An endocrine-disrupting compound was defined by the U.S. Environmental Protection Agency (EPA) as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process.” Our understanding of the mechanisms by which endocrine disruptors exert their effect has grown. Endocrine-disrupting chemicals (EDCs) were originally thought to exert actions primarily through nuclear hormone receptors, including estrogen receptors (ERs), androgen receptors (ARs), progesterone receptors, thyroid receptors (TRs), and retinoid receptors, among others. Today, basic scientific research shows that the mechanisms are much broader than originally recognized. Thus, endocrine disruptors act via nuclear receptors, nonnuclear steroid hormone receptors (e.g., membrane ERs), nonsteroid receptors (e.g., neurotransmitter receptors such as the serotonin receptor, dopamine receptor, norepinephrine receptor), orphan receptors [e.g., aryl hydrocarbon receptor (AhR)—an orphan receptor], enzymatic pathways involved in steroid biosynthesis and/or metabolism, and numerous other mechanisms that converge upon endocrine and reproductive systems. Thus, from a physiological perspective, an endocrine-disrupting substance is a compound, either natural or synthetic, which, through environmental or inappropriate developmental exposures, alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment. The group of molecules identified as endocrine disruptors is highly heterogeneous and includes synthetic chemicals used as industrial solvents/lubricants and their byproducts [polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), dioxins], plastics [bisphenol A (BPA)], plasticizers (phthalates), pesticides [methoxychlor, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT)], fungicides (vinclozolin), and pharmaceutical agents [diethylstilbestrol (DES)]. Natural chemicals found in human and animal food (e.g., phytoestrogens, including genistein and coumestrol) can also act as endocrine disruptors. These substances, whereas generally thought to have relatively low binding affinity to ERs, are widely consumed and are components of infant formula (1,2). A recent study reported that urinary concentrations of the phytoestrogens genistein and daidzein were about 500-fold higher in infants fed soy formula compared with those fed cow’s milk formula (3). Therefore, the potential for endocrine disruption by phytoestrogens needs to be considered. A challenge to the field of endocrine disruption is that these substances are diverse and may not appear to share any structural similarity other than usually being small molecular mass (<1000 Daltons) compounds. Thus, it is difficult to predict whether a compound may or may not exert endocrine-disrupting actions. Nevertheless, in very broad terms, EDCs such as dioxins, PCBs, PBBs, and pesticides often contain halogen group substitutions by chlorine and bromine. They often have a phenolic moiety that is thought to mimic natural steroid hormones and enable EDCs to interact with steroid hormone receptors as analogs or antagonists. Even heavy metals and metalloids may have estrogenic activity, suggesting that these compounds are EDCs as well as more generalized toxicants. Several classes of EDCs act as antiandrogens and as thyroid hormone receptor agonists or antagonists, and more recently, androgenic EDCs have been identified. The sources of exposure to EDCs are diverse and vary widely around the world. The situation is constantly evolving because some EDCs were banned decades ago and others more recently, with significant differences between countries. In this respect, migrating people provide a model to study cessation and/or onset of exposure depending on contamination of the original and new milieus. There are also several historical examples of toxic spills or contamination from PCBs and dioxins that show a direct causal relationship between a chemical and the manifestation of an endocrine or reproductive dysfunction in humans and wildlife. However, these types of single exposures are not representative of more common widespread persistent exposure to a broad mix of indoor and outdoor chemicals and contaminants. Industrialized areas are typically characterized by contamination from a wide range of industrial chemicals that may leach into soil and groundwater. These complex mixtures enter the food chain and accumulate in animals higher up the food chain such as humans, American bald eagles, polar bears, and other predatory animals. Exposure occurs through drinking contaminated water, breathing contaminated air, ingesting food, or contacting contaminated soil. People who work with pesticides, fungicides, and industrial chemicals are at particularly high risk for exposure and thus for developing a reproductive or endocrine abnormality. Some EDCs were designed to have long half-lives; this was beneficial for their industrial use, but it has turned out to be quite detrimental to wildlife and humans. Because these substances do not decay easily, they may not be metabolized, or they may be metabolized or broken down into more toxic compounds than the parent molecule; even substances that were banned decades ago remain in high levels in the environment, and