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GnRH, Gonadotropins, Gonadal Steroids and Reproduction

Neuroendocrinology 2009;89:441–447 Received: July 8, 2008
Accepted after revision: September 29, 2008
DOI: 10.1159/000197862
Published online: January 29, 2009

Body Mass Index and Body Composition in
Adolescents Treated with Gonadotropin-Releasing
Hormone Analogue Triptorelin Depot for Central
Precocious Puberty: Data at Near Final Height
Elena Chiocca a Eleonora Dati a Giampiero I. Baroncelli a Stefano Mora b
Donatella Parrini c Paola Erba d Silvano Bertelloni a
a
Adolescent Medicine, II Pediatric Division, Department of Obstetrics, Gynecology and Pediatrics,
Azienda Ospedaliero-Universitaria Pisana, Pisa, b Laboratory of Pediatric Endocrinology and BoNetwork,
San Raffaele Scientific Institute, Milan, c Laboratory of Reproductive Endocrinology, Department of Obstetrics,
Gynecology and Pediatrics, and d Nuclear Medicine, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

Key Words (0.4 8 1.0 SDS) to near adult height (0.2 8 1.0 SDS, p = NS
Central precocious puberty ⴢ GnRH analogue therapy ⴢ vs. 0). Total fat mass (TFM) was significantly increased (16,144
Adolescence ⴢ Body composition ⴢ Body mass index ⴢ 8 8,065 g; controls 10,712.1 8 4,120.4 g, p ! 0.02); glucose
Fat mass homeostasis and lipid profile corresponded to reference
ranges. Conclusions: GnRH analogue therapy did not show
long-term detrimental effects on BMI, but it may increase
Abstract TFM, suggesting that body composition should be moni-
Background/Aim: In children with central precocious pu- tored till adulthood. Copyright © 2009 S. Karger AG, Basel
berty (CPP), gonadotropin-releasing hormone (GnRH) ana-
logue treatment has been associated with an increase in
body mass index (BMI). We evaluated BMI and body compo-
sition in adolescents treated with GnRH analogue at their Introduction
near final height to assess the long-term effects of therapy
on these parameters. Patients and Methods: We studied 20 Central precocious puberty (CPP) is caused by the pre-
patients (14.8 8 1.6 years; 17 females) previously treated mature reactivation of gonadotropin-releasing hormone
with triptorelin depot for CPP (3.75 mg/28 days) from 8.1 8 (GnRH) pulse generator in the hypothalamus, leading to
0.8 to 11.5 8 0.8 years. 23 healthy adolescents with normal the appearance of secondary sexual characteristics before
onset of puberty (14.7 8 2.1 years, 19 females) were the con- the age of 8 years in females and before 9 years in males
trols. BMI and body composition (dual-energy x-ray absorp- [1, 2]. CPP may cause short stature in adulthood as well
tiometry) were assessed. Results: Patients reached their as psychological discomfort in childhood [1–3]. Thus, the
near adult height (–0.5 8 1.1 standard deviation score (SDS)); aims of therapy in CPP are to suppress the pituitary-go-
the girls were menstruating and the majority (15/17) had reg- nadal axis in order to stop and possibly reverse the pro-
ular cycles, the boys showed normal testicular function. BMI gression of secondary sexual characteristics, to slow
was unchanged from the start of GnRH analogue therapy down skeletal maturation, to delay epiphyseal closure

© 2009 S. Karger AG, Basel Silvano Bertelloni
0028–3835/09/0894–0441$26.00/0 Dipartimento Materno-infantile, Ospedale Santa Chiara – AOUP
Fax +41 61 306 12 34 Via Roma 67
E-Mail karger@karger.ch Accessible online at: IT–56125 Pisa (Italy)
www.karger.com www.karger.com/nen Tel. +39 050 992 743, Fax +39 050 993 044, E-Mail s.bertelloni@med.unipi.it

