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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0231
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3189-3196
Copyright © 2007 by The Endocrine Society

Serum Sex Hormone-Binding Globulin Levels in Healthy Children and Girls with Precocious Puberty before and during Gonadotropin-Releasing Hormone Agonist Treatment

K. Sørensen, A. M. Andersson, N. E. Skakkebæk and A. Juul

University Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Kaspar Soerensen, University Department of Growth and Reproduction, Rigshospitalet section 5064, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: kaspar.soerensen{at}rh.regionh.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The regulation of SHBG is complex and influenced by sex steroids and insulin.

Objective: Our objective was to describe serum levels and evaluate determinants of SHBG levels in healthy children and in girls with central precocious puberty (CPP) before and during GnRH analog (GnRHa) treatment.

Design: We conducted a cross-sectional study on healthy subjects and a 2-yr longitudinal study in girls with CPP.

Setting: The study took place at a tertiary referral center for pediatric endocrinology.

Participants/Patients: A total of 903 healthy schoolchildren served as healthy subjects, and 25 girls with precocious/early puberty participated.

Interventions: Girls with CPP were treated with the long-acting GnRHa triptorelin.

Results: SHBG levels declined with increasing age in both sexes until adulthood. In healthy children, SHBG was significantly negatively correlated with testosterone, estradiol, dehydroepiandrosterone sulfate, and body mass index (BMI) in boys (total model R2 = 0.71) but only with dehydroepiandrosterone sulfate and BMI in girls (total model R2 = 0.26). Body fat percentage was significantly negatively correlated with SHBG levels (P < 0.001) in both boys (R2 = 0.18) and girls (R2 = 0.23). Girls with CPP had significantly lower pretreatment SHBG levels compared with age-matched controls [SHBG SD score, –1.29 (–4.48; 0.01)], which declined even further during GnRHa treatment [–2.75 (–5.9; 0.53); P < 0.001]. Even after adjustment for BMI and pubertal stage, girls with CPP had lower SHBG levels (P < 0.001) compared with healthy controls.

Conclusions: SHBG levels were strongly dependent on body composition and sex steroid levels in children with normal and precocious puberty. Studies on insulin sensitivity and SHBG in puberty are needed to better understand the interaction between body composition and gonadal maturation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SHBG IS A PLASMA glycoprotein mainly synthesized and secreted by the liver. It binds gonadal steroids in the circulation and thereby functions as a major determinant of sex steroid bioavailability to target tissues as well as influence the metabolic clearance of its ligands. SHBG has a high affinity for testosterone and dihydrotestosterone and a lower affinity for estradiol (E2). SHBG is also believed to have roles distinct from its binding and transport functions. Thus, increasing evidence supports that steroid-free SHBG interacts with surface receptors located on different steroid-sensitive tissues and may therefore have a critical role in the regulation of steroid-induced cell growth (1). Moreover, SHBG has been located in numerous locations in the hypothalamus, suggesting neuroendocrine functions (2).

The regulation of SHBG is complex, involving sex steroids as well as nonsteroidal factors. Serum SHBG levels are reduced by androgens as shown in boys with constitutionally delayed puberty treated with testosterone substitution (3). Similarly, patients with precocious adrenarche have low baseline levels of SHBG (4). Estrogen administration increase SHBG levels (5), and high levels of SHBG have been reported in girls with premature thelarche (6). In contrast, low levels of SHBG at menarche have been reported in girls with constitutionally delayed puberty (7).

A negative correlation between circulating SHBG and insulin levels has been noted in obese children and adolescents (8, 9, 10). Observations in boys with GH deficiency have shown increased baseline SHBG levels that decline to normal levels after GH substitution (11). Finally, SHBG levels are regulated by thyroid hormones and consequently found to be elevated in patients with hyperthyroidism (12).

Few studies have addressed SHBG levels in healthy children and adolescents. Generally, low levels of SHBG have been found in neonates, followed by a steady increase until the end of infancy (13). Early childhood is characterized by high levels of SHBG with a gradual decline as puberty approaches, most notably in boys (10, 14). Normal adult levels are reached around 17 yr of age in both sexes (10, 15).

To our knowledge, no studies have described SHBG levels in girls with central precocious puberty (CPP). One would expect SHBG levels to be low at diagnosis and return to normal levels during treatment with a GnRH analogs (GnRHa).

