Developmental Origin of Reproductive and Metabolic Dysfunctions: Androgenic Versus Estrogenic Reprogramming

Department of Pediatrics, The University of Michigan, Ann Arbor, Michigan, USA.
Seminars in Reproductive Medicine (Impact Factor: 2.35). 05/2011; 29(3):173-86. DOI: 10.1055/s-0031-1275519
Source: PubMed


Polycystic ovary syndrome (PCOS) is one of the most common fertility disorders, affecting several million women worldwide. Women with PCOS manifest neuroendocrine, ovarian, and metabolic defects. A large number of animal models have evolved to understand the etiology of PCOS. These models provide support for the contributing role of excess steroids during development in programming the PCOS phenotype. However, considerable phenotypic variability is evident across animal models, depending on the quality of the steroid administered and the perinatal time of treatment relative to the developmental trajectory of the fetus/offspring. This review focuses on the reproductive and metabolic phenotypes of the various PCOS animal models that have evolved in the last decade to delineate the relative roles of androgens and estrogens in relation to the timing of exposure in programming the various dysfunctions that are part and parcel of the PCOS phenotype. Furthermore, the review addresses the contributory role of the postnatal metabolic environment in exaggerating the severity of the phenotype, the translational relevance of the various animal models to PCOS, and areas for future research.

