Hum. Reprod. Advance Access published online on December 15, 2006
Human Reproduction, doi:10.1093/humrep/del451
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
GnRH agonist treatment in girls with precocious puberty does not compromise post-pubertal uterine size
1 Helen Schneider Hospital for Women, Rabin Medical Center, Beilinson Campus 2 Epilepsy Center 3 Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva Israel 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
5 To whom correspondence should be addressed at: Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel. Tel: +972 3 925 3282; Fax: +972 3 925 3836; E-mail: liatd{at}clalit.org.il
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Abstract |
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BACKGROUND: Prompted by findings of a hypoestrogenic state in girls during prolonged treatment with GnRH agonist and a close association of estradiol serum concentrations with uterine volume in puberty, this study sought to evaluate uterine and ovarian size in girls with precocious puberty (PP) during and after treatment and the effect of age or duration of treatment.
METHODS: Patients with idiopathic central PP before (n=75), during (n=41) or after (n=30) treatment with GnRH agonist underwent transabdominal pelvic ultrasound examination. Findings were compared with those in 69 girls with epilepsy and no PP before initiation of anticonvulsant treatment.
RESULTS: The girls with PP had significantly greater uterine and ovarian volumes before, during and after treatment with GnRH agonist than the controls, after adjusting for age at examination, weight, height and pubic and breast status. The average interval between the last treatment and the ultrasound examination was 1.3 years. There was no significant correlation between age at first treatment and uterine volume after treatment. Uterine volume decreased during treatment. There was a significant negative correlation between treatment duration and uterine volume after treatment (R2=–0.175, P=0.024). Nevertheless, mean uterine volume was still greater in the treated group than in the control group (P=0.002).
CONCLUSION: The iatrogenic hypoestrogenic state in treated girls with PP does not compromise post-pubertal uterine size.
Key words: GnRH agonist/precocious puberty/uterine size
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Introduction |
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The size and morphology of the uterus and ovaries remain relatively stable from infancy to before puberty, with the uterine fundus and cervix, owing to their similar width, forming a tubular configuration (Ziereisen et al., 2005
). From around 9 years onwards, the uterus and ovaries undergo progressive increases in size which are strongly correlated with the pubertal stages (Holm et al., 1995). The uterus body also becomes wider than the cervix and takes on the typical adult pear shape (Haber and Mayer, 1994; Griffin et al., 1995a; Holm et al., 1995; Buzi et al., 1998; Orbak et al., 1998).
Studies have reported a close correlation of uterine volume with estradiol (E2) serum concentrations (Salardi et al., 1985; Shawker et al., 1986). Thus, uterine size may serve as an indicator of endogenous estrogen production or prior exogenous administration of estrogen. In young adult women with Turner syndrome, the lack of estrogen is reflected by the prepubertal or intermediate size of the uterus. Without estrogen substitution, their uterus becomes hypoplastic (Shawker et al., 1986; Mazzanti et al., 1997; Haber and Ranke, 1999).
Precocious puberty (PP) in girls is defined as the appearance of secondary sex characteristics before the age of 8 years. In most cases, it is caused by premature activation of the hypothalamic GnRH pulse generator (‘central’ PP) and is considered to be idiopathic. Central PP may lead to early epiphyseal maturation with compromised final height (Brauner et al., 1994; Kauli et al., 1997) as well as psychological stress (Ehrhardt and Meyer-Bahlburg, 1986; Kletter and Klech, 1994). The earlier the initiation of treatment with GnRH agonist, and the longer its duration, the greater the patient's final height (Antoniazzi et al., 2000; Klein et al., 2001).
In view of the close correlation of serum E2 levels and uterine size in puberty, combined with the hypoestrogenic effect of early and prolonged GnRH agonist treatment, we speculated that the lack of estrogen in treated girls with PP could compromise their final uterine size, which may be associated with an increased incidence of pregnancy complications later in life. The aim of the present study was to evaluate uterine and ovarian size in girls treated with GnRH agonist for central PP and to determine if age at initiation of treatment or duration of treatment affects uterine dimensions.
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Materials and Methods |
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Patients
A prospective cohort design was used. The study group consisted of consecutive girls referred to our centre who were diagnosed with idiopathic central PP after extensive evaluation. Girls with chronic disease, bone dysplasia, organic brain disease, congenital adrenal hyperplasia or other endocrinological abnormalities were excluded, as were girls after radiation therapy and/or chemotherapy. None of the patients had clinical features of McCune–Albright syndrome and none had known exposure to exogenous androgens or estrogens. The patients were described in our previous study on the ultrasound and clinical findings that discriminate PP from precocious thelarche (de Vries et al., 2006
).
