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ESTROGENS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Estrogens are naturally occurring hormones or synthetic steroidal or nonsteroidal compounds with estrogenic activity.

Specific Substances

    A) ESTRADIOL
    1) Beta-oestradiol
    2) Dihydrofolliculine
    3) Dihydrotheelin
    4) Dihydroxyestrin
    5) Estra-1,3,5(10)-triene-3,17beta-diol
    6) Oestradiol
    7) CAS 50-28-2
    ESTRONE
    1) 3-Hydroxyestra-1,3,5(10)-trien-17-one
    2) Folliculin
    3) Ketohydroxyoestrin
    4) Oestrone
    5) Oestronrum
    6) CAS 53-16-7
    ESTRIOL
    1) Estra-1,3,5(10)-trien-3,16alpha,17beta-triol
    2) Oestriol
    3) Theelol
    4) CAS 50-27-1
    EQUILIN
    1) 3-Hydroxyestra-1,2,5(10),7-tetraen-17-one
    2) CAS 474-96-2
    EQUILENIN
    1) 11,12,13,14,15,16-Hexahydro-3-hydroxy-13-methyl-
    2) 17H-cyclopenta (a)phenanthren-17-one
    3) CAS 517-09-9
    DIETHYLSTILBESTROL
    1) Diaethylstilboestrolum
    2) Diethylstilbestrolum
    3) Diethylstilboestrol
    4) (E)-alpha beta-Diethylstilbene-4-4'-diol
    5) NSC 3070
    6) Stilboestrol
    7) CAS 56-53-1
    DIENESTROL
    1) Dehydrostilbestrol
    2) Dienestrolum
    3) Dienoestrol
    4) Dienoestrolum
    5) (E,E)-4,4'-(Di(ethylidine)ethylene)diphenol
    6) Oestrodienolum
    7) CAS 84-17-3
    8) CAS 13029-44-2 (E,E)
    CHLOROTRIANISENE
    1) Chlorotris(4-methoxy phenyl)ethylene
    2) Chlortrianisenum
    3) Tri-p-anisylchloroethylene
    4) CAS 569-57-3
    GENERAL TERMS
    1) EE
    2) DES
    3) ESTORAL
    4) NORETHISTERONE

    1.2.1) MOLECULAR FORMULA
    1) ESTRADIOL: C18H24O2
    2) ESTRADIOL ACETATE: C20H26O3
    3) ESTRADIOL CYPIONATE: C26H36O3
    4) ESTRADIOL HEMIHYDRATE: C18H24O2.1/2 H2O
    5) ESTRADIOL VALERATE: C23H32O3
    6) ESTROPIPATE: C18H22O5S.C4H10N2

Available Forms Sources

    A) FORMS
    1) CHLOROTRIANISENE: 12 mg, 25 mg, and 72 mg liquid filled capsules (Tace(R), Merrell Dow).
    2) CONJUGATED ESTROGENS: 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, and 2.5 mg tablets; 25 mg for injection, 0.0625% vaginal cream:
    1) Premarin(R), Ayerst
    2) Progens(R), Major
    3) DIENESTROL: 0.01% vaginal cream
    1) DV(R), Merrell Dow
    2) Estraguard(R), Reid-Rowell
    3) Ortho(R) Dienestrol, Ortho
    4) DIETHYLSTILBESTROL: 1 and 5 mg tablets, 0.1 mg, 1 mg, and 5 mg enteric coated tablets
    5) ESTRADIOL: 1 mg and 2 mg tablets, 0.05 mg/24 hours (4 mg/10 cm(2)) and 0.1 mg/24 hours (8 mg/20 cm(2)) topical transdermal system, and 0.01% vaginal cream
    1) Estrace(R) tablets and vaginal cream (Mead Johnson)
    2) Estraderm(R) transdermal system (Ciba)
    6) ESTRADIOL CYPIONATE: 1 mg/mL and 5 mg/mL in oil for IM injection
    1) Depo(R)-Estradiol (Upjohn)
    2) Depanate(R) (Western Research)
    3) depGynogen(R) (Forest)
    4) Depogen(R) (Hyrex)
    5) Dura-Estrin(R) (Hauck)
    6) E-cypionate(R) (Legere)
    7) EstroCyp(R) (Keene)
    8) Estrofem(R) (Pasadena)
    9) Estroject-LA(R) (Mayrand)
    10) Estranol-LA(R) (Central)
    11) Hormogen(R) Depot (Mallard)
    7) ESTRADIOL VALERATE: 10 mg/mL, 20 mg/mL, and 40 mg/mL in oil for IM injection
    1) Delestrogen(R) (Squibb)
    2) Dioval(R) (Keene)
    3) Duragen(R) (Hauck)
    4) Estradiol LA(R) (Vortech)
    5) Feminate(R) (Western Research)
    6) Gynogen LA(R) (Forest)
    7) Valergen(R) (Hyrex)
    8) Estra-L(R) (Pasadena)
    8) ETHINYL ESTRADIOL: 0.02 mg, 0.05 mg, and 0.5 mg tablets
    1) Estinyl(R) (Schering)
    2) Feminone(R) (Upjohn)
    9) POLYESTRADIOL PHOSPHATE: 40 mg for injection
    1) Estradurin(R) (Ayerst)
    10) Zearalenone is an estrogenic mycotoxin produced by the grain mold Fusarium roseum (Long & Diekman, 1989).
    B) SOURCES
    1) Estrogens are hormones secreted primarily by the ovarian follicles and also by the adrenals, corpus luteum, placenta and testes, or they are synthetic steroidal and non-steroidal compounds.
    C) USES
    1) Estrogens are naturally occurring hormones secreted primarily by the ovarian follicles and also by the adrenals, corpus luteum, placenta and testes used pharmaceutically for female birth control, to treat prostate cancer and to treat symptoms of menopause (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info PREMARIN(R) injection, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Estrogens are naturally occurring hormones secreted primarily by the ovarian follicles and also by the adrenals, corpus luteum, placenta, and testes used pharmaceutically for female birth control, to treat prostate cancer, and to treat symptoms of menopause.
    B) PHARMACOLOGY: Endogenous estrogens are mostly responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. The primary source of estrogen in normally cycling adult female is the ovarian follicle. Estrogens bind to nuclear receptors in estrogen-responsive tissues to activate pituitary secretion of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone through negative feedback mechanisms.
    C) EPIDEMIOLOGY: Estrogens are widely used; however, overdose is rare and significant toxicity has not been reported after overdose.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Hypertension, edema, nausea, vomiting, migraine. LESS COMMON: Myocardial infarction, venous thromboembolism, anaphylaxis, cerebrovascular accident, and neoplasm.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding in women.
    0.2.20) REPRODUCTIVE
    A) Estrogens are contraindicated during pregnancy; however, inadvertent use of estrogens and progestins as an oral contraceptive during early pregnancy appears to cause little or no increased risk of birth defects. Maternal ingestion of diethylstilbestrol (DES) during early pregnancy increases the risk of vaginal adenocarcinoma and the incidence of epididymal cysts, maldescended testes, hypoplastic testes, varicoceles, spermatozoal defects, and perhaps seminoma, in the exposed offspring many years later. Estrogen is detectable in breast milk and may decrease the quantity of milk. Use during nursing is either contraindicated or not recommended, depending on the preparation.
    B) The following estrogens are classified as FDA pregnancy category X: CHLOROTRIANISENE, CONJUGATED ESTROGENS, DIENESTROL, DIETHYLSTILBESTROL, ESTERIFIED ESTROGENS, ESTERIFIED ESTROGENS/METHYLTESTOSTERONE, ESTRADIOL, ESTROPIPATE, ETHINYL ESTRADIOL, and MESTRANOL.
    0.2.21) CARCINOGENICITY
    A) In the Women’s Health Initiative (WHI) estrogen-alone substudy, invasive breast cancer was not associated with estrogen alone therapy, but a significant risk existed when estrogen was combined with a progestin. Unopposed estrogens will increase the risk for endometrial cancer if used by a woman with a uterus; the addition of a progestin will reduce the risk for endometrial hyperplasia, which may be a precursor to endometrial cancer. The WHI estrogen plus progestin substudy reported a nonsignificant increased risk of ovarian cancer with estrogen plus progestin; epidemiologic studies have demonstrated an increased risk with estrogen alone. Females who were exposed in utero to diethylstilbestrol have an increased risk of vaginal clear cell adenocarcinoma.
    B) At the time of this review, the manufacturer does not report any carcinogenic potential of conjugated estrogens/bazedoxifene.

