Effect of Diethylstilbestrol on Tissue Gain Merit Beef

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Birth Defects Res C Embryo Today. Writer manuscript; available in PMC 2013 Nov 5.

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PMCID: PMC3817964

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Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects

Casey E. Reed

^aNational Toxicology Programme (NTP) Laboratories Branch, Sectionalisation of the NTP, National Institute of Environmental Health Sciences, National Institutes of Wellness, Department of Health and Human Services, Research Triangle Park, NC 27709, USA

Suzanne E. Fenton

^aNational Toxicology Program (NTP) Laboratories Branch, Division of the NTP, National Institute of Environmental Health Sciences, National Institutes of Wellness, Department of Health and Human Services, Enquiry Triangle Park, NC 27709, U.s.a.

Abstract

Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to 1970s in hopes of preventing miscarriage in meaning women. Decades after, DES is known to raise breast cancer risk in exposed women, and crusade a variety of nascence related agin outcomes in their daughters such equally spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a peak compound which demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Futurity studies should focus on common target tissue pathways affected and the health of the DES grandchildren.

Keywords: diethylstilbestrol, DES, cancer, evolution, fetal basis of adult disease, chest, pregnancy

INTRODUCTION

Diethylstilbestrol (DES) is a synthetic estrogen, developed in 1938, that is estimated to be v times more potent than the naturally occurring estrogen, estradiol (Korach et al., 1978; IARC, 2012). It shares structural similarity with other xenoestrogens (Effigy 1), and is known to activate the estrogen receptor-alpha (ERα), with a like analogousness for the receptor every bit estradiol (Korach et al., 1978). DES is well absorbed in the trunk and is lipid soluble. Once in the man trunk, DES reaches elevation concentration within twenty–twoscore min, having a master half-life of iii–6 hr. It has a concluding half-life of 2–three days due to entero-hepatic apportionment, and is primarily excreted in urine (summarized in Giusti et al., 1995). DES has a brusque, biphasic half-life in dogs of approximately i hr, followed by a terminal half-life of 24 hr (Page 1991). Upon oral absorption and whole torso distribution, DES can be metabolized in all species evaluated to produce either hormonally inactive compounds (such every bit β-di-enestrol) or compounds that retain estrogenic activity (like DES-epoxide or quinone metabolites) (Korach et al., 1978; IARC, 2012), and is exclusively eliminated through biliary excretion in the feces of rats, hamsters and mice (IARC 2012).

Similarity in chemical structure of (A) the endogenous estrogen, 17-β estradiol (Korach et al., 1978), (B) the pharmaceutical, diethylstilbestrol (DES) (IARC 1974), (C) a bioactive phytoestrogen, genistein (Li et al., 2008), and (D) an estrogenic component of plastics, Bisphenol A (BPA) (Richter et al., 2007).

It is estimated that DES was prescribed to betwixt 2 and 10 million pregnant women world-wide as pills, injections, suppositories, and creams to forestall miscarriage between 1947–1971 (Harremoes et al., 2001; Rubin 2007; Newbold 2008). Few toxicological studies were done on the drug before it was produced and given to women in non-standardized doses worldwide (Harremoes et al., 2001; Rubin 2007). Although the apply of the pharmaceutical DES has been discontinued since the U.S. Nutrient and Drug Administration (FDA) advised physicians to cease prescribing the drug in 1971, the adverse wellness outcomes discovered in women who took DES, and the many reproductive bug acquired in their offspring and subsequent generations, continue to be characterized.

Latent wellness effects in DES-exposed offspring provide strong testify for report regarding the fetal basis of adult disease. The developing fetus is uniquely susceptible to latent health effects due to the several underdeveloped systems at nativity (i.e., DNA repair mechanisms, liver metabolism, claret/encephalon barrier, and immune system). Therefore, low doses of chemicals thought to be prophylactic for use in pregnant women may seriously impact the adult health of their offspring. The information on DES have shown that dose and timing of exposure may matter –cumulative dose, time since exposure, or age at diagnosis of disease are considered important variables in cohort information analyses.

The purpose of this review is to summarize the accumulated data on nascence related outcomes, cancer and endocrine related effects of DES in exposed mothers and their offspring, and to discuss electric current ideas on mechanisms of action and paths frontwards to insure that another product similar DES is never prescribed to significant women again.

DES EXPOSURE MAGNITUDE

DES was prescribed to meaning women in the kickoff trimester (typically betwixt weeks 7–8 post last menstrual wheel) to foreclose miscarriages induced by a progesterone deficiency, and later in pregnancy to forestall premature labor or to care for break-through bleeding (Smith 1948; NTP 2011). It has likewise been used to treat prostate and chest cancer, inhibit lactation and post-partum engorgement, command gynecological haemorrhage, stunt abnormal peak in girls, and every bit hormone-replacement therapy and a postal service-coital contraceptive (NTP 2011; Harris and Waring 2012). The exact number of women/fetuses prenatally-exposed to DES globe-wide is unknown (IARC 2012). The bulk of reports of DES use are from the U.South. where it is believed that betwixt the 1940s and 1970s, 5 to 10 million people either consumed DES during pregnancy or experienced in utero exposures (IARC 2012). DES use was likewise popular in Europe and Commonwealth of australia, and like the U.S., many women did not know that they were taking DES. Therefore, estimated numbers of people reporting exposure during pregnancy or in utero are around 300,000 in the United Kingdom and 200,000 in France (Harris and Waring 2012).

Total doses of DES prescribed ranged between less than 100 mg (in the majority of cases) up to 46,600 mg, with a median U.Southward. dose of 3,650 to 4,000 mg (IARC 2012). Most women started off with depression doses (i.east., five mg), that increased (upwards to 125 mg) equally symptoms or pregnancy progressed, translating to doses of about 100 μg/kg to 2 mg/kg DES per mean solar day (Hilakivi-Clarke et al., 2013). The peak employ of DES in the U.S. occurred between 1946 and 1964, whereas France, and potentially other parts of Europe, experienced a after peak – between 1966 and 1972 (Tournaire et al., 2012; Hilakivi-Clarke et al., 2013; (http://diethylstilbestrol.co.uk). Although express data is bachelor in a French accomplice, the median full dose was four,050 mg, with a 95% CI [3,000–iv,500]. This is in contrast to the "high dose cohorts" with median doses (mg) of 12,442, 8,575, and 7,550 from Chicago, Boston and California, respectively (Tournaire et al., 2012). "Low dose cohorts" besides existed in the U.S., with median doses (mg) of iii,175, 2,572, and 1,520 in Wisconsin, Texas, and Minnesota, respectively. Thus, comparison of effects based on dose may vary within the U.S. and across countries.

DES was not only used equally a human pharmaceutical, it was also used as a feed condiment for cattle, poultry, and sheep betwixt 1954 and 1979 (and peradventure later in other countries) to improve weight proceeds and produce leaner meat (Harris and Waring 2012). The high-dose (24–36 mg) subcutaneous pellets of DES were meant to last for extended periods in feedstock, and resulted in systemic release of 56–74 μg DES per day, with a one-half-life of 80–90 days (Rumsey et al., 1975). Every bit a single oral dose, DES demonstrated a much shorter biphasic half-life of 17 60 minutes and a afterwards phase of 5.5 d in cattle (Rumsey et al., 1975; IARC 2012). Therefore, DES was a contaminant in food sources for 8 or more years afterward the FDA banned its use in humans. Considering of this, information technology is unknown to what extent the full general population was exposed.

Mice and rats exposed prenatally or neonatally to DES provide first-class models for human being intrauterine exposure. Rodent models have been utilized to evaluate DES-induced infertility, chest cancer susceptibility, reproductive tract abnormalities and cancer development, every bit well as investigate the mechanisms involved in later on life disease. Murine genital tract development at nascence is similar to human fetal development at the end of the starting time trimester (Sato et al., 2004; Yamashita 2006; Ma 2009). Doses of DES given to pregnant mice or rats varied between 0.two to 12,000 μg/day, or approximately 1 μg/kg to 60 mg/kg DES per day in the rat (Hilakivi-Clarke et al., 2013), and these doses were typically oral or via subcutaneous injection in oil.

