1991 DES Case: Enright v. Eli Lilly & Co.

AbstractS

The question in this case is whether the liability of manufacturers of the drug diethylstilbestrol (DES) should extend to a so-called “third generation” plaintiff, the granddaughter of a woman who ingested the drug. According to the allegations of the complaint, the infant plaintiff’s injuries were caused by her premature birth, which in turn resulted from damage to her mother’s reproductive system caused by the mother’s in utero exposure to DES.” …

ENRIGHT v. ELI LILLY & CO., Leagle, 1990219155AD2d64_1211, March 22, 1990.

… ‘The Legislature and this Court have both expressed concern for the victims of this tragedy by removing legal barriers to their tort recovery — barriers which may have had their place in other contexts, but which in DES litigation worked a peculiar injustice because of the ways in which DES was developed, marketed and sold and because of the insidious nature of its harm.

For example, prior to 1986, the long-standing rule in this State was that a cause of action for personal injuries caused by a toxic substance accrued and the limitations period began to run upon exposure to the substance (see Fleishman v Lilly & Co.). The Legislature, recognizing that under this rule claims for injuries caused by exposure to DES and other toxic substances were often time barred before the harmful effects of the exposure could be discovered, changed the law to provide that the limitations period in exposure cases begins to run upon discovery of the injury At the same time, the Legislature revived for one year previously time-barred causes of action based on exposure to DES and four other toxic substances.

More recently, this Court responded to the fact that — for a variety of reasons unique to the DES litigation context — a DES plaintiff generally finds it impossible to identify the manufacturer of the drug that caused her injuries. We held that liability could be imposed upon DES manufacturers in accordance with their share of the national DES market, notwithstanding the plaintiff’s inability to identify the manufacturer particularly at fault for her injuries (see Hymowitz v Lilly & Co.).

In the present case, we are asked to do something significantly different. We are asked, not to remove some barrier to recovery that presents unique problems in DES cases, but to recognize a cause of action not available in other contexts simply (or at least largely) because this is a DES case.”…

” … the mother’s injuries in this case were caused by exposure to DES instead of by medical malpractice. A different rule is justified, therefore, only if that distinction alters the policy balance we struck in Albala.

The primary thrust of plaintiffs’ argument and the Appellate Division’s decision is that DES itself alters that balance. From the Legislature’s actions in modifying the applicable Statute of Limitations and reviving time-barred DES cases and from our adoption of a market-share liability theory in Hymowitz, plaintiffs perceive a public policy favoring a remedy for DES-caused injuries sufficient to overcome the countervailing policy considerations we identified in Albala. The implication, of course, is that the public interest in providing a remedy for those injured by DES is stronger than the public interest in providing a remedy for those injured by other means — medical malpractice, for example. We do not believe that such a preference has been established.

To be sure, recent developments demonstrate legislative and judicial solicitude for the victims of DES, but they do not establish DES plaintiffs as a favored class for whose benefit all traditional limitations on tort liability must give way. To the extent that special rules have been fashioned, they are a response to unique procedural barriers and problems of proof peculiar to DES litigation.

For example, the Legislature’s enactment of a “discovery” Statute of Limitations was directed at opening up traditional avenues of recovery by removing a procedural barrier that was unreasonable given the nature of DES injuries. Nothing in the legislation suggests that the Legislature intended to expand the basis for liability. Indeed, the language of the statute suggests the opposite conclusion. The discovery rule applies in cases of injury caused by “the latent effects of exposure to any substance * * * upon or within the body”. Exposure is defined as “direct or indirect exposure by absorption, contact, ingestion, inhalation or injection”. Implicit in this language is the notion that “some contact with the substance is essential to a cause of action”, an element lacking here. …

… “I am convinced that existing legal doctrine and established policy point unequivocally to a decision upholding Karen Enright’s cause of action. Let us assume for the sake of argument, however, that this is not so and that the appeal presents a “hard case” where there are no clearly discernible legal or policy guidelines. On this assumption, is there any underlying principled reason in fairness, justice or moral doctrine why Karen Enright’s claim should be turned away?

There are two fundamental principles of justice, however, which dictate that Karen Enright should be permitted to prove her case.

First, Karen Enright is a victim of what — if the allegations of her complaint are proven — amounts to a wrong of enormous proportions which inflicted grievous injuries on her and countless other innocent persons. Unless her case is barred on some legal or policy ground, she should be justly compensated for her injuries to the extent that our judicial system can accomplish this.

Second, she is damaged no less than other victims of DES who make up the class. If they are permitted to recover, so should she be. To say that Karen Enright cannot recover is to abrogate one of the most basic of all principles — that “like cases should be treated alike.”…

… Read the full paper ENRIGHT v. ELI LILLY & CO., on Leagle.

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1990 DES Case: Sorrells v. Eli Lilly & Company

Abstract

Plaintiff, Susan Sorrells, claims that she and her infant daughter Shanna were injured due to her mother’s ingestion of the drug diethylstilbestrol (“DES”) in 1951-1952 when she was pregnant with Susan..

Susan’s daughter, Shanna, was not exposed to DES in any way, but claims that her grandmother’s use of DES affected her mother’s ability to carry her to term, thus causing Shanna’s profound hearing loss and other injuries.

SORRELLS v. ELI LILLY AND COMPANY, Leagle, 19901415737FSupp678_11285, United States District Court, District of Columbia, May 24, 1990.

At bar is defendant’s motion to dismiss all of Shanna’s individual claims of negligence and strict liability on the grounds that Lilly owed no foreseeable duty to Shanna and plaintiff’s motion for certification of the issue to the Maryland Court of Appeals.. ” …

… continue reading SORRELLS v. ELI LILLY AND COMPANY on Leagle.

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Medicine and the Law : First DES third-generation injury claim, 1991

On Feb 19, 1991, the New York Court of Appeals rejected the right to claim for a third-generation injury resulting from ingestion of diethylstilboestrol (DES) during pregnancy. The plaintiff was a 9-year-old girl with cerebral palsy. Her grandmother had taken DES during pregnancy in 1959, and her mother (born in 1960) had deformities in her reproductive system which, it was claimed, led to premature birth and neurological injuries in the third generation.

Medicine and the Law Diethylstilboestrol: third-generation injury claims, sciencedirect, Feb 19,1991.

DES was marketed for about 30 years in the belief that it reduced the risk of miscarriage. Over two hundred firms manufactured it, and it was widely prescribed in the Netherlands and USA. In 1971 it was “banned” by the US Food and Drug Administration (FDA) because of evidence of an abnormal incidence of vaginal and cervical cancer in the daughters of women who had taken DES during pregnancy. There were also adverse effects in male children.

… the daughters reached puberty at the earliest. Another problem has been to identify which manufacturer produced the brand of DES that each woman took. Furthermore, records have been destroyed or lost, manufacturers have closed down, prescribers have retired or died, and memories have faded. Early claims named the FDA as co-defendants but all claims against the Administration were dismissed.

One approach was the “concerted action petition”, which aimed to identify all distributors who participated in the “common purpose” of supplying DES to a particular area in which the plaintiffs mother had lived at the time of ingestion. This ploy was seldom successful, but in Michigan and New York courts ruled that the manufacturer’s marketing strategy showed evidence of conscious parallel strategies, and two cases did succeed. An attempt to shift the burden of proof on to a defendant, so that a manufacturer would have to establish his innocence, failed. The courts ruled that it would be unjust to find a firm guilty of dispensing an unsafe product when that individual manufacturer was merely one of a group whose identity was doubted. In California in 1980 plaintiffs were allowed to sue, on the basis of market share, all DES manufacturers who had supplied the drug to a particular area. This approach, though much criticised, has been the model for the later cases in which the plaintiff has been able to prove the manufacturer’s failure to test the safety of the drug or to warn the users of potential harm.

The claims for third-generation injuries by about 100 “DES granddaughters” marks a new stage in the battle for compensation. They allege that maternal uterine hypoplasia, cervical stenosis, and/or endometriosis caused by their mothers’ exposure to DES ingestion while in utero are responsible for their own congenital deformities. They also claim for large sums to compensate for anxiety over the increased risk of clear-cell adenocarcinomas. In most cases, thirty years or more have elapsed since the original DES ingestion, and such cases would normally be well outside time limits for bringing a suit. Even under the Consumer Protection Act 1987, which is not retrospective and which came into force in Britain on March 1, 1988, there is a maximum time limit of ten years in which claims may be brought. Beyond that, the plaintiff must pursue a claim in negligence in the normal way, if not time barred.

By a majority of 6 to 1, the New York Court of Appeals rejected in principle the right to pursue a third-generation DES injury claim.

Giving the judgment of the majority, Chief Judge Sol Wachtler said:

“For all we know, the rippling effects of DES exposure may extend for generations. It is our duty to confine liability within manageable limits. Limiting liability to those who ingested the drug or who were exposed to it in utero serves this purpose.”

Judge Stewart F. Hancock Jr, dissenting, argued that the girl

“should have the same right to sue the drug makers for her injuries as her mother… she is one of a class of thousands of persons who have allegedly suffered devastating abnormalities and injuries resulting from defendants’ marketing of DES … Is there any basis in the law or social policy or any principled reason in justice and fairness for holding that she-unlike other members of the class–should not be permitted to prove her case?”

The New York decision is likely to be persuasive in other states, though it is not binding outside New York, and with so much at stake the large numbers of would-be plaintiffs are unlikely to give up the struggle just yet.

Diana Brahams, 1991.

Click to download the full paper.

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Preconception tort liability: recognizing a strict liability cause of action for DES grandchildren

” DES cases are breaking new ground in tort litigation. In March 1990, J. David Roberts filed a $ 2,000,000 lawsuit in the United States District Court for the District of Columbia against drug manufacturer Eli Lilly and Company, alleging that his in utero exposure to DES caused his daughter’s cancer. Roberts sued under theories of strict liability, emotional distress, breach of warranty, negligence and misrepresentation. He also alleged that DES manufacturers conspired to produce the drug after they knew of its dangers. “

Abstract

Over the past decade more than 1,000 “DES daughters” have filed lawsuits against the manufacturers of DES, alleging that their in utero exposure to the drug caused various reproductive tract abnormalities, including cancer.

Plaintiffs now allege that their grandmothers’ use of DES during pregnancy caused genetic damage leading to cancer in third generations. This Note addresses the validity of preconception tort liability in the context of third-generation DES cases.

Plaintiffs in preconception tort liability cases have sought recovery under both negligence and strict liability causes of action. Courts should recognize the validity of preconception tort liability and allow a strict liability cause of action in third-generation cases.

Sources and More Information
  • Preconception tort liability: recognizing a strict liability cause of action for DES grandchildren, American journal of law & medicine, NCBI PubMed PMID: 1812769, 1991.
  • Preconception Tort Liability: Recognizing a Strict Liability Cause of Action for DES Grandchildren, Boston University School of Law, LexisNexis, 17 Am. J. L. and Med. 435, 1991.
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Medical/legal implications of DES long-term sequelae, including 3rd generation

Abstract

The spectrum of teratogenic and carcinogenic effects which can be exerted when the unborn child is exposed to diethylstilbestrol (DES) has been shown to be broad.

Animal work indicates the need for vigilance as regards genetic susceptibility to DES sequelae. The emergence of third generation sequelae has been demonstrated in mice, and has been postulated to occur in humans.

Diethylstilbestrol, teratogenesis, and carcinogenesis: medical/legal implications of its long-term sequelae, including third generation effects, International Journal of Risk and Safety in Medicine, vol. 1, no. 3, pp. 171-193, 1990.

Given the emergent data establishing problems of infertility in men and women and of relatively late onset cancer, and the possibility that in utero exposure to DES may prime a variety of tissues to noxious environmental influences there is an urgent need for measures to provide just coverage for those harmed by the drug.

The DES disaster also raises important ethical and research questions which demand attention.

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EDCs: The Endocrine Society’s Second Scientific Statement

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Five years after the Endocrine Society’s first Scientific Statement in 2009, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life.

Abstract

Executive Summary to EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, The Endocrine Society, dx.doi.org/10.1210/er.2015-1093, September 28, 2015.
Full study: EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, The Endocrine Society, dx.doi.org/10.1210/er.2015-1010, November 06, 2015.

The Endocrine Society’s first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease.

Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans—especially during development—may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans.

In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest:

  1. obesity and diabetes;
  2. female reproduction;
  3. male reproduction;
  4. hormone-sensitive cancers in females;
  5. prostate;
  6. thyroid;
  7. and neurodevelopment and neuroendocrine systems.

Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health.

Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

Discussion (DES and Fertility-specific)

Diethylstilbestrol and beyond: perhaps the best-studied endocrine-based example is in utero exposure to diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen taken by pregnant women from the 1940s to 1975 to prevent miscarriage and other complications. DES was prescribed at doses from less than 100 mg (in most cases) upward to 47 000 mg, with a median dose of 3650 to 4000 mg in the United States (IARC 2012). Most women received low doses (ie, 5 mg) and increased their intake (up to 125 mg) as symptoms or pregnancy progressed, translating to doses of about 100 μg/kg to 2 mg/kg DES per day. In 1953, a study proved DES was ineffective. Its use was discontinued when a subset of exposed daughters presented with early-onset vaginal clear-cell adenocarcinoma, with a 40-fold increase in risk compared to unexposed individuals. A highly significant incidence ratio for clear-cell adenocarcinoma was also found in the Dutch DES cohort, a population that may have had lower exposures than US women. It was subsequently determined that exposed offspring of both sexes had increased risk for multiple reproductive disorders, certain cancers, cryptorchidism (boys), and other diseases, although the risk for sons is more controversial. New data are emerging to implicate increased disease risk in grandchildren. Not surprisingly, a plethora of examples is emerging for increased disease susceptibility later in life as a function of developmental exposures to EDCs that include BPA, phthalates, PCBs, pesticides, dioxins, and tributyltin (TBT), among others.

Epigenetics and transgenerational effects of EDCs: EDC-induced epigenetic changes are also influenced by dose of exposure, and they are tissue specific. Thus, it is important to consider both dose of EDC and the tissue before making firm conclusions about the epigenetic effects of EDCs. DNA methylation changes are the best-studied mechanism in this regard. For example, prenatal exposure to DES caused hypermethylation of the Hoxa10 gene in the uterus of mice and was linked to uterine hyperplasia and neoplasia later in life. Beyond the effects of prenatal exposure to DES on the daughters exposed in utero are suggestions that this leads to transgenerational effects of the chemical on the reproductive system, although whether this is linked to DNA methylation changes in humans is unknown.

Little is known about the ability of EDCs to cause histone modifications and whether this leads to transgenerational effects in animals or humans. The herbicides paraquat and dieldrin caused histone modifications in immortalized rat mesencephalic dopaminergic cells, and the insecticide propoxur causes histone modifications in gastric cells in vitro. DES caused histone deacetylation in the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene. Further studies, however, need to be conducted to identify other EDCs causing histone modifications in animals and humans and to determine whether such modifications lead to transgenerational effects.

Female Reproductive Health: in the past 5 years, no new information became available on the effects of DES on the postnatal human ovary. Recent animal studies indicate that DES adversely affected the postnatal ovary. Neonatal exposure to DES inhibited germ cell nest breakdown (408) and caused the formation of polyovular follicles in mice, likely by interfering with the ERβ pathway and inhibiting programmed oocyte death and germ cell loss. It also reduced the primordial follicle pool and increased atresia in prepubertal lambs, and it caused polyovular ovaries in hamsters. Although these previous studies provide solid evidence that DES adversely affects ovarian structure in a variety of species, studies are needed to determine whether other synthetic estrogens adversely affect the ovary.

Effects of EDCs on uterine structure and function: synthetic estrogens are well known disruptors of uterine structure and function in humans and animals. Consistent with previous studies, recent data indicate that neonatal DES exposure caused endometrial hyperplasia/dysplasia in hamsters and increased uterine adenocarcinoma and uterine abnormalities in Donryu rats. Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members, caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells and increased the incidence of cystic glands in rats.

Effects of EDCs on the vagina: only a limited number of studies assessed the effects of EDCs on the vagina, and of these, all but one on phthalates focused on DES. A recent study of women showed an association between in utero exposure to DES and clear cell carcinoma of the vagina, confirming previous findings. Furthermore, DES disrupted the expression of transformation-related protein 63, which makes cell fate decisions of Müllerian duct epithelium and induces adenosis lesions in the cervix and vagina in women.

Studies in mice showed that DES induced vaginal adenosis by down-regulating RUNX1, which inhibits the BMP4/activin A-regulated vaginal cell fate decision; induced epithelial cell proliferation and inhibited stromal cell proliferation (520); and caused persistent down-regulation of basic-helix-loop-helix transcription factor expression (Hes1, Hey1, Heyl) in the vagina, leading to estrogen-independent epithelial cell proliferation. Neonatal exposure to DES caused persistent changes in expression of IGF-1 and its downstream signaling factors in mouse vaginas. It also up-regulated Wnt4, a factor correlated with the stratification of epithelial cells, in mouse vaginas. Interestingly, the simultaneous administration of vitamin D attenuated the ability of DES to cause hyperplasia of the vagina in neonatal mice.

In the one study in the previous 5 years that did not focus on DES, polypropylene and polyethylene terephthalate did not increase vaginal weight in Sprague-Dawley rats. Although a few studies have been conducted during the previous 5 years on the effects of EDCs on the vagina, such studies are very few in number, small in scope, and focused on DES. Thus, future studies are needed in this largely understudied area before we fully appreciate whether other EDCs impair the vagina.

Premature ovarian failure/early menopause: combined data from three studies on DES indicated that in utero exposure was associated with an increased lifetime risk of early menopause in women (602). However, animal studies have not determined whether DES exposure causes premature ovarian failure. Thus, future studies should focus on this issue.

Fibroids: a few recent studies confirmed the known association between DES exposure and fibroids. In the Sister Study, in utero exposure to DES was positively associated with early-onset fibroids. Similarly, in the Nurses’ Health Study II, prenatal DES exposure was associated with uterine fibroids, with the strongest risk being for women exposed to DES in the first trimester. Given the consistency in findings, future studies should be focused on determining the mechanism by which DES exposure increases the risk of fibroids.

Click to download the summary.
Click to download the full study.

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DES-treated tall girls fertility, a dose-response relationship

Fertility of tall girls treated with high-dose estrogen.

Abstract

Fertility of tall girls treated with high-dose estrogen, a dose-response relationship, National Institutes of Health, NCBI PubMed PMID 22723330, 2012 Sep.

Full text: The Endocrine Society, dx.doi.org/10.1210/jc.2012-1078, June 20, 2012.

CONTEXT
High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life.

OBJECTIVE
The aim was to study the effect of estrogen dose on fertility outcome of these women.

DESIGN/SETTING
We conducted a retrospective cohort study of university hospital patients.

PATIENTS
We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 ?g and 43 with 200 ?g of ethinyl estradiol (EE) in adolescence.

MAIN OUTCOMES
Time to first pregnancy, treatment for infertility, and live birth rate were measured.

RESULTS
The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 ?g EE and 59% of women treated with 200 ?g EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 ?g EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 ?g EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 ?g EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 ?g EE.

CONCLUSIONS
We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility.

Discussion

It has been shown that high-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life (3, 4). Here, we studied the effect of estrogen dose on fertility outcome of these women. We compared women who received no treatment to women who received either 100 ?g EE or 200 ?g EE. Our study confirms that tall women treated with high-dose estrogen have an increased time to pregnancy and experience more fertility problems compared with untreated women. We demonstrate for the first time that the association between estrogen treatment and the observed infertility is dose-dependent.

Although human studies on the effects of treatment with estrogens have mostly focused on OCP users, animal studies have focused on environmental exposure to EE as an endocrine-disruptor and on the effects of diethylstilbestrol (DES). In rodents, both in utero and postnatal exposure to EE or DES produces permanent adverse effects on the developing female reproductive system. Animal studies on in utero exposure to DES have shown disruption at the follicle level. In DES-exposed mice, reduced numbers of primordial follicles and of oocytes after ovulation induction have been found. Neonatal exposure to DES in lambs reduces the primordial follicle pool by stimulating their initial recruitment, resulting in increased numbers of atretic follicles. Finally, DES induces transient changes in gene expression during gestation; these changes could be involved in follicle development, rate of atresia, or patterns of secretion or metabolism of steroid hormones. These animal studies suggest that pharmacological doses of estrogens may influence fertility in many ways and at various time points. This knowledge, although difficult to extrapolate, may help in better understanding the mechanism behind the observed infertility in tall women treated with high-dose estrogen.

Previously, it has been shown that a considerable number of tall women treated with high-dose estrogen in adolescence suffer from primary ovarian insufficiency with concomitant early follicle pool depletion diagnosed by increased serum FSH levels, decreased serum anti-Müllerian hormone levels, and low antral follicle counts. Although the mechanism behind this accelerated follicle loss observed in these women remains unknown, based on our results we conclude that estrogen may play a key dose-dependent role. This is supported by a study on in utero exposure of women to DES, who reported an earlier age at menopause with cumulating doses of DES.

Click to download the full study.

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EDCs: an Endocrine Society Scientific Statement

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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, 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.

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Fertility and Ovarian Function in High-Dose DES-Treated Tall Women

image of tall-girls
Back in the day, school photographers put the tall guys at the back in the middle, the shorter guys on the end. If you were really short, they put you on the end of the middle’ row with the plain Janes — note the gender symmetry. Middle of the front row was always reserved for the prettiest girls. My future wife and I – 1969.

Abstract

Fertility and Ovarian Function in High-Dose Estrogen-Treated Tall Women, National Institutes of Health, NCBI PubMed PMID 21289262, 2011 Feb 2.
Full text: The Endocrine Society, dx.doi.org/10.1210/jc.2010-2244, February 02, 2011.

BACKGROUND/OBJECTIVE
High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence.

METHODS
This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls.

RESULTS
Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76-6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased.

CONCLUSION
High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility.

Discussion

We evaluated fertility and ovarian function in tall women who did or did not receive high-dose estrogen treatment in adolescence. Our results indicate that treated women experience more difficulties getting pregnant compared with untreated women and more often receive infertility treatments. We show for the first time that abnormal serum levels of hormones related to the hypothalamus-pituitary-gonadal axis, especially FSH, may be involved in the observed subfertility.

First we studied fertility of treated women, which was significantly reduced compared with untreated women. Fifty-six percent of treated women conceived their first pregnancy within 12 months of unprotected intercourse. As a consequence, 43% of treated women visited a doctor because of fertility problems and 28% required some form of infertility treatment. More importantly, we observed a significantly reduced chance of achieving a live birth. At the time of study almost one third of the treated women were suffering from involuntary childlessness for a median of 40 months. This is unexpected in light of earlier findings indicating only a slight reduction in the probability of eventually having a live birth. This may be explained by the fact that we studied fertility only in women who had attempted to conceive, which we believe better represents the women at risk of involuntary childlessness. Our time to pregnancy data are self-reported and may be confounded by recall bias. However, we believe that our conclusions are not affected by such bias because we also assessed fertility based on data such as having received infertility treatments, which is not prone to recall bias and showed similar results.

We also studied the effects of treatment within treated women only. We found that although age at initiation of treatment was not associated with outcome, duration of treatment was significantly correlated with time to pregnancy. Women with a TTP of more than 12 months had on average been treated for 3 months longer. Although the effect of oral contraceptives on subsequent fertility has not been extensively studied, one study has reported an effect of estrogen dose on conception delay. Recent studies did not find such an association, possibly because low-dosage estrogen pills were used. Because of no variation in dosage in our population, we were unable to study the effect of estrogen dose more specifically.

Next, we analyzed ovarian function to study possible causes of the reduced fertility. Ovarian function was categorized based on serum gonadotropin levels. We observed an increased frequency of women with a hypergonadotropic profile. Our principal finding is that treated women are at increased risk of being diagnosed with IOF compared with untreated women. To account for normal changes in ovarian function in the late reproductive stages, treated and untreated women were divided into two age categories for the analysis of ovarian function. Taking these age categories into account, the odds of IOF diagnosis in treated women was almost 3-fold higher than in untreated women. Although ovarian function was primarily categorized based on serum FSH levels, the diagnosis of IOF was also supported by other parameters. We observed significantly decreased antral follicle counts and serum AMH levels in women with IOF as compared with normogonadotropic tall women. Serum AMH is currently the best marker for primordial follicle pool size because in the ovary it is expressed in granulose cells of follicles that have undergone recruitment but have not yet been selected for dominance. In addition, AMH plays an important role in regulating folliculogenesis because it is involved in determining the individual FSH threshold of early antral follicles. In addition, we believe some other possible pathologies, such as PCOS, can now be excluded as a potential cause of the observed infertility because of prevalence levels similar to the estimated population frequency.

Finally, we compared our results to a cohort of healthy fertile controls. Parameters of ovarian function were comparable between normogonadotropic tall women and these controls. Comparison with hypergonadotropic women confirmed that parameters of ovarian function in these women are indicative of accelerated follicle pool depletion.

The results of our study do not only validate earlier epidemiological findings from an Australian study but may also provide physicians with clinically useful information aiding in the diagnosis and treatment of estrogen-treated tall women with fertility problems. To our best knowledge, this is the first report establishing ovarian dysfunction in these women. It seems that follicle dynamics have changed in that respect that a considerable number of these women seem to suffer from accelerated follicle loss being reflected by increased serum FSH levels along with decreased AMH levels as well as low antral follicle counts. Hence, it seems that tall women who have been treated with estrogens in the past are prone to lose their reproductive capacity earlier in life, and they should be counseled accordingly.

In conclusion, we evaluated fertility and ovarian function in later life of tall women who did or did not receive high-dose estrogen treatment in adolescence. We found that estrogen-treated women experienced more difficulties conceiving and more often received medical treatment for infertility compared with untreated women. Treated women had a decreased chance of achieving at least one live birth. We observed a possible dose-response relationship because duration of treatment was correlated with time to pregnancy. Finally, we showed that treated women were at increased risk of being diagnosed with IOF. They exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility. However, the mechanism behind this accelerated follicle loss by high-dose estrogen treatment remains unknown and requires future research.

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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, 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.

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