Laboratory Monitoring

    A) Estrogen blood levels are not clinically useful after overdose.
    B) No specific lab work (CBC, electrolytes, urinalysis) are needed unless otherwise indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Acute toxicity is extremely rare from these compounds, except perhaps local effects from transdermal and intravenous or intramuscular administration. In terms of care for chronic use, the most immediate treatment would be cessation of use and then supportive care for associated symptoms.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Acute toxicity from estrogen use is not expected, and the mainstay of treatment would be cessation of use and supportive care of symptoms.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity is unlikely following acute single exposure of excessive amounts. Gastric decontamination is rarely necessary.
    2) HOSPITAL: Significant toxicity is not expected, GI decontamination is rarely indicated.
    D) ANTIDOTE
    1) There is no specific antidote for estrogens.
    E) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional exposures can be watched at home with follow up with their regular physician as needed.
    2) OBSERVATION CRITERIA: Patients with significant adverse effects or deliberate overdose should be sent to a healthcare facility.
    3) ADMISSION CRITERIA: Admission is rarely necessary after acute overdose. Patients with severe adverse reactions (eg, strokes) should be admitted, and depending on the severity of their symptoms, may merit an ICU admission. Criteria for discharge include resolution or treatment of their symptoms.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    G) PITFALLS
    1) When managing a suspected overdose with estrogens, the possibility of coingestants should be considered. If severe toxicity develops other causes should be sought.
    H) PHARMACOKINETICS
    1) Water-soluble and well absorbed from GI tract. Metabolism of exogenous estrogens are the same as endogenous estrogens. Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. Metabolites and conjugates (sulfate and glucuronide) are excreted in the urine.
    I) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis for some of the adverse reactions from the use of estrogens (eg, stroke, MI) can be quite large. However, there are some malignancies that can secrete hormones and might mimic estrogen overdose.
    0.4.6) PARENTERAL EXPOSURE
    A) Overdose of parenteral estrogens is expected to produce the same effects as overdose with the oral formulation. See ORAL EXPOSURE for further information.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. THERAPEUTIC DOSE: The oral therapeutic dose can range fro 0.3 mg to 10 mg, depending on the specific substance (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info PREMARIN(R) injection, 2008). Intramuscular and intravenous doses can range from 1.5 mg to 30 mg, depending on the specific substance (Prod Info DEPO(R)-ESTRADIOL estradiol cypionate concentration for IM injection, 2006; Prod Info DELESTROGEN(R) solution for IM injection, 2004). Intravaginal and transdermal delivered doses range from 0.025 mg/day to 0.1 mg/day (Prod Info Femring(R) vaginal ring, 2010; Prod Info CLIMARA(R) transdermal patch, 2007)

Clinical Effects

Summary Of Exposure

    A) USES: Estrogens are naturally occurring hormones secreted primarily by the ovarian follicles and also by the adrenals, corpus luteum, placenta, and testes used pharmaceutically for female birth control, to treat prostate cancer, and to treat symptoms of menopause.
    B) PHARMACOLOGY: Endogenous estrogens are mostly responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. The primary source of estrogen in normally cycling adult female is the ovarian follicle. Estrogens bind to nuclear receptors in estrogen-responsive tissues to activate pituitary secretion of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone through negative feedback mechanisms.
    C) EPIDEMIOLOGY: Estrogens are widely used; however, overdose is rare and significant toxicity has not been reported after overdose.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Hypertension, edema, nausea, vomiting, migraine. LESS COMMON: Myocardial infarction, venous thromboembolism, anaphylaxis, cerebrovascular accident, and neoplasm.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding in women.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) VISUAL DISTURBANCE: Contact lens intolerance and visual disturbances may occur in patients receiving estrogens therapeutically (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Rhinitis and sinusitis have been reported with the therapeutic use of estrogens (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    B) WITH POISONING/EXPOSURE
    1) NASAL CONGESTION has been reported in cases of estradiol implant overdose (Eden, 1990)