Health EFFECTS

DES is a transplacental carcinogen (a cancer-causing agent that crosses the placenta and causes reproductive cancer in offspring), a teratogen able to induce developmental defects, and an endocrine disrupting compound (EDC) that alters appropriate hormonal responses in a number of reproductive target tissues (Harremoes et al., 2001; Newbold 2008; NTP 2011; Harris and Waring 2012; IARC 2012). Cohort populations of DES-exposed individuals be in multiple countries and provide vital information on the long-reaching effects of DES. The overall risk of neoplasia in 'DES mothers' (the women who were prescribed DES handling) is low, merely in that location are numerous reproductive and structural issues institute at high frequency in gestationally exposed 'DES daughters' and 'DES sons' (Harremoes et al., 2001; Troisi et al., 2007; Newbold 2008; Palmer et al., 2009; Hoover et al., 2011; Kalfa et al., 2011; Virtanen and Adamsson 2012). Information technology is not completely articulate if a dose-response association for DES-exposed individuals and their health outcomes exists for some terminate points, but in that location is an association for timing of exposure in utero, suggesting that there is life stage susceptibility for maximal detrimental later-life health effects (Harris and Waring 2012). These long term abnormalities are primarily associated with exposure early in gestation (before gestation week eleven) and result in changes that typically do not manifest until after the onset of puberty (Newbold et al., 1990; Walker and Haven 1997; Ma 2009).

Animal models are a vital source of information as well. Animal models have confirmed human disease endpoints and more importantly predicted changes such as malformations of the oviduct and increased incidence of fibroids which were later found in DES-exposed women (Newbold 2008). Brute models exploring in utero DES exposure at doses modeling internal human exposures showed tumor risk values within the range of the calculated values for humans, giving farther credibility to using beast models and extrapolating findings to human wellness outcomes (Anderson 2004). These studies provided translational enquiry and informed policy to aid regulate the drug'due south use. DES is no longer used in significant women, making DES-exposed creature models essential in trying to predict future health issues and the mechanistic pathways that are targeted in multiple generations. These areas are worthy of more in depth discussion.

Effects in DES Mothers

DES mothers are the women who were prescribed DES in some grade during their pregnancy. A large case-control study with approximately 6,000 participants (Colton et al., 1993) reported that 20% of DES mothers vs. only 5% of historic period-adapted control women had 1 or more than miscarriages before their first term delivery, suggesting that DES mothers had reason for seeking assist in pregnancy maintenance. Although women were prescribed DES to meliorate the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous ballgame, prematurity or postmaturity, and the report suggested that DES enhanced premature labor (Dieckmann et al., 1953). Nevertheless, it continued to be used for another almost 20 years.

Numerous studies accept evaluated the possible health effects in cohorts of DES mothers. Only a slight increase of x% has been reported for overall neoplasia in DES mothers (Titus-Ernstoff et al., 2001). However, several well powered case-control studies (run into Table 1), that included evaluation of patient records, have institute that at that place is a slight, simply consistent and significant xxx–fifty% increase in risk for developing breast cancer in DES mothers, with the relative take a chance (RR) varying by model adjustments (Bibbo et al., 1978; Greenberg et al., 1984; Hadjimichael et al., 1984; Titius-Ernstoff et al., 2001; Colton et al., 1993). In a 1984 study of over 5,000 women that were seen at numerous medical institutes primarily in the northeast region of the U.S. (only including Mayo Clinic), Greenberg and co-workers (Greenberg et al., 1984) reported an adjusted RR for breast cancer of 1.47 [95% CI, 1.10–1.98], that increased farther for the oldest women in their study (30–39 year since exposure, RR=ii.5). Another well-powered follow-up study of northeast U.S. women also reported (ix years later) an adapted RR of 1.35 [95% CI, ane.05–i.74] for breast cancer in DES mothers, but did non written report an increased chance for women 30 or more years since exposure (Colton et al., 1993). Titus-Ernstoff et al. besides found a modest association with breast cancer run a risk and DES utilize during pregnancy with a RR of 1.27 [95% CI, 1.07–1.52; (Titus-Ernstoff et al., 2001)]. This study was analyzed from two combined cohorts of women and the nearly xxx% increased adventure that was observed is consistent with previous studies. Additionally, in the combined accomplice analyses, at that place was a significant increment in chest cancer gamble for women 30–39 years since exposure RR=1.52 [95%CI, 1.11–ii.07], which also happened to exist the largest grouping of women.

Table 1

Summary of breast cancer chance in women prescribed diethylstilbestrol (DES) during pregnancy. Data from numerous sources advise an increased relative risk (RR) and meaning 95% confidence interval (CI), peculiarly when historic period at diagnosis, fourth dimension since exposure, or cumulative dose are taken into consideration.

Study	Number exposed	Number unexposed	RISK (95% CI)
Bibbo et al., 1978 [thirty]	693	668	t=1.46, p=0.sixteen CT Tumor Registry as standard
Hadjimichael et al., 1984 [29]	1531	1404	RR 1.37 (0.83–2.28) RR 2.28 for dose mean 2100 mg RR 1.46 (1.07–ii.00) all cancers
Greenberg et al., 1984 [28]	2885	2816	RR one.4 (1.ane–one.9) unadjusted RR increased with fourth dimension since exposure and age at diagnosis
Colton et al., 1993 [25]	2864	2760	RR 1.35 (1.05–1.74) Reviewed obstetric records RR 1.47 (1.02–2.13) sixty+y @ diagn
Titus-Ernstoff et al., 2001 [27]	2434	2402	RR 1.27* (1.07–ane.52)

These analyses taken together advise that one in six women prescribed DES will develop breast cancer, versus one in eight women in the general population (not prescribed DES; Titus-Ernstoff et al., 2001). The increased risk, nevertheless, would non occur until at least 20 years later exposure, and equally two of the three reviewed studies study (Greenberg et al., 1984; Titus-Ernstoff et al., 2001), it would accept over 30 years post-exposure to come across the adverse effects of DES in the breast. For instance, in the women 0–9 and 10–19 years since DES exposure, there was an insignificant RR of one.0 and one.1, respectively, and in the women xx–29 and xxx–39 yr since exposure, there was increased RR of 1.six and ii.5, respectively (Greenberg et al., 1984). Similarly, the Titus-Ernstoff analyses (Titus-Ernstoff et al., 2001) demonstrated that the highest RR for breast cancer (i.52) was found once the women were 30–39 yr since exposure. These data indicate that DES may act equally a cancer initiator and a weak human carcinogen. Although a couple of earlier studies (Hoover et al., 1976; Hoover et al., 1977) suggested relative risks of endometrial and ovarian cancers amidst women who took DES, the more recent and robust cohort analyses to engagement have found no increased risk for ovarian, endometrial, or other cancers in women exposed as adults (Titus-Ernstoff et al., 2001).

Furnishings in animal research models mirrored the human furnishings of adult DES exposures, and provided additional sensitive endpoints of study. Adult oral DES exposure in experimental rodent models demonstrated mammary gland tumors in CD-1 and genetically modified mouse lines (IARC 2012). Adult, orally-exposed mice were too constitute to accept cancer of the ovary, cervix, uterus, vagina, testes, and bone, and some studies determined that life phase at exposure affected outcomes. Trivial oral exposure testing was performed on the parental generation in the rat model. The differences in health outcomes across the rodent species were pregnant and were probable due to the strain of rodent chosen for the studies. Some strains (i.e., Tg.AC) are more prone to ane type of tumor vs. another and animals were not kept until all spontaneous tumors could develop in these studies.

