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Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism

Endocrinology Unit (L.I., A.F., F.R-H.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Endocrinology Unit (M.V.M.), Consorci Hospitalari de Terrassa, 08227 Terrassa, Spain; and Department of Paediatrics (F.d.Z.), University of Leuven, 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

In nonobese girls with an adolescent variant of polycystic ovary syndrome, insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and hyperandrogenism and restores eumenorrhea; however, the effect on anovulation is unknown. We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory hyperandrogenism after precocious pubarche.

The study population consisted of 18 adolescents (mean age, 16 yr; body mass index, 21.4 kg/m²; 3–7 yr beyond menarche) with hyperinsulinemic hyperandrogenism. All girls received metformin for 6 months in a daily dose of 1275 mg. Before inclusion, persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml (months -3 and -1); the ovulation rate was assessed similarly after 2, 4 and 6 months on metformin; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker.

Regular menses were reported by 16 of 18 girls within 4 months on metformin, and all girls were eumenorrheic after 6 months on metformin. Of the 18 girls, 1 (6%) ovulated after 2 months on metformin, 7 (39%) after 4 months, and 14 (78%) after 6 months; ovulation induction failed in the girls with the lowest birth weight or most severe hyperandrogenism. Metformin treatment was well tolerated.

In conclusion, sensitization to insulin was found to be an effective approach to induce ovulation in nonobese adolescents with anovulatory hyperandrogenism.

EVEN IN THE absence of obesity, girls with precocious pubarche (PP; appearance of pubic hair <8 yr) are at risk for subsequently developing an adolescent variant of polycystic ovary syndrome (PCOS) characterized by hyperinsulinism, dyslipidemia, hyperandrogenism, and persistent anovulation; this risk seems to be particularly high if PP itself was preceded by prenatal growth restraint (1, 2, 3, 4, 5, 6, 7). Insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and hyperandrogenism and restores eumenorrhea in such adolescents (8); however, the effect on anovulation is unknown.

Administration of an insulin-sensitizing agent such as metformin or troglitazone decreases hyperinsulinemia and hyperandrogenism in obese women with PCOS and increases the rate of spontaneous and/or clomiphene- or gonadotropin-induced ovulation (9, 10, 11, 12, 13). We have now assessed whether metformin treatment is also capable of inducing ovulation in nonobese adolescents with persistent anovulation as part of PCOS after PP.

Subjects and Methods

Study population

The study population consisted of 18 adolescent girls (age, 16.5 ± 0.4 yr) who were between 3–7 yr beyond menarche. This is a phase in which the rate of spontaneous ovulation tends to decrease rather than to increase (2).

The two main inclusion criteria were anovulation (cfr. infra) and ovarian hyperandrogenism, the latter being defined as a combination of at least three of the following: a- or oligo-menorrhea (duration of menstrual cycles >45 d); hirsutism (Ferriman and Gallwey score >8) (14); elevated serum androstenedione, total testosterone, and/or free androgen index [testosterone x 100/sex hormone-binding globulin (SHBG), an index of free testosterone (15)]; 17-hydroxyprogesterone (17-OHP) hyperresponse (>160 ng/dl) to GnRH agonist (leuprolide acetate; Procrin, Abbott, Madrid, Spain; 500 µg sc) (3, 5).

Another inclusion criterium was a history of PP, provided PP was due to exaggerated adrenarche, as suggested by elevated serum androstenedione and/or dehydroepiandrosterone-sulfate (DHEAS) levels (1, 16), and corroborated by an ACTH test to exclude nonclassic adrenal hyperplasia (17, 18).

Glucose, insulin, and androgen levels of part of this study population have been reported in a previous study (8). At the time of inclusion, none of the adolescents had acanthosis nigricans, thyroid dysfunction, Cushing’s syndrome, a family or personal history of diabetes mellitus, or was receiving a medication known to affect gonadal function or carbohydrate- or lipid-metabolism.

