EDCs: an Endocrine Society Scientific Statement

EDC-statement banner
The group of molecules identified as endocrine disruptors include synthetic estrogens used as pharmaceutical agents such as Diethylstilbestrol DES.

Abstract

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, approved The Endocrine Society, dx.doi.org/10.1210/er.2009-0002, April 17, 2009.

There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction.

In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology.

Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor ?, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use.

We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness.

Discussion (DES and Fertility-specific)

General Introduction: 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)].

Reproduction: in the adult female, the first evidence of endocrine disruption was provided almost 40 yr ago through observations of uncommon vaginal adenocarcinoma in daughters born 15–22 yr earlier to women treated with the potent synthetic estrogen DES during pregnancy. Subsequently, DES effects and mechanisms have been substantiated in animal models. Thus, robust clinical observations together with experimental data support the causal role of DES in female reproductive disorders. However, the link between disorders such as premature pubarche and EDCs is so far indirect and weak, based on epidemiological association with both IUGR and ovulatory disorders. The implications of EDCs have been proposed in other disorders of the female reproductive system, including disorders of ovulation and lactation, benign breast disease, breast cancer, endometriosis, and uterine fibroids.

In the case of DES, there are both human and experimental observations indicating heritability.

Premature ovarian failure, decreased ovarian reserve, aneuploidy, granulosa steroidogenesis: 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. In women with in utero exposure to DES, Hatch et al 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. These observations are consistent with a smaller follicle pool and fewer oocytes ovulated, as in DES-exposed mice after ovulation induction.

Reproductive tract anomalies: disruption of female reproductive tract development by the EDC DES is well documented. A characteristic T-shaped uterus, abnormal oviductal anatomy and function, and abnormal cervical anatomy are characteristic of thisin utero exposure, observed in adulthood, as well as in female fetuses and neonates exposed in utero to DES. Some of these effects are believed to occur through ER? and abnormal regulation of Hox genes. 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. 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 exposurein 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.

Endometriosis is an estrogen-dependent gynecological disorder associated with pelvic pain and infertility. 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).

Environmental estrogens effects on the prostate: DES exposure is an important model of endocrine disruption and provides proof-of-principle for exogenous estrogenic agents altering the function and pathology of various end-organs. Maternal usage of DES during pregnancy resulted in more extensive prostatic squamous metaplasia in human male offspring than observed with maternal estradiol alone. Although this prostatic metaplasia eventually resolved during postnatal life, ectasia and persistent distortion of ductal architecture remained. These findings have led to the postulation that men exposed in utero to DES may be at increased risk for prostatic disease later in life, although the limited population studies conducted to date have not identified an association. Nonetheless, several studies with DES in mouse and rat models have demonstrated significant abnormalities in the adult prostate, including increased susceptibility to adult-onset carcinogenesis after early DES exposures. It is important to note that developmental exposure to DES, as with other environmental estrogens, has been shown to exhibit a biphasic dose- response curve with regard to several end-organ responses, and this has been shown to be true for prostatic responses as well. Low-dose fetal exposure to DES or BPA (see full study) resulted in larger prostate size in adulthood compared with controls, an effect associated with increased levels of prostatic ARs. This contrasts with smaller prostate sizes, dysplasia, and aging- associated increases in carcinogenesis found after perinatal high-dose DES exposures as noted above. This differential prostatic response to low vs. high doses of DES and other EDCs must be kept in mind when evaluating human exposures to EDCs because the lack of a response at high doses may not translate into a lack of negative effects at low, environmentally relevant doses of EDCs.

Linking basic research to clinical practice: it should be clear from this Scientific Statement that there is considerable work to be done. A reconciliation of the basic experimental data with observations in humans needs to be achieved through translation in both directions, from bench to bedside and from bedside (and populations) to bench. An example of how human observation and basic research have successfully converged was provided by DES exposure in humans, which revealed that the human syndrome is faithfully replicated in rodent models. Furthermore, we now know that DES exposure in key developmental life stages can have a spectrum of effects spanning female reproduction, male reproduction, obesity, and breast cancer. It is interesting that in the case of breast cancer, an increased incidence is being reported now that the DES human cohort is reaching the age of breast cancer prevalence. The mouse model predicted this outcome 25 yr before the human data became available. In the case of reproductive cancers, the human and mouse data have since been confirmed in rats, hamsters, and monkeys. This is a compelling story from the perspective of both animal models and human exposures on the developmental basis of adult endocrine disease.