body composition and serum levels of hormones of repro- ductive axis. Only minor adverse events have been Consent reported during their administration [6].3 nmol/l. 442 Neuroendocrinology 2009.and to improve final height.3 mIU/l. respectively. the improvement of psycho. weight. The ies have suggested that an increase in fat mass may be study was approved by the Ethics Committee for Human Investi- associated with the administration of GnRH analogues gations of our department. published data in GnRH analogue triptorelin depot (3.5. 7]. GnRH analogue therapy in children with CPP is gen- erally safe [2–6]. when the chronological age was !18 years. tivity were: ^3. GnRH analogues have been the treatment of choice for CPP. Standard deviation sient increase of BMI during treatment with a return to scores (SDS) were calculated in respect to Italian standards for baseline values after the discontinuation of the GnRH height and weight [14].0% and 0. Mid-parental height was calculated using measured parental The aim of the present study was to evaluate the long. and 0. in treated for CPP by GnRH analogue therapy in our department our laboratory. growth velocity 197th centile for chronolog. Blood samples were obtained in the fasting state between 08:00 and 09:00 h with each patient at rest for about 15 min. menarche and menstrual pattern were evaluated in a semistruc- plored body composition by dual-energy x-ray absorpti. 3]. inter-assay coefficients of variation were asked for permission for their children to participate in a (CV%) and sensitivity were as follows: LH: ^6. the normative Italian data of Cac- analogue has been described [13]. sayed by the IRMA method (Sorin Biomedica. approximately at the same hour of the day. total and HDL cholesterol and triglycerides were measured Patients and Methods by standard automatic method. event of increased prolactin values the sample was re-assayed af- 20 young adolescents were enrolled in the study. USA)]. and directly tion of the reproductive axis [3. Mean period of treatment was 2. some stud. N. All the subjects social well-being in childhood and in adolescence is an were at their near final height at the time of the present study.5 cm for females) or (+6. age at the start of GnRH agonist therapy and its duration [fasting insulin (mIU/l) ! fasting glucose (mmol/l)]/22.1% and 2. 6 males) previously son & Johnson SpA-Ortho Clinical Inc. No studies ex.0% and 0. Lower were not different between the subjects who participated to the HOMA-IR values indicate higher insulin sensitivity.7 pg/ ical and hormonal criteria (onset of puberty before 8 years in girls ml. All patients underwent complete physical examination. ^8. ents of the other ones refused to participate (mainly because they The insulin resistance index (homeostasis model assessment had to travel to Pisa from other Italian regions). ter precipitation with PEG to exclude macroprolactinemia [17]. ^5. Insulin was as- and 9 years in boys. while the par.0 year. ical age. Saluggia. the same day. heights adjusted for the child’s sex [(father height + mother term outcome of children with CPP treated by GnRH an.0%. in children [8–11].5 cm for males). 17␤-estradiol (testosterone in males) and prolactin levels were assessed in all the Patients patients by commercially available methods [VITROS ECi (John- The parents of 31 children (25 females. 0.89:441–447 Chiocca /Dati /Baroncelli /Mora /Parrini / Erba /Bertelloni . [14] were used for calculating the BMI SD score. (HOMA-IR)) was calculated using the formula: HOMA-IR = ings. Rochester. ly gonadal sex steroid secretion [3–5] and long-term fol. FSH. Target alogue in respect to BMI and body composition. For more than 25 years..5 cm/year and/or a bone age 114 years for additional aim of therapy [1. height)/2] (–6.7% and 1.4 ng/ml. Age at BMI at final height has been shown [5. other authors suggested Methods that an increased body mass index (BMI) is a feature of Height (mean of three separate measurements using a wall- girls with CPP before therapy and that GnRH analogue mounted stadiometer) and weight were measured in all patients administration did not worsen it [12]. whereas present study and those who did not. ^7. All the pa. LH peak after GnRH test 15 intra-assay. normal MRI scan of hy. inter-assay coefficients of variation (CV%) and sensi- IU/l with an LH-predominant response. ^5. All patients received the higher values indicate lower insulin sensitivity. intra-assay.6%. However. Age at menarche and menstrual history were re- proving of adult height in children with CPP [2–5]. Gly- cemia. 17␤-estradiol: ^6. tured interview by reviewing personal calendars of each girl. tients were affected by idiopathic CPP according to standard clin.8%. because these drugs ef. ometry (DXA) after the achievement of final height in Bone age was assessed according to the method of Greulich adolescents previously treated by GnRH analogues for and Pyle [15]. In addition. Baseline LH. year.5%. that is a growth velocity !0.0 cm. ^7. 3. and long-term Written informed consent was obtained from both the parents of each child before treatment and at the moment of the present follow-up studies have not shown any significant altera.9% and long-term evaluation study of GnRH analogue safety. CPP. a tran.5 IU/l.3%.. 7]. study. Study Protocol fectively inhibit gonadotropin secretion. corded in the girls by a dedicated semistructured questionnaire. bone age advanced 11 year.7 8 1. height. by contrast.1%. and normal values of ciari et al. Auxological find. prolactin: ^5. Italy). BMI was calculated according to the for- mula: weight (kg)/height (m2). insulin. FSH: ^2. ^8. 5. from each subject whose chronological age was 118 years. 4]. Predicted adult height (PAH) was calculated using the Bayley-Pinneau method [16]. height was defined as mid-parental height 8 8.J. and consequent.4%. females and 117 years for males. testosterone: ^2.5 IU/l. In the pothalamus-pituitary region) [2.75 mg/28 days) for at least 1 healthy Italian children were used as normative values [18]. glycemia and lipid profile were assessed in low-up studies clearly documented their efficacy in im.

