Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments.

Introduction: Polycystic ovary syndrome (PCOS) is often associated with metabolic-associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function, systemic dysmetabolism, and abnormal circulating levels of signaling molecules called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage, which were assessed longitudinally in the aforementioned studies as safety markers. Materials and methods: Liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) with those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 year. As a post hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI), and meteorin-like protein (METRNL) were assessed by ELISA after 6 months of OC (N = 26) or spiomet (N = 28). Auxological, endocrine-metabolic, body composition (using DXA), and abdominal fat partitioning (using MRI) were also evaluated. Healthy, age-matched adolescent girls (N = 17) served as controls. Results: Circulating ALT and GGT levels increased during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 months of treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls than in controls and spiomet-treated girls; and (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels were directly correlated with circulating METRNL levels only in OC-treated girls (R = 0.449, P = 0.036 and R = 0.552, P = 0.004, respectively). Conclusion: The on-treatment increase in ALT and GGT levels occurring only in OC-treated girls is associated with circulating METRNL levels, suggesting enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment. Clinical Trial Registration: https://doi.org, identifiers 10.1186/ISRCTN29234515, 10.1186/ISRCTN11062950.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Meteorin-like levels are associated with active brown adipose tissue in early infancy.

Introduction: Meteorin-like (METRNL) is a hormonal factor released by several tissues, including thermogenically active brown and beige adipose tissues. It exerts multiple beneficial effects on metabolic and cardiovascular systems in experimental models. However, the potential role of METRNL as brown adipokine in humans has not been investigated previously, particularly in relation to the metabolic adaptations taking place in early life, when brown adipose tissue (BAT) is particularly abundant. Methods and materials: METRNL levels, as well as body composition (DXA) and circulating endocrine-metabolic variables, were assessed longitudinally in a cohort of infants at birth, and at ages 4 and 12 months. BAT activity was measured by infrared thermography at age 12 months. METRNL levels were also determined cross-sectionally in adults; METRNL gene expression (qRT-PCR) was assessed in BAT and liver samples from neonates, and in adipose tissue and liver samples form adults. Simpson-Golabi-Behmel Syndrome (SGBS) adipose cells were thermogenically activated using cAMP, and METRNL gene expression and METRNL protein released were analysed. Results: Serum METRNL levels were high at birth and declined across the first year of life albeit remaining higher than in adulthood. At age 4 and 12 months, METRNL levels correlated positively with circulating C-X-C motif chemokine ligand 14 (CXCL14), a chemokine released by thermogenically active BAT, but not with parameters of adiposity or metabolic status. METRNL levels also correlated positively with infrared thermography-estimated posterior-cervical BAT activity in girls aged 12 months. Gene expression analysis indicated high levels of METRNL mRNA in neonatal BAT. Thermogenic stimulus of brown/beige adipocytes led to a significant increase of METRNL gene expression and METRN protein release to the cell culture medium. Conclusion: Circulating METRNL levels are high in the first year of life and correlate with indices of BAT activity and with levels of an established brown adipokine such as CXCL14. These data, in addition with the high expression of METRNL in neonatal BAT and in thermogenically-stimulated brown/beige adipocytes, suggest that METRNL is actively secreted by BAT and may be a circulating biomarker of BAT activity in early life.

Raised Thyroid-Stimulating Hormone in Girls with Polycystic Ovary Syndrome: Effects of Randomized Interventions.

INTRODUCTION: Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid-stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in nonobese adolescents with PCOS, including the effects of randomized interventions. METHODS: Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) in nonobese adolescents with PCOS. A post hoc analysis compared TSH levels in PCOS (N = 62) versus controls, TSH changes on treatment (for 1 year), and TSH levels posttreatment (for 1 year). RESULTS: Mean TSH levels were higher in PCOS patients than in control girls (p < 0.01). On-treatment TSH levels diverged (p < 0.001), remaining elevated on OC, and descending swiftly on SPIOMET, well into safe preconception range. Posttreatment TSH levels were stable in both subgroups. On-treatment changes of circulating TSH associated to those of liver fat (R = 0.307, p = 0.017). CONCLUSION: The endocrine signature of early PCOS is herewith extended to include modestly raised levels of circulating TSH; the normalizing effects of SPIOMET intervention in nonobese adolescents with PCOS are herewith extended to include on- and posttreatment TSH.

