Oral contraception vs insulin sensitization for 18 months in nonobese adolescents with androgen excess: posttreatment differences in C-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity.

BACKGROUND: An oral estro-progestagen is the standard medication given to adolescent girls with androgen excess, even when those girls are not at risk of pregnancy. AIM: The aim of this study was to compare on-treatment and post-treatment effects of intervention with an oral contraceptive vs an insulin-sensitizing treatment for androgen excess in nonobese adolescents. DESIGN: This was a randomized, open-label trial. STUDY POPULATION: Subjects were nonobese adolescent girls with hyperinsulinemic androgen excess and without risk of pregnancy (mean age, 16 years; body mass index, 23 kg/m²; n = 34). INTERVENTIONS: The effects of treatment with ethinylestradiol-cyproteroneacetate (EE-CA) vs a low-dose combination of pioglitazone (7.5 mg/d), flutamide (62.5 mg/d), and metformin (850 mg/d) (PioFluMet) for 18 months were studied. Posttreatment follow-up was for 6 months. MAIN OUTCOME MEASURES: Androgen excess (hirsutism and acne scores and serum testosterone), glucose-stimulated insulinemia, circulating C-reactive protein, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and menstrual regularity were measured. RESULTS: EE-CA and PioFluMet attenuated androgen excess similarly but had divergent, and even opposing, effects on other outcomes. Six months posttreatment, the PioFluMet-treated girls had a lower glucose-induced insulinemia, a lower C-reactive protein level, and a thinner intima media than the EE-CA-treated girls, and they were viscerally less adipose, had a higher lean mass, and were more likely to have regular cycles. CONCLUSIONS: The on-treatment and post-treatment effects of PioFluMet compared favorably with those of oral contraception in nonobese adolescents with androgen excess. The intervention whereby androgen excess is reduced in adolescence influences the post-treatment phenotype. PioFluMet-like interventions in adolescence may thus hold the potential to prevent part of the androgen-excess phenotype in adulthood, including adiposity and subfertility.

Endocrinology and gynecology of girls and women with low birth weight.

In girls, low birth weight (LBW), when followed by postnatal catch-up growth, is accompanied by endocrine-metabolic abnormalities which include a more adipose body composition (with increased visceral fat), insulin resistance and a less favorable adipokine profile as early as in the pre-school age. These girls also exhibit follicle-stimulating hormone hypersecretion both in early infancy and early post-menarche, with reduced uterine and ovarian size in adolescence. These endocrine and gynecological changes result in a decreased ovulation rate and in an advanced tempo of adrenarche, pubertal development and menarche (by nearly a year, compared to non-LBW girls). The earlier maturation in LBW girls may result in a loss of about 1 SD in height, as compared with target height. During the post-menarcheal period, LBW girls are at increased risk of developing polycystic ovary syndrome. Early insulin sensitization may prevent or delay some of the endocrine-metabolic abnormalities associated to LBW.

Pharmacokinetics of metformin in girls aged 9 years.

BACKGROUND AND OBJECTIVE: Metformin is a biguanide used in the treatment of type 2 diabetes mellitus. In girls with a low birth weight, and early-normal and rapidly progressive puberty, metformin therapy is capable of modifying this outcome, prolonging pubertal growth, increasing height gain, delaying the age at menarche towards normal and improving the endocrine-metabolic status of these girls. The pharmacokinetics of metformin have been studied in healthy adults and in patients with type 2 diabetes. The objective of this study was to study the pharmacokinetics of metformin in young, non-obese girls. METHODS: The study population consisted of six girls with a combined history of low birth weight and early-normal onset of puberty. At the time of the study, these girls were aged 9 years and had been receiving metformin (850 mg/day at dinner time) for a mean duration of 8 months. Blood samples were obtained from the girls before metformin intake and for 12 hours thereafter. Serum metformin concentrations were assessed by liquid chromatography with tandem mass spectrometry. The area under the serum concentration-time curve (AUC), maximum serum concentration (C(max)), time to reach the C(max) (t(max)), half-life (t(½)), volume of distribution (V(d)) and total clearance (CL) were calculated. RESULTS: Metformin concentration-time curves were similar in girls receiving similar metformin doses (range 21-29 mg/kg): in those girls, the mean AUC was 21 mg · h/L, with a C(max) of 3 mg/L, t(max) of 2.5 hours, t(½) of 4 hours, V(d) of 111 L and CL of 20 L/h. These values are comparable to those observed in adults. CONCLUSION: In girls aged 9 years, the pharmacokinetics of metformin were comparable to those in adults. Trial registration number (International Standard Randomized Controlled Trial Number Register): ISRCTN49334271.

Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence.

CONTEXT: Girls with a combined history of low(-normal) birth weight (LBW) and precocious pubarche (PP) are at high risk to develop polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to compare the capacity of early vs. late metformin treatment to prevent adolescent PCOS. DESIGN: This was a randomized, open-label study over 7 yr. SETTING: The study was conducted at a university hospital. PATIENTS: Thirty-eight LBW-PP girls were followed up from the mean age 8 until age 15 yr. INTERVENTION: Early metformin (study yr 1-4; age 8-12 yr) vs. late metformin (yr 6; age 13-14 yr). MAIN OUTCOME MEASURES: Measures included height; weight; hirsutism score; menstrual cycle; endocrine-metabolic screening (fasting; follicular phase); C-reactive protein; body composition (absorptiometry); abdominal fat partitioning (magnetic resonance imaging); ovarian morphology (ultrasound); PCOS (National Institutes of Health and Androgen Excess Society definitions) after yr 7 (all girls thus untreated for at least 1 yr). RESULTS: None of the girls dropped out of the study. At age 15 yr, early-metformin girls were taller (4 cm), were in a less proinflammatory state, and had less central fat due to reductions in visceral and hepatic fat. Hirsutism, androgen excess, oligomenorrhea, and PCOS were between 2- and 8-fold more prevalent in late- than early-treated girls. Abdominal adiposity was the first variable to diverge (at age 8-10 yr) between girls without vs. with PCOS at age 15 yr. CONCLUSIONS: In LBW-PP girls, early metformin therapy was found to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea, and PCOS more effectively than late metformin. The time window of late childhood and early puberty may be more critical for the development, and thus for the prevention, of adolescent PCOS than the first years beyond menarche.

Early metformin therapy to delay menarche and augment height in girls with precocious pubarche.

OBJECTIVE: To study the effects of early metformin treatment on menarche, height, and polycystic ovary syndrome (PCOS) markers. Low-birthweight (LBW) girls with precocious pubarche (PP) are at risk for an early menarche (<12 years), an adult stature below target level, and PCOS. Hyperinsulinemic insulin resistance is thought to be a key factor. DESIGN: Open-label, randomized study. SETTING: University hospital. PATIENT(S): Thirty-eight LBW-PP girls. INTERVENTION(S): At age 8 years, girls were randomly assigned to remain untreated or to receive metformin for 4 years; subsequently, both subgroups were followed without treatment until each girl was postmenarcheal. MAIN OUTCOME MEASURE(S): Age at menarche, height, weight, endocrine-metabolic state (fasting blood), body composition (by absorptiometry), abdominal fat (subcutaneous vs. visceral), and hepatic adiposity (by magnetic resonance imaging). RESULT(S): At last assessment, girls in each subgroup were on average 2 years beyond menarche; the mean growth velocity was below 2 cm/years. Age at menarche was 11.4 ± 0.1 years in untreated girls and 12.5 ± 0.2 years in metformin-treated girls; the latter girls were taller and much leaner (with less visceral and hepatic fat) and had more favorable levels of circulating insulin, androgens, and lipids. CONCLUSION(S): Early metformin therapy (age ∼ 8-12 years) suffices to delay menarche; to augment postmenarcheal height; to reduce total, visceral, and hepatic adiposity; and to curb the endocrine-metabolic course of LBW-PP girls away from adolescent PCOS.