Clinical, biochemical and bone age (BA) analyses were done in all cases. BA was assessed according to the guidelines of Greulich and Pyle (1959), and the BA standard deviation score (SDS) was calculated. Pubertal stage was determined according to Marshall and Tanner (1969). The hormonal evaluation included basal and GnRH-stimulated levels of LH and FSH using a solid-phase, two-site chemiluminescent immunometric assay (Immulite 2000, DPC, Los Angeles, CA, USA). Serum basal blood levels of E2 (Double Antibody Estradiol Procedure, PIC, Los Angeles, CA, USA), androstenedione (radioimmunoassay, Diagnostic Systems Laboratories, Webster, TX, USA) and 17-hydroxyprogesterone (radioimmunoassay, MP Biochemicals, Orangeburg, NT, USA) were determined. GnRH stimulation test was performed with 100 µg GnRH, given as an i.v. bolus; serum LH and FSH concentrations were measured at 0, 30 and 60 min. Peak LH levels over 5 mIU/ml were considered a ‘pubertal response’, as previously suggested for the immunochemiluminometric assay (Neely et al., 1995). Height was calculated as height SDS for all girls and both their parents, using the Centers for Disease Control growth charts (Kuczmarski et al., 2000). Body weight was expressed as body mass index (BMI=weight in kilograms/height in meters squared), and the BMI–SDS was calculated (Rosner et al., 1998).
The diagnosis of PP was based on the appearance of breast buds before 8 years of age accompanied by the presence of one or more of the following findings: menses, pubic hair, accelerated growth velocity or BA greater than 2SD above the chronological age. Cases that were equivocal on referral (premature thelarche with breast buds in the absence of bone or growth acceleration or pubic or axillary hair) were diagnosed after at least 6 months follow-up on the basis of clinical judgement by an experienced clinician and, sometimes, repeated GnRH test. Other forms of PP were ruled out by further laboratory tests (adrenal androgens, prolactin, liver functions, alpha-fetoprotein and beta-HCG) and imaging studies (magnetic resonance imaging of the central nervous system, abdominal ultrasound), according to clinical judgement. The diagnosis of PP after follow-up was based on the progression of breast development accompanied by at least one of the following findings: growth acceleration, BA acceleration and appearance of pubic hair. All girls with PP were treated with i.m. injections of 3.75 mg of the long-acting GnRH agonist depot triptorelin (Decapeptyl Depot, Ferring or Diphereline, Pharma) every 28 days. Treatment was initiated to prevent early epiphyseal closure and compromised final height and/or at the recommendation of the psychological team of our institute to diminish psychological stress.
Controls
The control group consisted of 69 girls who were recruited for another study at random from outpatients attending our epilepsy centre, before initiation of anticonvulsant therapy (de Vries et al., in press). Inclusion criteria were as follows: age 6–20 years old; absence of systemic or central nervous disease (apart from epilepsy) that could interfere with hypothalamic-pituitary-ovarian function and no treatment with hormonal and psychotropic medications. One pediatric endocrinologist (L.D.) examined all control patients; none presented with PP or premature thelarche. Analysis of the control findings against norms for healthy girls published in the literature (Orsini et al., 1984) yielded no difference in uterine volume, length, anteroposterior diameter or ovarian volume (de Vries et al., 2006).
Pelvic ultrasound
Transabdominal pelvic ultrasound scans were performed with a conventional full-bladder 5 MHz real-time sector scanner (Sonoline Prima, Siemens) by the same investigator (L.D.), either before (n=75, 208 examinations, Group 1), during (n=41, 194 examinations, Group 2) or after (n=30, 60 examinations, Group 3) treatment with GnRH agonist, and in the control group (69 examinations). The following parameters were analysed: (i) uterus: length, transverse diameter (width), endometrial thickness, fundal anteroposterior diameter and cervical anteroposterior diameter. The ratio between the fundal and cervical diameters (FCR) was calculated. (ii) Ovaries: height, width and length. Uterine and ovarian volumes were calculated according to the formula for ellipsoid bodies: V=longitudinal diameterxanteroposterior diameterxtransverse diameterx0.5233. To assess reproducibility, ultrasound examinations were performed twice on the same occasion in 15 girls in the study group by two experienced operators who were unaware of the other's results.
In the comparisons of findings before and after treatment in the study groups, only data for one visit for each patient were included. The latest ultrasound examinations were used in all cases. Owing to the age distribution (Figure 1), the comparison of findings between patients before and during treatment and controls included only data for girls aged 6–12. For further analysis, the patients examined after treatment were divided into two subgroups by age at treatment initiation: before 9 years (‘early treatment’) and after 9 years (‘late treatment’).
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Written informed consent was obtained from all families of patients and controls. The institutional Human Research Committee approved the study.
