Ethinylestradiol
ETHINYLESTRADIOL
International Programme on Chemical Safety
Poisons Information Monograph 221
Pharmaceutical
1. NAME
1.1 Substance
Ethinylestradiol
1.2 Group
1.3 Synonyms
Ethinyloestradiol;
Aethinyloestradiolum;
Etinilestradiol;
17 alpha-Ethynylestra-1,3,5(10)-triene-3,17 beta-diol;
19-Nor-17 alpha pregna-1,3,5(10)-trien-20-yne-3,17 beta-diol
1.4 Identification numbers
1.4.1 CAS number
57-63-6
1.4.2 Other numbers
No data available
1.5 Main brand names, main trade names
To be completed by centre using the monograph
1.6 Manufacturers, Importers
To be completed by centre using the monograph
2. SUMMARY
2.1 Main risks and target organs
Acute poisoning with ethinylestradiol results in mild,
self limiting effects, usually involving the gastrointestinal
tract. Chronic toxicity increases the risk of cardiovascular
disease, including myocardial infarction, cerebrovascular
disease, thromboembolic disease, gallbladder disease, and
certain cancers in some people.
2.2 Summary of clinical effects
Acute poisoning with ethinylestradiol is mild and self
limiting. Nausea, vomiting and occasionally vaginal
breakthrough bleeding may occur. Chronic toxicity from
ethinylestradiol, like other estrogens, increases the risk
for stroke, myocardial infarction and thromboembolic disease
in certain populations. Jaundice, hypertension, nasal
congestion, headache, dizziness and fluid retention may
occur. Endometrial, breast, and certain liver cancers may
occur at a higher incidence than the general
population.
2.3 Diagnosis
The diagnosis is based on a history of ingestion. Many
patients may remain asymptomatic. No typical constellation of
clinical findings aid the diagnosis. Laboratory analyses are
not helpful.
2.4 First aid measures and management principles
Gut decontamination measures should be considered for
all acute poisonings. Emesis is rarely indicated. Activated
charcoal, given according to weight and age, may be
appropriate. Cases of acute poisoning should otherwise be
managed with supportive care, potentially including
anti-emetic medication and or intravenous fluids for
rehydration, if vomiting is excessive. Patients suffering
from chronic toxicity should discontinue ethinylestradiol, in
conjunction with the prescribing physician, and be managed on
an individual basis, depending on clinical findings.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic steroid, prepared from estrone.
3.2 Chemical structure
Chemical name: 19-Nor-17 alpha pregna-1,3,5(10)-trien-20-yne-
3,17 beta-diol
Molecular Weight: 296.39.
3.3 Physical properties
3.3.1 Colour
White to creamy or slightly yellowish-white.
3.3.2 State/Form
Solid-crystals
Solid-powder.
3.3.3 Description
Odorless.
Insoluble in water. Soluble 1 part in 6 parts of
ethanol, and 1 part in 4 parts of ether.
Melting point as a hemihydrate: 141 to 146°C.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
United States formulations have a shelf life of
36 months.
3.4.2 Storage conditions
Storage at between 2 to 30°C is preferred.
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
The most frequent use is as the estrogen
component of combined oral contraceptives. Also used
for the treatment of menopausal and post menopausal
symptoms, especially the vasomotor effects. Used in
the treatment of female hypogonadism and as a
palliative treatment in malignant neoplasm of breast
and prostate. Also used in the treatment of some women
with acne, and in Turner's syndrome.
4.2 Therapeutic dosage
4.2.1 Adults
Combined contraceptive: 20 to 50 µg orally per
day. Menopausal and postmenopausal symptoms: 10 to 50
µg orally per day. Female hypogonadism: typically 50
µg orally three times per day for 14 consecutive days
in every 4 weeks.
Malignant prostate cancer: 0.15 to 2 mg orally per
day.
Malignant neoplasm of the breast: 1 mg orally three
times per day.
4.2.2 Children
No data available
4.3 Contraindications
Contraindications are those of the use of estrogens in
general, and include the following:
1. Known or suspected carcinoma of the breast, except in
selected patients being treated for metastatic disease.
2. Known or suspected estrogen dependent neoplasia.
3. Known or suspected pregnancy.
4. Undiagnosed abnormal genital bleeding.
5. Active thrombophlebitis or thromboembolic disease.
6. A past history of thrombophlebitis, thrombosis or
thromboembolic disease associated with the previous use of
estrogen containing compounds (Physicians GenRx, 1997).
5. ROUTES OF EXPOSURE
5.1 Oral
This is the main route of exposure. Generally exposure
may be either intentional overdose or therapeutic over
prescribing. Ethinylestradiol is readily absorbed by this
route.