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol.

BACKGROUND: A "mismatch" sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in "mismatch" girls with early puberty. METHODS: Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0-9.3 years; birthweight (BW) for gestational age in lower tertile (-1.96< Z-score <-0.44), body mass index (BMI) in upper tertile (+0.44< Z-score < +1.96) and early progressive puberty (Tanner B2 at 7.7-9.0 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in "mismatch" adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. INTERVENTIONS: randomization (1:1) for placebo vs mini-spiomet. PRIMARY OUTCOME: annualized bone age advancement (0-1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat. DISCUSSION: The present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight. TRIAL REGISTRATION: EudraCT 2021-006766-21. Registered on May 30, 2022.

Birth Weight and Early Postnatal Outcomes: Association with the Cord Blood Lipidome.

Being born small or large for gestational age (SGA and LGA, respectively), combined with suboptimal early postnatal outcomes, can entail future metabolic alterations. The exact mechanisms underlying such risks are not fully understood. Lipids are a highly diverse class of molecules that perform multiple structural and metabolic functions. Dysregulation of lipid metabolism underlies the onset and progression of many disorders leading to pathological states. The aim of this pilot study was to investigate the relationships between birth weight, early postnatal outcomes, and cord blood serum lipidomes. We performed a non-targeted lipidomics-based approach to ascertain differences in cord blood lipid species among SGA, LGA, and appropriate-for-GA (AGA) newborns. Moreover, we longitudinally assessed (at birth and at ages of 4 and 12 months) weight and length, body composition (DXA), and clinical parameters. We disclosed distinct cord blood lipidome patterns in SGA, LGA, and AGA newborns; target lipid species distinctly modulated in each SGA, AGA, and LGA individual were associated with parameters related to growth and glucose homeostasis. The distinct lipidome patterns observed in SGA, AGA, and LGA newborns may play a role in adipose tissue remodeling and future metabolic risks. Maternal dietary interventions may potentially provide long-term benefits for the metabolic health of the offspring.

Bone Morphogenetic Protein-8B Levels at Birth and in the First Year of Life: Relation to Metabolic-Endocrine Variables and Brown Adipose Tissue Activity.

Objective: Bone morphogenetic protein-8B (BMP8B) is an adipokine produced by brown adipose tissue (BAT) contributing to thermoregulation and metabolic homeostasis in rodent models. In humans, BAT activity is particularly relevant in newborns and young infants. We assessed BMP8B levels and their relationship with BAT activity and endocrine-metabolic parameters in young infants to ascertain its potentiality as biomarker in early life. Materials and Methods: BMP8B concentrations were assessed longitudinally by ELISA in a cohort of 27 girls and 23 boys at birth, and at age 4 and 12 months, together with adiposity parameters (DXA), and circulating endocrine-metabolic variables. BAT activity was measured by infrared thermography. BMP8B gene expression (qRT-PCR) was determined in BAT, white fat, and liver samples from neonatal necropsies, and in placenta and cord blood. Results: BMP8B levels were high at birth, particularly in boys (P = 0.04 vs. girls), declined progressively, and remained well above those in healthy adults and pregnant women at age 1 year (P < 0.05 and P < 0.001, respectively). Neonatal BMP8B transcript levels were higher in BAT than in white fat, liver and cord blood. Circulating BMP8B levels during the first year of life marginally correlated with bone mineral density and gains in lean mass. Conclusion: BMP8B levels are high at birth and decline progressively over the first year of life remaining above adult levels. Although changes in BMP8B concentrations overall reflect those in BAT activity during development, BMP8B levels are unlikely to be useful to predict individual variations in endocrine-metabolic status and BAT activity in healthy young infants.