Pubertal metformin therapy to reduce total, visceral, and hepatic adiposity.

OBJECTIVE: Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. We tested this hypothesis in low-birthweight (LBW) girls with precocious pubarche (PP), who are at risk for hyperinsulinemic body adiposity during and beyond puberty. STUDY DESIGN: LBW girls with PP (n = 38; mean age 8 years) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored for 1 year without intervention. Here we report on the latter year. RESULTS: The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, metformin therapy was associated with more lean mass; with less total, visceral, and hepatic fat; with lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin. CONCLUSION: In LBW girls with PP, pubertal metformin therapy was followed by a favorable adipokine profile and by a reduction of total, visceral, and hepatic adiposity beyond puberty.

Abdominal fat partitioning and high-molecular-weight adiponectin in short children born small for gestational age.

CONTEXT AND OBJECTIVE: Children born small for gestational age (SGA) tend to become hyperinsulinemic and viscerally adipose and to have low levels of circulating high-molecular-weight (HMW) adiponectin upon completion of catch-up growth. We studied whether the same applies to SGA children, who failed to develop spontaneous catch-up growth. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included 24 short SGA children (11 girls, 13 boys; mean age 7.5 yr, height -3.0 SD) as compared with appropriate-for-gestational-age (AGA) children (n = 32) and catch-up SGA children (n = 32) of similar height, weight, and body mass index. MAIN OUTCOMES: We measured fasting serum glucose, insulin, IGF-I, and HMW adiponectin; body composition by absorptiometry; and abdominal fat partitioning by magnetic resonance imaging. RESULTS AND CONCLUSION: Short SGA children were highly sensitive to insulin (P < 0.001 vs. AGA; P < 0.0001 vs. catch-up SGA), had low IGF-I levels, and had high-normal levels of HMW adiponectin (mean 14.0 vs. 7.4 mg/liter in catch-up SGA; P < 0.001). In the abdominal region, short SGA children had a normal amount of visceral fat (mean 17 vs. 18 cm(2) in AGA), but their sc fat was strikingly reduced (mean 18 vs. 29 cm(2) in AGA; P < 0.0001); this combination resulted in a markedly elevated ratio of visceral over sc fat (P < 0.0001 vs. AGA). The effects of GH therapy on these features of short SGA children remain to be studied.

Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism.

Premature pubarche-defined as the appearance of pubic hair before age 8 years in girls and 9 years in boys-has been traditionally considered a benign entity. However, recent evidence supports the notion that premature pubarche in girls may be a forerunner of the metabolic syndrome, and may precede the development of clinical ovarian androgen excess in adolescence. This sequence seems to occur more frequently when premature pubarche was preceded by reduced fetal growth and followed by excessive postnatal catch-up in height and particularly in weight; hyperinsulinemia appears to be a key factor in the development of this sequence of events. In girls with premature pubarche and a history of a low birth weight, puberty tends to start earlier and to have a faster course, so that final height may be moderately reduced. In these girls, metformin therapy may reverse the progression to clinical ovarian hyperandrogenism, normalize body composition and excess visceral fat, and delay pubertal progression without attenuating linear growth and bone mineralization, suggesting that adult height may be improved. Long-term follow-up of these patients is needed to fully determine the ultimate effects of insulin sensitization as well as the maintenance of these benefits after discontinuation of therapy.

Visceral adiposity without overweight in children born small for gestational age.