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild hypertension to clinically significant hypertension has been observed in some women receiving estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    B) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) A positive association exists between estrogen dosage and thromboembolic disorders (Lundgren et al, 1986).
    b) Risk for thromboembolic disorders and consequent pulmonary embolism is increased by current oral contraceptive estrogen use or postmenopausal estrogen use, but past use of postmenopausal hormones or oral contraceptives does not increase risk for thromboembolic disorders (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005; Grodstein et al, 1996).
    C) EDEMA, GENERALIZED
    1) WITH THERAPEUTIC USE
    a) Edema and fluid retention may occur with conjugated estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    D) MYOCARDIAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) Ischemic heart disease was seen in patients with prostatic cancer taking polyestradiol phosphate and ethinyl estradiol or estramustine phosphate (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005; Lundgren et al, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Subcortical disturbance was noted on a EEG performed on the first day following a single oral dose of 160 mg of estradiol valerate. The EEG 1 week after the overdose was normal (Punnonen & Salmi, 1983).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in approximately 36% of patients taking estrogens, with or without progestins (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Headache was reported following a single acute ingestion of 160 mg of estradiol valerate in a 19-year-old woman (Punnonen & Salmi, 1983).
    1) The occurrence of persistent severe headaches may be a sign of impending cerebrovascular occlusion (deMarinis & Arnett, 1978).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) In acute overdosage, the effects most frequently noted include abdominal cramping, nausea, vomiting, and diarrhea (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    B) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute pancreatitis in a 23-year-old woman was associated with the use of an estrogen-containing contraceptive (Parker, 1983).
    b) Pancreatitis due to elevated levels of triglycerides may also occur in women with preexisting hypertriglyceridemia(Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    C) BILIARY CALCULUS
    1) WITH THERAPEUTIC USE
    a) Estrogen is thought to promote the formation of gallstones by increasing cholesterol saturation of bile, altering bile acid composition, and decreasing bile flow (Uhler et al, 1998).
    b) Both transdermal and oral estrogens significantly increase the biliary saturation of cholesterol and decrease the time required to form cholesterol crystals in bile in vitro (Uhler et al, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Liver function tests may be elevated in patients receiving estrogens therapeutically (Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice may occur in patients receiving estrogens therapeutically (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    C) MALIGNANT NEOPLASM OF LIVER
    1) WITH THERAPEUTIC USE
    a) Liver tumors have been associated with estrogen-containing oral contraceptive use (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CHLOASMA
    1) WITH THERAPEUTIC USE
    a) Melasma or chloasma is the most frequent adverse dermatologic reaction seen during estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    B) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Hemorrhagic eruption, erythema multiforme, and erythema nodosum have also been associated with estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    C) EXCESSIVE HAIR GROWTH
    1) WITH THERAPEUTIC USE
    a) Hirsutism has been reported with estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    D) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been noted during estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    E) PORPHYRIA CUTANEA TARDA
    1) WITH THERAPEUTIC USE
    a) Porphyria cutanea tarda may occur as an adverse effect of estrogen therapy (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    F) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Contact dermatitis was described in 9 women who used transdermal estradiol patches in one report (McBurney et al, 1989). This is a common adverse effect due to the nature of the adhesive in the patches.

