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Original Studies |
Division of Pediatric Endocrinology, Department of Pediatrics, Christian Albrechts University of Kiel, D-24105 Kiel, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Wolfgang G. Sippell, Division of Pediatric Endocrinology, Department of Pediatrics, Christian Albrechts University, Schwanenweg 20, D-24105 Kiel, Germany. E-mail: sippell{at}pediatrics.uni-kiel.de
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Abstract |
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In conclusion, long term depot GnRH agonist treatment of CPP girls preserved genetic height potential and improved FH significantly combined with normal body proportions. No negative effect on bone mineral density and reproductive function was seen. Treatment neither caused nor aggravated obesity.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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Depot preparations of GnRH agonists have been available since the mideighties and have become the treatment of choice for CPP. The suppressive effect on the pituitary-gonadal axis has been well documented (9, 10), and its reversibility has been demonstrated (10, 11, 12). To date, a considerable number of CPP patients treated with depot GnRH agonists for many years have reached final height (FH) and adult age. Follow-up investigations show different results with regard to the effect and benefit of GnRH agonist therapy. The topic of FH improvement is still discussed controversially in the literature (13, 14, 15, 16, 17). It has been demonstrated that a constantly and fully suppressed hypothalamic-pituitary-gonadal axis is the prerequisite for height improvement (18).
With regard to the effect of GnRH agonist treatment on bone mineral density (BMD), which is influenced by exposure to gonadal sex steroids (19), Italian researchers reported a significant bone loss during therapy (20, 21, 22). Reversibility of the reduction in BMD has not yet been demonstrated. However, the investigation of a small group of CPP patients at FH suggested no impairment of peak bone mass (23). Important additional outcome parameters are reproductive function (24), appearance of polycystic ovaries (PCO) (25, 26) and PCO syndrome (27), as well as body proportions and body composition.
The aim of the present prospective multicentric study was to evaluate the outcome after long term GnRH agonist therapy not only with respect to FH but also in terms of body proportions and body composition, BMD, and reproductive function in former CPP patients at young adult age.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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Fifty young women (mean ± SD age, 16.7 ± 2.6 yr; range, 12.9 to 23.4 yr) were studied at FH. In a multicentric prospective trial, they had been treated for progressive CPP for a mean duration of 4.4 ± 2.1 yr (range, 1.0–9.7 yr). End of treatment was at a mean age of 11.0 ± 1.1 yr (range, 8.8–13.9 yr). The present follow-up study was carried out 5.7 ± 2.8 yr (range, 1.2–11.0 yr) after the end of treatment. The observation period after the end of therapy comprised 286 patient years.
Main criteria for the diagnosis of CPP were 1) secondary pubertal signs
before the chronological age (CA) of 8 yr, 2) accelerated growth rate,
3) advancement of bone age (BA) more than 1 yr above CA and a
BA/CA ratio more than 1.2, and 4) a pubertal response to
exogenous GnRH with a LH peak above 11 IU/L (28) and a ratio of
stimulated LH/stimulated FSH more than 1.0 (29, 30).
Clinical data of the patients before treatment are summarized in Table 1
. GnRH agonist treatment was initiated
after an observation period of up to 6 months to rule out transient or
slowly progressive forms of CPP.
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Patients were treated for progressive CPP in a prospective multicenter trial with depot triptorelin (D-Trp6-LHRH, Decapeptyl Depot, Ferring Pharmaceuticals Ltd., Kiel, Germany) (10). For ethical reasons, an untreated control group was not available. Injections were given im every 30 ± 2 days in a dose of 75 µg/kg BW. Suppression of pituitary-gonadal function was monitored by standard GnRH tests performed every 6 months over the entire treatment period. GnRH tests were performed 4 weeks after the last Decapeptyl injection (before the next injection). Adequate suppression was defined as a stimulated plasma LH level below 5 IU/L and an estradiol plasma level below 50 pmol/L.
Treatment started at age 6.7 ± 2.0 yr (range, 2.1–9.0 yr). Sufficient suppression of the hypothalamic-pituitary-gonadal axis was achieved in all patients. Therapy was discontinued in most cases at an age when normal puberty could be expected (11.0 ± 1.1 yr), the last individual predicted adult height (PAH) was within the TH range, and/or BA was above 15 yr. FH was defined as height velocity below 1 cm/yr and/or BA above 15 yr.