Furnishings in DES Daughters

A critical point in the discussion of effects in DES offspring is the fact that exposure during sensitive life stages led to a variety of permanent agin wellness outcomes in fairly large fractions of the exposed populations of both rodents and humans. These exposures were transplacental. The only example of adult exposure related to adverse outcomes was in the DES mothers, who were exposed during a period of rapid chest development (pregnancy), which is often regarded as a sensitive life stage (IBCERCC 2013). The outcome was an increased RR for breast cancer, with few other exceptions. That was not the case in the offspring.

In 1970, Herbst and Scully (Herbst and Scully 1970) reported the first conclusive evidence of vaginal articulate-prison cell adenocarcinoma (CCA) in 7 young women between the ages of 15–22. This very rare cancer is generally merely found in older women (>40 yr), and typically in squamous jail cell, not clear cell form. This finding was confirmed multiple times between 1970 and 1972 in women as young as 7 years quondam, and was consistently linked to in utero DES exposures [for review see Laronda et al., 2012]. These results led to the evolution of registries of women and men exposed to DES (5 major cohorts; DESAD – Diethylstilbestrol Adenosis Project, Women's Health Study, Mayo Clinic, Dieckmann, and Horne). The National Cancer Institute developed and funded the DES Follow-up Study, which continues to explore long-term wellness effects in over 21,000 exposed individuals in those cohorts.

DES daughters have almost a twoscore-fold increase in the risk of vaginal or cervical CCA and an estimated cumulative incidence rate of ane.6 per 1,000 (0.ii%) exposed women (Troisi et al., 2007; Hoover et al., 2011). The startling association of CCA and in utero DES exposures has led to numerous studies (in mice and humans) aimed at evaluating prenatal DES exposure of 2d generation females and the related DES-induced reproductive anomalies and malformations.

Structural abnormalities/changes

In that location are a range of agin reproductive tract abnormalities seen in DES daughters (see Table 2). Upper and lower genital tract structural changes take been documented in 25–33% of this population (Kaufman 1982). These include morphological changes in the cervix such as collars, hoods, septae, and cockscombs (Kaufman 1982; Giusti et al., 1995; Goldberg and Falcone 1999; Kaufman et al., 2000). Uterine malformations that have been diagnosed include hypoplastic cavity, T-shaped uterus, constriction bands, wide lower segment, and irregular borders (Goldberg and Falcone 1999; CDC 2012). Many of these structural changes are harmless and take no effect on development, risk of disease, or the power to excogitate. Mouse models using perinatal DES exposure have reproduced these effects and found additional reproductive tract abnormalities that include the absence of corpus luteum, hypertrophy-hyperplasia of interstitial tissues, induction of polyovular follicles in the ovary, and vaginal cornification (Newbold et al., 1998; Newbold et al., 2006; Kakuta et al., 2012).

Tabular array ii

Summary of hazard ratios for significant adverse health outcomes in women with in utero DES exposure compared to those without exposure. Reproduced from [21].

Adverse outcome	Exposed women (#/full #)	Unexposed women (#/full #)	Hazard Ratio (95% Conviction Interval)
Infertility	1144/3769	252/1654	two.37 (2.05–2.75)
Spontaneous abortion	916/2690	328/1291	i.64 (1.42–ane.88)
Ectopic pregnancy	255/2692	36/1293	3.72 (two.58–5.38)
Loss of second-trimester pregnancy	201/2692	35/1293	3.77 (2.56–five.54)
Preterm delivery	624/2385	100/1238	iv.68 (three.74–five.86)
Preeclampsia	216/2412	80/1159	1.42 (ane.07–1.89)
Stillbirth	54/2385	16/1239	two.45 (1.33–four.54)
Neonatal death	57/2383	seven/1238	8.12 (3.53–18.65)
Early menopause	181/3993	49/1682	2.35 (1.67–3.31)
Cervical intraepithelial neoplasia (CIN; class ≥ 2)	208/4120	forty/1785	2.28 (ane.59–three.27)
Breast cancer at ≥ 40 yr	61/3693	21/1647	1.82 (1.04–3.18)
Articulate-prison cell adenocarcinoma	4/4652	0/1926	∞

Other abnormalities documented in cohorts of women exposed in utero include paraovarian cysts, lesions in multiple reproductive tract tissues, beneficial vaginal adenosis, and uterine fibroids (Giusti et al., 1995; Newbold et al., 2006; Rubin 2007; CDC 2012; D'Aloisio et al., 2012). In fact, a contempo study found that in utero DES exposure was strongly associated with early onset leiomyomata (fibroids) in black women (D'Aloisio et al., 2012). It is estimated that DES daughters are more than twice as likely as unexposed women to take abnormal cellular changes in the lower reproductive tract upon cytological test (Senekjian et al., 1988). It is not clear if these aberrant cellular changes are precursors to cancer. Beneficial cervical or vaginal adenosis, a congenital bibelot of the surface epithelium, has been estimated to affect between 34–91% of DES-exposed daughters (Laronda et al., 2012), only ofttimes goes undetected. In fact, one study adamant that only 20–40% of patients with a histologically-adamant lesion had it detected in routine cytological screening. This benign lesion affecting upwards of 90% of the DES-exposed women, is also plant in a small per centum of unexposed women (4%). Adenosis is not currently thought of as a precursor to CCA, as DES exposure increases the incidence of both wellness outcomes by a similar 30–twoscore fold over the unexposed populations (Laronda et al., 2012).

Functional abnormalities

Possibly the about extensive effect of in utero DES exposure is on functional parameters of reproduction. In the largest and most recent cohort analyses, Hoover et al. determined that DES daughters accept an increased chance for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm commitment (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life (Hoover et al., 2011; Tabular array ii). Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery accept been reported in more than one report (Senekjian et al., 1988; Goldberg and Falcone 1999; Kaufman et al., 2000; Newbold et al., 2006; CDC 2012), and announced to exist exacerbated effects for which DES was prescribed to forestall.

The furnishings of prenatal DES exposure on the ability to reproduce are substantial. The gamble for infertility (defined as ≥ 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001) (Senekjian et al., 1988), and full-term infants were delivered in the first pregnancies of 84.v% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80) (Kaufman et al., 2000). The Dutch DES accomplice (Verloop et al., 2010) reports that 33% of DES daughters are nulliparous at the age of ≥ 40 yr, compared with just 17% in the Dutch population. Kaufman and co-workers (Kaufman et al., 2000) also reported that that one time pregnant, xx% of DES daughters feel preterm commitment (versus viii% of unexposed population (RR=ii.93; 95% CI, 2.23–iii.86)), their risk of ectopic pregnancy was 3 to v times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, i.54–two.sixty). These adverse pregnancy-related outcomes in DES daughters are as well experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant (Hoover et al., 2011). Also, there are strong data (Hoover et al., 2011) suggesting that the presence of vaginal epithelial changes at cohort entry exam adds to the cumulative adventure for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.

Data from mouse studies have confirmed poor reproductive outcomes and reduced fertility post-obit in utero/neonatal DES exposures in humans (McLachlan et al., 1982; Newbold et al, 1998; Newbold et al., 2006). DES-exposed female person mice had both fewer litters over their lifetime and fewer pups per litter, than unexposed controls. This effect was dose dependent. McLachlan and colleagues (McLachlan et al., 1982) also reported numerous structural/cellular reproductive tract abnormalities in mice following prenatal DES exposure, along with reduced ovarian response. A major component of the decreased fertility of DES exposed female person mice was related to a significant decrement in the number of ova recovered following induced ovulation (30% of control level).

Command of ovarian role is likewise a long-term deleterious consequence of DES in women. There is at present prove for DES effects at the offset, middle and end of ovarian cyclicity. A recent evaluation of information from the Sister Written report (information from over 33,000 women; D'Aloisio et al., 2013) indicates that prenatal DES exposure was significantly related to very early on menarche (≤ ten yr; [RR=1.56; 95% CI, 1.24–1.96]). This study also indicated that very early menarche was related to pregnancy-related hypertension, modest birth weight and existence a firstborn; risk factors which may all be linked to DES exposure and may be inter-related. Exposure to DES in utero may change menstrual function in females; another factor that may alter reproductive ability. There are reports of hirsutism and irregular catamenia in big percentages of small-scale cohorts of DES daughters, and increased serum prolactin and testosterone levels in other small cohorts of DES-exposed patients compared with controls [reviewed in Goldberg and Falcone 1999].