Posterior Cervical Brown Fat and CXCL14 Levels in the First Year of Life: Sex Differences and Association With Adiposity.

CONTEXT: Brown adipose tissue (BAT) is particularly abundant in neonates, but its association with measures of adiposity and metabolic health in early infancy is poorly delineated. Besides sustaining nonshivering thermogenesis, BAT secretes brown adipokines that act on systemic metabolism. The chemokine CXCL14 has been identified as a brown adipokine in experimental studies. OBJECTIVE: To determine the relationships among BAT activity, adiposity, and circulating CXCL14 levels in the first year of life in girls and boys. METHODS: Indices of fat accretion, circulating endocrine-metabolic parameters and serum CXCL14 levels were assessed longitudinally in a cohort of infants at birth and at 4 and 12 months. BAT activity was estimated using infrared thermography only at age 12 months.The main outcome measures were weight and length Z-scores, total and abdominal fat content (by dual X-ray absorptiometry), BAT activity at the posterior cervical and supraclavicular regions, serum levels of glucose, insulin, insulin-like growth factor-I, high-molecular-weight adiponectin, and CXCL14; CXCL14 transcript levels in neonatal BAT and liver. RESULTS: Posterior cervical BAT was more active in girls than in boys (P = .02). BAT activity was negatively associated with adiposity parameters only in girls. CXCL14 levels were higher in girls than in boys at age 12 months and correlated positively with the area of active posterior cervical BAT in girls. Neonatal BAT showed high CXCL14 gene expression levels. CONCLUSION: BAT activity and the levels of CXCL14-a potential surrogate of BAT activity-are sex specific in the first year of life. Posterior cervical BAT activity associates negatively with indices of adiposity only in girls.

microRNAs in newborns with low birth weight: relation to birth size and body composition.

BACKGROUND: Children with low birth weight (LBW) have a higher risk of developing endocrine-metabolic disorders later in life. Deregulation of specific microRNAs (miRNAs) could underscore the programming of adult pathologies. We analyzed the miRNA expression pattern in both umbilical cord serum samples from LBW and appropriate-for-gestational-age (AGA) newborns and maternal serum samples in the 3rd trimester of gestation, and delineated the relationships with fetal growth, body composition, and markers of metabolic risk. METHODS: Serum samples of 12 selected mother-newborn pairs, including 6 LBW and 6 AGA newborns, were used for assessing miRNA profile by RNA-sequencing. The miRNAs with differential expression were validated in a larger cohort [49 maternal samples and 49 umbilical cord samples (24 LBW, 25 AGA)] by RT-qPCR. Anthropometric, endocrine-metabolic markers and body composition (by DXA) in infants were determined longitudinally over 12 months. RESULTS: LBW newborns presented reduced circulating concentrations of miR-191-3p (P = 0.015). miR-191-3p levels reliably differentiated LBW from AGA individuals (ROC AUC = 0.76) and were positively associated with anthropometric and body composition measures at birth and weight Z-score at 12 months (P < 0.05). CONCLUSIONS: miR-191-3p was reliably different in LBW individuals, and could be a new player in the epigenetic mechanisms linking LBW and future endocrine-metabolic adverse outcomes. IMPACT: Children with low birth weight (LBW) have a higher risk of developing endocrine-metabolic disorders. Deregulation of specific microRNAs (miRNAs) could underscore the programming of those pathologies. miR-191-3p is downregulated in serum of LBW newborns, and its concentrations associate positively with neonatal anthropometric measures, with lean mass and bone accretion at age 15 days and with weight Z-score at age 12 months. miR-191-3p was reliably different in individuals with LBW, and could be a new player in the epigenetic mechanisms connecting LBW and future endocrine-metabolic adverse outcomes.

Gut microbiota in adolescent girls with polycystic ovary syndrome: Effects of randomized treatments.

