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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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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

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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

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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)

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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.

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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.

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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.

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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).

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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.