1 University Hospital for Children and Adolescents, Erlangen, 2 Paediatric Endocrinology Section, University Children's Hospital, Tübingen, 3 University Children's Hospital, Heidelberg, 4 Department of Paediatric Haematology/Oncology and Endocrinology, University Children's Hospital, Essen, 5 University Children's Hospital, Munich, 6 Paediatric Endocrinology, University Children's Hospital, Kiel and 7 Pfizer Corporation, Karlsruhe, 8 University Children's Hospital, Hamburg, Germany
9 To whom correspondence should be addressed at: Paediatric Endocrinology, University Hospital for Children and Adolescents, Loschgestr.15, D-91054 Erlangen, Germany. Email: hgdoerr{at}kinder.imed.uni-erlangen.de
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Abstract |
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Key words: estrogen therapy/gonadal dysgenesis/Turner syndrome/uterine size
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Introduction |
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Thus, our present analysis focused on uterine growth assessed by ultrasonographic imaging in young adult women with TS after induction of puberty with estrogens and therapy with human growth hormone (hGH). The auxological data of the identical women after hGH therapy were reported recently (Ranke et al., 2002).
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Materials and methods |
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In addition to anthropometric data, data were collected voluntarily for uterine size. Thus, out of a total of 188 TS women returned for examination, complete data on uterine length and volume were provided for 75. In all, puberty had to be induced with estrogens. For pubertal induction either low-dose ethinylestradiol (n=18), conjugated equine estrogen (n=17) or estradiol valerate (n=38) was used. In two women, a combined oral contraceptive was used to induce puberty. After 1218 months on estrogens, cyclic progesterone was added to mimic a normal menstrual cycle. At the time of the follow-up study, 66/75 women were on cyclic estrogen and progestin supplementation, n=2 (karyotype 45,X) received no estrogens, and data were missing for n=7 (karyotype 45,X).
The evaluation of uterine size by pelvic ultrasonography was carried out transabdominally within the participating institutions. An illustration of the requested planes was provided to the physicians in order to standardize the measurements of the uterus in the transverse, sagittal and longitudinal planes. Uterine length was reported in cm, and uterine volume was calculated by the formula: volume (ml)=transverse width x sagittal width x length x 0.5. The data on uterine length and volume were transferred into standard deviation score (SDS) values using reference values published by Pelzer for healthy German girls (Pelzer, 1991).
The anthropometric data were analysed according to previously described criteria (Ranke et al., 2000). We applied the height references for TS of Ranke et al. (1988)
. Standard deviation scores for ages were calculated. Pubertal development was assessed according to Tanner puberty stages. Medians and ranges are given, and one-way analysis of variance (ANOVA) was used to obtain P values. P<0.05 was considered significant.
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Results |
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It has been reported that the uterus measures between 5 and 8 cm after puberty in young healthy nulliparous adolescents (Cohen and Haller, 1989). Comparing our data with these values, 42/50 (84.0%) TS women with karyotype 45,X had a normal length, but 8/50 (16%) had a smaller uterus. All four women with karyotype 45,X/46,XX, 3/6 with 45, X/46,X,i(Xq), and 4/6 with 45,X/46,XY had a normal uterine length. Overall, 13/66 (19.6%) who received estrogens had a reduced length <5 cm. With respect to the data published by Pelzer (1991)
, which we used as reference for SDS calculations, 13/50 (26%) of the TS women with karyotype 45,X had a uterine length <2 SDS, and 9/50 (18%) a volume <2 SDS. In order to evaluate uterine size at follow-up, the variables' uterine length and volume were correlated with various parameters during the course of treatment, e.g. age at start of estrogens, age at cyclic substitution, duration of estrogens, and Tanner breast stage for TS girls with karyotype 45,X. No significant correlations between uterine size and the studied parameters were found. Also, final height data available for all patients showed no correlation between uterine size and height.
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Discussion |
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It was postulated that estrogens given at the age when puberty normally occurs might normalize uterine size in young TS women (McDonnell et al., 2003). Our data contrast with these data. The difference could be explained by the facts that the studied women were younger at last examination than ours, and that 5/18 girls had normal spontaneous puberty, whereas puberty was induced in all our women. Paterson et al. (2002)
found that estrogen therapy in Turner girls enhanced linear growth of the uterus but normal maturation was not achieved, and the uterus remained hypoplastic in half the girls. Recently published data by Snajderova et al. (2003)
confirmed this observation.
It was shown that GH treatment itself had a positive effect on uterine size in young TS girls in comparison to untreated girls (Sampaolo et al., 2003), whereas Snajderova et al. (2003)
found no effect of GH therapy on uterine size. Uterine sizes in our women after GH therapy correspond well to published data of TS women without GH therapy.
There is no doubt that adequate estrogen substitution is important to achieve a normal uterine size. However, the evidence showing that estrogen replacement for the induction of puberty limits further gains in height has postponed the introduction of estrogens in Turner girls on GH therapy (Cacciari and Mazzanti, 1999; Chernausek et al., 2000
). With respect to uterine size, it remains speculative whether an earlier low-dose estrogen substitution might induce a normal size in all women. On the other hand, there is also increasing evidence that even pre-pubertal ovaries of healthy girls are producing small amounts of estradiol. By using an ultrasensitive estradiol assay, it was shown that TS girls between the ages of 5 and 12 years have significantly lower levels of estradiol than normal pre-pubertal girls (Wilson et al., 2003
). Therefore, it could be speculated that a physiological secretion of small amounts of estradiol even through infancy is necessary for the development of a normal uterine size.