Multiple studies have evaluated menstrual irregularity in larger accomplice studies (Bibbo et al., 1978; Herbst et al., 1981; Barnes et al., 1984; Senekjian et al., 1988). Some analyses (Bibbo et al., 1978; Herbst et al., 1981) reported increased menstrual irregularity in DES-exposed women compared with unexposed controls, whereas other analyses (Barnes et al., 1984; Senekjian et al., 1988) found no significant departure between the exposure groups. According to one written report (Goldberg and Falcone 1999), the overall rate of menstrual irregularity, including 4 uncontrolled studies, was 32% in the 1,192 DES-exposed women and 15% in the 619 controls. The reasons for irregular period are not understood, but contributing issues may include a reduction in the duration and qualitative assessment of volume in menstrual flow, a smaller endometrial cavity area, reduction in the endometrial thickness, or hormonal dysmenorrhea in DES-exposed women (Kaufman 1982; Goldberg and Falcone 1999).

Along with irregular flow, DES daughters unremarkably undergo menopause before 45 years of age, which is earlier than the average unexposed woman (Hoover et al., 2011). Early menopause, along with early menarche, is a known take chances gene for breast cancer and other adverse health outcomes (IBCERCC 2013). In fact, in the most contempo cohort analyses (Hoover et al., 2011), DES daughters had a two–3 fold increased gamble of early on menopause, compared to unexposed, age-matched controls (RR=2.35; 95% CI, 1.67–three.31). Evaluation of data from the Sister Written report confirmed that DES-exposed women underwent menopause at 1.45 times the rate of unexposed women, which translates to about one year before than unexposed women (Steiner et al., 2010).

Cancer Incidence

The spark that caused regulators to deed on the safety of DES was not the fact that DES mothers developed breast cancer, but the early finding (Herbst and Scully 1970) of 7 cases of CCA in immature women who were prenatally exposed to DES [reveiwed in Harremoes et al., 2001]. Vii of eight cases of vaginal CCA, but none of the 32 controls, had confirmed prenatal DES exposure. It is now well established that gestational exposure to DES increases the risk of CCA (Giusti et al., 1995; Hatch et al., 1998; Troisi et al., 2007; Verloop et al., 2010; Hoover et al., 2011). Troisi and colleagues reported that approximately 1.half-dozen in every 1,000 (nearly 0.two%) of DES daughters will exist diagnosed with CCA, while the risk is almost non-existent among unexposed premenopausal women (Troisi et al., 2007). They also revealed that CCA hazard does not seem to be related to gestational historic period at exposure or DES dose. Even in the Dutch DES cohort (Verloop et al., 2010), where there are a minor percent of exposures confirmed by medical record, there is a highly significant standardized incidence ratio of 24.23 for CCA (95% CI, eight.89–52.74).

While the link between DES exposure in utero and CCA is indisputable, there is some disagreement on the risks for other cancers. Early studies suggested that at that place was no increment in risk of breast cancer in DES daughters (Hatch et al., 1998), only recent follow-up and more careful adjustment for age (since information technology takes decades for cancer to develop) take revealed consistent findings. Large accomplice studies reported that DES daughters have a significant 2-fold acme of risk for breast cancer at age 40 or older (Palmer et al., 2006; Troisi et al., 2007; Hoover et al., 2011), while women over the age of 50 may have an fifty-fifty greater risk (historic period-adjusted incidence rate ratio=3.00; 95% CI, 1.01–8.98; Palmer et al., 2006). The Dutch DES accomplice (Verloop et al., 2010) has not reported a significant effect of exposure on breast cancer risk in daughters; the most recent standardized incidence ratio of ane.94 (95% CI, 0.97–iii.57) for the lowest dose group approaches significance. It is possible that results in Europe and the U.S. will only be comparable if based on similar "dose" and time since peak apply or exposure. It has been hypothesized that DES changes the hormone profile that the fetus is exposed to, which may enhance receptor activation or increase the total number of ductal stalk cells that are at risk for boosted carcinogen insult (Palmer et al., 2006). However, the accomplice of DES daughters is however relatively young (hateful of 44 years onetime) so the link betwixt exposure and breast cancer incidence may become stronger every bit they historic period (Hoover et al., 2011).

Every bit far as all other cancers are concerned, in that location is picayune risk due to prenatal DES exposure in female offspring. Hoover et al. found an increased gamble of cervical intraepithelial neoplasia grade 2+ (CIN2+) (Hoover et al., 2011). Troisi et al. evaluated cancer hazard in the DES follow upwards study and they institute no increased risk for endometrial cancer or ovarian cancer (Troisi et al., 2007). Likewise, after following a cohort of DES daughters for 16 years, Hatch et al. constitute no correlation between DES exposure and increased hazard for 80 different types of cancer, presumably because the women were yet adequately immature at that time (Hatch et al., 1998). Farther follow-upwardly is needed.

Rodent models have found increases in the incidence of cancerous reproductive tract tumors including uterine adenocarcinoma, cervical cancer, vaginal cancer, and mammary tumors (Newbold et al., 1998; IARC 2012), in addition to many other types of abnormalities noted earlier (see Table 3). Umekita et al. treated rats neonatally with DES (1 μg to 1000 μg) and institute that the treatment significantly increased the number of terminal end buds (TEBs), the rapidly proliferating duct ends, at postnatal day 50 (Umekita et al., 2011). The early development of TEBs and the slow development of alveolar buds betoken the predisposition for an increased number of terminal ductal lobular units (TDLUs) in the breast tissue of DES daughters. The TEBs in rodents and TDLUs in humans are the principal sites for carcinogen initiation and activeness and then the earlier advent and longer life span of these structures increases the time period that carcinogens can initiate malignant growth (Umekita et al., 2011; Hilakivi-Clarke et al., 2013).

Table 3

Comparative developmental effects of prenatal exposure to DES in female offspring of humans and mice. Reproduced from [61] and updated.

Developmental event	Observed in humans	Observed in mice
Immune dysfunction	?	Yeah
Mammary tumors	Yes	Yes
Ectopic pregnancy	Yes	?
Subfertility and infertility	Yep	Yes
Uterine tumors	?	Yes
Ovarian cysts	?	Yes
Ovarian tumors	?	Yes
Elevated serum testosterone levels	Yep	?
Salpingitis isthmica nodosa of oviduct	Yes	Aye
Structural abnormalities of uterus	Yes	Yeah
Malformed cervical canal	Yes	Yes
Cervical and vaginal hood and polyps	Yep	Yeah
Vaginal adenocarcinoma	Yes	Yes
Vaginal adenosis	Yeah	Yes
Persistent vaginal cornification	?	Aye

Furnishings in DES Sons

Well-nigh of the research associated with prenatal exposure to DES has been focused on female reproductive outcomes. The studies that have been reported on male person in utero DES exposure have primarily focused on neoplasia or genital anomalies (see Tabular array 4 for summary). Genital abnormalities in DES sons are increased, and include elevated chance for non-cancerous epididymal cysts (21%–31% of exposed men versus 5%–8% of unexposed men) (Giusti et al., 1995; Palmer et al., 2009; NCI 2012. The main developmental problems that have been noted in the DES son population are cryptorchidism (undescended testicles), hypospadia (misplaced urethral opening), and microphallus (Klip et al., 2002; Palmer et al., 2009; Kalfa et al., 2011; Virtanen and Adamsson 2012). It is estimated that 15%–32% of the DES sons' population have these abnormalities versus 5%–8% of the general population (Klip et al., 2002; Newbold et al., 2006; CDC 2012). These studies are in agreement with meta-analyses that have found doubled gamble ratios for cryptorchidism and hypospadias in men exposed in utero to DES (Klip et al., 2002; Martin et al., 2008; Kalfa et al., 2011; Virtanen and Adamsson 2012). In fact, in their meta-assay of 3 large studies Martin et al (2008) written report a 3.7-fold increased risk of hypospadia following in utero DES exposure. An in-depth written report looking at the urogenital abnormalities in the DES sons accomplice found that exposure is not associated with varicocele (widening of veins along spermatic cord); structural abnormalities of the penis; urethral stenosis; beneficial prostatic hypertrophy; or inflammation/infection of the prostate, urethra, or epididymis (Palmer et al., 2009).