CONTEXT: Children born small for gestational age (SGA) tend to develop catch-up growth in infancy and become overweight by the age of 6 yr. Weight control is advocated as a preventive measure, but it is unknown whether such control suffices to prevent visceral fat excess and hypoadiponectinemia. SETTING: The study was performed at a university hospital. STUDY POPULATION AND DESIGN: A total of 64 children (32 matched pairs) aged 6 yr, of whom 32 were born appropriate for gestational age and 32 were born SGA, and had subsequently developed spontaneous catch-up growth were included in the study; matching was performed for gender, height, weight, and, thus, body mass index. MAIN OUTCOMES: Fasting insulin, IGF-I, high molecular weight adiponectin, leptin, visfatin, and lean and fat mass were calculated by absorptiometry, and abdominally sc and visceral fat by magnetic resonance imaging. RESULTS: After strict matching, SGA children had a total lean mass, total fat mass, leptinemia, and visfatinemia comparable to those in the appropriate for gestational age children, but they still had higher fasting insulin and IGF-I levels (P < 0.01), much lower high molecular weight adiponectin levels (P < 0.0001), and a striking shift from abdominally sc to visceral fat (P < 0.0001). Fasting insulin (r = 0.52; P < 0.00001) was a major determinant of visceral fat in boys and girls, explaining 28% of its variance. CONCLUSIONS: SGA children tend to be viscerally adipose and hypo-adiponectinemic, even if they are not overweight. Therefore, measures beyond weight control seem to be needed to allow most SGA children to normalize their body composition and endocrine-metabolic homeostasis.

Metformin treatment for four years to reduce total and visceral fat in low birth weight girls with precocious pubarche.

CONTEXT AND OBJECTIVE: A low birth weight (LBW) tends to be followed by overweight due to an excess of fat, including visceral fat. LBW girls with precocious pubarche (PP) (pubic hair < 8 yr) are at high risk for developing an adipose state of hyperinsulinemic androgen excess that leads toward early menarche. We explored the effects of insulin sensitization with metformin in LBW-PP girls. SETTING, DESIGN, PATIENTS, INTERVENTION: Prepubertal LBW girls with PP (mean body weight 2.4 kg; age 7.9 yr; body mass index 18.4 kg/m(2)) were studied. Girls were randomly assigned to remain untreated (n=19) or receive metformin for 4 yr (n = 19; 425 mg/d for 2 yr, then 850 mg/d for 2 yr). MAIN OUTCOMES: At the start and after 4 yr, height, weight, fasting insulin, glucose, IGF-I, testosterone, lipids, leptin, high molecular weight adiponectin, body composition by absorptiometry, abdominal fat partitioning (only 4 yr) by magnetic resonance imaging, and menarcheal status were determined. RESULTS: Metformin-treated girls gained on average 5.5 kg (or approximately 50%) less fat, after 4 yr were less insulin resistant and less hyperandrogenic, had lower IGF-I levels and a less atherogenic lipid profile, and were less likely to be post-menarcheal than untreated girls, whereas their gain in height, lean mass, and bone mineral density were similar. After 4 yr, untreated girls had more visceral fat, a higher ratio of visceral-to-sc fat, and a higher leptin-to-high molecular weight adiponectin ratio (all approximately 50% higher) than metformin-treated girls. CONCLUSION: Long-term metformin treatment appears to reduce total and visceral fat in LBW-PP girls, and to delay menarche without attenuating linear growth, thereby opening the perspective that adult height may be increased.

Metformin treatment to prevent early puberty in girls with precocious pubarche.

CONTEXT AND OBJECTIVE: Girls with precocious pubarche (PP, pubic hair at < 8 yr of age) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained, i.e. low birth weight (LBW), and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis. SETTING, DESIGN, AND PATIENTS: The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean body weight, 2.4 kg; age, 7.9 yr; body mass index (BMI), 18.4 kg/m(2)]. These girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr. MAIN OUTCOME MEASURES: Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, IGF-I, IGF-binding protein-1, testosterone, dehydroepiandrosterone sulfate, and SHBG were the main outcome measures. RESULTS: Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4-yr delay in the clinical onset of puberty (Tanner B2; 9.5 vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-I (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02). Gain in height and lean mass was not divergent between study subgroups. CONCLUSION: The efficacy of early metformin treatment in PP girls is here extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty, whereas height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.

Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment.