Statistical analysis
The Statistical Package for the Social Sciences, version 10.0 for Windows, was used for data management and analysis. Skewed data were subjected to logarithmic transformation. Analyses included Mann–Whitney test for non-parametric continuous data and chi-square test for categorical data. A multivariate general linear regression model was fitted to the data to compare mean uterine and ovarian volumes between groups, after adjusting for several covariates. Correlations and differences were considered significant when P-value was less than 0.05. All results are presented as mean±SD.
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Results |
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A total of 531 pelvic ultrasound evaluations were performed. The Pearson correlation coefficients between the two observers for the seven ultrasonographic parameters were 0.93–0.99 (P<0.001 for all), indicating good reproducibility of the findings.
The anthropometric characteristics of the study group (before treatment) and the control group are presented in Table I. In the PP group, mean basal and peak GnRH-stimulated blood levels werfe 0.9±1.1 and 12.0±13.2 mIU/ml, respectively, for LH and 2.99±3.8 and 13.3±6.7 mIU/ml for FSH; mean peak LH/peak FSH ratio was 0.9±0.8.
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The correlations between age at examination and uterine or mean ovarian volumes in girls with PP before, during and after treatment with GnRH agonist are presented in Figure 1. Uterine growth was evident from approximately 9 years onwards. After adjusting for age at examination, weight, height and pubic and breast status, we found uterine and ovarian volumes to be significantly higher in the patients before and during treatment than in the controls (Table II).
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The mean duration of GnRH agonist treatment was 813±322 days (range 365–1560 days). In the girls who underwent pelvic ultrasound after GnRH treatment (Group 3), the mean interval between the last treatment and the ultrasound examination was 478±299 days (range 103–1232 days). For the 20 girls in this group (66%) who were after menarche, the last ultrasound examination was performed 409±407 days (36–1131 days) after menarche, and the average interval between the last treatment with GnRH agonist and menarche was 422±421 days (range 90–1080 days). Figure 2 shows the correlation between age at ultrasound examination and uterine volume in the girls with PP after treatment and the controls. According to the calculated cubic regression line, maximal uterine volume was at the normal level for age 14–16 years.
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In the general linear model, adjusting for age at ultrasound examination, weight, height and pubic and breast status, the uterine volume was significantly higher in the study group (before and during treatment) than in the controls (P<0.001, Table II). The study group (after treatment) was also characterized by a higher proportion of adolescents with a pear-shaped configuration of the uterus, a higher FCR and ovarian volume and greater endometrial thickness (Table III).
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Within the control group, uterine volume correlated positively with levels of E2 (cubic regression: R2=0.541, P<0.001), LH (logarithmic regression: R2=0.737, P<0.001), FSH (cubic regression; R2=0.689, P<0.001), androstenedione (cubic regression: R2=497, P=0.014) and dehydroepiandrosterone sulphate (logarithmic regression: R2=0.476, P=0.001), but not with testosterone. In girls with PP, similar positive correlations were found between uterine volume and E2, LH, FSH, androstenedione and dehydroepiandrosterone sulphate (in cubic regression R2=0.345, 0.245, 0.200, 0.277 and 0.147, respectively, P<0.001 for all), but not with testosterone. In addition, uterine volume in the study group correlated positively with peak LH on GnRH test (cubic regression: R2=0.280, P<0.001), but not with peak FSH.
There was no significant correlation between age at first treatment and uterine volume after treatment in the study group (R2=0.019, P=0.477). A significant negative correlation was found between treatment duration and uterine volume after treatment (Figure 3). Table IV presents the data for the patients after treatment, stratified by early or late treatment initiation. In the general linear model, after adjusting for age at ultrasound examination, duration of treatment, weight, height, pubic and breast status and menarche status, the uterine volume was significantly higher in the early treatment group (P=0.002).
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Discussion |
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In the present study, we found that uterine and ovarian volumes in girls with PP are significantly higher before, during, and after treatment with GnRH agonist compared to controls, after adjusting for the important covariates. We did not find that the prolonged hypoestrogenic state during puberty in girls with PP leads to a smaller uterine size. Moreover, the girls with PP who were treated earlier had a larger uterine post-treatment volume than girls treated later, probably reflecting their earlier exposure to endogenous estrogen. Although uterine volume decreased during treatment, and there was a significant negative correlation between treatment duration and uterine volume after treatment, the ultimate post-treatment uterine volumes were still greater in the treated group than in the control group. Similarly, the proportion of adolescents with a pear-shaped configuration of the uterus was significantly higher in the girls with PP after treatment and their endometrial thickness was greater.