Auxological data in adolescents previously treated by GnRH analogue for CPP 1.2 Before Tx Stop Tx NFH Controls Fig. SDS.1 Mid-parental height (SDS) –0.8 8 1. BMI was above the 90th centile in 3 patients the mean age of 12.29 obtained by using SPSS Version 13.3 15. testosterone [21. The boys reached full sexual maturation (G5.0%).89:441–447 443 Treatment for CPP . at discontinuation Chronological age in the present study was 14.Table 1. Statistical Analysis Results are expressed as mean 8 SD. At near fi- years.8 p = NS Baseline Near final 1. Non-parametric statistical analysis ml) in the other one and they did not change after re- (Mann-Whitney rank sum test) was also used where suitable.1 years [p = NS vs.581. p ! 0. mean BMI-SDS resulted in not being signifi- nificantly higher (p ! 0.6 Predicted adult height (SDS) –1. total free fat mass (TFFM) and to.6 and at near final height are shown in figure 1.1 years.481. Values of TFFM re- Body Composition after GnRH Analogue Neuroendocrinology 2009.48 8 0.01) than PAH at the start of treat. Mean near final height –0.9 14. The Data of body composition assessed by DXA in patients menstrual pattern was regular in all but 2 girls (11%).5 Height for bone age (SDS) –1. Results Body Composition Auxological Features and Reproductive Function Mean values of BMI before therapy. Chicago.2 years)]. years 8.580.8 nmol/l (n. SDS).6 – –1.481..580. nal height. ing to the cycle period of sampling (data not shown).680.0 (SPSS Inc. the mean BMI- in the present study did not reach adult value in any of SDS resulted in not being significantly different from the the patients. USA). sex and pubertal stage) were used as the control group to evaluate the parameters of body composition.6 Height for chronological age (SDS) 0.0 8 201. BMI in con- tal body fat mass (TFM) were recorded. at near final height (NFH) are shown (mean 8 SD).v. for adult men in our laboratory 180 pg/ ml)]. while prolactin values in the patient group.1 0 Bone age. Ill. Ph5) and sidered to be significant in all statistic analyses. 1).6 8 1. peated assessment and serum precipitation with PEG. normal range 5–15 ng/ among patients and controls. In addition. at near final height. and controls are shown in figure 2.380.8 –0.9 –0. for adult men USA). 1.9 –0. These percentages were similar to the values ob- LH. at their near final height. Values before the begin- Body composition was measured by DXA (GE-Lunar Prodigy. p = NS vs.1 SDS was sig. Student’s t test for paired Clinical and laboratory findings were indicative of poly- samples was used to compare the data before and after treatment cystic ovary syndrome in 1 patient.5 8 1. Statistics were showed normal values for testicular volume (0. years 11. 1). 19 females. Final height was within the target height though a slight decrease was observed between the start range in all adolescents and not significantly different of GnRH analogue treatment and its discontinuation from their mid-parental height (table 1).881. The relationships between pairs of variables were assessed by the Pear.9 –0. son’s correlation and linear regression analysis.6 Age. (5.v.. 0) and also from the healthy control group All the girls experienced menarche and it occurred at (fig. Since bone age (fig. cantly different from those of previous time points. matched accord.081. the age of (15.2 height p = NS BMI (SDS) 0.0%. in our laboratory 10–35 nmol/l)] and inhibin B [317.7 8 4. ning of treatment (Before Tx). FSH and 17␤-estradiol levels were normal accord. Wisc. the possibility to increase actual height is reference normative values for age and sex (0. BMI in adolescents previously treated with a GnRH ana- logue triptorelin depot for CPP (n = 20). An unpaired test was used to compare data were slightly increased (42 ng/ml. at its discontinuation (Stop Tx) and Lunar. ing to age.380.2 8 1.5 pg/ml (n.580.6 8 2. Madison. al- ment (table 1).7 8 2. A group of 23 healthy trols (n = 23) are also reported for comparison with the patients Italian adolescents (14.0 still present (table 1). served before the start of therapy. 2 females) and below the 10th centile in 1 girl menarche in the respective mothers (12.05 was con..

