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Inhibin A, Inhibin B, Follicle-Stimulating Hormone, Luteinizing Hormone, Estradiol, and Sex Hormone-Binding Globulin Levels in 473 Healthy Infant Girls

University Department of Growth and Reproduction (M.C., I.M.S., K.A.B., I.N.D., C.M., J.H.P., A.J., N.E.S., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark; Departments of Paediatrics and Physiology (A.M.H.), University Hospital of Turku, FIN-20101 Turku, Finland; and Department of Biostatistics (J.H.P.), University of Copenhagen, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Marla Chellakooty, M.D., University Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen. E-mail: rh04632{at}rh.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20–175); FSH, 3.8 IU/liter (1.2–18.8); LH, 0.07 IU/liter (<0.05–1.07); estradiol, 31 pM (<18–83); SHBG, 137 nM (72–260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20–265)] than in term [80 pg/ml (<20–181), P = 0.002] and postmature girls [59 pg/ml (<20–152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18–128) vs. 31 pM (<18–85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend.

In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.

	Introduction

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THE PITUITARY-GONADAL AXIS is transiently active in infancy in a gender-specific pattern. In boys, high levels of FSH, LH, testosterone, estradiol, and inhibin B are found at 3–6 months of age. All hormones, except FSH, decrease after 6 months of age and remain low until puberty (1, 2, 3, 4, 5, 6, 7). In girls, FSH remains high until about 4 yr of age (4, 8, 9). Little is known about inhibins A and B in infant girls, because only very few and small studies exist (7, 10, 11). Inhibin B is the principal form of inhibin secreted in adult women in the follicular phase by the granulosa cells of the small antral follicles, whereas inhibin A is produced by the leading follicle at the time of ovulation and by the corpus luteum (12, 13). The function and importance of the early activation of the hypothalamus-gonadal axis in infancy is not completely understood but has been shown to be diagnostically useful in children suspected of hypogonadotropic hypogonadism (14). In boys, this activation of testosterone secretion contributes to postnatal phallic growth (15). A recent investigation suggested that girls born small for gestational age (SGA) had increased FSH levels in infancy (16). Furthermore, decreased ovarian volume, increased FSH levels (17), and reduced ovulation rate (18) have been reported in pubertal girls who were born SGA. These studies suggest that prenatal growth failure has some effects on differentiation of the gonads and, thereby, endocrine effects in later life. The aim of this study was to describe serum levels of inhibin A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of infant girls.

	Subjects and Methods

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Study participants and design

In a longitudinal prospective birth cohort study, 473 singleton girls had blood samples taken at approximately 3 months of age, corrected for expected date of delivery corresponding to approximately 370 d after conception. Mothers were recruited consecutively in the first trimester of pregnancy, during the period of May 1997 to October 2001, from two large University Hospitals in Copenhagen. Information regarding maternal medical history, smoking, parity, and parturition were obtained from hospital records. In one case, the pregnancy was complicated by gestational diabetes, and 18 mothers developed preeclampsia. Gestational age (GA) was routinely determined by ultrasound examination at 18–20 wk gestation. In case of discrepancy in clinical maturity at birth (>14 d), GA was corrected according to the clinical appearance (n = 6). All infant girls were thoroughly examined twice; approximately 3 d after birth and again at 3 months of age, when a blood sample was obtained. If the child was born pre- or postmaturely, blood sampling was performed 3 months after expected date of delivery. In the group of premature children (GA < 37 wk), four children had minor medical problems (mild hypoglycemia, brief postnatal mask ventilation), two developed transient respiratory distress syndrome, and one had ventricle rupture requiring surgery.

Anthropometric measurements

Length was measured with a portable infantometer (Kiddimeter; Raven Equipment Ltd., Essex, UK) to the nearest 0.1 cm. Weight was measured on a digital scale (Baby scale model; Solotop Oy, Helsinki, Finland) to the nearest 0.005 kg. The same team of trained doctors performed all examinations, and all methods of measuring were standardized at workshops attended by all examiners. The mean of three measurements was calculated for all measures.

Ethical aspects

The study was performed according to the Helsinki II declaration and approved by the local Ethical Committee [reference no. (KF) 01-030/97] and the Danish Registry Agency (journal no. 1997-1200-074). Only one attempt was made to obtain a blood sample from each child, and venipuncture was performed together with oral administration of sucrose syrup (19).

Laboratory methods

Nonfasting peripheral venous blood samples were taken from an antecubital vein between midmorning and late afternoon. Samples were separated by centrifugation and stored at -20 C until analysis.

Assays

FSH and LH were measured by a two-sided time-resolved fluoroimmunoassay (Delfia; Wallac, Inc., Turku, Finland) with detection limits of 0.06 and 0.05 IU/liter, respectively. The intra- and interassay coefficients of variation (CV) were less than 5% in both assays.

