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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3526-3530
Copyright © 2000 by The Endocrine Society

Special Articles

Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche1

Lourdes Ibáñez, Carme Valls, Neus Potau, Maria Victoria Marcos and Francis de Zegher2

Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona; Hormonal Laboratory, Hospital Materno-Infantil Vall d’Hebron, Autonomous University of Barcelona (N.P.), 08035 Barcelona; and Endocrinology Unit, Consorci Hospitalari de Terrassa (M.V.M.), 08227 Terrassa, Spain; and Department of Pediatrics, University of Leuven (F.d.Z.), 3000 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: libanez{at}hsjdbcn.org


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Precocious pubarche in girls is often preceded by low weight at birth and followed by hirsutism, ovarian hyperandrogenism, and oligomenorrhea in adolescence, the latter usually being accompanied by dyslipidemia and hyperinsulinism, which are, in turn, two major risk factors for cardiovascular disease in later life. We hypothesized that insulin resistance may be a key pathogenetic factor in this sequence.

We tested the hypothesis by assessing the effects of an insulin-sensitizing agent, metformin, given at a daily dose of 1275 mg for 6 months to 10 nonobese adolescent girls (mean age, 16.8 yr; body mass index, 21.9 kg/m2; birth weight, 2.7 kg) with hirsutism, ovarian hyperandrogenism (diagnosis by GnRH agonist test), oligomenorrhea, dyslipidemia, and hyperinsulinemia after precocious pubarche. Before the metformin trial, longitudinal studies in these girls had shown that hyperinsulinism was present at prepubertal diagnosis of precocious pubarche, and that it increased markedly in late puberty or early postmenarche.

Metformin treatment was well tolerated and was accompanied by a marked drop in hirsutism score, insulin response to oral glucose tolerance test, free androgen index, and baseline testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate levels (all P < 0.01). During metformin treatment, the LH and 17-hydroxyprogesterone hyperresponses to GnRH agonist were attenuated (P < 0.01); serum triglyceride, total cholesterol, and low density lipoprotein cholesterol levels decreased; and high density lipoprotein cholesterol rose. All girls reported regular menses within 4 months. Withdrawal of metformin treatment was followed, within 3 months, by a consistent reversal toward pretreatment conditions.

In conclusion, metformin treatment reduced hyperinsulinemia, hirsutism, and hyperandrogenism; attenuated the LH and 17hydroxyprogesterone hyperresponses to GnRH agonist; improved the atherogenic lipid profile; and restored eumenorrhea in nonobese adolescent girls with a history of precocious pubarche. These observations corroborate the idea that insulin resistance may indeed be a prime factor underpinning the sequence from reduced fetal growth, through precocious pubarche, to adolescent endocrinopathies that are reminiscent of so-called polycystic ovary syndrome.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRECOCIOUS PUBARCHE in girls [defined as the appearance of pubic hair before the age of 8 yr (1)] is often preceded by a low weight at birth (2) and followed by ovarian hyperandrogenism, a variant of polycystic ovary syndrome (3), hallmarked by hirsutism, menstrual disturbances, anovulation, hyperandrogenemia, and, specifically, a hyperresponse of 17-hydroxyprogesterone (17-OHP) to GnRH agonist (4, 5). The ovarian androgen excess is usually accompanied by hyperinsulinism and dyslipidemia (6, 7), which are two of the major risk indexes for subsequent cardiovascular disease (8, 9, 10).

Antiandrogen treatment reduces hirsutism and circulating levels of androgens, triglycerides, and low-density lipoprotein (LDL) cholesterol in women with ovarian hyperandrogenism (11, 12, 13), but it fails to restore menstrual cyclicity, reduce hyperinsulinemia, or increase high-density lipoprotein (HDL) cholesterol and, hence, does not reduce the risk for subsequent reproductive or cardiovascular disorders (12, 14, 15).

