Effects of a High-Fat Diet and Docosahexaenoic Acid during Pregnancy on Fatty Acid Composition in the Fetal Livers of Mice.

A high-fat diet (HFD) during pregnancy promotes fat accumulation and reduces docosahexaenoic acid (DHA) levels in the liver of the offspring at postnatal ages, which can depend on fetal sex. However, the prenatal mechanisms behind these associations are still unclear. Thus, we analyzed if an HFD alters DHA content and the expression of molecules related to fatty acid (FA) metabolism in the fetal liver. Female C57BL/6 mice were fed a control diet or HFD for 4-6 weeks before pregnancy until the gestational day (GD) 17.5. A subgroup of each diet received DHA (100 mg/Kg) orally from GD 6.5 until 16.5. On GD 17.5, maternal livers, placentas, and livers from male and female fetuses were collected for FA profiling with gas-chromatography and gene expression of molecules related to FA metabolism using qPCR. PPAR-α protein expression was evaluated using Western blot. The gene expression of placental FA transporters was also assessed. An HFD increased eicosapentaenoic acid (EPA) and decreased DHA levels and protein expression of PPAR-α in the fetal livers of both sexes. DHA increased the gene expression of Ppara, Cpt1, and Acsl1 in the livers of female fetuses. Therefore, an HFD reduces DHA levels and PPAR-α, a master regulator of gene expression, in the fetal liver. In turn, the livers of female fetuses seem to be more sensitive to DHA action.

Linoleic and arachidonic fatty acids and their potential relationship with inflammation, pregnancy, and fetal development.

BACKGROUND: A healthy maternal diet must consider an appropriate supply of long-chain polyunsaturated fatty acids (LCPUFAs) precursors to ensure adequate growth and development of the fetus. In this regard, n-6 PUFAs, predominantly linoleic (C18:2 n-6, LA) and arachidonic acid (C20:4 n-6), have a central role in the development of the central nervous system because they are part of the membrane structure and participate in the metabolism and signal transduction of cells. Nevertheless, they can also be transformed into inflammatory metabolites promoting the pathogenesis of cardiovascular diseases, cancer, and autoimmune or inflammatory conditions. In modern westernized societies, there is a high dietary consumption of foods rich in n-6 PUFAs which could have detrimental consequences for the fetus and neonate due to excessive exposure to these fatty acids (FAs). OBJECTIVE: To summarize the evidence of maternal, placental, and fetal alterations that an excessive intake of n-6 polyunsaturated FAs (PUFAs), LA, and AA), could produce during pregnancy. METHODS: A thorough review of the literature regarding the effects of n-6 PUFAs during pregnancy and lactation including in vivo and in vitro models, was carried out using the PubMed database from the National Library of Medicine-National Institutes of Health. RESULTS: An elevated intake of n-6 PUFA, specifically LA, during pregnancy influences children's motor, cognitive, and verbal development during infancy and early childhood. Similarly, they could harm the placenta and the development of other fetal organs such as the fat tissue, liver, and cardiovascular system. CONCLUSION: Maternal diet, specifically LA intake, could have significant repercussions on fetal development and long-term consequences in the offspring, including the possibility of future metabolic and mental diseases. It would be necessary to focus on the prevention of these alterations through timely dietary interventions in the target population.

Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome.

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1-F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline.

Association between maternal obesity, essential fatty acids and biomarkers of fetal liver function.

Maternal obesity and the imbalance in linoleic acid (C18:2 n-6, LA) and alpha-linolenic acid (C18:3 n-3, ALA) levels are related with hepatic disturbances in the offspring. However, whether these alterations are present during fetal life is not well understood. Obese and normal weight pregnant women were recruited to determine fatty acids (FAs) consumption, FAs profile (in maternal erythrocytes, placenta and neonatal very low-density lipoproteins VLDL) and biomarkers of fetal liver function, such as gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and albumin, in umbilical cord blood. Stearic acid (C18:0, ST) was lower, and total n-3 FAs tended to be lower in umbilical cord VLDLs of obese women compared to controls. Independently of maternal obesity, GGT levels in umbilical cord blood was positively correlated with the LA content and negatively correlated with the ALA content in maternal erythrocytes. We conclude that maternal obesity and its imbalance of LA and ALA are associated with changes in biomarkers of fetal liver function.

Rodent models in placental research. Implications for fetal origins of adult disease.

