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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2691-2695
Copyright © 1999 by The Endocrine Society

Original Studies

Anovulation after Precocious Pubarche: Early Markers and Time Course in Adolescence1

Lourdes Ibáñez, Francis de Zegher2 and Neus Potau

Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona (L.I.), and Hormonal Laboratory, Hospital Materno-Infantil Vall d’Hebron, Autonomous University of Barcelona (N.P.), Spain; and the Department of Pediatrics, University of Leuven (F.d.Z.), Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu 2, 08950 Esplugues (Barcelona), Spain. E-mail: lourdes.ibanez{at}deinfo.es


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Adolescent girls with a history of precocious pubarche (PP) are known to be at increased risk for ovarian hyperandrogenism, an endocrinopathy related to reduced fetal growth, but the characteristics of their ovulatory function have not been fully documented.

We assessed ovulatory function by weekly urinary LH and salivary progesterone measurements over 3 consecutive months in 85 adolescent girls with known weight and gestational age at birth: 49 girls had no history of PP (age, 14.7 ± 1.7 yr), and 36 had a history of PP (age, 14.4 ± 2.0 yr); 55 girls were in the early postmenarcheal phase (0–3 yr after menarche), and 30 were in the late postmenarcheal phase (>3 yr after menarche). In girls with PP, the 17-hydroxyprogesterone (17-OHP) response to ACTH was determined at prepubertal diagnosis of PP, and serum androgen and gonadotropin concentrations were measured in adolescence together with insulin responses to an oral glucose load.

Early postmenarche, the fraction of girls with ovulations was similar in the non-PP and PP subgroups (61% vs. 62%), as was the fraction of ovulatory cycles (25% vs. 22%). Late postmenarche, however, the fractions of ovulating girls and ovulatory cycles were strikingly higher (P <= 0.001) in the non-PP than in the PP subgroup (91% vs. 20% and 47% vs. 12%).

Within the PP subgroup, anovulatory girls were found to have a lower weight SD score at birth (mean ± SEM) than ovulatory girls (-1.22 ± 0.3 vs. -0.36 ± 0.3; P = 0.03), a higher 17-OHP response to ACTH before puberty (333.1 ± 31 vs. 203.8 ± 26 ng/dL; P < 0.002), and, in adolescence, lower serum sex hormone-binding globulin levels and higher circulating LH, free androgen indexes, and insulin responses.

In conclusion, these findings indicate that girls with PP are at increased risk for anovulation from late (not early) adolescence onward, particularly those girls with a low weight at birth and/or a high 17-OHP response to ACTH at prepubertal diagnosis of PP.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING the first years after menarche, cycle irregularity and anovulation are common in adolescent girls (1, 2, 3). A spontaneous switch from predominantly anovulatory to ovulatory cycles normally occurs within 3–5 yr after menarche (1, 4). The persistence of anovulatory cycles during adolescence has been associated with increased pulses and average levels of serum LH and with high testosterone and androstenedione ({Delta}4-A) concentrations (5). In turn, low fertility rates in the third decade of life have been associated with increased serum androgen levels during puberty (6).

In adolescent girls with a history of precocious pubarche [PP, defined as appearance of pubic hair before the age of 8 yr (7)], there is an increased prevalence of hyperinsulinism, dyslipemia, and ovarian hyperandrogenism (8, 9, 10, 11, 12). The hyperinsulinism and dyslipemia are detectable before puberty and throughout pubertal development and are usually associated with decreased insulin-like growth factor binding-protein-1 (IGFBP-1) and sex hormone-binding globulin (SHBG) concentrations, but, in those early stages, not necessarily with clinical signs of androgen excess (11, 12).

PP, hyperinsulinism, and ovarian hyperandrogenism in girls have recently been recognized as a sequence related to reduced fetal growth, indicating that this triad may have a prenatal origin (13). Here, we report on the noninvasive assessment of ovulatory function in adolescent girls with and without a history of PP, in an attempt to delineate the relative prevalence and time course of anovulation after PP and the possible relationship to prenatal growth and prepubertal adrenarche.


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

The total population consisted of 85 adolescent girls, 49 of whom had no history of PP (age, 14.7 ± 1.7 yr; range, 11–18 yr) and 36 of whom had a history of PP (age, 14.4 ± 2.0 yr; range, 11–18 yr). Fifty-five girls were in the early postmenarcheal phase (0–3 yr after menarche), and 30 were in the late postmenarcheal phase (>3 yr after menarche). Table 1Go describes the clinical characteristics of the four subgroups.


