Post Marketing WithdrawalDiethylsilbestrol (DES)

M. Faisal ShahidUniversity of Karachi

PBRS-2015

DES

l First oral non-steroidal estrogenl Used for/as:l Miscarriage preventionl Hormonal Replacementl Menopausal Symptomsl Atropic Vaginitisl Contraceptivel Dysfunctional Menstrual Cyclesl Prostrate Cancerl Anti-lactation agent

DES

l First Developed: 1938 by E. C. Dodds at University of London

l No patent ever claimed

l Approved for Human use in 1940 at USA

l FDA approved generic formulation in 1941

l 287 companies manufactured DES and related compounds

Hypothesis

l “Exogenous estrogen supply can stimulate body's estrogen and progesterone levels, thus, preventing

miscarriages”l Dr. Geroge Smith, Dr. Oliver Smith

l 1938: Natural estrogen administration started l Shifted to DES for high risk patientsl 1948: Published “Unlimited progesterone stimulation by DES”l Gained status of SUPER VITAMIN by 1958

l Dose:l 5md/day, 5 mg weekly increment up-to 150mg daily

Initial Alarms!

l Gynecomastia and sterility cases in poultry, FDA banned DES veterinary use (1959)

l Absolute use halted in cattle by 1980s

Initial Alarms on Humans!

l 1952 Dieckmann Study:l 2000 enrolled females testedl 1000 received DES l Treated women had HIGHER INCIDENCE of

miscarriage!l * Estimation: 2-4 million women received DES treatment

in USA

1962: FDA, NAS Verdict

l Drug manufacturers in addition to “Safety” had to demonstrate “Effectiveness” of “Intended

Purpose”

l Drugs not meeting criteria to be removed from market

1971: Herbst et. al.

l Reported seven cases of clear cell adenocarcinoma in “Adolescent girls” and “Young Women”

l All seven exposed to DES “Prenatally”l Result:l Registry for Research on Hormonal Transplacental Carcinogenesis establishedl Goal: Collect data on ALL CASES of CAA after 1948

1974: FDA recall of approved formulation

Other Studies

l Colton et. al., 1960l Reported slightly increased risk of breast cancer

treated with DESl Titus-Ernstoff et. al., 2001l Modest association of DES exposure and breast

cancerl Hatch et. al.,l Reported CAA in DES in-utero exposed daughtersl CAA risk increased between age 7-19, falls 30-39 and

increased at above 40 years

Studies on third generation women exposed to DES

l 1997: 2/2539 daughters reported Ovarian Cancer at age 7 and 20

years.l 2001: 2/463 exposed daughter's offspring

reported ovarian cancer.l No incidence of male specific cancer reported in third generation

l FDA recalled DES for human use in association with CAA to exposed offsprings in-utero exposure in 1974.

l DES CAS No. 56-53-1 is now declared as a Human Carcinogen (based on sifficient evidence from studies)

Conclusion