Objective: To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. Methods: In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. Results: HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. Conclusion: Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.

Adrenarche is the progressive maturational process of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) [1, 2]. Premature adrenarche (PA) is defined biochemically by concentrations of DHEAS above the prepubertal level before the age of 8 years in girls and 9 years in boys: 40 µg/dL (1.08 µmol/L) are within normal limits for early puberty but above average for children 6–8 years of age [3]. Adrenarche is clinically recognized by the presence of signs of androgen action, including adult-type body odor, oily skin, comedones/acne, and axillary and pubic hair growth.

PA has been associated with increased adiposity and metabolic risk [3, 4]. However, early infancy weight gain has also been associated with increased metabolic risk, earlier puberty, and PA [5‒7]. We recently found that high DHEAS (HD) around 7 years was associated with an increased risk of precocious pubertal events only in girls independent of adiposity and birth weight [8].

Areas of controversy regarding the comorbidities associated with biochemical adrenarche include whether there is an impact on the timing and sequence of pubertal events, and whether HD around 7 years determines an altered pattern of ovarian and adrenal androgen concentrations during pubertal development and ovarian morphology once menarche has occurred. Previously described associations may depend on the prevalence of low birth weight and ethnic background of the study population.

We took advantage of a well-characterized cohort of children enrolled in the Growth and Obesity Chilean Cohort Study (GOCS), a longitudinal study of Chilean children that included anthropometric determinations, pubertal assessment, and the measurement of hormonal concentrations during puberty. The two aims of this study were: first, to assess whether the presence of HD around 7 years determines a different timing, sequence, and rate of pubertal events. Second, we determined whether HD is followed by an altered pattern of adrenal androgen concentrations, early ovarian hyperandrogenism, and changes in ovarian morphology.

Subjects

We longitudinally evaluated 602 girls recruited in 2006 at the age of 3.0–4.9 years attending the Chilean National Nursery School Council Program (JUNJI) in the southeastern area of Santiago, Chile. The current study is a cross-sectional follow-up within GOCS, whose primary aim was to assess the association between early growth and development of adiposity and metabolic risk during childhood [9]. The initial inclusion criteria were as follows: singleton birth, gestational age 37–42 weeks, birth weight ≥2,500 and ≤4,500 g, and an absence of physical or psychological conditions that could severely affect growth [10].

Annual evaluations were conducted (anthropometry, body composition, skeletal and hormonal maturation, and metabolic/inflammatory markers), and, in 2009, we began to collect Tanner staging data on a 6-month basis. Maternal age at menarche was self-reported by the mother.

The Ethics Review Board of the Institute of Nutrition and Food Technology (INTA) of the University of Chile approved the study protocol. All parents or guardians of the children provided written informed consent, and the children gave their assent.

Pubertal Development

At the age of about 7 years, a single pediatric endocrinologist (V.M.) assessed pubertal staging via inspection and palpation according to the Tanner scale [11]. Subsequently, secondary sex characteristics were evaluated every 6 months by a single female dietitian trained specifically for this purpose, with permanent supervision of a single pediatric endocrinologist (V.M.). Breast Tanner stage concordance between the dietitian and the pediatric endocrinologist was 0.9 [12].

Age at menarche was self-reported. Girls were advised to call researchers from the first menses, and telephonic follow-up was performed every 6 months starting at breast Tanner stage 4 (B4); a questionnaire was developed to differentiate vaginal infections or other genitourinary conditions from the first menses.

Anthropometric Measurements

Weight and height were determined using standardized protocols (barefoot and light clothes) by 2 dietitians with inter- and intrarater correlation coefficients >0.80 for all measurements. Weight was measured with a portable electronic scale (Seca 770), with a precision of 0.1 kg, and height was measured with a portable stadiometer (Harpenden 603) to the nearest 0.1 cm. Body mass index (BMI) was calculated by dividing weight in kilograms (kg) by height in meters squared (m2). We described height for age and BMI for age in standard deviation scores (SDS) based on the WHO 2006 standards and the WHO 2007 growth reference [13].

We defined obesity as BMI-SDS ≥2. A complete description of the anthropometric methodology is found elsewhere [14]. Birth weight was obtained from medical records, and the quality of the data was previously assessed [15].