Insulin resistance and associated hyperinsulinemia are thought to be among the factors that induce hyperandrogenism in women, independently of obesity (16, 17). In vitro, insulin and insulin-like growth factor I (IGF-I) increase androgen production by thecal and adrenocortical cells (18, 19). In vivo, mild hyperinsulinemia stimulates the activity of ovarian and adrenal cytochrome P450, a key enzyme in androgen biosynthesis (20, 21). Insulin also modulates IGF-I and IGF-binding protein-1 action, and inhibits hepatic sex hormone-binding globulin (SHBG) production (22, 23).

Decreasing hyperinsulinemia with insulin-sensitizing agents, such as metformin or troglitazone, has been reported to reduce ovarian cytochrome P450c17 activity, improve hyperandrogenemia, and restore ovulation in women with ovarian hyperandrogenism (24, 25, 26, 27, 28, 29). These beneficial endocrine-metabolic effects have not been ubiquitously observed (30, 31, 32, 33); the discrepancies are presumably attributable to differences in treatment modalities and to the heterogeneity of the studied populations, in particular regarding the confounding factor of obesity.

There are adolescents and women whose ovarian hyperandrogenism and metabolic correlates originate early in life, being heralded by a low birth weight and precocious pubarche in childhood; insulin resistance has been proposed as a key pathogenetic factor in this sequence (2). We have now tested this hypothesis by exploring the effects of metformin treatment in nonobese adolescent girls with hyperinsulinism of prepubertal onset and with dyslipidemia and ovarian hyperandrogenism after precocious pubarche.


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

The study participants were 10 girls (age, 16.8 ± 0.7 yr; range, 13–20 yr) with a history of precocious pubarche, who were 3 yr or more postmenarche and who had ovarian hyperandrogenism, as defined by oligomenorrhea (duration of menstrual cycles, >45 days) and/or hirsutism (Ferriman-Gallwey score, >8) (34); elevated serum androstenedione, total testosterone, and/or free androgen index [testosterone x 100/SHBG; an index of free testosterone (35)]; and a 17-OHP hyperresponse (>160 ng/dL) to leuprolide acetate, a GnRH agonist (Procrin, Abbott, Madrid, Spain; 500 µg, sc) (5, 6).

In all girls, precocious pubarche had been attributed to pronounced adrenarche, as suggested by elevated androstenedione and/or dehydroepiandrosterone (DHEA) sulfate (DHEAS) levels at prepubertal diagnosis (1, 36). In 8 of the 10 girls, the tendency to hyperinsulinism had been evidenced longitudinally over nearly a decade, not only at diagnosis of precocious pubarche but also in early puberty (Table 1Go); the girls with higher insulin concentrations in early puberty were also those with higher insulin levels after menarche. Birth weight and gestational age data were obtained from hospital records and transformed into SD scores, as previously described (2).


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  		Table 1. Longitudinal results (mean ± SEM) over 10 yr in girls (n = 8) with precocious pubarche before puberty and with ovarian hyperandrogenism after puberty

 
At the time of study, the 10 girls had a body mass index (BMI) within 2 SD from the mean for age (37). None had thyroid dysfunction, hyperprolactinemia, a family or personal history of diabetes mellitus, or late-onset congenital adrenal hyperplasia (38, 39). None was receiving oral contraceptive medication or a drug known to affect gonadal function or carbohydrate or lipid metabolism.

Study design

A design with sequential on-off treatment phases was chosen, because ovarian hyperandrogenism and its metabolic correlates are characterized by a relatively large interindividual and a small intraindividual variability over time (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33). At the start of study, the 10 girls were considered to be in a steady state condition. Metformin was given in a daily lunchtime dose of 1275 mg for 6 months (Dianben, Andreu Roche, Barcelona, Spain); thereafter, metformin treatment was interrupted for 3 months. Before the start of metformin treatment, all girls were screened for blood count, serum electrolytes, liver and renal function, and lipid profile; a standard 2-h oral glucose tolerance test (oGTT) was performed after 3 days on a high carbohydrate diet (300 g/day) and an overnight fast. During the oGTT, the areas under the curves for glucose (mean serum glucose) and insulin (MSI) were calculated according to the trapezoidal rule. At the start of treatment, all girls had a normal mean serum glucose, but were hyperinsulinemic, as judged by peak serum insulin concentrations greater than 150 µU/mL during oGTT (40) and/or MSI values greater than 84 mU/L or MSI scores more than 2 SD (6, 7) (Table 1Go). The same examinations, including a leuprolide acetate test in the early follicular phase (days 3–8), were performed after 6 months on and 3 months off metformin treatment.

