1 Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, 2 Hormonal Laboratory and 3 Department of Radiology, Hospital Materno-Infantil Vall dHebron, Autonomous University of Barcelona, 4 Endocrinology Unit, Hospital de Terrassa, Terrassa, Spain and 5 Department of Pediatrics, University of Leuven, Belgium
6 To whom correspondence should be addressed at: Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. e-mail: libanez{at}hsjdbcn.org
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Abstract |
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Key words: FSH/LH/ovary/small-for-gestational-age/uterus
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Introduction |
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Materials and methods |
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The infant population (n = 26), who had been studied at the age of 4 months (Ibáñez et al., 2002a
), was assessed again at the age of 12 months. The original study cohort was recruited at Barcelona Hospital and was composed of infant girls (postnatal age range, 36 months) in good general condition. Blood was sampled from this cohort, independently of this study and of birthweight, for either follow-up or screening purposes, before elective minor surgery, or after recovery of intercurrent viral illness. Inclusion criteria were weight at term birth (3741 weeks) either appropriate for gestational age (AGA, birthweight between 1 and +1 SD, n = 10), or small for gestational age (SGA, birthweight <2.5 SD, n = 16). Exclusion criteria were: evidence for a syndromatic, chromosomal, or infectious aetiology of low birthweight; hypothyroidism; urogenital tract abnormalities; systemic disease or acute illness; and persistent growth failure (Ibáñez et al., 2002a
).
The teenage population (n = 36), who had been studied at the age of 14 years of age (Ibáñez et al., 2000a
), was assessed again at the age of
18 years, with the exception of eight girls, who were either on oral contraceptives (n = 6) or pregnant (n = 1), or could not be located (n = 1). Of the remaining 28 subjects, 18 were born AGA and 10 SGA.
To evaluate reproductive indices at the age of 18 years in a larger group, the longitudinal cohort was complemented by a cross-sectional cohort (mean age, 17.8 years; n = 19); of those, nine were born AGA and 10 SGA. These girls were recruited among healthy relatives of hospital staff (n = 31), and among asymptomatic girls attending the endocrine clinic for evaluation of thyroid function (n = 1), pubertal development (n = 5), or post-menarcheal growth status (n = 10). In the latter girls, we documented, respectively, euthyroidism, normal variation in timing of puberty, and post-menarcheal stature above/within (n = 7) or below (n = 3) target height range. The exclusion criteria were: evidence for a syndromatic, chromosomal, or infectious aetiology of low birthweight; thyroid dysfunction; Cushing syndrome; hyperprolactinaemia; previous or current use of oral contraceptive medication; and a family or personal history of diabetes mellitus (criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997).
Birthweight and gestational age data were obtained from hospital records or from the girls paediatricians, and transformed into SD scores (Ibáñez et al., 1998).
Study design
In the infant population, serum FSH was measured at 12 months, and the values were interpreted in view of those obtained at 4 months.
In the late-adolescent or young-adult population, body composition assessment and pelvic ultrasound examinations were performed together with blood sampling for measurement of serum glucose, insulin, LH, FSH, estradiol, testosterone, and sex hormone-binding globulin (SHBG). Ultrasound examinations and endocrine-metabolic measurements were performed in the follicular phase (range: day 5 ± 3) of the menstrual cycle.
Ultrasonography
The ultrasound examinations were performed in a full-bladder state. Scans were obtained by a single observer (G.E.) using an Acuson Sequoia 512 (Mountain View, CA, USA) with a 46 MHz multifrequency sector probe. Throughout the study, the observer remained blinded to the girls birthweight.
Longitudinal and transverse views of the uterus were obtained and measurements made of uterine length (from the top of the fundus to the cervix), anteroposterior diameters of the fundus and cervix, and uterine cross-sectional area (uterine length x uterine anteroposterior diameter).
Longitudinal and transverse views of the ovaries were obtained for measurement of length, breadth and depth of each ovary. Ovarian volume (right and left) was calculated using the formula for a modified prolate ellipsoid (depth x breadth x length/2) (Griffin et al., 1995; Buzzi et al., 1998
; Ibáñez et al., 2000a
). For comparisons between AGA and SGA groups, average volumes of right and left ovary of each girl were used.
Body composition
Body composition was assessed by dual-energy X-ray absorptiometry (DXA) using a Lunar Prodigy machine. All studies were performed using Lunar software programs (versions 3.4 and 3.5, Lunar Corp., Madison, USA) (Ibáñez et al., 2000b). Absolute fat and lean mass (kg) were assessed for the whole body, and also by specific body regions. The truncal region was defined as the tissue area bordered by a horizontal line below the chin, vertical borders lateral to the ribs, and oblique lines passing through the femoral necks. The abdominal region was defined as the area encompassed between the dome of the diaphragm (cephalad limit) and the top of the greater throcanter (caudal limit) (Taylor et al., 1998
). The total radiation dose in each examination was 0.1 mSv. The coefficients of variation (CV) for scanning precision, calculated from 30 consecutive scans of an external hydroxyapatite, luciate and high-density polyethylene Hologic phantom (Hologic Inc., Waltham, MA, USA), were 2.0 and 2.6% respectively for fat and lean body mass (Kiebzak et al., 2000
). The intra-individual CV for abdominal fat mass was 0.7%, as assessed by three consecutive scans of 14 persons.
