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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1157
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4896-4902
Copyright © 2006 by The Endocrine Society

Differences in Follicle-Stimulating Hormone Secretion between 45,X Monosomy Turner Syndrome and 45,X/46,XX Mosaicism Are Evident at an Early Age

Patricia Y. Fechner, Marsha L. Davenport, Rebecca L. Qualy, Judith L. Ross, Daniel F. Gunther, Erica A. Eugster, Carol Huseman, Anthony J. Zagar, Charmian A. Quigley on behalf of the Toddler Turner Study Group

Division of Pediatric Endocrinology (P.Y.F.), Stanford University, Stanford, California 94305-5208; Division of Pediatric Endocrinology (M.L.D.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; United States Medical Division (Endocrinology) (R.L.Q., A.J.Z., C.A.Q.), Lilly Research Laboratories, Indianapolis, Indiana 46285; Division of Endocrinology (J.L.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Children’s Hospital and Regional Medical Center (D.F.G.), University of Washington School of Medicine, Seattle, Washington 98105; Division of Pediatric Endocrinology (E.A.E.), Riley Hospital for Children, Indiana University, Indianapolis, Indiana 46202; and Children’s Mercy Hospital (C.H.), Kansas City, Missouri 64108

Address all correspondence and requests for reprints to: Patricia Y. Fechner, M.D., Division of Pediatric Endocrinology, Children’s Hospital and Medical Regional Center, 4800 Sand Point Way NE, Seattle, Washington 98105. E-mail: Patricia.Fechner{at}seattlechildrens.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Little information exists regarding FSH values in very young girls with Turner syndrome (TS).

Objectives: The objective of the study was to evaluate the pattern, natural progression, and karyotype-related differences in FSH secretion in young, prepubertal girls with TS.

Study Design: FSH was measured at study entry and annually for 2 yr.

Setting: The Toddler Turner study was conducted at 11 U.S. pediatric endocrine centers.

Study Participants: Eighty-eight girls with karyotype-proven TS aged 9 months to 4 yr participated in the study.

Main Outcome Measures: By-karyotype differences in FSH concentration and age-related changes in FSH were measured.

Results: Mean (± SD) FSH was markedly elevated in the 45,X (n = 56: 68.3 ± 36.0 IU/liter) and Other groups [n = 15 (excluding three subjects with Y-containing karyotypes): 52.7 ± 50.8 IU/liter] but was minimally elevated in girls with 45,X/46,XX mosaicism (n = 14: 10.1 ± 13.5 IU/liter, P < 0.005 both comparisons). Over the 2-yr period, FSH declined in the 45,X group (–13.4 IU/liter·yr, P < 0.0001). Nonetheless, only three of 159 FSH values fell within normal range for age at any time during the 2-yr study. FSH decline was similar in the Other group (–14.3 IU/liter·yr, P = 0.0032). In contrast, no significant decrease in FSH with age was observed in the 45,X/46,XX group.

Conclusions: In contrast to the original report of FSH concentrations in individuals with TS, this study demonstrates distinct differences in patterns of FSH secretion between young girls with monosomy TS, who have persistent elevation of FSH to age 6 yr, and those with 45,X/46,XX mosaicism, whose FSH values suggest retained ovarian function in the majority. These findings have implications for patient management and family counseling.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WITH A PREVALENCE of approximately 1:2000 live female births (1, 2), Turner syndrome (TS) is one of the most common chromosomal anomalies in females. Affected individuals have a broad but variable spectrum of physical and functional alterations, including short stature; gonadal dysgenesis; cardiac and renal anomalies; and a number of distinctive phenotypic features such as webbed neck, low-set ears and hairline, broad chest, cubitus valgus, and others. Some of the phenotypic variability of TS results from the wide variety of karyotypic abnormalities found in affected individuals, ranging from 45,X monosomy to structural defects of the X chromosome to various forms of mosaicism in which two or more cell populations are present, often including a normal 46,XX cell line (3).

