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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1800
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 1 196-199
Copyright © 2008 by The Endocrine Society

BRIEF REPORT

Polycystic Ovaries in Nonobese Adolescents and Young Women with Ovarian Androgen Excess: Relation to Prenatal Growth

Lourdes Ibáñez, Abel López-Bermejo, Justo Callejo, Ana Torres, Sergi Cabré, David Dunger and Francis de Zegher

Endocrinology Unit (L.I.) and Department of Gynecology (J.C., A.T., S.C.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Diabetes, Endocrinology & Nutrition Unit (A.L.-B.), Dr. Trueta Hospital, 17007 Girona, Spain; Department of Paediatrics (D.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; and Department of Woman & Child (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology, Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: Reduced growth before birth is known to associate with a smaller ovarian volume in adolescents and women without androgen excess. We studied whether prenatal growth relates also to ovarian size and polycystic ovary (PCO) morphology in nonobese adolescents and young women with ovarian androgen excess.

Design: A cross-sectional analysis of standardized case notes over a 2-yr period was performed.

Patients: Nonobese adolescents and young women (age ~17 yr; n = 86) seen for ovarian androgen excess, as confirmed by 17-hydroxy-progesterone hyperresponse to a GnRH agonist, were included in the study.

Measurements: Endocrine-metabolic assessment in fasting state, together with a vaginal ultrasound scan to verify the presence or absence of PCO was performed. Birth weight and gestational age were derived from medical records.

Results: PCO prevalence by ultrasound was 38%. Absence of PCO was associated with a shift (P < 0.0005) of the birth weight distribution toward lower values. Patients with a birth weight less than 3.0 kg were 6-fold more likely to have no PCO than to have PCO. Birth weight was across a wide range (1.5–4.0 kg) associated with ovarian volume in hyperandrogenic patients with noncystic ovaries (r = 0.60; P < 0.00001) and was, in a multiple regression analysis, the prime variable linked to ovarian volume (β = 0.57; P < 0.00001), explaining 32% of its variance.

Conclusions: The ovarian size and the development of a PCO morphology in nonobese adolescents and young women with ovarian androgen excess relate to prenatal growth. These findings indicate that there are two subgroups of nonobese patients with ovarian androgen excess: one with a normal birth weight distribution and with PCO, and one with lower birth weights and without PCO.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
The most dynamic phase of ovarian growth and development occurs in the second trimester of prenatal life, when ovarian weight gain is so rapid that it remains proportional to total body weight gain (1, 2). During the third trimester, ovarian weight increases to above 100 mg, but its fraction of total body weight decreases to less than 0.01% (2). After birth, ovarian volume slowly increases nearly 10-fold across childhood so that, by onset of puberty, ovarian volume has increased to an average of about 1 ml (3). Ovarian volume increases normally a further 3- to 7-fold during puberty, thereafter it remains stable across post-menarcheal adolescence and into early adulthood (4).

Prenatal growth restraint, as judged by a lower birth weight, has been linked to a lower ovulation rate at approximately 16 yr of age (5), to a smaller ovarian volume at approximately 14 and approximately 18 yr of age (6, 7), and to a lower prevalence of a polycystic ovary (PCO) morphology in women aged approximately 28 yr, who developed pubarche before the age of 8 yr (8). We have now studied whether ovarian volume and PCO morphology relate also to prenatal growth in nonobese adolescents and young women with ovarian androgen excess.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We analyzed standardized case notes, collected either retrospectively or prospectively in 2005–2006. Inclusion criteria for the analysis were:

1. All post-menarcheal patients seen at Sant Joan Hospital in 2005–2006 because of androgen excess symptoms (acne, hirsutism, and/or oligo- or amenorrhea) that had started before the age of 21 yr.

2. Results available from endocrine-metabolic screening and from a transvaginal PCO assessment (at least 2 yr after menarche), performed in fasting state, within the early follicular phase (or after ≥ 2 months of amenorrhea), by the same ultrasonographer (S.C.) unaware of the patient’s birth weight.

3. Diagnosis of ovarian androgen excess based on the full spectrum of: hirsutism (score of more than or equal to 8 on Ferriman-Gallwey scale); oligomenorrhea (cycles > 45 d) or amenorrhea (no menses for 6 months); a serum testosterone more than 60 ng/dl or androstenedione more than 280 ng/dl; and a 17-hydroxy-progesterone hyperresponse to GnRH-agonist (9).