BACKGROUND: Girls with obesity and polycystic ovary syndrome (PCOS) and women with PCOS have altered gut microbiota. OBJECTIVE: To study the gut microbiota composition of girls with PCOS without obesity (age, 15.8 years; body mass index [BMI] 25 kg/m2 ) and the effects of randomized treatments with an oral contraceptive (OC, N = 15) or with spironolactone-pioglitazone-metformin (SPIOMET, N = 15) for 1 year. Thirty-one age-matched girls served as controls. METHODS: 16S ribosomal subunit gene amplicon sequencing was performed in stool samples from all subjects; samples from 23 out of 30 girls with PCOS (OC, N = 12; SPIOMET, N = 11) were available for analysis post-treatment. Clinical and endocrine-metabolic variables were measured before and after intervention. RESULTS: Girls with PCOS had decreased diversity alpha, altered microbiota pattern and taxonomic profile with more abundance of Family XI (P = .002), and less abundance of family Prevotellaceae (P = .0006) the genus Prevotella (P = .0001) and Senegalimassilia (P < .0001), as compared to controls. Family XI abundance related positively to hepato-visceral fat (R = 0.453; P = .0003). SPIOMET treatment, but not OC, normalized the abundance of Family XI. Prevotellaceae, Prevotella and Senegalimassilia abundance remained unchanged after either treatment. CONCLUSION: SPIOMET's spectrum of normalizing effects in girls with PCOS is herewith broadened as to include Family XI abundance in gut microbiota.

Toward a Treatment Normalizing Ovulation Rate in Adolescent Girls With Polycystic Ovary Syndrome.

Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligomenorrhea, and commonly driven by hepato-visceral fat excess ("central obesity") ensuing from a mismatch between prenatal and postnatal nutrition, on a background of genetic susceptibility. There is no approved treatment for adolescent PCOS. We report the pooled results of 2 pilot studies in nonobese girls with PCOS (N = 62, age 15.8 years) that compared the effects of randomized treatment for 1 year, either with an oral estro-progestogen contraceptive (OC), or with a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET, targeting the excess of ectopic fat). Auxological and endocrine-metabolic variables (including fasting insulin, androgens, high-molecular-weight adiponectin [HMW-adiponectin], and microRNA [miR]-451a), body composition (dual x-ray absorptiometry) and hepato-visceral fat (magnetic resonance imaging) were assessed on- and posttreatment. Data from menstrual diaries were combined with weekly salivary progesterone measurements to infer ovulation rates during the second and fourth quarter of the posttreatment year. OC and SPIOMET treatment reduced the androgen excess comparably, and had no differential effects on total-body lean or fat mass. However, SPIOMET was accompanied by more broadly normalizing effects, including on hepato-visceral fat and on circulating insulin, HMW-adiponectin, and miR-451a. On average, there were 3-fold more ovulations post-SPIOMET than post-OC; normovulation was only observed after SPIOMET; anovulation was >10-fold more prevalent post-OC. Pooled results of randomized studies in nonobese adolescent girls with PCOS indicate that SPIOMET treatment leads to an overall healthier, more insulin-sensitive condition-with less ectopic fat-than OC treatment, and to a more normal posttreatment ovulation rate.

Reduced circulating levels of chemokine CXCL14 in adolescent girls with polycystic ovary syndrome: normalization after insulin sensitization.

