found in the Ovaries of Adolescent Girls with Turner's Syndrome J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3618 - 3623. [Abstract] [Full Text] [PDF]
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V. Rochira, A. Balestrieri, M. Faustini-Fustini, S. Borgato, P. Beck-Peccoz, and C. Carani Pituitary Function in a Man with Congenital Aromatase Deficiency: Effect of Different Doses of Transdermal E2 on Basal and Stimulated Pituitary Hormones J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2857 - 2862. [Abstract] [Full Text] [PDF]
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)
and GnRH-induced peak (
) LH (upper panel) and FSH
(lower panel) concentrations at the start and at 5
months of treatment. Boys in the no group did not receive any
treatment, boys in the t group received T, and boys in the t + lz group
received T and letrozole. Asterisks denote
significant changes within the group compared with values at the start
of treatment: *, P < 0.05; **,
P < 0.01; ***, P < 0.001.