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 61-year-old man employed by a pharmaceutical company that manufactured oral contraceptive pills was exposed to norethindrone and mestranol daily.
    1) He developed bilateral breast swelling, nipple tenderness, intermittent episodes of impotence, diminished libido, galactorrhea, gynecomastia, prolactin level of 66 nanograms/dL, and adenoma (Baron et al, 1983).
    B) ABNORMAL GLUCOSE TOLERANCE TEST
    1) WITH THERAPEUTIC USE
    a) Decreased glucose tolerance, increased serum triglyceride concentrations, and possible folate deficiency may occur in women receiving estrogens therapeutically (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    C) DISORDER OF MENSTRUATION
    1) WITH THERAPEUTIC USE
    a) Changes in the menstrual cycle (breakthrough bleeding, spotting, missed menses, amenorrhea, changes in menstrual flow) may occur in women receiving estrogens therapeutically (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).
    D) BREAST TENDERNESS
    1) WITH THERAPEUTIC USE
    a) Chronic exposure to estrogenic substances may produce breast tenderness, enlargement, and secretion (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info estradiol oral tablets, 2005; Prod Info MENEST(R) oral tablets, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Estrogens are contraindicated during pregnancy; however, inadvertent use of estrogens and progestins as an oral contraceptive during early pregnancy appears to cause little or no increased risk of birth defects. Maternal ingestion of diethylstilbestrol (DES) during early pregnancy increases the risk of vaginal adenocarcinoma and the incidence of epididymal cysts, maldescended testes, hypoplastic testes, varicoceles, spermatozoal defects, and perhaps seminoma, in the exposed offspring many years later. Estrogen is detectable in breast milk and may decrease the quantity of milk. Use during nursing is either contraindicated or not recommended, depending on the preparation.
    B) The following estrogens are classified as FDA pregnancy category X: CHLOROTRIANISENE, CONJUGATED ESTROGENS, DIENESTROL, DIETHYLSTILBESTROL, ESTERIFIED ESTROGENS, ESTERIFIED ESTROGENS/METHYLTESTOSTERONE, ESTRADIOL, ESTROPIPATE, ETHINYL ESTRADIOL, and MESTRANOL.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) ESTROGENS
    a) Estrogens are contraindicated during pregnancy; however, inadvertent use of estrogens and progestins as an oral contraceptive during early pregnancy appears to cause little or no increased risk of birth defects (Prod Info NuvaRing(R) vaginal ring, 2013; Prod Info Climara(R) transdermal system patch, 2013; Prod Info CombiPatch(R) transdermal system patch, 2013; Prod Info ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, 2010; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Femring(R) vaginal ring, 2010; Prod Info Vagifem(R) vaginal tablets, 2009).
    2) DIETHYLSTILBESTROL
    a) Maternal ingestion of diethylstilbestrol during early pregnancy increases the risk of vaginal adenocarcinoma, epididymal cysts, maldescended testes, urogenital abnormalities, hypoplastic testes, varicoceles, spermatozoal defects, and perhaps seminoma, in the exposed offspring (Conley et al, 1983; Ross et al, 1983; Whitehead & Leiter, 1981; Bibbo et al, 1977; Gill et al, 1977; Herbst et al, 1971).
    b) Postpubertal boys exposed in utero to diethylstilbestrol had significantly smaller testes (less than 3000 mm(2) in area) than control subjects in a study of 23 boys (Ross et al, 1983).
    c) In a study of 583 cases and 251 referents, when mothers were certainly or probably exposed to diethylstilbestrol (DES) in utero, their sons appeared to have an increased risk of hypospadias (odds ratio 2.6; 95% confidence interval (CI), 0.8 to 9). Conditional logistic regression analyses were performed on a subset of the parents of 232 cases for whom both referent parents were also available. The association between maternal DES exposure and hypospadias was much stronger in this analysis when compared with the initial analyses (odds ratio 4.9; 95% CI, 1.1 to 22.3). When the analyses were restricted to mothers certainly exposed to DES in utero the same was observed (odds ratio 3; 95% CI, 0.6 to 14.9) (Brouwers et al, 2006).
    B) LACK OF EFFECT
    1) ETHINYL ESTRADIOL/ETONOGESTREL
    a) An increased risk of birth defects has not been demonstrated in infants following maternal use before or during early pregnancy. There is no evidence of teratogenicity, particularly in limb reduction or cardiovascular defects when women inadvertently used the combination contraceptive early in pregnancy (Prod Info NuvaRing(R) vaginal ring, 2013).
    C) ANIMAL STUDIES
    1) CONJUGATED ESTROGENS WITH BAZEDOXIFENE
    a) RATS, RABBITS: During animal studies, administration of maternally toxic bazedoxifene doses greater than or equal to 1 mg/kg/day (greater than or equal to 0.3 times the human AUC at the 20 mg dose) in rats resulted in a reduction in live fetuses and/or a reduction in fetal body weight. There were no reports of fetal developmental anomalies. In a similar study, administration of maternally toxic bazedoxifene doses greater than or equal to 0.5 mg/kg/day (approximately 2 times the human AUC at the 20 mg dose) in pregnant rabbits resulted in abortion and increased heart and skeletal anomalies, including ventricular septal defects, ossification delays, and misaligned bones of the spine and skull (Prod Info DUAVEE(R) oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) CONJUGATED ESTROGENS WITH BAZEDOXIFENE
    1) Bazedoxifene acetate/conjugated estrogens combination is contraindicated during pregnancy and should not be used in women who are or may become pregnant. Use of bazedoxifene acetate/conjugated estrogens during pregnancy may result in fetal harm. Animal studies have not been conducted with the combination bazedoxifene acetate/conjugated estrogens. If pregnancy occurs, apprise patient of possible hazard to fetus (Prod Info DUAVEE(R) oral tablets, 2013).
    B) DIETHYLSTILBESTROL
    1) A follow-up study that combined 3 cohort studies found increased risks for 12 adverse health effects, including reproductive outcomes and cancer diagnoses, for women exposed to diethylstilbestrol (DES) in utero (n=4653) compared with unexposed controls (n=1927). Cumulative risks and hazard ratios (HRs), calculated with age as the time metric and adjusted for date of birth and cohort, were as follows for women exposed to DES as compared with women not exposed: for infertility, 33.3% vs 15.5% (HR, 2.37; 95% CI, 2.05 to 2.75); spontaneous abortion, 50.3% vs 38.6% (HR, 1.64; 1.42 to 1.88); ectopic pregnancy, 14.6% vs 2.9% (HR, 3.72; 2.58 to 5.38); loss of second-trimester pregnancy, 16.4% vs 1.7% (HR, 3.77; 2.56 to 5.54); preterm delivery, 53.3% vs 17.8% (HR, 4.68; 3.74 to 5.86); preeclampsia, 26.4% vs 13.7% (HR, 1.42; 1.07 to 1.89); stillbirth, 8.9% vs 2.6% (HR, 2.45; 1.33 to 4.54); neonatal death, 7.8% vs 0.6% (HR, 8.12, 3.53 to 18.65); early menopause, 5.1% vs 1.7% (HR, 2.35; 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs 3.4% (HR, 2.28; 1.59 to 3.27); breast cancer at 40 years of age or older, 3.9% vs 2.2% (HR, 1.82; 1.04 to 3.18); clear-cell adenocarcinoma, 0.1% vs 0%. Overall, exposed women with vaginal epithelial changes had significantly higher cumulative and excess risks for most outcomes than exposed women without vaginal epithelial changes (Hoover et al, 2011).
    C) PREGNANCY CATEGORY
    1) Manufacturers have classified the following estrogens as FDA pregnancy category X:
    1) CONJUGATED ESTROGENS WITH BAZEDOXIFENE (Prod Info DUAVEE(R) oral tablets, 2013)
    1) CHLOROTRIANISENE (Prod Info Tace(R), 1990)
    2) CONJUGATED ESTROGENS (Prod Info Premarin(R), 2003)
    3) DIENESTROL (Prod Info Ortho(R) Dienestrol Cream, 1996)
    4) DIETHYLSTILBESTROL (Prod Info Stilphostrol(R), 1996)
    5) ESTERIFIED ESTROGENS (Prod Info MENEST(R) oral tablets, 1999)
    6) ESTERIFIED ESTROGENS/METHYLTESTOSTERONE (Prod Info ESTRATEST(R) oral tablets, ESTRATEST(R) HS half-strength oral tablets, 2005)
    7) ESTRADIOL (Prod Info estradiol oral tablets, 2005)
    8) ESTROPIPATE (Prod Info estropipate oral tablets, 2002)
    9) ETHINYL ESTRADIOL (Prod Info Estinyl(R), 1986)
    10) MESTRANOL (Prod Info Necon(R)1/50 oral tablets, 2007)
    2) The manufacturer has not published a pregnancy category for these estrogens, but they are contraindicated during pregnancy:
    1) CONJUGATED ESTROGENS SYNTHETIC A (Prod Info synthetic conjugated estrogens, A vaginal cream, 2008)
    2) CONJUGATED ESTROGENS SYNTHETIC B (Prod Info ENJUVIA(TM) oral tablets, 2007)
    3) ETHINYL ESTRADIOL/ETONOGESTREL (Prod Info NuvaRing(R) vaginal ring, 2013)
    4) ESTRADIOL/NORETHINDRONE ACETATE (Prod Info CombiPatch(R) transdermal system patch, 2013; Prod Info ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, 2010)
    D) LACK OF EFFECT
    1) ESTRADIOL NORETHINDRONE ACETATE
    a) Estradiol/norethindrone acetate is contraindicated during pregnancy and there is no indication for use in pregnant women. However, inadvertent use of estrogens and progestins as an oral contraceptive during early pregnancy appears to cause little to no increased risk of birth defects (Prod Info CombiPatch(R) transdermal system patch, 2013; Prod Info ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, 2010).
    E) ANIMAL STUDIES
    1) CONJUGATED ESTROGENS WITH BAZEDOXIFENE
