Consumer Drug Information File (DEC. 1990)
Monograph Title: ESTROGEN
Pronunciation: ess' troe jen
Synonyms: conjugated estrogens 
Estinyl
Estrace 
Estraderm
estradiol 
ethinyl estradiol
Premarin
others

WHY is this drug prescribed?

Estrogen is a hormone, a substance produced by the body. 
It is needed for normal growth and development of female sex organs
and for natural functions such as bearing children. Estrogen is
used to relieve feelings of warmth in the face, neck, and chest,
"hot flashes", and sweating that occur during menopause (when your 
estrogen production declines). It also is used for conditions caused 
by insufficient estrogen (after menopause or due to other medical 
problems), including dry, itchy external genitals and vaginal 
irritation. It also is prescribed for young women who do not mature 
physically at the usual rate, for breast and prostate cancer, and to 
dry up breast milk after the birth of a baby. Estrogen also is used 
with diet, calcium supplements, and exercise to slow the progression 
of osteoporosis, a disease (common in women after menopause) resulting 
in bones that break easily.

DESCRIPTORS: Use WHEN should it be used?

Estrogen usually is taken on a cyclical basis once a day
for 21 days and then none for seven days, then the cycle is repeated. 
However, for cancer it usually is taken three times a day continuously 
for at least three months. Follow the instructions on your 
prescription label carefully, and ask your doctor or pharmacist to 
explain any part that you do not understand.

DESCRIPTORS: Dosage; Instructions HOW should it be used?

Estrogen comes in tablets, skin patches, vaginal cream, 
and injection form. Your prescription label tells you how much to take 
at each dose. Skin patches usually are applied twice weekly for three 
weeks (on the same two days each week), followed by one week without 
the drug, then the cycle is repeated. The package is specially 
designed to help you remember when to apply fresh skin patches.
To apply a skin patch, follow the instructions provided and
these steps: 1. Remove the skin patch from its protective pouch and 
peel off the protective strip, exposing the adhesive surface. 2. 
Place the adhesive side against a clean, dry, and not excessively 
hairy area of skin on the trunk of your body, preferably your abdomen 
(not your waistline, since tight clothing may rub the patch off, or 
breasts). Do not apply the patch to oily, broken, or irritated skin. 
3. Press the patch firmly with the palm of your hand for about 10 
seconds, making sure that the edges adhere to your skin.
If the patch accidentally comes off, you can either reapply 
it or apply a fresh patch, but follow your regular dosing schedule.
Remove and discard the patch and apply a fresh patch according to the 
schedule prescribed by your doctor. To prevent skin irritation, use 
a different site for each application and wait at least one week 
before using a particular site again.
Follow the instructions that come with the vaginal cream. 
Ask your doctor or pharmacist any questions you have about using it.
You may wish to wear a sanitary napkin after inserting the cream to 
keep your clothes clean. If you use the vaginal cream once a day, it 
is best to use it at bedtime. Ask your doctor or pharmacist any 
questions you have about refilling your prescription.

DESCRIPTORS: Administration; Instructions What SPECIAL 
INSTRUCTIONS should I follow while using this drug?

Ask your doctor or pharmacist for a copy of the 
manufacturer's information for the patient. Keep all appointments for 
checkups so that your doctor can evaluate your response to the drug. 
You should have a complete physical examination annually (including a 
Pap test to detect vaginal cancer in women). Ask your doctor to teach 
you how to examine your breasts, report any lumps immediately.

DESCRIPTORS: Instructions What should I do IF I FORGET to take 
a dose?

If you forget to apply a skin patch, apply it as soon as you 
remember, note the date on the package, and adjust your schedule. If 
you miss a dose of tablets or vaginal cream, take it as soon as you 
remember. However, if you remember a missed dose near the time you are 
scheduled to take the next dose, take only the regularly scheduled 
dose. Do not take a double dose.

