LH Dynamics in Overweight Girls with Premature Adrenarche and Slowly Progressive Sexual Precocity
© Brian Bordini et al. 2010
Received: 8 June 2010
Accepted: 5 August 2010
Published: 9 August 2010
Background. Excess adiposity and premature adrenarche (PA) are risk factors for the development of polycystic ovary syndrome (PCOS). Methods. Girls with slowly progressive precocious breast development, who were overweight and had PA (SPPOPA, 6.2–8.2 years, ), overweight PA (6.6–10.8 years, ), and overweight premenarcheal controls (OW-PUB, 10.6–12.8 years, ) underwent hormonal sleep testing and GnRH agonist (GnRHag) and ACTH tests. Results. Despite an insignificant sleep-related increase in LH and prepubertal baseline hormone levels, SPPOPA peak LH and estradiol responses to GnRHag were intermediate between those of PA and OW-PUB, the LH being significantly different from both. Conclusions. GnRHag tests indicate that SPPOPA is a slowly progressive form of true puberty with blunted LH dynamics. These results argue against the prepubertal hyperandrogenism of excess adiposity or PA enhancing LH secretion or causing ovarian hyperandrogenism prior to menarche. Excess adiposity may contribute to both the early onset and slow progression of puberty.
We have characterized a variant group of sexually precocious girls who presented diagnostic challenges that provided an opportunity to test hypotheses about pubertal pathophysiology. They met current criteria for sexual precocity, with breast and pubic hair development before 8 years of age [1–3]. However, they differed from girls with typical central precocious puberty (also termed complete, true, or gonadotropin-dependent premature puberty) because they had slowly progressive precocious breast development [4–6], were overweight, and had premature adrenarche (SPPOPA). Their early morning LH serum levels were also persistently prepubertal during the initial observation period. About one-third of girls with central precocity are overweight , about half have premature adrenarche (PA) , although it causes pseudoprecocity independently of true puberty , and only about 10% have early morning LH levels in the prepubertal range . Thus, our SPPOPA group presented an uncommon, but not rare, combination of findings.
Their peripubertal adiposity and hyperandrogenism suggested that they were at risk of developing polycystic ovary syndrome (PCOS), a hyperandrogenic anovulation disorder that is often accompanied by obesity . Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia [11–13]. PA, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese and African-American or Hispanic girls [10, 14, 15].
The diagnostic challenge was to determine whether SPPOPA girls had early activation of the neuroendocrine-gonadal axis that ordinary testing failed to capture, whether their thelarche was due to adiposity-related peripheral estrogen formation , or whether they simply had pseudothelarche due to adipomastia. If they had adipomastia or estrogen excess of peripheral origin, one would expect LH dynamics to be suppressed, that is, no greater than the prepubertal pattern expected in isolated PA. If they had central precocity related to PA predisposing to PCOS, it might be expected that their LH would be higher than that of controls in a similarly early stage of puberty because of peripubertal hyperandrogenemia [11–13]; it might also be expected that inherent ovarian dysfunction would be apparent in early puberty . Thus, definition of their pathophysiology was potentially instructive for understanding the developmental origins of PCOS [10, 18]. To test these possibilities, we surveyed their hypothalamic-pituitary-ovarian function by analyzing gonadotropin secretion during sleep, since the first hormonal changes of puberty begin then ; by assessing their gonadotropin and sex steroid responses to a GnRH agonist (GnRHag) test; and by testing their adrenal androgenic sensitivity to ACTH. The results indicate that these girls indeed have a slowly progressive form of central precocious puberty, with blunting of their early pubertal LH production in spite of peripubertal hyperandrogenemia; these results may be related to our recent findings in healthy girls that excess adiposity subtly blunts gonadotropin secretion during the early stages of puberty .