Ultrasonographic Study

Gynecological ultrasound examinations were performed 1 year after menarche by 2 observers using a GE Logiq P 5 Ultrasound system (GE KPI Health Care Inc., CA, USA) with a 5-MHz transabdominal probe. The ultrasound was performed during the early follicular phase of the menstrual cycle (postmenstrual days 2–7). Measurements were performed in real time with the highest possible magnification to view the ovaries. The longest medial axis (length) and its corresponding thickness and width were measured to calculate ovarian volume (OV) according to the formula of the volume of a sphere or prolate ellipse (0.5 × length × width x thickness in cm) [16]. Polycystic ovarian morphology (PCOM) was defined as the presence of an OV >12 mL in at least 1 ovary according to the definition of PCOM in adolescents by the World Pediatric Consensus for Polycystic Ovarian Syndrome (PCOS) [17]. The intra-observer variation coefficients of the ultrasonographic study were 3.2 and 4.1% for OV, respectively. In cases where a dominant follicle or cyst >10 mm was observed, the ultrasound was repeated during another menstrual cycle. Adolescents with pathological images in the ultrasound assessment were excluded from the analysis. In each patient, the ovary with the larger OV and larger number of follicles was reported. In total, 396 ultrasounds were performed, 26 measurements were repeated, and 1 girl was excluded because of pathological findings.

Hormonal Determinations

Hormonal levels were determined by a blood sample at around 7 years of age and during pubertal progression by a fasting venous sample obtained early in the morning.

Mothers were contacted the day before blood sampling to confirm the absence of fever (37.5°C) or symptoms of acute infection in the children. Samples were analyzed at the Institute of Maternal and Child Research, University of Chile. At around 7 years of age, serum DHEAS was determined by competitive specific binding RIA as we previously described [8] supplied by Diagnostic System Laboratories (Webster, TX, USA); the intra- and interassay coefficients of variation were 3.5 and 5.1%, respectively. Thereafter, samples were obtained at breast Tanner stage 2 (B2), B4, and 1 year after menarche. The latter sample was obtained in the early follicular phase (days 2–7 of the menstrual cycle) before 8:30 a.m.

Concentrations of DHEAS, androstenedione17-OH progesterone (17-OHP), and testosterone were analyzed by liquid chromatography-mass spectrometry in a high-performance liquid chromatography (HPLC) Agilent system (Santa Clara, CA, USA) 1260 coupled to an AB Sciex 3200 Quantum ultratriple quadrupole mass spectrometer (Foster City, CA, USA).

The liquid chromatography separation was carried out on a 150-mm long column with 300 μm of internal diameter packed with 4 μm Synergi Hydro-RP particles and maintained at 40°C. Samples were processed by a Chromsystems kit (Chromsystems Instruments & Chemicals, Gräfelfing, Germany). Samples, calibrators, and quality controls were run in duplicate and prepared according to the manufacturer’s instructions. Briefly, 25 μL of precipitation reagent and 200 μL of internal standard were added to 100 μL of serum sample. After an incubation period of 10 min, samples were centrifuged at 15,000 g for 5 min, and 200 μL were transferred into the vials. Fifty microliters were injected into the HPLC-tandem mass spectrometry system. The total run time was 10.5 min. Steroid recovery was between 81 and 108%. The sensitivities for DHEAS, androstenedione, 17-OHP, and testosterone were 75, 0.03, 0.05, and 0.01 ng/mL, respectively. The corresponding intra-assay coefficients of variation were 2.9, 1.2, 2.0, and 2.9%, respectively. The corresponding interassay coefficients of variation were 5.0, 6.8, 2.5, and 2.8%, respectively. The measurements of luteinizing hormone (LH), follicle-stimulating hormone (FSH) (sensitivity = 0.06 mIU/mL), and sex hormone-binding globulin (SHBG) (sensitivity = 0.5 nmol/L) were performed using an immunoradiometric assay (Izotop Laboratories, Budapest, Hungary). Serum estradiol was measured by RIA (Pantex, Santa Mónica, CA, USA). The sensitivity of this assay is 5.0 pg/mL. Serum antimüllerian hormone (AMH) was measured using the Beckman-Coulter Gen 2 ELISA assay with no predilution (Immunotech; Beckman Coulter Inc., Prague, Czech Republic). The intra- and interassay coefficients of variation for FSH, LH, SHBG, estradiol, and AMH were 4.0–5.3, 4.5–5.6, 3.9–6.9, and 5.7–7.9% and both less than 5%, respectively. SHBG and testosterone were used to calculate the free androgen index (FAI), as reported previously [18].

Statistical Analysis

Girls were categorized into the HD group or the normal DHEAS (ND) group based on the sample obtained in 2009 at around 7 years of age. The girls were classified as HD if they had a DHEAS level >42.1 µg/dL (>75th percentile of the distribution of our population) [14].