Traditionally gonadal dysgenesis, with delayed or absent puberty and subsequent infertility, has been considered an almost universal feature of TS, with most reviews citing rates of 80–95% in typical clinic populations (4, 5). This is an important issue because affected individuals report infertility to be one of their most troubling life problems (6, 7). However, given the significant ascertainment bias toward more severe presentation of TS in clinically diagnosed populations, the true prevalence of ovarian failure in the broad spectrum of patients with TS is unknown and may be lower than was originally thought. This is suggested by two studies in which puberty occurred spontaneously in about one in three girls with TS (8, 9). Nevertheless, even in those with spontaneous menses, FSH tended to be elevated, indicating some degree of gonadal dysfunction.

The original study that described a diphasic pattern of gonadotropin secretion in individuals with TS reported no difference between subjects with 45,X TS and those with various forms of X-chromosomal mosaicism (10). However, only three subjects with 45,X/46,XX mosaicism were studied, and there were few subjects at young ages. Subsequent studies of FSH secretion in TS have focused on older children and adolescents, and minimal data are available for infants and preschool-aged children. Therefore, the purposes of this study were to evaluate the prevalence of early gonadal failure in a large group of young, prepubertal girls with TS, more clearly define the changes in FSH secretion in early childhood, and determine any karyotype-related differences in FSH secretion in this patient population.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Eighty-eight girls with karyotype-proven TS, 9 months to 4 yr of age, were randomized into a 2-yr, multicenter, early intervention growth hormone trial (the Toddler Turner Study; Humatrope; Eli Lilly and Co.; 50 mg/kg·d vs. nontreatment control) approved by the institutional review board of each of the 11 participating institutions. Subjects were recruited from endocrine clinic and primary care referral populations and the Turner Syndrome Society of the United States and through advertising on various Web sites (www.turner-syndrome-us.org; www.magicfoundation.org; www.hgfound.org; www.centerwatch.com). Subjects with a Y chromosome component to their karyotype were permitted to enter the study only if they had undergone gonadectomy. Written informed consent was obtained from the subject’s parent(s) or guardian(s) at study entry.

Laboratory analyses

As part of the comprehensive laboratory evaluation, blood was drawn for FSH measurement at study entry and at 1 and 2 yr on study. FSH concentrations were measured at a central laboratory using the AxSYM FSH assay (Abbott Laboratories, Abbott Park, IL), a microparticle enzyme immunoassay with interassay coefficients of variation 6.2–10.1%. Subjects’ FSH values were compared with age- and sex-appropriate reference values (2.5th to 97.5th percentiles) for this assay (under 2 yr: 0.2–6.6 IU/liter; 2–5 yr: 0.2–3.8 IU/liter; 6–10 yr: 0.2–2.7 IU/liter) (11).

For girls with nonmosaic karyotypes whose families consented to this testing specifically, parental origin of the X chromosome (maternal vs. paternal) was determined at a central laboratory by DNA microsatellite analysis.

Statistical analyses

Subjects were grouped according to karyotype [45,X; 45,X/46,XX (mosaic); and all remaining karyotypes grouped as Other]. Differences in mean FSH concentration among karyotype groups were assessed using a one-way analysis of covariance with baseline age as a covariate. A repeated-measures regression model with unstructured covariance was used to assess the linear relationship between age and FSH concentration. The relationship between the parental origin of the X chromosome (maternal vs. paternal) and FSH concentrations was assessed by ANOVA. To examine the relationship between FSH concentrations and congenital cardiac or renal anomalies, subjects were classified based on the presence or absence of a structural abnormality on cardiac or renal imaging. The difference between groups (cardiac abnormality, yes/no; renal abnormality, yes/no) with respect to FSH concentration was assessed by an ANOVA for each of the systems.

All tests were two sided and considered statistically significant at P ≤ 0.05. All analyses were conducted using SAS (version 8.2; SAS Institute, Cary, NC). Unless otherwise stated, data are reported as mean ± 1 SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographic data

The average age at study entry was 24 ± 12 months (range 8.2–47.7). The majority of subjects had 45,X monosomy (56 of 88; 64%), whereas 14 (16%) had 45,X/46,XX mosaicism and 18 (20%) had a variety of other karyotypes (Table 1Go). As previously reported, 72 subjects (82%) were diagnosed clinically on the basis of either a prenatal karyotype analysis performed for abnormal ultrasound findings (n = 19) or a postnatal karyotype performed because of clinical anomalies (n = 53). Sixteen subjects (18%) were diagnosed incidentally on the basis of prenatal karyotype analysis performed for reasons unrelated to suspicion of TS (12).