they can be detected as part of the body burden of virtually every tested individual animal or human (4,5). In fact, some endocrine disruptors are detectable in so-called “pristine” environments at remote distances from the site they were produced, used, or released due to water and air currents and via migratory animals that spend part of their life in a contaminated area, to become incorporated into the food chain in an otherwise uncontaminated region. Others, such as BPA, may not be as persistent [although recent evidence (e.g., Ref. 6) suggests longer half-lives) but are so widespread in their use that there is prevalent human exposure. A number of issues have proven to be key to a full understanding of mechanisms of action and consequences of exposure to EDCs. These have been reviewed previously in detail (7), and several of them are listed here in brief. Exposure of an adult to an EDC may have very different consequences from exposure to a developing fetus or infant. In fact, the field of endocrine disruption has embraced the terminology “the fetal basis of adult disease” (8) to describe observations that the environment of a developing organism, which includes the maternal environment (eutherian mammals), the egg (other vertebrates), and the external environment, interacts with the individual’s genes to determine the propensity of that individual to develop a disease or dysfunction later in life. In this Scientific Statement, we extend this concept beyond the fetal period to the early postnatal developmental period when organs continue to undergo substantial development. Thus, we will henceforward use the terminology “the developmental basis of adult disease.” The developmental basis of adult disease also has implicit in its name the concept that there is a lag between the time of exposure and the manifestation of a disorder. In other words, consequences of developmental exposure may not be immediately apparent early in life but may be manifested in adulthood or during aging. If individuals and populations are exposed to an EDC, it is likely that other environmental pollutants are involved because contamination of environments is rarely due to a single compound. Furthermore, effects of different classes of EDCs may be additive or even synergistic (9). There are several properties of EDCs that have caused controversy. First, even infinitesimally low levels of exposure—indeed, any level of exposure at all—may cause endocrine or reproductive abnormalities, particularly if exposure occurs during a critical developmental window (10). Surprisingly, low doses may even exert more potent effects than higher doses. Second, EDCs may exert nontraditional dose-response curves, such as inverted-U or U-shaped curves (11). Both of these concepts have been known for hormone and neurotransmitter actions, but only in the past decade have they begun to be appreciated for EDCs. EDCs may affect not only the exposed individual but also the children and subsequent generations. Recent evidence suggests that the mechanism of transmission may in some cases involve the germline (12) and may be nongenomic. That is, effects may be transmitted not due to mutation of the DNA sequence, but rather through modifications to factors that regulate gene expression such as DNA methylation and histone acetylation. The field of endocrine disruption has particular pertinence to endocrinologists. In general, persistent endocrine disruptors have low water solubility and extremely high lipid solubility, leading to their bioaccumulation in adipose tissue. The properties of these substances are particularly well suited for study by endocrinologists because they so often activate or antagonize hormone receptors. There is no endocrine system that is immune to these substances, because of the shared properties of the chemicals and the similarities of the receptors (13) and enzymes involved in the synthesis, release, and degradation of hormones (Fig 1). Therefore, the role of this Scientific Statement is to provide perspectives on representative outcomes of exposures to endocrine disruptors and evidence for their effects in wildlife, laboratory animals, and humans.  Model of the endocrine systems targeted by endocrine-disrupting chemicals as discussed in this article. This figure demonstrates that all hormone-sensitive physiological systems are vulnerable to EDCs, including brain and hypothalamic neuroendocrine systems; pituitary; thyroid; cardiovascular system; mammary gland; adipose tissue; pancreas; ovary and uterus in females; and testes and prostate in males. Development and function of the female reproductive tract depends on coordinated biological processes that, if altered by endogenous or exogenous factors during critical periods of development or during different life stage, could have significantly adverse effects on women’s health and reproductive function and outcomes. For example, the full complement of cell types in the human ovary depends on successful germ cell migration from the yolk sac during the first trimester and differentiation into oocytes with associated somatic cells to form the functional unit of the primordial follicle by the second