Age at any pubertal event was considered as the midpoint between 2 consecutive visits, e.g., age at B2 was considered the age between the last visit at B1 and the visit in which B2 was detected. In the case that a girl was already at B2 or greater when we started Tanner evaluation (2009) (n = 39), we assumed that she was Tanner 1 at age 5 years (in 2006–2007, the girls did not have any signs of puberty).

Descriptive analyses (mean, SDS, and percentage) of anthropometric, hormonal characteristics, and sexual maturation data were performed by stratifying by HD and ND status. Statistical differences between the groups (HD vs. ND) were assessed using the χ2 and Student t test, as appropriate, and the Mann-Whitney test was used to compare differences in the medians of hormonal levels.

Linear regression models were performed to assess the relationship between DHEAS around 7 years of age and pubertal onset, timing and progression, hormonal profile during puberty, and ovarian morphology 1 year after menarche adjusting for chronological age at DHEAS sampling, BMI-SDS at age of DHEAS sampling, birth weight, and maternal age at menarche.

Analysis was carried out in STATA version 15.0, and the results were considered significant at a value of p < 0.05.

In 2009, we collected blood samples from 504 girls (84% of the original cohort) who were evaluated when they were around 7 years old and classified the participants by DHEAS level into the HD and ND groups. HD was present in the blood samples of 137 girls (27%). The mean birth weight of the HD group was slightly lower than that of the ND group (Table 1). Girls with HD had a higher mean BMI at age 7 years, a higher waist-to-hip ratio, and a greater prevalence of obesity. The percentage of girls with fast weight gain, defined as a change between birth and 2 years of ≥0.67 SDS, was not different between the girls in the HD and ND groups (Table 1).

Table 1.

Clinical and anthropometric characteristics of 504 girls by DHEAS levels at around 7 years of age

 Clinical and anthropometric characteristics of 504 girls by DHEAS levels at around 7 years of age
 Clinical and anthropometric characteristics of 504 girls by DHEAS levels at around 7 years of age

Timing, Sequence, and Rate of Pubertal Events

B2 was detected during biannual visits in 472 girls (HD, n = 127), and B4 was detected in 452 girls (HD, n = 124); 380 adolescents completed the follow-up 1 year after menarche (HD, n = 105). The girls with HD presented earlier B2, earlier pubarche (P2), earlier age at B4, and earlier menarche. There was no difference in the first clinical secondary sex characteristic detected, being thelarche in 50 and 49% of HD and ND girls, respectively. Nevertheless, the mean time difference between B2 and menarche was similar in the HD and ND girls (Table 2). In linear regression analyses between DHEAS levels around 7 years of age and pubertal timing and ovarian volume, the above findings persisted even after adjusting for age at DHEAS sampling, BMI-SDS around 7 years, birth weight, and mother’s age at menarche (online suppl. ­Table 1; for all online suppl. material, see www.karger.com/ doi/10.1159/000506632).

Table 2.

Pubertal timing, rate, and sequence of 504 girls participating in the Growth and Obesity Chilean Cohort Study according to DHEAS levels at around 7 years of age

 Pubertal timing, rate, and sequence of 504 girls participating in the Growth and Obesity Chilean Cohort Study according to DHEAS levels at around 7 years of age
 Pubertal timing, rate, and sequence of 504 girls participating in the Growth and Obesity Chilean Cohort Study according to DHEAS levels at around 7 years of age

Hormonal Profile

Girls with HD around 7 years had higher concentrations of DHEAS; androstenedione, testosterone, and FAI at B2 than those with ND. The situation was similar at B4 and 1 year after menarche, except for testosterone, which did not differ between the groups after B2. Furthermore, a lower AMH level was observed at B2, and a lower SHBG level was observed from B4 onwards in the HD group. No difference between the HD and ND girls was detected in serum gonadotropin or estradiol concentrations during the follow-up (Table 3). In linear regression models, once the hormonal concentrations and FAI were adjusted by age and BMI SDS at first DHEAS determination around 7 years of age, BMI at pubertal stage, and birth weight SDS, HD was associated with higher androstenedione and testosterone at B2 and B4 and with higher FAI 1 year after menarche. Moreover, HD around 7 years was associated with lower AMH levels at B2 and with lower SHBG levels 1 year after menarche (online suppl. Table 2).

Table 3.

Hormonal profile and ovarian morphology according to DHEAS levels at around 7 years of age and pubertal stage

 Hormonal profile and ovarian morphology according to DHEAS levels at around 7 years of age and pubertal stage
 Hormonal profile and ovarian morphology according to DHEAS levels at around 7 years of age and pubertal stage

Ultrasonographic Assessment

The mean OV was similar in the HD and ND groups 1 year after menarche. PCOM was equally frequent in girls with HD versus ND (Table 3). OV correlated with AMH (r = 0.24, p < 0.001), LH (r = 0.16, p < 0.005), total testosterone (r = 0.16, p < 0.005), androstenedione (r = 0.12, p < 0.05), FAI (r = 0.12, p < 0.05) in all postmenarcheal adolescents, even after adjusting for potential confounders (BMI and birth weight). OV was not correlated with DHEAS levels at 7 years.

