The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

I. Introduction IN THE adult ovary, folliculogenesis starts when follicles leave the pool of resting follicles (RF) to enter the growth phase. From there, the early growing follicle undergoes a developmental process including a dramatic course of cellular proliferation and differentiation. In primates, only one follicle commonly reaches the preovulatory stage every cycle; most follicles fail to complete this maturation scheme, dying in the process termed atresia. In recent years, a picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules (1–3). Different types of cell-cell interactions have been described. In paracrine regulations, a molecule synthesized by one cellular type is released into the interstitial milieu to act directly on another cellular type. In autocrine regulations, molecules synthesized by one cellular type are rel...

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Regulation of ovarian follicular development in primates: facts and hypotheses.

I. Introduction BASIC AND acidic fibroblast growth factors (FGFs) are closely related molecules that show a similar range of biological activities. They differ, however, in some of their physical and chemical properties and in their tissue distribution (1). Basic FGF [bFGF isoelectric point (pi) 9.6] was first identified by its ability to cause the proliferation and phenotypic transformation of BALB/c 3T3 fibroblasts (2, 3). Acidic FGF (aFGF, pi 5.6) was first identified by its ability to cause proliferation and delayed differentiation of myoblasts (4); it was later rediscovered on the basis of its ability to stimulate endothelial cell proliferation (5, 6). As expected from their structural relationship, both FGF and aFGF interact with the same receptor (7), thereby having similar, if not identical, properties. In contrast to aFGF, which has a cellular distribution more restricted than bFGF, many different cells synthesize bFGF, and essentially all have a specific high affinity receptor for this peptide. ...

Structural characterization and biological functions of fibroblast growth factor

Publisher Summary This chapter discusses the development of follicles in the mammalian ovary. The unresolved issues in follicular development are focused. Folliculogenesis culminates in the production of fully ripe, preovulatory follicles visible to the naked eye as large bulges on the surface of the ovary. Each ripe follicle contains thousands of highly differentiated cells. This complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope. All regulatory influences can only permit or prevent cells from completing the full maturation process; they cannot change the course of differentiation. A plethora of modulating influences act as permissive inducers, impeding or propelling the committed follicular cells through the process of clonal expansion. As each follicle progresses through its program of limited clonal expansion and maturation, its cells proliferate more and more rapidly. With every passing generation, the proliferative potential of the granulosa and theca cells continues to diminish, while the state of maturation increases.

Development of Follicles in the Mammalian Ovary

The effects of insulin and insulin-like growth factors (IGFs) on ovarian androgen production were examined in ovarian stroma obtained from four women with hyperandrogenism and three women without hyperandrogenism. In incubations of stroma obtained from all four hyperandrogenic patients, insulin alone (500 ng/ml) significantly stimulated androstenedione and testosterone release. LH alone (25 ng/ml) significantly stimulated androstenedione release in incubations of stroma obtained from three of the four hyperandrogenic patients and testosterone release in incubations of stroma obtained from one of the four hyperandrogenic patients. In stromal incubations from three of the four hyperandrogenic patients, insulin alone (500 ng/ml) resulted in a significantly greater release of androstenedione and testosterone than did LH alone (25 ng/ml). Dihydrotestosterone was released in measurable quantities in incubations of stromal tissue obtained from three of the four hyperandrogenic women. In all three instances in which dihydrotestosterone was detectable, insulin alone (500 ng/ml), but not LH alone (25 ng/ml), significantly stimulated dihydrostestosterone release. Incubations of stroma obtained from three nonhyperandrogenic, normally cycling women demonstrated low levels of androstenedione release and negligible testosterone and dihydrotestosterone release. Insulin alone (500 ng/ml) and LH alone (25 ng/ml) produced no significant increase in androstenedione release. Insulin (500 ng/ml) plus LH (25 ng/ml) significantly stimulated androstenedione accumulation in stroma obtained from two of the nonhyperandrogenic women. One insulin dose-response experiment was performed using stromal tissue obtained from a hyperandrogenic woman. In this experiment, insulin, at a dose of 50 ng/ml, was as effective as insulin at a dose of 500 ng/ml in stimulating androstenedione and testosterone release. In addition to insulin, IGF-I/somatomedin C (50 ng/ml) stimulated androstenedione and testosterone release. Relaxin (1 microgram/ml) and multiplication-stimulating activity (50 ng/ml) did not stimulate androstenedione and testosterone release. These studies suggest that human ovarian stroma may be a target tissue for insulin and IGF-I, and that hyperinsulinemia may be an important factor contributing to ovarian hyperandrogenism.