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  		TABLE 1. FSH concentrations by karyotype group at first and last measurement

 
FSH values by karyotype

Because there were no differences in FSH concentration between the GH-treated and control groups at any time point (data not shown), the analyses for age and karyotype effects on FSH were pooled across the treatment groups. As shown in Table 1Go, mean serum FSH concentration was markedly elevated at first measurement for the 45,X (68.3 ± 36.0 IU/liter) and Other karyotype groups (52.7 ± 50.8 IU/liter) but was close to normal for the mosaic 45,X/46,XX group (10.1 ± 13.5 IU/liter; P ≤ 0.005 for both comparisons).

Age-related changes in FSH

Over the 2-yr study period, FSH concentrations gradually declined with age in the 45,X group (–13.4 IU/liter·yr, P < 0.0001) and the Other group (–14.3 IU/liter·yr, P = 0.0032; Fig. 1Go, A and C) but not in the 45,X/46,XX group because values were elevated in only four of 14 girls in this group at baseline. Of the four 45,X/46,XX girls with values above the reference range throughout, two had only marginally increased values (10, 5, 5 and 6, 4, 5 IU/liter at baseline, 1 and 2 yr, respectively); the other two had significantly elevated values (49, 42, 26 and 32, 61, 69 IU/liter at baseline, 1 and 2 yr, respectively). These two girls had a similar degree of mosaicism on leukocyte karyotype to the girls with the 45,X/46,XX karyotype who did not have elevated FSH values. However, they appeared to have a more severe TS phenotype despite their mosaicism because both had significant aortic coarctation requiring early intervention, the only girls in the 45,X/46,XX group with this clinical feature. Thus, the degree of mosaicism represented by leukocyte karyotype analysis may not accurately represent the degree of mosaicism present in other organs such as the gonad and heart.


Figure 1
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  		FIG. 1. Scatter plots of serum FSH vs. age by karyotype group. Lines represent average rate of FSH decline. A, 45,X group: FSH decline = –13.4 IU/liter·yr, P < 0.0001. B, 45,X/46,XX group: no significant change with time (note different Y-axis scale). C, Other karyotypes (excluding subjects with Y component in karyotype, who had undergone gonadectomy): FSH decline = –14.3 IU/liter·yr, P = 0.0032. Reference ranges for FSH assay: under 2 yr: 0.2–6.6 IU/liter; 2–5 yr: 0.2–3.8 IU/liter; 6–10 yr: 0.2–2.7 IU/liter (14 ). The upper limit (97.5th percentile) of the reference range for age is shown by the horizontal dashed lines.

 
The age-related changes in FSH concentration for individual subjects are illustrated in Fig. 2Go. In the 45,X karyotype group, FSH decreased over the 2-yr study period in 50 of 55 (91%) girls and rose in five (9%). In girls with 45,X/46,XX karyotype, FSH showed no or minimal change in 11 of 13 (85%), fell substantially in one, and rose in one. There was wide variability in individual FSH patterns in the Other karyotype group, but in most girls the patterns were similar to those of the 45,X girls, with elevated initial values that fell with age. Three girls with karyotypes containing Y-chromosomal material had undergone prior gonadectomy: FSH was consistently elevated in two girls, one each with 45,X/46,XY and 45,X/46,XY/47,XYY karyotype but was normal between the ages of 42 and 67 months in one 45,X/46,XY girl. The early FSH nadir in this child is surprising in light of her history of gonadectomy and suggests that she entered the quiescent phase of hypothalamic-pituitary-gonadal function quite early.


