Toxicology

Diethylstilbestrol (DES)

General overview

Diethylstilbestrol, commonly known as DES, is a synthetic nonsteroidal compound belonging to the stilbene group. Its biological activity resembles that of naturally occurring estrogen.

Available forms

DES has been produced in several formulations, including oral tablets in strengths ranging from 0.1 mg to 5 mg, rectal suppositories, and an intravenous preparation containing 250 mg in 5 mL.

Therapeutic uses

Historically, DES was used as palliative treatment for advanced, inoperable prostate cancer and for certain breast cancers affecting men and postmenopausal women.

Reproductive and hormonal uses

Other past uses included postcoital contraception within 72 hours of intercourse, management of menopausal vasomotor symptoms, relief of postpartum breast engorgement, suppression of lactation after childbirth, and hormonal feminization.

Toxic dose

A large single overdose usually produces gastrointestinal symptoms such as nausea, vomiting, and diarrhea rather than severe systemic poisoning.

Effects of chronic exposure

Long-term ingestion at therapeutic doses is more likely to cause significant adverse effects. Exposure during pregnancy may also result in harmful effects on the developing fetus.

Mechanism of toxicity

During prolonged treatment, DES behaves similarly to endogenous estrogen and can therefore influence estrogen-sensitive tissues and physiological processes.

Prenatal exposure in females

Females exposed to DES before approximately the 18th week of fetal development have been reported to experience higher rates of irregular or infrequent menstruation, infertility, spontaneous abortion, and premature delivery later in life.

Prenatal exposure in males

Males exposed to DES during early fetal development may have an increased risk of epididymal cysts, undescended testes, reduced gonadal function, and decreased sperm production.

Cancer association

Females exposed to DES before birth and women who received DES therapeutically have demonstrated an increased incidence of vaginal clear-cell adenocarcinoma and cervical abnormalities, including adenocarcinoma.

Other malignancies

Although several additional cancers have been investigated in relation to DES exposure, definite causal relationships have not been established for all of them.

Major risk factor

Use of DES during pregnancy represents an important risk because the developing fetus may be exposed to its estrogenic effects.

Drug and disease interaction

DES may stimulate or accelerate the growth of certain hormone-responsive cancers, particularly in premenopausal women.

Pregnancy considerations

DES was formerly classified as FDA Pregnancy Category X because evidence demonstrated fetal abnormalities or significant fetal risk, and the potential harm during pregnancy was considered greater than any expected therapeutic benefit.

Diagnosis

Skin manifestations

Skin reactions, including rashes, may develop in individuals exposed to DES.

Cardiac effects

Prolonged DES use has been associated with an increased occurrence of myocardial ischemia.

Thrombotic effects

Chronic treatment may increase the risk of blood clot formation. Reported complications include cerebrovascular events, deep-vein thrombosis, pulmonary embolism, mesenteric thrombosis, and retinal vascular thrombosis.

Gastrointestinal effects

Acute overdose commonly produces nausea, vomiting, abdominal discomfort, and abdominal distension.

Liver effects

Long-term DES exposure may occasionally lead to hepatitis accompanied by cholestatic jaundice.

Renal and metabolic effects

Urethral strictures and porphyria have been reported during prolonged therapy.

Fluid retention

Chronic treatment may contribute to retention of body fluid and the development of edema.

Reproductive effects

Women receiving DES over an extended period may experience vaginal bleeding, painful menstruation, or absence of menstrual periods.

Calcium abnormalities

Elevated serum calcium may occur, especially in immobilized patients or in individuals with osteoporosis, kidney impairment, or metastatic cancer involving bone.

Hormonal effects in males

Long-term DES exposure in males may cause breast enlargement, breast tenderness, excessive hair growth, hair loss, or other changes related to altered hormonal activity.

Investigations

Testing after isolated ingestion

Extensive laboratory testing may not be necessary for an asymptomatic patient following a single acute ingestion.

Blood count

For individuals receiving chronic therapy, a complete blood count may be performed to identify possible abnormalities involving bone marrow function.

Calcium assessment

Serum calcium should be considered when there is concern for abnormal calcium concentrations, including either reduced or elevated levels.

Cardiovascular investigations

An electrocardiogram, chest radiograph, and other appropriate investigations may be required when myocardial ischemia or thromboembolic disease is suspected.

Liver assessment

Measurement of liver enzymes can assist in identifying possible chemically induced hepatitis associated with chronic exposure.

Screening for additional substances

In an overdose setting, serum acetaminophen and salicylate concentrations may be measured when there is a possibility of an unrecognized coingestion.

Treatment

General approach

Management is primarily directed toward the patient’s clinical condition and any complications that develop, as a single DES ingestion generally has relatively low acute toxicity.

Poison control consultation

Specialist toxicology or poison-control advice should be considered when severe or persistent symptoms develop or when a coingestant, drug interaction, or underlying illness makes the case more complicated.

Referral for medical assessment

Evaluation in a health-care facility is appropriate when toxic effects appear or when another substance, medication interaction, or pre-existing disease may increase clinical risk.

Admission considerations

Hospital admission may be required when intentional self-harm is suspected or when significant hematologic or cardiovascular complications develop.

Accidental ingestion

Children and adults who remain well following an isolated accidental ingestion may often be managed with observation outside the hospital when appropriate medical guidance and reliable supervision are available.

Out-of-hospital decontamination

The historical source advises against the use of ipecac following an isolated DES ingestion because a single exposure generally produces limited acute toxicity.

In-hospital decontamination

The historical source also describes gastric lavage as rarely necessary because severe acute toxicity is uncommon. It was mainly considered when a dangerous coingestant was present or when other serious clinical circumstances justified gastric emptying.

Activated charcoal

A single dose of activated charcoal was historically described for a substantial recent ingestion when clinically appropriate and when the airway could be adequately protected.

Specific antidote

No specific antidote is available for DES poisoning. Treatment therefore focuses on supportive care and management of individual complications.

Follow-up

Long-term monitoring

Women who previously received DES and females who were exposed to DES before birth require appropriate long-term medical surveillance because some complications may appear years after the original exposure.

Gynecologic surveillance

Regular pelvic examinations and appropriate cytologic screening have historically been recommended for women at increased risk because of prenatal or therapeutic DES exposure.

Monitoring for complications

Additional investigations should be based on the complications being considered. For example, symptoms suggesting pulmonary embolism require appropriate cardiovascular and respiratory evaluation.

Expected course after acute overdose

An acute overdose most commonly produces gastrointestinal symptoms that persist for several hours and then gradually resolve.

Prognosis after chronic exposure

For individuals exposed to DES over a prolonged period, the eventual outcome depends largely on whether significant complications such as thromboembolic disease, cardiac ischemia, reproductive abnormalities, or malignancy develop.

Discharge criteria

Patients may be discharged from the emergency department or hospital once toxic effects have resolved or become clinically stable and no further acute medical intervention is required.

Psychiatric evaluation

Mental health assessment may be appropriate when ingestion was intentional or when self-harm is suspected.

Clinical pitfalls

Inadequate long-term surveillance

Failure to monitor individuals with prolonged DES exposure may allow hematologic, reproductive, gynecologic, or cardiovascular complications to develop without early recognition.

Diagnostic awareness

Clinical findings should not automatically be attributed to DES exposure. Other medical conditions, medications, and toxic substances should also be considered when the patient’s presentation is unusual.

Classification

ICD-9-CM 962 refers to poisoning caused by hormones and synthetic hormonal substitutes.