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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 3945-3949
Copyright © 1999 by The Endocrine Society

Original Studies

Intrauterine Growth Retardation Predisposes to Insulin Resistance But Not to Hyperandrogenism in Young Women

D. Jaquet, J. Leger, D. Chevenne, P. Czernichow and C. Levy-Marchal

INSERM U-457 (D.J., J.L., P.C., C.L.-M.), and the Department of Hormonology and Biochemistry (D.C.), Hôpital R. Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Dr. D. Jaquet, INSERM U-457, Hôpital R. Debré, 48 boulevard Sérurier, 75019 Paris, France. E-mail: djacquet{at}infobiogen.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
It was recently suggested that precocious pubarche associated with subsequent functional ovarian hyperandrogenism and hyperinsulinemia could have a common origin in reduced fetal growth. We previously reported that young women born with intrauterine growth retardation (IUGR: birth weight less than the third percentile) were hyperinsulinemic and less insulin sensitive than women born with normal birth weight. The aim of the present study was to investigate whether these IUGR-born women demonstrated hyperandrogenism compared with controls. Our study population was composed of 130 IUGR-born women and 150 controls, of similar age (20.6 ± 3.2 vs. 20.4 ± 2.0 yr). Hormonal contraception in terms of frequency and medication, including antiandrogenic therapy, was identical in the 2 groups. After adjustment for hormonal contraception, being born with IUGR had no independent effect on serum androgen concentrations. In women who were not receiving hormonal contraception, no statistical differences were found between IUGR-born women (n = 67) and controls (n = 64) for {Delta}4-androstenedione (2.26 ± 0.68 vs. 2.24 ± 0.55 ng/mL; P = 0.76), dehydroepiandrosterone sulfate (2294 ± 1117 vs. 2489 ± 1235 ng/mL; P = 0.24), testosterone (0.82 ± 0.85 vs. 0.70 + 0.26 ng/mL; P = 0.80), or serum sex hormone-binding protein concentrations (45.5 ± 28.2 vs. 53.1 ± 30.3 nmol/L; P = 0.27). In both IUGR and control groups, sex hormone-binding protein correlated negatively with fasting insulin (r = -0.23; P = 0.03 and r = -0.26; P = 0.05), but serum androgen levels did not correlate with insulin. In summary, hyperinsulinemia observed in young women born with IUGR is not associated with hyperandrogenism. Consequently, our results do not support the hypothesis of a common in utero programming of hyperandrogenism and hyperinsulinemia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRECOCIOUS pubarche has been shown to be associated with an increased frequency of postpubertal functional ovarian hyperandrogenism (FOH) and hyperinsulinemia (1, 2). Postpubertal girls who exhibited the complete triad were found to have birth weights significantly lower than those of postpubertal controls (3). Consequently, it was hypothesized that this triad (precocious pubarche, FOH, and hyperinsulinemia) may result from a common early origin in reduced fetal growth (3).

When studying the long term metabolic consequences of intrauterine growth retardation (IUGR) in a case/control study, we observed hyperinsulinemia during an oral glucose tolerance test (OGTT) and peripheral insulin resistance in young IUGR-born women (4, 5).

Hyperinsulinemia and insulin resistance are common features of FOH (6, 7, 8). The mechanism underlying the relation between hyperandrogenism and insulin resistance or hyperinsulinemia remains unresolved. However, it has been demonstrated that insulin increases the androgen response to LH in rodent and human ovary (9, 10). Insulin also increases androgen activity through down-regulation of the sex hormone-binding protein (SHBP) (11, 12).

The aim of the present study was to investigate whether IUGR-born women demonstrate hyperandrogenism compared with controls by recording clinical characteristics usually associated with hyperandrogenism and measuring serum androgen concentrations.


