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Published: May 2006
ADR update

Stilboestrol - Gone but not forgotten

Prescriber Update 27(1): 9-11.
May 2006

Professor Charlotte Paul, Department of Preventive and Social Medicine, Otago University Medical School, Dunedin; and Dr Mira Harrison-Woolrych, New Zealand Pharmacovigilance Centre, Dunedin

Stilboestrol was prescribed for pregnant women in New Zealand up until the 1960s and long-term adverse effects are still being clarified.  For daughters exposed in-utero, clear cell adenocarcinoma of the vagina and cervix continue to be observed rarely as these women reach their 50s, and there may be a second peak in later life.  Mothers are at modestly increased risk of breast cancer, sons may be at increased risk of testicular cancer, and there are unconfirmed observations of third generation effects.  Prescribers are reminded of the need to continue to monitor women exposed in-utero.

First evidence of transplacental carcinogenesis

Diethylstilboestrol (DES, known in New Zealand as stilboestrol; a synthetic oestrogen) was prescribed to about 1,000 pregnant women in New Zealand in the 1940s, 50s and 60s – in the belief it would reduce the risk of miscarriage.1  In 1971 it was shown that daughters born to exposed mothers were at risk of clear cell adenocarcinoma (CCA) of the vagina.  Since that time, other adverse effects have been documented in the daughters of women who took stilboestrol, as well as in the women themselves and their sons who were exposed in-utero.

Effects of stilboestrol persist

Although there has never been a systematic attempt to identify exposed women in New Zealand, publicity over the years has made many people aware of possible exposure.  Most who think they have been exposed find that their medical records no longer exist.  Therefore, clinicians need to be aware of the effects of stilboestrol, and of when the medicine was used, so that they can advise potentially affected mothers, daughters and sons appropriately.  In the last 10 years – since the Ministry of Health last provided advice2 – further research has clarified a number of issues.  Hence it is timely to update practitioners and provide a reminder of ongoing monitoring recommendations.

Adverse effects include cancers and reproductive tract abnormalities

Exposed Mothers (i.e. women prescribed stilboestrol when they were pregnant)

Women who took stilboestrol during pregnancy have a modest increased risk of breast cancer of about 30% (corresponding to an extra 23 cases per 100,000 women per year).  The risk of other cancers does not seem to be elevated.3

Exposed Daughters (i.e. women exposed to stilboestrol in-utero)

Clear cell adenocarcinoma of the vagina and cervix
This cancer occurs in about 1 in 1000 exposed daughters up to the age of 35 years,4 making the risk about 40 times that in the unexposed.5  The peak age of onset is late teens and early 20s, although cases have been reported in women up to their 50s.5,6  There is concern that there may be a second peak as these women age (there is a second age peak for diagnosis for CCA in non-exposed women in their 70s).7

Other Cancers
A possible increase in risk of breast cancer in exposed daughters has been reported, with a marginally significant elevation for women aged over 40 years.8  However, further investigation of all cancers in this combined cohort showed no increased risk of breast cancer or any other cancer apart from CCA.5  There has been a particular concern that stilboestrol might increase the risk of squamous cell carcinoma of the cervix, but as yet there is no definitive answer.  There is some evidence of an increase in high grade squamous intraepithelial neoplasia in exposed daughters, though this may be due to more intensive screening.9  Another cohort study with a low (and hence potentially biased) ascertainment of outcomes showed a three-fold increased risk of invasive cervical cancer among exposed daughters.10

Reproductive tract abnormalities
The following abnormalities are very common in stilboestrol-exposed daughters: vaginal adenosis, cervical ectropion, transverse cervical and vaginal ridges, hypoplastic uterus and a T-shaped uterus.11  Recently, increases in paraovarian cysts,12 endometriosis13 and uterine fibroids14 have been observed, but these associations are unconfirmed.

Reproductive function and pregnancy outcome
Primary infertility and pregnancy loss are both more common in exposed daughters.15  Long-term follow-up of stilboestrol-exposed daughters has confirmed an increased frequency of pre-term delivery, first trimester spontaneous abortion, second trimester pregnancy loss and ectopic pregnancy.  Nevertheless among all exposed daughters in one cohort, 75% became pregnant and among these women 85% delivered at least one live full-term infant.16

Exposed Sons (i.e. men exposed to stilboestrol in-utero)

An increased risk of testicular cancer was suggested in earlier studies, but is not confirmed.  The largest cohort study to date reported a two to three times elevation in risk amongst exposed sons, though this finding was not statistically significant.17  Abnormalities of the urogenital tract have been reported but study findings have been inconsistent.11

Third generation effects (i.e. grandchildren of exposed mothers)

Studies in animals support the possibility of multi-generational carcinogenesis due to in-utero stilboestrol exposure.18  These effects have begun to be studied in humans.  One cohort study suggested an increased risk of hypospadias in the sons of exposed daughters.19  This finding has not been supported in a subsequent study.20  Nevertheless both studies involved small numbers of exposed cases.  A small study of third generation daughters, which included a detailed history and pelvic examination, showed that none of these granddaughters had changes usually associated with stilboestrol exposure.21