    a) RATS, RABBITS: During animal studies, administration of maternally toxic bazedoxifene doses greater than or equal to 1 mg/kg/day (greater than or equal to 0.3 times the human AUC at the 20 mg dose) in rats resulted in a reduction in live fetuses and/or a reduction in fetal body weight. There were no reports of fetal developmental anomalies. In a similar study, administration of maternally toxic bazedoxifene doses greater than or equal to 0.5 mg/kg/day (approximately 2 times the human AUC at the 20 mg dose) in pregnant rabbits resulted in abortion and increased heart and skeletal anomalies, including ventricular septal defects, ossification delays, and misaligned bones of the spine and skull (Prod Info DUAVEE(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Estrogen administration may decrease the quantity of breast milk and is not recommended during nursing. Detectable amounts of estrogen have been identified in breast milk (Prod Info NuvaRing(R) vaginal ring, 2013; Prod Info Climara(R) transdermal system patch, 2013; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Femring(R) vaginal ring, 2010; Prod Info Vagifem(R) vaginal tablets, 2009).
    2) CONJUGATED ESTROGENS WITH BAZEDOXIFENE
    a) Bazedoxifene acetate/conjugated estrogens combination is contraindicated in nursing mothers. It is unknown whether bazedoxifene acetate/conjugated estrogens is excreted into human milk however, estrogens have been detected in the milk of women, and estrogen administration may decrease the quality and quantity of breast milk (Prod Info DUAVEE(R) oral tablets, 2013).
    3) ETHINYL ESTRADIOL/ETONOGESTREL
    a) The effects of using etonogestrel/ethinyl estradiol while nursing are unknown. However, combined hormonal contraceptives are excreted in breast milk and can reduce milk production. It is recommended that an alternate form of contraception be used during breastfeeding and until the child is completed weaned from breast milk (Prod Info NuvaRing(R) vaginal ring, 2013).
    4) ESTRADIOL WITH NORETHINDRONE ACETATE
    a) Estradiol/norethindrone acetate should not be used during lactation. Estrogens and progestins have been detected in breast milk during use. Estrogen administration may decrease the quality and quantity of breast milk (Prod Info CombiPatch(R) transdermal system patch, 2013; Prod Info ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, 2010).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info DUAVEE(R) oral tablets, 2013; Prod Info CombiPatch(R) transdermal system patch, 2013; Prod Info ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, 2010).
    B) ANIMAL STUDIES
    1) RATS: Fertility impairment was temporary in rats, with fertility returning after treatment was withdrawn (Prod Info NuvaRing(R) vaginal ring, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) In the Women’s Health Initiative (WHI) estrogen-alone substudy, invasive breast cancer was not associated with estrogen alone therapy, but a significant risk existed when estrogen was combined with a progestin. Unopposed estrogens will increase the risk for endometrial cancer if used by a woman with a uterus; the addition of a progestin will reduce the risk for endometrial hyperplasia, which may be a precursor to endometrial cancer. The WHI estrogen plus progestin substudy reported a nonsignificant increased risk of ovarian cancer with estrogen plus progestin; epidemiologic studies have demonstrated an increased risk with estrogen alone. Females who were exposed in utero to diethylstilbestrol have an increased risk of vaginal clear cell adenocarcinoma.
    B) At the time of this review, the manufacturer does not report any carcinogenic potential of conjugated estrogens/bazedoxifene.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) CONJUGATED ESTROGENS/BAZEDOXIFENE: At the time of this review, the manufacturer does not report any carcinogenic potential (Prod Info DUAVEE(R) oral tablets, 2013).
    B) BREAST CARCINOMA
    1) The Women’s Health Initiative (WHI) substudy demonstrated no increased risk of invasive breast cancer for patients taking oral conjugated estrogens 0.625 mg/day alone over an average of 7.1 years when compared with placebo (relative risk (RR), 0.8). However, the WHI substudy found that estrogen plus progestin therapy (conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day) was associated with an increased risk of invasive breast cancer after a mean follow-up of 5.6 years when compared with placebo (RR, 1.24). The absolute risk for developing breast cancer with estrogen plus progestin was 41 versus 33 cases per 10,000 women-years when compared with placebo, and the risk increased with a history of prior hormone therapy. Observational studies have also found that the use of estrogen plus progestin over several years will increase the risk for breast cancer and that therapy with estrogen alone will lead to a smaller increased risk. The risk increased with duration of use and returned to baseline approximately 5 years after stopping therapy. No significant variation in cancer risk was demonstrated between estrogen or progestin products, doses, or routes of administration (Prod Info Climara(R) transdermal system patch, 2013; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Vagifem(R) vaginal tablets, 2009; Prod Info Femring(R) vaginal ring, 2010).
    2) Endogenous gonadal hormones (estrogen and progesterone) have an important role in causing breast cancer. Early age at menarche and late menopause increase the risk of breast cancer. Postmenopausal women taking unopposed estrogen or taking estrogen combined with progestin have an increased risk of breast cancer compared with postmenopausal women taking no hormone replacement therapy. Older women (60 to 64 years of age) have the highest increased risk (Colditz et al, 1995).
    C) CLEAR CELL ADENOCARCINOMA
    1) A cohort study described 4536 diethylstilbestrol-exposed daughters (81% responded) and 1544 unexposed daughters (79% responded) who were first identified in the mid 1970s. Results showed no increased overall risk for all cancers (rate ratio, 0.96; 95% confidence interval (CI), 0.58 to 1.56) or for individual cancer sites, with the exception of clear cell adenocarcinoma (CCA). Among the exposed daughters, 3 cases of vaginal CCA were identified, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1 to 126.2) in comparison with population-based incidence rates. A limitation of this study is the average age of the daughters, which was 38 years old. Continued studies are necessary to determine cancer risks occurring during menopausal years (Hatch et al, 1998).
    D) ENDOMETRIAL CARCINOMA
    1) Unopposed estrogens will increase the risk for endometrial cancer if used by a woman with a uterus. The risk for cancer is about 2- to 12-fold greater for estrogen users when compared with nonusers, and the risk is duration- and dose-dependent. There is no significant increased risk when estrogens are used for less than one year; however, the risk increases 15- to 24-fold when estrogens are used for 5 to 10 years or longer. When comparing equivalent doses, natural and synthetic estrogens have a similar endometrial risk profile. The addition of a progestin to estrogen therapy will reduce the risk for endometrial hyperplasia, which may be a precursor to endometrial cancer (Prod Info Climara(R) transdermal system patch, 2013; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Vagifem(R) vaginal tablets, 2009; Prod Info Femring(R) vaginal ring, 2010).
    2) There is a lower risk of endometrial cancer associated with use of a combined estrogen plus progestogen regimen in postmenopausal women than with unopposed estrogens. However, long-term (5 years or more) use of combined therapy, even when the cyclic progestin (eg, medroxyprogesterone acetate) is added for more than 10 days per month, is associated with an increased risk of endometrial cancer (Beresford et al, 1997).
    3) Continuous combined replacement therapy (adding progestin to each dose of estrogen) and taking progestin for 10 days or more each month with estrogen had similar results in reducing the risk for endometrial cancer in postmenopausal women using estrogen replacement hormones (Pike et al, 1997).
    E) OVARIAN CANCER
    1) The Women’s Health Initiative (WHI) substudy reported a nonsignificant increased risk of ovarian cancer for patients taking oral estrogen plus progestin therapy (conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day) over an average of 5.6 years when compared with placebo (relative risk, 1.58; 95% confidence interval, 0.77 to 3.24; absolute risk, 4 vs 3 cases per 10,000 women-years). Epidemiologic studies have demonstrated an increased risk of ovarian cancer for patients using estrogen alone for 5 or more years; the duration of exposure associated with an increased cancer risk was inconsistent (Prod Info Climara(R) transdermal system patch, 2013; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Vagifem(R) vaginal tablets, 2009; Prod Info Femring(R) vaginal ring, 2010).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Animal studies indicate long-term continuous administration of natural and synthetic estrogens increase the frequency of breast, uterine, cervical, vaginal, testicular, and hepatic carcinomas (Prod Info Climara(R) transdermal system patch, 2013; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info Vagifem(R) vaginal tablets, 2009; Prod Info Femring(R) vaginal ring, 2010; Prod Info DUAVEE(R) oral tablets, 2013).
    B) HEPATIC CARCINOMA
    1) A correlation between the prolonged use of oral contraceptives and the development of liver cancer was demonstrated in rats. The effects on the development of liver neoplasia included: potent promotion of hepatocarcinogenesis in female rats; stimulation of liver growth at doses that were not hepatotoxic; enhancement of a serum/plasma growth factor with enhanced responsiveness of hepatocytes to epidermal growth factor and decreased sensitivity of hepatocytes to growth inhibition; co-mitogenic effects of synthetic estrogens that extended to endogenous estrogens and natural product estrogens; and increased epidermal growth factor receptor protein levels caused by an increase in the half-life of the receptor protein. This process may involve indirect genotoxicity mediated through redox cycling and formation of hydroxylated DNA bases (Yager et al, 1991).