2. Subjects and Methods
SPPOPA girls (4 African-American, 1 Hispanic) presented with premature breast and pubic hair development; thelarche had occurred at 5–7.5 years of age, was predominantly at stage 3 at admission, and was uniformly preceded by pubarche, by a median of 0.5 years. Preadmission early morning blood sampling showed that these girls' premature pubarche was accompanied by adrenarcheal levels of dehydroepiandrosterone sulfate (DHEAS) and testosterone; however, despite their obvious thelarche, they had prepubertal gonadotropin and estradiol levels. PA girls (3 African-American, 4 Caucasian) presented with pubarche that began at 3–8 years of age, and 6/7 had above average height velocity, high bone age/height age ratio, obesity, acanthosis nigricans, or high DHEAS for pubic hair stage, which are sometimes considered to be signs of "exaggerated adrenarche" [10, 21, 22], but none had breast development. Healthy overweight pubertal (OW-PUB, 7 African-American, 1 Hispanic) female volunteers were recruited by advertisement and were premenarcheal and predominantly breast stage 3, as previously described . For the purposes of this study "overweight" was used in the sense of "excessive" and defined as body mass index (BMI) 85th percentile and, thus, included obese subjects ( 95th percentile) . Patients were followed for 0.4 years or more (median ). Congenital adrenal hyperplasia was excluded from all by ACTH-testing (see below). These studies were approved by the University of Chicago Institutional Review Board and were performed after obtaining assent of the girls and consent of the parents.
2.2. Study Protocol
Outline of study protocol.
Overnight hormonal sleep test
Baseline sampling begins
Oral glucose tolerance test
Pelvic ultrasound examination
Dexamethasone 0.25 mg/m2 PO
Basal sample for steroids
ACTH1-24 (1.0 mcg/m2 IV) test begins
Basal GnRHag test LH&FSH sampling begins
GnRHag test (leuprolide 10 mcg/m2 SC) test begins
Post-GnRHag 18 hr sampling
Dexamethasone 0.25 mg/m2 PO
Post-GnRHag sampling resumes (20 hr)
GnRHag test sampling ends (24 hr)
2.3. Laboratory and Procedural Methods
As previously reported, serum LH and FSH were measured by immunofluorometric assays (Delphia, Wallach, Finland); total testosterone and cortisol by Diagnostic Products Corporation radioimmunoassay kits (Los Angeles, CA); dehydroepiandrosterone sulfate (DHEAS) by Diagnostic Systems Laboratory kits (Webster, TX); estradiol by Pantex immunoassay kit (Santa Monica, CA); free testosterone and sex hormone binding globulin binding capacity were calculated from a competitive protein binding assay . Postchromatographic radioimmunoassays were used for steroid intermediates (17-hydroxyprogesterone, androstenedione, 11-deoxycortisol, 17-hydroxypregnenolone, and DHEA). Serum insulin was initially assayed by a double-antibody RIA; the method was changed to Immulite assay in 2004, and the data are expressed in terms of the latter assay . Each hormone on a study subject was assayed simultaneously. Values below the limits of assay sensitivity were set to this limit for statistical analysis, as previously reported. Plasma glucose was measured using a glucose analyzer (YSI Model 2300 STAT; Yellow Springs Instruments, Yellow Springs, OH). Insulin resistance was approximated by homeostatic model assessment (HOMA) according to the equation HOMA [fasting plasma insulin (mU/L) fasting plasma glucose (mmol/L)]/22.5 . Real-time pelvic ultrasound imaging was performed in the Pediatric Radiology Department by the abdominal route using an Acuson Sequoia with a 4 Mhz transducer (Acuson, Mountainview, CA) according to the manufacturer's specifications using standard algorithms and a phantom probe for periodic calibration . There was no significant variation between readings by the two radiologists who performed these studies. Ovarian volume was calculated according to the formula for ellipsoid bodies. Bone age was determined by a modification of the Greulich-Pyle method , and adult height was predicted by the Bayley-Pinneau method . BMI percentiles were obtained from a national database  and height velocity norms from Tanner and Davies .
2.4. Data Analyses
Group data, including hormonal responses log-transformed as necessary for data normalization, were compared by one-way ANOVA (comparisons among groups) with subsequent pairwise comparisons performed by Tukey's method (sleep tests) or paired and unpaired Student's -tests (baseline hormones), Fisher's exact test (for categorical variables), two-way repeated measures ANOVA (GnRHag test), and paired and unpaired Student's -tests (2-sample comparisons). Primary outcome variables were the comparisons of SPPOPA to PA and to OW-PUB for sleep and GnRHag tests. Correction for multiple comparisons was carried out by Fisher's protected least significant differences post hoc testing. Results are expressed as mean SEM, unless otherwise stated. Two-tailed -values were considered significant.