Figure 2
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  		FIG. 2. Change in FSH for individual subjects over 2-yr follow-up period by karyotype group. Lines connect the first and last FSH measurements for each subject with at least two measurements. Almost all subjects had declining FSH values over time; however, a few patients had increases in FSH over the 2-yr study. A, 45,X group: five of 55 (9%). B, 45,X/46,XX group: two of 13 (15%) (note different Y-axis scale). C, Other karyotypes (excluding subjects with Y-component in karyotype, who had undergone gonadectomy): one of 13 (8%). Reference ranges for FSH assay are provided in legend to Fig. 1Go.

 
To provide age-specific FSH ranges for patients with 45,X karyotype, FSH values are summarized in 1-yr increments in Fig. 3Go. Mean and ranges of FSH concentration were highest in the under-1-yr-old, 1- to 2-yr-old, and 2- to 3-yr-old groups, no subject having a normal value at these ages. From 3 yr of age onward, two subjects had values at the upper limit of the normal range for age, although mean values were still significantly abnormal. Age-specific results were similar for girls in the Other karyotype group (data not shown).


Figure 3
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  		FIG. 3. FSH values by age group for subjects with 45,X karyotype. Median and interquartile range (25th to 75th percentile) are indicated by the solid symbols with bars. Open symbols represent individual subject values. The upper limit (97.5th percentile) of the reference range for age is shown by the horizontal dashed lines.

 
Relationship between FSH values and parental origin of the X chromosome

The parental origin of the X chromosome was determined in 35 subjects with nonmosaic karyotypes whose families agreed to this testing (this was not mandatory for participation in the study). Twenty-nine subjects (83%) had maternal X chromosomes; six (17%) had paternal X chromosomes. Average FSH values for the maternal group were about 30–40% higher than those of the paternal group, but by ANOVA this difference did not reach statistical significance (first measurement: maternal 76.7 ± 42.6, paternal 58.7 ± 31.9, P = 0.34; last measurement: 40.8 ± 33.3, paternal 29.3 ± 16.7, P = 0.42).

Relationship between FSH values and presence or absence of cardiac and renal anomalies

To assess the relationship between the severity of the TS phenotype in terms of its effects on organogenesis and the presence of elevated FSH, we evaluated the differences in mean FSH concentration between girls who had a history of congenital cardiac or renal anomaly and those who did not. By ANOVA, the mean of the first available FSH measurements for girls with a cardiac anomaly (n = 49) was significantly greater than for those without (n = 37): 69.1 ± 46.8 vs. 42.2 ± 36.4, P = 0.005 (cardiac status was unknown for two subjects). Similarly, mean FSH for girls with a renal anomaly (n = 18) was significantly greater than for those without (n = 66): 81.8 ± 53.6 vs. 51.3 ± 40.3, P = 0.01 (renal status was unknown for four subjects).

Utility of FSH as a diagnostic marker for TS

The utility of FSH as a diagnostic marker for TS was evaluated by calculating the proportion of subjects in each karyotype group whose lowest FSH value at any time in the 2-yr study period fell above the upper limit of the age-specific normal reference range. For the 45,X group, 155 of 159 of FSH values fell above the normal reference range. Thus 96.4% of 45,X girls (54 of 56 subjects) had supranormal FSH values at all measurements (Table 2Go). Of the 15 girls in the Other karyotype group without Y-chromosomal material, 13 (86.7%) had high FSH values at all measurements. In contrast to the very high proportion of girls in the 45,X and Other groups with consistently abnormal FSH values, only four of 14 (29%) girls in the 45,X/46,XX group had their lowest value above the upper limit of the reference range (two significantly, two slightly). Of the 16 girls whose TS had been diagnosed incidentally (i.e. not on the basis of typical clinical features), seven (44%) had elevated FSH concentrations on all occasions.


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  		TABLE 2. Proportions of subjects with FSH measurements within or above the reference range over the course of the study

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Gonadal dysgenesis is considered a cardinal feature of TS, and the accompanying increases in gonadotropin, especially FSH, secretion have been reported in girls and women with TS since soon after these hormones became measurable (13, 14, 15, 16, 17, 18, 19, 20). However, early reports were limited by small patient numbers, few subjects at young ages, absence of longitudinal data, and an ascertainment bias toward inclusion of subjects with the most marked clinical features. The present study, reporting longitudinal data over 2 yr for a large group of young prepubertal girls who were not ascertained on the basis of pubertal delay, provides a clearer estimate of the prevalence of ovarian dysfunction in girls with TS. Furthermore, this study refines our understanding of the dynamics of FSH secretion in early childhood and clarifies the differences in apparent gonadal function between patients with 45,X monosomy and those with 45,X/46,XX mosaicism.