DESCRIPTORS: Dosage; Instructions Side Effects

Nausea, vomiting, cramps, bloating, diarrhea, appetite and
weight changes. Eat a light snack if you experience nausea. If these 
effects persist or are severe, contact your doctor. Brown or black 
skin patches, swelling of hands, feet, or lower legs (fluid retention), 
bleeding or spotting between menstrual periods, changes in menstrual 
flow, painful or missed menstrual periods, breast tenderness, 
enlargement, or secretion, intolerance to contact lenses. Contact your 
doctor if these effects are bothersome. Skin redness and irritation 
(from skin patches). Use a different site for each application. If 
these effects are severe or persist for more than a day, contact your
doctor. Sudden, severe headache or vomiting, vision or speech 
problems, sudden partial or complete loss of vision, dizziness or 
faintness, weakness or numbness of an arm or leg, sharp, crushing
chest pain or heaviness in chest, cough, coughing up of blood,
sudden shortness of breath, calf pain, severe abdominal pain,
yellowing of skin or eyes, itching, and loss of appetite, severe
mental depression, unusual bleeding. Contact your doctor immediately.

DESCRIPTORS: Cautions Precautions

Before you take estrogen, tell your doctor your entire
medical history, including family medical history, especially breast 
lumps or cancer, high blood pressure, diabetes, asthma, epilepsy 
(seizures), migraine headaches, liver, heart, or kidney disease, 
mental depression, toxemia (high blood pressure during pregnancy), 
jaundice (yellowing of skin or eyes) during pregnancy, and excessive 
weight gain and fluid retention (bloating) during the menstrual cycle. 
Tell your doctor if you are allergic to aspirin or tartrazine (a 
yellow dye in some processed foods and medications, including 
estrogen). Estrogen may affect the way your body responds to certain 
other drugs. Tell your doctor what prescription and nonprescription
medications you are taking. Before having surgery, tell the doctor 
that you take estrogen. Before you have any laboratory tests, tell 
the laboratory personnel and doctor that you take estrogen. Before 
you take estrogen, tell your doctor if you are pregnant or breast-
feeding. Estrogen can harm an unborn baby. If you become pregnant 
while taking estrogen, stop taking it and contact your doctor 
promptly. Do not allow anyone else to take this medication.

DESCRIPTORS: Cautions; Interactions Storing Your Medication

Keep this medication in the container it came in, tightly
closed, and out of the reach of children. Store it at room temperature. 
Do not remove skin patches from their protective pouches until just 
before applying them.

DESCRIPTORS: Storage Copr., 1991, Am. Soc. of Hospital
Pharmacists, Inc. All Rights Reserved. DRUG
INFORMATION FULL TEXT - OCT 1990 (COPR. ASHP 1990)

AHFS NO: 68.16
AHFS CLASS: Estrogens
SUBFILE: HANDBOOK ON INJECTABLE DRUGS
MONOGRAPH TITLE: Estrogens, Conjugated
GENERIC NAME: ESTROGENS, CONJUGATED
TRADE NAME(S): Premarin Intravenous Wyeth-Ayerst
PRODUCTS (PD):
PRIMARY TEXT: [5305,5315] Estrogens, conjugated (Wyeth-
Ayerst), is available in packages containing
a vial with lyophilized estrogens, conjugated, 
25 mg; lactose 200 mg; sodium citrate 12.5 mg;
simethicone 0.2 mg; and sodium hydroxide or 
hydrochloric acid for pH adjustment. Also in 
the package is a 5-ml ampul of sterile diluent
composed of water for injection and benzyl 
alcohol 2%. [5455] To constitute, withdraw the
air from the vial of estrogens, conjugated; flow
the sterile diluent slowly against the side of
the vial, and agitate gently--not violently (2).
pH [5155] The pH is adjusted to 7.2 (1-10/74).

CHEMISTRY AND STABILITY (CH):

PRIMARY TEXT: [5345] The manufacturer recommends refrigeration
of the intact containers at 2 to 8 DGC (2). Such 
storage provides a shelflife of up to 60 months.
At room temperature, the product in intact vials
is stable for 24 months (853). The constituted
solution should be stored at 2 to 8 DGC (2). The
constituted drug is stable for 60 days. Do not
use it, however, if precipitation or 
discoloration occurs (2).

DOSAGE AND ADMINISTRATION (DO):

PRIMARY TEXT: [5575] Administration may be made by deep
intramuscular injection or direct intravenous 
injection.
[5575,5605] Direct intravenous injection should
be performed slowly to obviate flushing.
[5575] Intravenous infusion is not recommended,
but injection into the tubing of a running
infusion may be expedient (2; 4; 8). 
[5525] The dosage of estrogens, conjugated, must 
be individualized to the patient's condition, 
tolerance, and response. The lowest effective 
dosage should be used; therapy should be discontinued as soon as possible, if indicated (4). 
The usual dose is 25 mg, repeated in six to 12 
hours if needed.
[5555] Safe and effective use in children has
not been established (2; 4).