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  		Table 1. Clinical characteristics of subjects

 
Body mass indexes (BMIs) were normal in all subjects (14) and did not differ significantly between the non-PP and PP subgroups. Girls with PP were only included in the study when PP was attributable to pronounced adrenarche, as suggested by elevated {Delta}4-A and/or dehydroepiandrosterone sulfate (DHEAS) levels at prepubertal diagnosis of PP (7, 15, 16); lack of evidence for nonclassic adrenal hyperplasia (serum 17-OHP and 17-hydroxypregnenolone measurement after ACTH administration) (17, 18), thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia, or diabetes mellitus; and lack of clinical evidence for acanthosis nigricans or hirsutism.

Birth weight and gestational age data were obtained from hospital records and transformed into SD scores, as previously described (13, 19).

Endocrine and metabolic studies

Baseline serum LH, testosterone, 17-OHP, {Delta}4-A, DHEAS, and SHBG concentrations in the PP subgroup were determined by RIA, as previously described (20). The free androgen index, an index of free testosterone, was calculated as follows: testosterone (nmol/L) x 100/SHBG (nmol/L) (20).

Standard oral glucose tolerance tests (OGTT; 75 g glucose; 0800–1000 h) were performed after 3 days of a high carbohydrate diet (300 g/day) and an overnight fast in the PP subgroup. Serum glucose and insulin were measured during the OGTT after 0, 30, 60, and 120 min (10, 11). All girls had normal glucose tolerance according to current criteria (21). The areas under the curve for glucose (mean serum glucose) and insulin [mean serum insulin (MSI)] were calculated according to the trapezoidal rule. A MSI value above 84 mU/L was defined as an insulin hyperresponse (10, 11).

Serum gonadotropin and androgen measurements and OGTT tests were performed in the follicular phase of the cycle. Serum samples were kept frozen at -20 C until assay.

Cycle characteristics and ovulation assessment

The adolescents were asked to maintain prospective diaries over 3 months, from which the cycle and menstrual characteristics were derived. A girl was considered to have regular cycles when the intervals between menses were consistently normal (between 25–35 days) and had a variation of 5 days or less (22).

Urine and saliva samples were collected once weekly over the same 3 months for measurement of urinary LH and salivary progesterone concentrations. Urine samples were collected from the first morning voided urine and stored in glycerol-preserved polypropylene tubes to prevent the loss of immunoreactive LH activity (23, 24). Urinary LH was measured by an automated microparticle enzyme immunoassay (AXSYM, Abbott Laboratories, Chicago, IL). The addition of glycerol was confirmed not to interfere with the immunoassay by dilution and cold recovery experiments. Creatinine was measured in each urine sample according to the Jaffé cynetic method without deproteinization (Cobas-Integra, Roche, Madrid, Spain); the LH results were corrected for creatinine concentrations and expressed as milliinternational units per mg creatinine (24). Morning saliva was collected by spitting into plastic tubes after rinsing the mouth with water and before breakfast or teeth brushing (25). Salivary progesterone was determined by RIA (CIS-Bio International, Gif-sur-Ivette, France), with a calibration range between 150-5600 pg/mL using a high sample volume (0.150 mL) (25, 26). The mean intra- and interassay coefficients of variation were 5.1% and 6.8%, respectively, for LH at a LH concentration of 4.8 mIU/mL, and 5.7% and 6.6% for progesterone at a progesterone concentration of 0.4 pg/mL

The girls were considered to display ovulatory function when in at least one urinary or salivary sample collected within 15 days before menses progesterone or LH concentration was higher than 2 SD above the mean reference level for the follicular phase (27, 28). Ovulatory function was considered present when urinary LH was more than 7 mIU/mg creatinine and/or salivary progesterone was more than 563 pg/mL within 15 days before menses.

Saliva and urine samples were stored in a domestic freezer at -20 C and once monthly delivered to the laboratory, where they were stored at -20 C until assayed. Whole saliva and urine were centrifuged (1000 x g for 10 min) before assay.

Statistical analysis and ethics

Results are expressed as the mean ± SEM, unless stated otherwise. To assess trends in cycle lengths over time, the deviation from the normal range was viewed relative to time, using a random subject-effect model (22). Percentages of ovulating girls and ovulatory cycles in girls with and without PP were compared by the one-sample hypothesis test for independent samples. Independent variables were compared by Mann-Whitney test. P < 0.05 was considered statistically significant.