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

All women were selected according to their growth status at birth. Subjects were identified from a population-based registry of the metropolitan area of the city of Haguenau in France. This registry recorded information on all pregnancies, deliveries, and perinatal events in the area from 1971–1985 (13). Local standard growth curves by gestational age were derived from all live births registered. Our cohort was of all female singleton subjects born full term (>=37 weeks) during 1971–1978 with IUGR (weight and/or height below the 3rd percentile for gestational age and gender, according to the local standard growth curve; n = 241). Control subjects were selected as the next full-term singleton female in the registry, with weight between the 25th and 75th percentiles (n = 225). Fifty-five percent of the IUGR-born women (n = 133) and 67% of the control women (n = 151) agreed to participate in the study. Reasons for nonparticipation have been previously reported, and birth data did not significantly differ between IUGR-born and control women who agreed or did not agree to participate (4). Gestational age did not significantly differ between the two groups (39.7 ± 1.2 vs. 39.9 ± 1.2 weeks). As expected, weight and height at birth were significantly lower in the IUGR group than in the control group [2550 ± 334 vs. 3410 ± 216 g (P = 0.0001) and 47 ± 2.1 vs. 50.4 ± 0.8 cm (P = 0.0001)].

In the present study, exclusion criteria included pregnancy, congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, and thyroid dysfunction. Three women in the IUGR group were excluded for pregnancy (n = 1) and nonclassic adrenal hyperplasia (n = 2). One woman in the control group was excluded for thyroid dysfunction.

The IUGR group included 130 women, and the control group contained 150, all aged 16–23 yr. As functional hyperandrogenism predisposes to the use of hormonal therapy, we included all women regardless of hormonal contraception to minimize treatment bias.

Blood samples were collected after obtained informed consent from the subjects. The study protocol was approved by the local university ethical committee.

Study protocol

All subjects underwent a medical visit at which time clinical data were recorded. Information about medical history, age of menarche, acne (not scored), regularity of menstrual cycles (defined as 25–35 days in length), medications with specific use of hormonal contraception, and antiandrogenic therapy was collected in a standardized questionnaire. Clinical evaluation of hirsutism has not been assessed. Serum {Delta}4-androstenedione ({Delta}4-A), dehydroepiandrosterone sulfate (DHEAS), testosterone, and SHBP were measured in the IUGR-born (n = 120) and control (n = 136) women who did not receive antiandrogenic therapy. Biological hyperandrogenism was defined as {Delta}4-A, DHEAS, testosterone, and/or free androgen index (testosterone x 100/SHBP) > 2 SD of the mean values observed in the eumenorrheic control women without hormonal contraception (n = 41). Sera were collected regardless of stage of the menstrual cycle.

All subjects underwent during the same visit a 75-g OGTT, with plasma glucose and insulin measured at 0, 30, and 120 min after a glucose load. Fasting plasma triglycerides, cholesterol, and high density lipoprotein (HDL) cholesterol were also measured.

Analytical methods

All serum samples were stored at -20 C until assayed. Serum {Delta}4-A, DHEAS, and testosterone concentrations were measured using RIAs (Immunotech, Marseilles, France). SHBP was measured with a specific RIA (I125-SBP-COATRIA, Biomérieux, Marcy l’Etoile, France). Serum insulin concentrations were measured using a two-site immunoassay (ERIA Diagnostics Pasteur, France). Cross-reactivity with proinsulin and derived metabolites was less than 1%. Assay sensitivity was 1.3 pmol/L. Glucose, cholesterol, HDL cholesterol, and triglycerides were measured using enzymatic methods.

Statistical analysis

All data were entered and analyzed using the StatView 4.5 software (Abacus Concepts, Berkeley, CA). Results are expressed as the mean ± SD for the continuous variable and as a percentage for the category variables.

Differences between the IUGR and control groups were tested using the {chi}2 test for the category variables and Student’s t test for the continuous variables. Insulin, testosterone, SHBP, and FAI were log transformed before statistical analyses.

An independent effect of group (IUGR vs. control) on serum androgen concentrations after adjustment for hormonal contraception was tested using an ANOVA. Additionally, a statistical interaction between groups and hormonal contraception was tested at the level of each serum androgen concentration by adding a term groupxhormonal contraception in the model.

Correlations between fasting insulin and SHBP, testosterone, {Delta}4-A, and DHEAS concentrations were tested using linear regression models in women who did not receive hormonal contraception only. P <= 0.05 was considered statistically significant.


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

Clinical characteristics are summarized in Table 1Go. Mean age did not significantly differ between the IUGR and control groups. As previously reported, mean body weight and height were significantly lower in the IUGR-born women (4). Menarche occurred at a similar age in IUGR-born women and controls. All women were studied at least 2.5 yr after menarche. Obesity, oligomenorrhea, and acne are common features of functional ovarian hyperandrogenism. In the present study, we did not observe any significant differences between the IUGR and control groups for mean body mass index, waist to hip ratio, prevalence of irregular menses, or evidence of acne. Hormonal contraception in terms of frequency and medication, including antiandrogen therapy, did not significantly differ between the IUGR and control groups.