5.2 Inhalation
No data available
5.3 Dermal
No data available
5.4 Eye
No data available
5.5 Parenteral
No data available
5.6 Other
No data available
6. KINETICS
6.1 Absorption by route of exposure
Ethinylestradiol is rapidly and completely absorbed from
the gastrointestinal tract. The ethinyl substitution in the
C17 position inhibits first-pass metabolism. Bioavailability
is reported at 40% (Kanarkowski 1988, Goebelsmann 1986,
Physicians GenRx, 1997).
6.2 Distribution by route of exposure
Extensively plasma protein bound, mainly to albumin.
Unboundmolecules distribute widely in the tissues due to
their lipophilic nature. Volume of distribution is stated as
3.8 L/Kg. Peak plasma concentrations occur initially at 2 to
3 hours after oral ingestion. A second, 12 hour peak, is
thought to represent extensive enterohepatic circulation
(Hardman 1996, Kanarkowski 1988, Goebelsmann 1986, Physicians
GenRx 1997).
6.3 Biological half-life by route of exposure
Biological half life is approximately 7.7 hours
following a single oral therapeutic dose. (Kanarkowski 1988,
Goebelsmann 1986). Elimination phase half life is reported
between 13 and 27 hours (Hardman 1996).
6.4 Metabolism
Compared to other estrogens, metabolism is slow. Primary
route of biotransformation is via 2-hydroxylation and the
formation of 2- and 3-methyl ethers (Hardman 1996).
First-pass metabolism occurs primarily in the gut wall (Back
1982).
6.5 Elimination by route of exposure
Some enterohepatic circulation of sulfate and
glucuronide metabolites does occur, hence some is excreted
via the feces. Excretion is also via the kidneys (Reynolds,
1993).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Generally, the mechanism of how
ethinylestradiol exerts its toxic and adverse effects
are based on the principles outlined in 7.1.2.
However, a 2 to 3 fold increase in the incidence of
gallbladder disease is reported with the use of
estrogens. This is thought due to an increased
saturation of bile with cholesterol and a reduction of
bile acid secretion. Also, many studies have been
performed investigating the adverse effects of
estrogens, including ethinylestradiol, on coagulation.
These have used estrogens alone, and estrogens in
combination with progestins. However a consensus of
the net outcome of physiologic or pharmacological
doses has not occurred as yet (Beller, 1994).
7.1.2 Pharmacodynamics
Like other steroid hormones, ethinylestradiol
is thought to act primarily through the regulation of
gene expression. As a lipophilic hormone, it diffuses
readily through cellular membranes to bind to estrogen
receptors situated in the nucleus. Estrogen receptors
are found in the female reproductive tract, breast,
pituitary, hypothalamus, bone, liver and other tissues
(Evans, 1988). The receptor interacts with a
specialized nucleotide sequence, resulting in either
an increase or decrease in the transcription of
hormone-regulated genes. Tissues may vary in the way
in which they respond to receptor activation.
Desirable therapeutic effects, include its action on
the female reproductive tract, (usually in combination
with a progesterone), where ethinylestradiol
stimulates proliferation and differentiation in the
fallopian tube, and increase the tubal muscular
activity. Ethinylestradiol also increases the water
content of cervical mucus and favors contraction of
the uterine myometrium. Estrogens, including
ethinylestradiol, block resorption of bone, resulting
in a positive effect on bone mass (Prince, 1991;
Belchetz, 1994). Control of the vasomotor symptoms
associated with the perimenopausal period is thought
to occur because of a blocking of the central nervous
system outflow that regulates blood flow to cutaneous
vessels. Like other estrogens, ethinylestradiol has a
beneficial effect on plasma lipoprotein profiles,
slightly elevating serum triglycerides, reducing serum
cholesterol, increasing high-density lipoprotein
levels and reducing low-density lipoprotein levels.
This beneficial effect may be due to action at
estrogen receptors within the liver itself (Lobo,
1991; Walsh, 1994) This alteration in lipoproteins is
thought to be the basis for the beneficial effect on
cardiovascular disease, particularly myocardial
infarction, in postmenopausal women.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
No minimal lethal or toxic dose has
been established. There is no dose of
ethinylestradiol which is therapeutically
effective and side effect free. Present
recommendations state that with long term
therapy, the minimally effective dose should
be prescribed œ 0.015 mg only, for 25 days
per month (Horeman 1983).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
Yager et al. (1991) demonstrated a correlation
between the prolonged use of oral contraceptives and
the development of liver cancer in rats. Han and Liehr
(1994b) induced DNA breaks in hamster kidneys, but not
in livers, following 2 weeks of treatment with a
single 25 mg estradiol implant. Lacassagne (1936),
induced tumors of kidney, bone, testis, uterus and
breast, in animals exposed to estrogens.
