Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study

Palmer, Julie R.; Herbst, Arthur L.; Noller, Kenneth L.; Boggs, Deborah A.; Troisi, Rebecca; Titus-Ernstoff, Linda; Hatch, Elizabeth E.; Wise, Lauren A.; Strohsnitter, William C.; Hoover, Robert N.

doi:10.1186/1476-069x-8-37

Cited by 137 publications

(80 citation statements)

References 24 publications

(28 reference statements)

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“…This was supported by clinical studies showing that the xenoestrogen diethylstilbestrol (DES) given to pregnant mothers in the 1940s-1970s led to a high incidence of cryptorchidism in the male children (Palmer et al 2009), as well as the key experimental study showing that DES given to pregnant mice caused bilateral cryptorchidism and a downregulation of Insl3 gene expression in the fetal testis (Emmen et al 2000b). Later studies on rats then showed that the cryptorchidism and other TDS-like effects induced in rats by administering phthalates during a critical window of testis differentiation also led to a marked downregulation of fetal Insl3 expression (McKinnell et al 2005, Mahood et al 2006.…”

Section: Fetal Insl3 and Endocrine Disruptionmentioning

confidence: 96%

Insulin-like factor 3 as a monitor of endocrine disruption

Anand‐Ivell

Ivell

2014

Reproduction

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Insulin-like factor 3 (INSL3) is generated and secreted by differentiated interstitial Leydig cells of the testes in both fetal and adult males of all mammalian species so far analyzed. All evidence to date suggests that it is produced constitutively, independently of acute regulation by the hypothalamo-pituitary-gonadal (HPG) axis, in amounts which reflect the numbers and differentiation status of the Leydig cells. This Leydig cell functional capacity is otherwise monitored only by androgen output, which, however, is massively confounded by acute regulation from the HPG axis and other factors leading to substantial and irregular short-term variation. Leydig cells are a primary target of endocrine-disrupting agents in the context of the testicular dysgenesis syndrome in the fetal male, as well as in the adult. In the male fetus, INSL3 is responsible for the first phase of testicular descent, and hence is directly linked to the etiology of cryptorchidism. In this study, by measuring INSL3 production, for example, during fetal life via amniotic fluid, or as secretions from fetal testis explants, or in adult peripheral blood, we and others have shown that INSL3 represents a useful quantitative and sensitive endpoint for assessing the impact of endocrine-disrupting agents and their mechanisms of action.Reproduction (2014) 147 R87-R95

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Section: Fetal Insl3 and Endocrine Disruptionmentioning

confidence: 96%

Insulin-like factor 3 as a monitor of endocrine disruption

Anand‐Ivell

Ivell

2014

Reproduction

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“…For example, prenatal exposure to estrogen can feminize male external genitalia in humans (16,48,49) but has little effect in mice. Such differences likely reflect differences in gestational time because humans have a relatively long period of prenatal development compared with mice and, therefore, the neonatal phase of genital development in mice is comparable with prenatal development in humans (47,50).…”

Section: Discussionmentioning

confidence: 99%

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Zheng

Armfield

Cohn

2015

Proc. Natl. Acad. Sci. U.S.A.

100

129

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Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.sexual differentiation | external genitalia | congenital malformation | androgen | hypospadias

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“…6 Mothers administered DES during pregnancy have an increased risk of breast cancer incidence 7 and mortality. 8 Sons who were exposed in utero have an increased risk of genitourinary defects 9 and a possible increase in testicular cancer. 10 The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation.…”

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confidence: 99%

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016

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NIHAlthough the basic tenet of medicine is "First, do no harm, " history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population's level of risk, the morbidity and/or mortality associated with the disease, and the intervention's efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short-and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for "routine by guest on May 10, 2018 http://pediatrics.aappublications.org/ Downloaded from PEDIATRICS Volume 138 , number s1 , November 2016 S43 prophylaxis in ALL pregnancies" and administered to women with otherwise healthy pregnancies ( Fig 1).By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, 1 showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death. 2 ) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. 3 Several months later, the Food and Drug Administrati...

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Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study

Cited by 137 publications

References 24 publications

Insulin-like factor 3 as a monitor of endocrine disruption

Insulin-like factor 3 as a monitor of endocrine disruption

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy

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