Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants.

Background: It is still unelucidated how hormonal alterations affect developing organisms and their descendants. Particularly, the effects of androgen levels are of clinical relevance as they are usually high in women with Polycystic Ovary Syndrome (PCOS). Moreover, it is still unknown how androgens may affect males' health and their descendants. Objectives: We aimed to evaluate the multigenerational effect of prenatal androgen excess until a second generation at early developmental stages considering both maternal and paternal effects. Design And Methods: This is an animal model study. Female rats (F0) were exposed to androgens during pregnancy by injections of 1 mg of testosterone to obtain prenatally hyperandrogenized (PH) animals (F1), leading to a well-known animal model that resembles PCOS features. A control (C) group was obtained by vehicle injections. The PH-F1 animals were crossed with C males (m) or females (f) and C animals were also mated, thus obtaining 3 different mating groups: Cf × Cm, PHf × Cm, Cf × PHm and their offspring (F2). Results: F1-PHf presented altered glucose metabolism and lipid profile compared to F1-C females. In addition, F1-PHf showed an increased time to mating with control males compared to the C group. At gestational day 14, we found alterations in glucose and total cholesterol serum levels and in the placental size of the pregnant F1-PHf and Cf mated to F1-PHm. The F2 offspring resulting from F1-PH mothers or fathers showed alterations in their growth, size, and glucose metabolism up to early post-natal development in a sex-dependent manner, being the females born to F1-PHf the most affected ones. Conclusion: androgen exposure during intrauterine life leads to programing effects in females and males that affect offspring health in a sex-dependent manner, at least up-to a second generation. In addition, this study suggests paternally mediated effects on the F2 offspring development.

Role of Hormones During Gestation and Early Development: Pathways Involved in Developmental Programming.

Accumulating evidence suggests that an altered maternal milieu and environmental insults during the intrauterine and perinatal periods of life affect the developing organism, leading to detrimental long-term outcomes and often to adult pathologies through programming effects. Hormones, together with growth factors, play critical roles in the regulation of maternal-fetal and maternal-neonate interfaces, and alterations in any of them may lead to programming effects on the developing organism. In this chapter, we will review the role of sex steroids, thyroid hormones, and insulin-like growth factors, as crucial factors involved in physiological processes during pregnancy and lactation, and their role in developmental programming effects during fetal and early neonatal life. Also, we will consider epidemiological evidence and data from animal models of altered maternal hormonal environments and focus on the role of different tissues in the establishment of maternal and fetus/infant interaction. Finally, we will identify unresolved questions and discuss potential future research directions.

Intrauterine androgen exposure impairs gonadal adipose tissue functions of adult female rats.

Prenatal androgen exposure induces fetal programming leading to alterations in offspring health and phenotypes that resemble those seen in women with Polycystic Ovary Syndrome. It has been described that prenatal androgenization affects the reproductive axis and leads to metabolic and endocrine disorders. Adipose tissue plays a crucial role in all these functions and is susceptible to programming effects. Particularly, gonadal adipose tissue is involved in reproductive functions, so dysfunctions in this tissue could be related to fertility alterations. We aimed to investigate the extent to which prenatal hyperandrogenization is able to alter the functionality of gonadal adipose tissue in female adult rats, including lipid metabolism, adipokines expression, and de novo synthesis of steroids. Pregnant rats were treated with 1 mg of testosterone from day 16 to day 19 of pregnancy, and female offspring were followed until 90 days of age, when they were euthanized. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov). Regarding lipid metabolism, both PH groups displayed disruptions in the main lipid pathways with altered levels of triglyceride and increased lipid peroxidation levels. In addition, we found that Peroxisome Proliferator-Activated Receptors (PPARs) alpha protein expression was decreased in both PH phenotypes (p < 0.05), but no changes were found in PPARγ protein levels. Furthermore, regarding adipokines, no changes were found in Leptin and Adiponectin protein levels, but Chemerin protein levels were decreased in the PHiov group (p < 0.05). Regarding de novo synthesis of steroids, the PHanov group showed increased protein levels of Cyp17a1 and Cyp19, while the PHiov group only showed decreased protein levels of Cyp19 (p < 0.05). These results suggest that prenatal androgen exposure affects females' gonadal adipose tissue in adulthood, disturbing different lipid pathways, Chemerin expression, and de novo synthesis of steroids.

