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Urogenital Tract Abnormalities in Sons of Women Treated With Diethylstilbestrol


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in Sons of Women




Brian E. Henderson, M.D., Barbara Benton, R.N., Malcolm Cosgrove, M.D., Joyce Baptista, M.A., James Aldrich, M.S., Duane Townsend, M.D., William Hart, M.D., and

Thomas M. Mack, M.D.

Frommi the Departments of Pathology, Conmnmunity Medicine and Public Ilealtim, and Surgery ( Urology). University of Southern California School of Medicine, Los Angeles

ABSTRACT. Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located,

surveyed by mail, amid compared with unexposed male

offsprimig froni the samiie period and medical practices. The exposed and imnexposed respondents appeared comparable amid did not differ in their response to most medical

qimes-tiomis. However, a larger proportion of exposed than of

unexposed boys had experienced problems in passing urine

(12.9% vs. 1.8%; P = .0003) and abnormalities of the penile

urethra (4.4% vs. 0%; P .017). Pediatrics, 58:505-507, 1976,


After the 1971 report of Herbst et a!.’ linking

diethylstilbestrol (DES) therapy in mothers with

vaginal adenocarcinoma in their daughters, we

established a registry of DES-exposed male and

female offspring. Initially, all efforts2 were

directed toward evaluation of the risk of female

genital tract abnormalities and we have only

recently exanlined the characteristics and

medi-cal histories of the exposed males. It now appears that male urogenital tract abnormalities are also associated with DES therapy.


In November 1971, a mail inquiry regarding

the past and current use of DES was made of the

members of the Los Angeles County Obstetrical

and Gynecological Society. From the replies, 30

physicians were identified who had used DES in

the past. From this group we were able to identify


physicians (working out of tell offices) who still

had records of office visits back to 1945, and who

agreed to participate in this study.

The office records of these physicians were

reviewed for the period from 1942 to 1971 and

the record of every pregnancy resulting in a live

birth and with a documented history of DES

therapy was abstracted; 1,024 such pregnancies

were identified. Unexposed, control pregnancies

were chosen from the files of tile same group of

physicians. These controls were chosen to

(Received December 15, 1975; revision accepted for

publi-cation March 1 1, 1976.)

Supported by contracts 1-CP-5350() amid 1-CN-45122 fromi the National Cancer Imistitute, Bethesda, Marylamid.

ADDRESS FOR REPRINTS: (T.M.M.) Cancer Surveillance

Program, 1840 North De Soto Street, Los Angeles, California


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Exposed (No. 225)

,-No. % (Jnexpos .Vo. ed (No. A-111) % Risk Ratio

Heart disease 6 2.7 3 2.7 1.0

Asthma 14 6.2 9 8.1 0.8

Measles 105 46.7 57 51.4 0.9

Appendicitis 7 3.1 3 2.7 1.2

Broken bones 67 29.8 37 33.3 0.9

Urogenital tractsymptomns or abnormalities 55 24.4 17 15.3 1.6

Infections 14 6.2 3 2.7 2.3

Problems passing urimie 29 12.9 2 1.8 7.2#{176}

Abnormality of penile urethra (stenosis or hypospadias) 10 4.4 0 0.0 Infinity

Other physical abnormiiality 8 3.6 3 2.7 1.3

Kidney or bladder pain 16 7.1 5 4.5 1.6

Penile bleeding or discharge 1 1 4.9 2 1.8 2.7

#{176}P= .0003 (Fisher’s one-sided exact test); approximate 95% confidence level, 1.7 to 29.4.

1P = .017 (Fisher’s one-sided exact test); approximate one-sided 95% confidence level lower bound, 1.4.

conform to the exposed pregnancies by outcome

(live birth), sex, and month of birth. They were

u.sually, but not always, matched by individual

physician. Rosters of unexposed births were

prepared in file order as records were screened. As exposed pregnancies were discovered, controls

comparable for the above factors were then

chosen in the same order from these rosters. In all,

787 comparable unexposed pregnancies were

found before time considerations curtailed the


For each exposed and unexposed pregnancy,

charts were abstracted for demographic

informa-tion, gestational age at birth, general medical

condition of the mother, birthweight and sex of

the offspring, and as much detail as was available

about drugs and procedures (e.g., diagnostic X-ray

films) prescribed during the pregnancy. The

specific indications for DES therapy (i.e., factors

indicating high risk of abortion) were not

uniformly recorded.

The exposed and unexposed groups were

iden-tical in terms of demographic and socioeconomic

variables. Mean birthweight and gestational age

at first visit were predictably different (smaller) in the exposed than in the unexposed pregnancies.

Exposed and unexposed pregnancies received

similar treatment with vitamins, iron, diuretics,

and other drugs except progestin (54.2% in the

exposed es. 9.0% in the unexposed), other

exoge-noits estrogens (13.8% vs. 0.9%), and possibly

exogenous thyroid (25.3% vs. 14.4%). DES dosage

and the trimester of first dose could be abstracted from the records of most of the exposed. Of these,

86.7% received the drug in the first trimester and

42.8% received a mean daily dose of more than 25


An attempt was made to locate each of the

exposed and unexposed mothers through their

driver’s registrations. If a mother was located, she

was contacted by mail and asked to complete a

questionnaire about her own health and a similar

questionnaire for each of her children. The

ques-tions were structured, but with space for

elabora-tion. A wide spectrunl of genitourinary, infectious

disease, and chronic disease problems were

surveyed without any indication of specific areas

of concern. Information resulting from the

ques-tionnaires concerning daughters will be reported



Of the 500 DES-exposed and 389 unexposed

males identified in office records, we were able to

locate, respectively, the mothers of 306 (61%) and

231 (60%) and to obtain completed questionnaires

from 225 (45%) and 111 (29%). Information

pertaining to the siblings of exposed offspring was sparse and will not be presented here.