It might also be of interest to analyse the used estrogens for pubertal induction, since it has been shown that normal uterine maturation occurred in only 50% of girls who received a treatment protocol using low-dose oral ethinyl estradiol (Paterson et al., 2002). Additionally, positive effects on uterine development in relation to a higher daily dose of estrogen during the post-menarcheal period were reported (Snajderova et al., 2003
).
Structural anomalies of the uterus in some TS women may also prevent a normal uterine development. This is supported by data showing that uterine dimensions in TS girls with spontaneous puberty increased with advancing puberty but remained lower than values in a control group (Mazzanti et al., 1997; Haber and Ranke, 1999
). It is also interesting that in relation to poor uterine development, breast development was also impaired in 18.6% of our women with karyotype 45,X and stopped at Tanner stage 3, despite appropriate estrogen replacement therapy. Since onset and course of breast development and uterine growth are closely correlated (Bridges et al. 1996
), our results are in agreement with the hypothesis of a disturbance affecting the uterine anlage as well as the mammary anlage.
In conclusion, our data show that only TS women with karyotype 45,X/46,XX had normal uterine sizes, whereas 26% of the TS women with karyotype 45,X had a reduced uterine length (<2 SDS), and 18% a reduced volume (<2 SDS). However, the data also show that the majority of young adult TS women with different karyotypes can achieve normal adult uterine dimensions with the use of adequate HRT.
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Acknowledgements |
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References |
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Cacciari E and Mazzanti L (1999) Final height of patients with Turner's syndrome treated with growth hormone (GH): indications for GH therapy alone at high doses and late estrogen therapy Italian Study Group for Turner Syndrome. J Clin Endocrinol Metab 84, 45104515.
Chernausek SD, Attie KM, Cara JF et al. (2000) Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc, Collaborative Study Group. J Clin Endocrinol Metab 85, 24392445.
Cohen HL and Haller JO (1989) Pediatric and Adolescent Genital Anormalities. In Babcock DS (ed.) Neonatal and Pediatric Ultrasonography. Churchill Livingstone, New York, pp. 187215.
Haber HP and Ranke MB (1999) Pelvic ultrasonography in Turner syndrome: standards for uterine and ovarian volume. J Ultrasound Med 18, 271276.
Massarano AA, Adams JA, Preece MA et al. (1989) Ovarian ultrasound appearances in Turner syndrome. J Pediatr 114, 568573.[ISI][Medline]
Mazzanti L, Cacciari E, Bergamaschi R et al. (1997) Pelvic ultrasonography in patients with Turner syndrome: age-related findings in different karyotypes. J Pediatr 131, 135140.[ISI][Medline]
McDonnell CM, Coleman L and Zacharin MR (2003) A 3-year prospective study to assess uterine growth in girls with Turner's syndrome by pelvic ultrasound. Clin Endocrinol (Oxf) 58, 446450.[CrossRef][ISI][Medline]
Paterson WF, Hollman AS and Donaldson MD (2002) Poor uterine development in Turner syndrome with oral oestrogen therapy. Clin Endocrinol (Oxf) 56, 359365.[CrossRef][ISI][Medline]
Pelzer V (1991) [The value of ultrasonography in pediatric and adolescent gynecology]. Gynakologe 24, 9196.[ISI][Medline]
Ranke MB, Stubbe P, Majewski F et al. (1988) Spontaneous growth in Turner's syndrome. Acta Paediatr Scand Suppl 343, 2230.[Medline]
Ranke MB, Lindberg A, Chatelain P et al. (2000) Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models KIGS International Board Kabi International Growth Study. J Clin Endocrinol Metab 85, 42124218.
Ranke MB, Partsch CJ, Lindberg A et al. (2002) Adult height after GH therapy in 188 UllrichTurner syndrome patients: results of the German IGLU Follow-up Study 2001. Eur J Endocrinol 147, 625633.
Sampaolo P, Calcaterra V, Klersy C et al. (2003) Pelvic ultrasound evaluation in patients with Turner syndrome during treatment with growth hormone. Ultrasound Obstet Gynecol 22, 172177.[ISI][Medline]
Shawker TH, Garra BS, Loriaux DL et al. (1986) Ultrasonography of Turner's syndrome. J Ultrasound Med 5, 125129.[Abstract]
Snajderova M, Mardesic T, Lebl J et al. (2003) The uterine length in women with Turner syndrome reflects the postmenarcheal daily estrogen dose. Horm Res 60, 198204.[CrossRef][ISI][Medline]
Wilson CA, Heinrichs C, Larmore KA et al. (2003) Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay. J Pediatr Endocrinol Metab 16, 9196.[ISI][Medline]
Submitted on June 1, 2004; resubmitted on December 19, 2004; accepted on January 7, 2005.