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Available from: Vasantha Padmanabhan,
    • "PCOS is clinically evident at puberty, but emerging data from suitable animal models suggest that exposure to excess androgen during critical periods of gestation can programme the appearance of PCOS traits in adulthood (Abbott et al. 2002, Padmanabhan & Veiga-Lopez 2011, 2012). In one of these models, the prenatally androgenised (PA) sheep, animals are exposed during gestation to high doses of testosterone, administered to their mothers (Sharma et al. 2002, Forsdike et al. 2007, Padmanabhan & Veiga-Lopez 2011, 2013). Prenatal testosterone excess leads to reproductive and metabolic abnormalities in offspring during puberty "
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    ABSTRACT: The prenatally androgenised (PA) sheep is a well-recognised model for the study of developmental programming of adult polycystic ovary syndrome (PCOS). Most of the studies to date have involved examination of the reproductive and metabolic effects in the offspring after puberty, but more recently, it has been reported that there is disruption of follicle formation and steroid gene expression in ovaries of foetal sheep after exposure of the mother to excess androgen. Our study examines evidence for precocious primordial follicle formation at day 90 of gestation in ovaries of foetal Poll Dorset sheep. Using a specific marker of germ cells (VASA homologue protein) in ovarian sections, we found that androgenised sheep had nearly double the proportion of germ cells enclosed in follicles compared with control animals. When analysed by follicle stage, there was no significant difference between groups in the proportion of primordial follicles and growing (transitional and primary) follicles. Differences between PA and control foetal sheep were found in both mRNA and in protein expression of steroidogenic enzymes and androgen receptor. Our results in Dorset ewes are complementary to previous reports, but suggest that the timing of follicle formation and steroidogenic activity may vary between different breeds as well as in response to androgen. These data show that granulosa cells constitute a specific target for programming by androgen in utero and raise key questions about the role of exposure to androgen in utero in developmental origins of PCOS. © 2015 Society for Endocrinology.
    Journal of Endocrinology 04/2015; 225(1):39-46. DOI:10.1530/JOE-14-0150 · 3.72 Impact Factor
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    • "In human pregnancy, androgens are metabolized to estrogens by placental P450 aromatase (Thompson and Siiteri, 1974). Thus, the effects induced by testosterone in pregnancy could partly be mediated by estrogen (Padmanabhan and Veiga-Lopez, 2011). "
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    ABSTRACT: Does polycystic ovary syndrome (PCOS) in women without pregnancy complications affect placental signal transducer and activator of transcription 3 (STAT3) and mechanistic target of rapamycin (mTOR) signaling? Placental STAT3 signaling is activated but mTOR signaling is unaffected in PCOS. Women with PCOS have increased risk of poor pregnancy outcomes (e.g. restricted or accelerated fetal growth), indicating placental dysfunction. Placental STAT3 and mTOR pathways regulate placental function and indirectly affect fetal growth. In a case-control study, placental tissue and maternal blood were collected at delivery from 40 control pregnant women and 38 PCOS women with uncomplicated pregnancy. Women with PCOS were recruited at two medical centers and pregnant controls were recruited at one of these centers. Placental mRNA expression of genes encoding proteins related to steroid action, metabolic pathways and cytokines was analyzed by quantitative RT-PCR. Phosphorylated placental STAT3 (P-STAT3) and mTOR targets was measured by western blot. Levels of sex steroids in serum were determined by mass spectrometry. Placental P-STAT3 (Tyr-705) was increased in women with PCOS (P < 0.05) versus controls. Placental mTOR signaling was not affected in PCOS women when compared with controls. Circulating levels of androstenedione, androst-5-ene-3β, 17β-diol, testosterone, 5α-dihydrotestosterone and etiocholanolone glucuronide were higher and estradiol lower in women with PCOS than in controls (all P < 0.05). No correlation between sex steroid levels in serum and P-STAT3 was observed. Women with PCOS and pregnancy complications were excluded to avoid the confounding effects of placental pathologies, which could modify STAT3 and mTOR signaling. Moreover, 97.4% of women with PCOS in the study displayed oligoamenorrhea at diagnosis. Thus, the current findings could be restricted to PCOS women with the oligo-anovulatory phenotype without pregnancy complications. Phosphorylation of STAT3 is increased in the placenta from women with PCOS and uncomplicated pregnancies, indicating that specific metabolic placental pathways are activated in the absence of obstetric and perinatal complications. The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrens's Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
    Human Reproduction 01/2015; 30(3). DOI:10.1093/humrep/deu351 · 4.57 Impact Factor
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    • "Also, we have reason to believe that acupuncture enhances the beneficial effects of exercise. Thus, the combination of these treatments may be optimal [54]. "
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    ABSTRACT: In rats with dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), repeated low-frequency electrical stimulation of acupuncture needles restores whole-body insulin sensitivity measured by euglycemic hyperinsulinemic clamp. We hypothesized that electrical stimulation causing muscle contractions and manual stimulation causing needle sensation have different effects on insulin sensitivity and related signaling pathways in skeletal muscle and adipose tissue, with electrical stimulation being more effective in DHT-induced PCOS rats. From age 70 days, rats received manual or low-frequency electrical stimulation of needles in abdominal and hind limb muscle five times/wk for 4-5 wks; controls were handled but untreated rats. Low-frequency electrical stimulation modified gene expression (decreased Tbc1d1 in soleus, increased Nr4a3 in mesenteric fat) and protein expression (increased pAS160/AS160, Nr4a3 and decreased GLUT4) by western blot and increased GLUT4 expression by immunohistochemistry in soleus muscle; glucose clearance during oral glucose tolerance tests was unaffected. Manual stimulation led to faster glucose clearance and modified mainly gene expression in mesenteric adipose tissue (increased Nr4a3, Mapk3/Erk, Adcy3, Gsk3b), but not protein expression to the same extent; however, Nr4a3 was reduced in soleus muscle. The novel finding is that electrical and manual muscle stimulation affect glucose homeostasis in DHT-induced PCOS rats through different mechanisms. Repeated electrical stimulation regulated key functional molecular pathways important for insulin sensitivity in soleus muscle and mesenteric adipose tissue to a larger extent than manual stimulation. Manual stimulation improved whole-body glucose tolerance, an effect not observed after electrical stimulation, but did not affect molecular signaling pathways to the same extent as electrical stimulation. Although more functional signaling pathways related to insulin sensitivity were affected by electrical stimulation, our findings suggest that manual stimulation of acupuncture needles has a greater effect on glucose tolerance. The underlying mechanism of the differential effects of the intermittent manual and the continuous electrical stimulation remains to be elucidated.
    PLoS ONE 01/2013; 8(1):e54357. DOI:10.1371/journal.pone.0054357 · 3.23 Impact Factor
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