DIENOESTROL
DESCRIPTION:
* 1. ESTROGENS HAVE BEEN REPORTED TO INCREASE *
* THE RISK OF ENDOMETRIAL CARCINOMA. *
* Three independent case control studies have *
* shown an increased risk of endometrial *
* cancer in postmenopausal women exposed to *
* exogenous estrogens for prolonged periods. *
* (REF. 1-3) This risk was independent of the *
* other known risk factors for endometrial *
* cancer. These studies are further supported *
* by the finding that incidence rates of *
* endometrial cancer have increased sharply *
* since 1969 in eight different areas of the *
* United States with population-based cancer *
* reporting systems, an increase which may be *
* related to the rapidly expanding use of *
* estrogens during the last decade. (REF. 4) *
* The three case control studies reported *
* that the risk of endometrial cancer in *
* estrogen users was about 4.5 to 13.9 times *
* greater than in nonusers. The risk appears *
* to depend on both duration of treatment *
* (REF. 1) and on estrogen dose. (REF. 3) In *
* view of these findings, when estrogens are *
* used for the treatment of menopausal *
* symptoms, the lowest dose that will control *
* symptoms should be utilized and medication *
* should be discontinued as soon as possible. *
* When prolonged treatment is medically *
* indicated, the patient should be reassessed *
* on at least a semiannual basis to determine *
* the need for continued therapy. Although *
* the evidence must be considered *
* preliminary, one study suggests that cyclic *
* administration of low doses of estrogen may *
* carry less risk than continuous *
* administration; (REF. 3) it therefore *
* appears prudent to utilize such a regimen. *
* Close clinical surveillance of all women *
* taking estrogens is important. In all cases *
* of undiagnosed persistent or recurring *
* abnormal vaginal bleeding, adequate *
* diagnostic measures should be undertaken to *
* rule out malignancy. *
* There is no evidence at present that *
* "natural" estrogens are more or less *
* hazardous than "synthetic" estrogens at *
* equiestrogenic doses. *
* 2. ESTROGENS SHOULD NOT BE USED DURING *
* PREGNANCY *
* The use of female sex hormones, both *
* estrogens and progestogens, during early *
* pregnancy may seriously damage the *
* offspring. It has been shown that females *
* exposed In Utero to diethylstilbestrol, a *
* non-steroidal estrogen, have an increased *
* risk of developing in later life a form of *
* vaginal or cervical cancer that ordinarily *
* is extremely rare. (REF. 5,6) This risk has *
* been estimated as not greater than 4 per *
* 1000 exposures. (REF. 7) Furthermore, a *
* high percentage of such exposed women (from *
* 30 to 90 percent) have been found to have *
* vaginal adenosis, (REF. 8-12) epithelial *
* changes of the vagina and cervix. Although *
* these changes are histologically benign, it *
* is not known whether they are precursors of *
* malignancy. Although similar data are not *
* available with the use of other estrogens, *
* it cannot be presumed they would not induce *
* similar changes. *
* Several reports suggest an association *
* between intrauterine exposure to female sex *
* hormones and congenital anomalies, *
* including congenital heart defects and limb *
* reduction defects. (REF. 13-16) One case *
* control study (REF. 16) estimated a 4.7 *
* fold increased risk of limb reduction *
* defects in infants exposed in utero to sex *
* hormones (oral contraceptives, hormone *
* withdrawal tests for pregnancy, or *
* attempted treatment for threatened *
* abortion). Some of these exposures were *
* very short and involved only a few days of *
* treatment. The data suggest that the risk *
* of limb reduction defects in exposed *
* fetuses is somewhat less than 1 per 1000. *
* In the past, female sex hormones have been *
* used during pregnancy in an attempt to *
* treat threatened or habitual abortion. *
* There is considerable evidence that *
* estrogens are ineffective for these *
* indications, and there is no evidence from *
* well controlled studies that progestogens *
* are effective for these uses. *
* If DIENOESTROL Cream is used during *
* pregnancy, or if the patient becomes *
* pregnant while using this drug, she should *
* be apprised of the potential risks to the *
* fetus, and the advisability of pregnancy *
* continuation. *
* *
*************************************************
DIENOESTROL CREAM
CREAM FOR INTRAVAGINAL USE ONLY
Active ingredient: Dienestrol 0.01%.
Dienestrol is a synthetic, non-steroidal estrogen. It is compounded in a cream
base suitable for intravaginal use only. The cream base is composed of glyceryl
monostearate, peanut oil, glycerin, benzoic acid, glutamic acid, butylated
hydroxyanisole, citric acid, sodium hydroxide and water. The pH is approximately
4.3.
ACTIONS/CLINICAL PHARMACOLOGY:
Systemic absorption and mode of action of dienestrol are undetermined.
INDICATIONS AND USAGE:
DIENOESTROL Cream is indicated in the treatment of atrophic vaginitis and
kraurosis vulvae.