Prevention and the “precautionary principle”: although more experiments are being performed to find the hows and whys, what should be done to protect humans? The key to minimizing morbidity is preventing the disorders in the first place. However, recommendations for prevention are difficult to make because exposure to one chemical at a given time rarely reflects the current exposure history or ongoing risks of humans during development or at other life stages, and we usually do not know what exposures an individual has had in utero or in other life stages.

In the absence of direct information regarding cause and effect, the precautionary principle is critical to enhancing reproductive and endocrine health. As endocrinologists, we suggest that The Endocrine Society actively engages in lobbying for regulation seeking to decrease human exposure to the many endocrine-disrupting agents. Scientific societies should also partner to pool their intellectual resources and to increase the ranks of experts with knowledge about EDCs who can communicate to other researchers, clinicians, community advocates, and politicians.

Click to download the full study.

More DES DiEthylStilbestrol Resources

Reproductive performance of women with müllerian anomalies

uterinecongenitalanomalies
Classification of the anomalies of Müllerian duct developed by American Fertility Society (1988) and reproduced by Troiano and McCarthy.

Abstract

Reproductive performance of women with müllerian anomalies, viagra 100mg Current opinion in obstetrics & gynecology, NCBI PubMed PMID: 17495638, 2007 Jun.

PURPOSE OF REVIEW
This review discusses current diagnostic techniques for müllerian anomalies, reproductive outcome data, and management options in reproductive-age women.

RECENT FINDINGS
Multiple retrospective studies have investigated reproductive outcomes with müllerian anomalies, but few current prospective studies exist. Uterine anomalies are associated with normal and adverse reproductive outcomes such as recurrent pregnancy loss and preterm delivery, but not infertility. Furthermore, unicornuate, didelphic, bicornuate, septate, arcuate, and diethylstilbestrol-exposed uteri have their own reproductive implications and associated abnormalities. Common presentations of müllerian anomalies and current diagnostic techniques are reviewed. Surgical intervention for müllerian anomalies is indicated in women with pelvic pain, endometriosis, obstructive anomalies, recurrent pregnancy loss, and preterm delivery. Although surgery for most uterine anomalies is a major intervention, the uterine septum is preferentially managed with a hysteroscopic procedure. Several recent studies and review articles discuss management of the septate uterus in asymptomatic women, infertile women, and women with a history of poor reproductive outcomes. Current assessment of reproductive outcomes with uterine anomalies and management techniques is warranted.

SUMMARY
Müllerian anomalies, especially uterine anomalies, are associated with both normal and adverse reproductive outcomes, and management in infertile women remains controversial.

More DES DiEthylStilbestrol Resources

IVF: effect of in-utero DES exposure on human egg quality and fertilization

Factors such as aneuploidy, embryonic genome expression and ultrastructure have not been assessed in this 1999 study.

Abstract

Effect of in-utero diethylstilboestrol exposure on human oocyte quality and fertilization in a programme of in-vitro fertilization, Human reproduction (Oxford, adiposity England), NCBI PubMed PMID 10357979, 1999 Jun.
Full study: Oxford Journals, Medicine & Health Human Reproduction Volume 14, Issue 6 Pp. 1578-1581 doi: 10.1093/humrep/14.6.1578, February 15, 1999.

Genital tract abnormalities and adverse pregnancy outcome are well known in women exposed in utero to diethylstilboestrol (DES).

Data about adverse reproductive performance in women exposed to DES have been published, including controversial reports of menstrual dysfunction, poor responses after ovarian stimulation, oocyte maturation and fertilization abnormalities.

We compared oocyte quality, in-vitro fertilization results and embryo quality for women exposed in utero to DES with a control group. Between 1989 and 1996, 56 DES-exposed women who had 125 in-vitro fertilization (IVF) attempts were retrospectively compared to a control group of 45 women with tubal disease, who underwent 73 IVF attempts. Couples suffering from male infertility were excluded. The parameters compared were oocyte quality (maturation abnormalities, immature oocyte, mature oocyte), fertilization and cleavage rate (per treated and metaphase II oocytes), and embryo quality (number and grade).