Monitoring recommendations for stilboestrol-exposed daughters

Women who may have been exposed to stilboestrol in-utero should be informed about the small risk of CCA of the vagina and cervix, and offered regular examinations.  There are no specific New Zealand guidelines but the New Zealand Committee of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) advises clinicians to follow the advice of the US National Cancer Institute,22 which recommends the following annual examination:

This annual examination may be performed by a general practitioner.  The part of the examination most important for detection of CCA is the examination of the vagina and cervix.  Careful visual examination and palpation are essential.  Cytological smears of the vagina (ideally taken as a circumferential sweep of the vaginal vault using the handle end of an Ayre’s-type spatula23) and cervix should be taken; although cases of CCA have been diagnosed in the presence of negative smears.  If a grossly visible or palpable lesion is observed, referral to a gynaecologist for biopsy regardless of cytology results is advised.22  The New Zealand Committee of the RANZCOG can advise general practitioners of those gynaecologists practising colposcopy in their local area.

Exposed daughters who are planning a pregnancy, or are in early pregnancy, should be referred to an obstetrician.  There are no specific monitoring requirements for women who took stilboestrol or their sons who were exposed in-utero.

Information is available for stilboestrol-exposed patients

Authoritative and well-presented information for affected mothers, daughters and sons is available on the following web sites:

Competing interests (authors): none declared

Correspondence to: charlotte.paul@stonebow.otago.ac.nz

References
  1. Paul C, Skegg DCG, Seddon R. Past use of oestrogens during pregnancy in New Zealand. NZ Med J 1984;97:831.
  2. Connor J, Paul C and NZ Ministry of Health. Information sheet on stilboestrol use in pregnancy 1995.
  3. Titus-Ernstoff L, Hatch EE, Hoover RN, et al. Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer 2001;84(1):126-133.
  4. Melnick S, Cole P, Anderson D, et al. Rates and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. N Engl J Med 1987;316:514-516.
  5. Hatch EE, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA 1998;280(7):630-634.
  6. Registry for Research on Hormonal Transplacental Carcinogenesis. Clear Cell Adenocarcinoma – Collaborative Studies: University of Chicago DES (Diethylstilbestrol) Program. http://obgyn.bsd.uchicago.edu/registry.html (accessed 20.1.06).
  7. Hanselaar A, van Loosbroek M, Schuurbiers O, et al. Clear cell adenocarcinoma of the vagina and cervix. Cancer 1997;79:2229-2236.
  8. Palmer JR, Hatch EE, Rosenberg CL, et al. Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control 2002;13:753-758.
  9. Hatch EE, Herbst AL, Hoover RN, et al. Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States). Cancer Causes Control 2001;12:837-845.
  10. Verloop J, Rookus MA, van Leeuwen FE. Prevalence of gynecologic cancer in women exposed to diethylstilbestrol in utero. N Engl J Med 2000;342(24);1838-1839.
  11. Swan SH. Intrauterine exposure to diethylstilbestrol: long-term effects in humans. APMIS 2000;108:793-804.
  12. Wise LA, Palmer JR, Rowlings K, et al. Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure. Obstet Gynecol 2005;105:167-173.
  13. Missmer SA, Hankinson SE, Spiegelman D, et al. In utero exposures and the incidence of endometriosis. Fertil Steril 2004;82:1501-1508.
  14. Baird DD, Newbold R. Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reproductive Toxicology 2005;20:81-4.
  15. Palmer JR, Hatch EE, Rao RS, et al. Infertility among women exposed prenatally to diethylstilbestrol. Am J Epidemiol 2001;154(4):316-321.
  16. Kaufman RH, Adam E, Hatch EE, et al. Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring. Obstet Gynecol 2000;96(4):483-489.
  17. Strohsnitter WC, Noller KL, Hoover RN, et al. Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst 2001;93:545-551.
  18. Newbold RR. Lessons learned from perinatal exposure to diethylstilbestrol. Toxicol Appl Pharmacol 2004;199:142-150.
  19. Klip H, Verloop J, van Gool JD, et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 2002;359:1102-1107.
  20. Palmer JR, Wise LA, Robboy SJ, et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero. Epidemiology 2005;16(4):583-586.
  21. Kaufman RH, Adam E. Findings in female offspring of women exposed in utero to diethylstilbestrol. Obstet Gynecol 2002;99:197-200.
  22. Centers for Disease Control and Prevention (CDC), United States Department of Health and Human Services. DES update: Health care providers. Information to identify and manage DES patients. www.cdc.gov/des/hcp/information/daughters/risks_daughters.html (accessed 17.02.06).
  23. Black J (Specialist Obstetrician & Gynaecologist, Australia). DES: Information for GPs. www.drjulesblack.com/html/dr_jules_black_DES.htm (accessed 7.04.06). Also personal communication, 26 February 2006.

 

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