DIENOESTROL CREAM HAS NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING
PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (SEE BOXED WARNING).
CONTRAINDICATIONS:
Estrogens may cause fetal harm when administered to a pregnant woman (see Boxed
Warning). Estrogens are contraindicated in women who are or may become pregnant.
If this drug is used during pregnancy, or if the patient becomes pregnant while
using this drug, the patient should be apprised of the potential hazard to the
fetus.
Estrogens should also not be used in women with any of the following conditions:
1. Known or suspected cancer of the breast.
2. Known or suspected estrogen-dependent neoplasia.
3. Undiagnosed abnormal genital bleeding.
4. Active thrombophlebitis or thromboembolic disorders.
5. A past history of thrombophlebitis or thromboembolic disorders associated
with previous estrogen use.
WARNINGS:
*************************************************
* *
* 1. ESTROGENS HAVE BEEN REPORTED TO INCREASE *
* THE RISK OF ENDOMETRIAL CARCINOMA. *
* Three independent case control studies have *
* shown an increased risk of endometrial *
* cancer in postmenopausal women exposed to *
* exogenous estrogens for prolonged periods. *
* (REF. 1-3) This risk was independent of the *
* other known risk factors for endometrial *
* cancer. These studies are further supported *
* by the finding that incidence rates of *
* endometrial cancer have increased sharply *
* since 1969 in eight different areas of the *
* United States with population-based cancer *
* reporting systems, an increase which may be *
* related to the rapidly expanding use of *
* estrogens during the last decade. (REF. 4) *
* The three case control studies reported *
* that the risk of endometrial cancer in *
* estrogen users was about 4.5 to 13.9 times *
* greater than in nonusers. The risk appears *
* to depend on both duration of treatment *
* (REF. 1) and on estrogen dose. (REF. 3) In *
* view of these findings, when estrogens are *
* used for the treatment of menopausal *
* symptoms, the lowest dose that will control *
* symptoms should be utilized and medication *
* should be discontinued as soon as possible. *
* When prolonged treatment is medically *
* indicated, the patient should be reassessed *
* on at least a semiannual basis to determine *
* the need for continued therapy. *
* Although the evidence must be considered *
* preliminary, one study suggests that cyclic *
* administration of low doses of estrogen may *
* carry less risk than continuous *
* administration; (REF. 3) it therefore *
* appears prudent to utilize such a regimen. *
* Close clinical surveillance of all women *
* taking estrogens is important. In all cases *
* of undiagnosed persistent or recurring *
* abnormal vaginal bleeding, adequate *
* diagnostic measures should be undertaken to *
* rule out malignancy. *
* There is no evidence at present that *
* "natural" estrogens are more or less *
* hazardous than "synthetic" estrogens at *
* equiestrogenic doses. *
* 2. ESTROGENS SHOULD NOT BE USED DURING *
* PREGNANCY *
* The use of female sex hormones, both *
* estrogens and progestogens, during early *
* pregnancy may seriously damage the *
* offspring. It has been shown that females *
* exposed In Utero to diethylstilbestrol, a *
* non-steroidal estrogen, have an increased *
* risk of developing in later life a form of *
* vaginal or cervical cancer that ordinarily *
* is extremely rare. (REF. 5,6) This risk has *
* been estimated as not greater than 4 per *
* 1000 exposures. (REF. 7) Furthermore, a *
* high percentage of such exposed women (from *
* 30 to 90 percent) have been found to have *
* vaginal adenosis, (REF. 8,13) epithelial *
* changes of the vagina and cervix. Although *
* these changes are histologically benign, it *
* is not known whether they are precursors of *
* malignancy. Although similar data are not *
* available with the use of other estrogens, *
* it cannot be presumed they would not induce *
* similar changes. *
* Several reports suggest an association *
* between intrauterine exposure to female sex *
* hormones and congenital anomalies, *
* including congenital heart defects and limb *
* reduction defects. (REF. 13-16) One case *
* control study (REF. 16) estimated a 4.7 *
* fold increased risk of limb reduction *
* defects in infants exposed in utero to sex *
* hormones (oral contraceptives, hormone *
* withdrawal tests for pregnancy, or *
* attempted treatment for threatened *
* abortion). Some of these exposures were *
* very short and involved only a few days of *
* treatment. The data suggest that the risk *
* of limb reduction defects in exposed *
* fetuses is somewhat less than 1 per 1000. *
* In the past, female sex hormones have been *
* used during pregnancy in an attempt to *
* treat threatened or habitual abortion. *
* There is considerable evidence that *
* estrogens are ineffective for these *
* indications, and there is no evidence from *
* well controlled studies that progestogens *
* are effective for these uses. *
* If DIENOESTROL Cream is used during *
* pregnancy, or if the patient becomes *
* pregnant while using this drug, she should *
* be apprised of the potential risks to the *
* fetus, and the advisability of pregnancy *
* continuation. *
* *
*************************************************
1. Induction Of Malignant Neoplasms.
Long-term continuous administration of natural and synthetic estrogens in
certain animal species increases the frequency of carcinomas of the breast,
cervix, vagina, and liver. There is now evidence that estrogens increase the
risk of carcinoma of the endometrium in humans. (See Boxed Warning.)