Total serum estradiol was measured by a RIA (Pantex Corp.; Immunodiagnostic Systems Limited, Santa Monica, CA). The intraassay CV was less than 7.5%, and the interassay CV was less than 13%. The detection limit was 18 pM. Serum inhibins A and B were measured, in duplicate, in a double antibody enzyme-immunometric assay using a monoclonal antibody raised against the inhibin ß_A- or ß_B-subunit, respectively, in combination with a labeled antibody raised against the -subunit. The detection limits were 17 and 20 pg/ml for inhibin A and inhibin B, respectively. Intra- and interassay CV were less than 15% and less than 16% for inhibin A and less than 15% and less than 18% for inhibin B, respectively (7, 12). The cross-reactivities for inhibin B and A in these two specific assays were 0.1% and 0.5%, respectively (13).

Statistical analysis

Descriptive statistics are given as median hormone values and reference ranges (2.5th and 97.5th percentiles). If a measured hormone concentration was below the limit of detection for the given assay, it was expressed as the limit of detection. Statistical analyses were repeated with undetectable values set at 1, but this did not change our results.

Hormone values were also grouped according to maturity and weight for GA: premature girls (GA < 37 wk), mature girls (37 wk GA 42 wk), and postmature (GA > 42 wk). Weight for GA was calculated using the reference data of Marsal (20). SGA was defined as birth weight for GA being below -22% (corresponding to -2 SD), appropriate for GA (AGA) being between -22% and +22% (equivalent to -2 SD to 2 SD), and large for GA (LGA) being larger than +22% (corresponding to +2 SD).

Statistical analysis was either performed on the total population (n = 473) or on a standardized population consisting of 355 AGA girls with blood samples taken around 370 d (±14 d) from time of conception (GA plus time since birth).

Differences in hormone concentration between groups were tested by Kruskal-Wallis tests, and thereafter they were compared two-by-two using the Mann-Whitney U test. Confidence intervals (CIs) are given as 95% intervals.

Before linear regression analysis, a log transformation was applied to improve the approximation to a normal distribution and to obtain better variance homogeneity. The final regression model included the following covariates: GA, physical age (age from conception to age at blood sampling), weight for GA, and weight at time of blood sampling. Residual plots were used to validate the models. Relationships between individual hormones were tested by Spearman rank correlation. The statistical analyses were carried out using the statistical package SPSS (version 11; SPSS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows the basic clinical characteristics of the study population. The median age at blood sampling was 3.1 months (range, 2.3–5.6). Maternal age was slightly higher in mothers who gave birth to SGA children (P = 0.049). There were no significant differences in other maternal characteristics among SGA, AGA, and LGA groups.

All hormones, except inhibin A, were measurable in the majority of individuals (Table 2). In 124 girls (38%), FSH values were above 4.5 IU/liter (periovulatory range in adult women). There was a considerable interindividual variation in FSH, LH, estradiol, SHBG, and inhibin B (Fig. 1). In the final multiple linear regression analyses (including GA > 37 to 42 wk, physical age, weight for GA, and weight at 3 months), both GA and weight at 3 months were significantly associated with estradiol (P = 0.001 and P = 0.048, respectively), i.e. AGA girls with low GA and low body weight at 3 months had the highest estradiol levels. There was a 3.5% decrease in estradiol per week of gestation (CI, 1.4–4.9%) and a 3.8% decrease per kilogram body weight (CI, 3.6–7.4%).

View larger version (33K): [in this window] [in a new window]   FIG. 1. Median FSH, LH, inhibins A and B, estradiol, and SHBG levels in infant girls, in relation to chronological age (age from birth to time of blood sampling). FSH and LH levels are plotted on a logarithmic y-axis. The lines represent 2.5, 50, and 97.5 percentiles.

Maturity (total population)

Inhibin B levels were significantly higher in girls born before 37 wk gestation, compared with girls born at term (P = 0.002) and post mature (P = 0.012) (Table 3). The same was true for estradiol levels in premature girls compared with mature (P = 0.009). In the multiple linear regression analysis (see above), inhibin B levels correlated negatively to GA, with a decrease in inhibin levels by 2.8% (CI, 0.7–4.9%) per week (P = 0.014).

Physical age had a significantly positive effect on SHBG (P = 0.006) at 3 months, with a 0.7% increase (CI, 0.4–2.1%) in SHBG per week. GA had a negative, but not significant, effect on FSH and LH.

Weight for GA (total population)

We found no significant differences in reproductive hormones if children were grouped into three categories as SGA, AGA, and LGA (Table 4). In the linear regression model (see above), however, which evaluates intrauterine growth as a continuum, estradiol was significantly negatively correlated to weight for GA (P = 0.046).