Rodent models in rats, mice, and guinea pigs have been extremely helpful to gain insight into pregnancy physiology and pathologies-related. Moreover, they have allowed understanding the mechanism that links an adverse intrauterine environment with the origin of adult disease. In this regard, the effects of diverse maternal conditions, such as undernutrition, obesity, hypoxia, and hyperandrogenism on placental function and its long-term consequences for the offspring, have been widely analyzed through rodents models involving dietary manipulations, modifications in environmental oxygen, surgical and pharmacological procedures that reduce uteroplacental blood flow and administrations of exogenous testosterone and dihydrotestosterone (DHT) mimicking maternal androgen excess. Both in human and in rodent models, these interventions induce modifications of placental morphology, transport of glucose, amino acid, and fatty acids, steroid synthesis, and signaling pathways control placental function. These changes are associated with the increase of pro-inflammatory and oxidative stress markers. For its part, offspring exhibit alterations in organs involved in metabolic control such as the hypothalamus, adipose tissue, liver, skeletal muscle, and pancreas altering the intake and preferences for certain foods, the metabolism of glucose and lipid, and hormonal function leading to fat accumulation, insulin resistance, fatty liver, dyslipidemia, and elevated glucose levels. Therefore, the present review discusses the evidence emerging from rodent models that relate maternal nutrition, hypoxia, and androgen exposure to the maternal mechanisms that lead to fetal programming and their metabolic consequences in postnatal life.

Respuesta a metformina en el síndrome de ovario poliquístico (SOP): rol de las variantes genéticas / Response to metformin in polycystic ovary syndrome (PCOS): role of genetic variants

La metformina es un hipoglicemiante ampliamente utilizado en el tratamiento de mujeres con síndrome de ovario poliquístico (SOP) por su acción como sensibilizante a la insulina, demostrando tener múltiples efectos favorables en parámetros clínicos y bioquímicos. Especial interés ha causado la variabilidad interindividual en el tratamiento con metformina, que se manifiesta con una respuesta subóptima en diversos grados o con la presencia de efectos adversos, principalmente gastrointestinales. Hasta ahora, pocos estudios han caracterizado este fenómeno en el SOP, así como los mecanismos que le subyacen. Se ha propuesto que variantes de genes envueltos en el transporte y acción de metformina podrían contribuir a la heterogeneidad de su respuesta. En este sentido, se han identificado polimorfismos de nucleótidos únicos (SNPs) en los transportadores de cationes orgánicos, en las proteínas de extrusión de múltiples fármacos y toxinas, y en proteínas quinasas; cuyas principales acciones son a nivel intestinal, hepático y renal, afectando la absorción, distribución y excreción de metformina, probablemente por modificaciones en su farmacocinética. Hasta ahora los escasos estudios disponibles en el SOP han identificado SNPs que estarían afectando la eficacia del tratamiento, sin embargo, no se ha profundizado en los efectos adversos asociados a las variantes genéticas. Es evidente que dichas variantes tienen relevancia clínica y que debieran ser consideradas al diseñar un tratamiento farmacológico, para optimizar su efectividad y minimizar reacciones adversas. El objetivo de este artículo es revisar la información sobre las variantes genéticas asociadas a la variabilidad en la respuesta del tratamiento con metformina en el SOP.

Metformin is a hypoglycemic agent widely used in the treatment of women with Polycystic Ovary Syndrome (PCOS) due to its action as an insulin sensitizer and its multiple favorable effects on clinical and biochemical parameters. There is great concern regarding the inter-individual variability in the response to metformin treatment, which may manifest as a suboptimal effect to varying degrees or by the presence of adverse effects, mainly gastrointestinal. Until now, scarce studies have characterized this phenomenon in PCOS, as well as the mechanisms that underlie it. It has been proposed that genetic variants involved in metformin transport and action could contribute to the heterogeneity of its response. In this sense, single nucleotide polymorphisms (SNPs) have been identified in organic cation transporters, in multidrug and toxin extrusion proteins, and in protein kinases; whose main actions are at the intestinal, hepatic and renal levels, affecting the absorption, distribution and excretion of metformin, probably due to modifications in the pharmacokinetics of the drug. Until now, the few studies available on PCOS have identified SNPs that may be affecting the efficacy of the treatment. However, the adverse effects associated with genetic variants have not been studied in depth. These variants may have clinical relevance and should be considered when designing a pharmacological treatment, to optimize its effectiveness and minimize adverse reactions. The objective of this article is to review the information on genetic variants associated with variability in the response to metformin treatment in PCOS.