At the present time there is no satisfactory evidence that estrogens given to
postmenopausal women increase the risk of cancer of the breast, (REF. 18)
although a recent long-term followup of a single physician's practice has raised
this possibility. (REF. 18a) Because of the animal data, there is a need for
caution in prescribing estrogens for women with a strong family history of
breast cancer or who have breast nodules, fibrocystic disease, or abnormal
mammograms.
2. Gall Bladder Disease. A recent study has reported a 2- to 3-fold increase in
the risk of surgically confirmed gall bladder disease in women receiving
postmenopausal estrogens, (REF. 18) similar to the 2-fold increase previously
noted in users of oral contraceptives. (REF. 19-24) In the case of oral
contraceptives the increased risk appeared after two years of use. (REF. 24)
3. Effects Similar To Those Caused By Estrogen- Progestogen Oral Contraceptives.
There are several serious adverse effects of oral contraceptives, most of which
have not, up to now, been documented as consequences of postmenopausal estrogen
therapy. This may reflect the comparatively low doses of estrogen used in
postmenopausal women. It would be expected that the larger doses of estrogen
used to treat prostatic or breast cancer or postpartum breast engorgement are
more likely to result in these adverse effects, and, in fact, it has been shown
that there is an increased risk of thrombosis in men receiving estrogens for
prostatic cancer and women for postpartum breast engorgement.(REF. 20-23)
a. Thromboembolic Disease. It is now well established that users of oral
contraceptives have an increased risk of various thromboembolic and thrombotic
vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and
myocardial infarction. (REF. 24-31) Cases of retinal thrombosis, mesenteric
thrombosis, and optic neuritis have been reported in oral contraceptive users.
There is evidence that the risk of several of these adverse reactions is related
to the dose of the drug. (REF. 32,33) An increased risk of postsurgery
thromboembolic complications has also been reported in users of oral
contraceptives. (REF. 34,35) If feasible, estrogen should be discontinued at
least 4 weeks before surgery of the type associated with an increased risk of
thromboembolism, or during periods of prolonged immobilization.
While an increased rate of thromboembolic and thrombotic disease in
postmenopausal users of estrogens has not been found, (REF. 18-36) this does not
rule out the possibility that such an increase may be present or that subgroups
of women who have underlying risk factors or who are receiving relatively large
doses of estrogens may have increased risk. Therefore estrogens should not be
used in persons with active thrombophlebitis or thromboembolic disorders, and
they should not be used (except in treatment of malignancy) in persons with a
history of such disorders in association with estrogen use. They should be used
with caution in patients with cerebral vascular or coronary artery disease and
only for those in whom estrogens are clearly needed.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those
used to treat cancer of the prostate and breast, have been shown in a large
prospective clinical trial in men to increase the risk of nonfatal myocardial
infarction, pulmonary embolism and thrombophlebitis. When estrogen doses of this
size are used, any of the thromboembolic and thrombotic adverse effects
associated with oral contraceptive use should be considered a clear risk.
b. Hepatic Adenoma. Benign hepatic adenomas appear to be associated with the use
of oral contraceptives. (REF. 38-40) Although benign, and rare, these may
rupture and may cause death through intra-abdominal hemorrhage. Such lesions
have not yet been reported in association with other estrogen or progestogen
preparations but should be considered in estrogen users having abdominal pain
and tenderness, abdominal mass, or hypovolemic shock. Hepatocellular carcinoma
has also been reported in women taking estrogen- containing oral contraceptives.
(REF. 39) The relationship of this malignancy to these drugs is not known at
this time.
c. Elevated Blood Pressure. Increased blood pressure is not uncommon in women
using oral contraceptives. There is now a report that this may also occur with
the use of estrogens during menopause (REF. 41). Blood pressure should be
monitored with estrogen use, especially if high doses are used.
d. Glucose Tolerance. A worsening of glucose tolerance has been observed in a
significant percentage of patients on estrogen-containing oral contraceptives.
For this reason, diabetic patients should be carefully observed while receiving
estrogen.
4. Hypercalcemia. Administration of estrogens may lead to severe hypercalcemia
in patients with breast cancer and bone metastases. If this occurs, the drug
should be stopped and appropriate measures taken to reduce the serum calcium
level.
PRECAUTIONS:
A. General.
1. A complete medical and family history should be taken prior to the initiation
of any estrogen therapy. The pretreatment and periodic physical examinations
should include special reference to blood pressure, breasts, abdomen, and pelvic
organs, and should include a Papanicolaou smear. As a general rule, estrogen
should not be prescribed for longer than one year without another physical
examination being performed.