Because gonadal dysgenesis has long been regarded as an archetypal feature of TS, it has generally been assumed that early ovarian failure and infertility are almost inevitable features of the condition. However, our findings of very different patterns of FSH secretion in girls with 45,X/46,XX mosaicism, compared with those with 45,X karyotype, highlight the fact that the diagnosis of TS in and of itself should not lead to the foregone conclusion that ovarian failure will occur. Such assumptions regarding gonadal failure in TS reflect the history of the condition and the fact that many patients presented for investigation and were diagnosed on the basis of pubertal delay. In his original 1938 description of the syndrome, Henry Turner (21) reported "congenital absence of the ovaries." Similarly, other early studies also concluded that the ovaries in TS were simply absent (22, 23) until 1944 when streak gonads were first described, based on the finding of ovarian stroma on gonadal biopsy of a woman with TS (24). The pathophysiology of ovarian dysgenesis in TS became clearer in the 1960s with the work of Singh and Carr (25), who found gonads that were grossly and histologically normal in 45,X fetuses to 3 months’ gestation, with apparently normal numbers of primordial germ cells. In contrast, the gonads of the older fetuses (4 to 5 months’ gestation) were characterized by absence of folliculogenesis and increased connective tissue. These findings were confirmed in a subsequent study of 17- to 37-wk 45,X fetuses (26).

Increasingly more abnormal gonadal histology with advancing gestational age reflects the fact that gonadal dysgenesis is a progressive rather than a static process. The 45,X ovary begins its development normally, with migration of germ cells from the coelomic epithelium and colonization of the primordial gonad. Thereafter, the gonad undergoes premature and accelerated apoptosis of germ cells, resulting in stromal fibrosis and degeneration of the gonad to a fibrous streak (27). These defects are thought to relate to failure of germ cell meiosis, for which two active X chromosomes are required (28) (unlike somatic cells, in which most of the second X chromosome is inactivated). Inefficient meiosis results in reduced numbers of oocytes, which in turn leads to failure of folliculogenesis because follicle formation is dependent on the presence of oocytes. Absent or reduced negative feedback on FSH secretion by follicle-produced inhibin likely explains the increased FSH secretion.

The pathogenesis of the germ cell demise and premature ovarian failure in individuals lacking a full complement of X chromosomes remain a subject of investigation. One hypothesis suggests that this primarily results from haploinsufficiency of important X-chromosomal oocyte survival genes. A small number of candidate genes have been postulated on the basis of informative patients with TS who have limited, well-localized X-chromosomal break points (29, 30, 31, 32). These genes include USP9X, a noninactivated gene at Xp11.4 that encodes a factor involved in intracellular protein degradation (29), and BMP15 (GDF9B), a gene located at Xp11.2 encoding a member of the TGFß family expressed specifically in oocytes (30, 31). Four novel variants of BMP15 have been identified in women with isolated premature ovarian failure (33, 34), providing additional support for the hypothesis that gonadal failure in TS results from haploinsufficiency of critical X-chromosomal genes. The alternative hypothesis to explain ovarian dysgenesis, based on studies of chromosomal translocation break points in other cohorts of women with isolated premature ovarian failure, proposes that the detrimental effect of X chromosome deficiency results from aberrations in chromosomal pairing or X inactivation during meiosis in fetal oocytes (28). In this scenario, structural defects of the X chromosome would affect chromosomal pairing in a manner similar to complete absence of the second X. In light of these hypotheses, it is of interest that three of our four subjects with nonmosaic karyotypes that include a structurally abnormal second X chromosome lacking at least part of Xp [46,X,i(Xq); 46,X,idic(X); 46,X,Xp–] had elevated FSH concentrations consistent with gonadal dysgenesis (the 46,X,Xp– subject with normal FSH was almost 4 yr old at study entry).

The patterns of FSH secretion in the large group of young girls in our study extend, and in some respects contrast with, the seminal observations of Conte et al. (10) that established the concept of a diphasic pattern of FSH secretion in TS characterized by a marked FSH rise during infancy, followed by a decline to the normal range by 6 yr of age, and a secondary rise to castrate levels at the normal age for onset of puberty. Despite its importance, that study provided limited information on FSH secretion in early childhood because only seven girls under 6 yr of age were studied longitudinally, and only three FSH values were reported between the ages of 4 and 6 yr, the age at which FSH was reported to decline. Indeed, our data for 45,X girls between ages of 4 and 6 yr indicate that FSH remains elevated during this period of childhood, contrasting with the traditional expectation. Furthermore, the limited patient numbers in the original study by Conte et al. led to the conclusion that FSH secretion was similar among individuals with 45,X karyotype and those with mosaicism. In contrast, the present study demonstrates clear differences between young 45,X and 45,X/46,XX girls, with a slow FSH decline between 2 and 6 yr of age in the 45,X population, which was not seen in the 45,X/46,XX group because the majority had normal FSH values throughout the 2-yr study period. Despite the gradual fall, FSH remained elevated until 6 yr of age in almost all 45,X girls, indicating that the onset of the quiescent phase of childhood hypothalamic-pituitary-gonadal function may be later than was previously thought.

In the more than 30 yr since the original report by Conte et al. (10), scant data have been published regarding FSH measurements in young girls with TS. Although review of the literature reveals a number of studies reporting FSH data in TS (9, 13, 17, 19, 20, 35, 36, 37, 38), values for individual patients in early childhood are difficult to discern, and all but one of these studies (38) include data for just a handful of girls in the under-6-yr age range, amounting to fewer than 50 girls across all studies; there is an even greater paucity of longitudinal FSH data in this age range. Thus, our study, providing 244 FSH measurements assayed at a central laboratory over a 2-yr period in 88 under-6-yr-old girls, substantially expands and redefines the understanding of the natural progression and age-related changes in pituitary-ovarian function in young prepubertal girls with TS. Furthermore, because no prior study has systematically examined karyotype-specific FSH values in substantial patient numbers, our study clarifies the distinct differences in FSH concentration between girls with 45,X monosomy and those with 45,X/46,XX karyotype.

The significant karyotype-related differences in FSH secretion determined in our study underscore the relevance of ascertainment bias in TS. In our previous paper on this patient cohort (12), we reported distinctly lower prevalences of a number of the classical phenotypic features of TS in patients diagnosed incidentally (i.e. not on the basis of clinical suspicion of TS), of whom approximately 60% had the 45,X/46,XX karyotype. The data reported here expand this concept by demonstrating a substantially greater frequency of apparently retained ovarian function in the young 45,X/46,XX population. Lower FSH values and the presence of a cell line containing a second X chromosome appear to be important prognostic signs of ovarian structure and function in TS (9, 39); spontaneous menses have been reported in approximately 40% of 45,X/46,XX patients, vs. only approximately 10% of those with 45,X karyotype (8, 40). Therefore, to provide early information regarding potential gonadal function, we recommend that FSH measurements be obtained for all girls in whom the diagnosis of TS is made in early childhood, preferably as soon as possible after diagnosis, and that the measurements be repeated at 1- or 2-yr intervals thereafter to follow gonadal function longitudinally.

A novel finding of this study was the association between increased FSH concentrations and the presence of cardiac or renal defects: mean FSH values for girls with congenital cardiac or renal anomalies were more than 50% greater than mean FSH values of girls without such anomalies, and the differences were significant. The basis for this association is speculative but perhaps reflects the global impact of haploinsufficiency of X-chromosomal genes on fetal organogenesis across a variety of mesodermally derived tissues. The finding also has clinical relevance: although all girls with TS should undergo imaging studies of the heart, great vessels, and renal tract as soon as the diagnosis of TS is made, the presence of an elevated FSH should prompt even greater vigilance.