The aim of the current study is to report on serum SHBG levels in a large population of healthy children and adolescents and to evaluate determinants of SHBG. In addition, SHBG levels in patients with idiopathic CPP or early normal puberty before and during 24 months of treatment with GnRHa were evaluated.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Healthy subjects

A total of 903 healthy schoolchildren (501 girls) participated in the study. Age range was 5.8–19.9 yr. All participants were of Caucasian descent. None had any acute or chronic diseases, and none were taking any medication (including contraceptive pills). Two girls were excluded due to SHBG measurements above 450 nmol/liter. Both girls were postmenarcheal and not pregnant or thyrotoxic from a clinical point of view. None of them reported use of estrogen-containing contraception at the time of examination or in the questionnaire.

Other aspects of the study have previously been published (16).

Patients with CPP or early puberty

Twenty-five girls with idiopathic CPP participated in the study. All were of Caucasian descent. Age at start of treatment was 7.9 ± 2.1 yr (mean ± 2 SD). Other aspects of the study have previously been published (17). In brief, the diagnosis was based on a combination of clinical and biochemical parameters such as accelerated growth, development of secondary sexual characteristics before 9 yr of age, advanced bone age, and a pubertal peak LH of more than 6.0 U/liter in response to a GnRH test of 100 µg LHRH (Relefact; Hoechst, Frankfurt, Germany) given iv. One girl did not match the peak LH criterion but was included due to advanced bone age, advanced breast development, and E2 levels in the pubertal range. All girls were treated with the long-acting GnRHa triptorelin (Decapeptyl-Depot; Ferring, Kiel, Germany), which was administered im every 28th day. Data from the first 2 yr of GnRHa treatment are included in the present study.

Auxology

Height was measured by a stadiometer (Harpenden Ltd., Crymych, United Kingdom) to the nearest 0.1 cm. Weight was measured on a digital scale with a precision of 0.1 kg (SECA, model 707). Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. Data on height, weight, and BMI in the healthy children have been published elsewhere (18). Pubertal developmental stage was recorded according to the classification by Tanner (19, 20).

Bioelectric impedance analysis was done with a Holtain body composition analyzer (Holtain Ltd., Crymych, UK) in 232 (98 boys) healthy subjects. The total body water (TBW) content was calculated by the equation developed by De Lorenzo (21). Total body fat mass percentage (BF%) was calculated by the equation (100 x (body weight – TBW)/ body weight). Five children (four boys and one girl) were excluded due to negative BF%.

A nonfasting blood sample was drawn from an antecubital vein between 0800 and 1300 h and centrifuged, and serum was stored for up to 2 yr at –20 C until hormonal analyses.

Assays

SHBG was determined by a time-resolved immunofluorescence assay (Delfia, Wallac Oy, Turku, Finland) with a sensitivity of 0.23 nmol/liter. Intra- and interassay coefficients of variation were 5.8 and 6.4%, respectively.

Dehydroepiandrosterone sulfate (DHEAS) was measured by a RIA (Immunotech, Marseille, France) with a sensitivity of 0.11 µmol/liter. Intra- and interassay coefficients of variation were 3.5 and 7.0%, respectively.

Testosterone was measured with the DPC Coat-A-Count RIA kit (Diagnostic Products, Los Angeles, CA). The detection limit was 0.20 nmol/liter, and the intra- and interassay coefficients of variation were 7.6 and 8.6%, respectively (10.4% for samples less than 1 nmol/liter). Testosterone levels in healthy boys have previously been published (22).

E2 was measured with a RIA kit (IDS Ltd., Bolton, UK). Detection limit was 18 pmol/liter. Intra- and interassay coefficients of variation were 5.9 and 12.1%, respectively. Data on E2 levels have previously been published for healthy boys (22) and healthy girls (23).

Statistical calculations

All statistical analyses were done using SSPS 13.0 for Windows. All SHBG values on the healthy children were log-transformed to approximate homoscedacity before construction of reference ranges. The age-related mean curve was estimated by a smoothing spline on a logarithmic scale. The corresponding variance curve was estimated on the log-transformed residuals and transformed to an approximately 95% prediction interval (equal to ± 2 SD). This allowed calculations of SHBG SD scores (SDS) in relation to chronological age.