LD50 Rats: 2952 mg/Kg
Mice: 1737 mg/Kg œ the mode of death is not reported
(Goldenthal, 1971).
7.2.3 Relevant in vitro data
No data available
7.3 Carcinogenicity
It is well established that the risk of endometrial
hyperplasia and cancer is increased in women receiving
unopposed estrogen replacement therapy, including
ethinylestradiol. Data from the 1970's and 1980's reported a
2 to 15 fold increase in the risk of endometrial carcinoma
(Henderson, 1989). The higher the dose and the longer the
length of therapy the greater the risk. However, the addition
of progestogen to estrogen replacement therapy was protective
(Rubin, 1990; Persson, 1989).
More research is needed before a conclusion can be drawn on
whether ethinylestradiol therapy, and other estrogens,
increase the risk of breast carcinoma. Conflicting findings
have been reported. A review of data from the 1970's and
1980's suggests that there is a moderate increase in the risk
of breast carcinoma, but this did not occur until after 5
years of therapy (Henderson, 1989; Steinberg, 1991). A study
of 1369 cases of recently diagnosed breast cancer and 1645
controls among postmenopausal women showed no increase in
overall risk for those women taking estrogens (Wingo,
1987).
Benign hepatic adenomas may be associated with the use of
oral contraceptives (Baum, 1973). These lesions have not been
reported with the use of ethinylestradiol alone, however
should be considered if abdominal pain and tenderness suggest
hepatic involvement.
There is limited evidence regarding the incidence of
colorectal cancer in individuals taking estrogen replacement
therapy. Meta-analysis has reported no overall increase in
risk (MacLennan, 1995).
7.4 Teratogenicity
No specific data available for ethinylestradiol. Reports
suggest a link between fetal exposure to female sex hormones
and congenital abnormalities. These include heart defects,
and limb defects (Levy, 1973; Nora, 1973; Janerich, 1974).
Janerich (1974) estimated the increased risk at 4.7 fold for
developing limb defects in infants exposed to in-utero sex
hormones. Other estrogens, namely diethylstilbestrol, have
been associated with the development of vaginal and cervical
adenocarcinoma in female offspring of mothers who had taken
this drug during the first trimester (Greenwald, 1971;
Herbst, 1971). Diethylstilbestrol ingestion during pregnancy
is also associated with a number of other abnormalities in
male offspring, including, smaller testes and urogenital
abnormalities (Ross, 1983; Whitehead, 1981). Although no
studies relating ethinylestradiol directly to these findings
were identified, the pharmacological similarities in this
class of compounds suggest caution should be used.
7.5 Mutagenicity
No specific data available for ethinylestradiol. After 2
weeks Han and Liehr, (1994), induced DNA breaks in hamster
renal cells, but not in hepatocytes, with 25 mg estradiol
implants. Roy and Pathak (1995) have shown rat liver nuclei
converted diethylstilbestrol to histone-binding metabolites.
In vivo modification in the chromatin histone proteins by
diethylstilbestrol metabolites may influence gene
function.
7.6 Interactions
Increased ethinylestradiol and 17-beta-estradiol effect,
probably via a decreased first pass metabolism, has been
seen, with the concurrent use of grapefruit juice (Weber,
1996). Possible antidepressant toxicity may occur with
estrogens or oral contraceptives, the mechanism of which is
not fully established. Krishnan (1984) reports on this case
which suggests that estrogens may facilitate the development
of akathisia. Also, a possibility for corticosteroid
toxicity, through an unknown mechanism, has been reported on
(Legler, 1986). A decrease in estrogen effect is seen with
phenytoin use, secondary to induction of hepatic enzymes and
increased metabolism (Notelovitz, 1981). Through a similar
mechanism, smoking is thought to reduce the clinical efficacy
of estrogens, including ethinylestradiol (Jensen, 1985).
Increased serum concentration and possible toxicity of
estrogens may be seen with 1 gram/day of vitamin C, secondary
to decreased metabolism (Morris, 1981).