Polycystic ovary syndrome in Latin American populations: What is known and what remains unresolved.

Polycystic ovary syndrome (PCOS) is one of the main endocrine and reproductive disorders affecting women in their reproductive age. The syndrome is considered a multifactorial pathology. Therefore, genetic susceptibility and environmental factors contribute to PCOS development and phenotypic manifestation. Ethnicity and socioeconomic factors influence the development of PCOS and could affect the possibility of its diagnosis. Latin America is a unique case of study because of the heterogeneity within the region, complex socioeconomic status, and the mixed ancestry found in these populations. Up-to-date, most studies have focused on developed countries' populations, and there is a lack of evidence regarding Latin-American countries. We propose to review the state of the art of PCOS knowledge regarding Latin American populations, including the metabolic and reproductive aspects of the syndrome and the different influencing factors, and suggest future directions to deepen the study of PCOS.

Hyperandrogenism and Polycystic ovary syndrome: Effects in pregnancy and offspring development.

Polycystic ovary syndrome (PCOS) is one of the major endocrine disorders affecting women of reproductive age. Its etiology remains unclear. It is suggested that environmental factors, and particularly the intrauterine environment, play key roles in PCOS development. Besides the role of androgens in PCOS pathogenesis, exposure to endocrine disruptors, as is Bisphenol A, could also contribute to its development. Although PCOS is considered one of the leading causes of ovarian infertility, many PCOS patients can get pregnant. Some of them by natural conception and others by assisted reproductive technique treatments. As hyperandrogenism (one of PCOS main features) affects ovarian and uterine functions, PCOS women, despite reaching pregnancy, could present high-risk pregnancies, including implantation failure, an increased risk of gestational diabetes, preeclampsia, and preterm birth. Moreover, hyperandrogenism may also be maintained in these women during pregnancy. Therefore, as an altered uterine milieu, including hormonal imbalance, could affect the developing organisms, monitoring these patients throughout pregnancy and their offspring development is highly relevant. The present review focuses on the impact of androgenism and PCOS on fertility issues and pregnancy-related outcomes and offspring development. The evidence suggests that the increased risk of pregnancy complications and adverse offspring outcomes of PCOS women would be due to the factors involved in the syndrome pathogenesis and the related co-morbidities. A better understanding of the involved mechanisms is still needed and could contribute to a better management of these women and their offspring. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors.

Impact of COVID-19 pandemic on research and careers of early career researchers: a DOHaD perspective.

The COVID-19 pandemic has exposed several inequalities worldwide, including the populations' access to healthcare systems and economic differences that impact the access to vaccination, medical resources, and health care services. Scientific research activities were not an exception, such that scientific research was profoundly impacted globally. Research trainees and early career researchers (ECRs) are the life force of scientific discovery around the world, and their work and progress in research was dramatically affected by the COVID-19 pandemic. ECRs are a particularly vulnerable group as they are in a formative stage of their scientific careers, any disruptions during which is going to likely impact their lifelong career trajectory. To understand how COVID-19 impacted lives, career development plans, and research of Developmental Origins of Health and Disease (DOHaD) ECRs, the International DOHaD ECR committee formed a special interest group comprising of ECR representatives of International DOHaD affiliated Societies/Chapters from around the world (Australia and New Zealand, Canada, French Speaking DOHaD, Japan, Latin America, Pakistan and USA). The anecdotal evidence summarized in this brief report, provide an overview of the findings of this special interest group, specifically on the impact of the evolving COVID-19 pandemic on daily research activities and its effects on career development plans of ECRs. We also discuss how our learnings from these shared experiences can strengthen collaborative work for the current and future generation of scientists.

Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats.

It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators' expression at adult age.

Telomere Length Differently Associated to Obesity and Hyperandrogenism in Women With Polycystic Ovary Syndrome.

Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL). Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters. Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR. Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp). Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.

Lipid Metabolism and Relevant Disorders to Female Reproductive Health.