Testosterone and DHEAS values were square root-transformed and estradiol log-transformed to approximate homoscedacity before construction of reference ranges. The age-related mean curves were estimated by smoothing spline on a transformed scale. Comparisons of healthy boys and girls were done on transformed data using independent-samples t tests. Comparison of healthy girls vs. girls with CPP was done using Mann-Whitney U tests.

Univariate ANOVA (general linear model) was made on the total population with SHBG as dependent variable and BMI, testosterone, E2, and DHEAS as continuous variables. A second variance analysis was done on the subpopulation on which we had bioelectric impedance analysis data. This was done with testosterone, E2, DHEAS, and either BMI or BF% as continuous variables. Both analyses were done gender specifically, and all variables were transformed as mentioned above to approximate homoscedacity.

In addition, a univariate ANOVA was done on all healthy girls with Tanner stage 2–4 combined with the girls with CPP at all measurement points. This was done with SHBG (log-transformed) as dependent variable and age, BMI, pubertal stage, and healthy vs. CPP as covariables.

Ethical considerations

All participants and their parents gave informed consent. The study was approved by the local ethical committee of Copenhagen, Denmark (approval no. V200.1996/90).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
SHBG levels on all healthy subjects divided into age groups are presented in Table 1Go. Prepubertal boys (aged 6–8 yr) had significantly higher SHBG levels compared with similar-aged prepubertal girls (P < 0.01). The SHBG levels declined with increasing age in both sexes, although most notable in boys (Fig. 1Go). Postpubertal SHBG levels were reached at a median age of 17 yr in both sexes with significantly higher levels in girls compared with boys (P < 0.001). SHBG was significantly negatively correlated with testosterone, E2, DHEAS, and BMI in boys (total model R2 = 0.71) and significantly negatively correlated with BMI and DHEAS in girls (total model R2 = 0.26) in multivariate analyses (Table 2Go).


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  		TABLE 1. SHBG reference values according to age and gender based on 903 healthy children and adolescents

 

Figure 1
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  		FIG. 1. Serum concentrations of SHBG, testosterone, E2, and DHEAS in 402 healthy boys ({blacktriangleup}) and 501 healthy girls ({square}) in relation to chronological age. Lines represent geometric mean ± 2 SD (equal to the 95% prediction interval). Data on SHBG levels at baseline in 25 girls with CPP are included ({blacksquare}). Data on E2 and testosterone levels in boys (22 ) and estradiol levels in girls (23 ) have previously been published.

 

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  		TABLE 2. Gender-specific multivariate ANOVA (general linear model) with SHBG as dependent variable and BMI, testosterone, E2, and DHEAS as covariates

 
Serum levels of testosterone, E2, and DHEAS according to age in healthy children are shown in Fig. 1Go.

SHBG levels were significantly negatively correlated with estimated BF% (P < 0.001) in a multivariate analysis after adjustment for testosterone, E2, and DHEAS in boys (total model R2 = 0.67) as well as girls (total model R2 = 0.32). SHBG levels in relation to BF% and BMI are shown in Fig. 2Go.


Figure 2
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  		FIG. 2. SHBG levels in relation to BMI in 501 healthy girls (R2 = 0.24) and 25 girls with CPP at baseline and after 2 months of GnRHa treatment (A) and in 402 healthy boys (R2 = 0.35) (B). C, SHBG levels in relation to total BF% determined by bioelectric impedance for a subpopulation of 98 healthy boys (R2 = 0.18) and 134 healthy girls (R2 = 0.23). Linear regression lines are shown in solid black lines for healthy boys and in dashed lines for healthy girls.

 
The basic characteristics of girls with CPP are shown in Table 3Go. Girls with CPP had significantly lower pretreatment SHBG levels compared with age-matched healthy girls [SHBG SDS, –1.29 (–4.48; 0.01); median, 2.5; 97.5 percentiles)] (Fig. 1Go), which declined even further during the 2 yr of GnRHa treatment [–2.75 (–5.9; 0.53); P < 0.001]. SHBG was statistically significantly lower in girls with CPP at baseline when compared with healthy girls matched for pubertal stage (P = 0.027) and reached highly significantly lower levels after 2 months of treatment and during the rest of the study period (P < 0.001).