2. Fluid retention--Because estrogens may cause some degree of fluid retention,
conditions which might be influenced by this factor such as epilepsy, migraine,
and cardiac or renal dysfunction, require careful observation.
3. Certain patients may develop undesirable manifestations of excessive
estrogenic stimulation, such as abnormal or excessive uterine bleeding,
mastodynia, etc.
4. Oral contraceptives appear to be associated with an increased incidence of
mental depression. (REF. 24) Although it is not clear whether this is due to the
estrogenic or progestogenic component of the contraceptive, patients with a
history of depression should be carefully observed.
5. Preexisting uterine leiomyomata may increase in size during estrogen use.
6. The pathologist should be advised of estrogen therapy when relevant specimens
are submitted.
7. Patients with a past history of jaundice during pregnancy have an increased
risk of recurrence of jaundice while receiving estrogen- containing oral
contraceptive therapy. If jaundice develops in any patient receiving estrogen,
the medication should be discontinued while the cause is investigated.
8. Estrogens may be poorly metabolized in patients with impaired liver function
and they should be administered with caution in such patients.
9. Because estrogens influence the metabolism of calcium and phosphorus, they
should be used with caution in patients with metabolic bone diseases that are
associated with hypercalcemia or in patients with renal insufficiency.
10. Because of the effects of estrogens on epiphyseal closure, they should be
used judiciously in young patients in whom bone growth is not complete.
11. The lowest effective dose appropriate for the specific indication should be
utilized. Studies of the addition of a progestin for seven or more days of a
cycle of estrogen administration have reported a lowered incidence of
endometrial hyperplasia. Morphological and biochemical studies of endometrium
suggest that 10 to 13 days of progestin are needed to provide maximal maturation
of the endometrium and to eliminate any hyperplastic changes. Whether this will
provide protection from endometrial carcinoma has not been clearly established.
There are possible additional risks which may be associated with the inclusion
of progestin in estrogen replacement regimens. The potential risks include
adverse effects on carbohydrate and lipid metabolism. The choice of progestin
and dosage may be important in minimizing these adverse effects.
B. Information for Patients: See Patient Package Insert (PPI).
C. Drug/Laboratory Test Interactions
Certain endocrine and liver function tests may be affected by estrogen-
containing oral contraceptives. The following similar changes may be expected
with larger doses of estrogen:
1. Increased sulfobromophthalein retention.
2. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin
3; increased norepinephrine-induced platelet aggregability.
3. Increased thyroid-binding globulin (TBG) leading to increased circulating
total thyroid hormone, as measured by PBI, T4 by column, or T4 by
radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated
TBG; free T4 concentration is unaltered.
4. Impaired glucose tolerance.
5. Decreased pregnanediol excretion.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
8. Increased serum triglyceride and phospholipid concentration.
D. Carcinogenesis, Mutagenesis, Impairment of Fertility: See "Warnings" section
for information on carcinogenesis, mutagenesis and impairment of fertility.
E. Pregnancy:
Teratogenic Effects.
Pregnancy Category X.
See "CONTRAINDICATIONS" section.
F. Nursing Mothers: It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
estrogens are administered to a nursing woman.
DRUG INTERACTIONS:
SEE PRECAUTIONS.
ADVERSE REACTIONS:
(See Warnings regarding induction of neoplasia, adverse effects on the fetus,
increased incidence of gall bladder disease, and adverse effects similar to
those of oral contraceptives, including thromboembolism.) The following
additional adverse reactions have been reported with estrogenic therapy,
including oral contraceptives:
1. Genitourinary system.
Increase in size of uterine fibromyomata.
Vaginal candidiasis.
Breakthrough bleeding, spotting, change in menstrual flow.
Dysmenorrhea.
Premenstrual-like syndrome.
Amenorrhea during and after treatment.
Change in cervical eversion and in degree of cervical secretion.
Cystitis-like syndrome.
2. Breasts.
Tenderness, enlargement, secretion.
3. Gastrointestinal.
Cholestatic jaundice.
Nausea, vomiting.
Abdominal cramps, bloating.
4. Skin.
Erythema multiforme.
Erythema nodosum.
Hemorrhagic eruption.
Loss of scalp hair.
Hirsutism.
Chloasma or melasma which may persist when drug is discontinued.
5. Eyes.
Steepening of corneal curvature.
Intolerance to contact lenses.
6. CNS.
Mental depression.
Headache, migraine, dizziness.
Chorea.
7. Miscellaneous.
Reduced carbohydrate tolerance.
Aggravation of porphyria.
Edema.
Changes in libido.
Increase or decrease in weight.
OVERDOSAGE:
Numerous reports of ingestion of large doses of estrogen-containing oral
contraceptives by young children indicate that serious ill effects do not occur.