The protocol was approved by the institutional review board of the Barcelona Hospital. Informed consent was obtained from the parents and assent from the girls.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The deviation of cycle length from normal decreased with advancing time postmenarche in all subjects (P < 0.05). The prevalence of cycles with normal duration was similar in the non-PP and PP subgroups (75% vs. 72%, respectively), as was the prevalence of regular cycles (57% vs. 55%, respectively). Twenty-eight percent of ovulatory cycles were detected by both urinary LH and salivary progesterone; the remaining fraction was detected only by urinary LH. All elevated progesterone levels (20 of 20) were detected between 3–9 days before menses, and all but 2 elevated LH levels (68 of 70) were detected between days 10–16 before menses.

Early postmenarche, the fraction of girls with ovulations detected by urinary LH was similar in the non-PP and PP subgroups (61% vs. 62%), as was the fraction of ovulatory cycles (25% vs. 22%; Fig. 1Go). Based on progesterone values, the fractions of girls with ovulations in the non-PP and PP subgroups were 29% and 19%, respectively, whereas the fractions of ovulatory cycles were 9% and 7%, respectively. Late postmenarche, however, the fractions of ovulating girls and ovulatory cycles detected by urinary LH were strikingly higher (P < 0.001) in the non-PP than in the PP subgroup (91% vs. 20%, and 47% vs. 12%, respectively; Fig. 1Go). The fractions of ovulating girls and ovulatory cycles based on progesterone values in the non-PP and PP subgroups were 26% vs. 6%, and 11% vs. 2%, respectively. In ovulatory cycles, urinary LH ranged from 10.1–42.7 mIU/mg creatinine, whereas salivary progesterone was between 593-2300 pg/mL. The values for these variables in anovulatory cycles were 1.8–4.8 and 95–425, respectively.



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  		Figure 1. Fractions of adolescent girls with detectable ovulatory function (upper panels) and fractions of ovulatory cycles (lower panels) assessed early postmenarche (left panels) or late postmenarche (right panels). Late postmenarche, ovulatory function is decreased in adolescents with a history of PP.

 
Birth weight SD scores of non-PP girls (0.19 ± 0.1) were higher (P < 0.0001) than those of PP girls (-1.05 ± 0.2). Regardless of the timing postmenarche, ovulatory PP girls had higher SD scores than anovulatory PP girls (-0.34 ± 0.3 vs. -1.22 ± 0.3; P = 0.03). Similarly, ovulatory PP girls had lower 17-OHP responses to ACTH administration at prepubertal diagnosis of PP than anovulatory PP girls (203.8 ± 26 vs. 333.1 ± 31 ng/dL; P = 0.002; Fig. 2Go).



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  		Figure 2. Birth weight SD scores of ovulatory and anovulatory adolescents with a history of PP (left panel) and their peak serum 17-OHP concentrations after ACTH administration at diagnosis of PP (right panel). Among girls with PP, those with a lower birth weight and/or a higher 17-OHP response appear to be at increased risk for subsequent anovulation. *, P <= 0.03.

 
Table 2Go summarizes other comparisons of endocrine and metabolic variables between ovulatory and anovulatory adolescents with a history of PP. Anovulation after PP appears to be associated with a relatively higher baseline serum LH, free androgen index, and MSI after the OGTT as well as a lower serum SHBG concentration.


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  		Table 2. Body mass indexes (BMI); basal serum androgen, sex hormone-binding globulin (SHBG), and gonadotropin levels; mean serum glucose (MSG); and mean serum insulin (MSI) values in ovulatory and anovulatory precocious pubarche girls in adolescence

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We performed a noninvasive attempt to assess ovulatory function in adolescent girls with and without a history of PP. Urinary LH and salivary progesterone concentrations have both been shown to correlate well with respective serum levels (24, 25, 28, 29). In this study, urinary LH measurements detected nearly 4-fold more ovulatory cycles than salivary progesterone determinations and missed none of the cycles detected by the latter method. The present findings remain to be confirmed by studies using different methods for ovulation detection. For example, we may have underestimated the number of LH and progesterone surges by measuring urinary LH concentrations on a weekly instead of daily basis and by determining salivary progesterone instead of urinary pregnanediol (22). On the other hand, we may have overestimated the ovulatory rates by including LH surges without detectable progesterone increases as indicative of ovulation. Consequently, the relative differences and the time courses that were identified may be more relevant than the absolute numbers of ovulatory rates that we report. It is likely that when more refined methods are used, the identified differences will prove to be more pronounced than those described here.