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  		TABLE 3. Anthropometry and SHBG data in 25 girls with CPP/early puberty at baseline and during 24 months of GnRHa treatment

 
Pretreatment BMI was significantly increased in girls with CPP compared with age-matched girls [BMI SDS, 1.45 (–1.69; 2.80)] and increased during 2 yr of gonadal suppression [2.08 (–0.61; 3.12); P < 0.001]. When CPP patients were compared with healthy Tanner stage-matched girls, the difference in BMI was not significant at baseline, but the CPP girls reached significantly higher BMI levels after 2 months of treatment and during the rest of the study period (P < 0.001).

The relation between SHBG and BMI in patients with CPP in comparison with healthy controls is shown in Fig. 2Go. After adjusting for BMI, SHBG levels were significantly lower in girls with CPP from 2 months of GnRHa treatment to the end of the study period compared with healthy controls (P < 0.001).

SHBG levels were significantly lower in girls with CPP at baseline and at all subsequent visits compared with healthy girls after adjusting for age, BMI, and pubertal stage in a multivariate analysis (P < 0.001; total model R2 = 87.9).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In our large study of 903 healthy children and adolescents, we found high concentrations of SHBG in the prepubertal period with higher levels in boys compared with girls. SHBG decreased in both genders with increasing age, and adult levels were reached at 16–18 yr of age with the lowest levels found in males.

The decreasing SHBG levels during puberty were associated with increasing fat mass and increasing circulating levels of androgens. Interestingly, we found low SHBG levels in girls with CPP and that SHBG levels were further lowered during gonadal suppression with GnRHa.

Steroids and SHBG

We found a strong negative correlation between DHEAS and SHBG in both genders, which remained strong even after correction for testosterone, E2, and BMI. Moreover, in boys, SHBG was negatively correlated with both testosterone and E2.

The declining levels of SHBG in prepuberty could be a result of increasing adrenal androgens. Adrenarche has been shown to be a gradual process with steadily rising adrenal androgen levels from childhood until puberty (24, 25). This is in accordance with our study showing steadily increasing DHEAS levels from the prepubertal period onwards for both genders.

The decline in SHBG levels appears to be steeper in boys compared with that of girls even before the onset of puberty, despite having similar DHEAS levels. After the onset of puberty, SHBG levels continue to decline in boys but seem to plateau in girls in late puberty. This could be explained by the rising androgen levels in boys exerting additional negative impact on SHBG production, whereas the rising levels of E2 in female adolescents would have the opposite effect on the production of SHBG.

BMI, fat mass, and SHBG

The decrease in SHBG was strongly negatively associated with BMI and body fat percentage in both genders, which remained so even after adjustment for steroid hormones.

SHBG has been shown to be negatively associated with BMI in obese children (10) as well as insulin levels in healthy adolescents (26). Increasing BMI and fat mass is generally accepted to have a negative influence on insulin sensitivity, and markers of body fat mass correlate positively with measures of insulin resistance (27, 28). It is well known that insulin down-regulates the hepatic SHBG production in experimental as well as clinical studies (10, 29). Thus, it is likely that the steadily increasing fat mass during childhood and adolescence could be partly responsible for the decline in SHBG. In addition, a period of transient reduced insulin sensitivity independent of fat mass is evident early in normal puberty (14, 28, 30), which hypothetically could lower SHBG levels and explain our findings.

There is evidence to suggest that prepubertal girls have lower insulin sensitivity and higher fat mass compared with that of similarly aged boys (27, 31). In accordance, we found much lower fat mass in prepubertal boys compared with similarly aged girls, which theoretically could explain the differences in SHBG levels between genders seen in this age group.

Comparison with previous studies on SHBG

The SHBG levels in our healthy volunteers were in accordance with previous studies, although minor differences in the absolute concentrations were evident in most age groups (10, 13, 14). Compared with other investigators, we found slightly higher SHBG levels in all age groups in girls, whereas the concentrations in boys were higher prepubertally and lower postpubertally. The most plausible reason for these differences may be the use of different SHBG assays. It has been shown that measurements of SHBG can differ up to 4-fold between different methods (32). Differences in affinities of the SHBG antibodies used in different assays could therefore explain the differences in absolute concentrations of SHBG. Moreover, during childhood and puberty, the relative distribution of SHBG isoforms changes due to differences in the extent of hepatic glycosylation of SHBG (33), which could influence the measurements of SHBG. Nevertheless, we provide valuable normative data for SHBG in healthy boys and girls, which enable calculation of individual SHBG SDS.