to third trimesters of gestation. Factors that interfere with germ cell migration or follicle formation can result in abnormal functioning of this tissue with significant reproductive consequences. Also, the oocyte is arrested in the diplotene stage of late prophase until meitic divisions occur beginning at puberty (meiosis I) and after fertilization (meiosis II), and abnormalities in these processes can have a profound impact on reproductive outcomes, such as aneuploidy, premature ovarian failure (POF), and miscarriage. In addition, whereas Mullerian tract formation begins at 8 wk gestation with fusion of the Mullerian ducts and subsequent differentiation into the uterus (endometrium, myometrium), cervix, and upper vagina, uterine differentiation with regard to formation of luminal epithelium, glandular epithelium, and stromal components is mostly a postnatal event, with functionality of response to steroid hormones beginning at puberty. Interference with these processes can predispose women to infertility, ectopic gestation, poor pregnancy outcomes, and other reproductive disorders that may be programmed during development (e.g., endometriosis, uterine fibroids). Thus, abnormal development or alterations at other times in the life cycle can alter anatomy and functionality of the female reproductive tract and thus can alter the reproductive potential of affected individuals and their offspring. Most female reproductive disorders are well described with regard to clinical presentation, histological evaluation of involved tissues where applicable, and diagnostic classification. However, whereas few are polygenic inherited traits and some are due to infections, the pathogenesis of the vast majority of female reproductive disorders is not well understood. This has hindered a preventive strategy to their development and/or exacerbation, and in some cases limited the development of effective therapies for symptoms and associated morbidities. A key question arises as to whether EDCs contribute to the development of female reproductive disorders, particularly those occurring during a critical window of susceptibility: in utero, neonatally, in childhood, during puberty, and during adulthood. There are increasing data from wildlife studies and laboratory studies with rodents, ungulates, and nonhuman primates that support a role of EDCs in the pathogenesis of several female reproductive disorders, including polycystic ovarian syndrome, aneuploidy, POF, reproductive tract anomalies, uterine fibroids, endometriosis, and ectopic gestation (for reviews, see Refs. 29 and 49,50,51,52,53,54; also see Table 4). Many of the mechanisms are understood and, moreover, are conserved between animals and humans. Herein, we describe some of the clinical implications of these associations. Female reproductive disorders and their possible relationships to EDCs: Some experimental and human data
PCOS is a heterogeneous syndrome characterized by persistent anovulation, oligo- or amenorrhea, and hyperandrogenism in the absence of thyroid, pituitary, and/or adrenal disease (55,56,57). At the level of the ovary, there is recruitment and growth of follicles to the small antral stage, without selection of a dominant, preovulatory follicle, leading to accumulation of multiple, small, antral follicles (58). Hyperfunctioning of the theca and relative hypofunctioning of the granulosa cells accompany the acyclicity of the syndrome. Many, but not all women with PCOS have relatively high circulating levels of LH, compared with FSH, believed to be due to insensitivity to steroid hormone feedback. However, this does not fully account for the observed increase in thecal androgen production or the relative quiescence and sometimes frank FSH resistance of the granulosa cells. This complex disorder likely has its origins both within and outside the hypothalamic-pituitary-ovarian axis, and metabolic, neuroendocrine, and other endocrine regulators likely contribute to its manifestation. Obesity and insulin resistance occur in about 50% of women with PCOS, and obese women have a 12% risk of having PCOS (59). PCOS has multiple physiological processes (e.g., neuroendocrine functioning and feedback mechanisms, ovarian steroidogenesis, insulin resistance, and obesity) that are regulated by hormonal and metabolic parameters. Hence, endocrine disruption by environmental chemicals may indeed contribute to the pathogenesis of PCOS. In sheep and rhesus monkeys, prenatal exposure to high levels of testosterone results in fetal programming of PCOS traits (60). Specifically, high levels of testosterone exposure at gestational d 40–60 and 100–115 result in rhesus monkey females who, in adulthood, have anovulatory infertility, hypersecretion of LH, elevated circulating levels of testosterone, neuroendocrine feedback defects, central adiposity and compensatory insulin resistance, and polycystic ovaries with ovarian hyperandrogenism and follicular arrest in adulthood (60,61). In the sheep model, a similar PCOS phenotype, along with IUGR and compensatory catch-up growth after birth, derives from prenatal exposure to exogenous testosterone (60,62). In rhesus monkey and sheep, unlike