Methods
Pubertal stages were determined according to Marshall and Tanner (31). Height and sitting height (SH) were measured with a stadiometer. German longitudinal normative data were used as standards for height and growth velocity (32, 33), and the longitudinal normative data of Prader et al. (34) were used as standards for SH and lower leg length (LLL). BA was estimated by the method of Greulich and Pyle (35), and PAH was calculated according to the method of Bayley and Pinneau (36). BAs were read centrally by one blinded experienced investigator. TH and TH range (±8.5 cm) were determined according to Tanner et al. (37).
The normative data of Rolland-Cachera et al. (38) were used for calculating the body mass index [BMI; weight (kilograms)/height (meters)2] SD score.
Plasma gonadotropins and estradiol were determined centrally by RIA or enzyme immunoassay at the Endocrine Laboratory of the University Department of Pediatrics (Kiel, Germany). The sensitivity of the enzyme immunoassay was 0.3 IU/L for LH and FSH (28). A value of 0.2 IU/L was assigned to LH and FSH below the detection limit. The detection limit of estradiol was 15 pmol/L. A value of 14 pmol/L was assigned to samples below the detection limit.
Ovarian structure and volume were assessed by pelvic ultrasound, using the normative data reported by Salardi et al. (39) and Polson and co-workers (40). PCO syndrome was suspected on the basis of clinical features according to Franks (41).
Menstrual pattern and the psychosocial situation were evaluated in a semistructured interview.
BMD was assessed using the technique of dual energy x-ray absorptiometry (DXA) at lumbar spine (L1–L4) and right femoral neck. DXA machines from Lunar Corp. (Madison, WI) and Hologic, Inc. (Waltham, MA), were used in the participating centers. The DXA machine from Hologic, Inc. (QDR-4500A, fan-beam DXA), located at the Radiology Department, University of Kiel, equipped with adult and children software for lumbar spine and adult software for right femoral neck, was assigned as a reference instrument.
A spine phantom for cross-calibration was measured in every participating center. A coefficient was calculated to standardize BMD measurements according to the reference instrument. To obtain equivalency of BMD (grams per cm2) between the Lunar Corp. and Hologic, Inc., instruments we used the following equations to convert manufacturer-specific BMD units (grams per cm2) into standardized BMD units (sBMD; milligrams per cm2): spine: Hologic, Inc., instrument, sBMD = 1000 (1.0755 BMD Hologic, Inc.); Lunar Corp. instrument, sBMD = 1000 (0.9522 BMD Lunar Corp.) (42); femoral neck: Hologic, Inc., instrument, sBMD = 1000 (1.008 BMD Hologic, Inc., +0.006); Lunar Corp. instrument, sBMD = 1000 (0.979 BMD Lunar Corp., -0.031) (43). Quality requirements for BMD were monitored by daily measurements of a spine phantom during the study period.
The Hologic, Inc., normative data, based on CA, were used as reference for lumbar spine BMD; for femoral neck BMD, the normative data of Faulkner et al. (44) were used until the age of 21 yr. From age 22 yr onward, Hologic, Inc., normative data were used. For comparison with patient data, the reference data were transferred into sBMD.
Body composition was determined by DXA as bone mineral content (BMC), fat, and lean mass.
Statistics
Statistical comparison of different parameters was performed by one-way ANOVA. In those cases where the data showed a significant deviation from the normal distribution, Kruskal-Wallis one-way ANOVA on ranks was performed as a nonparametric test. Dunn’s test was used as a post-hoc test for evaluation of statistical differences between two parameters.
In the case of longitudinal comparison of the same parameter, repeated measures ANOVA was performed. If normal distribution was not present, Friedman’s ranked ANOVA was applied. For evaluation of statistical differences between two time points, the Student-Newman-Keuls test was used as a post-hoc test (SigmaStat 2.0, Jandel Scientific, Erkrath, Germany). Fisher’s exact test was used to analyze the number of patients reaching their individual TH range. Data are presented as the mean and SD. P < 0.05 was considered significant.
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Results |
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FH
Mean FH was 160.6 ± 8.0 cm (-1.3 ± 1.6 height
SD score; Fig. 1 and Table 2). Of the 50 patients, 47 reached a FH
above 150 cm. FH was significantly higher than PAH at the start of
treatment (154.9 ± 9.6 cm; -2.4 ± 1.9 SD
score). FH was not significantly different from TH, which was
163.6 ± 6.2 cm (-0.7 ± 1.2 SD score).