7.7 Main adverse effects
The main adverse effects of ethinylestradiol given in
therapeutic dose are directly related to its estrogenic and
metabolic effects. They include water and sodium retention,
which may result in edema, weight gain and tender breast
enlargement. Changes in libido, and withdrawal vaginal
bleeding is also reported. Liver function impairment,
jaundice and gallstones may occur. Headache, depression,
dizziness, glucose intolerance, and a sensitivity to contact
lenses are described. Large doses may produce hypercalcemia
when used in the treatment of metastatic carcinoma. Nausea,
vomiting and diarrhea are not uncommon. Dermatological
effects include chloasma, melasma, rashes and urticaria.
Erythema multiforme and erythema nodosum occur. Hypertension
and thromboembolic disease are reported (Reynolds, 1993;
Cornbleet, 1977; Fedorkow, 1989). Some cancers occur at a
higher incidence, see 7.3.
8. TOXICOLOGICAL ANALYSES ETC.
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
Specific levels of ethinylestradiol
are not available.
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomed. investigations etc.
8.5 Overall Interpretation
Sample collection
Ethinylestradiol levels are not available. Estradiol levels
are available, however the clinical relevance of these to
poisoning from ethinylestradiol is unknown.
Biomedical analysis
Not relevant.
Toxicological analysis
Not relevant.
Other investigations
Generally no laboratory analysis would be needed following
acute poisoning. In chronic toxicity laboratory work should
be performed according to the individual patient needs.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Acute poisoning effects are mild and self
limiting. Nausea, vomiting and break through vaginal
bleeding have been reported following oral
contraceptive overdose. Nasal congestion, visual
disturbances, headache and hypertension have also been
reported in association with estrogen overdose (AHFS
1997; Eden 1990; Punnonen, 1983).
9.1.2 Inhalation
No data available
9.1.3 Skin exposure
No data available
9.1.4 Eye contact
No data available
9.1.5 Parenteral exposure
No data available
9.1.6 Other
No data available
9.2 Chronic poisoning
9.2.1 Ingestion
Gallbladder disease, glucose intolerance,
edema, leg cramps, porphyria cutanea tarda, chloasma,
gynecomastia, thromboembolism, hypertension,
myocardial infarction, depression, psychosis, and
liver impairment have been reported with the prolonged
therapeutic use of estrogen containing contraceptives
or other estrogen medications (AHFS, 1997; Kane, 1969;
Kern, 1978; Pittman, 1974; BCDSP, 1973; Wynn, 1986;
Slone, 1981; CGSSYW, 1975; RCGP, 1978).
9.2.2 Inhalation
No data available
9.2.3 Skin exposure
No data available
9.2.4 Eye contact
No data available
9.2.5 Parenteral exposure
No data available
9.2.6 Other
No data available
9.3 Course, prognosis, cause of death
Based on data from exposure to ethinylestradiol and
other estrogen compounds acute poisoning from
ethinylestradiol would be expected to result in mild, self
limiting symptoms and signs. Death from exposure to this
medication has not been reported. Secondary complications
from the long term use of ethinylestradiol may result in
death from myocardial infarction, stroke or cancer.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Varying degrees of systemic hypertension are
reported with the therapeutic use of estrogen
products, including those containing ethinylestradiol.
This is occasionally clinically significant (AHFS,
1997; Pittman, 1974). Hypertension has also been
reported following an estrogen implant overdose (Eden
1990). Myocardial ischemia, myocardial infarction,
thromboembolic disease, and fluid retention are also
associated with the therapeutic use of estrogen
products in the premenopausal age group (BCDSP, 1973;
AHFS, 1997; Pittman, 1974; Mann, 1975; RCGP, 1981;
RCGP, 1978; Slone, 1981). More recent studies suggest
that the use of hormone replacement therapy in the
post menopausal group may be protective against
cardiovascular disease (Henderson, 1991).
9.4.2 Respiratory
Respiratory effects from acute overdose of
ethinylestradiol are not reported. Todd (1985)
reported on a 22 year old female with a history of
systemic lupus erythematosus who developed pulmonary
hypertension after beginning the oral contraceptive
pill. Pulmonary emboli are reported in patients taking
ethinylestradiol containing oral contraceptive
medication therapeutically (Fiechtner, 1978; AHFS,
1997).
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Headache, dizziness, psychosis and
mental depression are reported with the
therapeutic use of ethinylestradiol
containing oral contraceptives (AHFS 1997;
Herzberg, 1971; Kane 1969; Dennerstein,
1978). The risk of stroke in those taking
ethinylestradiol containing medication
therapeutically is dependent on the
menopausal state. Premenopausal women seem to
have a higher incidence, while those taking
hormone replacement therapy, i.e.
postmenopausal women, have no increased risk,
or a reduced risk (Reynolds, 1993; Finucane,
1993; CGSSYM, 1975). Punnonen (1983) reported
on a 19 year old female who ingested 160 mg
of estradiol valerate. She demonstrated
temporary electroencephalogram changes and
headache.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Nausea and vomiting may occur following acute
overdose of ethinylestradiol containing oral
contraceptives (AHFS, 1997). Parker (1983) described a
young female who developed acute pancreatitis
associated with the ethinylestradiol containing
contraceptive medication.