Genotoxicity

    A) Estradiol acetate did not induce mutation in 4 histidine-requiring strains of Salmonella typhimurium and two tryptophan-requiring strains of Escherichia coli (Prod Info Femring(R) vaginal ring, 2010).
    B) CONJUGATED ESTROGENS/BAZEDOXIFENE: At the time of this review, the manufacturer does not report any genotoxic or mutagenic potential (Prod Info DUAVEE(R) oral tablets, 2013).
    C) In vivo studies involving estradiol showed induced single-strand DNA breaks in hamster kidneys, but not in the liver (Han & Liehr, 1994).
    D) Rat liver nuclei were able to convert diethylstilbestrol to histone-binding metabolites, and the activation of diethylstilbestrol was cytochrome P450-dependent. In vivo modification to the active chromatin histone proteins by diethylstilbestrol metabolites may influence gene function. Chromosomal proteins, histones, and non-histones provide structural support to chromatin and have an important role in various aspects of gene function (Roy & Pathak, 1995).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Estrogen blood levels are not clinically useful after overdose.
    B) No specific lab work (CBC, electrolytes, urinalysis) are needed unless otherwise indicated.
    4.1.2) SERUM/BLOOD
    A) ENDOCRINE
    1) Estrogen overdose secondary to estradiol implants should be confirmed by measuring the serum estradiol level. One author recommends that further implants not be administered until serum estradiol concentration is between 200 and 300 pmol/L (Eden, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admission is rarely necessary after overdose. Patients with severe adverse reactions (eg, strokes) should be admitted, and depending on the severity of their symptoms, may merit an ICU admission. Criteria for discharge include resolution or treatment of their symptoms.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional exposures can be watched at home with follow up with their regular physician as needed.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with significant adverse effects or deliberate overdose should be sent to a healthcare facility.

Monitoring

    A) Estrogen blood levels are not clinically useful after overdose.
    B) No specific lab work (CBC, electrolytes, urinalysis) are needed unless otherwise indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Toxicity is unlikely following acute single exposure of excessive amounts. Gastric decontamination is rarely necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity is unlikely following acute single exposure of excessive amounts. Gastric decontamination is rarely necessary unless toxic coingestants are involved.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, particularly blood pressure.
    2) Monitor ECG in patients with cardiac symptoms or severe hypertension.
    3) Routine laboratory monitoring is generally not necessary. Monitor serum electrolytes, serum acetaminophen and salicylated concentrations after self harm ingestion.
    B) DRUG OVERDOSE
    1) In acute single overdosage, toxicity is unlikely and treatment to ease gastrointestinal irritation is all that is required.
    C) CHRONIC POISONING
    1) In chronic toxicity, discontinue medication and monitor for severe signs of toxicity and treat symptomatically.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution.

Abstracts

Case Reports

    A) ADULT
    1) ADVERSE EFFECTS
    a) Three cases of overdose with estradiol implants have been reported (Eden, 1990; Eden, 1988) . The frequency of implantation ranged from 2 to 4 implants per year, in doses of 100 to 200 mg for each implant.
    1) Nasal congestion was reported in 2 cases, and severe facial edema in the other. In one case, markedly elevated serum estradiol levels (2246 pmol/L) persisted 3 years after the last dose was implanted.
    b) Nine cases of contact dermatitis were reported in women using transdermal estradiol patches (McBurney et al, 1989). Patch testing with individual components was inconclusive, suggesting that more than 1 antigen could be implicated (patch adhesive or a component of the vehicle).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. THERAPEUTIC DOSE: The oral therapeutic dose can range fro 0.3 mg to 10 mg, depending on the specific substance (Prod Info PREMARIN(R) oral tablets, 2011; Prod Info PREMARIN(R) vaginal cream, 2008; Prod Info PREMARIN(R) injection, 2008). Intramuscular and intravenous doses can range from 1.5 mg to 30 mg, depending on the specific substance (Prod Info DEPO(R)-ESTRADIOL estradiol cypionate concentration for IM injection, 2006; Prod Info DELESTROGEN(R) solution for IM injection, 2004). Intravaginal and transdermal delivered doses range from 0.025 mg/day to 0.1 mg/day (Prod Info Femring(R) vaginal ring, 2010; Prod Info CLIMARA(R) transdermal patch, 2007)