In this longitudinal sample of term-born girls with normal birth size recruited from the community, we observed that having high concentrations of DHEAS at 7 years was associated with earlier age at thelarche, pubarche, and menarche with persistent higher concentrations of androgens (although within the normal range) through puberty, even after adjusting for BMI-SDS and age at DHEAS stratification and birth weight. Higher DHEAS levels at around 7 years of age were associated with lower AMH levels at the beginning of puberty. Finally, HD and ND adolescents had similar OV 1 year after menarche, and a similar percentage of PCOM prevalence. OV correlated positively with LH, AMH, testosterone, and androstenedione in all adolescents.

In 2014, in a study by Mäntyselkä et al. [19], the prevalence of PA, defined by a serum DHEAS concentration ≥1 µmol/L (≥37 µg/dL) and any clinical sign before the age of 8 years in girls and 9 years in boys, was 8.6% in girls and 1.8% in boys, despite a similar prevalence of biochemical adrenarche between the sexes. This cross-sectional study did not evaluate later associations of adrenarche. We previously reported, in the same cohort analyzed in this study, that HD was associated with a 2.6-times greater risk of precocious thelarche and a 3-times higher risk of precocious pubarche compared to ND girls [8]. Therefore, we decided to follow these girls to study whether the described clinical and biochemical associations described in Catalonian PA girls [20‒23] persisted throughout pubertal development in our study subjects with higher DHEAS at the age of 7 years.

Previous studies have not been able to fully elucidate the relationship of biochemical PA (i.e., high DHEAS concentrations) with ovarian hyperandrogenism. Most of the studies included patients with clinically evident signs of adrenarche. Ibañez et al. [20, 22], in a group of 35 Catalonian adolescents with PA (premature pubarche as a clinical sign), reported that 45% of the adolescents developed PCOS characterized by hirsutism, menstrual disturbances, and elevated androgen levels. Ovarian stimulation with a GnRH analog in this cohort resulted in exaggerated levels of 17-OHP and androstenedione, which correlated with baseline DHEAS and androstenedione levels at the time of premature pubarche. The pattern of ovarian hyperresponsiveness was more pronounced during mid- and late puberty and was associated with hyperinsulinism [20]. Furthermore, they also observed adrenal hyperresponsiveness following ACTH stimulation before and after menarche [23]. In contrast, both ACTH and GnRH stimulation tests in a smaller sample of American girls with precocious pubarche revealed exclusively adrenal hyperresponsiveness, not supporting the hypothesis that premature pubarche was associated with prepubertal evidence of ovarian hyperandrogenism [24]. Adrenal androgen excess has been described to occur in up to 50% of patients with PCOS [25‒27]. However, a more careful cluster analysis of 213 women with PCOS and 182 age-matched healthy eumenorrheic nonhirsute women indicated that the prevalence of supranormal DHEAS levels was 33.3 and 19.9% among black and white women with PCOS, respectively [28].

Two studies on precocious pubarche in girls have measured AMH, a marker of ovarian granulosa cell function that is increased in women with PCOS. In a cross-sectional study in Scottish girls with exaggerated adrenarche, AMH levels were elevated, suggesting advanced ovarian follicular development [29]. Another case-control study found normal AMH levels in Finnish prepubertal girls with PA, in contrast to prepubertal daughters of women with PCOS [30]. Intravenous GnRH tests induce lower serum AMH levels, which have a negative correlation with the increase in gonadotrophins; nevertheless, gonadotropin concentrations did not differ in our girls at early pubertal stage [31]. The lower serum concentration of AMH at the beginning of puberty in HD girls might be related to the milder hyperandrogenic milieu observed. It is known that androgen exposure results in reduced AMH, amhr2,and Bmp15 expression in pre-antral follicles in vitro [32].

In this study, 96 of the girls were born within the lower third of the birth weight distribution of this sample: 2.5–3 kg, and 36% of them belonged to the HD group. All our results persisted after adjusting for birth weight and BMI-SDS around 7 years of age. Furthermore, it seems that by early adulthood, the subjects born small for gestational age do not show any higher DHEAS secretion than those born appropriate for gestational age [33‒35]. Four birth cohort studies have not found a relationship between low birth weight and PCOS in adult women; actually, a high birth weight was associated with PCOS [36‒39]. Nevertheless, premature subjects born small for gestational age may behave differently, as they have been reported to maintain higher serum DHEAS concentrations than full-term controls until 20 years of age [40, 41].

