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Spontaneous Pubertal Development in Turner’s Syndrome¹

Pediatric Endocrinology Unit, Pediatric Department, University La Sapienza, Rome, Italy

Address all correspondence and requests for reprints to: Anna Maria Pasquino, M.D., Pediatric Endocrinology Unit, Pediatric Department, University La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.

	Abstract

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The incidence of spontaneous puberty in Turner’s syndrome is reported to be between 5–10% and, more recently in some series, as high as 20%. In an Italian retrospective multicenter study, of 522 patients older than 12 yr with Turner’s syndrome, 84 patients (16, 1%) presented spontaneous pubertal development with menarche that occurred at a chronological age of 13.2 ± 1.5 yr (mean ± SD) and a bone age of 12.9 ± 1.9 yr. Karyotype distribution in the whole group was as follows: 52.1% (272 patients) X-monosomy (45,X), 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X. Menstrual cycles were still regular in 30 patients at 9.2 ± 5.0 yr after menarche, 12 developed secondary amenorrhea 1.6 ± 2.0 yr after menarche, and 19 had irregular menstrual cycles 0.9 ± 1.8 yr after menarche. As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X seems to have a cardinal influence on the appearance of spontaneous puberty. Spontaneous pregnancy occurred in 3 patients (3.6%). The presence of chromosomal abnormalities and malformations in 2 of 3 pregnancies led us to agree with other investigators in discouraging unassisted pregnancies.

Treatment with GH does not seem to exert any influence on either the age of onset or the prevalence of spontaneous pubertal development in Turner’s syndrome. The increased percentage of spontaneous menarche is Turner’s syndrome reported in the recent literature might be due to increased ascertainment by diligent screening for Turner’s syndrome in girls with short stature and mild or no Turner’s syndrome stigmata, even though they may be menstruating.

	Introduction

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HISTOLOGICAL evidence shows that the ovary of the fetus with a 45,X karyotype undergoes an initial phase of normal differentiation until approximately the third month of intrauterine life, followed by an acceleration of the normal process of oocyte loss with a concomitant acceleration of stromal fibrosis that leads to the formation of streak gonads (1). Primary gonadal failure and subsequent infertility are not to be considered an inevitable event in Turner’s syndrome; cases of spontaneous pubertal development have been reported in the literature both in patients with cell lines with more than one X (in which the nonstreak gonad is more frequent) and in X-monosomic patients (2, 3, 4, 5, 6, 7, 8, 9). Turner’s syndrome patients may present a wide spectrum of ovarian function that may even allow the appearance and maintenance of menstrual cycles, but eventually, due to the progressive and inevitable decline of gonadal function, these patients will undergo early menopause (2).

The aim of our study was to evaluate the incidence of spontaneous pubertal development in a population of Turner’s syndrome patients, the largest reported to date, the influence of karyotype on the appearance and evolution of spontaneous puberty, the effect of spontaneous pubertal development on final height, and the possible influence exerted by GH treatment, where performed, on spontaneous sexual development.

	Subjects and Methods

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Data on the pubertal development of 522 patients with Turner’s syndrome older than 12 yr from 20 Italian Centers belonging to the Italian Turner’s Syndrome Study Group are reported. Before collecting and evaluating the data, the informed consent of the patients or their parents and ethical committee approval have been obtained at each institution. As at least 50% of normal girls shows signs of pubertal development before their 12th birthday, as stated by Brook et al. (10), the chronological age of 12 yr has been assumed as a pubertal age. Breast development stage B2 has been considered the first sign of spontaneous puberty. The appearance of breast budding (B2) in those patients receiving treatment for short stature with low dose of ethinyl estradiol was considered an index of spontaneous puberty only when it showed progression after discontinuation of treatment and when supported by an adequate pelvic ultrasound pattern.

Bone age was determined according to the method of Greulich and Pyle (11). Measurements of plasma gonadotropins and estradiol were performed at different centers; therefore, only data comparable to the assay performed have been used for the analysis. The same limitation was present for the pelvic ultrasound data.

All patients were regularly observed in each center for periods ranging from 1–26 yr.

Karyotype distribution was as follows: 52.1% (272 patients) X-monosomy (45,X), 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X (Table 1).

Thirty-two of the 314 patients who did not receive hGH received treatment with androgens alone at a dose of 2.5 mg/day, orally, for a mean period of 2.0 ± 1.7 yr (range, 0.33–7.0 yr). Age at onset and prevalence of spontaneous pubertal development were compared between GH-treated and untreated groups.

Data are expressed as the mean ± SD unless otherwise stated. Statistical analysis was performed by unpaired Student’s t test, ² test, and linear regression analysis. P < 0.05 was considered significant. The ² test has been used to evaluate the influence on sexual development exerted by different karyotypes; within each karyotypic category, comparison between observed and expected cases with either spontaneous menarche or induced menarche has been analyzed.

