Three independent, case-controlled studies have reported an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for more than one year. 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. 4
    The three case-controlled 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 1 and on estrogen dose. 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. 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.
    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 nonsteroidal estrogen, have an increased risk of developing, in later life, a form of vaginal or cervical cancer that is ordinarily extremely rare. 5,6 This risk has been estimated as not greater than 4 per 1,000 exposures. 7 Furthermore, a high percentage of such exposed women (from 30% to 90%) have been found to have vaginal adenosis, 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. 13 - 16 One case-controlled study 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 1,000.
    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 Premarin Intravenous (conjugated estrogens, USP) for injection is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation

Each Secule® vial contains 25 mg of conjugated estrogens, USP, in a sterile lyophilized cake which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric acid. A sterile diluent (5 mL) containing 2% benzyl alcohol in sterile water is provided for reconstitution. The reconstituted solution is suitable for intravenous or intramuscular injection.

Premarin (conjugated estrogens, USP) is a mixture of estrogens, obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It contains estrone, equilin, and 17 (alpha)-dihydroequilin, together with smaller amounts of 17 (alpha)-estradiol, equilenin, and 17 (alpha)-dihydroequilenin as salts of their sulfate esters.

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Decline of estrogenic activity at the end of the menstrual cycle can bring on menstruation, although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However, in the preovulatory or nonovulatory cycle, estrogen is the primary determinant in the onset of menstruation. Estrogens also affect the release of pituitary gonadotropins.

The pharmacologic effects of conjugated estrogens are similar to those of endogenous estrogens. They are soluble in water and may be administered by intravenous or intramuscular injection.

In responsive tissues (female genital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. As a result of estrogen action, specific RNA and protein synthesis occurs.

Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and, therefore, ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal.


Premarin Intravenous (conjugated estrogens, USP) for injection is indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.


Estrogens should not be used in women with any of the following conditions:

  1.   Known or suspected cancer of the breast, except in appropriately selected patients being treated for metastatic disease.
  2.   Known or suspected estrogen-dependent neoplasia.
  3.   Known or suspected pregnancy (see Boxed Warning).
  4.   Undiagnosed abnormal genital bleeding.
  5.   Active thrombophlebitis or thromboembolic disorders.
  6.   A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy).

  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 are now reports 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, 17 although a recent long-term follow-up of a single physician' practice has raised this possibility. 18 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.    Gallbladder disease. A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens, 17 similar to the 2-fold increase previously noted in users of oral contraceptives. 19, 24a
  3.    Effects similar to those caused by estrogen-progestogen oral contraceptives.  There are several serious adverse effects of oral contraceptives, some 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 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. 20 - 23
    1.    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. 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. 32, 33 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives. 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.
      In some studies, women on estrogen replacement therapy, given alone or in combination with a progestin, have been reported to have an increased risk of thrombophlebitis, and/or thromboembolic disease. The physician should be aware of the possibility of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen replacement therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation. 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 36 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 contraceptives or estrogen replacement therapy should be considered a clear risk.
    2.    Hepatic adenoma. Benign hepatic adenomas appear to be associated with the use of oral contraceptives. 37 - 39 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. 38 The relationship of this malignancy to these drugs is not known at this time.
    3.    Elevated blood pressure. Women using oral contraceptives sometimes experience increased blood pressure which, in most cases, returns to normal on discontinuing the drug. There is now a report that this may occur with use of estrogens in the menopause 40 and blood pressure should be monitored with estrogen use, especially if high doses are used.
    4.    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.


  1. General Precautions
    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 asthma, 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. 24a 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 yet complete.
    11.   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.
    12.  Familial hyperlipoproteinemia. Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pacreatitis and other complications in patients with familial defects of lipoprotein metabolism.
  2. Information for the Patient
    See text which appears after the "PHYSICIAN REFERENCES."
  3. Pregnancy Category X
    See " CONTRAINDICATIONS " and Boxed Warning.
  4. Nursing Mothers
    As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary, since many drugs are excreted in human milk.


(See " " regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder 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: Breakthrough bleeding, spotting, change in menstrual flow; dysmenorrhea; premenstrual-like syndrome; amenorrhea during and after treatment; increase in size of uterine fibromyomata; vaginal candidiasis; change in cervical erosion and in degree of cervical secretion; cystitis-like syndrome.
  2. Breasts:  Tenderness, enlargement, secretion.
  3. Gastrointestinal:  Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; pancreatitis.
  4. Skin:  Chloasma or melasma which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
  5. Cardiovascular:  Venous thromboembolism; pulmonary embolism.
  6. Eyes:  Steepening of corneal curvature; intolerance to contact lenses.
  7. CNS:  Headache, migraine, dizziness; mental depression; chorea.
  8. Miscellaneous:  Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.


Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.


Abnormal uterine bleeding due to hormonal imbalance: One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more rapid response can be expected from this mode of administration.