Hormonal assays, statistics, and ethics

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott Diagnostics, Santa Clara, CA). The mean intra- and interassay coefficients of variation (CVs) were 4.7% and 7.2%, respectively. LH and FSH were measured using a microparticle enzyme immunoassay (IMX System, Abbott, Chicago, IL) with CVs of 3.0% and 5.4% for LH and 4.1% and 6.9% for FSH. Testosterone, 17-OHP, androstenedione, and estradiol were determined using commercially available RIA kits (35); serum SHBG and DHEAS levels were measured by enzymo-immunochemiluminiscence (41). DHEA was assayed using a tritiated kit (ICN Biomedicals, Inc., Carson, CA) with CVs of 7% and 14%. Serum samples were kept frozen at -20 C until assay.

Anthropometric data and hormonal results are expressed as the mean ± SEM unless stated otherwise. Comparisons were made by two-sided t test; P < 0.05 was considered statistically significant.

The institutional review board of Barcelona Hospital granted study approval. Informed consent was obtained from parents and/or girls as well as assent from minors.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 2Go displays the clinical and endocrine-metabolic indexes before treatment, after 6 months of metformin treatment, and after 3 months off metformin. The sequential on and off treatment effects on major variables are highlighted in Fig. 1Go. Metformin treatment was associated with a striking decrease in hirsutism and the free androgen index, and in circulating total testosterone, androstenedione, and DHEAS; regular cycles were reported by all girls within 4 months. Metformin treatment was also accompanied by a reduction in the hyperresponses of LH, 17-OHP, androstenedione, and DHEA to GnRH agonist; serum triglycerides, total cholesterol, and LDL cholesterol levels dropped, whereas those of HDL cholesterol rose. Upon withdrawal of metformin treatment, all of the aforementioned variables consistently returned toward pretreatment levels within 3 months; menstrual cyclicity was lost.


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  		Table 2. Clinical characteristics, serum hormone concentrations, and metabolic variables (mean ± SEM) in controls and in 10 girls with functional ovarian hyperandrogenism after precocious pubarche, before metformin, after 6 months on metformin and then 3 months off metformin treatment

 


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  		Figure 1. Selected clinical, endocrine, and metabolic indexes before treatment (-), after 6 months on treatment (+), and then 3 months off (-) metformin treatment in adolescent girls with hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. The upper panels display changes in hirsutism score, free androgen index (FAI), serum DHEAS levels, and peak serum responses of LH and 17-OHP to GnRH agonist. The lower panels show changes in serum LDL cholesterol, HDL cholesterol, LDL/HDL ratio, fasting glucose, and mean serum insulin (MSI) during oGTT. **, P < 0.01; ***, P < 0.001.

 
Metformin treatment or withdrawal did not detectably affect BMI or basal serum concentrations of LH, FSH, or estradiol.

At start of metformin treatment, glucose tolerance was normal in all girls (42), and it remained so throughout the study. Metformin treatment and withdrawal had no detectable effect on fasting glycemia or insulinemia, but were accompanied, respectively, by a marked fall and rise of MSI (expressed as the SD score in Table 1Go).

After starting metformin treatment, three girls reported abdominal discomfort and postprandial diarrhea; these inconveniences resolved spontaneously within 2 weeks.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Available evidence indicates that the constellation of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in lean young women may be a late stage of a developmental disorder that started early in life. Nonobese adolescents have been identified in whom the appearance of ovarian hyperandrogenism was heralded by precocious pubarche, hyperinsulinism, and dyslipidemia before puberty and, even earlier, by a low weight at birth (1, 2, 3, 4, 5, 6, 7).