Impact of Maternal Obesity on the Metabolism and Bioavailability of Polyunsaturated Fatty Acids during Pregnancy and Breastfeeding.

Abstract: Prenatal and postnatal development are closely related to healthy maternal conditions that allow for the provision of all nutritional requirements to the offspring. In this regard, an appropriate supply of fatty acids (FA), mainly n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA), is crucial to ensure a normal development, because they are an integral part of cell membranes and participate in the synthesis of bioactive molecules that regulate multiple signaling pathways. On the other hand, maternal obesity and excessive gestational weight gain affect FA supply to the fetus and neonate, altering placental nutrient transfer, as well as the production and composition of breast milk during lactation. In this regard, maternal obesity modifies FA profile, resulting in low n-3 and elevated n-6 PUFA levels in maternal and fetal circulation during pregnancy, as well as in breast milk during lactation. These modifications are associated with a pro-inflammatory state and oxidative stress with short and long-term consequences in different organs of the fetus and neonate, including in the liver, brain, skeletal muscle, and adipose tissue. Altogether, these changes confer to the offspring a higher risk of developing obesity and its complications, as well as neuropsychiatric disorders, asthma, and cancer. Considering the consequences of an abnormal FA supply to offspring induced by maternal obesity, we aimed to review the effects of obesity on the metabolism and bioavailability of FA during pregnancy and breastfeeding, with an emphasis on LCPUFA homeostasis.

Metformin during Pregnancy: Effects on Offspring Development and Metabolic Function.

Maternal obesity during pregnancy and gestational diabetes mellitus (GDM) are both associated with of several postnatal diseases in the offspring, including obesity, early onset hypertension, diabetes mellitus, and reproductive alterations. Metformin is an oral drug that is being evaluated to treat GDM, obesity-associated insulin resistance, and polycystic ovary syndrome (PCOS) during pregnancy. The beneficial effects of metformin on glycemia and pregnancy outcomes place it as a good alternative for its use during pregnancy. In this line of thought, improving the metabolic status of the pregnant mother by using metformin should avoid the consequences of insulin resistance on the offspring's fetal and postnatal development. However, some human and animal studies have shown that metformin during pregnancy could amplify these alterations and be associated with excessive postnatal weight gain and obesity. In this minireview, we discuss not only the clinical and experimental evidence that supports the benefits of using metformin during pregnancy but also the evidence showing a possible negative impact of this drug on the offspring's development.

DNA methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS.

Clinical and experimental evidences indicate that epigenetic modifications induced by the prenatal environment are related to metabolic and reproductive derangements in polycystic ovary syndrome (PCOS). Alterations in the leptin and adiponectin systems, androgen signalling and antimüllerian hormone (AMH) levels have been observed in PCOS women and in their offspring. Using a targeted Next-Generation Sequencing (NGS), we studied DNA methylation in promoter regions of the leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), adiponectin receptor 1 and 2 (ADIPOR1 and ADIPOR2), AMH and androgen receptor (AR) genes in 24 sons and daughters of women with PCOS (12 treated with metformin during pregnancy) and 24 children born to non-PCOS women during early infancy (2-3 months of age). Genomic DNA was extracted from whole blood, bisulphite converted and sequenced by NGS. Girls showed differences between groups in 1 CpG site of LEPR, 2 of LEP, 1 of ADIPOR2 and 2 of AR. Boys showed differences in 5 CpG sites of LEP, 3 of AMH and 9 of AR. Maternal metformin treatment prevented some of these changes in LEP, ADIPOR2 and partially in AR in girls, and in LEP and AMH in boys. Maternal BMI at early pregnancy was inversely correlated with the methylation levels of the ChrX-67544981 site in the whole group of girls (r = -0.530, p = 0.008) and with the global Z-score in all boys (r = -0.539, p = 0.007). These data indicate that the intrauterine PCOS environment predisposes the offspring to acquire certain sex-dependent DNA methylation patterns in the promoter regions of metabolic and reproductive genes.

Biotic and abiotic sounds affect calling activity but not plasma testosterone levels in male frogs (Batrachyla taeniata) in the field and in captivity.