The similar ovarian volume and prevalence of PCOM 1 year after menarche in HD and ND adolescents, who showed differences in androstenedione levels and FAI, could be attributed to the fact that PCOM is an inconsistent finding in healthy girls, especially during early puberty [42, 43].

We and others have described that the condition of PA is associated with increased BMI. An early childhood acceleration in BMI has been recently reported to be highly predictive of persistent obesity into young adulthood [44]. Therefore, lifestyle interventions including increasing physical activity and eating a healthy diet, which reduce overweight, are the cornerstone for the prevention of this condition.

Progress in defining the mechanisms that regulate adrenal androgen production has been hampered by the fact that research has focused on DHEAS, which is abundant only in some primates. As we previously mentioned, HD is not always linked to clinical manifestations of androgen actions. In fact, in the above-mentioned study, 16.6% of girls had high DHEAS, but only 50% of them had clinical manifestations [19]. Clinical manifestations may depend on hair follicle sensitivity to androgens, androgen metabolism, and other more potent adrenal androgens, which have recently been described as part of the adrenarche repertoire and may increase in a different proportion to DHEAS [45, 46].

Our study is not exempt from limitations: (1) we could have misclassified age at sexual appearance because we used the midpoint between 2 consecutive visits; however, to overcome this problem, we carried out sensitivity analysis modifying the cutoff point in the interval of the 2 visits, and we confirmed our findings; (2) in 36 girls, DHEAS determination around 7 years of age occurred at the moment of thelarche, increasing the possibility of reverse causality, but our analysis remained significant after excluding these girls; (3) the results are only applicable to girls born at term and within the birth weight range of the participants included; and (4) results of ovarian ultrasound have the inherent limitations of ultrasound performed using the transabdominal route and after 1 year of menarche. The anatomic appearance of the ovary changes with age; the volume increases during puberty and reaches the adult volume in the years following menarche [47]. Nevertheless, this study has also several strengths: (1) a unique longitudinal follow-up of unselected girls beginning at age 3–4 years; (2) visits every 6 months to assess sexual maturation; (3) a highly trained evaluator to assess sexual maturation data (κ > 0.8); and (4) methods used to assess androgens are highly specific and sensitive.

In summary, in a longitudinal sample of Chilean girls, high DHEAS levels at 7 years in normal girls without clinical symptoms or signs was associated with earlier breast and pubic hair development and menarche in addition to a mild increase in androgen levels, although within normal concentrations, throughout puberty. We believe our findings support continuous follow-up of this cohort as a unique opportunity to prospectively address the inter­relationships between childhood DHEAS levels, early growth, and adiposity as determinants of ovarian function.

We thank the GOCS families and children for their participation. Everyone who contributed significantly to the work has been listed.

The Ethics Review Board of the Institute of Nutrition and Food Technology (INTA) of the University of Chile approved the study protocol. All parents or guardians of the children provided written informed consent, and the children gave their assent.

The authors have no conflicts of interest to disclose.

The study was supported by FONDECYT grant 1140447 to V.M., FONDECYT grant 1120326 to C.C. and FONDECYT grant 11170670 to A.P., and a scientific career award from the European Society of Pediatric Endocrinology to V.M. Sponsors were not involved in the study design; collection, analysis, or interpretation of data; manuscript writing; or submission decision.

This work was supported by FONDECYT grants 1140447, 1120326, and 11170670 from the Fondo Nacional de Desarrollo Científico y Tecnológico, Chile.