4. Birth weight and gestational age available from hospital or other medical records.

5. Body mass index (BMI) less than 30 kg/m2.

Exclusion criteria were: use of a contraceptive or another medication known to affect gonadal or adrenal function; and evidence for thyroid dysfunction, hypercortisolism, hyperprolactinemia, glucose intolerance, diabetes mellitus, or late-onset adrenal hyperplasia.

Assessments and ethics

A history and physical examination documented the presence of acne, hirsutism (Ferriman-Gallwey scale), and/or oligo- or amenorrhea. Height and weight were measured; BMI was calculated (kg/m2). Assessments were performed in the follicular phase (d 3–7) or after 2 or more months of amenorrhea, and included an ovarian ultrasound scan and a fasting blood sample for measurement of serum glucose, insulin, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), LH, and FSH, all of which are standard procedures after referral to Sant Joan Hospital for suspected ovarian hyperandrogenism.

PCO appearance was judged by transvaginal ultrasound scans of the ovaries. Scans were performed by a single observer (S.C.) (see the aforementioned inclusion criteria), with a digital Sonoline G40 scanner (Siemens, Erlangen, Germany), using a 5-MHz multifrequency EV9–4 sector probe. PCO was diagnosed according to the Rotterdam criteria, which require the presence of at least one of the following in one ovary: 12 or more follicles with a diameter of 2–9 mm, or an ovarian volume more than 10.0 ml (10).

The institutional review board of Sant Joan University Hospital approved the statistical analysis of the clinically available data and waived the need for written informed consent before publication of anonymous evidence. None of the present results has been published before.

Assays and statistics

Serum insulin, testosterone, DHEAS, and androstenedione were assayed as described (11); Table 1Go shows indicative results from healthy females of similar age (12). Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) [= fasting insulin in mU/liter) x (fasting glucose in mM)/22.5)]. LH and FSH were measured by immunochemiluminiscence (IMMULITE 2000; Diagnostic Products Corp., Los Angeles, CA) with interassay and intraassay coefficients of variation of 3.5% and 5.0% for LH, and 4.6% and 6.3% for FSH, respectively.


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  		TABLE 1. Characteristics in the total study population of nonobese adolescents and young women with ovarian androgen excess, and in the subpopulations without and with ovarian PCO

 
Statistical analyses were performed with SPSS 12.0 (SPSS, Inc., Chicago, IL). t tests were used to seek differences between subgroups defined by the presence or absence of PCO. Stepwise multiple regression analysis was used to examine the independent predictive value of birth weight on mean ovarian volume. Logistic regression analysis was used to predict a cystic appearance. The level of statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 86 cases analyzed, 68 (79%) were collected prospectively and 18 (21%) retrospectively. The PCO prevalence by vaginal ultrasound was 38% (33 of 86); seven patients had PCO by the criterion of ovarian volume, another seven by the criterion of follicle number ("polycystic aspect"), and the remaining 19 by both criteria. Neither dominant follicles nor major asymmetries of ovarian volumes were observed. Mean ovarian volume was 7.6 ± 0.4 ml in the total study population, being, as expected, higher (P < 0.00001) in patients with PCO (10.8 ± 0.5 ml; n = 33) than in those without PCO (5.6 ± 0.2 ml; n = 53).

Table 1Go and Fig. 1Go show that the absence of PCO was particularly associated with a shift of the birth weight distribution toward lower values (P < 0.0005). Patients with a birth weight less than 3.0 kg were 6-fold more likely [95% confidence interval (CI) 2–21; P = 0.002) to have no PCO than to have PCO.


Figure 1
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  		FIG. 1. Distribution of birth weights in nonobese adolescents and young women with ovarian androgen excess. Birth weights in patients without PCO are lower (P < 0.0005) than in patients with PCO. The birth weight distribution of the PCO patients compares with that of the general population, the birth weight centiles 25, 50, and 75 in Catalunya being 3.1, 3.3, and 3.5 kg.

