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.

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.

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.

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.