9.4.5 Hepatic
Hepatic impairment is not reported following
acute overdose of ethinylestradiol. Hepatobiliary
effects are associated with the therapeutic use of
ethinylestradiol containing contraceptive medications.
These include elevated liver function tests,
cholestatic jaundice, and gallbladder disease,
especially cholelithiasis (Kern, 1978; BCDSP, 1973;
AHFS, 1997; Fedorkow, 1989). Liver tumors are
discussed in 7.3.
9.4.6 Urinary
9.4.6.1 Renal
No data available
9.4.6.2 Other
No data available
9.4.7 Endocrine and reproductive systems
Breakthrough vaginal bleeding is reported
following acute overdose of ethinylestradiol
containing contraceptives(Physicians GenRx, 1997;
AHFS, 1997). Glucose intolerance may occur with the
therapeutic use of estrogens (Wynn, 1986). Breast
tenderness is reported with routine use of oral
contraceptives (AHFS, 1997). Baron et al. (1983)
reported on a male employed by a pharmaceutical
company involved in the manufacture of
ethinylestradiol containing oral contraceptive
medication who developed a prolactin secreting
adenoma.
9.4.8 Dermatological
The therapeutic use of ethinylestradiol
containing medication has been associated with the
development of chloasma, melasma, erythema multiforme,
erythema nodosum, and porphyria cutanea tarda
(Physicians GenRx 1997; AHFS, 1997; Sixel-Dietrich
1985).
9.4.9 Eye, ear, nose, throat: local effects
Nasal congestion was reported by Eden (1990)
following an estrogen implant overdose. This may also
occur with the therapeutic use of ethinylestradiol
containing medications (AHFS, 1997). Contact lens
irritation has been reported with the therapeutic use
of ethinylestradiol containing oral contraceptives
(Goldberg 1970).
9.4.10 Haematological
Hematological effects with acute overdose of
ethinylestradiol are not reported. Therapeutic use of
ethinylestradiol containing medication has been
associated with a decrease in antithrombin III, and an
increase in factors VII, III, IX and X. The exact
clinical significance of these changes is not known
(AHFS, 1997).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
No data available.
9.4.12.3 Others
The therapeutic use of
ethinylestradiol containing medication may
also elevate triglyceride levels (Wynn,
1986). Slight increases in triglyceride,
phospholipid and cholesterol levels were
reported by Punnonen (1983), following an
overdose of 160 mg of estradiol
valerate.
9.4.13 Allergic reactions
Some formulations of ethinylestradiol contain
FD & C Yellow No. 5, (tartrazine), which may induce
allergic reactions in sensitive individuals (Product
Information 1992).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Ethinylestradiol has a pregnancy category of
X. Because of the potential for mutagenicity and
teratogenicity ethinylestradiol should not be used
during pregnancy (See 7.4 and 7.5). The effects of
single acute overdose involving ethinylestradiol on
the developing fetus are unknown. Ethinylestradiol is
excreted in breast milk. Jaundice and breast
enlargement have been reported in infants of nursing
mothers concurrently using estrogens (AHFS,
1997).
9.5 Other
Not relevant.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Acute poisoning from ethinylestradiol is mild and self
limiting, and as such treatment is essentially supportive.
However, as in all poisoned patients initially attention
should be given to resuscitative measures, and evaluation of
the patients condition and vital signs. Consideration should
be given to the possibility of concurrent co-ingestions.
Given that gastrointestinal upset usually accompanies acute
poisoning, there may be a need for anti-emetics and or fluid
replacement. In those patients where chronic poisoning is
suspected, treatment depends on the individuals findings, but
may involve the management of acute thromboembolic events,
stroke, myocardial infarction and hypertension.
10.2 Life supportive procedures and symptomatic/specific
treatment
Life supportive measures are generally not required.
However, in all poisoned patients one should make a proper
assessment of the airway, breathing, circulation and
neurological status of the patient. A clear airway should be
maintained. Aspirate secretions from the airway and
administer oxygen if required. Endotracheal intubation should
be performed on an individual basis. Control convulsions with
appropriate drug regimen. Open and maintain at least one
intravenous route. Administer intravenous fluids on an
individual basis. Monitor vital signs. Correct hypotension
and/or hypertension as required. Ethinylestradiol should be
discontinued, after consultation with the prescribing
physician, if signs of chronic toxicity occur.