BACKGROUND: Lipids are essential components of cells that participate in metabolic and endocrine regulation and reproductive functions. The main organs where lipid regulation takes place are the liver and adipose tissue. Besides, when each tissue- specific action cannot be exerted, it could lead to several endocrine-metabolic disorders closely related to PCOS, such as non-alcoholic fatty liver disease (NAFLD) and obesity. OBJECTIVE: This work aims to discuss the impact of lipid alterations on metabolic and reproductive health. Therefore, this review focus on the importance of carrying out an integrated study of the molecular pathways affected in PCOS for developing target therapies. RESULTS: Lipids play a major role in PCOS pathogenesis. In this regard, failures in lipid regulation, synthesis, and/or homeostasis contribute to metabolic and reproductive abnormalities, such as those seen in PCOS. Several lipid pathways and regulators are altered in this pathology, leading to dysfunctions that worsen reproductive functions. Therefore, there are several treatments to manage dyslipidemias. Non-pharmacological therapies are considered a first-line treatment being the pharmacological treatments a second-line option. CONCLUSION: The best treatment to improve the lipid profile is lifestyle intervention, a combination of hypocaloric diet and exercise. Regarding pharmacological therapies, a combination of fibrate and statins would be the most recommended drugs. Still, in PCOS women, treatment with metformin or TZDs not only modulates the lipid metabolism, but also improves ovulation. In addition, metformin with lifestyle interventions has positive effects on the metabolic and reproductive features of PCOS patients.

Prenatal testosterone exposure induces insulin resistance, uterine oxidative stress and pro-inflammatory status in rats.

Prenatal androgen excess is considered one of the main causes of the development of polycystic ovary syndrome. In this study, we investigated the effect of prenatal hyperandrogenization (PH) on the physiology of the adult uterine tissue using a murine model of fetal programming caused by androgen excess in adult female rats. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. Our results showed that PH leads to hyperglycemia and hyperinsulinemia. Consequently, PH developed insulin resistance and a systemic inflammatory state reflected by increased C-reactive protein. In the uterine tissue, levels of PPAR gamma-an important metabolic sensor in the endometrium-were found to be impaired. Moreover, PH induced a pro-inflammatory and an unbalanced oxidative state in the uterus reflected by increased COX-2, lipid peroxidation, and NF-κB. In summary, our results revealed that PH leads to a compromised metabolic state likely consequence of fetal reprogramming.

Prenatal androgen exposure affects ovarian lipid metabolism and steroid biosynthesis in rats.

Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldlr and Srb1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.

Increased chemerin serum levels in hyperandrogenic and normoandrogenic women from Argentina with polycystic ovary syndrome.

AIM: To assess serum chemerin levels and investigate the association of chemerin with the hyperandrogenic and normoandrogenic phenotypes of Polycystic Ovary Syndrome (PCOS) and with the metabolic status of the analyzed population. MATERIAL AND METHODS: A cross-sectional study was conducted on 106 women with PCOS and 60 healthy controls from Argentina. Patients were classified as showing a hyperandrogenic or normoandrogenic phenotype. Participants underwent anthropometric and clinical evaluation and markers of cardiovascular risk, insulin resistance, metabolic syndrome (MS), and serum chemerin levels were assessed. RESULTS: PCOS patients showed increased levels of chemerin. In adjusted models for age and body mass index (BMI), chemerin was associated with markers of metabolic status. The analysis of chemerin levels considering the cutoff values of BMI, homeostatic model of insulin sensitivity (HOMA-IR) and TG/HDL marker showed that PCOS patients always presented higher levels of chemerin than controls. PCOS group showed increased chemerin levels independently of the presence of MS. CONCLUSION: PCOS patients always showed increased levels of chemerin independently of their phenotype and presence of overweight, as well as higher levels of chemerin than controls when considering the cutoff values of HOMA-IR and TG/HDL. Therefore, argentine women with PCOS display increased chemerin levels independently of their metabolic or androgenic status.

Prenatally androgenized female rats develop uterine hyperplasia when adult.

Prenatal hyperandrogenization (PH) is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal exposure to androgen excess on the uterus when animals reach their adulthood. We found that PH altered the morphology of the uteri that show a hyperplastic morphology with increased total uterine thickness as well as luminal epithelium thickness, with both enhanced and altered distribution of glands as compared with controls. Morphological alterations were associated with an unbalanced homeostasis as assessed by the expression of regulators of cell cycle progression and cell death dynamics. PH also causes disturbances in the cell cycle of the uterine tissue and dysregulates cell death and survival pathways leading to the development of uterine hyperplasia. These findings suggest that PH may have a deleterious effect on the uterus.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system.

