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Hormonally Active Agents in the Environment (1999)

Chapter: Appendix A: Reproductive Effects Caused by Deithylstilbesterol

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Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 399

Appendix A—
Reproductive Effects Caused by Diethylstilbesterol

Much of the conceptual background for the investigation of the actions of hormonally active agents (HAAs) is based on results of studies on the actions of diethylstilbesterol (DES), a potent synthetic estrogen (see Chapter 1). Because this compound is not an environmental toxicant and because to date, no known environmental toxicant has been demonstrated to be more potent than DES, its actions are not discussed extensively in the corpus of this report. Nevertheless, because some workers in the field believe that DES is an important model for the effects of other HAAs, the relevant aspects of the actions of this compound are discussed here.

There is extensive literature concerning the long-term effects of in utero exposure of humans to DES (Herbst and Bern 1981; Takasugi and Bern 1988; Mittendorf 1995) and of fetal and neonatal exposure in other animals (Vannier and Raynaud 1980; Bern et al. 1987; Brody and Cunha 1989; Newbold 1995). There is also evidence that developmental exposure to DES can alter the immune-system functioning of laboratory animals (Kalland et al. 1979; Kalland and Forsberg 1980, 1981; Ways et al. 1980; Blair 1981: Holsapple et al. 1983: Luster et al. 1984; Pung et al. 1984, 1985) and humans (Ways et al. 1987; Noller et al. 1988: Blair 1992). Effects on other tissues, such as bone, also have been noted (Migliaccio et al. 1992). However, the major concern has focused on prenatal exposure to DES and its effects on the reproductive system.

Table A-1 lists the various female and male reproductive-tract abnormalities in humans and rodents exposed prenatally to DES. Studies show that exposure to DES during the critical period of organogenesis can profoundly disturb differentiation of the reproductive organs. Some of the effects are not observed until adulthood, demonstrating the latent developmental effects of exposure to this potent estrogen.break

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Page 400

TABLE A-1 Reproductive Tract Abnormalities in Humans and Rodents Exposed Prenatally to Diethylstilbestrol (DES)

Abnormality

Organ

Study

Details

Reference

Females

       

Cancer

Vagina and cervix

Human

Clear cell adenocarcinoma

IARC 1979

   

Rodent

Adenocarcinoma

McLachlan 1979: Newbold and McLachlan 1982

 

Ovary

Human

Germ Cell Cancer

Walker et al. 1988

   

Rodent

Not reported

 
 

Breast

Human

No increased risk of breast cancer observed

Hatch et al. 1998

   

Rodent

Not reported

 

Other genital tract changes

Uterus

Human

T-shaped: hypoplasia

Haney et al. 1979; Kaufman et al. 1980. 1986: Mittendorf 1995

 
   

Rodent

Decreased muscle development: hyperplasia followed by hypoplasia

Medlock et al. 1988: Brody and Cunha 1989: Wordinger et al. 1991

 
 

Cervix

Human

Adenosis: ectropion; ridging; hooding incompetence

Herbst et al. 1972: Scully et al. 1974: Sherman et al. 1974; Sandberg 1976; Poskanzer and Herbst 1977: Kaufman and Adam 1978: Robboy et al. 1979

   

Rodent

NA

 
 

Ovary

Human

Parovarian cysts

DeCherney et al. 1981

   

Rodent

Intra and parovarian cysts

Newbold et al. 1983

 

Oviduct

Human

Withered fimbria

DeCherney et al. 1981: Robboy et al. 1982

(table continued on next page)break

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 401

(table continued from previous page)break

Abnormality

Organ

Study

Details

Reference

   

Rodent

Developmental arrest

Newbold et al. 1983

 

Vagina

Human

Adenosis; ridging, epithelial changes

Herbst et al. 1972; Scully et al. 1974; Sherman et

       

al. 1974; Sandberg 1976; Poskanzer and Herbst

       

1977; Kaufman and Adam 1978; Johnson et al.

       

1979: Robboy et al. 1979

   

Rodent

Adenosis

Newbold and McLachlan 1982: Bern et al. 1987

     

Lesions

 

Pregnancy-

 

Human

Infertility; ectopic pregnancy; premature

Barnes et al. 1980; Cousins et al. 1980; Kaufman et

related

   

delivery; spontaneous abortion

al. 1980; Herbst and Bern 1981; Mangan et al

changes

     

1982; Stillman 1982; Thorp et al. 1990.