Repeat in 6 to 12 hours if necessary. The use of Premarin® Intravenous (conjugated estrogens, USP) for injection does not preclude the advisability of other appropriate measures.

The usual precautionary measures governing intravenous administration should be adhered to. Injection should be made SLOWLY to obviate the occurrence of flushes.

Infusion of Premarin Intravenous (conjugated estrogens, USP) for injection with other agents is not generally recommended. In emergencies, however, when an infusion has already been started it may be expedient to make the injection into the tubing just distal to the infusion needle. If so used, compatibility of solutions must be considered.

Compatibility of solutions:   Premarin Intravenous is compatible with normal saline, dextrose, and invert sugar solutions. IT IS NOT COMPATIBLE WITH PROTEIN HYDROLYSATE, ASCORBIC ACID, OR ANY SOLUTION WITH AN ACID pH.

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.

Directions For Storage and Reconstitution

Storage before reconstitution: Store package in refrigerator, 2°-8°C (36°-46°F).

To reconstitute:   First withdraw air from Secule® vial so as to facilitate introduction of sterile diluent. Then, flow the sterile diluent slowly against side of Secule® vial and agitate gently. DO NOT SHAKE VIOLENTLY.

Storage after reconstitution: It is common practice to utilize the reconstituted solution within a few hours. If it is necessary to keep the reconstituted solution for more than a few hours, store the reconstituted solution under refrigeration (2°-8°C). Under these conditions, the solution is stable for 60 days, and is suitable for use unless darkening or precipitation occurs.


NDC 0046-0749-05--Each package provides: (1) One Secule® vial containing 25 mg of conjugated estrogens, USP, for injection (also lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg). The pH is adjusted with sodium hydroxide or hydrochloric acid. (2) One 5 mL ampul sterile diluent with 2% benzyl alcohol in sterile water.

Premarin Intravenous (conjugated estrogens, USP) for injection is prepared by cryodesiccation.

SECULE®--Registered trademark to designate a vial containing an injectable preparation in dry form.


 1.Ziel, H. K. et al. : N. Engl. J. Med. 293  :1167-1170, 1975.

 2. Smith, D. C. et al. : N. Engl. J. Med. 293  :1164-1167, 1975.

 3. Mack, T. M. et al. : N. Engl. J. Med. 294  :1262-1267, 1976.

 4. Weiss, N. S. et al. : N. Engl. J. Med. 294  :1259-1262, 1976.

 5. Herbst, A. L. et al. : N. Engl. J. Med. 284  :878-881, 1971.

 6. Greenwald, P. et al. : N. Engl. J. Med. 285  :390-392, 1971.

 7. Lanier, A. et al. : Mayo Clin. Proc. 48  :793-799, 1973.

 8. Herbst, A. et al. : Obstet. Gynecol. 40  :287-298, 1972.

 9. Herbst, A. et al. : Am. J. Obstet. Gynecol. 118  :607-615, 1974.

10. Herbst, A. et al. : N. Engl. J. Med. 292  :334-339, 1975.

11. Stafl, A. et al. : Obstet. Gynecol. 43  :118-128, 1974.

12. Sherman, A. I. et al. : Obstet. Gynecol. 44  :531-545, 1974.

13. Gal, I. et al. : Nature 216  :83, 1967.

14. Levy, E. P. et al. : Lancet 1  :611, 1973.

15. Nora, J. et al. : Lancet 1  :941-942, 1973.

16.Janerich, D. T. et al. : N. Engl. J. Med. 291  :697-700, 1974.

17. Boston Collaborative Drug Surveillance Program: N. Engl. J. Med. 290  :15-19, 1974.

18. Hoover, R. et al. : N. Engl. J. Med. 295  :401-405, 1976.

19. Boston Collaborative Drug Surveillance Program: Lancet 1  :1399-1404, 1973.

20. Daniel, D. G. et al. : Lancet 2  :287-289, 1967.

21. The Veterans Administration Cooperative Urological Research Group: J. Urol. 98  :516-522, 1967.

22. Bailar, J. C.: Lancet 2  :560, 1967.

23. Blackard, C. et al. : Cancer 26  :249-256, 1970.

24. Royal College of General Practitioners: J. R. Coll. Gen. Pract. 13  :267-279, 1967.

24a. Royal College of General Practitioners: Oral Contraceptives and Health, New York, Pitman Corp., 1974.