0%) in com. In addition.4 161. controls: 10. mg/dl 63. polycystic ovary syndrome [24]. A similar tendency olescent girls experienced menarche within 2.01) in the female patient group (32.000 p < 0. as absolute values (center) and percent body mass (right)] in adolescents previously treated with a GnRH ana- logue for CPP (CPP) at their near final height (I) and in controls height [3. while TFM was increased both as absolute values near final height [7]. and oligomenorrhea was alogue was below or above the normal reference interval. p = and that of their mothers. Table 2.3 (0. [7].0 (51–155)b 0 0 CPP Controls CPP Controls CPP Controls a Mean (range) [18].4%.02 25 Glucose.2811.2–5. Values (mean 8 SD) of total free fat mass (TFFM) (left). the previous GnRH analogue did not to restore growth potential in children with idiopathic seem to be the cause of mild hyperprolactinemia in 1 of CPP. The well as in the controls.3 8 2.6826.000 45 viously treated by GnRH analogue for CPP 40 40. that the mother and the aunt were also affected by the marized in table 2.4780. not related to the previous GnRH analogue therapy. in addition.05 10 HDL cholesterol.0 (117–215)b 10. in keeping with the mean age at menarche in Italy [14] tions (patients: 19.4 8 8. They demonstrate that mean values same disorder.000 Patients Reference range 35 [mean (5–95th centile)] 30 30.8 8 4. Glucose homeostasis and lipid profile in adolescents pre- 50. TFFM (g) TFM (g) FM (%) b Reference values from Carrillo and Lifshitz [39]. showing an improvement of height sulted in being non-significantly different in the two in the third decade of life in comparison with the data at groups.9%). subjects of both groups were in.89:441–447 Chiocca /Dati /Baroncelli /Mora /Parrini / Erba /Bertelloni .5)a p = NS 20 HOMA-IR 1. our ad- parison with controls (25. Subdividing data according to Our data also demonstrated the full reversibility of sex. mg/dl 55.04).000 p < 0. In this were very close to reference means.2 814. Transient mild increase of prolactin has been reported in girls who underwent triptorelin depot administration for Discussion CPP. 2. Fig. nmol/l 3. Residual height growth is still present in our series of patients and this finding agrees with the data of Heger et al.4)a 20.8 48. although a delayed men- and BMI-SDS (r = 0.5–5. 5]. 2). because she stopped triptorelin depot 444 Neuroendocrinology 2009. total fat mass [TFM. Thus. and as % body fat (fig.85 1.7 (3.7 95. majority of our adolescents reported regular menses for volved in the scholastic programs of physical education their gynecological age [23]. irregularities presented disorders affecting menstrual cy- cle as mild hyperprolactinemia or polycystic ovary syn- Glucose Homeostasis and Lipid Profile drome [24]. the family history demonstrated Data on glucose homeostasis and lipid profile are sum. no value in patient. arche up to 5–6 years after the discontinuation of GnRH Physical activity was not restricted in the patients as analogue has been reported in some girls (table 3). CPP likely represented an early manifestation of our group of adolescents previously treated with GnRH an. FM resulted in being significantly increased (p ! suppression of the pituitary-gonadal axis after the dis- 0. The only significant correlation was between age other studies (table 3) [18–22]. ing significantly increased in comparison with PAH at the start of therapy.0 years af- was observed in males but it did not reach a statistical ter the discontinuation of treatment at a mean age that is significance likely due to the small number of observa. however.97 4. p ! 0.5%. In fact. The 2 girls with menstrual and in one sport in the afternoon (2 h twice weekly).380.000 15 Total cholesterol. mg/dl 153. allowing them to fully reach their genetic target our adolescents. Our data largely agree with NS). near final height resulted in be- (j). continuation of GnRH analogue therapy.0815. In the latter. suggesting a familial inheritance.0 (31–66)b 5 Triglycerides. the hormone values normalized within 6–12 months after the discontinuation of the GnRH ana- Our study confirms that GnRH agonist therapy is able logue [25].588.