1.
Palmert
MR
,
Hayden
DL
,
Mansfield
MJ
,
Crigler
JF
Jr
,
Crowley
WF
Jr
,
Chandler
DW
, et al
.
The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process
.
J Clin Endocrinol Metab
.
2001
Sep
;
86
(
9
):
4536
42
.
[PubMed]
0021-972X
2.
Remer
T
,
Boye
KR
,
Hartmann
MF
,
Wudy
SA
.
Urinary markers of adrenarche: reference values in healthy subjects, aged 3-18 years
.
J Clin Endocrinol Metab
.
2005
Apr
;
90
(
4
):
2015
21
.
[PubMed]
0021-972X
3.
Utriainen
P
,
Jääskeläinen
J
,
Romppanen
J
,
Voutilainen
R
.
Childhood metabolic syndrome and its components in premature adrenarche
.
J Clin Endocrinol Metab
.
2007
Nov
;
92
(
11
):
4282
5
.
[PubMed]
0021-972X
4.
Ibáñez
L
,
Potau
N
,
Marcos
MV
,
de Zegher
F
.
Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age
.
J Clin Endocrinol Metab
.
1999
Dec
;
84
(
12
):
4739
41
.
[PubMed]
0021-972X
5.
Ibáñez
L
,
Potau
N
,
de Zegher
F
.
Precocious pubarche, dyslipidemia, and low IGF binding protein-1 in girls: relation to reduced prenatal growth
.
Pediatr Res
.
1999
Sep
;
46
(
3
):
320
2
.
[PubMed]
0031-3998
6.
Salgin
B
,
Norris
SA
,
Prentice
P
,
Pettifor
JM
,
Richter
LM
,
Ong
KK
, et al
.
Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche
.
Int J Obes
.
2015
Jun
;
39
(
6
):
939
44
.
[PubMed]
0307-0565
7.
Ozerlat
I
.
Growth and development: high early postnatal weight gain linked to adult metabolic syndrome
.
Nat Rev Endocrinol
.
2012
May
;
8
(
8
):
448
.
[PubMed]
1759-5029
8.
Pereira
A
,
Iñiguez
G
,
Corvalan
C
,
Mericq
V
.
High DHEAS Is Associated With Earlier Pubertal Events in Girls But Not in Boys
.
J Endocr Soc
.
2017
May
;
1
(
7
):
800
8
.
[PubMed]
2472-1972
9.
Corvalán
C
,
Uauy
R
,
Kain
J
,
Martorell
R
.
Obesity indicators and cardiometabolic status in 4-y-old children
.
Am J Clin Nutr
.
2010
Jan
;
91
(
1
):
166
74
.
[PubMed]
0002-9165
10.
Kain
J
,
Corvalán
C
,
Lera
L
,
Galván
M
,
Uauy
R
.
Accelerated growth in early life and obesity in preschool Chilean children
.
Obesity (Silver Spring)
.
2009
Aug
;
17
(
8
):
1603
8
.
[PubMed]
1930-7381
11.
Marshall
WA
,
Tanner
JM
.
Variations in pattern of pubertal changes in girls
.
Arch Dis Child
.
1969
Jun
;
44
(
235
):
291
303
.
[PubMed]
0003-9888
12.
Pereira
A
,
Garmendia
ML
,
González
D
,
Kain
J
,
Mericq
V
,
Uauy
R
, et al
.
Breast bud detection: a validation study in the Chilean growth obesity cohort study
.
BMC Womens Health
.
2014
Aug
;
14
(
1
):
96
.
[PubMed]
1472-6874
13.
de Onis
M
,
Garza
C
,
Victora
CG
,
Onyango
AW
,
Frongillo
EA
,
Martines
J
.
The WHO Multicentre Growth Reference Study: planning, study design, and methodology
.
Food Nutr Bull
.
2004
Mar
;
25
(
1
Suppl
):
S15
26
.
[PubMed]
0379-5721
14.
Corvalán
C
,
Uauy
R
,
Mericq
V
.
Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight
.
Am J Clin Nutr
.
2013
Feb
;
97
(
2
):
318
25
.
[PubMed]
0002-9165
15.
Kain
J
,
Galván
M
,
Taibo
M
,
Corvalán
C
,
Lera
L
,
Uauy
R
.
[Evolution of the nutritional status of Chilean children from preschool to school age: anthropometric results according to the source of the data]
.
Arch Latinoam Nutr
.
2010
Jun
;
60
(
2
):
155
9
.
[PubMed]
0004-0622
16.
Porter
MB
.
Polycystic ovary syndrome: the controversy of diagnosis by ultrasound
.
Semin Reprod Med
.
2008
May
;
26
(
3
):
241
51
.
[PubMed]
1526-8004
17.
Witchel
SF
,
Oberfield
S
,
Rosenfield
RL
,
Codner
E
,
Bonny
A
,
Ibáñez
L
, et al
.
The Diagnosis of Polycystic Ovary Syndrome during Adolescence
.