25. Inman, W. H. W. et al. : Br. Med. J. 2  :193-199, 1968.

26. Vessey, M. P. et al. : Br. Med. J. 2  :651-657, 1969.

27. Sartwell, P. E. et al. : Am. J. Epidemiol. 90  :365-380, 1969.

28. Collaborative Group for the Study of Stroke in Young Women: N. Engl. J. Med. 288  :871-878, 1973.

29. Collaborative Group for the Study of Stroke in Young Women: J.A.M.A. 231  :718-722, 1975.

30. Mann, J. I. et al. : Br. Med. J. 2  :245-248, 1975.

31. Mann, J. I. et al. : Br. Med. J. 2  :241-245, 1975.

32. Inman, W. H. W. et al. : Br. Med. J. 2  :203-209, 1970.

33. Stolley, P. D. et al. : Am. J. Epidemiol. 102  :197-208, 1975.

34. Vessey, M. P. et al. : Br. Med. J. 3  :123-126, 1970.

35. Greene, G. R., et al. : Am. J. Public Health 62  :680-685, 1972.

36. Coronary Drug Project Research Group: J.A.M.A. 214  :1303-1313, 1970.

37. Baum, J. et al. : Lancet 2  :926-928, 1973.

38. Mays, E. T. et al. : J.A.M.A. 235  :730-732, 1976.

39. Edmondson, H. A. et al. : N. Engl. J. Med. 294  :470-472, 1976.

40. Pfeffer, R. I. et al. : Am. J. Epidemiol. 103  :445-456, 1976.


What You Should Know 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 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, the risks involved in their use, and how to use them as safely as possible.

This leaflet includes the most important information about estrogens, but not all the information. If you want to know more, you should ask your doctor for more information, or 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 stop producing a majority of her estrogens, in order to prevent certain uncomfortable symptoms of estrogen deficiency. (With the menopause, which generally occurs between the ages of 45 and 55, women produce a much smaller amount of estrogens.)
  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.

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 before natural menopause by an operation, 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. Some women may also develop changes in the vagina (called "atrophic vaginitis") that 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 overstimulation of the uterus (womb), estrogens are usually given cyclically during each month of use, such as 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 without associated vasomotor symptoms. In the absence of vasomotor symptoms, estrogens should not be used to treat nervous symptoms, 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.

The Dangers of Estrogens

  1.    Endometrial cancer. There are reports that if estrogens are used in the postmenopausal period for more than a year, there is an increased risk of endometrial cancer (cancer of the lining of the uterus). Women taking estrogens have roughly 5- to 10-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 1 chance in 1,000 each year of getting endometrial cancer, a woman taking estrogens has 5 to 10 chances in 1,000 each year. For this reason it is important to take estrogens only when they are really needed.
    The risk of this cancer is greater the longer estrogens are used and when larger doses are taken. Therefore, you should not take more estrogen than your doctor prescribes. 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 vaginal bleeding to their doctors; such bleeding may be of no importance, but it can be an early warning of endometrial cancer. If you have undiagnosed vaginal bleeding, you should not use estrogens until a diagnosis is made and you are certain there is no endometrial cancer.
    Note:   If you have had your uterus removed (total hysterectomy), there is no danger of developing endometrial cancer.
  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 estrogens 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 cancers, 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.    Gallbladder disease. Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens. Birth-control pills have a similar effect.
  4.    Abnormal blood clotting.  Taking estrogens may 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 (a 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.
    It is recommended that if you have had clotting in the legs or lungs, or a heart attack or stroke, while you were using estrogens or birth-control pills, you should not use estrogens (unless they are being used to treat cancer of the breast or prostate). If you have had a stroke or heart attack, or if you have angina pectoris, estrogens should be used with great caution and only if clearly needed (for example, if you have severe symptoms of the menopause).
  5.    Inflammation of the pancreas (Pancreatitis).  Women with high triglyceride levels may have an increased risk of developing inflammation of the pancreas.

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.

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. These effects are not dangerous.
  3.    Effects on the uterus. Estrogens may cause benign fibroid tumors of the uterus to get larger.
  4.    Effects on liver. Women taking oral contraceptives develop, on rare occasions, a tumor of the liver which can rupture and bleed into the abdomen and may cause death. So far, these tumors have not been reported in women using estrogens in the menopause, but 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. If this occurs, stop taking estrogens and see your doctor.
  5.    Other effects.  Estrogens may cause excess fluid to be retained in the body. This may make some conditions worse, such as asthma, epilepsy, migraine, heart disease, or kidney disease.


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, clotting in the legs or lungs, or have had a stroke, heart attack or angina, or clotting in the legs or lungs in the past while you were taking estrogens.

You can use estrogens as safely as possible by understanding that your doctor will require regular physical examinations while you are taking them, will try to discontinue the drug as soon as possible, and use the smallest dose possible. Be 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.
  3.   Severe headache, dizziness, faintness, or changes in vision.
  4.   Breast lumps (you should ask your doctor how to examine your own breasts).
  5.   Jaundice (yellowing of the skin).
  6.   Mental depression.

Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else.


Premarin® (conjugated estrogens tablets, USP) tablets for oral administration.

Premarin® Vaginal Cream--Premarin® in a nonliquefying base, designed for vaginal use.

Premarin® Intravenous--Premarin® specially prepared for intravenous and intramuscular use.

Manufactured by:

Ayerst Laboratories Inc.

A Wyeth-Ayerst Company

Philadelphia, PA 19101

CI 3902-6  Revised April 29, 1998