10.3 Decontamination
Given the relatively benign course of ethinylestradiol
poisoning the induction of emesis or the use of gastric
lavage is rarely indicated, unless other more toxic
co-ingestants are involved. Administer a single dose of
activated charcoal following an acute poisoning. The amount
should be adjusted according to patient age and size.
10.4 Enhanced elimination
No data available. No reports of the use of methods to
enhance the elimination of ethinylestradiol or other estrogen
products were found. Given its relatively benign course in
acute poisoning, it is unlikely that such methods would be
warranted.
10.5 Antidote treatment
10.5.1 Adults
No antidote exists.
10.5.2 Children
No antidote exists.
10.6 Management discussion
Acute poisoning following ethinylestradiol exposure is
uncommon, mild, and self limiting. Following consideration to
the use of methods to decontaminate the gut the treatment is
essentially supportive. Patients with evidence of chronic
poisoning should stop taking ethinylestradiol, after
consultation with the prescribing physician. Their treatment
is on an individual basis, depending on clinical
findings.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Punnonen (1983) reported on a 19 year old female who
ingested 160 mg of estradiol valerate. Her estradiol level
was elevated at 2 nmol/L, as was her serum cholesterol,
triglycerides and phospholipids. An electroencephalogram,
(EEG), demonstrated subcortical disturbance. At one week post
ingestion her EEG was normal.
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
These relate primarily to chronic toxicity.
Ethinylestradiol should be taken only under the supervision
of a physician, who should undertake periodic medical
examinations to check for adverse reactions or signs of
chronic toxicity. Patients with recognized contraindications
(See 4.3) should avoid its use. Patients with a history of
pregnancy induced jaundice should be prescribed
ethinylestradiol with caution. As should patients with a
history of psychosis, mental depression, liver impairment,
and metabolic bone disease. Because estrogens may enhance
epiphyseal plate closure, ethinylestradiol should be used
carefully in young patients. Patients with known tartrazine
allergy should not be prescribed those brands of
ethinylestradiol containing this coloring. Ethinylestradiol
has no known risk of abuse (Product Information,
1992).
12.2 Other
No data available.
13. REFERENCES
AHFS: American Hospital Formulary Service (1997) American
Society of Hospital Pharmacists. Bethesda, MD.
Back DJ, et al (1982) The gut wall metabolism of ethinyloestradiol
and its contribution to the pre-systemic metabolism of
ethinyloestradiol in humans. Br J Clin Pharmacol. 13:325-330.
Baron SH, Sowers JR, Feinberg M (1983) Prolactinoma in a man
following industrial exposure to estrogens. West J Med. 138:720-
722.
Baum J, Holtz F, Bookstein JJ, et al (1973) Possible association
between benign hepatomas and oral contraceptives. Lancet. 2:926-
928.
BCDSP: Boston Collaborative Drug Surveillance Program (1973) Oral
contraceptives and venous thromboembolic disease, surgically
confirmed gallbladder disease, and breast tumors. Lancet. 1:1399-
1404.
Belchetz PE (1994) Hormonal treatment of postmenopausal women.
N Engl J Med. 330:1062-1071
Beller FK (1994) Cardiovascular system: coagulation, thrombosis,
and contraceptive steroids:Is there a link? In: Goldzieher JW ed.
Pharmacolog of the Contraceptive Steroids. Raven Press, New York,
pp. 309-333.
CGSSW Collaborative Group for theStudy of Stroke in Young Women
(1975) Oral contraceptives and stroke in young women: associated
risk factors. JAMA. 231:718-722.
Cornbleet M, et al (1977) Fatal irreversible hypercalcemia in
breast cancer. Br Med J. 1:145.
Dennerstein L, Laby B, Burrows GD, Hyman GJ (1978) Headache and
sex hormone therapy. Headache. 18:146-153.
Eden J (1990) Too much of a good thing? Two cases of oestrogen
overdosage associated with oestradiol implants (letter). Med J
Aust 152:558.
Evans RM (1988) The steroid and thyroid hormone receptor
superfamily. Science. 240:889-895.
Fedorkow DM, et al (1989) Cholestasis induced by estrogen after
liver transplantation. Br Med J. 299: 1080-1081.
Fiechtner JJ, Magnin GE (1978) Multiple pulmonary thromboemboli
and pneumothorax: Complications of exogenous estrogen in an alpha-
1-antitrypsin deficient woman. Wisc Med J. 77:103-106.