We found no significant difference in oocyte maturational status, fertilization rates, cleavage rates, embryo quality and development between DES-exposed subjects and control subjects. These results suggest that in-utero exposure to DES has no significant influence on oocyte quality and fertilization ability as judged during IVF attempts.

Discussion

In the group of in-utero DES-exposed women analysed here, the prevalence of ovulatory dysfunction and endometriosis was very high, but the number and quality of oocytes retrieved after stimulation were similar to those from women not exposed to DES.

The clinical pregnancy rate (number of cycles with fetal sacs on ultrasound) per embryo transfer was not significantly different between the two groups although lower in the IVF cycles performed in DES-exposed patients. Thus, lower delivery rate could be related to other important variables such as uterine defects and endometrial morphology and thickness as previously reported.

Click to download the full study.

More DES DiEthylStilbestrol Resources

Intractable primary infertility in DES-exposed women

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

Abstract

Intractable primary infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 3712361, 1986 April.

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls.

Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls.

When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls.

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

More DES DiEthylStilbestrol Resources

Infertility in women exposed to DES in utero

fertility-test
Infertility among women exposed prenatally to DES. Image © Woman holding pregnancy test

Abstract

Infertility in women exposed to diethylstilbestrol in utero, page The Journal of reproductive medicine, NCBI PubMed PMID 6663585, 1983 Dec.

To evaluate the reproductive consequences of prenatal diethylstilbestrol (DES) exposure, 33 infertile couples were studied in whom the female had been exposed to DES in utero.

Infertility was attributed to

  • uterotubal junction obstruction in 3 couples,
  • anovulation in 7,
  • endometriosis in 11,
  • cervical obstruction in 2,
  • adnexal adhesions in 2,
  • oligospermia in 1
  • and luteal insufficiency in 3;
  • in 4 couples no cause of infertility could be identified.

No unique intraabdominal abnormalities attributable to DES exposure were observed. Four tubal pregnancies occurred in women with grossly normal oviducts. Nine of 11 women who had previously undergone surgical manipulation of the cervix (cryosurgery, cautery or conization) developed cervical stenosis, and 8 of them were found to have endometriosis.

Despite our not having an appropriate referral infertility population for comparison, these findings are consistent with the following hypotheses regarding women prenatally exposed to DES:

  1. surgical manipulation of the cervix more frequently leads to cervical stenosis and ultimately pelvic endometriosis,
  2. tubal pregnancies may occur by a mechanism unrelated to salpingitis,
  3. the spectrum of problems causing infertility is similar to that in the non-DES-exposed population.
More DES DiEthylStilbestrol Resources

Pregnancy after gamete intrafallopian transfer in a DES Daughter with primary infertility

Gamete-Intrafallopian-Tube-transfer image
This GIFT reproductive technique, tested here in 1988, may prove to be an effective treatment for some of the DES-exposed women.

Abstract

Pregnancy after gamete intrafallopian transfer in a woman with primary infertility and in utero exposure to diethylstilbestrol. A case report, The Journal of reproductive medicine, NCBI PubMed PMID: 3290479, 1988 May.

In utero exposure to diethylstilbestrol (DES) has an adverse effect on reproductive performance and may be associated with infertility.

Gamete intrafallopian transfer (GIFT) is a new reproductive technique that has been advocated as an alternative to in vitro fertilization in women with at least one normally functioning fallopian tube. The process involves the translaparoscopic placement of oocytes and sperm into the fallopian tube. The technique has been successful in treating infertility due to endometriosis, male factors and immunologic factors as well as unexplained infertility.

We accomplished the first successful GIFT procedure in a woman with significant uterine effects from prenatal DES exposure. This technique may prove to be an effective treatment for infertile women with DES exposure who have no adequate explanation for their infertility.

More DES DiEthylStilbestrol Resources

Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters

trying-to-rest
Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. trying to rest.

Abstract

Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters, American journal of obstetrics and gynecology, NCBI PubMed PMID: 7315913, 1981 Dec.

Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago.

  • A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less.
  • A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known.
  • Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001).
  • The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005).
  • An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges.
  • However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child.
  • More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group.
  • The spectrum of diseases at operation in both groups was similar.
  • Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar.
  • For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
More DES DiEthylStilbestrol Resources