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Original Studies |
Department of Pediatrics, University of Bologna, 40138 Bologna, Italy
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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Therapy regimens
Patients with TS were divided into three groups (Table 1
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Group A2 consisted of 27 patients, who, before the treatment with high doses of GH, were treated with a combination of GH at low doses for 1.2 ± 0.9 yr (range, 0.5–4.7) and ethinyl estradiol (100 ng/kg·day for 0.9 ± 0.4 yr; range, 0.3–1.8) in 17 patients or oxandrolone (0.05 mg/kg·day for 1.8 ± 0.7 yr; range, 0.8–3.0) in 10 patients.
The karyotypes of the patients of group A were 45,X (55%), X mosaicism
(10%), and X structural abnormalities (35%; Table 2). Forty-five patients of this group had
an evaluation of endogenous GH secretion and underwent 2
pharmacological tests (arginine and L-dopa), 13 of them
were GH deficient (GH peak <8 µg/L in both tests), as previously
reported (13, 14), whereas 32 were not. Our patients were evaluated for
GH secretion without estrogen priming (14). Thirty-five patients were
followed longitudinally for ovarian data with real-time pelvic
ultrasonography and were evaluated for the spontaneous appearance of
breast stage 2 or greater; 24 patients had no gonadal activity and 11
patients showed transient ovarian function (detectable ovaries,
spontaneous breast development, but not spontaneous menarche). Four of
these 11 patients were not given sex steroid replacement therapy,
because they demonstrated low gonadotropin levels, at least until they
reached final height. In 63 patients parental height was available to
calculate TH. For 53 patients of group A birth weight was recorded, and
they were divided into 3 groups: normal weight subjects (10th-90th
percentile; n = 40), small for gestational age (SGA; <10th
percentile; n = 7), and large for gestational age (LGA; >90th
percentile; n = 6) subjects. Furthermore, we considered separately
the patients that had completed at least 4 (n = 30) and 6 (n
= 10) yr of therapy (Table 3). All of
these patients began estrogen therapy after 14 yr of chronological
age.
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and 3). Nineteen of them received a combination of GH and
estrogen for a mean period of 1.81 ± 1.32 yr (range, 0.3–5.2
yr), 15 received GH plus oxandrolone for 1.8 ± 0.9 yr (range,
0.5–4.2 yr), and 17 received GH alone. Karyotypes were 45,X (36%),
X-mosaicism (16%), and X-structural abnormalities (48%).
Group C (Tables 1 and 2). Ten patients were treated with
high doses of GH for more than 2 yr and experienced spontaneous
menarche. Five patients had previously received low doses of GH for
1.1 ± 0.3 yr (range, 0.8–1.5 yr), and 1 patient had received
oxandrolone for 2.5 yr. Karyotypes were 45,X (20%), X-mosaicism
(30%), and X-structural abnormalities (50%). At pelvic
ultrasonography all of them showed detectable ovaries.
In patients of all groups GH therapy was given with six or seven weekly injections sc. In the patients without spontaneous menarche, puberty was induced at a bone age above 13 yr, taking into account the psychological situation of each patient, giving at the beginning only ethinyl estradiol at a dose of 100 ng/kg·day, then 200 ng/kg·day. Once an acceptable uterine maturation was reached, medroxyprogesterone was added to ethinyl estradiol from the 11th to the 21st day of the cycle. At the discontinuation of every cycle of treatment menses occurred regularly.
Growth and bone age were evaluated each year. The mean final height of untreated Italian girls with TS is 142.5 cm (15). Height SD score was calculated from these Turner-specific standards.
Projected adult height was calculated by the method of Lyon et al. (3), using the SD score for chronological age (standards for Italian girls with TS). Height was measured using a Harpenden stadiometer. Bone ages were analyzed according to the method of Greulich and Pyle (16).
Statistical analysis
For statistical analysis, the computer program Statistical Package for Social Science (SPSS, Inc., Chicago, IL) was used. Mean and SD values were calculated for each baseline parameter and after each year of therapy. Statistical significance was assessed using Student’s t test and ANOVA. All results nominally significant at P < 0.05 were indicated.
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Results |
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, the data for patients of group A (74 patients) with
the 2 subgroups (A1 and A2), and of groups B and C are summarized. In
contrast to the patients of groups B and C, the patients of group A
showed a significantly higher final height than their projected height.