Overdosage of estrogen may cause nausea, and withdrawal bleeding may occur in
females.
DOSAGE AND ADMINISTRATION:
Given Cyclically For Short Term Use Only: For treatment of atrophic vaginitis,
or kraurosis vulvae associated with the menopause.
The lowest dose that will control symptoms should be chosen and medication
should be discontinued as promptly as possible.
Attempts to discontinue or taper medication should be made at 3 to 6 month
intervals.
The usual dosage range is one or two applicatorsful per day for one or two
weeks, then gradually reduced to one half initial dosage for a similar period. A
maintenance dosage of one applicatorful, one to three times a week, may be used
after restoration of the vaginal mucosa has been achieved.
Treated patients with an intact uterus should be monitored closely for signs of
endometrial cancer and appropriate diagnostic measures should be taken to rule
out malignancy in the event of persistent or recurring abnormal vaginal
bleeding.
REFERENCES:
1. Ziel, H.K. and W.D. Finkle, "Increased Risk of Endometrial Carcinoma Among
Users of Conjugated Estrogens," New England Journal of Medicine, 293:1167-1170,
1975.
2. Smith, D.C., R. Prentic, D.J. Thompson, and W.L. Hermann, "Association of
Exogenous Estrogen and Endometrial Carcinoma," New England Journal of Medicine,
293:1164-1167, 1975.
3. Mack, T.M., M.C. Pike, B.E. Henderson, R.I. Pfeffer, V.R. Gerkins, M. Arthur,
and S.E.Brown, "Estrogens and Endometrial Cancer in a Retirement Community," New
England Journal of Medicine, 294:1267-1287, 1976.
4. Weiss, N.S., D.R. Szekely and D.F. Austin, "Increasing Incidence of
Endometrial Cancer in the United States," New England Journal of Medicine,
294:1259-1262, 1976.
5. Herbst, A.L., H. Ulfelder and D.C. Poskanzer, "Adenocarcinoma of Vagina," New
England Journal of Medicine, 284:878-881, 1971.
6. Greenwald, P., J. Barlow, P. Nasca, and W. Burnett, "Vaginal Cancer after
Maternal Treatment with Synthetic Estrogens," New England Journal of Medicine,
285:390-392, 1971.
7. Lanier, A., K. Noller, D. Decker, L. Elveback, and L. Kurland, "Cancer and
Stilbestrol. A Follow-up of 1719 Persons Exposed to Estrogens in Utero and Born
1943-1959," Mayo Clinic Proceedings, 48:793-799, 1973.
8. Herbst, A., R. Kurman, and R. Scully, "Vaginal and Cervical Abnormalities
After Exposure to Stilbestrol In Utero," Obstetrics and Gynecology, 40:287-298,
1972.
9. Herbst, A., S. Robboy, G. Macdonald, and R. Scully, "The Effects of Local
Progesterone on Stilbestrol-Associated Vaginal Adenosis," American Journal of
Obstetrics and Gynecology 118:607-615, 1974.
10. Herbst, A., D. Poskanzer, S. Robboy, L. Friedlander, and R. Scully,
"Prenatal Exposure to Stilbestrol, A Prospective Comparison of Exposed Female
Offspring with Unexposed Controls," New England Journal of Medicine, 292:334-
339, 1975.
11. Staffi, A., R. Mattingly, D. Foley, and W. Fetherston, "Clinical Diagnosis
of Vaginal Adenosis," Obstetrics and Gynecology, 43:118-128, 1974.
12. Sherman, A.I., M. Goldrath, A. Berlin, V. Vakhariya, F. Banooni, W.
Michaels, P. Goodman, S. Brown, "Cervical-Vaginal Adenosis After In Utero
Exposure to Synthetic Estrogens," Obstetrics and Gynecology, 44:531-545, 1974.
13. Gal, I., B. Kirman, and J. Stern, "Hormone Pregnancy Tests and Congenital
Malformation," Nature, 216:83, 1967.
14. Levy, E.P., A. Cohen, and F.C. Fraser, "Hormone Treatment During Pregnancy
and Congenital Heart Defects," Lancet, 1:611, 1973.
15. Nora, J. and A. Nora, "Birth Defects and Oral Contraceptives," Lancet,
1:941-942, 1973.
16. Janerich, D.T., J.M. Piper, and D.M. Glebatis, "Oral Contraceptives and
Congenital Limb-Reduction Defects," New England Journal of Medicine, 291:697-
700, 1974.
17. "Estrogens for Oral or Parenteral Use," Federal Register, 40:8212, 1975.
18. Boston Collaborative Drug Surveillance Program, "Surgically Confirmed Gall
Bladder Disease, Venous Thromboembolism and Breast Tumors in Relation to Post-
Menopausal Estrogen Therapy," New England Journal of Medicine, 290:15-19, 1974.
