Table 1.

Human clinical effects induced by DES.

	Generation Exposed To Des	Human Clinical Effects	Authors
Female abnormalities in the reproductive tract	DES daughters (F1) and DES granddaughters (germ cells; F2)	28 DES granddaughters did not show abnormalities in the lower genital tract contrary to their DES mothers (high frequency).	[30] Kaufman et al.
	DES granddaughters (germ cells; F2)	DES granddaughters with irregular menstrual periods and amenorrhea; no risk of reproductive dysfunction.	[31] Titus-Ernstoff et al.
	DES granddaughters (germ cells; F2)	Increased risk of irregular menstrual periods (more common in DES granddaughters of DES mothers with vaginal epithelial changes) and amenorrhea. Possible increased risk of ectopic pregnancy.	[77] Titus et al.
	DES granddaughters (F2)	No differences in age at menarche between DES granddaughters and DES daughters.	[80] Wilcox et al.
Female lower genital tract and breast cancers	DES mothers (F0)	Modest increased risk of breast cancer (not aggravated by a family history of breast cancer, oral contraceptives, or hormone replacement therapy). No evidence of a risk for ovarian, endometrial, or other cancers.	[47] Titus-Ernstoff et al.
	DES mothers (F0)	Moderate increase in the risk of breast cancer (risk rises over time).	[53] Greenberg et al.
	DES mothers (F0)	Increase in fatal breast cancers (did not increase over time).	[54] Calle et al.
	DES mothers (F0)	Modest increased risk of breast cancer (statistically significant); it did not increase over time.	[55] Colton et al.
	DES daughters (F1)	High risk of cervical intraepithelial neoplasia and breast cancer (at 40 years or older). Also, early menopause, infertility, abortion, premature delivery, ectopic pregnancy, stillbirth. The risk was higher in women with vaginal epithelial changes.	[32] Hoover et al.
	DES daughters (F1)	Increase in adenocarcinoma of the vagina in young women (cluster of 15–22-year-old women).	[43] Herbst et al.
	DES daughters (F1)	Increased risk of CCA of the vagina and cervix, and breast cancer.	[44] Troisi et al.
	DES daughters (F1)	Increased risk of CCA of the vagina and cervix; marginally increased risk of melanoma (before age 40). No increased risk of breast cancer (cohort relatively young).	[45] Verloop et al.
	DES daughters (F1)	Excess risk of breast cancer, increased risk of lower genital tract malignancies (relatively small absolute risk), and pancreatic cancer. No increased risk of overall cancer.	[48] Troisi et al.
	DES daughters (F1)	No postnatal cofactors were identified in association with the risk of developing CAA.	[49] Palmer et al.
	DES daughters (F1)	Elevated risk of breast cancer only in women 40 years of age or older.	[56] Palmer et al.
	DES daughters (F1)	Increased risk of breast cancer after 40 years old.	[57] Palmer et al.
	DES daughters (F1)	Significant increase of breast cancer in women (younger than 40 years) and CCA of the cervix or vagina. No significant increase in overall cancer.	[58] Tournaire et al.
	DES daughters (F1)	No association between prenatal exposure to low doses of DES and increased mammographic density in premenopausal or postmenopausal women (did not discard the possibility of an association with higher doses of DES exposure).	[59] Strohsnitter et al.
	DES granddaughters (and DES grandsons) (germ cells; F2)	Moderate increase in the risk of breast cancer (risk rises over time). Increased risk of CCA of the vagina and cervix, and higher than expected incidence of ovarian cancer (3 cases). No overall increase of cancer risk in DES grandchildren.	[52] Titus-Ernstoff et al.
	DES granddaughter (germ cells; (F2)	Case report of CCA of the vagina and cervix of an 8-year-old girl (with a history of severe vaginal bleeding). DES mother had a hysterectomy.	[78] Gaspari et al.
	DES granddaughter (germ cells; F2)	Case report of a 15-year-old girl with small-cell carcinoma of the ovary.	[79] Blatt et al.
Male abnormalities and cancers of the reproductive tract	DES sons (F1)	DES sons showed an increased risk of urogenital abnormalities (strongest association with early gestational exposure).	[35] Palmer et al.
	DES sons (F1)	No increased risk of overall cancer in DES sons; testicular cancer may be increased in DES sons.	[40] Strohsnitter et al.
	DES sons (F1)	Threefold increase in testicular cancer.	[41] Hom et al.
	DES sons (F1)	Increased risk of hypospadias (few cases).	[82] Klip et al.
	DES sons (F1)	No increase in overall or prostate cancer. Unexpected reduction in the risk of cancers of the urinary system.	[42] Strohsnitter et al.
	DES grandsons (and DES granddaughters) (germ cells; F2)	Increased incidence of cryptorchidism and hypoplasia of the penis; no increased incidence of hypospadias. No increase of genital anomalies in girls. All grandchildren were born to DES sons.	[36] Tournaire et al.
	DES grandsons (germ cells; F2)	Increase in hypospadias in DES grandsons (born to DES daughters), even though the absolute risk is low; no mutations and no polymorphisms of the AR and MAMLD1 genes were found. Results based on few cases.	[81] Kalfa et al.
	DES grandsons (germ cells; F2)	Increased risk of hypospadias when DES grandsons were born to DES daughters but not to DES sons.	[83] Brouwers et al.
	DES grandsons (germ cells; F2)	11 DES grandsons with “idiopathic partial androgen insensitivity-like syndrome”.	[86] Gaspari et al.
Other alterations	DES daughters (F1)	Associations with coronary artery disease and myocardial infarction, but not with stroke.	[99] Troisi et al.
	DES children (F1)	Increased risk of pancreatic cancer in DES daughters but not in DES sons.	[100] Troisi et al.
	DES grandchildren (germ cells; F2)	Increased cerebral palsy, increased defects in lip/palate, esophagus, musculoskeletal and circulatory systems. Also, increased male genital tract anomalies. No significant abnormalities in female genital tract and no increase of breast, uterus, and ovary cancers.	[76] Tournaire et al.
	DES grandchildren (germ cells; F2)	Increased ADHD risk (only first trimester of DES exposure during pregnancy).	[87] Kioumourtzoglou et al.
	DES grandchildren (germ cells; F2)	Overall birth defects were elevated in grandchildren. Granddaughters appeared to have an increased risk of heart defects.	[88] Titus-Ernstoff et al.