Horm Res Paediatr
.
2015
Apr
;
83
(
6
):
376
89
.
[PubMed]
1663-2818
18.
Vermeulen
A
,
Verdonck
L
,
Kaufman
JM
.
A critical evaluation of simple methods for the estimation of free testosterone in serum
.
J Clin Endocrinol Metab
.
1999
Oct
;
84
(
10
):
3666
72
.
[PubMed]
0021-972X
19.
Mäntyselkä
A
,
Jääskeläinen
J
,
Lindi
V
,
Viitasalo
A
,
Tompuri
T
,
Voutilainen
R
, et al
.
The presentation of adrenarche is sexually dimorphic and modified by body adiposity
.
J Clin Endocrinol Metab
.
2014
Oct
;
99
(
10
):
3889
94
.
[PubMed]
0021-972X
20.
Ibáñez
L
,
Potau
N
,
Zampolli
M
,
Street
ME
,
Carrascosa
A
.
Girls diagnosed with premature pubarche show an exaggerated ovarian androgen synthesis from the early stages of puberty: evidence from gonadotropin-releasing hormone agonist testing
.
Fertil Steril
.
1997
May
;
67
(
5
):
849
55
.
[PubMed]
0015-0282
21.
Ibanez
L
,
Potau
N
,
Zampolli
M
,
Prat
N
,
Virdis
R
,
Vicens-Calvet
E
, et al
.
Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism
.
J Clin Endocrinol Metab
.
1996
Mar
;
81
(
3
):
1237
43
.
[PubMed]
0021-972X
22.
Ibañez
L
,
Potau
N
,
Virdis
R
,
Zampolli
M
,
Terzi
C
,
Gussinyé
M
, et al
.
Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism
.
J Clin Endocrinol Metab
.
1993
Jun
;
76
(
6
):
1599
603
.
[PubMed]
0021-972X
23.
Ibáñez
L
,
Potau
N
,
Marcos
MV
,
De Zegher
F
.
Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche
.
Clin Endocrinol (Oxf)
.
2000
Oct
;
53
(
4
):
523
7
.
[PubMed]
0300-0664
24.
Mathew
RP
,
Najjar
JL
,
Lorenz
RA
,
Mayes
DE
,
Russell
WE
.
Premature pubarche in girls is associated with functional adrenal but not ovarian hyperandrogenism
.
J Pediatr
.
2002
Jul
;
141
(
1
):
91
8
.
[PubMed]
0022-3476
25.
Carmina
E
,
Stanczyk
FZ
,
Chang
L
,
Miles
RA
,
Lobo
RA
.
The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women
.
Fertil Steril
.
1992
Jul
;
58
(
1
):
148
52
.
[PubMed]
0015-0282
26.
Hoffman
DI
,
Klove
K
,
Lobo
RA
.
The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women
.
Fertil Steril
.
1984
Jul
;
42
(
1
):
76
81
.
[PubMed]
0015-0282
27.
Carmina
E
,
Rosato
F
,
Jannì
A
.
Increased DHEAs levels in PCO syndrome: evidence for the existence of two subgroups of patients
.
J Endocrinol Invest
.
1986
Feb
;
9
(
1
):
5
9
.
[PubMed]
0391-4097
28.
Kumar
A
,
Woods
KS
,
Bartolucci
AA
,
Azziz
R
.
Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS)
.
Clin Endocrinol (Oxf)
.
2005
Jun
;
62
(
6
):
644
9
.
[PubMed]
0300-0664
29.
Paterson
WF
,
Ahmed
SF
,
Bath
L
,
Donaldson
MD
,
Fleming
R
,
Greene
SA
, et al
.
Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry
.
Clin Endocrinol (Oxf)
.
2010
Apr
;
72
(
4
):
496
501
.
[PubMed]
0300-0664
30.
Utriainen
P
,
Jääskeläinen
J
,
Voutilainen
R
.
Serum anti-müllerian hormone concentrations in prepubertal girls with and without premature adrenarche: the influence of body mass index
.
Horm Res Paediatr
.
2010
;
74
(
3
):
207
11
.
[PubMed]
1663-2818
31.
van Helden
J
,
Evliyaoglu
O
,
Weiskirchen
R
.
Has GnRH a direct role in AMH regulation
.
Clin Endocrinol (Oxf)
.
2019
Jun
;
90
(
6
):
827
33
.
[PubMed]
0300-0664
32.
Laird
M
,
Thomson
K
,
Fenwick
M
,
Mora
J
,
Franks
S
,
Hardy
K
.
Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily
.
Endocrinology
.
2017
Apr
;
158
(
4
):
920
35
.
[PubMed]
0013-7227
33.
Jaquet
D
,
Leger
J
,
Chevenne
D
,
Czernichow
P
,
Levy-Marchal
C
.
Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women
.
J Clin Endocrinol Metab