Response rate (questionnaire received /

off-spring identified) for both exposed and unexposed groups was independent of year of birth, maternal age, individual physician, hospital of birth, race,

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paternal occupation, birth order, maternal age at

first live birth, and maternal history of allergies, heart disease, cancer and diabetes. As expected

from the above, the composition of the exposed

respondents for each variable was similar to that of the unexposed respondents.

There was no difference between the

DES-exposed and DES-unexposed males in the

frequency of a history of heart disease, diabetes,

asthma, hay fever, childhood infectious diseases,

appendectomy, or tonsillectomy. However, the

DES-exposed males did report a significant excess

experience with disease of the urogenital tract

(Table I). In total, 55 of the DES-exposed and 17

of the DES-unexposed males reported one or

more such problems, and each problem was

reported more frequently by the exposed than the

unexposed. The niost striking specific finding was a history of abnormalities of the penile urethra in

ten of the exposed and none of the unexposed

boys. One of these was a hypospadias, but all nine others volunteered descriptions of urethral

steno-sis (i.e., “penis opening too narrow” or “passage

too snlall to pass urine”). All ten had been

circunlcised, but over 95% of both exposed and

unexposed had been as well. One exposed boy had

a horseshoe kidney, and testicular maldescent and

varicocele occurred in both exposed and

unex-posed boys.


One hpospadias anomaly might be expected

among the 306 boys surveyed,M and congenital

meatal stenosis is at least as common. However, even with 39% of those surveyed not responding,

29 exposed boys (12.9% of those responding and

9.5% of the total) described problems in passing urine with or without mention of specific anoma-lies. The composition of these 29 was not distin-guishable frolll that of all exposed respondents, all

unexposed respondents, and, indeed, from that of

both original groups of exposed and unexposed

offspring with respect to year of birth, maternal age, individual physician, hospital of birth, race,

paternal occupation, birth order, maternal age at

first live birth, and maternal history of allergies, heart disease, cancer, and diabetes. It was also not

distinguishable frolll the total exposed group by

mean birthweight or frequency of exposure to

progestin (44.8%), other estrogens (10.3%), or

thyroid (24.1%). DES dosage and timing

informa-tion was available for most of these 29; 73.1%

were treated in the first trimester and 36.0%

received more than 25 mg/day. In short, none of

these factors offers an alternative explanation for

the finding and none can be used to define a

particularly high- or low-risk group. Although in

this setting it is not possible to distinguish

between DES therapy and the conditions for

which it was given as alternative causes for the

finding, there is no reason to believe that tilreat-ened abortion would be followed by particularly urogenital anomalies. Moreover, a DES-induced

abnormality of the male urethra is

embryologi-cally consistent with DES-induced abnormalities

of the vagina whether the latter are of Mullerian

or urethral fold origin.



Because of this, and despite the low response

rate, especially in the unexposed group, we

believe it very possible that in utero DES

expo-sure is related to urogenital tract anomalies in

sons. While the most characteristic anomaly

seems to be urethral stenosis, there may l)e an

association between DES exposure and a variety

of urinary tract anomalies. The findings suggest

that more detailed historical and clinical exami-nation of such boys is warranted.

NOTE: Detailed tables on demographic,

socio-economic, and medical history factors are

avail-able upon request.


1. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinomiia of the vagina: Association of maternal stilbestrol therapy with tumnor appearamice in yoLmng women.

N Engl


Med 284:878, 1971.

2. Linden G, Henderson BE: Genital-tract cancers in

adolescents and young adults. N Engl



286:760, 1972.

3. Henderson BE, Bentomi BB, \Veaver PT, ci a!: Stilbestrol and urogenital-tract cancer in adolescents and

young adults. N Engl


Med 288:354, 1973.

4. Lanier AP, Noller KL, Decker DC, ci a!: Camicer and stilbestrol: A follow-up of 1,719 persons exposed to estrogens in utero and born 1943-1959. Mayo Clin Proc 48:793, 1973.

5. Greenwald P, Barlow


Nasca PC, et al: Vaginal cancer after maternal treatment with synthetic estrogens.

N EngI


Med 285:390, 1971.

6. Herbst AL, Poskanzer DC, Robboy SJ, et a!: Prenatal exposure to stilbestrol: A prospective comimparison of exposed female offspring with unexposed controls. N Engl


Med 292:334, 1975.

7. Hart WR, Townsend DE, Aldrich JO, ci a!: Histopatho-logic spectruni of vaginal adenosis and related

changes in stilbestrol-exposed females. Cancer

37:763, 1976.

8. Center for Disease Control: Congenital Malformation Surveillance Amimitmal Summary 1974. July 1975.

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Duane Townsend, William Hart and Thomas M. Mack

Brian E. Henderson, Barbara Benton, Malcolm Cosgrove, Joyce Baptista, James Aldrich,

Urogenital Tract Abnormalities in Sons of Women Treated With Diethylstilbestrol


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Duane Townsend, William Hart and Thomas M. Mack

Brian E. Henderson, Barbara Benton, Malcolm Cosgrove, Joyce Baptista, James Aldrich,

Urogenital Tract Abnormalities in Sons of Women Treated With Diethylstilbestrol


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