and/or direct effect of the GnRH significantly during GnRH agonist therapy.581. 26]. We also excluded a false posi.5 a Mean. in girls with CPP and that GnRH analogue therapy does dren with CPP [8–12. GnRH analogues also showed altered body composition This finding is in keeping with our results showing un.1–4. c after the discontinuation of GnRH treatment (range). Age at menarche after GnRH therapy: data in the present series and in literature studies Group n Age at start of Duration Age at Time to (first author) GnRH analogue of therapya menarcheb menarchec years years years years Arrigo [23] 101 7.7 12.5 Bouvattier [22] 20 9. body composition we found may be related to the shorter crine regulation of body weight might be operative.3 3. [8] demonstrated a persistent increase in kisspeptin/GPR54 system [28.0 Present series 17 8.0 0.0 Paterson [20] 29 8.6 – Feuillan [10] 32 4. while overweight was not increased before the start of treat- this possibility was not explored in the other report [25]. 29]. pos. To better explore the effect of GnRH analogue therapy logue treatment on BMI.581. dif- explain the association between overweight/obesity with ferent genetic backgrounds as well as familial and socio- CCP demonstrated in some studies [8–12]. creased percentage of TFM. 9. the onset of puberty may be triggered by the achieve.880. The modifications of direct effect of GnRH analogue therapy on neuroendo.8 (3. [32]. remarkable variations of BMI-SDS from the start of sion of her clinical records did not reveal any hormone GnRH analogue treatment to final height.381. although in. nificant BMI decrease 2 years after the discontinuation plained.1 Heger [5] 50 6. 31] and it did not worsen at discontinuation testicular function. 27]. [33] resembling the changes observed during menopause Body Composition after GnRH Analogue Neuroendocrinology 2009.6–15. in our group of patients.4 12.5 – 12.3–2. we also performed DXA scans in increased BMI of girls with CPP may persist or even our group of patients. although in their report mean BMI was still above the ment of a critical body fat mass.8 0.4–5.6 (10.381. According to Frisch’s critical weight hypothesis of treatment has been reported by van der Sluis et al.681. development of prepubertal body composition. but at the cultural influences may be involved.2–3. [28].2 13.581.180.7 2. pos.8 Jay [19] 46 7.5 4. the ab- sibly persisting after the discontinuation of treatment [8].380. the unsuppressed hormonal milieu. a direct or in.5 2. normal pattern of development. the prevalence of tive increase due to macroprolactinemia [17. our adolescents were sibly leading to overt obesity [12]. likely through the Traggai et al.780. Thus. administration 12 years before our evaluation and revi.0 0. pothalamic nuclei by fat hormones.3 Pasquino [21] 87 6.6e 12. Some data indicated that the on body composition. d mean (range). which side effects of GnRH analogue therapy on male reproduc. A sig- with CCP may experience a BMI increase remains unex.7 6.1–5. signaling to specific hy. showing for the first time an in- worsen during GnRH analogue treatment [8. in comparison with the current Italian prevalence The small group of boys showed normal endocrine of 24% [30.181. e median. increase during treatment. Thus. confirming the absence of long-term of GnRH analogue and at final height. are in agreement with Arrigo et al.5 years from with hypothalamic hamartoma [10]. The reason why many girls not have a long-term detrimental effect on BMI.0 4.3–8.8–2. normal mean at the end of follow-up [32].8 12. BMI increase likely does not represent a constant finding An increased rate of obesity has been reported in chil. 11]. ment.581. Thus.2–2.4 0. [13] indicate that a tive axis [3].6 12. This hypothesis could BMI during and after GnRH analogue therapy. about 2.2)d 0.1 0. Table 3. Adult women who had been treated with and decreases of BMI during the course of treatment [5].9)d 3. especially in patients slightly fatter at their final height. By contrast. agonist therapy on adipose tissue through a sort of ‘meno- dividual patients may experience significant increases pausal effect’.6 12.282.7 0. In addition. Our data.580. subdivided in two peri- Other reports showed that mean BMI does not change ods by the treatment.89:441–447 445 Treatment for CPP . same time it may confound the impact of GnRH ana. b mean 8 SDS.

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