3.1. Clinical Characteristics
Study group baseline clinical characteristics. Observed range for each study group is shown, as is 5th–95th percentile reference range of healthy prepubertal volunteers .
Pubic Hair (Tanner)
Max Ov (cc)
Max Foll (#)
SPPOPA HOMA index was intermediate between PA and OW-PUB (Table 2), with one subject having insulin resistance (HOMA 10.8) in association with impaired glucose tolerance. However, impaired glucose tolerance prevalence was not significantly different among groups.
Study group baseline pubertal hormone levels. Observed range for each study group is shown, as is 5th–95th percentile reference range of healthy prepubertal volunteers .
Total T (ng/dL)
Free T (pg/mL)
DHEAS ( g/dL)
3.2. Sleep Test
Study group wake and sleep gonadotropin and estradiol levels. Observed range for each study group is shown, as is 5th–95th percentile reference range of healthy prepubertal volunteers .
Peak sleep LH and estradiol of all but one SPPOPA and one PA girl were in the prepubertal range, as were all their FSH peaks (Table 4). The peak sleep LH of PA and OW-PUB girls differed significantly, and that of SPPOPA was intermediate. None of the groups had a significant sleep-related LH rise: mean sleep LH in PA was , in SPPOPA and in OW-PUB U/L. Sleep estradiol levels of both SPPOPA and PA were significantly lower than in OW-PUB (Table 4).
3.3. GnRHag Test
Hormonal responses to GnRHag postdexamethasone. Post-GnRHag gonadotropin levels are shown at 4 hr and steroid levels at 22 hr. Mean SEM (observed range).
PRE Reference Range 
SPPOPA estradiol responses were intermediate between those of PA and OW-PUB girls, which differed significantly (Figure 1). The modal time of estradiol peak responses was not significantly different among groups but tended to be earliest within the 18–24 hr period in the PA group and latest within the OW-PUB group. SPPOPA estradiol peak responses ( pg/mL) occurred 18–22 hr post-GnRHag and were between those of PA ( pg/mL) and those of OW-PUB ( pg/mL), which differed significantly (Table 5).
SPPOPA and PA had similar 17-hydroxyprogesterone responses to GnRHag, and both were significantly less than those of OW-PUB (Table 5). The SPPOPA post-GnRHag testosterone 22-hr level was pubertal, significantly greater than that of PA, while that of androstenedione was intermediate between PA and OW-PUB, which differed significantly. The responses of progesterone and DHEA to GnRHag did not differ among groups.
3.4. ACTH Test
SPPOPA girls present an infrequent, but not rare, diagnostic challenge. The clinical presentation with premature breast and pubic hair development and course of these cases was typical of the slowly progressive form of central precocity [4, 5]. However, while early morning hormone sampling in these SPPOPA girls showed premature adrenarche, it did not show pubertal gonadotropin levels. Two mechanisms were considered as possibly underlying this clinical picture, aside from the possibility of the pseudothelarche of obesity. The first was that outpatient testing failed to detect early puberty, the alternate was that the combination of premature adrenarche and excessive adiposity caused premature thelarche via the enhanced peripheral estrogen formation of obesity. We also tested the hypotheses that if they were indeed pubertal, their peripubertal hyperandrogenism would predispose to increased LH levels as an early manifestation of PCOS [11–13] and premature adrenarche would predispose them to a unique ovarian androgenic response to GnRHag .
Consistent with the first mechanistic possibility, SPPOPA girls had responses to GnRHag testing that were significantly greater than those of PA girls, and thus had undergone pubertal gonadotrope activation. While diagnostic criteria for this test are not well established, their LH levels 4 hr post-GnRHag were all 4.0 U/L, which is in the midst of ranges of cut-offs proposed for diverse assays in diagnosing central precocity by GnRH testing (3.3–5.0 U/L) .