CPP and SHBG

The group of girls with idiopathic CPP had lower levels of SHBG at diagnosis compared with age-, BMI-, and puberty-matched controls. During the 24-month treatment period with GnRHa treatment, the low SHBG levels decreased even further, with the decline most notable in the first 2–6 months of treatment. No tendency toward normalization was observed during the entire study period, although all subjects showed sufficient gonadal suppression.

The unexpected decline in SHBG during treatment could be explained by a shift in the estrogen/androgen balance induced by the treatment with GnRHa. GnRHa treatment suppresses only sex hormones of gonadal origin (24), which is predominantly E2 in the case of girls with CPP. The reduced levels of estradiol will shift the sex hormone balance toward androgen dominance, which in turn could result in further down-regulation of the SHBG levels. GnRHa have been shown to decrease the E2 levels to near maximal effect after 2 months of treatment (34), which is in accordance with the decline in circulating levels of SHBG after 2 months of treatment noted in our present study.

It has been shown that normal prepubertal children have low but measurable serum concentrations of E2 when determined with an ultrasensitive assay (34). GnRHa may suppress E2 levels in girls with CPP to lower than normal prepubertal levels (34), a theory that is in accordance with results showing hypersuppression of inhibin B levels in girls with CPP treated with GnRHa (35). This relative hypersuppression of E2 from the gonads could theoretically also play a role in the concomitant suppression of SHBG. Our result showed unmeasurable levels of E2 in most girls from 2 months of GnRHa treatment.

In addition, adrenal androgens are increased in some patients with CPP (36) and continue to increase despite GnRHa treatment (24). This increase in adrenal androgen, especially in the light of falling E2 levels induced by the GnRHa treatment, might reduce the SHBG levels further.

Another plausible explanation for the declining SHBG levels despite gonadal suppression could be increasing BMI, which is seen in some girls with CPP during GnRHa treatment. We found that girls with CPP had increased pretreatment BMI at diagnosis in accordance with most other studies (37, 38). However, BMI kept rising in our study after initiation of GnRHa treatment. It is debated whether or not long-term gonadal suppression by GnRHa treatment results in increasing BMI (37, 39). Several studies have found that in obese children, increased BMI is correlated to increased insulin resistance and decreased levels of SHBG (8, 9, 10). The increasing obesity seen in our girls with precocious puberty during treatment could theoretically reduce insulin sensitivity, which would lower SHBG further. In addition, reduced insulin sensitivity is seen in normal puberty (28, 30), but insulin sensitivity has never to our knowledge been studied in patients with CPP. Moreover, the low SHBG levels in our girls with CPP could not be explained solely by increased obesity, and a puberty-related fall in insulin sensitivity, which does not reverse with GnRHa treatment, could be a theoretical explanation.

Furthermore, obesity is associated with increased adrenal androgens in prepubertal children (40). The greatest increase in androgen production has been shown to occur when the increase in BMI is greatest (25). The rise in BMI seen in our study group, especially during the first 6 months of GnRHa treatment, could have induced a rise in adrenal androgens, resulting in decreased SHBG production.

In conclusion, we demonstrated 1) a marked pubertal decline in SHBG levels in a large sample of 903 healthy boys and girls; 2) that SHBG was negatively correlated with testosterone, E2, and DHEAS in boys and with DHEAS in girls; and 3) that for both genders, a strong negative association exists between SHBG and body fat mass and BMI, respectively. In addition, we found 4) significantly lower SHBG levels in girls with precocious/early puberty compared with healthy girls after adjustment for age, BMI, and pubertal stage. SHBG levels decreased even further upon gonadal suppression with GnRHa.

Thus, even though GnRH treatment normalizes elevated gonadal steroids, treatment certainly does not create a normal prepubertal hormonal/metabolic environment as illustrated by our current results.


   Footnotes
 
Disclosure Statement: K.S., A.M.A., and N.E.S. have nothing to declare. A.J. received lecture fees from NovoNordisk, Pfizer, and Ipsen.

First Published Online May 22, 2007

Abbreviations: BF%, Body fat mass percentage; BMI, body mass index; CPP, central precocious puberty; DHEAS, dehydroepiandrosterone sulfate; E2, estradiol; GnRHa, GnRH analog; SDS, SD score.

Received January 31, 2007.

Accepted May 10, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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