Table four

Comparative developmental furnishings of prenatal exposure to DES in male person offspring of humans and mice. Reproduced from [61].

Developmental consequence	Observed in humans	Observed in mice
Subfertility	Yes	Yes
Sperm abnormalities	Aye	Yes
Decreased sperm counts	Yes	Yes
Epididymal cysts	Yes	Yes
Hypoplastic and cryptorchid testes	Yes	Yes
Testicular tumors	Yes	Yep
Anatomical feminization	Yep	Aye
Microphallus	Yes	Yes
Hypospadias	Yeah	Yes
Retention of Müllerian duct remnants	Yes	Yes
Seminal vesicle tumors	?	Yes
Prostatic inflammation	Aye	Aye
Prostatic tumors	?	Yes
Immune dysfunction	?	Yes

In rodents, neonatal DES exposure causes increased thickness of the smooth muscle layer of the seminal vesicles as well equally a permanent disability of the tissue to reach and maintain a normal size (Walker et al., 2012). The seminal vesicles become refractory to androgen stimulation during adulthood and they get feminized (as indicated past expression of lactoferrin, ltf, an estrogen-responsive gene; Walker et al., 2012). These findings have not been shown in the homo population. There are too reports of DES impacting circulating hormone levels necessary for proper reproduction. In a validated assay of man, mouse, and rat Leydig cells, DES significantly decreased relative testosterone secretion in the cultures of mouse and rat, but not human Leydig cells when compared to controls (Northward'Tumba-Byn et al., 2012).

Studies regarding sexual function and fertility in DES sons are inconsistent. Some studies written report lower than average sperm density and decreased sperm counts [summarized in Guisti et al., 1995; Rubin 2007; CDC 2012], while others have seen no impairment in fertility or sexual role (Wilcox et al., 1995). In some private cases there may be decreases in fertility caused by hypospadias due to misdirected ejaculate (Klip et al., 2002).

The association between DES exposure and testicular cancer is uncertain. Some studies have shown no association while others accept institute an increased risk. The overall cancer rate for testicular cancer is increased in DES sons versus the national rate just this increase is not statistically significant (Strohsnitter et al., 2001; NCI 2012). I meta-analysis, however, found that the risk ratio for testicular cancer after DES exposure was doubled (Martin et al., 2008). This lack of consistency may be related to historic period since exposure, as was the instance for chest cancer. Ane proposed mechanism for DES-induced testicular cancer has to do with the reduction of Müllerian inhibiting hormone acquired by DES. Müllerian inhibiting hormone degrades the Müllerian ducts (the female structures) in the male fetus; even so the incomplete breakup of these structures caused by DES may become cancerous later in life (Strohsnitter et al., 2001; Newbold et al., 2006). Mouse studies accept constitute an association between DES exposure and an increased rate of rete testis cancer and prostate cancer (Newbold 1995). No human studies have constitute similar risks but these increased rates were found in older animals and the DES sons' cohort may not be old plenty to meet these effects (NCI 2012). Therefore, diligent follow up and individual screening are needed to detect early reproductive cancers.

Furnishings OF DES IN A 3^rd GENERATION

Walker and Oasis (1997) predicted that "if the high intensity of DES multigenerational carcinogenicity seen in mice is applicable to the man population, this is a health problem of major proportions." They continue to say that information technology "could take over 50 years" to detect the effects in futurity generations, due to the length of fourth dimension required for diseases such as cancer to manifest. It is predicted that cross-generational responses to DES exposure are possible due to epigenetic changes in the Deoxyribonucleic acid and that the "germ jail cell pool could have get massively contaminated". For example, early on exposure to EDCs, like DES, is thought to reprogram mouse female person reproductive tract development and touch on how the reproductive tract responds to endogenous estrogens later on in life (Ma 2009; Hilakivi-Clarke et al., 2013). They (Walker and Haven 1997) suggest that "environmental estrogens may be more potent than previously suspected, due to synergistic activity from concurrent exposures."

The studies on the cohort of men (grandsons) and women (granddaughters) whose mothers were exposed prenatally to DES (grandchildren had no direct exposure) are limited as they are just outset to reach the age when relevant wellness problems can be studied (CDC 2012). Studies that accept been performed incorporate preliminary information, as the power is low. Therefore, the primary sources of information for tertiary generation effects are rodent studies. In general, multi-generational mouse studies have shown an increased susceptibility to tumor formation in the tertiary generation which suggests that DES grandchildren are too at an increased hazard for cancer (Newbold et al., 1998; Newbold et al., 2006).

Granddaughters

Currently there are no human studies that definitively show any adverse effects of DES for the third generation of females. A small accomplice written report of 28 DES granddaughters found no abnormalities in the lower genital tract and no cases of CCA (Kaufman et al., 2002). These results led authors to conclude that tertiary generation effects were unlikely even after they acknowledged that the number of participants was also small and the women were also young for the findings to take any real significance.

Multigenerational rodent studies, as a principal source for information on the effects of DES exposure, disagree with those preliminary findings in humans. Although severe effects of DES were apparent in the first round of CD-1 mouse offspring (second generation), the tertiary generation did not exhibit the same subfertility, regardless of exposure timing or dose (Newbold et al., 1998). However, these studies have found an increased susceptibility to tumor germination in the third generation. Aged third generation female mice had increased risks for uterine cancers, benign ovarian tumors, and lymphomas (Newbold et al., 1998). One study found cervical adenocarcinomas, which are non generally seen in untreated mice, in tertiary generation females similar to those induced by directly prenatal DES exposure (DES daughters; Walker and Haven 1997). In the same report, third generation female person mice had increases in ovarian, uterine, and mammary tumors with the total number of reproductive tumors existence statistically significant from the control mice.

Grandsons

The early reports of DES grandsons show an increase in hypospadias in this population. Hypospadias occurred 20 times more ofttimes in the DES grandsons' cohort, which suggests that their mothers (DES daughters) may have had a disturbed hormonal balance during their reproductive life that interfered with the genital evolution of the male person fetus. The prevalence of hypospadias was institute to be >3% in DES grandsons but the run a risk of the defect is all the same low (Klip et al., 2002; Kalfa et al., 2011). Mouse studies in the third generation DES-exposed male population accept institute an increased susceptibility for reproductive tumor germination (Newbold 1995; Newbold et al., 1998), specifically in the testes, prostate, and seminal vesicles. No result on reproductive capacity or other deformities was seen in DES grandsons.

Gene CHANGES AND PROPOSED MECHANISMS OF Activeness

The fact that DES causes developmental changes in the second generation through gestational exposure has required evaluation of the mechanisms involved in several target tissues. DES is classified as a carcinogen by the World Health Organisation, U.South. Environmental Protection Agency, National Toxicology Programme, and the International Agency for Cancer Research. Studies on the genotoxicity of DES in humans have non revealed striking outcomes; to date, it does not modify ploidy patterns, cause specific mutations known to induce high risk of breast cancer, or induce loss of heterozygosity of allelic imbalance [reviewed in IARC 2012]. In directed in vitro tests, the information on induction of sister chromatid exchange, induction of micronuclei, and unscheduled Dna synthesis, were negative or equivocal. Notwithstanding, DES caused aneuploidy, induced adduct formation in mitochondrial Deoxyribonucleic acid, and altered the ability of microtubules to form (IARC 2012).