The body mass indices (BMIs) of all girls were within 2 SD from the mean for age (19). Birth weight and gestational age data were obtained from hospital records.

Study design

At the start of the study, the girls were considered to be in a steady state condition. Metformin (Dianben, Andreu Roche, Barcelona, Spain) was given in a daily lunch-time dose of 1275 mg for 6 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 tests (oGTT, starting at 0800 h) was performed after 3 d on a high-carbohydrate diet (300 g/d) and an overnight fast. Blood was sampled 0, 30, 60, and 120 min after oral glucose intake, for measurement of glucose and immunoreactive insulin, as described (2, 3). For calculation of mean serum insulin (MSI) during the oGTT, the area under the insulin curve was calculated according to the trapezoidal rule. All girls had normal glucose tolerance (20) but were hyperinsulinemic, as judged by peak serum insulin concentrations higher than 150 µU/ml during oGTT (21) and/or MSI values greater than 84 mU/liter (2, 3).

After 6 months on metformin, fasting glucose and insulin were reassessed together with serum LH, FSH, estradiol, testosterone, androstenedione, DHEAS, SHBG, and lipid profile.

Ovulation assessment

Before inclusion, the anovulatory state was documented twice (months -3 and -1) by measuring serum progesterone concentrations less than 4 ng/ml in four consecutive samples obtained with an interval of 1 wk. Ovulation rate was assessed similarly after 2, 4, and 6 months on metformin; ovulation was postfactum, considered to have occurred if a serum progesterone level higher than 8 ng/ml was found in a sample obtained 5–8 d before menses (9).

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 were 4.7% and 7.2%, respectively. LH, FSH, and progesterone were measured by immuno-chemiluminiscence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA), with coefficients of variation of 3.5% and 5.0% for LH, 4.6% and 6.3% for FSH, and 7.8% and 8.5% for progesterone. Testosterone, 17-OHP, androstenedione, and estradiol were determined using commercial RIA kits (15); serum SHBG and DHEAS levels were measured by enzymo-immuno-chemiluminiscence (8). Serum samples were kept frozen at -20 C until assay.

Anthropometric data and hormonal results are expressed as mean ± SEM, unless stated otherwise. Comparisons were made by two-sided t test, P values of 0.05 or greater being considered as statistically significant.

The study was approved by the Institutional Review Board of Barcelona Hospital. Informed consent was obtained from parents and/or adolescents, assent being obtained from minors.

Results

Table 1 summarizes the clinical characteristics, as well as the hormonal and metabolic status, of the adolescents before and after 6 months on metformin treatment.

Regular menses were reported by 16 of 18 girls within 4 months of metformin treatment, and all girls were eumenorrheic after 6 months on metformin.

Fig. 1 summarizes the ovulation results. Among the four girls in whom ovulation induction with metformin failed within 6 months were the girl with the lowest birth weight (-4 SD) and the two girls with the most severe hyperandrogenism; one adolescent had detectable ovulation after 4 months and not after 6 months on metformin. In girls ovulating after 6 months on metformin, peak progesterone levels averaged 15.0 ± 1.3 ng/ml.

View larger version (11K): [in this window] [in a new window]   Figure 1. Number and fraction of ovulatory adolescents before and after metformin treatment.

Discussion

Sensitization to insulin was found to be strikingly effective to induce ovulation in nonobese, anovulatory girls with an adolescent variant of PCOS.

In nonobese adolescents with hyperinsulinism, hyperandrogenism, and dyslipidemia, metformin treatment tends to normalize these three anomalies in concert (8). Hence, it is at present difficult to infer to which extent the virtually synchronized onset of ovulation in these girls results from reduced hyperinsulinism itself, from correlated changes in androgen or lipid metabolism, or from concerted alterations. It seems plausible that the effects of metformin on ovarian function are at least partially exerted through reduction of insulin resistance and hyperinsulinemia. On one hand, metformin is known to stimulate the insulin receptor tyrosine kinase activity and, hence, insulin action (22, 23); on the other, metformin does not seem to exert direct effects on ovarian steroidogenesis or on hypothalamo-pituitary function (24, 25). Moreover, improving insulin sensitivity with D-chiro-inositol, a purported precursor for inosytol-glycan mediators involved in insulin signal transduction, has been associated with a decrease in serum androgen levels and in ovarian androgen production, and also with a resumption of spontaneous ovulation in obese women with PCOS (26). It is anticipated that future studies comparing the effects of antiandrogens, insulin-sensitizers, and/or combinations of these will allow to differentiate some primary from secondary effects of these compounds and will hereby provide more insight into the mechanisms generating and/or perpetuating the anovulatory state.

The present observations may also be relevant for our understanding of the normal onset of ovulation. Early after menarche, most adolescent girls experience a transient state of anovulation that is poorly understood and mostly considered as a physiological episode within the ontogeny of fertility (27, 28). If spontaneous progression to ovulatory cycles and regular menses fails to occur within 2–3 yr postmenarche, then the anovulatory state tends to persist well beyond adolescence into the normally reproductive years (29). Persistent anovulation in adolescent girls has been associated with pulsatile hypersecretion of LH and with elevated serum concentrations of ovarian androgens, thus mimicking some endocrine features of women with PCOS (30, 31, 32). The adolescents studied here were 3–7 yr beyond menarche and had failed to progress spontaneously into the ovulatory phase. It is unknown whether such persistent anovulation is attributable to factors different from those governing the normal episode of late-pubertal anovulation, or related to the same mechanisms that have here been prolonged or exaggerated to a pathological extent. The latter mechanisms may, for example, involve hyperinsulinism induced by GH action. Indeed, hypersecretion of GH is a normal pubertal event whereby insulin resistance is either induced or amplified (33, 34, 35), and whereby its proposed correlate, the anovulatory state, is maintained until skeletal growth is completed. In other words, GH-induced hyperinsulinism may act as an endogenous contraceptive in pubertal girls, and prolonged/exaggerated GH hypersecretion is proposed as a co-responsible for persistent hyperinsulinism-anovulation in nonobese adolescents with hyperandrogenism. This hypothesis was recently corroborated by documenting GH hypersecretion in nonobese PCOS adolescents and evidencing its close correlation with indices of hyperandrogenism (36). Combined GH hypersecretion and hyperinsulinism may be implied in the impaired feedforward- and feedback-signaling that have been observed between LH and ovarian androgens in adolescents with PCOS (37). Abnormalities in the somatotropic axis are not ubiquitously reported in adolescents with hyperinsulinism and ovarian hyperandrogenism (38, 39); these apparent discrepancies may be partly attributable to the heterogeneity of the studied populations and to methodological differences in the assessment of the somatotropic axis.

In conclusion, metformin treatment not only tends to normalize the endocrine-metabolic status of nonobese adolescents with anovulatory hyperandrogenism, but also seems capable to swiftly induce ovulation in these girls. As with any new therapeutic model, long-term efficacy and safety issues need to be addressed. So far, clinical experience with insulin sensitizers is limited in adolescents with PCOS (40). To our knowledge, this is the first study assessing the effect of insulin sensitization on ovulatory function in a nonobese population; a previous study was conducted in obese women with longstanding PCOS (41). Randomized, controlled trials with safe insulin sensitizers will have to be conducted in lean women with anovulatory PCOS before the use of these compounds can be considered for recommendation to induce ovulation within a context of female subfertility.

Acknowledgments

We thank Montserrat Gallart for hormone measurements and Inge Laleeuwe for editorial assistance.

Footnotes

This work was supported by a Visiting Scholarship from the European Society for Pediatric Endocrinology. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium).

Abbreviations: BMI, body mass index; DHEAS, dehydroepiandrosterone-sulfate; MSI, mean serum insulin; oGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PP, precocious pubarche; 17-OHP, 17-hydroxyprogesterone; SHBG, sex hormone-binding globulin.

Received February 26, 2001.

Accepted April 20, 2001.

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