18a. Hoover, R., L.A. Gray, Sr., P. Cole, and B. MacMahon, "Menopausal Estrogens
and Breast Cancer," New England Journal of Medicine, 295:401-405, 1976.
19. Boston Collaborative Drug Surveillance Program, "Oral Contraceptives and
Venous Thromboembolic Disease, Surgically Confirmed Gall Bladder Disease, and
Breast Tumors," Lancet 1:1399-1404, 1973.
20. Daniel, D.G., H. Campbell, and A.C. Turnbull, "Puerperal Thromboembolism and
Suppression of Lactation," Lancet, 2:287-289, 1967.
21. The Veterans Administration Cooperative Urological Research Group,
"Carcinoma of the Prostate: Treatment Comparisons," Journal of Urology, 98:516-
522, 1967.
22. Bailer, J.C., "Thromboembolism and Oestrogen Therapy," Lancet, 2:560, 1967.
23. Blackard, C., R. Doe, G. Mellinger, and D. Byar, "Incidence of
Cardiovascular Disease and Death In Patients Receiving Diethylstilbestrol for
Carcinoma of the Prostate," Cancer, 26:249-256, 1970.
24. Royal College of General Practitioners, "Oral Contraception and
Thromboembolic Disease," Journal of the Royal College of General Practitioners,
13:267-279, 1967.
25. Inman, W.H.W. and M.P. Vessey, "Investigation of Deaths from Pulmonary,
Coronary, and Cerebral Thrombosis and Embolism in Women of Child-Bearing Age,"
British Medical Journal, 2:193-199, 1968.
26. Vessey, M.P. and R. Doll, "Investigation of Relation Between Use of Oral
Contraceptives and Thromboembolic Disease, A Further Report," British Medical
Journal, 2:651-657, 1969.
27. Sartwell, P.E., A.T. Masi, F.G. Arthes, G.R. Greene, and H.E. Smith,
"Thromboembolism and Oral Contraceptives: An Epidemiological Case Control
Study," American Journal of Epidemiology, 90:365-380, 1969.
28. Collaborative Group for the Study of Stroke In Young Women, "Oral
Contraception and Increased Risk of Cerebral Ischemia or Thrombosis," New
England Journal of Medicine, 288:871-878, 1973.
29. Collaborative Group for the Study of Stroke in Young Women, "Oral
Contraceptives and Stroke in Young Women: Associated Risk Factors," Journal of
the American Medical Association, 231:718-722, 1975.
30. Mann, J.I. and W.H.W. Inman, "Oral Contraceptives and Death from Myocardial
Infarction," British Medical Journal, 2:245-248, 1975.
31. Mann, J.I., M.P. Vessey, M. Thorogood, and R. Doll., "Myocardial Infarction
in Young Women with Special Reference to Oral Contraceptive Practice," British
Medical Journal, 2:241-245, 1975.
32. Inman, W.H.W., V.P. Vessey, B. Westerholm, and A. Engelund, "Thromboembolic
Disease and the Steroidal Content of Oral Contraceptives," British Medical
Journal, 2:203-209, 1970.
33. Stolley, P.D., J.A. Tonascia, M.S. Tockman, P.E. Sartwell, A.H. Rutledge,
and M.P. Jacobs, "Thrombosis with Low-Estrogen Oral Contraceptives," American
Journal of Epidemiology, 102:197-208, 1975.
34. Vessey, M.P., R. Doll, A.S. Fairbairn, and G. Glober, "Post-Operative
Thromboembolism and the Use of the Oral Contraceptives," British Medical
Journal, 3:123-126, 1970.
35. Greene, G.R. and P.E. Sartwell, "Oral Contraceptive Use in Patients with
Thromboembolism Following Surgery, Trauma or Infection," American Journal of
Public Health, 62:680-685, 1972.
36. Rosenberg, L., M.B. Armstrong and H. Jick, "Myocardial Infarction and
Estrogen Therapy in Postmenopausal Women," New England Journal of Medicine,
294:1256-1259, 1976.
37. Coronary Drug Project Research Group, "The Coronary Drug Project: Initial
Findings Leading to Modifications of Its Research Protocol," Journal of the
American Medical Association, 214:1303-1313, 1970.
38. Baum, J., F. Holtz, J.J. Bookstein, and E.W. Klein, "Possible Association
between Benign Hepatomas and Oral Contraceptives," Lancet, 2:926-928, 1973.
39. Mays, E.T., W.M. Christopherson, M.M. Mahr, and H.C. Williams, "Hepatic
Changes in Young Women Ingesting Contraceptive Steroids, Hepatic Hemorrhage and
Primary Hepatic Tumors." Journal of the American Medical Association, 235:730-
782, 1976.