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) CONJUGATED ESTROGENS
    a) INTRAVAGINAL: 0.5 g to 2 g once daily given cyclically (Prod Info PREMARIN(R) vaginal cream, 2008).
    b) INTRAVENOUS or INTRAMUSCULAR: 25 mg IV or IM, repeat once in 6 to 12 hours as needed for uterine bleeding (Prod Info PREMARIN(R) injection, 2008).
    c) ORAL: 0.3 mg to 10 mg, up to 3 times daily, depending on indication (Prod Info PREMARIN(R) oral tablets, 2007).
    d) TRANSDERMAL: The recommended dose is 0.025 mg/day applied to skin once weekly. Attempts to taper or discontinue drug should only be done at 3 to 6 month intervals (Prod Info Climara(R) transdermal system patch, 2013).
    2) CONJUGATED ESTROGENS/BAZEDOXIFENE
    a) The recommended dose is 1 tablet (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) orally once daily (Prod Info DUAVEE(R) oral tablets, 2013).
    3) ESTERIFIED ESTROGENS
    a) ORAL: 0.3 mg to 10 mg, up to 3 times daily, either continuous or cyclically, depending on the indication (Prod Info MENEST(R) oral tablets, 2005).
    4) ESTRADIOL
    a) ORAL: 0.5 mg to 10 mg, up to 3 times daily, either continuous or cyclically, depending on the indication. INTRAVAGINAL: 1 ring (estradiol 0.0075 mg/day, 2 mg/ring) inserted once every 3 months, 10 mcg tablet daily, or 1 to 4 g cream daily. TOPICAL: 0.25 mg/day to 8.7 mg/day as gel, emulsion, or spray. TRANSDERMAL: 0.025 mg/day to 0.05 mg/day, once to twice weekly (Prod Info estradiol oral tablets, 2005; Prod Info CLIMARA(R) transdermal patch, 2007; Prod Info ESTRADERM(R) transdermal system, 2005; Prod Info VIVELLE-DOT(R) transdermal system, 2004).
    b) INTRAVAGINAL: 1 ring (estradiol 0.05 mg/day) inserted once every 3 months (Prod Info Femring(R) vaginal ring, 2014).
    5) ESTRADIOL CYPIONATE
    a) INTRAMUSCULAR: 1.5 mg to 5 mg IM at monthly intervals (Prod Info DEPO(R)-ESTRADIOL estradiol cypionate concentration for IM injection, 2006)
    6) ESTRADIOL/NORETHINDRONE ACETATE
    a) Continuous Combined Regimen
    1) Estradiol 0.05 mg/norethindrone acetate 0.14 mg/day (9 cm(2)) OR estradiol 0.05 mg/norethindrone acetate 0.25 mg (16 cm(2)) transdermally to the lower abdomen. System is to be worn continuously and uninterrupted. Replace with a new system every 3 to 4 days (twice weekly) during a 28-day cycle (Prod Info CombiPatch(R) transdermal system patch, 2015).
    b) Sequential Combined Regimen
    1) For the first 14 days of a 28-day cycle:, 1 Vivelle-Dot(R) system (estradiol 0.05 mg/day) transdermally. Replace the system every 3 to 4 days (twice weekly) (Prod Info CombiPatch(R) transdermal system patch, 2015).
    2) For the remaining 14 days of a 28-day cycle: 1 CombiPatch(R) system (estradiol 0.05 mg/norethindrone acetate 0.14 mg/day (9 cm(2)) OR estradiol 0.05 mg/norethindrone acetate 0.25 mg (16 cm(2))) transdermally on the lower abdomen. Wear the system continuously, and replace the system every 3 to 4 days (twice weekly) (Prod Info CombiPatch(R) transdermal system patch, 2015).
    7) ESTRADIOL VALERATE
    a) INTRAMUSCULAR: 10 mg to 30 mg IM every 2 to 4 weeks (Prod Info DELESTROGEN(R) solution for IM injection, 2004)
    8) ESTROPIPATE
    a) ORAL: 0.75 mg to 9 mg per day, either continuous or cyclically, depending on the indication (Prod Info OGEN(R) oral tablets, 2005)
    7.2.2) PEDIATRIC
    A) The safety and efficacy of estrogens have not been established in pediatric patients (Prod Info CombiPatch(R) transdermal system patch, 2015; Prod Info Femring(R) vaginal ring, 2014; Prod Info Climara(R) transdermal system patch, 2013; Prod Info DUAVEE(R) oral tablets, 2013; Prod Info PREMARIN(R) oral tablets, 2007; Prod Info synthetic conjugated estrogens, A vaginal cream, 2008; Prod Info ENJUVIA(TM) oral tablets, 2007; Prod Info MENEST(R) oral tablets, 2005; Prod Info estradiol oral tablets, 2005; Prod Info DELESTROGEN(R) solution for IM injection, 2004).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Exact toxic doses have not been determined.

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) A 19-year-old women developed a slight increase in serum phospholipid and triglyceride concentrations soon after an ingestion of 160 milligrams of estradiol valerate (Punnonen & Salmi, 1983).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Following a single oral dose of 160 mg of estradiol valerate, the serum estradiol valerate, the serum estradiol concentration was 3 nanomoles/liter at 15 hours after ingestion (Punnonen & Salmi, 1983).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Endogenous estrogens are mostly responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. The primary source of estrogen in normally cycling adult female is the ovarian follicle, which can secrete up to 500 mcg of estradiol per day, depending on the menstrual cycle. Estrogens bind to nuclear receptors in estrogen-responsive tissues to activate pituitary secretion of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone through negative feedback mechanisms. Most of the known actions of estrogens and many that are made use of in therapy can be regarded as physiological (Prod Info ESTROGEL(R) topical gel, 2008; Prod Info PREMARIN(R) oral tablets, 2011; Prod Info Delestrogen(R), 2004).

Physicochemical

Physical Characteristics

    A) ESTRADIOL is a white crystalline powder (Prod Info ESTROGEL(R) topical gel, 2008) that is soluble in dioxane, slightly soluble in chloroform and ether, sparingly soluble in alcohol and acetone, and practically insoluble in water (Reynolds, 1988).
    B) ESTRADIOL HEMIHYDRATE is a white, almost white, or colorless crystalline solid (Prod Info Vagifem(R) vaginal tablets, 2009).
    C) ESTRIOL is a white or off-white, tasteless, odorless crystalline powder (JEF Reynolds , 1988).
    D) ESTRONE is a colorless to off-white or white, tasteless, odorless, crystals (JEF Reynolds , 1988).
    E) ESTROPIPATE is appreciably soluble in water and has almost no odor or taste (Prod Info OGEN(R) oral tablets, 2005).

Molecular Weight

    A) ESTRADIOL: 272.39 (Prod Info ESTROGEL(R) topical gel, 2008)
    B) ESTRADIOL ACETATE: 314.42 (Prod Info Femring(R) vaginal ring, 2010)
    C) ESTRADIOL HEMIHYDRATE: 281.4 (Prod Info Vagifem(R) vaginal tablets, 2009)
    D) ESTRADIOL VALERATE: 356.5 (Prod Info DELESTROGEN(R) solution for IM injection, 2004)
    E) ESTRIOL: 288.4 (JEF Reynolds , 1988)
    F) ESTRONE: 270.4 (JEF Reynolds , 1988)
    G) ESTROPIPATE: 436.56 (Prod Info OGEN(R) oral tablets, 2005)

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) CHICKENS -
    1) An acute exposure to 15 grams of zearalenone per kilogram of body weight produced no effect in young chicks (Sundlof & Strickland, 1986). Signs of chronic exposure include increases in comb, oviduct, and testicular weight which may go unnoticed in a flock (Sundlof & Strickland, 1986).
    11.1.2) BOVINE/CATTLE
    A) DAIRY CATTLE -
    1) Consumption of moldy feed containing as low as 14 ppm zearalenone (estrogenic substance) was associated with an increased incidence of abortion (Sundlof & Strickland, 1986).
    B) BEEF CATTLE -
    1) A growth promoting implant, zeranol (estrogenic derivative) is approved for use in beef cattle.
    2) Effects noted from use of this product include decreased conception rate, increased incidence of mastitis, increased perinatal calf mortality, and vulva and mammary gland enlargement (Sundlof & Strickland, 1986).
    11.1.10) PORCINE/SWINE
    A) Hyperestrogenism may prevent gilts and sows from cycling, inhibit ovulation, and prevent implantation and nourishment of the fertilized ovum (Sundlof & Strickland, 1986).
    1) Successfully implanted fetuses may not develop properly (small litter size, stillbirths, weak pigs) (Sundlof & Strickland, 1986).
    2) Swine appear to be most sensitive of the domestic animals to hyperestrogenism (Sundlof & Strickland, 1986).
    B) Zearalenone is an estrogenic mycotoxin produced by the grain mold Fusarium roseum and ingested with food. This agent will interrupt swine pregnancy on days 7 to 10. Gilts wil show signs of hyperestrogenism (Long & Diekman, 1989).
    1) Progesterone 100 mg/day did not reverse the effects of 1 mg of zearalenone per day (Green et al, 1991).