Thirty-nine of 50 patients (78%) reached their individual TH range
(Table 3). The mean age at the start of
treatment of the 11 patients who did not reach their individual TH was
5.5 ± 2.5 yr. The mean height gain (FH minus initial PAH) was
5.9 ± 8.5 cm.
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The mean pretreatment BA advancement was 3.7 ± 1.8 yr in subgroup
I and 2.6 ± 1.3 yr in subgroup II (P < 0.05).
There was a significant correlation (r = 0.734; P
< 0.0001) between BA acceleration at the start of treatment (BA
- CA) and height gain (FH - initial PAH; Fig. 2). The age at first pubertal signs in
subgroups I and II was 5.7 ± 1.9 yr (range, 1.9–8.0 yr) and
4.8 ± 2.2 yr (range, 0.5–5.5 yr), respectively. There was no
significant difference in the age of onset of puberty between subgroup
I and subgroup II. The patients in subgroups I and II were tall for CA
(mean height SD scores for CA, 1.2 ± 1.9
and 2.2 ± 1.9, respectively; P = NS), but short
for BA. Patients in subgroup I were significantly shorter than those in
subgroup II (mean height SD score for BA,
-3.0 ± 1.2 and -1.1 ± 1.4, respectively;
P < 0.05). The rate of bone maturation (BA/CA)
was not significantly different in the two groups at the start of
treatment (subgroup I, 2.43 ± 1.52, subgroup II, 2.00 ±
1.23) and, thus, did not predict treatment benefit in FH (r =
0.144; P = NS).
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and 3). Body proportions
SH SD score and LLL SD score were -0.5 ± 1.6 and -0.6 ± 1.3, respectively. The SD score of the ratio of SH and LLL was 0.3 ± 1.2, demonstrating normal body proportions.
Reproductive function
Menarche or re-menarche started at age 12.3 ± 1.4 yr. Time duration between last injection of depot GnRH agonist and menarche was 1.1 ± 0.9 yr (range, 0.1–5.8 yr).
The history of menstrual patterns showed that 1 of 50 patients suffered from metrorrhagia, and 2 suffered from oligomenorrhea due to bulimia and anorexia. Nine patients reported irregular cycles, with bleeding intervals between 3 and 7 weeks, 5 of them were therefore treated with contraceptives.
Two patients gave birth to healthy, mature, singleton children after normal pregnancies. Ultrasound investigations were performed on 34 patients. Ovarian volume was above 10 mL in 20.5% (7 of 34) of patients; in 2 of them more than 10 microcysts were observed. One of these 2 patients was obese and had an elevated basal LH level of 28.2 IU/L, and mild 3ß-hydroxysteroid dehydrogenase deficiency was diagnosed. There was no significant difference between the mean ovarian volume of patients with normal menstrual patterns and that of those who reported irregularities (7.0 ± 4.5 vs. 8.5 ± 7.7 mL; P = NS).
We used the clinical definition reviewed by Franks to identify patients with PCO syndrome (41). PCO syndrome is the association of hyperandrogenism with chronic anovulatory cycles in women without specific underlying diseases of adrenal or pituitary glands. Two patients fulfilled these criteria. Ultrasound investigation of internal genitalia in one of them showed evidence of PCO. At the date of investigation she was treated with a combination of cyproterone acetate and ethinyl estradiol. This patient was not obese. The ultrasound investigation in the other patient was not successful for technical reasons.
Single symptoms of PCO syndrome were observed in 14 patients. Six of them had acne, and the other 8 suffered from irregular menses; 3 were obese (BMI SD score, >2).
BMD
Investigations of sBMD were carried out in 41 patients at the
lumbar spine (L1–L4) and in 38 patients at the right femoral neck. The
sBMDs for L1–L4 and femoral neck were 1040.9 ± 124.2 and
902.2 ± 115.4 mg/cm2, respectively (Fig. 3). The corresponding SD
score for L1–L4 and femoral neck was 0.0 ± 1.0 (range, -1.9 to
2.0 SD score) and 0.2 ± 1.0 (range, -1.9 to 2.3),
respectively. With respect to WHO recommendations concerning osteopenia
(BMD between -1.0 and -2.5 SD score) and osteoporosis
(BMD below -2.5 SD score) (45), 7 patients had a sBMD
SD score below -1 SD score (6 at lumbar spine
and 3 at femoral neck). Four of 6 patients who had low sBMD levels at
lumbar spine showed normal sBMD at femoral neck. Osteoporosis was not
observed.