Adrenal androgen baseline levels and responses to ACTH of the SPPOPA and PA girls were elevated for age and tended to be higher than those of premenarcheal pubertal volunteers. SPPOPA girls did not have higher LH parameters than comparably overweight early pubertal controls, as might be expected if the hypothesis were true that peripubertal hyperandrogenism predisposes to elevated LH secretion of PCOS commencing during stage 3 of puberty [11–13]. Indeed, LH was lower, as discussed below. However, our SPPOPA group was not hyperandrogenic for their stage of pubertal maturation, so it remains unclear at what point in pubertal development, and at what level, hyperandrogenemia becomes capable of stimulating pulsatile LH secretion, as it does after menarche [32, 33]. Additionally, SPPOPA girls had no evidence of the pubertal ovarian DHEA hyperresponsiveness that has been reported to follow presentation with PA and has been suspected of indicating risk for developing PCOS ; the difference in findings may be explicable by the difference in BMI status of our PA population or our study design in which low-dose dexamethasone was used to eliminate artifacts arising from coincidental adrenal secretion. However, our limited long-term follow-up revealed one PA girl to develop PCOS after menarche; there was nothing in her study that distinguished her from the others in the PA group except the maternal history of PCOS.
The slowly progressive form of central precocious puberty generally differs from classical (rapidly progressive) central precocity in its lesser activation of hypothalamic GnRH secretion . Thus, these patients ordinarily have lower LH peaks and LH/FSH ratios in response to GnRH [6, 34, 35], fewer and lower LH pulses during sleep , and tend to be less estrogenized [5, 35]. Clinically, pubertal tempo is not accelerated [4, 5], the age of menarche is, on average, within normal limits [6, 35], and adult height potential is preserved without treatment .
Although the SPPOPA group was typical of slowly progressive precocity in these general ways, their LH dynamics were significantly attenuated for their level of pubertal maturation in comparison to ordinary OW early pubertal controls. Wake gonadotropins and LH responses to GnRHag were significantly lower than those of the comparably overweight pubertal controls. These overweight controls themselves had a blunted sleep-related rise in LH pulse amplitude and pulse frequency relative to normal-BMI controls; however, they had responses to GnRHag like those of normal-weight pubertal girls . The data are compatible with the possibility that early pubertal girls are particularly sensitive to the gonadotropin-suppressive effects of obesity.
Evidence is accumulating that excess adiposity reduces LH production. LH levels and pulse amplitude are low in morbidly obese men with hypogonadism  and low in eumenorrheic obese women with anovulatory cycles ; the LH responses to GnRH of obese women increase with weight loss ; and LH levels, pulse amplitude; and response to GnRH are lower in obese than in nonobese PCOS . The lower LH of obese PCOS women is partly attributable to increased LH clearance . The available longitudinal data are compatible with excess adiposity after the onset of puberty slowing pubertal tempo in girls, though less so than prepubertal adiposity advances puberty onset [41–43]. Thus, these considerations raise the possibility that the excess adiposity of SPPOPA aggravates the relatively low LH production of slowly progressive precocity and contributes to the slow progression.
Since there is considerable evidence that excess adiposity advances the onset of puberty [2, 3, 44], it is possible that it paradoxically contributes to both the early onset of puberty in SPPOPA as well as to its slow progression thereafter. We speculate that overweight may be a factor in the precocity of girls in whom, like these, onset of puberty is only mildly premature; many sexually precocious girls in this 6–8 year age range do not require treatment to preserve height potential .
The limitations of this study should be kept in mind. It is descriptive and associative and should be considered exploratory. Furthermore, while the SPPOPA presentation is not rare, it is uncommon, and our group was small. Because our study was designed as a survey of the many aspects of puberty potentially disturbed in these young girls, our sleep data are sparse. In addition, we have not been able to obtain follow-up into the postmenarcheal stage of development in most. In spite of these limitations, our data indicate that mild peripubertal hyperandrogenism and excess adiposity do not predispose to elevated LH secretion during early puberty before menarche and are indeed compatible with the possibility of a suppressive effect of excess adiposity on circulating LH during puberty that deserves further study.