The development of ovarian hyperandrogenism after PP is preceded by an apparently normal phase, with regular cycles lasting for about 3–5 yr after the menarche (30). The present study unmasks that ovulatory function may already be deteriorating during the latter part of that apparently normal phase. The endocrine-metabolic profiles of anovulatory girls after PP are characterized by relatively elevated serum LH levels, higher free androgen indexes and insulin hyperresponses, as well as lower SHBG concentrations, whereas these girls have no clinical signs of androgen excess. Hyperinsulinemia, acting in concert with decreased SHBG and IGBP-1 levels, is thought to be one of the drives eliciting both adrenal and ovarian hyperandrogenism; an independent influence of insulin on androgen secretion in the developmental stage of ovarian hyperandrogenism is supported by studies showing a correlation between insulin and androgen levels after LH suppression by a GnRH antagonist (31, 32, 33, 34). Therefore, the aforementioned endocrine-metabolic profile and anovulation in late adolescence may herald the advent of clinical hyperandrogenism. Anovulation, in turn, was found to be, to some extent, heralded by a relatively elevated 17-OHP response to ACTH at prepubertal diagnosis of PP and, even earlier, by a low weight at birth.

Reduced fetal growth has previously been associated with insulin resistance in children and young adults (35, 36), with amplified adrenarche and PP before puberty (13, 37), and with gonadal dysfunction, specifically with subfertility in males (19) and ovarian hyperandrogenism in adolescent girls (13). The present findings extend the association between reduced fetal growth and gonadal dysfunction to include ovulatory dysfunction in late adolescence.

In conclusion, these observations indicate that girls with PP are at increased risk for anovulation from late, not early, adolescence onward, particularly those girls with a low weight at birth and/or a high 17-OHP response to ACTH at prepubertal diagnosis of PP.


   Acknowledgments
 
Anna Belmonte and Helena Jaumandreu facilitated the collection of the study samples. The authors are grateful to Dr. Begoña Bermejo at the Epidemiology Department, Hospital Universitari Vall d’Hebron, for contributing to the statistical analysis; to Montserrat Llop at the Hormonal Laboratory, Hospital Universitari Materno-Infantil Vall d’Hebron, for performing the urinary LH and salivary progesterone assays; and to Karin Vanweser, R.N., at the Pediatric Endocrine Unit, Leuven, for assistance with the preparation of the manuscript.


   Footnotes
 
1 This work was supported by the Fondo de Investigaciones de la Seguridad Social (Madrid, Spain). Back

2 Clinical Research Investigator with the Fund for Scientific Research (Flanders, Belgium). Back

Received November 2, 1998.

Revised December 17, 1998.

Accepted March 4, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. R. Denburg, M. E. Silfen, A. M. Manibo, D. Chin, L. S. Levine, M. Ferin, D. J. McMahon, C. Go, and S. E. Oberfield
Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5604 - 5609.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, N. Potau, A. Ferrer, F. Rodriguez-Hierro, M. V. Marcos, and F. de Zegher
Reduced Ovulation Rate in Adolescent Girls Born Small for Gestational Age
J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3391 - 3393.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, C. Valls, A. Ferrer, K. Ong, D. B. Dunger, and F. de Zegher
Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia, and Anovulation
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2870 - 2874.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, C. Valls, A. Ferrer, M. V. Marcos, F. Rodriguez-Hierro, and F. de Zegher
Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3595 - 3598.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
L. Ibáñez, J. DiMartino-Nardi, N. Potau, and P. Saenger
Premature Adrenarche--Normal Variant or Forerunner of Adult Disease?
Endocr. Rev., December 1, 2000; 21(6): 671 - 696.
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 PediatricsHome page
L. Ibáñez, A. Ferrer, M. V. Marcos, F. R. Hierro, and F. de Zegher
Early Puberty: Rapid Progression and Reduced Final Height in Girls With Low Birth Weight
Pediatrics, November 1, 2000; 106(5): 72e - 72.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
S. E. Oberfield
Metabolic Lessons from the Study of Young Adolescents with Polycystic Ovary Syndrome--Is Insulin, Indeed, the Culprit?
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3520 - 3525.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibáñez, C. Valls, N. Potau, M. V. Marcos, and F. de Zegher
Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3526 - 3530.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibáñez, N. Potau, M. V. Marcos, and F. de Zegher
Treatment of Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism in Nonobese, Adolescent Girls: Effect of Flutamide
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3251 - 3255.
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 J. Clin. Endocrinol. Metab.Home page
R. S. Legro, H. M. Lin, L. M. Demers, and T. Lloyd
Rapid Maturation of the Reproductive Axis during Perimenarche Independent of Body Composition
J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1021 - 1025.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
Corticotropin-Releasing Hormone: A Potent Androgen Secretagogue in Girls with Hyperandrogenism after Precocious Pubarche
J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4602 - 4606.
[Abstract] [Full Text]

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