   

Rodent

Infertility, abortion, stillbirths, malformations

Halling and Forsberg 1992; Walker 1983

Malesa

       

Cancer

Testis

Human

Inconsistent results

Henderson et al. 1979; Schottenfeld et al. 1980;

       

Depue et al. 1983; Brown et al. 1986; Gershman

       

and Stolley 1988

   

Rodent

Adenocarcinoma of the rete testes,

Newbold et al. 1985, 1987

     

interstitial cell carcinoma

 
 

Prostate

Human

No data available

 
   

Rodent

Squamous cell of dorsolateral prostate

Arai et al. 1978

Other genital

Penis

Human

Reduced size; hypospadias

Gill et al. 1976, 1979; Henderson et al. 1976;

tract changes

     

Wilcox et al. 1995

 

Testis

Human

Cryptorchidism: hypertrophy; capsular

Gill et al. 1976, 1979: Rothman and Louik 1978;

     

induration; epididymal cysts

Depue 1984; Newbold 1995; Wilcox et al. 1995

       

(table continues)

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 402

TABLE A-1 Continued

     

Abnormality

Organ

Study

Details

Reference

Rodent

   

Cryptorchidism

Bullock et al. 1988: McLachlan et al. 1975

     

Epididymal cysts

 
 
 

Prostate

Human

Hyperplasia and metaplasia of the prostatic

Driscoll and Taylor 1980; Blacklock 1983

     

ducts

 
   

Rodent

Abnormal development: squamous

McLachlan et al. 1975: Turner et al. 1989; Prins

     

metaplasia of prostatic and coagulating

1992: Pylkkanen et al. 1993: vom Saal et al. 1997

     

gland ductal epithelium

 

Fertility-

 

Human

Impaired semen quality and sperm

Gill et al. 1976. 1979: Andonian and Kessler 1979:

related

   

concentration; impaired fertility

Leary et al. 1984: Shy et al. 1984; Newbold 1995;

changes

   

inconsistent

Wilcox et al. 1995

   

Rodent

Impaired semen quality and sperm

McLachlan 1981

     

concentration: impaired fertility

 

a Details of some of these studies are provided in Table A-4.

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 403

TABLE A-2 Incidence of Adverse Pregnancy Outcomes in DES-Exposed Daughters and Estimates

of their Relative Riska

   

Incidence in DES Daughters

 

Estimate of Relative Riskb

 

Incidence in

Abnormal DESc

 

(95% Confidence Interval)

Outcome

Controls

Vagina-Cervix

Uterus

All DES

Abnormal DESc

All DES

Ectopic pregnancy

0.01

0.063

0.076

0.044

13.5 (2.1, 84.7)

8.6 (3.4, 21.9)

Premature live birth

0.02

0.75

0.38

0.13

9.6 (4.0, 23.4)

4.7 (2.8, 7.9)

Spontaneous abortion

0.13

0.19

0.36

0.23

2.6 (1.8, 3.8)

1.8 (1.5, 2.2)

Not full-term birthd

0.15

 

0.67

0.41

4.9 (3.1, 7.7)

2.7 (2.2, 3.0)

a Based on controlled studies by Herbst et al. (1980, 1981); Barnes et al. (1980); Kaufman et al. (1980); Cousins (1980);

Mangan et al. (1982); Thorp et al. (1990).

b Mantel-Haenzel estimate of relative risk; Robins-Greenland estimate of 95% confidence interval.

cDES-associated abnormality.

d Includes ectopic pregnancy, premature birth, and spontaneous abortion.

SOURCES: Adapted from Swan 1992 and Stillman 1982.

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 404

Table A-2 provides estimates of adverse pregnancy outcomes in DES-exposed daughters. Because DES was used to treat women with histories of reproductive difficulties, it might be expected that their daughters also would have high-risk pregnancies independent of DES exposure. However, Barnes et al. (1980) has shown that the incidence of these unfavorable outcomes in DES daughters is not related to the obstetric history of the mothers. In fact, as shown in this table, the incidence is related to the presence of genital-tract abnormalities, which are in turn related to the gestational age of first exposure to DES.

Table A-3 presents case-control studies of testicular cancer in men in relation to prenatal exposure to DES and other hormones. Exposure assessment for these studies was problematic because none of the study protocols restricted exposure to the critical period of testicular development, and all combined prenatal exposure to all prenatal hormones, rather than to DES alone. Because prenatal DES exposure occurred in about 1% of pregnancies, the power of these studies to isolate a DES effect is limited.

Table A-4 shows the effects of exposure to DES on sperm concentration and on abnormalities of the male reproductive system.

