Abstract
Polycystic ovary syndrome (PCOS) is a complex disorder that results from a combination of multiple factors, including genetic, epigenetic, and environmental influences. Evidence from clinical and preclinical studies indicates that elevated intrauterine androgen levels increase the susceptibility of the female offspring to develop the PCOS phenotype. Additionally, early postnatal endocrine and metabolic imbalances may act as a “second-hit”, which, through activational effects, might unmask or amplify the modifications programmed prenatally, thus culminating in the development of adult disease. Animal models provide unparalleled resources to investigate the effects of prenatal exposure to androgen excess and to elucidate the etiology and progression of disease conditions associated with this occurrence, such as PCOS. In sheep, prenatal treatment with testosterone disrupts the developmental trajectory of the fetus, culminating in adult neuroendocrine, ovarian, and metabolic perturbations that closely resemble those seen in women with PCOS. Our longitudinal studies clearly demonstrate that prenatal exposure to testosterone excess affects both the reproductive and the metabolic systems, leading to a self-perpetuating cycle with defects in one system having an impact on the other. These observations in the sheep suggest that intervention strategies targeting multiple organ systems may be required to prevent the progression of developmentally programmed disorders.
Highlights
Approximately 60–80 million people experience difficulty conceiving [1], and, in 30–40%of couples of childbearing age seeking fertility counseling, infertility is exclusively a problem with the female
The “two-hit” hypothesis is supported by our observations in the sheep model of polycystic ovary syndrome (PCOS), in which many reproductive disease traits programmed by prenatal testosterone excess can be prevented from manifesting themselves if postnatal endocrine and metabolic imbalances are managed properly
Because the use of sheep allows detailed hormonal profiling, our studies indicate that the progressive reproductive failure seen in prenatal testosterone-treated females stems, at least in part, from tonic activation of the reproductive neuroendocrine axis
Summary
Approximately 60–80 million people experience difficulty conceiving [1], and, in 30–40%. In addition to the well-characterized impact during fetal development, recent research observations support a “two-hit” hypothesis to explain the onset as well as severity of diseases [20,21] This hypothesis proposes that an insult occurring during the prenatal life constitutes a “first-hit” that combined with genetic susceptibility can lead to reorganization of several organ systems. Despite these modifications during early life, in many occasions this “first-hit” alone might be insufficient to alter the adult phenotype resulting in disease. The “two-hit” hypothesis is supported by our observations in the sheep model of PCOS, in which many reproductive disease traits programmed by prenatal testosterone excess can be prevented from manifesting themselves if postnatal endocrine and metabolic imbalances are managed properly.
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