Insulin Stimulates Androgen Accumulation in Incubations of Ovarian Stroma Obtained from Women with Hyperandrogenism

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Granulosa Cell Differentiation in vitro: Effect of Insulin on Growth and Functional Integrity

The ovarian granulosa cell has recently been shown to be a site of insulin-like growth factor-I (IGF-I) production, reception, and action. In large measure, IGF-I action (in the rat) appears contingent upon its ability to synergize with FSH, a major promoter of granulosa cell differentiation. It is the objective of the in vitro studies reported herein to elucidate the cellular mechanism(s) whereby IGF-I amplifies FSH hormonal action, placing special emphasis on the potential role of the putative intracellular second messenger cAMP in this regard. Basal FSH binding (115.7 ± 2.1 fmol/mg cell protein) to rat granulosa cells cultured under serum-free conditions remained unchanged after 72 h of treatment with IGF-I (50 ng/ml) by itself (107.1 ± 1.0 fmol/mg cell protein). In contrast, treatment with FSH (20 ng/ml) resulted in a significant (P < 0.05) decrease in FSH binding capacity (but not affinity) relative to controls in either the absence or presence of IGF-I. Whereas treatment with FSH resulted in a subst...

Insulin-like growth factor-I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured rat granulosa cells.

Basic fibroblast growth factor as a regulator of ovarian granulosa cell differentiation: a novel non-mitogenic role

The LH/hCG receptor content of porcine ovarian granulosa cells from 1- to 3-mm follicles can be increased to 4–5 times the preculture level during monolayer culture in serumcontaining media supplemented with insulin and FSH. The binding of [125I]iodo-hCG declines during the first 2 days of culture, but then uniformly increases through 6 days, achieving a 14- to 15-fold increase relative to the 2-day level under optimal conditions. Analysis of receptor binding by autoradiography indicates that after 2 days, the number of cells specificallybinding [125I]iodo-hCG increases significantly during culture, as does the intensity of binding on receptor-bearing cells. Granulosa cells in monolayer culture exhibit heterogeneous receptor induction, indicating that normalized [125I]iodo-hCG binding data cannot be used to estimate receptor concentration per cell. Receptor affinities in the initial and induced populations are identical. LH/hCG receptors induced in granulosa cells during culture are functional, as demonst...

Follicle-Stimulating Hormone-Mediated Induction of Functional Luteinizing Hormone/Human Chorionic Gonadotropin Receptors during Monolayer Culture of Porcine Granulosa Cells*

https://soar.wichita.edu/bitstream/handle/10057/10561/bousfield_butnev_et_all_2013.pdf?sequence=2

Jeffrey V. May

Papers

Granulosa Cell Differentiation in vitro: Effect of Insulin on Growth and Functional Integrity

Insulin-like growth factor-I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured rat granulosa cells.

Basic fibroblast growth factor as a regulator of ovarian granulosa cell differentiation: a novel non-mitogenic role

Follicle-Stimulating Hormone-Mediated Induction of Functional Luteinizing Hormone/Human Chorionic Gonadotropin Receptors during Monolayer Culture of Porcine Granulosa Cells*

Hypo-glycosylated human follicle-stimulating hormone (hFSH(21/18)) is much more active in vitro than fully-glycosylated hFSH (hFSH(24)).