rodents, follicular differentiation is completed during fetal life. Thus, it is plausible that in utero exposure of human female fetuses to androgen-like EDCs could result in PCOS in adulthood, along with associated metabolic disorders. Very recent evidence for androgenic properties of personal-care products such as triclocarban (63) add to the possibility of environmental androgens, although a connection to PCOS has not yet been drawn. There are numerous candidate genes associated with predisposition to developing PCOS in women (57,64), and how and if these interact with prenatal androgen-like factors to promote the PCOS phenotype in women has not been determined. Nonetheless, PCOS is a debilitating disorder in women, occurring in 6.6% of the reproductive-age population (65,66,67); it is a leading cause of subfertility and is associated with increased lifetime risks for cardiovascular disease and type II diabetes (55). In addition to these clinical impacts on patients, the cost to the health care system for PCOS diagnosis and treatment is substantial, totaling in 2004 about $4.4 billion in the United States alone (68). These facts underscore the need to understand potential EDC contributions to the development of PCOS in an effort to minimize such exposures and maximize prevention. Other pathways may be involved in endocrine disruption of PCOS. Women with PCOS have higher levels of the EDC BPA (69), and increased testosterone in these women is consistent with decreased clearance of BPA (70). Although adult exposures do not necessarily imply earlier exposures in life, especially with EDCs of relatively short half-lives, there are data demonstrating nearly 5-fold higher levels of BPA in amniotic fluid compared with other body fluids, suggesting significant prenatal exposure (71). Although a cause and effect of BPA and PCOS have not been demonstrated definitively, the biological plausibility is interesting and worthy of further consideration. POF (cessation of proper ovarian function before the age of 40) occurs in about 1% of reproductive-age women (72). Although in some cases the causation is known, for the vast majority of women with POF this is not the case, and there are stages of susceptibility during organogenesis and adult exposures that could contribute to POF. Because the total ovarian follicle complement is established before birth in humans (73), anything that interferes with this, resulting in a decreased ovarian follicle resting pool, can result in POF. For example, disruption of germ cell migration from the genital ridge into the developing gonad results in ovarian dysgenesis. The resting pool undergoes a baseline level of apoptosis, and TNF-α, Fas ligand, and androgens stimulate this in the resting pool, as well as in the growing pool (74). Also, once a cohort of follicles is recruited during a given cycle in women, survival factors (FSH, estradiol, and growth factors, e.g., IGFs) are important for escape from apoptosis of the dominant follicle. Recent data in the mouse show that selective activation of the K-ras pathway in the oocyte results in rapid follicular development and depletion (75). Interestingly, adult and in utero exposures of mice to BPA have resulted in damage to oocytes (76,77). Specifically, adult exposures result in abnormalities in alignment of chromosomes on the meiotic spindle and aneuploidy, which, while not leading to ovarian senescence, does lead to aneuploid gametes and offspring (76). However, BPA given to pregnant dams during midgestation affects the developing ovary with resulting abnormalities in meiotic prophase, including synaptic defects, and mature animals exposed in utero have an increase in aneuploid oocytes and embryos (77). Such alterations also lead to cell cycle arrest and oocyte death, thus depleting the complement of normal oocytes (77). Currently, there are no data on in utero or adult exposure to BPA and aneuploidy in humans, but the possibility that there are parallels is compelling. Interestingly, mice exposed in utero to DES, between d 9–16 gestation, have a dose-dependent decrease in reproductive capacity, including decreased numbers of litters and litter size and decreased numbers of oocytes (30%) ovulated in response to gonadotropin stimulation with all oocytes degenerating in the DES-exposed group, as well as numerous reproductive tract anatomic abnormalities (78). In women with in utero exposure to DES, Hatch et al. (79) reported an earlier age of menopause between the 43–55 yr olds, and the average age of menopause was 52.2 yr in unexposed women and 51.5 yr in exposed women. The effect of DES increased with cumulative doses and was highest in a cohort of highest in utero exposure during the 1950s (79). These observations are consistent with a smaller follicle pool and fewer oocytes ovulated, as in DES-exposed mice after ovulation induction (78). Of interest are human data that demonstrate unequivocally that adult exposure in women to cigarette smoke results in decreased fecundity, decreased success rates in in vitro fertilization (IVF), decreased ovarian reserve (higher basal cycle d 3 FSH and stimulated parameters), earlier menopause by 1–4 yr, and an increased