In animals, the expression of diverse reproductive behaviors is hormonally regulated. In particular, vocalizing during courtship has been related to circulating androgen levels, and reciprocally, conspecific vocalizations are known to modulate androgen secretion in vertebrates. The effect of natural sounds of abiotic origin on hormonal status has virtually not received attention. Therefore, we evaluated the vocal responses of male Batrachyla taeniata frogs to conspecific chorus and rainfall sounds in natural and controlled laboratory settings, measuring the testosterone levels of exposed individuals. In field and laboratory conditions, testosterone levels of frogs exposed to 31.5 min of chorus and rain sounds and non-exposed individuals were similar. In the field, frogs increased their call rate in response to playbacks of chorus and rain sound, but the evoked calling activity was unrelated to plasma testosterone. In contrast to the field, frogs showed limited responsiveness to 31.5-min acoustic exposures in the laboratory. Similarly to the field, for vocally active males tested in the laboratory there was no association between call rate and testosterone levels. Additionally, in this group, testosterone levels were higher in vocally active males relative to non-calling individuals. Overall, these results indicate that in B. taeniata testosterone levels are not altered following a short-term exposure to conspecific biotic and to abiotic sounds. Our results are suggestive of a threshold influence of testosterone on the vocal activity of the species studied. Further explorations of the influence of abiotic sounds on endocrine activation are required to understand how animals respond to variable acoustic environmental conditions.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

Mice exposed to maternal androgen excess and diet-induced obesity have altered phosphorylation of catechol-O-methyltransferase in the placenta and fetal liver.

BACKGROUND/OBJECTIVES: Maternal obesity together with androgen excess in mice negatively affects placental function and maternal and fetal liver function as demonstrated by increased triglyceride content with dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage. To identify changes in molecular pathways that might promote diseases in adulthood, we performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess. METHODS: After ten weeks on a control diet (CD) or high fat/high sugar-diet, dams were mated with males fed the CD. Between gestational day (GD) 16.5 and GD 18.5, mice were injected with vehicle or dihydrotestosterone (DHT) and sacrificed at GD 18.5 prior to dissection of the placentas and fetal livers. Four pools of female placentas and fetal livers were subjected to a global proteomic analysis. Total and phosphorylated proteins were filtered by ANOVA q < 0.05, and this was followed by two-way ANOVA to determine the effect of maternal obesity and/or androgen exposure. RESULTS: In placenta, phosphorylated ATP-citrate synthase was decreased due to maternal obesity, and phosphorylated catechol-O-methyltransferase (COMT) was differentially expressed due to the interaction between maternal diet and DHT exposure. In fetal liver, five total proteins and 48 proteins phosphorylated in one or more sites, were differentially expressed due to maternal obesity or androgen excess. In fetal liver, phosphorylated COMT expression was higher in fetus exposed to maternal obesity. CONCLUSION: These results suggest a common regulatory mechanism of catecholamine metabolism in the placenta and the fetal liver as demonstrated by higher phosphorylated COMT expression in the placenta and fetal liver from animals exposed to diet-induced maternal obesity and lower expression of phosphorylated COMT in animals exposed to maternal androgen excess.

Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovary syndrome.

OBJECTIVE: To study the reproductive and metabolic differences between daughters of women with polycystic ovary syndrome (PCOSd) and control women (Cd) after menarche. DESIGN: Case-control study. SETTING: Clinical endocrinology unit. PATIENT(S): We studied 43 PCOSd and 28 Cd 1.5-6 years after menarche. INTERVENTION(S): Determination of anthropometry, pubertal development, hirsutism, oral glucose tolerance test, and GnRH analogue test. MAIN OUTCOME MEASURE(S): Ferriman score, sex steroids, gonadotropins, antimüllerian hormone (AMH), ovarian volumes, and glucose and insulin levels. RESULT(S): The groups were similar in chronologic, gynecologic, and menarchal ages and anthropometric variables. Ferriman score, ovarian volumes, and AMH were higher in PCOSd. Propensity score analysis showed that there were significant differences in LH, LH-FSH ratio, T and free androgen index, post-stimulated LH and LH-FSH ratio, and 2-hour insulin that could be attributed only to the fact of being a PCOS daughter. The generalized linear model showed that higher LH levels were positively associated with AMH and T levels. CONCLUSION(S): We found that higher LH, androgen, and insulin levels are present in PCOSd during the postmenarchal period, which may establish the basis for the development of PCOS during adulthood. Moreover, LH levels were associated with AMH levels, which supports that the neuroendocrine feedback proposed for AMH and LH is present in humans and that this feature is probably programed in utero, as recently shown in mice.