In summary, we demonstrate that sleep-related gonadotropin production and LH responses to GnRH agonist testing are blunted in girls with slowly progressive sexual precocity who are overweight and have premature adrenarche. These studies indicate that SPPOPA is a slowly progressive form of true puberty. In spite of maturational indices similar to OW-PUB, SPPOPA had lower LH responses to GnRHag. The data argue against the hypotheses that the prepubertal hyperandrogenism of excess adiposity or premature adrenarche enhance LH secretion or cause ovarian hyperandrogenism prior to menarche, although they seem to be modest risk factors for PCOS thereafter. These data are also compatible with the possibility that early pubertal girls are particularly sensitive to the gonadotropin-suppressive effects of excess fat mass, although obesity predisposes to the early onset of puberty.
Body mass index
Slowly progressive precocious breast development, overweight, and premature adrenarche
Homeostatic index model assessment of insulin resistance
Polycystic ovary syndrome
This research was supported in part by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement [U54-041859] as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and HD-39267 (R. L. Rosenfield); 5T32DK064582 and a Lawson Wilkins Pediatric Endocrine Society Research Fellowship (B. Bordini); RR-00055 and UL1RR024999 from the National Center For Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. The authors thank Kristen Kasza for biostatistical support, and Kate Feinstein and David Yousefzadeh for ultrasonographic support; A preliminary report was presented at the Endocrine Society Annual Meeting, Washington DC, June 10, 2009.
- Carel J-C, Eugster EA, Rogol A: Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009, 123 (4): e752-e762. 10.1542/peds.2008-1783.View ArticlePubMedGoogle Scholar
- Rosenfield RL, Lipton RB, Drum ML: Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index (Erratum). Pediatrics. 2009, 123 (1): 84-88. 10.1542/peds.2008-0146.View ArticlePubMedGoogle Scholar
- Rosenfield RL, Lipton RB, Drum ML: Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index (Pediatrics (2009) 123, 1, (84-88). Pediatrics. 2009, 123 (4): 1255-View ArticleGoogle Scholar
- Fontoura M, Brauner R, Prevot C, Rappaport R: Precocious puberty in girls: early diagnosis of a slowly progressing variant. Archives of Disease in Childhood. 1989, 64 (8): 1170-1176. 10.1136/adc.64.8.1170.PubMed CentralView ArticlePubMedGoogle Scholar
- Kreiter M, Burstein S, Rosenfield RL, Moll GW, Cara JF, Yousefzadeh DK, Cuttler L, Levitsky LL: Preserving adult height potential in girls with idiopathic true precocious puberty. Journal of Pediatrics. 1990, 117 (3): 364-370. 10.1016/S0022-3476(05)81074-1.View ArticlePubMedGoogle Scholar
- Palmert MR, Malin HV, Boepple PA: Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20 untreated patients. Journal of Clinical Endocrinology and Metabolism. 1999, 84 (2): 415-423. 10.1210/jc.84.2.415.PubMedGoogle Scholar
- Palmert MR, Mansfield MJ, Crowley WF, Crigler JF, Crawford JD, Boepple PA: Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty. Journal of Clinical Endocrinology and Metabolism. 1999, 84 (12): 4480-4488. 10.1210/jc.84.12.4480.PubMedGoogle Scholar
- Sklar CA, Kaplan SL, Grumbach MM: Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. Journal of Clinical Endocrinology and Metabolism. 1980, 51 (3): 548-556. 10.1210/jcem-51-3-548.View ArticlePubMedGoogle Scholar
- Neely EK, Wilson DM, Lee PA, Stene M, Hintz RL: Spontaneous serum gonadotropin concentrations in the evaluation of precocious puberty. Journal of Pediatrics. 1995, 127 (1): 47-52. 10.1016/S0022-3476(95)70255-5.View ArticlePubMedGoogle Scholar
- Rosenfield RL: Clinical review: identifying children at risk for polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2007, 92 (3): 787-796. 10.1210/jc.2006-2012.View ArticlePubMedGoogle Scholar