They also showed a significantly higher final height (centimeters
andSD score) and a greater height SD score
increment (final height SD score - pretherapy
height SD score) compared to the subjects of groups B and
C. Pretreatment projected height was not significantly different in the
3 groups. Among the patients of group A, the best results were obtained
by the patients of group A1 treated with GH alone. Bone ages at final height were determined for only some patients, and no difference was found between the therapy groups (group A, n = 49; group A1, n = 30; group A2, n = 19; group B, n = 20; group C, n = 8).
The height SD score increment correlated positively with the years of duration of high dose GH treatment (P = 0.0001) and negatively with pretreatment bone age (P = 0.006).
Table 2 summarizes auxological data before therapy and final height
results in the 74 patients of group A subdivided by karyotype, GH
secretion, birth weight, ovarian activity, and TH less than or more
than 160 cm and in 10 patients with spontaneous menarche (group C).
Final height, projected height, and pretreatment height SD score were significantly higher in the patients with GH deficiency than in the patients without GH deficiency, in normal weight subjects than in SGA, and in the patients with TH above 160 cm than in the patients with TH below or equal to 160 cm. The patients with spontaneous menarche had a significantly lower final height than the patients without ovarian activity.
Table 3 shows auxological data before therapy and the final height
results in 51 patients of group B compared with patients from group A,
who were treated with high doses of GH, 30 of them for at least 4 yr
and 10 for 6 yr. At ANOVA final height was significantly different in
the 3 groups. In particular, the subjects treated for 6 yr showed a
significantly higher final height than the patients treated for 4 yr
and the patients of group B. Furthermore, the patients treated for 4 yr
had a significantly higher final height than the patients of group B.
No differences were found in pretreatment height SD score
and projected height in the groups considered, even though the group B
patients were older both in chronological and bone age than group A
patients at the start of therapy.
In Table 4 the pretreatment values for
chronological age, bone age, height, and projected height are reported
with the final height and the TH in 30 patients treated with high doses
of GH therapy for at least 4 yr, subdivided by chronological age less
than or equal to or more than 11 yr and by bone age less than or equal
to or more than 9.5 yr. The patients treated at younger chronological
and bone ages showed a higher final height, although no statistically
significant differences were found between the 2 groups.
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) showed a final
height below 142.5 cm (50th percentile for untreated Italian TS girls)
(15). There was no difference in the percentage of these patients in
the various therapy groups. The number of patients with
X-mosaicism was no higher in the group with final height below
142.5 cm than in the group with final height above 142.5 cm, and no
differences were found in the number of patients who required sex
steroid replacement therapy. However, with the multiple regression
analysis it was possible to see that a poorer outcome was mainly
influenced by the low TH (t = 3.82; P =
0.0004) and by a higher prevalence of spontaneous ovarian activity
(t = 2.1; P = 0.04) and not by
karyotype.
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Discussion |
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In each therapy group some patients demonstrated an unsatisfactory result. In fact, some of them reached a final height below 142.5 cm (15). The percentage of these patients was not different in the various therapy groups considered. Among the predictive factors that influenced this result negatively, the low TH and the high prevalence of spontaneous ovarian activity are the only ones with statistical relevance. In any case a progressively better height SD score increment was reached in those patients treated with high dose GH, and a high positive correlation was found with the duration of the therapy and the younger pretreatment age.
The reasons for short stature in TS subjects have not yet been completely clarified. However, both hormonal status and an intrinsic bone factor linked to the loss of material on the X chromosome have been suggested. The study of growth factors in subjects with TS suggest a reduced secretion of GH, although at differing ages (19, 20). If this pattern of GH behavior has an effect on growth, the results of GH therapy and pretreatment auxological status should be different in patients with a GH deficit from those in patients with normal GH secretion. This seems to be confirmed by our study; the 32 patients with normal GH reached a mean final height of 145.4 cm, whereas that of the 13 patients with pathological GH secretion was 149.5 cm (P = 0.03). However, considering the initial height SD score and the projected height, we found that both of these values were significantly higher (P = 0.006) in the group with GH deficit than in the group with normal GH. This seems to suggest that GH secretion did not significantly affect the growth of the patients examined before or during therapy, in agreement with the work of Schmitt et al. (21).