miscarriage rate (80,81). The mechanism appears to be mediated by the AhR-mediated apoptosis of oocytes, with accelerated loss of ovarian follicles. Interestingly, exposure of rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in utero and through the end of reproductive life results in a dose-dependent onset of premature reproductive senescence, likely due to direct effects on ovarian function (82). Thus, whereas POF may occur in a relatively small percentage of the population, there are several alarming signals that should not be ignored. For example, the age group with the fastest growing rate of involuntary subfertility is 15- to 24-yr-old women (83). Also, the known effects of environmental contaminants on oocyte survival, aneuploidy, decreased ovarian reserve, and infertility described above underscore how much at risk the population may be for reproductive compromise. With regard to ovarian granulosa steroidogenesis, several EDCs have effects on this process (84). For example, TCDD (10 ppm) decreases FSH-stimulated LH receptor mRNA expression and half-life in cultured granulosa (85). DDE increases vascular endothelial growth factor and IGF-I expression in luteinized granulosa from IVF patients, suggesting a contribution to impaired steroidogenesis and perhaps infertility (86). Recently, Kwintkiewicz and Giudice (87,88) have shown, in preliminary studies, that BPA decreases proliferation and FSH-induced aromatase expression via activation of peroxisome proliferator-activated receptor γ (PPAR-γ) and increases IGF-I and IGF receptor type I in human granulosa-like tumor cells and luteinized human granulosa from IVF subjects. These data suggest that EDCs may have local effects on ovarian function in adult women. Disruption of female reproductive tract development by the EDC DES is well documented (89). A characteristic T-shaped uterus, abnormal oviductal anatomy and function, and abnormal cervical anatomy are characteristic of this in utero exposure, observed in adulthood (90), as well as in female fetuses and neonates exposed in utero to DES (91). Some of these effects are believed to occur through ERα (92) and abnormal regulation of Hox genes (93,94). Clinically, an increased risk of ectopic pregnancy, preterm delivery, miscarriage, and infertility all point to the devastating effect an endocrine disruptor may have on female fertility and reproductive health (89). It is certainly plausible that other EDCs with similar actions as DES could result in some cases of unexplained infertility, ectopic pregnancies, miscarriages, and premature deliveries. Although another major health consequence of DES exposure in utero was development of rare vaginal cancer in DES daughters, this may be an extreme response to the dosage of DES or specific to pathways activated by DES itself. Other EDCs may not result in these effects, although they may contribute to the fertility and pregnancy compromises cited above. Of utmost importance clinically is the awareness of DES exposure (and perhaps other EDC exposures) and appropriate physical exam, possible colposcopy of the vagina/cervix, cervical and vaginal cytology annually, and careful monitoring for fertility potential and during pregnancy for ectopic gestation and preterm delivery (89,95). Uterine leiomyomas (fibroids) are benign smooth muscle tumors of the myometrium that can cause morbidity for women, including menorrhagia, abdominal pain, pelvic prolapse, and infertility and miscarriage (96). They are the most common tumor of the reproductive tract in women and comprise the leading cause for hysterectomy and the second leading cause of inpatient surgery in the United States, with health care costs exceeding $2 billion in 2004 (97). The prevalence rate of uterine leiomyomas is approximately 25–50%, with a preponderance occurring in African-American women (97). The greatest risk factor in adult women is prolonged exposure to unopposed estrogen. Whether in utero exposure to DES increases a woman’s lifetime risk of developing uterine fibroids is controversial, as the method to detect fibroids in two different studies influenced the outcome (98,99). Specifically, in a study of 1731 women exposed to DES and 848 matched unexposed controls, no association was found (P = 0.68) when histological confirmation after myomectomy or hysterectomy was used to document uterine fibroids (98). In contrast, when ultrasound was used to determine the presence of fibroids in DES-exposed vs. DES-unexposed women, a significant relationship was found (odds ratio, 2.4; 95% confidence interval, 1.1–5.4) in DES-exposed women and uterine fibroids (99). However, there are strong animal data to support development of uterine fibroids in adulthood after in utero exposure to EDCs, especially DES (for reviews, see Refs. 49, 50, and 52). Newbold et al. (100) reported that CD-1 mice develop uterine leiomyomas if exposed in utero or neonatally to DES, whereas unexposed mice do not. Furthermore, the Eker rat, which has a germ-line mutation in the rat homolog of the tuberus sclerosis complex 2 tumor suppressor gene, spontaneously develops uterine leiomyomas (101). The number, size, and growth rate of the fibroids increase