- McCartney CR, Prendergast KA, Chhabra S, Eagleson CA, Yoo R, Chang RJ, Foster CM, Marshall JC: The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. Journal of Clinical Endocrinology and Metabolism. 2006, 91 (5): 1714-1722. 10.1210/jc.2005-1852.View ArticlePubMedGoogle Scholar
- McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster CM, Caprio S, Marshall JC: Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. Journal of Clinical Endocrinology and Metabolism. 2007, 92 (2): 430-436. 10.1210/jc.2006-2002.PubMed CentralView ArticlePubMedGoogle Scholar
- McCartney CR, Prendergast KA, Blank SK, Helm KD, Chhabra S, Marshall JC: Maturation of luteinizing hormone (gonadotropin-releasing hormone) secretion across puberty: evidence for altered regulation in obese peripubertal girls. Journal of Clinical Endocrinology and Metabolism. 2009, 94 (1): 56-66. 10.1210/jc.2008-1252.PubMed CentralView ArticlePubMedGoogle Scholar
- Ibanez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinye M, Carrascosa A, Vicens-Calvet E: Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. Journal of Clinical Endocrinology and Metabolism. 1993, 76 (6): 1599-1603. 10.1210/jc.76.6.1599.PubMedGoogle Scholar
- Vuguin P, Linder B, Rosenfeld RG, Saenger P, DiMartino-Nardi J: The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche. Journal of Clinical Endocrinology and Metabolism. 1999, 84 (6): 2037-2042. 10.1210/jc.84.6.2037.PubMedGoogle Scholar
- Edman CD, MacDonald PC: Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulatory young women. American Journal of Obstetrics and Gynecology. 1978, 130 (4): 456-461.PubMedGoogle Scholar
- 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. Fertility and Sterility. 1997, 67 (5): 849-855. 10.1016/S0015-0282(97)81396-9.View ArticlePubMedGoogle Scholar
- Abbott DH, Dumesic DA, Franks S: Developmental origin of polycystic ovary syndrome—a hypothesis. Journal of Endocrinology. 2002, 174 (1): 1-5. 10.1677/joe.0.1740001.View ArticlePubMedGoogle Scholar
- Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E, Hellman L: Synchronization of augmented luteinizing hormone secretion with sleep during puberty. New England Journal of Medicine. 1972, 287 (12): 582-586. 10.1056/NEJM197209212871203.View ArticlePubMedGoogle Scholar
- Bordini B, Littlejohn E, Rosenfield RL: Blunted sleep-related luteinizing hormone rise in healthy premenarcheal pubertal girls with elevated body mass index. Journal of Clinical Endocrinology and Metabolism. 2009, 94 (4): 1168-1175. 10.1210/jc.2008-1655.PubMed CentralView ArticlePubMedGoogle Scholar
- Charkaluk M-L, Trivin C, Brauner R: Premature pubarche as an indicator of how body weight influences the onset of adrenarche. European Journal of Pediatrics. 2004, 163 (2): 89-93. 10.1007/s00431-003-1358-9.View ArticlePubMedGoogle Scholar
- Utriainen P, Voutilainen R, Jääskeläinen J: Girls with premature adrenarche have accelerated early childhood growth. Journal of Pediatrics. 2009, 154 (6): 882-887. 10.1016/j.jpeds.2008.12.038.View ArticlePubMedGoogle Scholar
- Barlow SE: Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007, 120: S164-S192. 10.1542/peds.2007-2329C.View ArticlePubMedGoogle Scholar
- Mortensen M, Ehrmann DA, Littlejohn E, Rosenfield RL: Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. Journal of Clinical Endocrinology and Metabolism. 2009, 94 (5): 1579-1586. 10.1210/jc.2008-2771.PubMed CentralView ArticlePubMedGoogle Scholar
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985, 28 (7): 412-419. 10.1007/BF00280883.View ArticlePubMedGoogle Scholar
- de Vries L, Horev G, Schwartz M, Phillip M: Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. European Journal of Endocrinology. 2006, 154 (6): 891-898. 10.1530/eje.1.02151.View ArticlePubMedGoogle Scholar
- Roche AF, Eyman SL, Davila GH: Skeletal age prediction. The Journal of Pediatrics. 1971, 78 (6): 997-1003. 10.1016/S0022-3476(71)80430-4.View ArticlePubMedGoogle Scholar
- Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age: revised for use with the greulich-pyle hand standards. The Journal of Pediatrics. 1952, 40 (4): 423-441. 10.1016/S0022-3476(52)80205-7.View ArticlePubMedGoogle Scholar
- Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL: CDC growth charts: United States. Advance data. 2000, 1-27. 314
- Tanner JM, Davies PSW: Clinical longitudinal standards for height and height velocity for North American children. Journal of Pediatrics. 1985, 107 (3): 317-329. 10.1016/S0022-3476(85)80501-1.View ArticlePubMedGoogle Scholar
- Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF: The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility. 2009, 91 (2): 456-488. 10.1016/j.fertnstert.2008.06.035.View ArticlePubMedGoogle Scholar
- Ropelato MG, Rudaz MCG, Escobar ME, Bengolea SV, Calcagno ML, Veldhuis JD, Barontini M: Acute effects of testosterone infusion on the serum luteinizing hormone profile in eumenorrheic and polycystic ovary syndrome adolescents. Journal of Clinical Endocrinology and Metabolism. 2009, 94 (9): 3602-3610. 10.1210/jc.2009-0402.View ArticlePubMedGoogle Scholar
- Blank SK, McCartney CR, Chhabra S, Helm KD, Eagleson CA, Chang RJ, Marshall JC: Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls—implications for regulation of pubertal maturation. Journal of Clinical Endocrinology and Metabolism. 2009, 94 (7): 2360-2366. 10.1210/jc.2008-2606.PubMed CentralView ArticlePubMedGoogle Scholar
- Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler GB: Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinizing hormone-releasing hormone. Journal of Clinical Endocrinology and Metabolism. 1988, 67 (3): 474-479. 10.1210/jcem-67-3-474.View ArticlePubMedGoogle Scholar
- Brauner R, Adan L, Malandry F, Zantleifer D: Adult height in girls with idiopathic true precocious puberty. Journal of Clinical Endocrinology and Metabolism. 1994, 79 (2): 415-420. 10.1210/jc.79.2.415.PubMedGoogle Scholar
- Kaufman JM, Vermeulen A: The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocrine Reviews. 2005, 26 (6): 833-876. 10.1210/er.2004-0013.View ArticlePubMedGoogle Scholar
- Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N: Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. Journal of Clinical Endocrinology and Metabolism. 2007, 92 (7): 2468-2473. 10.1210/jc.2006-2274.View ArticlePubMedGoogle Scholar
- Newmark SR, Rossini AA, Naftolin FI, Todd R, Rose LI, Cahill GF: Gonadotropin profiles in fed and fasted obese women. American Journal of Obstetrics and Gynecology. 1979, 133 (1): 75-80.PubMedGoogle Scholar
- Arroyo A, Laughlin GA, Morales AJ, Yen SSC: Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. Journal of Clinical Endocrinology and Metabolism. 1997, 82 (11): 3728-3733. 10.1210/jc.82.11.3728.PubMedGoogle Scholar
- Srouji SS, Pagán YL, D'Amato F, Dabela A, Jimenez Y, Supko JG, Hall JE: Pharmacokinetic factors contribute to the inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism. 2007, 92 (4): 1347-1352. 10.1210/jc.2006-2716.View ArticlePubMedGoogle Scholar
- de Ridder CM, Thijssen JHH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WBM: Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. Journal of Clinical Endocrinology and Metabolism. 1992, 75 (2): 442-446. 10.1210/jc.75.2.442.PubMedGoogle Scholar
- Biro FM, Huang B, Crawford PB, Lucky AW, Striegel-Moore R, Barton BA, Daniels S: Pubertal correlates in black and white girls. Journal of Pediatrics. 2006, 148 (2): 234-240. 10.1016/j.jpeds.2005.10.020.View ArticlePubMedGoogle Scholar
- Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC: Weight status in young girls and the onset of puberty. Pediatrics. 2007, 119 (3): e624-e630. 10.1542/peds.2006-2188.View ArticlePubMedGoogle Scholar
- Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME: Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001, 108 (2): 347-353. 10.1542/peds.108.2.347.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.