Among girls with precocious pubarche (PP), those with low birth weight (LBW) are, even if nonobese, at risk for progression to polycystic ovary syndrome (PCOS) including hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central fat excess. Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were postmenarche. In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: 1) metformin therapy was started before puberty; and 2) we assessed the effects of metformin discontinuation in girls who had started metformin treatment after menarche. Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body mass index, 18.5 kg/m(2)) were randomly assigned to remain untreated or to receive metformin (425 mg/d) for 6 months. Postpubertal LBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m(2)) had been randomized (at -12 months) to remain untreated or to receive metformin (850 mg/d) for 12 months, at which time (0 month) a treatment cross-over was performed for 6 months. Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosterone sulfate, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition (by dual x-ray absorptiometry). In the prepubertal study (group A), comparisons of untreated vs. treated girls disclosed normalizing effects of metformin on SHBG, androstenedione, dehydroepiandrosterone sulfate, low and high density lipoprotein cholesterol, triglycerides, IL-6, adiponectin, total and abdominal fat mass, and lean body mass. In the postpubertal study (group B), treatment cross-over at 0 month was in each subgroup followed by a striking reversal in the course of the endocrine-metabolic state, adipocytokinemia, and body composition; all changes pointed to normalizing effects of metformin treatment. In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin's normalizing effects are reversed as soon as metformin therapy is discontinued.

Hypergonadotrophinaemia with reduced uterine and ovarian size in women born small-for-gestational-age.

BACKGROUND: Fetal growth restraint has been associated with FSH hypersecretion in early infancy and in early post-menarche, and with reduced uterine and ovarian size in adolescence. It is unknown whether these reproductive anomalies persist, respectively, into late infancy and into the reproductive age range. METHODS: We report follow-up findings in two age groups of girls. A cohort of infants [n=26; n=10 born appropriate-for-gestational-age (AGA) and n=16 born small-for-gestational-age (SGA)], who had been studied at the age of approximately 4 months, was assessed again at the age of 12 months. A cohort of teenagers (n=28), who had been studied at the age of approximately 14 years, was assessed again at the age of approximately 18 years; this group was complemented by a transversal cohort of similar age (n=19) for a total of 47 young women (n=27 AGA; n=20 SGA). In infants, only serum FSH was measured; adolescents underwent endocrine-metabolic screening, ultrasound assessment of uterine-ovarian size, and evaluation of body composition by dual X-ray absorptiometry. RESULTS: Serum FSH levels were higher in SGA than AGA infant girls at 4 and 12 months, and higher in SGA than AGA adolescents at 14 and 18 years (all P<0.01). Longitudinal ultrasound assessments disclosed a late-adolescent increment of uterine size that was less obvious in SGA than AGA girls. In contrast, ovarian volume remained stable in both subgroups. Compilation of longitudinal and transversal results at 18 years of age corroborated the persistent reduction in the uterine size of SGA girls (by approximately 20%; P<0.005) and in their ovarian volume (by approximately 40%; P<0.0001); moreover, SGA girls displayed not only a persistent elevation of FSH (by approximately 50%; P<0.001), but also a rise of LH and fasting insulin, as well as an excess of abdominal fat (all P<0.01). CONCLUSIONS: The gynaecology of young women born SGA was found to be characterized by hypergonadotrophinaemia and by a reduced uterine and ovarian size.

Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.

Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4-19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7-31 repeats vs. 22.0, 15-32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean

Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche.