significantly when the rat is exposed to DES on postnatal d 3–5 and 10–12, but not 17–19 (102), an effect that can be diminished with prior oophorectomy (102). These data overall strongly suggest developmental programming and gene-environment interactions for the increased risk of uterine lyomyomas in this rat model (103). In addition to mice, the Eker rat, and some dogs, the Baltic gray seal that has high organochlorine body burden also develops uterine leiomyomas (104). As with most environmental causes of abnormalities in the reproductive tract (and other tissues and organs), direct cause and effect relationships are difficult to establish. However, as in many of the other abnormalities in this Scientific Statement, the likelihood of such a relationship is plausible. Endometriosis is an estrogen-dependent gynecological disorder associated with pelvic pain and infertility. It occurs in 6–10% of women and up to 50% of women with pelvic pain and infertility. In 2002, the total health care costs estimated in the United States for diagnosis and treatment of endometriosis totaled approximately $22 billion (105). There are suggestive animal data of adult exposure to EDCs and development of or exacerbation of existing disease, and there is evidence that in utero exposure in humans to DES results in an increased relative risk = 1.9 (95% confidence interval, 1.2–2.8) (106). Most striking are the observations of rhesus monkeys administered different doses of TCDD and their subsequent development of endometriosis (107,108). Although this study had low sample size and confounding variables that brought into question the relationship between endometriosis and TCDD (49,52,109), another study revealed that adult exposure of cynomolgus monkey to TCDD promotes growth and survival of endometriosis implants (110), indicating that this EDC is involved in the progression, if not pathogenesis, of this disorder. Similar data were obtained in rodent models of endometriosis in which human endometrium is transplanted into mouse and rat peritoneum, and the established lesions grew larger when animals were exposed to TCDD in utero and as adults (111,112), underscoring the estrogen (and EDC) dependence of this disorder. There are also correlative findings of phthalate levels in plasma and endometriosis. For example, Cobellis et al. (113) found high plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis, and an association of phthalate esters with endometriosis was found among Indian women (114). Thus, the evidence is accumulating of correlations between EDCs in the circulation of women with endometriosis, although a cause-and-effect relationship has yet to be established, which is not uncommon in reproductive environmental toxicity. Endometriosis is believed to be due to retrograde menstruation and transplantation of endometrial fragments and cells into the peritoneal cavity. Because nearly all women have retrograde menstruation but relatively few have endometriosis, the disorder is also believed to involve a dysfunctional immune response, i.e., activated macrophages in the peritoneal cavity with robust secretion of inflammatory cytokines but without clearance of disease. An interesting model of early-life immune insult and developmental immunotoxicity suggests that in utero exposures to specific insults may reprogram the immune system, resulting in disorders such as chronic fatigue syndrome, cancer, and autoimmune disorders. Whether this has any relevance to the development or progression of endometriosis in adult women has not been explored but warrants further evaluation. Interestingly, TCDD and a therapy for endometriosis, danazol, both have effects on the adult immune system, although effects on the developing immune system are not known. Although the infertility associated with endometriosis for the most part can be treated with advanced reproductive technologies, less success has been achieved with treatment of endometriosis-related pain. Because the pathogenesis of the associated pain is not known with certainty, therapies are empiric and include agents directed to minimize inflammation (nonsteroidal antiinflammatory drugs, danazol), progestins and androgens (to oppose estrogen actions), GnRH analogs (to inhibit gonadotropin secretion and thus ovarian estradiol production), and aromatase inhibitors (to inhibit estradiol synthesis by the ovary and endometriotic lesions), as well as surgical ablation or excision of the disease, when possible. Most of these therapies are effective in up to 50–60% of affected women, with either intolerable side effects (e.g., profound hypoestrogenism) or recurrence of pain (e.g., after surgery) (115). Thus, prevention is key to this disorder, as is understanding the pathogenesis so that therapies for pain can be devised appropriately and administered.
Page 2Disorders of the human reproductive system possibly involving EDCs in their pathogenesis: A sexually dimorphic life cycle perspective
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Which of the following statements best expresses the relationship between the nervous system and the endocrine system?
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