References

General Bibliography

    1) Baron SH, Sowers JR, & Feinberg M: Prolactinoma in a man following industrial exposure to estrogens. West J Med 1983; 138:720-722.
    2) Beresford SAA, Weiss NS, & Voigt LF: Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997; 249:458-461.
    3) Bibbo M, Gill WB, & Azizi F: Follow-up study of male and female offspring of DES-exposed mothers. Am J Obstet Gynecol 1977; 49:1-8.
    4) Brouwers MM, Feitz WF, Roelofs LA, et al: Hypospadias: a transgenerational effect of diethylstilbestrol?. Hum Reprod 2006; 21(3):666-669.
    5) Buchwald A: Serum copper elevation from estrogen effect, masquerading as fungicide toxicity. J Med Toxicol 2008; 4(1):30-32.
    6) Colditz GA, Hankinson SE, & Hunter DJ: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332:1589-1593.
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    23) Product Information: CLIMARA(R) transdermal patch, estradiol transdermal patch. Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, 2007.
    24) Product Information: Climara(R) transdermal system patch, estradiol transdermal system patch. Bayer HealthCare Pharmaceuticals Inc. (per Manufacturer), Whippany, NJ, 2013.
    25) Product Information: CombiPatch(R) transdermal system patch, estradiol norethindrone acetate transdermal system patch. Novartis Pharmaceuticals Corp. (per FDA), East Hanover, NJ, 2013.
    26) Product Information: CombiPatch(R) transdermal system patch, estradiol norethindrone acetate transdermal system patch. Noven Therapeutics, LLC (per FDA), Miami, FL, 2015.
    27) Product Information: DELESTROGEN(R) solution for IM injection, estradiol valerate solution for IM injection. Monarch Pharmaceuticals,Inc, Bristol, TN, 2004.
    28) Product Information: DEPO(R)-ESTRADIOL estradiol cypionate concentration for IM injection, estradiol cypionate concentration for IM injection. Pharmacia & Upjohn Company, New York, NY, 2006.
    29) Product Information: DEPO(R)-ESTRADIOL injection, estradiol cypionate injection. Pharmacia & Upjohn Company, New York, NY, 2004.
    30) Product Information: DUAVEE(R) oral tablets, conjugated estrogens/bazedoxifene oral tablets. Wyeth Parmaceuticals Inc (per Maufacturer), Philadlephia, PA, 2013.
    31) Product Information: Delestrogen(R), estradiol valerate injection. Monarch Pharmaceuticals, Inc., Bristol, TN, 2004.
    32) Product Information: ENJUVIA(TM) oral tablets, synthetic conjugated estrogens B oral tablets. Duramed Pharmaceuticals,Inc, Pomona, NY, 2007.
    33) Product Information: ESTRADERM(R) transdermal system, estradiol transdermal system. Novartis, East Hanover, NJ, 2005.
    34) Product Information: ESTRADIOL / NORETHINDRONE ACETATE oral film-coated tablets, estradiol and norethindrone acetate oral film-coated tablets. Breckenridge Phamaceuticals, Inc. (per DailyMed), Boca Raton, FL, 2010.
    35) Product Information: ESTRATEST(R) oral tablets, ESTRATEST(R) HS half-strength oral tablets, esterified estrogens, methyltestosterone oral tablets, half-strength oral tablets. Solvay Pharmaceuticals,Inc, Marietta, GA, 2005.
    36) Product Information: ESTROGEL(R) topical gel, estradiol topical gel. ASCEND Therapeutics,Inc, Herndon, VA, 2008.
    37) Product Information: Estinyl(R), ethinyl estradiol. Scherint Corporation, Kenilworth, NJ, 1986.
    38) Product Information: Evamist transdermal spray, estradiol transdermal spray. Ther-Rx Corporation (per FDA), St. Louis, MO, 2011.
    39) Product Information: Femring(R) vaginal ring, estradiol acetate vaginal ring. Warner Chilcott (US), LLC (per FDA), Rockaway, NJ, 2014.
    40) Product Information: Femring(R) vaginal ring, estradiol acetate vaginal ring. Warner Chilcott (US), LLC, Rockaway, NJ, 2010.
    41) Product Information: MENEST(R) oral tablets, esterified estrogen oral tablets. Monarch Pharmaceutical, Bristol, TN, 1999.
    42) Product Information: MENEST(R) oral tablets, esterified estrogens oral tablets. Monarch Pharmaceuticals, Inc., Bristol, TN, 2005.
    43) Product Information: Necon(R)1/50 oral tablets, norethindrone and mestranol oral tablets. Watson Pharma, Inc, Corona, CA, 2007.
    44) Product Information: NuvaRing(R) vaginal ring, etonogestrel ethinyl estradiol vaginal ring. Merck, Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    45) Product Information: OGEN(R) oral tablets, estropipate oral tablets. Pfizer,Inc, New York, NY, 2005.
    46) Product Information: Ortho(R) Dienestrol Cream, dienestrol. Ortho Pharmaceutical Corporation, Raritan, NJ, 1996.
    47) Product Information: PREMARIN(R) injection, conjugated estrogens injection. Wyeth Pharmaceuticals,Inc, Philadelphia, PA, 2008.
    48) Product Information: PREMARIN(R) oral tablets, conjugated estrogens oral tablets. Wyeth Pharmaceuticals,Inc, Philadelphia, PA, 2007.
    49) Product Information: PREMARIN(R) oral tablets, conjugated estrogens oral tablets. Wyeth Pharmaceuticals Inc. (per FDA), Philadelphia, PA, 2011.
    50) Product Information: PREMARIN(R) vaginal cream, conjugated estrogens vaginal cream. Wyeth Pharmaceuticals,Inc, Philadelphia, PA, 2008.
    51) Product Information: Premarin(R), conjugated estrogens. Ayerst Laboratories, Inc., Philadelphia, PA., 2003.
    52) Product Information: Stilphostrol(R), diethylstilbestrol. Miles Inc, Pharmaceutical Division, West Haven, CT, 1996.
    53) Product Information: Tace(R), chlorotrianisene. Merrell Dow Pharmaceuticals, Inc, Cincinnati, OH, 1990.
    54) Product Information: VIVELLE-DOT(R) transdermal system, estradiol transdermal system. Novartis, East Hanover, NJ, 2004.
    55) Product Information: Vagifem(R) vaginal tablets, estradiol vaginal tablets. Novo Nordisk A/S, Bagsvaerd, Denmark, 2009.
    56) Product Information: estradiol oral tablets, estradiol oral tablets. Watson Laboratories,Inc, Corona, CA, 2005.
    57) Product Information: estropipate oral tablets, estropipate oral tablets. Watson Laboratories,Inc, Corona, CA, 2002.
    58) Product Information: synthetic conjugated estrogens, A vaginal cream, synthetic conjugated estrogens, A vaginal cream. Duramed Pharmaceuticals, Inc, Pomona, NY, 2008.
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