	Results

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Of the 522 patients, 84 (16.1%) showed complete spontaneous pubertal development with menarche, 34 (6.5%) show at the present time only spontaneous breast development, 57 (10.9%) had pubertal arrest and subsequently received estrogen-progestin replacement, 255 (48.6%) had totally induced puberty, and 92 (17.6%) have not yet developed breast enlargement. Table 1 shows the types of sexual development in the total group of 522 patients and the distribution among the various karyotypes.

Chronological age and bone age at spontaneous menarche in the 84 patients were 13.2 ± 1.5 and 12.9 ± 1.9 yr, respectively. Chronological age at the appearance of spontaneous breast development in those patients with subsequent spontaneous menarche was 11.8 ± 1.3 yr, significantly lower than that in patients with subsequent pubertal arrest (13.7 ± 1.7 yr; P < 0.05).

Table 2 is designed to show the results of ² analysis of the influence of karyotype on puberty by comparing observed puberty in the groups vs. expected puberty given the observed karyotypes and the original percent distribution of karyotypes. A significantly higher frequency of complete spontaneous puberty compared to the expected cases was found among patients with mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X and among patients with structural abnormalities of the second X (P < 0.001 and P < 0.05, respectively). Among patients with the 45,X karyotype, the number of cases observed with spontaneous sexual development was significantly lower than the number of expected cases (P < 0.05).

View this table: [in this window] [in a new window]   Table 2. 2 analysis of the influence of karyotype on complete pubertal development in Turner’s syndrome

Hormonal data were comparable in a limited, but representative, number of patients examined longitudinally. Gonadotropin and estradiol baseline plasma levels progressively increased from prepuberty to puberty in those patients with spontaneous menarche, as occurs during puberty in normal girls, but with markedly higher gonadotropin levels; FSH (mean ± SEM) increased from 16.0 ± 5.0 (n = 25) to 35.6 ± 7.2 mIU/mL (n = 53), LH (mean ± SEM) increased from 9.1 ± 3.5 (n = 24) to 16.3 ± 3.3 mIU/mL (n = 53), and estradiol (mean ± SEM) increased from 12.4 ± 2.0 (n = 17) to 37.5 ± 5.8 pg/mL (n = 47). Due to the limited number of patients and the wide range of values, no statistical significance was found except for estradiol values (P < 0.05). Prepubertal gonadotropin levels in these patients were significantly lower (P < 0.001) than prepubertal values in patients with subsequent induced puberty; the mean ± SEM FSH level was 112.7 ± 6.4 mIU/mL (n = 114) vs. 16.0 ± 5.0, and the mean ± SEM LH value was 37.3 ± 2.4 mIU/mL (n = 114) vs. 9.1 ± 3.5.

Plasma FSH and LH levels, measured at the appearance of breast development, were significantly higher (P < 0.001) in patients who later developed pubertal arrest (n = 22) than those in patients who subsequently had spontaneous menarche (n = 20); the mean ± SEM FSH level was 69.5 ± 19.8 vs. 11.0 ± 3.0 mIU/mL, whereas the mean ± SEM LH level was 22.4 ± 3.9 vs. 5.6 ± 1.5 mIU/mL.

Pelvic ultrasound was routinely performed at most of the centers, but in only a limited number of cases were data comparable. Taking into account these limitations, in patients with spontaneous menarche, uterine longitudinal diameter (mean ± SEM) progressively increased from premenarche to postmenarche, from 3.7 ± 0.3 cm (n = 21) to 7.1 ± 0.2 cm (n = 47). Ovarian volume before pubertal development was significantly higher (P < 0.001) in subjects with spontaneous menarche (n = 16) compared to patients with induced menarche (n = 27; right ovary, 1.5 ± 0.2 vs. 0.7 ± 0.1 cm³; left ovary, 1.4 ± 0.2 vs. 0.6 ± 0.06 cm³).

Final height, determined according to the criteria of Naeraa et al. (12), of the 57 patients who developed complete spontaneous puberty was not significantly different from that of the 132 patients with induced puberty (142.3 ± 5.2 vs. 143.4 ± 6.2 cm).

As to the influence of different karyotypes on final height, only within the non-hGH-treated, induced puberty group was a significantly higher final height found in patients with X-mosaic monosomy and cellular line without structural abnormalities of the second X (n = 13) vs. that in monosomic X-patients (n = 38; 145.7 ± 6.7 vs. 141.8 ± 5.1 cm; P < 0.05). hGH treatment had no effect on the age of spontaneous appearance of thelarche, which was 12.8 ± 1.8 yr in the untreated subjects and 12.7 ± 1.7 yr in the GH-treated patients. Furthermore, no statistically significant difference was found between the observed and the expected cases of spontaneous pubertal development in both treated and untreated groups.