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara ), PPARδ (Ppard ), PPARγ (Pparg ), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a ) and nuclear receptor co-repressor 1 (Ncor1 ) and cyclo-oxygenase (COX)-2 (Ptgs2 ), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2 . The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant-antioxidant state and a proinflammatory status.

Fetal programming by androgen excess in rats affects ovarian fuel sensors and steroidogenesis.

Fetal programming by androgen excess is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS is more than a reproductive disorder, as women with PCOS also show metabolic and other endocrine alterations. Since both ovarian and reproductive functions depend on energy balance, the alterations in metabolism may be related to reproductive alterations. The present study aimed to evaluate the effect of androgen excess during prenatal life on ovarian fuel sensors and its consequences on steroidogenesis. To this end, pregnant rats were hyperandrogenized with testosterone and the following parameters were evaluated in their female offspring: follicular development, PPARG levels, adipokines (including leptin, adiponectin, and chemerin as ovarian fuel sensors), serum gonadotropins (LH and FSH), the mRNA of their ovarian receptors, and the expression of steroidogenic mediators. At 60 days of age, the prenatally hyperandrogenized (PH) female offspring displayed both an irregular ovulatory phenotype and an anovulatory phenotype with altered follicular development and the presence of cysts. Both PH groups showed altered levels of both proteins and mRNA of PPARG and a different expression pattern of the adipokines studied. Although serum gonadotropins were not impaired, there were alterations in the mRNA levels of their ovarian receptors. The steroidogenic mediators Star, Cyp11a1, Cyp17a1, and Cyp19a1 were altered differently in each of the PH groups. We concluded that androgen excess during prenatal life leads to developmental programming effects that affect ovarian fuel sensors and steroidogenesis in a phenotype-specific way.

Effects of in utero androgen excess and metformin treatment on hepatic functions.

This study aimed to evaluate the role of prenatal hyperandrogenization in liver functions and the extent of metformin as treatment. Pregnant rats were hyperandrogenized with subcutaneous testosterone (1mg/rat) between 16 and 19 of pregnancy. Prenatally hyperandrogenized (PH) female offspring displayed, at the adult life, two phenotypes; a PH irregular ovulatory phenotype (PHiov) and a PH anovulatory (PHanov) phenotype. From day 70 to the moment of sacrifice (90 days of age), 50% of the animals of each group received a daily oral dose of 50 mg/kg of metformin. We found that both PH phenotypes displayed a hepatic disruptions of insulin and glucose pathway and that metformin treatment reversed some of these alterations in a specific-phenotype manner. Our findings show, for the first time, that androgen excess in utero promotes hepatic dysfunctions and that metformin treatment is able to specifically reverse those hepatic alterations and sheds light on the possible mechanisms of metformin action.

Metformin improves ovarian insulin signaling alterations caused by fetal programming.

Insulin resistance is the decreased ability of insulin to mediate metabolic actions. In the ovary, insulin controls ovulation and oocyte quality. Alterations in ovarian insulin signaling pathway could compromise ovarian physiology. Here, we aimed to investigate the effects of fetal programming on ovarian insulin signaling and evaluate the effect of metformin treatment. Pregnant rats were hyperandrogenized with testosterone and female offspring born to those dams were employed; at adulthood, prenatally hyperandrogenized (PH) offspring presented two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov). Half of each group was orally treated with metformin. Metformin treatment improved the estrous cyclicity in both PH groups. Both PH groups showed low mRNA levels of IR, IRS1 and Glut4. IRS2 was decreased only in PHanov. Metformin upregulated the mRNA levels of some of the mediators studied. Protein expression of IR, IRS1/2 and GLUT4 was decreased in both PH groups. In PHiov, metformin restored the expression of all the mediators, whereas, in PHanov, metformin restored only that of IR and IRS1/2. IRS1 phosphorylation was measured in tyrosine residues, which activates the pathway, and in serine residues, which impairs insulin action. PHiov presented high IRS1 phosphorylation on tyrosine and serine residues, whereas PHanov showed high serine phosphorylation and low tyrosine phosphorylation. Metformin treatment lowered serine phosphorylation only in PHanov rats. Our results suggest that PHanov rats have a defective insulin action, partially restored with metformin. PHiov rats had less severe alterations, and metformin treatment was more effective in this phenotype.

