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BACKGROUND The endocrine hallmark of polycystic ovary syndrome (PCOS) is hyperinsulinaemic hyperandrogenism; another facet of PCOS is low-grade inflammation. METHODS In adolescents and young women with hyperinsulinaemic hyperandrogenism (n = 118; mean age 16 years, body mass index 22 kg/m(2)), we analysed whether the PCOS-associated rise in leukocyte count is already detectable at young age and, if so, whether such elevation is lowered by metformin, flutamide-metformin, oral contraception (OC), or their combination. RESULTS Leukocyte count (x 1000/mm(3)) in patients was high versus controls (7.5 +/- 0.1 versus 6.4 +/- 0.1; P < 0.001) due to a rise in neutrophils (4.2 +/- 0.1 versus 3.0 +/- 0.1; P < 0.001). Randomized studies at mean ages of 12.5 years (n = 24) and 15.2 years (n = 33) demonstrated normalizing effects of metformin (850 mg/day; P < 0.001) and, respectively, metformin plus flutamide (62.5 mg/day) on neutrophil counts; in young women (18.3 years; n = 41), the neutrophil count rose further on OC monotherapy (P = 0.003), but normalized on the same OC plus flutamide-metformin (P < 0.001 versus OC alone). CONCLUSIONS (i) A high leukocyte count is already present in girls with hyperinsulinaemic hyperandrogenism, and this is due to a raised neutrophil count; (ii) this hyperneutrophilia is attenuated by metformin or flutamide-metformin, and is amplified by OC monotherapy; (iii) if these treatments are combined, the normalizing effect of flutamide-metformin overcomes the OC effect on neutrophil count.

Flutamide is a nonsteroidal antiandrogenic agent that to date has been used chiefly in treating prostate cancer. Hepatotoxicity, although rare, is a potentially fatal side effect that has been documented with doses of 750 to 1500 mg daily. Minor hepatotoxicity has been associated with doses as low as 250 mg daily. This study examined the risk of hepatotoxicity when flutamide was given in ultralow doses for up to 3 years and for periods as long as 54 months. Participants were 190 hyperandrogenic girls and young women, 150 of whom had established and 40 incipient polycystic ovary syndrome (PCOS); none were obese. Flutamide was given alone or in combination with metformin, an insulin sensitizer, and/or an estro-progestagen oral contraceptive containing gestodene or drospirenone. Doses of flutamide ranged from 62.5 to 250 mg daily. Circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) served as markers of hepatic toxicity. All participants had normal levels of ALT and AST at baseline, and concentrations were unchanged during flutamide treatment-both 3 months after the start of treatment and at the last assessment, which took place after a mean of 19 months on treatment. Treatment times ranged up to 54 months. No subject had an AST or ALT level of 45 U/L or higher at any time. These findings suggest that flutamide is a safe treatment when used in low dosage to treat hyperandrogenic, nonobese girls and young women having actual or impending PCOS. It remains possible that hepatic toxicity may, in rare instances, develop in patients taking ultralow doses of flutamide. Nevertheless, the investigators anticipate that such doses may become a part of treating hyperandrogenic girls and young women with PCOS. They do recommend that transaminase levels be monitored during flutamide treatment.

Objective Girls with low birth weight (LBW) and with a history of precocious pubarche in childhood (PP) are at high risk of polycystic ovary syndrome (PCOS) in adolescence. In formerly LBW-PP girls, we examined whether initiation of insulin sensitization therapy early after menarche could prevent progression of PCOS features. Study design Twenty-four girls, small at term birth (mean weight, 2.4 kg), who presented with PP (at mean age 6.7 years) and were currently (mean age, 12.4 years) postmenarcheal, with hyperinsulinemic hyperandrogenemia but nonobese, were randomly assigned to receive metformin (850 mg/d) or no treatment for 12 months. Six-month fasting blood samples were collected, and body composition was assessed by dual-energy x-ray absorptiometry. In addition, overnight growth hormone (GH) and gonadotropin secretion was analyzed in 10 girls (6 treated; 4 untreated) at 0 and 6 months. Results At baseline, compared with healthy control subjects, LBW-PP girls had dyslipidemia, excess truncal fat, reduced lean body mass, and increased insulin-like growth factor-I and GH levels. In untreated girls, insulin sensitivity, serum androgens, lipids, total and truncal fat mass, and lean body mass significantly diverged further from normal over 12 months. In metformin-treated girls, all these abnormalities significantly reversed within 6 months, and body composition continued to improve between 6 and 12 months. Conclusions Early metformin therapy prevents progression from PP to PCOS in a high-risk group of formerly LBW girls. This confirms the key role of hyperinsulinemic insulin resistance in the ontogeny of PCOS. Furthermore, normalization of body composition, lipid profiles, and GH secretion could reduce long-term cardiovascular risk.