Finucane FF, et al (1993) Decreased risk of stroke among
postmenopausal hormone users: results from a national cohort. Arch
Intern Med. 153:73-79.
Goebelsmann U (1986) Pharmacokinetics of contraceptive steroids in
man. In: Gregoire AT, Blye RR, eds. Contraceptive Steroids:
Pharmacology and safety. New York: Plenum, 1986. 67-111.
Goldberg JB (1970) A commentary on oral contraceptive therapy and
contact lens wear. J Amer Opt Assoc. 41(3):237-241.
Goldenthal EI (1971) A compilation of LD50 values in newborn and
adult animals. Tox Appl Pharmacol. 18:185-207.
Greenwald P, Barlow JJ, Nasca PC, Burnett WS (1971) Vaginal cancer
after maternal treatment with synthetic estrogens. N Engl J Med.
285:390-392.
Han XL, Liehr JG (1994) DNA single-strand breaks in kidneys of
Syrian hamsters treated with steroidal estrogens: hormone induced
free radical damage preceding renal malignancy. Carcinogenesis.
15:997-1000.
Hardman JG, Limbird LE, eds. (1996) Goodman and Gilman's The
pharmacological basis of therapeutics, 9th ed. McGraw-Hill, New
York.
Henderson BE (1989) The cancer question: and overview of recent
epidemiologic and retrospective data. Am J Obstet Gynecol.
161:1859-1864.
Henderson BE, et al (1991) Decreased mortality in users of
estrogen replacement therapy. Arch Intern Med. 151:75-78.
Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the
vagina. Association of maternal stilbestrol therapy with tumor
appearance in young women. N Engl J Med. 284:878-881.
Herzberg BN, Draper KC, Johnson AL, Nicol GC (1971) Oral
contraceptives, depression and libido. Br Med J. 3:495-500.
Horeman A, Jones M, Frances, et al (1983) The effect of estrogen
dose on postmenopausal bone loss. N Eng J Med. 309:1405-1407.
Janerich DT, Piper JM, Glebatis DM (1974) Oral contraceptives and
congenital limb-reduction defects. N Eng J Med. 291:697-700.
Jensen J, et al (1985) Cigarette smoking, serum estrogens, and
bone loss during hormone-replacement therapy early after
menopause. N Engl J Med. 313:973.
Kanarkowski R, Tornatore KM, D'Ambrosia R, et al (1988)
Pharmacokinetics of single and multiple doses of ethinylestradiol
and levonorgestrel in relation to smoking. Clin Pharmacol Ther.
43:23-31.
Kane FJ (1969) Psychosis associated with the use of oral
contraceptive agents. S Med J. 62:190-192.
Kern F, Erfling W, Simon F, Dahl R, Mallory A, Starzl T (1978)
Effect of estrogens on the liver. Gastroenterology. 75:512-
522.
Krishnan KRR, et al (1984) Tricyclic-induced akathisia in patients
taking conjugated estrogens. Am J Psychiatry. 141:696.
Lacassagne A (1936) Tumeurs malignes apparus au cours d'un
traitement hormonal combine, chez des souris appartenant a des
lignees refractaires au cancer spontane. CR Soc Biol. 121:607-609.
(in French)
Legler UF, Benet LZ (1986) Marked alterations in dose-dependent
prednisolone kinetics in women taking oral contraceptives. Clin
Pharmacol Ther. 39:425.
Levy EP, Cohen A, Fraser FC (1973) Hormone treatment during
pregnancy and congenital heart defects. Lancet. 1:611.
Lobo RA (1991) Clinical review 27: effects of hormonal replacement
on lipids and lipoproteins in postmenopausal women. J Clin Endo
Metab. 73:925-930.
MacLennan SC, et al (1995) Colorectal cancer and estrogen
replacement therapy: a meta-analysis of epidemiological studies.
Med J Aust. 162:491-493.
Mann J, Vessey MP, Thorogood M, Doll R (1975) Myocardial
infarction in young women with special reference to oral
contraceptive practice. Br Med J. 2(5956):241-245.
Morris JC, et al (1981) Interaction of ethinyloestradiol with
ascorbic acid in man. Br Med J. 283:503.
Nora JJ, Nora AH (1973) Birth defects and oral contraceptives.
Lancet. 1:941-942.
Notelovitz M, et al (1981) Interaction between estrogen and
Dilantin in a menopausal woman. N Engl J Med. 304:788.
Parker WA (1983) Estrogen-induced pancreatitis. Clin Pharm. 2:75-
79
Persson I, et al (1989) Risk of endometrial cancer after treatment
with estrogens alone or in conjunction with progestogens: results
of a prospective study. Br Med J. 298:147-151.