In our patients the factors that seem to influence the improvement in final height are TH and the absence of spontaneous ovarian activity or menarche. This is shown by the well known positive correlation between TH and final height, by the different final heights of our patients, subdivided according to TH more than 160 cm or 160 cm or less. This is confirmed by the finding that the patients in each therapy group who had a final height below 142.5 cm showed a lower TH and a higher prevalence of spontaneous ovarian activity than the patients with a final height above 142.5 cm.
Other important genetic factors influence the growth of these patients. Weight for gestational age clearly affects final height. This is not due to an unsuccessful response to therapy, but to the fact that SGA are probably already conditioned at birth. In fact, the difference between projected and final heights is the same in normal subjects and SGA, but the final height of the latter is significantly lower (P = 0.03) than that of normal subjects.
In our series, considering the 30 patients with at least 4 yr of high dose GH therapy subdivided by chronological age less than or equal to or more than 11 yr and bone age less than or equal to or more than 9.5 yr at the start of treatment, no differences between the final heights of the 2 groups were found, as reported by Haeusler et al. (22). Unfortunately, the small number of cases and the many variables characterizing the 2 groups (therapy duration, karyotype pattern, height SD score by chronological age at the start of treatment, TH) make it impossible to give a statistical significance to these results. Nevertheless, there is a positive correlation between height SD score increment and the duration of high dose GH treatment, particularly at a younger bone age. Perhaps only a multicenter study will be able to state the importance of the optimal duration of GH therapy and the age for starting treatment. In fact, the different studies published are discordant (6, 23, 24, 25, 26, 27, 28) with regard to the correlation between age at start of therapy and statural gain, with different effects of the therapy on bone maturation at different ages (4, 18, 28, 29, 30, 31). As observed by Rochiccioli et al. (7), our series did not show any apparent differences in the final heights reached by patients subdivided by karyotype. Therefore, the numerous variables that affect auxological outcome, in the three different karyotype groups make the results less significant.
In conclusion, this study seems to show that GH therapy provides a satisfactory auxological result, especially with high doses and long periods of GH alone, even though we used GH doses lower than those recommended in the U.S.
We suggest postponing the addition of estrogens as long as possible, taking into consideration the psychological situation. The use of small doses of oxandrolone is not effective in our experience. GH secretion did not influence final height in our patients, and we may conclude that pretreatment GH provocative tests are not useful and need not be performed. A low TH and a high prevalence of a spontaneous ovarian activity or menarche are to be considered as predictive factors that may negatively influence the effect of GH therapy on final height. Optimization of the treatment requires identification of the ideal age for starting therapy, and this is only possible with a specially designed multicenter study.
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Acknowledgments |
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Footnotes |
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1 Participating investigators: The Italian Study Group for Turner
Syndrome: Rosalba Bergamaschi, M.D., Annamaria Perri, M.D., and
Emanuela Scarano, M.D. (Bologna); Giuseppe Chiumello, M.D., and Maria
Pia Guarnieri, M.D. (Milan); Franco Rigon, M.D., and Anna Licursi, M.D.
(Padova); Anna Maria Pasquino, M.D., and Ida Pucarelli, M.D. (Rome);
Salvatore Di Maio, M.D., and Mariacarolina Salerno, M.D. (Naples);
Francesca Severi, M.D., and Daniela Larizza, M.D. (Pavia); Francesco
Prisco, M.D. (Naples); Sergio Bernasconi, M.D. (Parma); Fabio Buzi,
M.D. (Brescia); Patrizia Matarazzo, M.D. (Torino); Luciano Cavallo,
M.D. (Bari); Giuseppe Saggese, M.D. (Pisa); Giorgio Tonini, M.D.
(Trieste); Maria Carlotta Ragusa, M.D. (Catania); Maddalena Sposito,
M.D. (Perugia); Orazio Gabrielli, M.D. (Ancona); Fabrizio De Matteis,
M.D. (L’Aquila); Lodovico Benso, M.D. (Torino); Brunetto
Boscherini, M.D. (Rome); Giorgio Radetti, M.D. (Bolzano); Carmelo La
Cauza, M.D. (Firenze); Filippo De Luca, M.D. (Messina); Patrizia
Borrelli, M.D. (Rome); Francesco Morabito, M.D.
(Piancavallo); and Gianni Bona, M.D. (Novara). 
Received December 1, 1998.
Revised June 28, 1999.
Accepted July 7, 1999.
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References |
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