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  		Table 1. Clinical characteristics of the IUGR and control groups

 
Metabolic parameters

As previously reported, all women had normal glucose tolerance. Mean blood glucose excursion, under OGTT, was higher in the IUGR-born women than in the controls, and the differences in mean plasma glucose values were significant at fasting and at 30 min [85 ± 6 vs. 83 ± 6 mg/dL (P = 0.05) and 135 ± 35 vs. 128 ± 33 mg/dL (P = 0.03), respectively]. At any time point, serum insulin concentrations under OGTT were significantly higher in IUGR-born women [fasting, 6.3 ± 4.3 vs. 5.0 ± 2.1 µIU/mL (P = 0.001); +30 min, 70.0 ± 45.0 vs. 53.3 ± 31.5 µIU/mL (P = 0.0004); +120 min, 45.7 ± 39.9 vs. 33.9 ± 20.5 µIU/mL (P = 0.003)]. The mean fasting insulin to glucose ratio, taken as a surrogate of insulin resistance, was significantly higher in women born with IUGR (7.4 ± 4.8 vs. 6.0 ± 2.6; P = 0.004). The serum lipid profile (fasting triglycerides, total cholesterol, and HDL cholesterol concentrations) did not significantly differ between the IUGR and control groups (data not shown).

Serum androgen concentrations

After adjustment for hormonal contraception, being born with IUGR had no independent effect on {Delta}4-A (P = 0.59), DHEAS (P = 0.35), testosterone (P = 0.94), SHBP (P = 0.55), or the free androgen index (P = 0.63). As expected, hormonal contraception significantly reduced {Delta}4-A (P < 0.0001), DHEAS (P < 0.0001), testosterone (P < 0.0001), and the free androgen index (P < 0.0001) and significantly increased SHBP (P < 0.0001). We did not observe any significant interaction between the group variable (IUGR vs. control) and hormonal contraception in our study population.

As hormonal contraception had significant effects on serum androgen concentrations, the subsequent analyses were restricted to women who were not receiving hormonal contraception. As expected, we did not observe any significant difference between the two groups for {Delta}4-A (2.26 ± 0.68 vs. 2.24 ± 0.55 ng/mL; P = 0.76), DHEAS (2294 ± 1117 vs. 2489 ± 1235 ng/mL; P = 0.24), testosterone (0.82 ± 0.85 vs. 0.70 + 0.26 ng/mL; P = 0.80; Fig. 1Go), or the free androgen index (2.47 ± 2.15 vs. 2.30 ± 2.80; P = 0.37). Serum SHBP concentrations were slightly lower in IUGR-born women than in controls. This difference did not, however, reach statistical significance (45.5 ± 28.2 vs. 53.1 ± 30.3 nmol/L; P = 0.27; Fig. 1Go). In both IUGR and control groups, SHBP correlated negatively with fasting insulin (r = -0.23; P = 0.03 and r = -0.26; P = 0.05, respectively; Fig. 2Go). In contrast, no significant correlation was observed between fasting insulin and testosterone (r = 0.07; P = 0.58 and r = 0.02; P = 0.87), {Delta}4-A (r = 0.08; P = 0.55 and r = 0.10; P = 0.46), or DHEAS (r = 0.09; P = 0.51 and r = 0.20; P = 0.19). Biological hyperandrogenism (more than +2 SD of the references values, as described in Materials and Methods) was defined as an {Delta}4-A level greater than 3.58 ng/mL, a DHEAS level greater than 5149 ng/mL, a testosterone level more than 1.21 ng/mL, and/or a free androgen index greater than 6.2. It was observed in 8 of 67 (11.9%) IUGR-born women and 8 of 64 (12.5%) control women (P = 0.81). Four IUGR-born women vs. 2 control women demonstrated 2 or more serum androgen concentrations more than +2 SD of the references values. This difference was not statistically significant (P = 0.40).



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  		Figure 1. Comparisons of mean serum androgens concentrations between IUGR-born (n = 67) and control women (n = 64) who were not receiving hormonal contraception. Results are expressed as the mean ± SD.