Prenatal metformin treatment improves ovarian function in offspring of obese rats.

Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.

Pregnancy outcomes in women with polycystic ovary syndrome in two Latin American populations.

Pregnancy complications and obstetric outcomes were compared in 80 Chilean (PPCOSCh) and 70 Argentinian (PPCOSAr) pregnant women. Reference groups of Chilean and Argentinian normal pregnant women from the same antenatal care units were also compared. PPCOSCh showed a higher prevalence of gestational diabetes mellitus (GDM) (OR, 2.28, 95% CI: 1.08-4.77, p = .030) and a lower prevalence of pregnancy-induced hypertension (PIH) (OR, 0.20, 95% CI: 0.07-0.54, p = .001) compared to PPCOSAr. In the normal pregnant groups, the prevalence of PIH was lower in Chilean women compared to Argentinian women (OR, 0.24, 95% CI: 0.10-0.62, p = .001). Similar to the pattern observed in the normal populations, newborns from PPCOSCh had higher birth weight and length compared with the newborns of PPCOSAr (p = .006 and .014, respectively). In conclusion, differences in pregnancy complications and obstetric outcomes between Chilean and Argentinian pregnant women with PCOS could be determined by ethnic diversity together with environmental factors of both populations. Impact Statement What is already known on this subject: The reproductive and metabolic phenotypes of women with polycystic ovary syndrome vary between different populations, which could significantly influence the obstetric and neonatal outcomes in this syndrome. What the results of this study add: Pregnant women with PCOS from two Latin American countries (Chile and Argentina) exhibit differences in the prevalence of gestational diabetes and pregnancy-induced hypertension, and in the birth weight of their newborns. What the implications are of these findings for clinical practice and/or further research: Ethnic diversity together with environmental factors are fundamental elements that must be considered in the management of pregnant women with PCOS.

Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

Maternal polycystic ovary syndrome (PCOS), a condition associated with hyperandrogenism, is suggested to increase anxiety-like behavior in the offspring. Because PCOS is closely linked to obesity, we investigated the impact of an adverse hormonal or metabolic maternal environment and offspring obesity on anxiety in the offspring. The obese PCOS phenotype was induced by chronic high-fat-high-sucrose (HFHS) consumption together with prenatal dihydrotestosterone exposure in mouse dams. Anxiety-like behavior was assessed in adult offspring with the elevated-plus maze and open-field tests. The influence of maternal androgens and maternal and offspring diet on genes implicated in anxiety were analyzed in the amygdala and hypothalamus with real-time PCR ( n = 47). Independent of diet, female offspring exposed to maternal androgens were more anxious and displayed up-regulation of adrenoceptor α 1B in the amygdala and up-regulation of hypothalamic corticotropin-releasing hormone ( Crh). By contrast, male offspring exposed to a HFHS maternal diet had increased anxiety-like behavior and showed up-regulation of epigenetic markers in the amygdala and up-regulation of hypothalamic Crh. Overall, there were substantial sex differences in gene expression in the brain. These findings provide novel insight into how maternal androgens and obesity exert sex-specific effects on behavior and gene expression in the offspring of a PCOS mouse model.-Manti, M., Fornes, R., Qi, X., Folmerz, E., Lindén Hirschberg, A., de Castro Barbosa, T., Maliqueo, M., Benrick, A., Stener-Victorin, E. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women. DESIGN: Twelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20-35 kg/m2) were included, with measurements of whole-body composition assessed by dual-energy X-ray absorptiometry, and abdominal subcutaneous and visceral adipose tissue (VAT) volume, by magnetic resonance imaging. An oral glucose tolerance test was performed with measurements of glucose and insulin, and sex steroids, lipid profile and serum adipocytokines were determined in the fasting sample. Adipocytokine gene expression, mean adipocyte area and macrophage infiltration were evaluated in SAT biopsies. RESULTS: Both groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = -0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014). CONCLUSIONS: Our results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations.

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes.

OBJECTIVES:: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS:: A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS:: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-ß and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS:: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

Reproductive and metabolic features during puberty in sons of women with polycystic ovary syndrome.

CONTEXT: Intrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty. METHODS: Sixty-nine PCOS sons (PCOSs) and 84 control sons of 7-18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17α-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample. RESULTS: Waist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II-III. In Tanner stages II-III and IV-V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups. CONCLUSIONS: Sons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls.

The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams.

Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.