DES is too known to bear upon endocrine sensitive tissues and may have hereditary furnishings due to Dna modifications (IARC 2012); like many other breast cancer risk factors, it may accept multiple mechanisms of activeness, depending on the target tissue (come across Figure 2). Through molecular studies many potential mechanisms of action take been proposed amid them are different genetic and epigenetic pathways that have been implicated in the DES-induced carcinogenesis and reproductive developmental abnormalities seen in humans and animals. These effects appear to occur in specific target tissues and may be related to gene expression of the ER-α at the time of exposure (Korach et al., 1978; Newbold et al., 1990; Yamashita 2006; IARC 2012). DES may create an surroundings conducive to the development of cancer over time.

Mechanisms involved in breast cancer etiology. Numerous mechanisms are reported to be associated with increased chest cancer adventure. These mechanisms autumn into 2 main categories: DNA mediated and not-Deoxyribonucleic acid mediated. Mutagenic factors affect the Dna sequence, whereas epigenetic factors modify the DNA conformation; both atomic number 82 to heritable changes in breast cancer risk. Non-DNA mediated factors deed in a more indirect manner, causing altered inflammatory response, changes in stromal tissue, or modified hormone deportment. More than 1 mechanism may exist involved in an private'south cancer risk. Reproduced from IBCERCC Written report (2013).

In mouse models, pre-and neonatal DES exposure induces a broad range of factor expression changes that persist into adulthood (Newbold 1995; Newbold et al., 2007; LeBaron et al., 2010). Molecular mechanistic studies accept shown that many of the changes acquired past DES, including structural and cellular abnormalities, are caused by altered programming of hox and wnt genes which play roles in reproductive tract differentiation (Newbold et al., 2006; Newbold 2008). DES potentially inhibits the expression of wnt7a, hoxa10, and hoxa11 during critical periods of reproductive tract development (Yamashita 2006; Ma 2009). Changes in hox factor expression accept led to abnormalities in tissues that depend on their expression for normal developmental signaling (Newbold et al., 2007; Bromer et al., 2009). Down regulation of hoxa11 (which is found in the stroma and epithelial cells of the uterus) may be partly responsible for DES-induced uterine malformations, every bit like malformations are seen in hoxa11-nil mice (Yamashita 2006). Hoxa10 (which is expressed in the uterine horns) controls uterine organogenesis and its expression is increased in cultured human endometrial cells but repressed in mice later in utero exposure to DES (Newbold et al., 2007; Bromer et al., 2009). Female mice exposed to DES in utero had aberrant methylation in the promoter and intron of hoxa10, which persisted into adulthood (Bromer et al., 2009).

Genetic modifications by DES take besides been implicated in the initiation and progression of neoplasms and cancer. Neonatal DES exposure in mice can reprogram uterine differentiation past changing genetic pathways controlling uterine morphogenesis and/or altering gene expression in stalk cells (Newbold 1995; Sato et al., 2004; Ma 2009). DES affects the methylation patterns of genes that are associated with proliferation (c-jun, c-fos, c-myc, ltf); genes associated with apoptosis (bcl-2, bcl-x); and growth factors associated with proliferation and differentiation (EGF, TGF-α) (Sato et al., 2004; Newbold 2006; LeBaron et al., 2010). This alter in methylation is referred to as estrogen imprinting (Yamashita 2006). Estrogen imprinting is an epigenetic mechanism where early on-life exposure to estrogens (i.eastward., DES, Bisphenol A) permanently alters Dna methylation and gene expression of estrogen-responsive genes. Once changed, the altered gene profiles tin proceed to be expressed without further hormonal stimulation.

Proto-oncogenes assistance regulate normal cell proliferation and differentiation. When these genes are changed through mutation or methylation they can crusade neoplastic jail cell transformation. Studies have shown changes in patterns of expression of estrogen-related proto-oncogenes in the genital tract of female mice exposed to DES (Yamashita 2006). Changes in the proto-oncogenes and growth factors that cause elevations in their expression are associated with increased proliferation in the tissues (similar the uterus and vagina) which can lead to cancer (Newbold et al., 2007; Ma 2009). Genetic modifications of the apoptotic genes that cause decreases in apoptosis are also associated with an increased incidence of cancer (Newbold 1995; Sato et al., 2004; Ma 2009).

DES treatment affects male mice at the genomic level. DES altered Insl3 mRNA expression in male mice exposed in utero (Emmen et al., 2000). Emmen et al. establish a threefold decrease in Insl3 mRNA, which is expressed in fetal Leydig cells and is associated with the transabdominal stage of testis descent and development of the gubernaculum (Emmen et al., 2000). This finding may provide a mechanism for DES-induced cryptorchidism. Another group found that gestational DES exposure in C57Bl/6 mice decreased the expression of two transcription factors (GATA4 and ID2) in the testes of adult males (LaRocca et al., 2011). GATA4 (expressed in Sertoli cells, Leydig cells, and other testicular somatic cells) is required for the correct expression of Sry and all the steps in testicular organogenesis that follow (LaRocca et al., 2011). ID2 is associated with the inhibition of differentiation of different cell types, and the decrease in GATA4 and ID2 may exist associated with fertility issues later in life.

The research into tissue-specific mechanisms of activeness for DES is still underway. There are other unique attributes of DES that likely lead to its long-term effects post-obit brief periods of exposure. A written report of metabolism and disposition of DES in the pregnant rat, demonstrated enhanced disposition of DES and DES oxidative metabolites to the fetal reproductive tissues vs. liver following a single maternal exposure (Miller et al., 1982). Studies in mice demonstrate an accumulation of DES in the fetal reproductive tract, where information technology can reach levels iii times higher than fetal blood (IARC 2012). These findings of accumulated DES in reproductive tissues relate specifically to the location of ER-α, the known receptor for DES (Korach et al., 1978). The fact that in that location are multiple metabolic DES products has complicated the understanding of its furnishings. DES metabolites (especially quinines) are reactive [reviewed in IARC 2012]; they are formed in vivo, demark DNA and have been found in mammary tissue of rat, adult mouse reproductive tract, and mouse fetal tissues. These oxidative metabolites touch on CYP gene activation and likely play a role in cancer mediation.

DES is no longer used in the homo population which makes research less of a priority for funding organizations. Even so, for individuals/families already exposed, DES seems to be an initiating issue in an initiation/promotion model for hormonal carcinogenesis (Newbold et al., 2007) and in that location is ample reason to fund research on effects in their unexposed children. Therefore, thoughtful follow-up of all generations and justified/planned use of stored samples (blood) will be disquisitional in the futurity to make up one's mind those at highest risk for adverse health consequences.

SUMMARY

The legacy of the agin effects that stem from DES assistants to pregnant women in the 1950s to 1970s has not completely formed. The male person and female person offspring of those women take reported significant fertility, cancer, and birth-related outcomes, but the cancer outcomes are not completely understood, with few exceptions (CCA and breast cancer in women over 40 yr sometime). Information on DES mothers and daughters, in addition to substantial animal data, earned DES a place in the First Annual Report on Carcinogens, a critical review of carcinogenic compounds produced by the National Toxicology Program, in 1980 and was noted by the International Agency for Research on Cancer in their Monographs (IARC 1974). As the male person and female person offspring of those women age, the overall effect of DES on reproductive cancers will exist better understood. Fifty-fifty more important to sympathize is the potential issue of this endocrine disruptor and carcinogen on the 3rd generation offspring who were not direct exposed, just may be affected in a heritable fashion through estrogen reprogramming and DNA modification. Further inquiry is needed to point the mechanisms of activeness on the target tissues, so that future pharmaceuticals/ecology estrogen mimics will avoid these pathways, leading to healthier future generations.

​

Highlights

1. DES is both an endocrine disruptor and human carcinogen

2. In utero exposure acquired increased birth-related outcomes in DES daughters

3. DES increased the risk of breast cancer in mothers and daughters

4. Exposure period and dose decide extent of many health effects

Abbreviations

CCA	articulate-cell adenocarcinoma
CI	confidence interval
DES	diethylstilbestrol
EDC	endocrine disrupting compound
ERα	estrogen receptor-alpha
FDA	U.S. Nutrient and Drug Administration
RR	relative risk
TDLU	last ductal lobular units
TEB	last stop buds

Footnotes

Disclaimer: This article is the work of National Institutes of Health (NIH) employees. However, the statements, opinions and conclusions contained herein represent those of the authors and not the NIH or the United States government.