 


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  		Figure 2. Relation between fasting insulin and SHBP in the IUGR-born (n = 67) and control women (n = 64) without hormonal contraception. The relationship was tested with a linear regression model using log-transformed variables.

 
Similarly, mean serum androgens concentrations did not also significantly differ between the IUGR-born and control women who were receiving hormonal contraception (Table 2Go).


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  		Table 2. Serum androgens concentrations in the IUGR-born and control women taking hormonal contraception

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main finding of our study is that there is no evidence for an increased prevalence of hyperandrogenism in IUGR-born women compared with that in controls. Clinical and biological characteristics of hyperandrogenism did not significantly differ between IUGR-born and control women. It is noteworthy that 50% or more of our study population were under hormonal contraception that could mask symptoms of hyperandrogenism. However, the proportion of women taking hormonal contraception and the type of contraceptive pills, including antiandrogenic therapy, were similar in both groups. Hence, we did not find any independent effect of IUGR on serum androgen concentrations after adjustment for hormonal contraception. Moreover, there was no interaction between hormonal therapy and IUGR.

Our data are not in agreement with the previous observations by Ibañez et al., who reported an association between a low birth weight and a precocious pubarche with subsequent FOH and hyperinsulinemia (3). The population studied by these researchers was selected on puberty maturation criteria, whereas our population was selected on birth data. The different selection criteria used in the two studies might explain the discrepancies found between these studies, and we believe that selection on birth data is more appropriate for studying the long term consequences of reduced fetal growth. We conclude, therefore, that in our study being born with IUGR does not appear to favor hyperandrogenism in adulthood. This conclusion is consistent with the lack of relationship between a low birth weight and the later development of polycystic ovaries observed in a cohort of 42-yr-old women (14).

The long term metabolic consequences of reduced fetal growth are well documented. In adulthood, low birth weight is known to be associated with increased type 2 diabetes, impaired glucose tolerance, and insulin resistance syndrome (15, 16, 17, 18). In our study population IUGR-born women were hyperinsulinemic compared with controls at 20 yr of age (4). It has been demonstrated that insulin increases ovarian androgen production in vitro (9, 10). In polycystic ovary syndrome serum insulin concentrations have been shown to be closely correlated to serum androgen concentrations (19, 20, 21). Likewise, insulin is involved in androgen metabolism by decreasing SHBP and thus increasing free androgen concentrations. This relationship has been well documented in several populations of normal, insulin-resistant, and type 2 diabetic subjects (11, 12, 22, 23, 24) and suggests a physiological regulation of serum SHBP concentrations by insulin. In our study population, SHBP concentrations were negatively correlated with fasting insulin concentrations in IUGR-born and control groups. This inhibitory effect of insulin on SHBP is not sufficient to favor hyperandrogenism in the hyperinsulinemic IUGR-born women of our study. These data suggest that hyperandrogenism associated with hyperinsulinemia and insulin resistance, which is observed under special conditions, such as polycystic ovary syndrome or other forms of FOH (1, 2, 6, 7, 8, 19, 20, 21), results from a complex pathological mechanism, probably independent of fetal nutritional status itself.

As we have no detailed information about the onset of puberty in our study population, we could not exclude any association between precocious pubarche and low birth weight. Previous reports about increased adrenal androgens in children born small for gestational age is consistent with such an association (25, 26, 27). Clark et al. hypothesized that the raised adrenal androgen concentrations might reflect an earlier adrenarche or a change in hypothalamo-pituitary-adrenal axis function (25). However, Dahlgren et al. reported that the negative correlation between DHEAS and birth weight he observed in young children disappears after 9 yr of age (27). This study, rather, supports the hypothesis of an earlier onset of adrenarche associated with reduced fetal growth. However, if IUGR favors precocious adrenarche, it does not necessary predispose to the subsequent development of FOH. Further explorations are required to understand whether fetal undernutrition might influence the outcome of puberty during childhood.

In conclusion, hyperinsulinemia observed in young women born with IUGR is not associated with clinical and/or biological hyperandrogenism. Consequently, our results do not support the hypothesis of a common in utero programming of functional ovarian hyperandrogenism and hyperinsulinemia.

Received May 4, 1999.

Revised June 9, 1999.

Accepted July 22, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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