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6–18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7–87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

Even nonobese girls with precocious pubarche may develop a variant of polycystic ovary syndrome (PCOS) characterized by hyperinsulinism, hyperandrogenism, abnormal lipids, and persistent anovulation. Insulin-sensitizing treatment has limited hyperinsulinism and hyperandrogenism and restored eumenorrhea in women with PCOS. Extrapolating from observations in obese women with PCOS who receive an insulin-sensitizing agent such as metformin or troglitazone and become more likely to ovulate, this study examined the effects of metformin in 18 nonobese adolescent girls with a mean age of 16½ years who were 3 to 7 years past menarche. All were anovulatory and met clinical and hormonal criteria for ovarian hyperandrogenism. The participants also had a history of precocious pubarche caused by exaggerated adrenarche. All the girls were hyperinsulinemic but had normal glucose tolerance. Anovulation was confirmed twice by obtaining four consecutive serum progesterone levels below 4 ng/ml at 1-week intervals. Metformin was given for 6 months in a daily dose of 1275 mg. Hirsutism scores decreased with metformin therapy, as did levels of fasting serum insulin, luteinizing hormone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and the free androgen index. Serum levels of sex hormone-binding globulin increased at the same time, and the lipid profiles became less atherogenic. There were no changes in body mass index, fasting glycemia, or serum levels of estradiol or follicle-stimulating hormone. All but 2 of the 18 girls reported regular menses within 4 months of the start of metformin therapy and, after 6 months, all were eumenorrheic. Ovulation induction failed in 4 of the 18 girls (Fig. 1), including the 2 with the most severe hyperandrogenism. Abdominal discomfort in 4 girls resolved spontaneously within 2 weeks. Metformin treatment tends to normalize endocrine-metabolic function in nonobese adolescent girls with anovulatory hyperandrogenism and induces ovulation in many of them.

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.

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.

Adolescent girls who were small for gestational age when born are, even if not obese, at risk for numerous abnormalities, including hyperinsulinism, subnormal ovarian responsiveness to FSH, subclinical hyperandrogenism, areduced rate of ovulation, and abnormal blood lipids. Hyperinsulinemic insulin resistance has been suggested as an important pathogenetic factor. The authors tested this possibility by determining the effects of insulin sensitization in 13 such girls. They were not obese and had normal menses, but they did not ovulate and had central adiposity and dyslipidemia. In addition, subclinical hyperandrogenism was documented. All had weighed below 2 standard deviations at term birth and had a body mass index less than 25 kg/m 2 . The participants, 14 to 18 years of age at the time of study, had begun menstruating 3 to 6 years earlier. Metformin was given in a dose of 850 mg daily for 3 months. Blood levels of insulin, androgens, triglycerides, and FSH were elevated in these girls, but fasting insulin levels and androgens declined when metformin was given, and the lipid profile became less atherogenic in all cases. Initially the waist-to-hip ratio was high with excess fat, especially abdominally, and a reduced lean body mass. After 3 months on metformin, all of these abnormalities were less evident. The most marked changes were a reduction in abdominal fat mass and an increase in lean body mass (Fig. 1). Body weight remained unchanged. Six of the 13 girls (46%) began ovulating about 6 weeks after the start of treatment, and within 11 weeks, 69% were ovulating. The increase in lean body mass that followed from metformin therapy raises the question of whether it reduces growth hormone secretion in adolescent girls with hyperinsulinemic hyperandrogenism. If so, this would reinforce the importance of insulin sensitivity in maintaining a normal body shape and ovulatory function.

Objective. To assess whether, in girls with early onset of puberty, low birth weight is a risk factor for rapid progression to menarche and for short adult stature. Design. Longitudinal clinical assessment of 54 Catalan (Northern Spanish) girls followed from early onset of puberty (onset of breast development between 8.0 and 9.0 years of age) to final height. The timing of menarche and the final height were analyzed a posteriori according to birth weight, the cutoff level between normal and low birth weight subgroups being −1.5 standard deviation (SD; ∼2.7 kg at term birth). Results. Normal and low birth weight girls had similar target heights and characteristics at diagnosis of early puberty. However, menarche occurred on average 1.6 years earlier in low versus normal birth weight girls (11.3 ± .3 years vs 12.9 ± .2 years), and final height was >5 cm shorter in low birth weight girls (parental adjusted height SD: −.6 ± .2 cm vs .3 ± .2 cm). Conclusion. The timing of menarche and the level of final height in Catalan girls with early onset of puberty was found to depend on prenatal growth. Girls with normal birth weight tend to progress slowly through puberty with a normal timing of menarche and normal final height. In contrast, girls with low birth weight tend to progress relatively rapidly to an early menarche and to a reduced final height. If these findings are confirmed in other ethnic and/or larger groups, then a subgroup has been identified that will most likely benefit from any therapeutic intervention aiming at a delay of pubertal development and/or an increase of final height.

Postoperative low cardiac output syndrome has been shown to have both a central and a peripheral vascular involvement. Therefore, inodilators which provide with a combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of treatment. However, contradictory data on these drugs exist. Phosphodiesterase inhibitors (e.g., milrinone) and more recently calcium sensitizers (e.g., levosimendan) have been most commonly used groups in the clinical setting. This review will summarize the pharmacology of inodilators with a special foccus on current clinical evidence. This article addresses the sixth of eight topics comprising the special issue entitled "Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery".