Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development

doi:10.1016/j.reprotox.2005.01.002

Reproductive Toxicology

Volume 20, Issue 1, May–June 2005, Pages 81-84

https://doi.org/10.1016/j.reprotox.2005.01.002 Get rights and content

Abstract

Early life exposure to DES causes uterine leiomyomata in laboratory animals. We examined the relationship between prenatal DES exposure and development of uterine leiomyomata in women. Among randomly selected study participants (819 black women, 504 white women), leiomyoma status was determined by ultrasound screening (70%) or surgical record review (7%). We relied on self-report of prior diagnosis in 13%. Leiomyoma status could not be ascertained for 10% and they were excluded from analyses. Prenatal DES exposure was assessed by interview. All five of the black women who reported DES exposure had leiomyomata. Among white women, 76% who reported prenatal DES exposure had leiomyomata compared with 52% of the unexposed (adjusted odds ratio for whites: 2.4; 95% confidence interval CI: 1.1–5.4). Exposed women tended to have larger tumors. Results were robust to sensitivity analyses. Findings support experimental animal data and indicate a role for prenatal estrogen exposure in the etiology of human uterine leiomyoma.

Introduction

Uterine leiomyomata, commonly called fibroids, are benign tumors that can cause pain, bleeding, infertility and pregnancy complications [1]. They are the leading indication for hysterectomy [2], [3]. The tumors are of smooth muscle origin and develop as clonal growths [4]. Incidence increases with premenopausal age, and they regress after menopause [5]. Both estrogen and progesterone have been implicated in their growth, though the mechanisms by which these hormones stimulate tumor development is not understood [6].

In mice, early-life exposure to the exogenous estrogen, diethylstilbestrol (DES), causes uterine leiomyoma development in adult animals [7], [8]. Data obtained from our developmentally-exposed DES animal model has shown uterine leiomyomata occurring in ∼9% of treated mice, compared to <1% incidence in unexposed mice. Characterization of these DES fibroids shows similarities with human tumors [8].

The relationship between prenatal DES exposure and uterine fibroid development has not been investigated in humans, though prenatal exposure occurred in an estimated 2–10 million pregnancies in the United States and Europe from the late 1940s to the early 1970s [9]. In 1970, vaginal adenosis and adenocarcinoma were discovered in women who had been prenatally exposed to DES [10]. As a consequence, DES treatment was banned in the U.S. in 1971 and throughout Europe by 1978 [11]. Although DES was used to prevent miscarriage and other complications in high-risk pregnancies (despite a trial showing no efficacy in 1953 [12]), many women with normal pregnancies were also treated [11]. Research has mainly focused on DES-induced epithelial lesions, but smooth muscle cells are also DES targets [13].

We examined the relationship between self-reported prenatal DES exposure and uterine fibroids in women aged 35–49, born during years when DES was being prescribed. Because DES daughters know that they can have reproductive problems, they might initiate more gynecological investigation and thus be more likely than unexposed women to receive a clinical diagnosis of fibroids. To avoid such diagnostic bias, we examined the relationship between prenatal DES exposure and uterine fibroids among randomly selected participants who were screened for fibroids with pelvic ultrasound, regardless of any prior diagnosis of fibroids.

Section snippets

Materials and methods

The NIEHS Uterine Fibroid Study was designed to estimate uterine fibroid prevalence. Detailed methods have been described [14]. Briefly, the computerized membership records of a prepaid health plan in Washington, DC, were used to randomly select 35–49 year old women. This age group was selected because it is the age-group most likely to be clinically treated for fibroids, and these women were born during years when DES could have been prescribed. Those selected were screened for eligibility by

Results

A higher proportion of both black and white women who reported prenatal DES exposure had developed fibroids (Table 1). Large fibroids tended to be more common in those reporting DES exposure. Of unexposed white women, 15% had developed large tumors compared with 26% of the DES-exposed. Among blacks, 32% of the unexposed had developed large fibroids compared with 60% for the DES-exposed. Only five black women reported prenatal exposure; all five (100%) had developed fibroids. Therefore, we

Discussion

The adverse effects of prenatal exposure to DES have been documented in both human and animal studies [15], but, typically, research has focused on DES-induced epithelial lesions. However, alterations in smooth muscle cells following developmental DES treatment have also been reported in numerous laboratory studies [13], [16], [17]. Furthermore, exogenous administration of estrogens has been associated with the development of uterine leiomyoma in guinea pigs [18] as well as other rodents [7],

Acknowledgments

Michael Hill supervised the ultrasound screening examinations, and Joel Schectman administered the clinical aspects of the NIEHS Uterine Fibroid Study. Glenn Heartwell managed the study, and Deborah Cousins provided programming support. Allen Wilcox, Matthew Longnecker, and Barbara Davis reviewed an earlier draft of the manuscript. The study was funded as intramural research at the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human

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Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

Lancet

Obstet Gynecol

Med Clin North Am

Am J Obstet Gynecol

The epidemiology of hysterectomy: findings in a large cohort study

Br J Obstet Gynaecol

Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene

Gynecol Obstet Invest

Risk factors for uterine fibroids: reduced risk associated with oral contraceptives

Br Med J

Uterine leiomyomata

Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens

Environ Health Perspect

Characterization of uterine leiomyomas in CD-1 mice following developmental exposure to diethylstilbestrol (DES)

Toxicol Pathol