Physicians GenRx (1997) 7th ed. Mosby-Year Book Inc., St. Louis.
Prince RL, Smith M, Dick IM, Price RI, Webb PG, Henderson NK,
Harris MM (1991) Prevention of postmenopausal osteoporosis. A
comparative study of exercise, calcium supplementation, and
hormone-replacement therapy. N Engl J Med. 325:1189-1195.
Product Information (1992) Estinyl (R), ethinylestradiol. Schering
Corporation. New Jersey, USA.
Punnonen R, Salmi T (1983) Effects of a massive single oral dose
of oestradiol valerate in a young woman. Ann Clin Res. 15:134-
136.
RCGP: Royal College of General Practitioners (1974) Oral
contraceptives and health. New York, Pittman.
RCGP: Royal College of General Practitioners (1978) Oral
Contraceptives, venous thrombosis, and varicose veins. J Royal
Coll Gen Pract. 28:393-399.
RCGP: Royal College of General Practitioners' Oral Contraception
Study (1981) Further analyses of mortality in oral contraceptive
users. Lancet. 1:541-546.
Reynolds JEF, et al eds. (1993) Martindale the extra
pharmacopoeia. 13th ed. Pharmaceutical Press, London.
Ross RK, Garbeff P, Paganini-Hill A, et al (1983) Effect of
in-utero exposure to diethylstilbestrol on age at onset of puberty
and on postpubertal hormone levels in boys. Can Med Assoc J.
128:1197-1198.
Roy D, Pathak DN (1995) Histone nuclear proteins are irreversibly
modified by reactive metabolites of diethylstilbestrol. J Tox
Environ Health. 44:449-459.
Rubin GL, et al (1990) Estrogen replacement therapy and the risk
of endometrial cancer: remaining controversies. Am J Obstet
Gynecol. 162:148-154.
Sixel-Dietrich F, Doss M (1985) Hereditary uroporphyrinogen-
decarboxylase deficiency predisposing porphyria cutanea tarda
(chronic hepatic porphyria) in females after oral contraceptive
medication. Arch Derm Res. 278(1):13-16.
Slone D, Shapiro S, Kaufman DW, Rosenburg L, Miettinen OS, Stolley
PD (1981) Risk of myocardial infarction in relation to current and
discontinued use of oral contraceptives. N Engl J Med. 305:420-
424.
Steinberg KK, et al (1991) A meta-analysis of the effect of
estrogen replacement therapy on the risk of breast cancer. JAMA.
265:1985-1990.
Todd GRG, McAteer EJ, Jack CM, Haire M, Roberts DS, Buchanan KD
(1985) Pulmonary hypertension, systemic lupus erythematosus, and
the contraceptive pill. Annal Rheum Dis. 44:266-267.
Walsh BW, Li H, Sacks FM (1994) Effects of postmenopausal hormone
replacement with oral and transdermal estrogen on high density
lipoprotein metabolism. J Lipid Res. 35:2083-2093.
Weber A, et al (1996) Can grapefruit juice influence
ethinylestradiol bioavailability? Contraception. 53:41.
Whitehead ED, Leiter E (1981) Genital abnormalities and abnormal
semen analyses in male patients exposed to diethylstilbestrol in
utero. J Urol. 125:47-50.
Wingo PA, et al (1987) The risk of breast cancer in postmenopausal
women who have used estrogen replacement therapy. JAMA. 257:209-
215.
Wynn V, Godsland I (1986) Effects of oral contraceptives on
carbohydrate metabolism. J Reprod Med. 31(9) (Supplement):892-
897.
Yager JD, Zurlo J, Ni N (1991) Sex hormones and tumor promotion in
liver. Proceedings of the Society for Experimental Biology and
Medicine. 198:667-674.
14. AUTHOR(S), ETC.
Author: John Fergus Kerr MBBS
Toxicology Treatment Program
University of Pittsburgh Medical Center
Room NE-583, MUH
200 Lothrop Street
Pittsburgh, Pennsylvania, USA, 15213.
Tel: 412-6486800
Fax: 412-6486855
Date: 1997
Co-author: John G. Benitez MD MPH
Toxicology Treatment Program
University of Pittsburgh Medical Center
Room NE-583, MUH
200 Lothrop Street
Pittsburgh, Pennsylvania, USA, 15213.
Tel: 412-6486800
Fax: 412-6486855
Peer review: INTOX-10 Meeting, Rio, Brazil, September 1997 (Drs
Cobaugh