Insulin resistance with hyperinsulinism has been proposed as the key pathogenic factor in the aforementioned sequence. This hypothesis is now corroborated 1) by longitudinal evidence of hyperinsulinism, already present well before puberty and increasing markedly after the early stages of puberty; and 2) by the observation that metformin treatment concomitantly reduces hyperinsulinemia, hirsutism, and hyperandrogenemia; normalizes LH and 17-OHP hyperresponses to GnRH agonist; improves the lipid profile; and restores eumenorrhea, whereas all of these changes consistently revert after withdrawal of metformin.

It is difficult to compare the marked effect of metformin on hirsutism with any effects observed in previous reports, because those studies either did not assess hirsutism (20, 24, 25, 31, 33) or were performed in frankly obese women (26, 32).

Metformin administration was followed by an increase in circulating SHBG, a decrease in serum androgens, and a reduction of the 17-OHP hyperresponse to GnRH agonist, which may point to an attenuation of ovarian P450c17 activity (25). It seems plausible that these effects of metformin on circulating androgens are exerted indirectly through modulation of insulin secretion and action, rather than directly by affecting androgen synthesis or release. Indeed, metformin stimulates the insulin receptor tyrosine kinase activity and, hence, insulin action (43, 44). Moreover, serum androgen levels also drop when hyperinsulinemia is reduced by diazoxide (45) or somatostatin (46), two drugs that are structurally unrelated to metformin.

Hyperinsulinism and ovarian androgen excess are often accompanied by adrenal androgen excess, which can also be reduced by decreasing the hyperinsulinism (47, 48). After sequential on-off treatment with metformin, we observed a drop followed by a rise of serum DHEAS, an androgen that is virtually exclusively of adrenal origin. These findings corroborate the purported role of insulin as an enhancer of adrenal androgen steroidogenesis (21, 49, 50).

The administration of metformin was also followed by a reversible decrease in the LH hyperresponse to GnRH agonist. This observation is consistent with the postulate that hyperinsulinism may increase gonadotroph responsiveness and/or LH pulse amplitude (20, 51); insulin may also augment LH-induced testosterone production by human ovarian thecal cells (52). Hence, part of the metformin-associated reduction of ovarian androgen excess may be mediated by an attenuation of LH release and action.

Metformin treatment was accompanied by a reversible drop of total cholesterol, LDL cholesterol and triglycerides and a marked increase in HDL cholesterol levels. The metformin effects on lipid metabolism can also be ascribed to the reduction of hyperinsulinemia. In epidemiological studies, hyperinsulinemia has been associated with elevated triglycerides and total cholesterol and with low HDL cholesterol levels (53). The reduction of hyperinsulinism by metformin is followed not only by a less atherogenic lipid profile (26), but also by a decrease in the serum concentration of plasminogen activator inhibitor type 1, which is thought to be a major inhibitor of fibrinolysis and, hence, a risk factor for myocardial infarction (54, 55).

In conclusion, metformin treatment was found to have a normalizing effect on multiple aberrations within the endocrine-metabolic status of adolescents with ovarian hyperandrogenism after precocious pubarche. As the hyperinsulinism is already present at the diagnosis of precocious pubarche and seems to increase before the appearance of the complete polycystic ovary syndrome-like condition, our findings raise the possibility that the latter condition can be prevented by administering an insulin-sensitizing treatment at a younger age in a target population of girls at risk, e.g. girls with precocious pubarche and hyperinsulinism, in particular if preceded by reduced fetal growth (2, 4, 56).


   Acknowledgments
 
We thank Montserrat Gallart and Maria Jesús Gras for hormone measurements, Carmen Sanchez-Ufarte for MSI calculations, and Karin Vanweser for editorial assistance.


   Footnotes
 
1 This work was supported by a scholarship from the European Society for Pediatric Endocrinology. Back

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

Received April 28, 2000.

Revised June 6, 2000.

Accepted June 15, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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