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BMI was 18.2 ± 2.7 kg/m2 before treatment, 21.3 ± 3.7 kg/m2 at the end of treatment, and 24.5 ± 5.7 kg/m2 at FH. The BMI SD score for CA did not change significantly during GnRH agonist therapy (2.0 ± 2.0 before treatment, 2.1 ± 1.9 at the end of treatment, and 1.7 ± 2.2 at FH).
In 27 patients (mean age, 17.5 ± 2.8 yr; range, 13.2–24.4 yr), body composition was measured by DXA as BMC, fat, and lean mass. Total BMC was 3.1%, fat mass was 37.1%, and lean mass was 59.8% of total body weight.
Psychosocial situation
Patients were requested to assess their situation with regard to quality of life. All patients reported good self esteem; none had severe problems at the time of interview. None was unemployed or had dropped out of the educational system. One patient reported a period of bulimia, and another reported an anorectic reaction in the past.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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FH
Approximately 80% of our patients reached a FH within their TH range. Before treatment the initial PAH was within TH range in 28 of 50 patients only (56%). Of the 11 patients who did not reach their TH range, 9 had a PAH below their TH range at the start of therapy.
In those patients who had an initial height prediction below their TH range, a high initial BA advancement and a low height SD score for BA were seen, compromising FH. However, 60% of this group reached a FH within their genetic height potential. Only two patients whose initial PAH was within the TH range, showed a FH below their TH range. Thus, GnRH agonist treatment preserved height potential within the genetically determined range in the majority of patients (46) and improved FH compared with the TH in patients with an unfavorable initial PAH.
Various attempts have been made to identify the patient groups that benefit the most with respect to height gain and acceptable FH. The age at onset of CPP and at the start of therapy were important predictors of FH outcome (13, 15, 47). Paul et al. (15) demonstrated that girls in whom therapy was started before a CA of 5 yr reached a FH of 164.3 ± 7.7 cm, whereas patients who were older than 5 yr reached a FH of only 157.6 ± 6.6 cm. FHs of 160.4 and 157.5 cm were reported for girls younger and older than 6 yr at the onset of puberty, respectively (13). These FH results were not significantly different. The validity of this report is compromised by the fact that Kletter et al. (13) used heterogeneous data collected from numerous centers from the U.S. and Europe.
We analyzed our patients with respect to the age of onset of pubertal signs and divided them into subgroup III (pubertal signs before age 5 yr) and subgroup IV (pubertal signs after age 5 yr). FH was not significantly different between subgroups III and IV. However, 58% of the young patient subgroup (III) whose PAH was below the TH range reached a FH within their TH range. Subgroup III showed a significantly higher height gain of 12.2 ± 10.7 cm compared to 3.9 ± 7.8 cm in subgroup IV. These findings are in accordance with those of Paul et al. (15), who found, using first short acting and later depot GnRH agonists, a comparably high height gain in the young patient group. In contrast, Carel et al. (47), using depot triptorelin, did not find a better height gain in their 16 female patients below 6 yr at the start of puberty.
In addition, patients were analyzed in two subgroups, which were defined as initial PAH within or below the individual TH range. It was clearly shown that patients with a height prognosis at the start of treatment below the TH (subgroup I) and a short stature for their advanced BA did benefit from depot GnRH therapy with a mean height gain of 8.7 ± 9.6 cm, whereas subgroup II (initial PAH within TH range) achieved a height gain of 2.3 ± 7.3 cm only. FH in subgroup I was significantly higher than initial PAH, whereas FH in subgroup II did not differ significantly from PAH. The age distributions at the onset of CPP were similar in the two groups (P = 0.159).
We therefore conclude that the age at onset of CPP, the initial bone age advancement, and the initial deficit in height potential compared to TH are strong determinants for defining patients who will benefit the most from depot GnRH agonist therapy with respect to the auxological outcome.
Body proportions
Historically, groups of untreated CPP patients have shown a characteristic body disproportion, with short limbs compared to relatively normal trunk length (7, 48, 49). In contrast, our GnRH agonist-treated patients reached a mean SD score of the SH/LLL ratio within the normal range. Only 2 of 40 patients (5%) showed abnormal body proportions (+2.7 and +3.4 SD score). Thus, depot GnRH agonist treatment prevents disadvantageous body proportions in the vast majority of patients with CPP.