References

• Anderson LM. Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol. 2004;199:162–74. [PubMed] [Google Scholar]
• Barnes AB. Menstrual history and fecundity of women exposed and unexposed in utero to diethylstilbestrol. J Reprod Med. 1984;29:651–5. [PubMed] [Google Scholar]
• Bibbo G, Haenszel WM, Wied GL, Husband K, Herbst AL. A 20-five-year follow-up report of women exposed to diethylstilbestrol during pregnancy. North Engl J Med. 1978;298:763–7. [PubMed] [Google Scholar]
• Bromer JG, Wu J, Zhou Y, Taylor HS. Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic machinery for altered developmental programming. Endocrinology. 2009;150:3376–82. [PMC complimentary article] [PubMed] [Google Scholar]
• CDC. Center for Disease Control and Prevention. DES Update: Consumers. 2012 http://www.cdc.gov/des/consumers/alphabetize.html.
• Colton T, Greenberg ER, Noller 1000, Resseguie L, Van Bennekom C, Heeren T, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Farther follow-up. JAMA. 1993;269:2096–100. [PubMed] [Google Scholar]
• D'Aloisio AA, Baird DD, DeRoo LA, Sandler DP. Early on-life exposures and early-onset uterine leiomyomata in blackness women in the Sis Study. Environ Health Perspect. 2012;120:406–12. [PMC gratuitous commodity] [PubMed] [Google Scholar]
• D'Aloisio AA, Deroo LA, Baird DD, Weinberg CR, Sandler DP. Prenatal and babe exposures and age at menarche. Epidemiology. 2013;24:277–84. [PMC costless article] [PubMed] [Google Scholar]
• Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Amer J Obstet Gynecol. 1953;66:1062–81. [PubMed] [Google Scholar]
• Emmen JM, McLuskey A, Adham IM, Engel W, Verhoef-Post M, Themmen AP, et al. Interest of insulin-like cistron 3 (Insl3) in diethylstilbestrol-induced cryptorchidism. Endocrinology. 2000;141:846–9. [PubMed] [Google Scholar]
• Giusti RM, Iwamoto Grand, Hatch EE. Diethylstilbestrol revisited: a review of the long-term health furnishings. Ann Intern Med. 1995;122:778–88. [PubMed] [Google Scholar]
• Goldberg JM, Falcone T. Effect of diethylstilbestrol on reproductive function. Fertil Steril. 1999;72:one–7. [PubMed] [Google Scholar]
• Greenberg ER, Barnes AB, Resseguie Fifty, Barrett JA, Burnside Due south, Lanza LL, et al. Breast cancer in mothers given diethylstilbestrol in pregnancy. N Engl J Med. 1984;311:1393–eight. [PubMed] [Google Scholar]
• Hadjimichael OC, Meigs JW, Falcier FW, Thompson WD, Flannery JT. Cancer risk among women exposed to exogenous estrogens during pregnancy. J Nat Cancer Inst. 1984;73:831–4. [PubMed] [Google Scholar]
• Harremoes P, Gee D, MacGarvin M, Stirling A, Keys J, Wynne B, et al. Environmental issue report no. 22. Chapter eight. Copenhagen: Official Publications of the European Communities; 2001. Late lessons from early warnings: the precautionary principle 1896–2000. European Environment Bureau. http://www.eea.europa.eu/publications/environmental_issue_report_2001_22. [Google Scholar]
• Harris RM, Waring RH. Diethylstilboestrol--a long-term legacy. Maturitas. 2012;72:108–12. [PubMed] [Google Scholar]
• Hatch EE, Palmer JR, Titus-Ernstoff L, Noller KL, Kaufman RH, Mittendorf R, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA. 1998;280:630–iv. [PubMed] [Google Scholar]
• Herbst AL, Married man MM, Azizi F, Makii MM. Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters. Am J Obstet Gynecol. 1981;141:1019–28. [PubMed] [Google Scholar]
• Herbst AL, Scully RE. Adenocarcinoma of th evagina in boyhood. A report of 7 cases including 6 articulate-prison cell carcinomas (so-called mesonephromas) Cancer. 1970;25:745–757. [PubMed] [Google Scholar]
• Hilakivi-Clarke L, de Assis S, Warri A. Exposures to synthetic estrogens at different times during the life, and their event on breast cancer risk. J Mammary Gland Biol Neoplasia. 2013;eighteen:25–42. [PMC complimentary commodity] [PubMed] [Google Scholar]
• Hoover R, Fraumeni JF, Jr, Everson R, Myers MH. Cancer of the uterine corpus after hormonal treatment for breast cancer. Lancet. 1976;307:885–887. [PubMed] [Google Scholar]
• Hoover R, Gray LA, Fraumeni JF., Jr Stilbestrol (Diethylstilbestrol) and the take chances of ovarian cancer. Lancet. 1977;2:533–534. [PubMed] [Google Scholar]
• Hoover RN, Hyer M, Pfeiffer RM, Adam E, Bond B, Cheville AL, et al. Agin health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med. 2011;365:1304–14. [PubMed] [Google Scholar]
• IARC. Diethylstilbestrol (stilboestrol). IARC Monographs on the Evaluation of Carcinogenic Gamble of Chemicals to Humans. Lyon, France: International Agency for Research on Cancer; 1974. pp. 55–76. [Google Scholar]
• IARC. International Agency for Enquiry on Cancer. Pharmaceuticals. Diethylstilbestrol. A review of human being carcinogens. IARC Monogr Eval Carcinog Risks Hum. 2012;100A:175–218. [Google Scholar]
• IBCERCC; Inter-bureau Breast Cancer and the Environment Enquiry Coordinating Committee. Dept of Wellness and Human being Services. Breast Cancer and the Environment: Prioritizing Prevention. 2013 http://world wide web.niehs.nih.gov/nigh/avails/docs/ibcercc_full_508.pdf.
• Kakuta H, Tanaka M, Chambon P, Watanabe H, Iguchi T, Sato T. Involvement of gonadotropins in the induction of hypertrophy-hyperplasia in the interstitial tissues of ovaries in neonatally diethylstilbestrol-treated mice. Reprod Toxicol. 2012;33:35–44. [PubMed] [Google Scholar]
• Kalfa North, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertil Steril. 2011;95:2574–seven. [PubMed] [Google Scholar]
• Kaufman RH, Adam E, Hatch EE, Noller K, Herbst AL, Palmer JR, et al. Continued follow-upwards of pregnancy outcomes in diethylstilbestrol-exposed offspring. Obstet Gynecol. 2000;96:483–9. [PubMed] [Google Scholar]
• Kaufman RH, Adam E. Findings in female offspring of women exposed in utero to diethylstilbestrol. Obstet Gynecol. 2002;99:197–200. [PubMed] [Google Scholar]
• Kaufman RH. Structural changes of the genital tract associated with in utero exposure to diethylstilbestrol. Obstet Gynecol Ann. 1982;11:187–202. [PubMed] [Google Scholar]
• Klip H, Verloop J, van Gool JD, Koster ME, Burger CW, van Leeuwen Atomic number 26. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet. 2002;359:1102–7. [PubMed] [Google Scholar]
• Korach KS, Metzler M, McLachlan JA. Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs. Proc Natl Acad Sciences Usa. 1978;75:468–71. [PMC free article] [PubMed] [Google Scholar]
• LaRocca J, Boyajian A, Brownish C, Smith SD, Hixon Yard. Effects of in utero exposure to Bisphenol A or diethylstilbestrol on the adult male person reproductive system. Birth Defects Res B Dev Reprod Toxicol. 2011;92:526–33. [PMC costless commodity] [PubMed] [Google Scholar]
• Laronda MM, Unno K, Butler LM, Kurita T. The evolution of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero. Differentiation. 2012;84:252–60. [PMC gratis article] [PubMed] [Google Scholar]