 
Across ranges of birth weight (1.5–4 kg) and normal ovarian volume (<10 ml), there was a striking association between these two indices, especially in patients whose ovaries had no polycystic aspect (Fig. 2Go). In multiple regression analysis, birth weight was the prime variable associated with ovarian volume (β = 0.57; P < 0.00001), explaining 32% of its variance; BMI, HOMA-IR, LH, and androstenedione were nonpredictive variables in this model.


Figure 2
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  		FIG. 2. Correlation between birth weight (1.5–4 kg) and mean ovarian volume (up to 10 ml) in nonobese adolescents and young women with ovarian androgen excess and without a polycystic aspect of the ovaries.

 
Ovarian volume was the major factor linking to a polycystic aspect of the ovaries (subjects with PCO diagnosed by the criterion of ovarian volume were excluded from this analysis), so that each ml of increase in volume conferred an odds ratio of 1.6 for polycystic aspect (95% CI 1.3–2.0; P < 0.0005, by logistic regression analysis). BMI (odds ratio 1.4; 95% CI 1.0–1.8; P = 0.03), but not HOMA-IR, androstenedione, or LH, was an additional but weak predictor of a polycystic aspect.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In nonobese adolescents and young women with androgen excess, the presence or absence of a PCO morphology was found to relate to prenatal growth, as judged by birth weight. These findings align well with earlier evidence linking a smaller body size in fetal life to a smaller ovarian size in later life (6, 7, 8). However, the present results are even more striking than those of previous studies. Among the many factors that may have contributed to sharpen the link, we mention: the young age of the study population; thorough diagnosis of ovarian androgen excess, including 17-hydroxy-progesterone hyperresponsiveness to a GnRH-agonist; absence of confounders such as obesity and/or prior therapy, including oral contraception; and ovarian visualization by a single ultrasonographer, unaware of the clinical status.

One of the enigmatic aspects of our results is that the birth weight distribution of PCO patients was much closer to that of the reference population than was the birth weight distribution of non-PCO patients with androgen excess. Future studies will verify whether in patients with androgenemia, insulinemia, BMI, or birth weight in the high-normal range, the presence of a mildly positive PCO morphology could be viewed as a physiological response rather than a strictly pathological remodeling.

Among nonobese women with ovarian androgen excess, those with a lower birth weight appear to be at lower risk for having an ovarian PCO morphology. These findings allow to predict that any introduction of PCO as an inclusion criterion into the definition (13) of polycystic ovary syndrome (PCOS) will reduce the fraction of women with a low-normal birth weight among women with "PCOS," will weaken the attention for an evolutionarily and developmentally major pathway to increase androgens in women (14, 15, 16), and will draw even more attention on risk factors, such as obesity. It may be no coincidence that the vast majority of women in recent "PCOS" cohorts are obese, up to half of them having a BMI more than 35 kg/m2 or even more than 40 kg/m2 (17, 18), and that the prevalence of PCO in those women is almost 100% (19). A common link between PCO development in association with increasing birth weight and increasing overweight may be the ovarian exposure to high circulating levels of insulin.

In conclusion, the ovarian size and development of a PCO morphology in nonobese adolescents and young women with ovarian androgen excess relate to prenatal growth. These findings indicate that there are two subgroups of nonobese patients with ovarian androgen excess: one with a normal birth weight distribution and with PCO, and one with lower birth weights and without PCO.


   Footnotes
 
This work was supported by the Social Security Research Fund, Health Institute Carlos III, Spain (PI/021013). L.I. is a clinical investigator of Red Temática en Diabetes Mellitus y Enfermedades Metabólicas Asociadas (REDIMET), R676D (Fondo de Investigación Sanitaria, Health Institute Carlos III, Spain). A.L.-B. is an investigator of the Fund for Scientific Research "Ramon y Cajal" (Ministry of Education and Science, Spain). F.d.Z. is a clinical investigator of the Fund for Scientific Research (Flanders, Belgium).

Disclosure Statement: The authors have nothing to declare.

First Published Online October 23, 2007

Abbreviations: BMI, Body mass index; CI, confidence interval; DHEAS, dehydroepiandrosterone sulfate; HOMA-IR, homeostasis model assessment of insulin resistance; PCO, polycystic ovary; PCOS, polycystic ovary syndrome.

Received August 13, 2007.

Accepted October 15, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Macklon NS, Fauser BC 1999 Aspects of ovarian follicle development throughout life. Horm Res 52:161–170[CrossRef][Medline]
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