Reproductive function
Our investigations confirm previous reports that the hormonal suppression achieved with the GnRH agonist is fully reversible (12, 16, 27, 50, 51). Menses started spontaneously in all patients after the end of treatment.
It has been observed by others and is important to note (12, 24, 26) that the ovarian volumes were larger than those in normal girls (39) and were comparable in size to the upper normal range in women (40). The prevalence of enlarged ovaries was 20.5% in our patient group. However, only 6% of our patients had more than 10 ovarian microcysts. In asymptomatic healthy women, a PCO prevalence of 23% was reported (40). Literature data with respect to the occurrence of PCO in CPP patients are quite heterogeneous. Boepple (27) observed PCO in approximately half of the patients after GnRH agonist therapy, Bridges et al. (25) reported a prevalence of 24% of PCO during GnRH agonist therapy compared to only 2% in an age-matched control group, whereas Baek-Jensen et al. (26) did not observe any PCO during or after treatment with GnRH agonist.
The incidence of PCO syndrome after GnRH agonist therapy in patients with CPP, defined as the association of hyperandrogenism with chronic anovulatory cycles in women without specific underlying diseases of adrenal or pituitary glands (41), has not been evaluated to date. We found no increased incidence of PCO syndrome in our group (one patient only) compared to that in healthy women (41).
BMD
A significant decrease in BMD during long acting GnRH agonist therapy was reported in women with endometriosis and in men with benign prostatic hyperplasia (52, 53). In children with CPP, several investigators observed an increased BMD for age (20, 54), but appropriate BMD for BA (21, 22, 55). However, a low BMD for BA before treatment was also reported (56). Mean lumbar spine BMD exceeded the normal mean for CA in untreated CPP patients at an age between 6.0–11.3 yr, but was decreased when adjusted to BA (57). Some investigators did not find a significant change during treatment (55, 56), whereas Italian researchers observed a significant decrease (20, 21, 54).
Our findings of normal BMD for age at lumbar spine and femoral neck confirm previous data in a relatively small group of patients at a younger age (13.4 ± 1.0 yr) (23). Our investigation of CPP patients with a mean age (16.7 ± 2.6 yr) close to the physiological age of peak bone mass (58, 59) showed that long term depot GnRH agonist treatment is not associated with a reduction of mean BMD compared to normative age-related data. It must be noted that 15% and 7.5% of our patients were between -1.0 and -2.5 SD score for BMD (osteopenic) at lumbar spine and femoral neck, respectively. However, the prognostic significance of the measuring site for the development of osteoporosis in this age group is still unclear. It is reassuring that none of the patients was osteoporotic (BMD below -2.5 SD score).
Body composition
Patients with CPP are obese compared to normal girls of similar age, and some researchers observed increased obesity during therapy exceeding the weight development of normal girls (24). The mean BMI SD score of our patients was increased before treatment, but did not change significantly during therapy. It has been shown that the BMI gives a relatively imprecise estimate of body fat mass (60). Body fat mass at FH, determined by more precise DXA measurements, was 37% in our patients, which represents approximately double the fat mass of healthy girls at Tanner stage 5 (61, 62). Thus, obesity is a common problem in girls with CPP. However, obesity does not seem to be aggravated by GnRH agonist treatment.
We conclude that long term treatment of CPP with the depot GnRH agonist triptorelin improves FH, preserves height potential, and prevents unfavorable body disproportion. In particular, young patients with a low initial height prediction benefit most. No negative effects on BMD and reproductive function were observed. Our observation of enlarged ovarian volume is noteworthy and difficult to interpret. Further studies are necessary to investigate this finding. GnRH agonist therapy does not cause or aggravate obesity. The overall psychosocial situation and quality of life appear to be within normal limits.
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Erratum |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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The Clinical Neuroscience Branch, National Institutes of
Health, Bethesda, Maryland 20892 should have been listed as the first
affiliation. The revised versions of figures 2 and 3 were inadvertently
omitted from the article. The correct figures and legends appear here.
The printer regrets the errors.
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Acknowledgments |
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Footnotes |
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Received July 21, 1999.
Revised August 27, 1999.
Accepted September 17, 1999.
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References |
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