PEDIATRICS Vol. 58
No.
4October
1976
505Urogenital
Tract
Abnormalities
in Sons of Women
Treated
With
Diethylstilbestrol
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,
ESTROGENS, DIETHYLSTILBESTROL, URETHRAL STRICTURE.
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.
PATIENTS AND METHODS
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
18
physicians (working out of tell offices) who stillhad 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
90032.
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506 UROGENITAL ABNORMALITIES AND DES TABLE I
SELECTED MEDICAL HISTORIES IN DES-EXPOSED AND DES-UNEXPOSED MALES
History
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
search.
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
mg.
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
separately.
RESULTS
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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ARTICLES 507
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.
DISCUSSION
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.
SPECULATION
AND RELEVANCE
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.
REFERENCES
1. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinomiia of the vagina: Association of maternal stilbestrol therapy with tumnor appearamice in yoLmng women.
N Engl
J
Med 284:878, 1971.2. Linden G, Henderson BE: Genital-tract cancers in
adolescents and young adults. N Engl
J
Med286:760, 1972.
3. Henderson BE, Bentomi BB, \Veaver PT, ci a!: Stilbestrol and urogenital-tract cancer in adolescents and
young adults. N Engl
J
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
JJ,
Nasca PC, et al: Vaginal cancer after maternal treatment with synthetic estrogens.N EngI
J
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
J
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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1976;58;505
Pediatrics
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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1976;58;505
Pediatrics
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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