A positive significant correlation was found between target height and final height in both patients with spontaneous puberty and those with induced puberty.

	Discussion

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Our data agree with the more recent reports (4, 5, 13, 14) concerning the incidence of menarche in Turner’s syndrome, showing a percentage of 16.1%, which is markedly higher than that reported previously (2, 3, 9, 15).

If we add cases with incomplete sexual development either arrested (10.9%) or in evolution but not yet ready for menarche (6.5%), we then reach a percentage of 33.5%, which is quite high compared with the traditional reports and in contrast with the cardinal features of Turner’s syndrome in relation to sexual development (sexual infantilism). This change in incidence is due, in our opinion, to the screening diagnosis of Turner’s syndrome in girls with short stature and no or mild stigmata and to the widespread knowledge that sexual development can occur in Turner’s syndrome, which prompts physicians not to exclude performing a karyotype in a prepubertal or even menstruating short girl.

The chronological age at onset of spontaneous sexual development in our 84 patients (11.8 ± 1.3 yr) seems to be slightly higher than that in normal population, which is 11.15 ± 1.1 yr according to the method of Marshall and Tanner (16).

As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X seems to have a cardinal influence on the appearance of spontaneous puberty (Table 1).

Spontaneous sexual development in Turner patients seems not to exert a significant influence on their final height. Therefore, girls with complete spontaneous puberty do not reach a taller stature than those with induced puberty (2, 7, 8, 17, 18), although the growth pattern of the former patients is characterized by an earlier spurt leading to a transitory higher stature compared with that in the latter patients.

The diagnosis of ovarian failure in Turner’s syndrome is not easy and must take into account the following considerations: 1) a careful evaluation of pubertal development, if absent or nonprogressive, is basic; 2) plasma gonadotropin levels, even when they are very high, are not decisive considering the wide range of values documented in our study and the few recent data (13, 19); 3) plasma estradiol assay does not always directly reflect ovarian function; 4) a careful evaluation of uterine volume, which is the most significant marker of estrogenic activity, is important; and 5) a careful ultrasound ovarian morphological and volumetric evaluation is necessary.

The limited number of hormonal and pelvic ultrasound data in the present retrospective study cannot give reliable information as to the possible correlation between estradiol, FSH, LH levels, ultrasound imaging, and spontaneous pubertal development outcome. However, a negative correlation between elevated plasma FSH and LH levels and outcome of sexual development is suggested by hormonal data, and a positive correlation between uterine length, as marker of estrogen activity, and pattern of puberty is suggested by ultrasound findings.

The presence of chromosomal abnormalities and malformations in two of three pregnancies leads us to agree with other investigators in discouraging unassisted pregnancies and even encouraging ovum donation (9, 20, 21). Spontaneous ovarian function in the presence of involuting gonads, while gonadotropin levels are elevated, does not appear advantageous and probably should be suppressed or supported with replacement therapy. In fact, beside the well known risk of endometrial hyperplasia due to nonovulatory unopposed estrogen stimulation, the high gonadotropin levels may involve the possible risk of ovarian cysts appearance and ovarian torsion, as reported by Missov et al. (13). Therefore, in the presence of irregular bleeding or amenorrhea and increasing gonadotropin levels it is advisable to undertake estrogen and progesterone replacement treatment.

Treatment with GH seems not to exert any influence either on the age of onset or the prevalence of spontaneous pubertal development in Turner’s syndrome. Because of potential adverse effects of estrogen therapy on final height, estrogen therapy should not commence before 14 yr of age (22).

	Footnotes

 
¹ Presented in part at the 10th National Meeting of the Italian Society of Pediatric Endocrinology and Diabetology, Stresa, Italy, September 21–23, 1995.

² Participating investigators: Emanuele Cacciari, Laura Mazzanti (Bologna), Maria Pia Guarneri, Giuseppe Russo (Milan), Francesca Severi, Daniela Larizza (Pavia), Sergio Bernasconi, Cecilia Volta (Parma), Cinzia Galasso (Rome), Gianni Bona (Novara), Fabio Buzi (Brescia), Luciano Cavallo (Bari), Filippo De Luca (Messina), Fabrizio De Matteis (L’Aquila), Vincenzo De Sanctis (Ferrara), Patrizia Matarazzo (Torino), Giorgio Radetti (Bolzano), Giustiniano Reitano (Catania), Franco Rigon (Padova), Giuseppe Saggese (Pisa), Maria Carolina Salerno (Naples), G. Piero Stoppoloni Ü (Naples), and Giorgio Tonini (Trieste).

Received August 5, 1996.

Revised December 9, 1996.

Revised February 5, 1997.

Accepted February 18, 1997.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pasquino, A. M. Articles by Municchi, G. Search for Related Content PubMed PubMed Citation Articles by Pasquino, A. M. Articles by Municchi, G.