OBJECTIVE: CXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements. Adipose tissue may be involved in the metabolic alterations of PCOS, and it is a likely target of therapeutic action. We investigated the alterations in CXCL14 levels and the effects of drugs composing SPIOMET treatment on CXCL14 in human adipocytes. RESEARCH DESIGN AND METHODS: We studied 51 adolescent patients with PCOS and 21 age-matched healthy controls. Thirty-one adolescent patients with PCOS under SPIOMET or oral contraception-based treatment were also studied. For studies in vitro, Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used. Gene expression for CXCL14 and other genes was quantified using quantitative real-time PCR. The levels of CXCL14 and adipokines in serum and cell culture media were determined by ELISA. RESULTS: Serum CXCL14 levels are reduced in patients with PCOS. One-year SPIOMET treatment normalized CXCL14 concentrations and improved the metabolic status of patients with PCOS. Pioglitazone induced CXCL14 expression in differentiating human SGBS adipocytes, in parallel with the induction of marker genes of brown adipogenesis. Spironolactone induced CXCL14 expression and release in differentiated human adipocytes. CONCLUSION: Insulin sensitization with SPIOMET normalizes the abnormally low levels of CXCL14 in girls with PCOS. This is consistent with the effects of pioglitazone and spironolactone inducing CXCL14 expression and promoting a brown-like phenotype in adipocytes. CXCL14 may be a novel biomarker for PCOS as well as a potential mediator of the beneficial effects of the SPIOMET combination and may hold promise as a therapeutic modulator of the disorder. TRIAL REGISTRATION NUMBERS: ISRCTN29234515 and ISCRCTN11062950.

Towards a simple marker of hepato-visceral adiposity and insulin resistance: The Z-score change from weight-at-birth to BMI-in-childhood.

BACKGROUND: Insulin resistance and hepato-visceral (central) fat excess are thought to contribute to an earlier timing of adrenarche/pubarche and puberty/menarche; this earlier timing in turn relates often to a mismatch between prenatal and postnatal weight gain, which can be estimated by calculating the Z-score change from birth weight (BW) to body mass index (BMI) in childhood. METHODS: We tested the hypothesis that this calculation may serve as a proxy of insulin resistance and hepato-visceral adiposity in prepuberty by reappraising a cohort of children (mean age, 8.5 years), born appropriate- (AGA, n = 41) or small-for-gestational age (SGA, n = 45), followed since birth (n = 76) or since the age of 3 years (n = 10). Assessments included anthropometry; fasting glucose and insulin; liver volume; and hepatic fat, subcutaneous fat, and visceral fat in the abdominal region (by magnetic resonance imaging [MRI]). RESULTS: Z-score change BW-BMI closely associated to central fat (R = 0.74; P < .0001) and insulin resistance (R = 0.71; P < .0001). CONCLUSION: These results suggest that Z-score change BW-BMI could be viewed as a simple candidate-marker for hepato-visceral adiposity and insulin resistance in prepubertal children.

Towards a circulating marker of hepato-visceral fat excess: S100A4 in adolescent girls with polycystic ovary syndrome - Evidence from randomized clinical trials.

S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m2 ), and 1-year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato-visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato-visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato-visceral fat excess in adolescents with PCOS.

Metformin for Rapidly Maturing Girls with Central Adiposity: Less Liver Fat and Slower Bone Maturation.

BACKGROUND/AIMS: Girls with low-birth weight (LBW) and postnatal weight catch-up tend to develop visceral and hepatic fat excess, which may be accompanied by an upregulated adrenarche with precocious pubarche (PP) and by a rapidly progressive puberty with early menarche and shorter stature. A pilot study suggested that metformin treatment for 4 years reduces central adiposity in LBW-PP girls and normalizes puberty and adult height. In this cohort, we studied the relationship between metformin treatment, bone maturation, and body composition. METHODS: Longitudinal hand X-rays (0-4 years, analyzed by BoneXpert) were available from 34 LBW-PP girls (89% of the original cohort; n = 17 untreated, n = 17 metformin-treated; age at the start of treatment 8 years) along with body composition (0-4 years, by DXA), hepatic fat, and abdominally subcutaneous and visceral fat (posttreatment, by MRI). RESULTS: The tempo of bone aging was accelerated in untreated girls (≈16% faster vs. chronological aging) and normal in metformin-treated girls (≈20% slower vs. untreated girls). Metformin-treated girls gained more height per bone-age year and had less visceral and hepatic fat. The tempo of bone maturation was associated (R = 0.55; p < 0.001) with hepatic fat. CONCLUSION: Metformin treatment in rapidly maturing girls with central adiposity normalized bone maturation. This normalization was accompanied by less central fat and was related closely to hepatic fat.