OBJECTIVE: Precocious pubarche (PP) in girls is associated with hyperinsulinaemia and dyslipidaemia of prepubertal onset, and with ovarian hyperandrogenism and ovulatory dysfunction in adolescence, particularly if they also had prenatal growth restraint and postnatal growth acceleration. Hyperinsulinaemia may be the pathogenic key factor, possibly amplified by hyperandrogenaemia. While such PP girls do not have increased body mass index (BMI), we hypothesized that body fat mass and fat distribution may differ between PP girls and matched controls, and may relate to insulin and androgen levels. PATIENTS AND DESIGN: Sixty-seven PP girls (age range 6.0-18.0 years) and 65 control girls matched for age and pubertal stage (5.9-18.0 years) had height, weight, waist and hip circumferences measured, and dual-energy X-ray absorptiometry (DXA) assessment of total body fat mass, and fat mass in abdominal and truncal regions. All girls had fasting plasma glucose, serum insulin, lipids, testosterone and SHBG levels measured; PP girls also had a standard 2-h oral glucose tolerance test (oGTT). RESULTS: Despite no differences in BMI, PP girls had significantly larger waist circumference, waist-to-hip ratio, total fat mass, percentage fat mass, abdominal fat mass, and truncal fat mass vs. controls in each pubertal stage. Overall, fasting insulin levels, free androgen index (FAI) and blood lipid levels were more closely related to central fat than to total body fat mass. In a multiple regression analysis, truncal fat mass was independently related to both fasting insulin (P = 0.009) and FAI (P < 0.0001). Abdominal fat mass was inversely related to birthweight (r = -0.25, P = 0.001). In PP girls, central fat mass was positively related to insulin levels after oGTT (truncal fat vs. 30 min insulin; r = 0.46, P < 0.0005). CONCLUSIONS: Precocious pubarche girls had excess total body and central fat mass throughout all pubertal stages, and increased central fat was related to hyperinsulinaemia and hyperandrogenaemia. It remains to be verified whether body composition in PP girls can be normalized by insulin-sensitization and/or antiandrogen therapy.

Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism.

Adolescent girls born small for gestational age (SGA) are at risk for anovulation, hyperinsulinism, subclinical hyperandrogenism, dyslipidemia, and central adiposity. Hyperinsulinemic insulin resistance has been proposed as a key pathogenetic factor underpinning these associations. We have tested this hypothesis in an intervention study by assessing the effects of insulin sensitization (metformin treatment, 850 mg/d for 3 months) in eumenorrheic, nonobese, anovulatory SGA adolescents [n = 13; mean birth weight, 2.3 kg; age, 15 yr; body mass index (BMI), 20.5 kg/m(2); >or=3 yr post-menarche] who were in a steady state (over approximately 6 months) for BMI, hyperinsulinism, subclinical hyperandrogenism, and dyslipidemia, and who presented a deficit of lean body mass and an excess of (truncal and abdominal) fat mass. Metformin treatment was accompanied by a drop in fasting insulin and serum androgens and by a less atherogenic lipid profile (all P

Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche.

To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism.Association study. Academic research environment. Adolescent girls with a history of PP and healthy adolescent female control subjects. Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

Reduced ovulation rate in adolescent girls born small for gestational age.

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.

Hypersecretion of FSH in infant boys and girls born small for gestational age.

Prenatal growth restraint, as reflected in a low birthweight for gestational age, is a risk factor for postpubertal FSH hypersecretion and for reduced gonadal size. The ontogeny of the low-birthweight effect on the FSH-inhibin B feedback loop is unknown. Infancy is an episode of choice to study the possibility of an early low-birthweight effect on the FSH-inhibin B loop because this phase is characterized by high activity within the gonadal axis. We assessed serum concentrations of FSH and inhibin B in 46 infants [26 girls and 20 boys; mean age, 4 months; range, 3-6 months; 17 appropriate for gestational age (AGA), 29 small for gestational age (SGA); mean birthweight, 3.2 kg for AGA vs. 2.3 kg for SGA], together with circulating levels of LH, E2, and free androgen index. In SGA girls and boys, serum FSH levels were 2- and 4-fold higher (P < 0.001), respectively, than in AGA controls of the same gender (7.3 +/- 0.9 vs. 3.8 +/- 0.4 IU/ml and 2.9 +/- 0.5 vs. 0.7 +/- 0.2 IU/ml). Serum LH, inhibin B, and free androgen index/E2 concentrations were similar in AGA and SGA infants. In conclusion, prenatal growth restraint was found to be followed by elevated serum FSH concentrations in infant girls and boys. SGA infants seem to need an augmented FSH drive to fulfill inhibin B requirements on the afferent side of the feedback loop. The late-endocrine correlates of early growth restraint are herewith extended to include the main axis of reproduction in both genders. It remains to be studied whether FSH hypersecretion in infancy is a marker of subsequent subfertility.