High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception.

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.

Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.

BACKGROUND: Flutamide is a pure non-steroidal anti-androgen that may be hepatotoxic, when given in high-dose (750 mg/d). Low- to ultralow-doses (250-62.5 mg/day) have been recently explored in patients with Polycystic Ovary Syndrome (PCOS), and these lower doses were found to confer benefit on multiple PCOS markers. There is a need for evidence on the potential hepatotoxicity of low- and ultralow-dose flutamide therapy. METHODS: We assessed circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of hepatotoxicity in a total of 190 hyperandrogenic girls and young women receiving low- or ultralow-dose flutamide because of established (n = 150) or incipient (n = 40) PCOS without obesity. Assessments were performed before start of flutamide, after 3 months, and subsequently at least twice yearly. RESULTS: AST and ALT results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment, which was after a mean time of 19 months on low- or ultralow-dose flutamide (range 3-54 months). None of the AST or ALT levels at any time during flutamide treatment was > or = 45 U/L. CONCLUSION: We found no evidence for hepatotoxicity in 190 hyperandrogenic girls or young women receiving low- or ultralow-dose flutamide for up to 54 months. These results may represent a first step in a long process whereby the status of low- and ultralow-dose flutamide may gradually evolve from 'absence of evidence on toxicity' towards 'evidence of absence of hepatic toxicity'. Ultralow-dose flutamide may become a key component within future therapies for hyperandrogenic states in girls and young women.

Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome.

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.

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.

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.

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

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.

Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation.

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.

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.