Endocrinology
Serum glucose was assessed by the glucose oxidase method. Serum LH, FSH, SHBG and insulin were measured by immuno-chemiluminiscence (IMMULITE 2000, Diagnostic Products Corp, Los Angeles, CA, USA), the intra-and inter-assay CVs were 6.2 and 7.0% for LH, 4.3 and 6.3% for FSH, 4.2 and and 6.6% for SHBG, and 4.4 and 8.6% for insulin. Serum estradiol was determined by third generation RIA (DSL, Webster, Texas, USA), with a detection limit of 0.6 pg/ml; the intra- and inter-assay CVs were 3.5 and 4.9% respectively; serum testosterone was assessed by RIA, as described previously (Ibáñez et al., 2001a).
Statistics and Ethics
Results are expressed as mean ± SEM, unless stated otherwise. Two-sided t-test was used for statistical comparisons; significance level was set at P < 0.05.
The study protocol was approved by the Institutional Review Board of the Barcelona Hospital. Informed consent was obtained from the parents and/or the girls.
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Results |
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Longitudinal ultrasound assessments disclosed a late-adolescent increment of uterine size. This increment was less obvious in SGA than AGA girls, possibly as a reflection of the differences already apparent at 14 years; consequently, these differences in uterine size were amplified, rather than attenuated, by
18 years of age. In contrast, ovarian volume remained stable in both AGA and SGA girls (Figure 2); this observation implies that the striking difference of ovarian size between AGA and SGA adolescents persists into adulthood (Table I).
The compiled longitudinal and cross-sectional results at 18 years corroborated the persistent reduction in the uterine size of SGA girls (mean difference
20%; P < 0.005) and in their ovarian volume (mean difference
40%; P < 0.0001); moreover, SGA girls displayed a persistent elevation of FSH (by
50%; P < 0.001) and a raised LH and fasting insulin, as well as an excess of abdominal fat (all P < 0.01; Figure 3 and Table II).
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Discussion |
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The present longitudinal findings were obtained at older ages within these phases (at 12 months and 18 years), and they indicate that the SGA-related alterations persist over time, not only into late infancy, but also into the reproductive age range.
The infant and adolescent girls participating in this study were selected according to birthweight for gestational age. Besides gonadotrophin and gynaecological ultrasound abnormalities, the SGA adolescents in this cohort also presented hyperinsulinaemia, abdominal fat excess, a reduced lean body mass, and subclinical hyperandrogenism, as previously reported in adolescent SGA girls who had been selected through similar (Barker et al., 1997; Ibáñez et al., 1999,
2002b) or other criteria, e.g. precocious pubarche (Ibáñez et al., 1998
; 2001b, 2003), anovulation (Ibáñez et al., 2002d
), early puberty and/or short stature (Chiarelli et al., 1999
; Ibáñez et al., 2000d
).
The LH increase at 18 years in the SGA population can be a sign of incipient polycystic ovary syndrome (PCOS); in fact, autonomous hypothalamic GnRH signalling resulting in disorderly LH secretion has been described in PCOS adolescents (Veldhuis et al., 2001). The relatively unrestrained LH production may be partly driven by hyperinsulinemia.
The longitudinal data obtained between 14 and 18 years of age evidenced that the uterus tends to grow further in late adolescence, whereas this is not the case for the ovaries; the AGA-versus-SGA differences for FSH and for uterine-ovarian size remained stable or were slightly amplified over this timespan. Hence, any SGA-related anomalies of these endocrine-ultrasound indices in young women seem to be largely predictable by early post-menarche; conversely, normal results in early post-menarche may be viewed as reassuring with respect to reproductive potential, although SGA-related anovulation or oligo-ovulation may still occur (Ibáñez et al., 2002c).
The early detection of SGA-related anomalies in reproductive organs and body composition is a perspective of mounting relevance, as it starts to have therapeutic consequences. For example, SGA-related central adiposity with anovulation or oligo-ovulation responds well, in teenage girls, to therapy with metformin (Ibáñez et al., 2002d). It remains to be studied, however, whether metformin treatment also has the capacity to modify uterine-ovarian size in SGA girls, and to attenuate any potential inter-generational effects of reduced uterine size. Indeed, birthweight of the mother is the prime factor accounting for the variability in the birthweight of human infants (Ounsted and Ounsted, 1968
; Klebanoff et al., 1989
; Hennessy et al., 1998
), and women born SGA are at risk for delivering, in turn, SGA and preterm infants (Klebanoff et al., 1989
; Magnus et al., 1997
; Hennessy et al., 1998
). Conceivably, a non-genomic mechanism, that modulates uterine size prenatally, provides a survival advantage, as it would allow the adaption of fetal growth in each generation, according to the growth conditions that the mother herself experienced as a fetus.
In conclusion, the gynaecology of young women born SGA was found to be characterized by persisting hypergonadotrophinaemia and by a reduced uterine and ovarian size; this is one more example of a gynaecological entity with an obstetric history. That the link between this entity and fetal restraint has escaped attention for so long, may in part be attributable to the fact that the majority of SGA women do not have a strikingly short stature, and therefore do not present an obvious reminder of their prenatal growth restraint.
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Acknowledgements |
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References |
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Submitted on April 2, 2003; accepted on May 8, 2003.