Our findings of almost universally abnormal FSH in young 45,X girls, but normal or near normal FSH concentrations in the great majority of 45,X/46,XX girls, have implications for patient and family counseling because reproduction is a key issue for women and families dealing with TS (6, 7). Evidence of ovarian failure at a young age provides the opportunity for early discussion with the family of the likely need for pubertal induction, whereas in contrast, evidence for relatively normal ovarian function provides families with hope that an affected child will undergo pubertal development normally with her peers. The likelihood of spontaneous pubertal development may be an important factor in decisions regarding growth-promoting therapies because earlier puberty typically shortens the time available for linear growth. Furthermore, girls with functional ovaries need counseling regarding contraception (a subject that may be overlooked in the context of the expected infertility of TS) because individuals with TS who achieve pregnancy are at increased risk of chromosomal aneuploidy in the offspring (41).

In summary, this study elucidates the patterns of early FSH secretion in young, prepubertal girls with TS and clarifies the relationship between karyotype and FSH concentration, providing information of relevance to patient counseling. Long-term follow-up of this patient cohort is underway to determine the predictive value of early childhood FSH concentrations for later ovarian function.


   Acknowledgments
 
We thank the other members of the Toddler Turner Study Group for their enthusiastic participation in the conduct of this study. They are listed below alphabetically (excluding those listed as authors) by the state in which the study site is located: Arkansas Children’s Hospital, Little Rock, AR, Kathryn M. Thrailkill, M.D. (previously at University of Kentucky, Lexington, KY), Sarah Webb, R.N. (Children’s Hospital, Lexington, KY); Los Angeles Children’s Hospital, Los Angeles, CA, and University of California, Los Angeles, CA, Linda Burkett, R.N., Mindy Cahan, R.N., Mitchell E. Geffner, M.D.; Stanford University Medical Center, Stanford, CA, Bonnie Baker, L.S.C.; Children’s Hospital, Denver, CO, Gail Neuenkirchen, R.N., Sharon H. Travers, M.D.; Connecticut Children’s Medical Center, Hartford, CT, Paula Gendreau, R.N., Karen Rubin, M.D.; Children’s Memorial Hospital, Chicago, IL, Wendy Brickman, M.D., Reema L. Habiby, M.D., Denise McDaniel, R.N.; Indiana University/Riley Hospital for Children, Indianapolis, IN, Debbie LeMay, R.N.; Children’s Mercy Hospital, Kansas City, MO, Sandy Berg, R.N.; Thomas Jefferson University, Philadelphia, PA, Karen Kowal, R.N.; and Children’s Hospital Medical Center, Seattle, WA, Susan Kearns, R.N. The authors also gratefully acknowledge Connie Bryant and Charlie Liu for performing the data analyses. Finally, we sincerely thank the girls and their families for their participation in this study.


   Footnotes
 
This work was funded by Eli Lilly and Co. Portions of this work were conducted through and supported by the National Institutes of Health-funded General Clinical Research Center facilities at the University of Washington and Children’s Hospital and Regional Medical Center (RR00037) and the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (RR00046).

Disclosure statement: P.Y.F., M.L.D., J.L.R., D.F.G., E.A.E., and C.H. received grant support from Eli Lilly and Co. for participation as investigators in this study from August 1999–October 2003. P.Y.F., M.L.D., J.L.R., D.F.G., E.A.E., and C.H. all receive current grant support from Eli Lilly and Co. for participation as investigators in the extension phase of this study. M.L.D. received consulting fees for participation in protocol design for this study. R.L.Q., A.J.Z., and C.A.Q. are employees of Eli Lilly and Co.

First Published Online September 12, 2006

Abbreviation: TS, Turner syndrome.

Received May 30, 2006.

Accepted September 5, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. L. Davenport, B. J. Crowe, S. H. Travers, K. Rubin, J. L. Ross, P. Y. Fechner, D. F. Gunther, C. Liu, M. E. Geffner, K. Thrailkill, et al.
Growth Hormone Treatment of Early Growth Failure in Toddlers with Turner Syndrome: A Randomized, Controlled, Multicenter Trial
J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3406 - 3416.
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