40. Edmondson, H.A., B. Henderson, and B. Benton, "Liver Cell Adenomas
Associated with the Use of Oral Contraceptives," New England Journal of
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PATIENT PACKAGE INSERT:
PATIENT INFORMATION ABOUT ESTROGENS
Estrogens are female hormones produced by the ovaries. The ovaries make several
different kinds of estrogens. In addition, scientists have been able to make a
variety of synthetic estrogens. As far as we know, all these synthetic estrogens
have similar properties and therefore much the same usefulness, side effects,
and risks. This leaflet is intended to help you understand what estrogens are
used for, some of the risks involved in their use, and to help minimize these
risks.
This leaflet includes important information about estrogens, but not all the
information. If you want to know more, you can ask your doctor or pharmacist to
let you read the package insert prepared for the doctor.
USES OF ESTROGEN: THERE IS NO PROPER USE OF ESTROGENS IN A PREGNANT WOMAN
Estrogens are prescribed by doctors for a number of purposes, including:
1. To provide estrogen during a period of adjustment when a woman's ovaries no
longer produce it, in order to prevent certain uncomfortable symptoms of
estrogen deficiency. (All women normally decrease the production of estrogens,
generally between the ages of 45 and 55; this is called the menopause.)
2. To prevent symptoms of estrogen deficiency when a woman's ovaries have been
removed surgically before the natural menopause.
3. To prevent pregnancy. (Estrogens are given along with a progestogen, another
female hormone; these combinations are called oral contraceptives or birth
control pills. Patient labeling is available to women taking oral contraceptives
and they will not be discussed in this leaflet.)
4. To treat certain cancers in women and men.
5. To prevent painful swelling of the breasts after pregnancy in women who
choose not to nurse their babies.
ESTROGENS IN THE MENOPAUSE: In the natural course of their lives, all women
eventually experience a decrease in estrogen production. This usually occurs
between ages 45 and 55 but may occur earlier or later. Sometimes the ovaries may
need to be removed by an operation before natural menopause, producing a
"surgical menopause."
When the amount of estrogen in the blood begins to decrease, many women may
develop typical symptoms: Feelings of warmth in the face, neck, and chest or
sudden intense episodes of heat and sweating throughout the body (called "hot
flashes" or "hot flushes"). These symptoms are sometimes very uncomfortable. A
few women eventually develop changes in the vagina (called "atrophic vaginitis")
which cause discomfort, especially during and after intercourse.
Estrogens can be prescribed to treat these symptoms of the menopause. It is
estimated that considerably more than half of all women undergoing the menopause
have only mild symptoms or no symptoms at all and therefore do not need
estrogens. Other women may need estrogens for a few months, while their bodies
adjust to lower estrogen levels.
Sometimes the need will be for periods longer than six months. In an attempt to
avoid over- stimulation of the uterus (womb), estrogens are usually given
cyclically during each month of use, that is three weeks of pills followed by
one week without pills.
Sometimes women experience nervous symptoms or depression during menopause.
There is no evidence that estrogens are effective for such symptoms and they
should not be used to treat them, although other treatment may be needed.
You may have heard that taking estrogens for long periods (years) after the
menopause will keep your skin soft and supple and keep you feeling young. There
is no evidence that this is so, however, and such long-term treatment carries
important risks.
ESTROGENS TO PREVENT SWELLING OF THE BREASTS AFTER PREGNANCY
If you do not breast-feed your baby after delivery, your breasts may fill up
with milk and become painful and engorged. This usually begins about three to
four days after delivery and may last for a few days to up to a week or more.
Sometimes the discomfort is severe, but usually it is not and can be controlled
by pain-relieving drugs such as aspirin and by binding the breasts up tightly.
Estrogens can be used to try to prevent the breasts from filling up. While this
treatment is sometimes successful, in many cases the breasts fill up to some
degree in spite of treatment. The dose of estrogens needed to prevent pain and
swelling of the breasts is much larger than the dose needed to treat symptoms of
the menopause and this may increase your chances of developing blood clots in
the legs or lungs (see below). Therefore, it is important that you discuss the
benefits and the risks of estrogen use with your doctor if you have decided not
to breast-feed your baby.
SOME OF THE DANGERS OF ESTROGEN:
1. Cancer Of The Uterus. If estrogens are used in the postmenopausal period for
more than a year, there is an increased risk of endometrial cancer (cancer of
the uterus).
Women taking estrogens have roughly five to ten times as great a chance of
getting this cancer as women who take no estrogens. To put this another way,
while a postmenopausal woman not taking estrogens has one chance in 1,000 each
year of getting cancer of the uterus, a woman taking estrogens has five to ten
chances in 1,000 each year. For this reason It Is Important To Take Estrogens
Only When You Really Need Them.
The risk of this cancer is greater the longer estrogens are used and also seems
to be greater when larger doses are taken. For this reason It Is Important To
Take The Lowest Dose Of Estrogen That Will Control Symptoms And To Take It Only
As Long As It Is Needed. If estrogens are needed for longer periods of time,
your doctor will want to reevaluate your need for estrogens at least every six
months.