• LeBaron MJ, Rasoulpour RJ, Klapacz J, Ellis-Hutchings RG, Hollnagel HM, Gollapudi BB. Epigenetics and chemic safety assessment. Mutat Res. 2010;705:83–95. [PubMed] [Google Scholar]
• Li HQ, Xue JY, Shi L, Gui SY, Zhu HL. Synthesis, crystal structure and antimicrobial action of deoxybenzoin derivatives from genistein. Eur J Med Chem. 2008;43:662–7. [PubMed] [Google Scholar]
• Ma L. Endocrine disruptors in female reproductive tract evolution and carcinogenesis. Trends Endocrinol Metab. 2009;20:357–63. [PMC free article] [PubMed] [Google Scholar]
• Martin O, Shialis T, Lester J, Scrimshaw 1000, Boobis A, Voulvoulis Northward. Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-assay. Cien Saude Colet. 2008;13:1601–18. [PubMed] [Google Scholar]
• McLachlan JA, Newbold RR, Shah HC, Hogan Doctor, Dixon RL. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES) Fertil Steril. 1982;38:364–71. [PubMed] [Google Scholar]
• Miller RK, Heckmann ME, McKenzie RC. Diethylstilbestrol: placental transfer, metabolism, covalent binding and fetal distribution in the Wistar rat. J Pharmacol Exp Ther. 1982;220:358–65. [PubMed] [Google Scholar]
• NCI. National Cancer Found. Clinician Data: DES Sons - Men Exposed in Utero. 2012 http://www.cancer.gov/cancertopics/causes/des/sons-exposed-to-des.
• Newbold R. Cellular and molecular furnishings of developmental exposure to diethylstilbestrol: implications for other ecology estrogesn. Environ Health Perspect. 1995;103(Suppl vii):83–7. [PMC gratuitous article] [PubMed] [Google Scholar]
• Newbold RR. Prenatal exposure to diethylstilbestrol (DES) Fertil Steril. 2008;89:e55–6. [PubMed] [Google Scholar]
• Newbold RR, Bullock BC, McLachlan JA. Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis. Cancer Res. 1990;50:7677–81. [PubMed] [Google Scholar]
• Newbold RR, Hanson RB, Jefferson WN, Bullock BC, Haseman J, McLachlan JA. Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis. 1998;nineteen:1655–63. [PubMed] [Google Scholar]
• Newbold RR, Jefferson WN, Grissom SF, Padilla-Banks Eastward, Snyder RJ, Lobenhofer EK. Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life. Mol Carcinog. 2007;46:783–96. [PMC complimentary article] [PubMed] [Google Scholar]
• Newbold RR, Padilla-Banks Due east, Jefferson WN. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology. 2006;147:S11–7. [PubMed] [Google Scholar]
• NTP National Toxicology Program. Diethylstilbestrol. 12th Written report on Carcinogens. 2011;12:159–61. [PubMed] [Google Scholar]
• N'Tumba-Byn T, Moison D, Lacroix K, Lecureuil C, Lesage L, Prud'homme SM, et al. Differential effects of bisphenol A and diethylstilbestrol on human, rat and mouse fetal leydig jail cell function. PLoS One. 2012;7:e51579. [PMC free commodity] [PubMed] [Google Scholar]
• Page SW. Diethylstilboestrol--clinical pharmacology and alternatives in small animal practise. Aust Vet J. 1991;68:226–30. [PubMed] [Google Scholar]
• Palmer JR, Herbst AL, Noller KL, Boggs DA, Troisi R, Titus-Ernstoff L, et al. Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study. Environ Wellness. 2009;viii:37. [PMC gratuitous article] [PubMed] [Google Scholar]
• Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, et al. Prenatal diethylstilbestrol exposure and run a risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;xv:1509–14. [PubMed] [Google Scholar]
• Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007;24:199–224. [PMC free article] [PubMed] [Google Scholar]
• Rubin MM. Antenatal exposure to DES: lessons learned…time to come concerns. Obstet Gynecol Surv. 2007;62:548–55. [PubMed] [Google Scholar]
• Rumsey TS, Oltjen RR, Kozak Equally, Daniels FL, Aschbacher PW. Fate of radiocarbon in beefiness steers implanted with 14C-diethylstilbestrol. J Anim Sci. 1975;xl:550–60. [PubMed] [Google Scholar]
• Sato T, Fukazawa Y, Ohta Y, Iguchi T. Interest of growth factors in induction of persistent proliferation of vaginal epithelium of mice exposed neonatally to diethylstilbestrol. Reprod Toxicol. 2004;19:43–51. [PubMed] [Google Scholar]
• Senekjian EK, Potkul RK, Frey K, Herbst AL. Infertility amidst daughters either exposed or not exposed to diethylstilbestrol. Am J Obstet Gynecol. 1988;158:493–8. [PubMed] [Google Scholar]
• Smith OW. Diethylstilbestrol in the prevention and handling of complications of pregnancy. Amer J Obstet Gynecol. 1948;56:821–34. [PubMed] [Google Scholar]
• Steiner AZ, D'Aloisio AA, DeRoo LA, Sandler DP, Baird DD. Association of intrauterine and early on-life exposures with age at menopause in the Sister Report. Am J Epidemiol. 2010;172:140–eight. [PMC free article] [PubMed] [Google Scholar]
• Strohsnitter WC, Noller KL, Hoover RN, Robboy SJ, Palmer JR, Titus-Ernstoff L, et al. Cancer adventure in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001;93:545–51. [PubMed] [Google Scholar]
• Titus-Ernstoff L, Hatch EE, Hoover RN, Palmer J, Greenberg ER, Ricker W, et al. Long-term cancer chance in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer. 2001;84:126–33. [PMC costless article] [PubMed] [Google Scholar]
• Tournaire M, Devouche E, Epelboin S, Cabau A. Diethylstilbestrol exposure: evaluation of the doses received in France. Eur J Epidemiol. 2012;27:315–6. [PubMed] [Google Scholar]
• Troisi R, Hatch EE, Titus-Ernstoff L, Hyer M, Palmer JR, Robboy SJ, et al. Cancer take a chance in women prenatally exposed to diethylstilbestrol. Int J Cancer. 2007;121:356–60. [PubMed] [Google Scholar]
• Umekita Y, Souda M, Hatanaka K, Hamada T, Yoshioka T, Kawaguchi H, et al. Cistron expression profile of terminal terminate buds in rat mammary glands exposed to diethylstilbestrol in neonatal catamenia. Toxicol Lett. 2011;205:15–25. [PubMed] [Google Scholar]
• Verloop J, van Leeuwen Iron, Helmerhorst TJ, van Boven HH, Rookus MA. Cancer gamble in DES daughters. Cancer Causes Control. 2010;21:999–1007. [PMC free article] [PubMed] [Google Scholar]
• Virtanen HE, Adamsson A. Cryptorchidism and endocrine disrupting chemicals. Mol Cell Endocrinol. 2012;355:208–20. [PubMed] [Google Scholar]
• Walker Exist, Oasis MI. Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis. 1997;xviii:791–three. [PubMed] [Google Scholar]
• Walker VR, Jefferson WN, Couse JF, Korach KS. Estrogen receptor-alpha mediates diethylstilbestrol-induced feminization of the seminal vesicle in male person mice. Environ Health Perspect. 2012;120:560–five. [PMC gratuitous commodity] [PubMed] [Google Scholar]
• Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, Herbst AL. Fertility in men exposed prenatally to diethylstilbestrol. Northward Engl J Med. 1995;332:1411–6. [PubMed] [Google Scholar]
• Yamashita Southward. Expression of estrogen-regulated genes during development in the mouse uterus exposed to diethylstilbestrol neonatally. Curr Pharm Des. 2006;12:1505–20. [PubMed] [Google Scholar]

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817964/

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