.
1999
Nov
;
84
(
11
):
3945
9
.
[PubMed]
0021-972X
34.
Beck Jensen
R
,
Vielwerth
S
,
Larsen
T
,
Hilsted
L
,
Cohen
A
,
Hougaard
DM
, et al
.
Influence of fetal growth velocity and smallness at birth on adrenal function in adolescence
.
Horm Res Paediatr
.
2011
;
75
(
1
):
2
7
.
[PubMed]
1663-2818
35.
Todorova
B
,
Salonen
M
,
Jääskeläinen
J
,
Tapio
A
,
Jääskeläinen
T
,
Palvimo
J
, et al
.
Adrenocortical hormonal activity in 20-year-old subjects born small or appropriate for gestational age
.
Horm Res Paediatr
.
2012
;
77
(
5
):
298
304
.
[PubMed]
1663-2818
36.
Cresswell
JL
,
Barker
DJ
,
Osmond
C
,
Egger
P
,
Phillips
DI
,
Fraser
RB
.
Fetal growth, length of gestation, and polycystic ovaries in adult life
.
Lancet
.
1997
Oct
;
350
(
9085
):
1131
5
.
[PubMed]
0140-6736
37.
Laitinen
J
,
Taponen
S
,
Martikainen
H
,
Pouta
A
,
Millwood
I
,
Hartikainen
AL
, et al
.
Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms
.
Int J Obes Relat Metab Disord
.
2003
Jun
;
27
(
6
):
710
5
.
[PubMed]
38.
Meas
T
,
Deghmoun
S
,
Lévy-Marchal
C
,
Bouyer
J
.
Fertility is not altered in young adults born small for gestational age
.
Hum Reprod
.
2010
Sep
;
25
(
9
):
2354
9
.
[PubMed]
0268-1161
39.
Mumm
H
,
Kamper-Jørgensen
M
,
Nybo Andersen
AM
,
Glintborg
D
,
Andersen
M
.
Birth weight and polycystic ovary syndrome in adult life: a register-based study on 523,757 Danish women born 1973-1991
.
Fertil Steril
.
2013
Mar
;
99
(
3
):
777
82
.
[PubMed]
0015-0282
40.
Szathmári
M
,
Vásárhelyi
B
,
Tulassay
T
.
Effect of low birth weight on adrenal steroids and carbohydrate metabolism in early adulthood
.
Horm Res
.
2001
;
55
(
4
):
172
8
.
[PubMed]
0301-0163
41.
Meuwese
CL
,
Euser
AM
,
Ballieux
BE
,
van Vliet
HA
,
Finken
MJ
,
Walther
FJ
, et al
.
Growth-restricted preterm newborns are predisposed to functional adrenal hyperandrogenism in adult life
.
Eur J Endocrinol
.
2010
Oct
;
163
(
4
):
681
9
.
[PubMed]
0804-4643
42.
Codner
E
,
Villarroel
C
,
Eyzaguirre
FC
,
Lopez
P
,
Merino
PM
,
Perez-Bravo
F
, et al
.
Polycystic ovarian morphology in postmenarchal adolescents.
Fertil Steril.
2011
;95(2):702-6 e1-2.
43.
Merino
PM
,
Villarroel
C
,
Jesam
C
,
López
P
,
Codner
E
.
New Diagnostic Criteria of Polycystic Ovarian Morphology for Adolescents: Impact on Prevalence and Hormonal Profile
.
Horm Res Paediatr
.
2017
;
88
(
6
):
401
7
.
[PubMed]
1663-2818
44.
Geserick
M
,
Vogel
M
,
Gausche
R
,
Lipek
T
,
Spielau
U
,
Keller
E
, et al
.
Acceleration of BMI in Early Childhood and Risk of Sustained Obesity
.
N Engl J Med
.
2018
Oct
;
379
(
14
):
1303
12
.
[PubMed]
0028-4793
45.
Lardone
MC
,
Castro
A
,
Pereira
A
,
Corvalán
C
,
Ortíz
E
,
Mericq
V
.
Role of the androgen receptor gene CAG repeat polymorphism on the sequence of pubertal events and adiposity in girls with high dehydroepiandrosterone sulfate
.
J Pediatr Adolesc Gynecol
.
2019
Jun
;
32
(
3
):
271
7
.
[PubMed]
1083-3188
46.
Rege
J
,
Turcu
AF
,
Kasa-Vubu
JZ
,
Lerario
AM
,
Auchus
GC
,
Auchus
RJ
, et al
.
11-Ketotestosterone Is the Dominant Circulating Bioactive Androgen During Normal and Premature Adrenarche
.
J Clin Endocrinol Metab
.
2018
Dec
;
103
(
12
):
4589
98
.
[PubMed]
0021-972X
47.
Holm
K
,
Laursen
EM
,
Brocks
V
,
Müller
J
.
Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls
.
Ultrasound Obstet Gynecol
.
1995
Sep
;
6
(
3
):
175
81
.
[PubMed]
0960-7692

Additional information

P.M.M. and A.P. contributed equally to this study.