Table A-5 presents observed effects on the mature reproductive system in workers exposed to DES and DES-like compounds.break

TABLE A-3 Case-Control Studies of Testicular Cancer, Relation to Prenatal

Exposure to DES and Other Hormones

Cases

Controls

Relative Risk

Reference

78

78

5.0a (p = 01)

Henderson et al. (1979)

   

4.3b (p = .01 )

 

190c

166d

1.8c (p = .20)

Schottenfeld et al. (1980)

 

143e

2.0c (p = .17)

 

108

108

8.0f (p = .02)

Depue et al. (1983)g

225

213

0.8h (not significant)

Brown et al. (1986)

79

79

2 DES-exposed cases vs. 0 DES-exposed

Gershman and Stolley (1988)

   

controlsc (not significant)

 

aHormone treatment not further specified.

bHormone treatment for excessive nausea.

cDrug use for bleeding, spotting, and/or threatened abortion (DES. other hormones, or unknown).

dHospital.

eNeighborhood.

fExogenous hormones during first trimester of index pregnancy.

gContinuation of Henderson et al. 1979.

hExogenous hormones during the index pregnancy.

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 405

TABLE A-4 Effects of DES on Abnormalities of the Male Reproductive System and Sperm Concentration

   

Urogenital Abnormalities

 

Impaired Sperm

Sperm count

 

Exposed

Unexposed

(Other Than Varicocele)

Cryptochidism

Concentration

(106/mL)

Reference

163

168

25% vs. 6.5%''

 

28% vs. 0%b

 

Gill et al. (1976)c

   

p < 0.0005

 

p < 0.05

   

225

111

24.4% vs. 15.3%d

3% vs. 1%e

   

Henderson et al. (1976)

24

24

13% vs. 8% not

 

17% vs. 20%b

 

Andonian and Kessler (1979)

   

significant

 

not significant

   

307

308

32% vs. 7.8%

17% vs. 1%

18% vs. 8%b

91 s. 115

Gill et al. (1979)

   

p < 0.0005

p < .005

p < 0.05

p < 0.05

 

31

28

p < 0.001f

     

Driscoll and Taylor (1980)g

265

274

Not significant

   

12% vs. 15%b

Leary et al. (1984)

         

not significant

 

51

29

35% vs. 4%.

8% vs. 0%

21% vs. 0%h

74 vs. 77

Shy et al. (1984)

   

p = 0.0006

p = 0.07

p < 0.02

not significant

 

253

241

15% vs. 5%

       
   

p < 0.01i

     

Wilcox et al. (1995)c

a Epididymal cycts. hypertrophic testis, capsular induration, hypoplastic penis.

b Severely pathologic Eliasson score (>10).

c Dieckmann cohort.

d Problems passing urine (p = .0006) and penile stenosis or hypospadias (p = .034).

e Published in Cosgrove et al. 1977 (same population).

f For each of hypertrophy and squamous metaplasia of the prostatic utricle; high ratio of Leydig cells to spermatogenic cells in the testis.

g Autopsy findings in male perinates.

h Poor forward progression.

i Significantly higher rate of abnormalities among men exposed before week 11 of gestation (p < .05).

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 406

TABLE A-5 Effects of Occupational Exposure to DES or DES-like

Compounds on the Mature Reproductive System

 

Sex of

   

Compound

Workers

Observed Effects

Reference

DES

Male

Gynecomastia, decreased

Shmunes and Burton 1981

   

libido, decreased genital

 
   

size


 

4,4'-diaminostilbene-

Male

Decreased total circulating

Quinn et al. 1990

2,2'-disulfonic acida

 

testosterone

 
 

Male

Decreased total circulating

Grajewski et al. 1996

   

testosterone, decreased

 
   

libido, increased impotence

 
 

Estrogens

Females

Increased incidence of

Taskinen et al. 1986

   

spontaneous abortion

 

aStilbene derivative (DAS: CAS 81-11-8). similar in structure to DES.

Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 397
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 398
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 399
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 400
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 401
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 402
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 403
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 404
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 405
Suggested Citation:"Appendix A: Reproductive Effects Caused by Deithylstilbesterol." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×
Page 406
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Some investigators have hypothesized that estrogens and other hormonally active agents found in the environment might be involved in breast cancer increases and sperm count declines in humans as well as deformities and reproductive problems seen in wildlife.

This book looks in detail at the science behind the ominous prospect of "estrogen mimics" threatening health and well-being, from the level of ecosystems and populations to individual people and animals. The committee identifies research needs and offers specific recommendations to decision-makers.

This authoritative volume:

  • Critically evaluates the literature on hormonally active agents in the environment and identifies known and suspected toxicologic mechanisms and effects of fish, wildlife, and humans.
  • Examines whether and how exposure to hormonally active agents occurs—in diet, in pharmaceuticals, from industrial releases into the environment—and why the debate centers on estrogens.
  • Identifies significant uncertainties, limitations of knowledge, and weaknesses in the scientific literature.

The book presents a wealth of information and investigates a wide range of examples across the spectrum of life that might be related to these agents.

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