Women using estrogens should report any irregular vaginal bleeding to their
doctors; such bleeding may be of no importance, but it can be an early warning
of cancer of the uterus. If you have undiagnosed vaginal bleeding, you should
not use estrogens until a diagnosis is made and you are certain there is no
cancer of the uterus.
If you have had your uterus completely removed (total hysterectomy), there is no
danger of developing cancer of the uterus.
2. Other Possible Cancers. Estrogens can cause development of other tumors in
animals, such as tumors of the breast, cervix, vagina, or liver, when given for
a long time. At present there is no good evidence that women using estrogen in
the menopause have an increased risk of such tumors, but there is no way yet to
be sure they do not; and one study raises the possibility that use of estrogens
in the menopause may increase the risk of breast cancer many years later. This
is a further reason to use estrogens only when clearly needed. While you are
taking estrogens, it is important that you go to your doctor at least once a
year for a physical examination. Also, if members of your family have had breast
cancer or if you have breast nodules or abnormal mammograms (breast x-rays),
your doctor may wish to carry out more frequent examinations of your breasts.
3. Gall Bladder Disease. Women who use estrogens after menopause are more likely
to develop gall bladder disease needing surgery than women who do not use
estrogens. Birth control pills have a similar effect.
4. Abnormal Blood Clotting. Oral contraceptives, some of which contain
estrogens, increase the risk of blood clotting in various parts of the body.
This can result in a stroke (if the clot is in the brain), a heart attack (clot
in a blood vessel of the heart), or a pulmonary embolus (a clot which forms in
the legs or pelvis, then breaks off and travels to the lungs). Any of these can
be fatal. Blood clots may result in the loss of a limb, paralysis or loss of
sight, depending on where the blood clot is formed or lodges if it breaks loose.
The larger doses of estrogen used to prevent swelling of the breasts after
pregnancy have been reported to cause clotting in the legs and lungs.
It is recommended that if you have had any blood clotting disorders including
clotting in the legs or lungs, or a heart attack or stroke, you should not use
estrogens.
SPECIAL WARNING ABOUT PREGNANCY
You should not receive estrogen if you are pregnant. If this should occur, there
is a greater than usual chance that the developing child will be born with a
birth defect, although the possibility remains fairly small. A female child may
have an increased risk of developing cancer of the vagina or cervix later in
life (in the teens or twenties). Every possible effort should be made to avoid
exposure to estrogens during pregnancy. If exposure occurs, see your doctor.
SOME OTHER EFFECTS OF ESTROGENS
In addition to the serious known risks of estrogens described above, estrogens
have the following side effects and potential risks:
1. Nausea And Vomiting. The most common side effect of estrogen therapy is
nausea. Vomiting is less common.
2. Effects On Breasts. Estrogens may cause breast tenderness or enlargement and
may cause the breasts to secrete a liquid.
3. Effects On The Uterus. Estrogens may cause benign fibroid tumors of the
uterus to get larger.
Some women will have menstrual bleeding when estrogens are stopped. But if the
bleeding occurs on days you are still taking estrogens you should report this to
your doctor.
4. Effects On Liver. Women taking estrogens develop on rare occasions a tumor of
the liver which can rupture and bleed into the abdomen. You should report any
swelling or unusual pain or tenderness in the abdomen to your doctor
immediately.
Women with a past history of jaundice (yellowing of the skin and white parts of
the eyes) may get jaundice again during estrogen use.
5. Other Effects. Estrogens may cause excess fluid to be retained in the body.
This may make some conditions worse, such as epilepsy, migraine, heart disease,
or kidney disease.
If any of the above occur, stop taking estrogens and call your doctor.
SUMMARY: Estrogens have important uses, but they have serious risks as well. You
must decide, with your doctor, whether the risks are acceptable to you in view
of the benefits of treatment. Except where your doctor has prescribed estrogens
for use in special cases of cancer of the breast or prostate, you should not use
estrogens if you have cancer of the breast or uterus, are pregnant, have
undiagnosed abnormal vaginal bleeding, blood clotting disorders including
clotting in the legs or lungs, or have had a stroke, heart attack or angina.
You must understand that your doctor will require regular physical examinations
while you are taking them and will try to discontinue the drug as soon as
possible and use the smallest dose possible. You can help minimize the risk by
being alert for signs of trouble including:
1. Abnormal bleeding from the vagina.
2. Pains in the calves or chest or sudden shortness of breath, or coughing blood
(indicating possible clots in the legs, heart or lungs).
3. Severe headache, dizziness, faintness, or changes in vision (indicating
possible developing clots in the brain or eye).
4. Breast lumps (you should ask your doctor how to examine your own breasts).
5. Jaundice (yellowing of the skin).
6. Mental depression.
7. ANY other unusual condition or problem.
Based on his or her assessment of your medical needs, your doctor has prescribed
this drug for you. Do not give the drug to anyone else.
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