In another hypoestrogenic state, Turner syndrome, the lack of estrogens is reflected by the smaller prepubertal uterus (Shawker et al., 1986; Mazzanti et al., 1997; Haber and Ranke, 1999). Doerr et al. (2005), in a recent study of 75 girls with Turner syndrome, found that only those with karyotype 45,X/46,XX had a uterus of normal size, whereas 26% of the patients with karyotype 45,X had a uterine length of <2.2 SDS and 18% had a uterine volume of <2.2 SDS. Several others have shown that adolescents or young adult women with Turner syndrome who do not receive estrogen substitution have a hypoplastic uterus (Mazzanti et al., 1997; Haber and Ranke, 1999). In the study of Massarano et al. (1989), girls who did not have streak ovaries showed a marked increase in uterine length at the expected age. Normal uterine maturation occurred in only 50% of the girls with Turner syndrome who received treatment with low-dose oral ethinyl E2 (Paterson et al., 2002). Additionally, higher daily dose of estrogen during the postmenarcheal period had a positive effect on uterine development (Snajderova et al., 2003). These findings stress the importance of estrogens in the development of uterus size in this population.
Several studies have verified the use of ultrasound in the evaluation of girls with PP (Herter et al., 2002a; Battaglia et al., 2003; de Vries et al., 2006), demonstrating an increase in uterine size at the time of diagnosis. However, little information is available on follow-up of ultrasound findings in girls with PP treated with long-acting GnRH agonist. Jensen et al. (1998) investigated 33 girls with idiopathic PP treated with Decapeptyl Depot. They reported that the ovaries and the uterus were enlarged in 50% of the girls at the time of diagnosis and significantly decreased to normal values appropriate for age within 3 months of treatment. The ovarian and uterine volumes remained within normal range (<2 SDS) after discontinuation of treatment. In our study, although uterine and ovarian size decreased during treatment, the girls with PP had increased uterine and ovarian volumes before, during, and after treatment compared with controls. Ambrosino et al. (1994) evaluated the use of pelvic ultrasound in monitoring the efficacy of suppressive therapy with GnRH agonist in 10 girls with PP. Sonographic trends of decreasing ovarian volume and uterine length (rather than uterine volume) indicated early suppression, but the results for uterine volume were not stated. Jensen et al. (1998), too, failed to examine uterine configuration or the presence of endometrial echo or the FCR, which others suggested to be the best ultrasound parameters discriminating central PP from other forms of sexual precocity (Griffin et al., 1995b). Furthermore, Bridges (1996) suggested that the change in the uterus from tubular (prepubertal) to pear-shaped (pubertal) is one of the first signs of the effect of estrogen. In our study, a pear-shaped configuration of the uterus and the presence of endometrium were more prevalent at diagnosis in the study group.
Several studies investigated uterine size until the ages of 13 (Orsini et al., 1984; Salardi et al., 1985; Herter et al., 2002b), 14 (Bridges et al., 1996), 15 (Buzi et al., 1998; Griffin et al., 1995a; Haber and Mayer, 1994), 18 (Porcu et al., 1989) or 25 years (Holm et al., 1995). Holm et al. (1995) studied 166 healthy girls aged 6–18, in addition to 25 medical students aged 19–25. On multiple regression analysis, postmenarcheal uterine growth was related to number of years after menarche, but not to height, weight or age. Uterine growth ceased about 7 years after menarche, at approximately 20 years of age. In an earlier study, Porcu et al. (1989) evaluated uterine volume during the first postmenarcheal years in 143 women and found that the normal volume was not yet reached by the highest postmenarcheal (6 years) or chronologic (18 years) age. Therefore, the question of the age at which the uterus reaches final size is still open. According to our data, the greatest uterine volume was evident at about the age of 14–16 years. However, the small number of girls older than 16 years precludes a definite conclusion. As 20 (66%) of the treated girls with PP were evaluated after menarche, it may be assumed that the greater uterine size detected reflects the final uterine size and that the prolonged hypoestrogenic state during puberty in these girls did not lead to a smaller uterine size. A follow-up study, a few years after menarche, in the same population with similar controls is needed to corroborate our findings.
In conclusion, uterine and ovarian volumes are significantly higher in girls with PP than in age-matched controls before, during and after treatment with GnRH agonist, at least for the first postmenarcheal years. Unlike girls with Turner syndrome, the iatrogenic hypoestrogenic state in treated girls with PP does not affect the already above-normal uterine size. The long-term clinical significance of hypoestrogenic state in puberty on the final maturation of the uterus should be evaluated in other clinical settings, such as in girls with delayed puberty, who are treated with estrogens only at an advanced age.
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Submitted on July 16, 2006; resubmitted on October 16, 2006; accepted on October 20, 2006.
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