Treatment with the synthetic PPARG ligand pioglitazone ameliorates early ovarian alterations induced by dehydroepiandrosterone in prepubertal rats.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear factor that may act on the early development of ovarian follicles and on follicular steroidogenesis. However, the exact mechanism of PPARG action remains unknown. We have previously found that androgen excess alters early ovarian function and the PPARG system. The aim of the present study was to evaluate whether PPARG activation (using the synthetic ligand pioglitazone (PGZ)) ameliorates the alterations in early ovarian function induced by androgen excess. METHODS: Female prepubertal rats were treated with equine chorionic gonadotropin (eCG) to induce folliculogenesis, together with dehydroepiandrosterone (DHEA) to induce hyperandrogenism and/or PGZ to evaluate PPARG activation. We assessed i) very early ovarian folliculogenesis, ii) PPARG activation, iii) ovarian steroidogenic enzymes, iv) the estradiol/testosterone ratio, v) the ovarian inflammatory status and vi) oxidative stress. RESULTS: PGZ prevented the inactivation of ovarian PPARG induced by androgen excess by increasing PPARG itself and the gene expression of PPARG-coactivator 1 alpha (PGC1A), and by decreasing the gene expression of nuclear co-repressor (NCOR). PGZ also prevented the altered ovarian steroidogenesis, pro-inflammatory status and oxidative stress induced by androgen excess. CONCLUSIONS: Our findings suggest that PPARG activation plays important roles in modulating early ovarian function, and highlight the importance of understanding the role(s) of PPARG activation in the ovary, and the possible involvement in the treatment of ovarian pathologies, and/or the impact in regulating/improving fertility.

Developmental programming of the female neuroendocrine system by steroids.

Developmental programming refers to processes that occur during early life that may have long-term consequences, modulating adult health and disease. Complex diseases, such as diabetes, cancer and cardiovascular disease, have a high prevalence in different populations, are multifactorial, and may have a strong environmental component. The environment interacts with organisms, affecting their behaviour, morphology and physiology. This interaction may induce permanent or long-term changes, and organisms may be more susceptible to environmental factors during certain developmental stages, such as the prenatal and early postnatal periods. Several factors have been identified as responsible for inducing the reprogramming of various reproductive and nonreproductive tissues. Among them, both natural and synthetic steroids, such as endocrine disruptors, are known to have either detrimental or positive effects on organisms depending on the dose of exposure, stage of development and biological sexual background. The present review focuses on the action of steroids and endocrine disruptors as agents involved in developmental programming and on their modulation and effects on female neuroendocrine functions.

Lipid Accumulation Product (LAP) and Visceral Adiposity Index (VAI) as Markers of Insulin Resistance and Metabolic Associated Disturbances in Young Argentine Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disorder. PCOS women are at high risk of developing insulin resistance (IR) and cardiovascular disorders since young age. We aimed to study the reliability of lipid accumulation product (LAP) and visceral adiposity index (VAI) as markers of metabolic disturbances (MD) associated with IR in young reproductive aged PCOS patients. We also evaluated the association between LAP and VAI and the presence of hyperandrogenism. In a cross-sectional study, 110 PCOS patients and 88 control women (18-35 years old) were recruited. PCOS patients were divided into 2 groups, as hyperandrogenic and non-hyperandrogenic considering the signs of hyperandrogenism (clinical or biochemical). Anthropometric measurements were taken and blood samples collected. Metabolic and anthropometric characteristics and their association with IR and associated MD were evaluated and LAP and VAI were calculated. LAP and VAI were compared with TC/HDL-c and TG/HDL-c to define the best markers of MD in this population. Independently of the phenotype, young PCOS patients showed high IR and dyslipidemia. Both LAP and VAI showed to be more effective markers to assess MD and IR in these young women than TG/HDL-c or TC/HDL-c [cut-off values: LAP: 18.24 (sensitivity: 81.43% specificity: 73.49%), positive predictive value (PPV): 75.0%, negative predictive value (NPV): 77.27%, VAI: 2.19 (sensitivity: 81.16% specificity: 72.15% PPV: 74.65% NPV: 72.22%)]. LAP and VAI are representative markers to assess MD associated with IR in young PCOS patients. All PCOS patients, independently of their androgenic condition, showed high metabolic risk.