Relationship between hormones (total population)

Although inhibin A was below detection limit in the majority of samples, there was a significant (P < 0.0001) positive correlation to inhibin B levels (r = +0.35) in measurable samples. Inhibin B was significantly (P < 0.0001) positively correlated to estradiol (r = +0.32) and negatively to FSH (r = -0.45) and LH (r = -0.2). FSH and LH were strongly correlated to each other (r = +0.72, P < 0.0001). Estradiol showed significant correlation to SHBG (r = +0.15, P = 0.002) and LH (r = 0.22, P < 0.0001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this large prospective cohort of healthy infant girls, we found measurable inhibin B levels in 85% of the girls, whereas inhibin A levels were only detectable in 6% of the individuals. All other reproductive hormones were detectable as well, but they exhibited large interindividual variation, especially FSH. Levels of FSH and inhibins are important biomarkers of ovarian function in adult women. It is well known that the fetal oocyte number in midpregnancy is high but decreases rapidly in late pregnancy and early postnatal life (21). In infants, a sonographic study of ovaries showed a decrease in ovarian volumes and cysts that occurs with age within the first 2 yr of life, which may be related to the decreasing levels of gonadotropins (22). Interestingly, the median serum value of inhibin B in our study was higher than reported for prepubertal children and close to values seen in the follicular phase of the menstrual cycle in adult women (23). However, serum levels of inhibin B are considerably lower in girls than found in comparable studies of boys (the median in females was less than half of that in boys) (7, 11, 24).

Our data, which were generated with new specific and sensitive assays and based on a large unselected cohort of healthy infant girls, may be useful as future reference for clinical purposes. The median FSH level corresponded to high ranges observed in childhood, whereas the median level of LH was close to the detection limit of the assay and comparable with levels measured in early puberty (23). In 38% of the girls, FSH levels exceeded median values observed in periovulatory women (24). Our study design is not suitable for addressing the question of cyclic ovarian activity in infant girls. However, we speculate that the very high levels of FSH in some, together with the large interindividual variation in inhibin B and estradiol, as well as the correlations between reproductive hormones in infant girls, may be indicative of such a cyclic regulation (25).

FSH and inhibin B levels in infant girls were overlapping with concentrations found in premenarcheal girls at different pubertal stages (10, 23). We found overall low estradiol concentrations, comparable with levels seen in early pubertal girls (23); however, these still may exert biological actions (26). The median SHBG concentration corresponded to that of prepubertal girls (27). Girls with a high body weight had low levels of SHBG, a finding which also is seen in prepubertal obese girls (28).

GA showed an effect on reproductive hormone levels at 3 months of age, i.e. premature infants had significantly higher levels of inhibin B and estradiol than those of mature infants. A Finnish study also found that gonadotropin levels in premature girls were higher than in full-term girls, reaching the same levels at 10 wk. They suggested that the peak of reproductive hormones in premature girls was earlier, compared with term girls (29). Our study was not designed to address this question, because blood samples in our population were not taken longitudinally. However, our data seem to indicate that estradiol and inhibin B values in premature girls remain higher for a longer period postnatally than in girls born at term. Because blood samples in the premature children in this study were taken at the corrected age of 3 months, our data cannot address the question of whether or not serious illness has a short or long lasting impact on the hypothalamus-pituitary-gonadal axis in these children.

We found significantly higher levels of serum estradiol and a trend of higher levels of inhibin B and LH, as well as lower levels of FSH, in SGA girls, compared with AGA girls. This is in contradiction to the work recently presented by Ibanez et al. (16). They found higher levels of FSH in SGA girls and boys, suggesting that these infants need an augmented gonadotropin drive to fulfill the inhibin B requirements. In our study population, there was no such evidence of impaired ovarian function in SGA girls, even if the group of AGA girls was redefined, according to the definition of Ibanez et al., to include only children between -1 and +1 SD. Both studies include rather small numbers of SGA children and should therefore be interpreted with great care. The selection of individuals in the two studies also differs significantly. Our study group represents a random sample of the population before the outcome of pregnancy was known, whereas children were specifically selected for being SGA in the article of Ibanez et al. Given the large variation in physiological levels of reproductive hormones in normal infant girls, true longitudinal studies may be needed to study the aspect of reproductive function in infant girls with low birth weight.

In conclusion, based on a large cohort of unselected healthy 3-month-old infant girls, we have established detailed reference ranges for all reproductive hormones. FSH and inhibin B showed large interindividual variations. Concentrations of reproductive hormones in female infancy support the concept of a so-called mini puberty in infant girls, in line with findings in male infants.

	Acknowledgments

 
We thank pediatric nurse Helle Kelkeland, as well as technicians Kirsten Jørgensen, Ulla Højelse, and Ole Nielsen, for skilled technical assistance and are especially grateful to all families who participated in this study. We also thank the staff of the Obstetric and Neonatal Units of both University Hospitals for warm support and practical help in conducting the study.

	Footnotes

 
This work was supported by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422), and EXPORED (QLK4-2001-00269), by The Danish Medical Research Council (Grants 9700833 and 9700909), and by the Svend Andersens Foundation.

Abbreviations: AGA, Appropriate for gestational age; CI, confidence interval; CV, coefficient(s) of variation; GA, gestational age; LGA, large for gestational age; SGA, small for gestational age.

Received September 19, 2002.

Accepted March 24, 2003.

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