COMPATIBILITY INFORMATION (CI): SEE TABLE FORMAT OF THIS RECORD. 

Solutions [5335] Dextrose, saline, and invert sugar
solutions have been stated to be compatible 
with estrogens, conjugated (2).
Additives [5365] Estrogens, conjugated, has been stated
to be incompatible with ascorbic acid or any
solution with an acid pH (2; 4).

REFERENCES (RF): For a list of references cited in the text of 
this monograph, search the monograph titled HID
References.
TABLES: 
--------------------------------------------------------------------
[5352] Y-Site Injection Compatibility
(1:1 Mixture) Estrogens, conjugated
DRUG (IN SYRINGE) MFR AMT MFR AMT REMARKS REF C
I Heparin sodium RI 1000 AY 5 mg/ Physically compatible 322 
with units + ml for at least 4 hr at 
hydrocortisone 100mg/ room temperature by
sodium succinate La visual and microscopic
examination 
Potassium chloride 40 mEq/ AY 5 mg/ Physically compatible 322 C 
La ml for at least 4 hr at
room temperature by
visual and microscopic
examination 
Vitamin B complex RC 2 ml/La AY 5 mg/ Physically compatible 322 C
with C ml for at least 4 hr at
room temperature by 
visual and microscopic
examination 

aTested in dextrose 5% in water, sodium chloride 0.9%, and
Ringer's injection, lactated.

DESCRIPTORS: [5155] pH;
[5305] Stability;
[5315] Expiration date;
[5455] Reconstitution mixing;
[5525] Dosage schedule;
[5555] Age dosage relation;
[5575] Administration route;
[5605] Adverse reaction (side effect);
[5345] Storage;
[5352] Equipment compatibility (Table);
[5335] Vehicle compatibility;
[5365] Additive compatibility 

AHFS NO: 68.16
AHFS CLASS: ESTROGENS
SUBFILE: American Hospital Formulary Service
MONOGRAPH TITLE: Estrogens, Conjugated
GENERIC NAME: Estrogens, Conjugated
SYNONYMS: Estrogenic Substances, Conjugated
TRADE NAME(S): Premarin Cycle Pack Wyeth-Ayerst
Premarin Intravenous Wyeth-Ayerst
Premarin Wyeth-Ayerst
PMB 200 Wyeth-Ayerst
Milprem-400 Wallace
PMB 400 Wyeth-Ayerst 
Premarin with Methyltestosterone Wyeth-Ayerst
CHEMISTRY AND STABILITY (CH):
PRIMARY TEXT: CHEMISTRY [3115] Conjugated estrogens is a mixture
containing the sodium salts of the water-soluble
sulfate esters of estrone and equilin.
STABILITY [3345] Commercially available conjugated 
estrogens tablets should be stored in well-
closed containers. Conjugated estrogens tablets
and vaginal cream should be stored at a temperature less than 40DGC, preferably between 15-30DGC; 
freezing of the vaginal cream should be avoided.
Conjugated estrogens powder for injection should
be stored at a temperature of 2-8DGC prior to
reconstitution.
[3345,3303] Following reconstitution, solutions of 
the drug are stable for up to 60 days when stored
at 2-8DGC; however, solutions should not be used
if they darken or if a precipitate is present.
ADDITIONAL TEXT: CHEMISTRY AND STABILITY
CHEMISTRY [3103] Conjugated estrogens may be derived
wholly or in part from equine urine or may be
prepared synthetically from estrone and equilin.
[3113] Conjugated estrogens may also contain
conjugated estrogenic substances of the type 
excreted by pregnant mares including 17-alphadihydroequilin, 17-alpha-estradiol, equilenin,
and 17-alpha-dihydroequilenin. Conjugated
estrogens contains 50-63% sodium estrone sulfate
and 22.5-32.5% sodium equilin sulfate.
[3133] Conjugated estrogens obtained from
natural sources occurs as a buff-colored, 
amorphous powder and is odorless or has a slight,
characteristic odor. Conjugated estrogens that
is prepared synthetically occurs as a white to
light buff, crystalline or amorphous powder and
is odorless or has a slight odor.
[3143] Conjugated estrogens is soluble in water.
[3113] Conjugated estrogens injection is commercially available as a sterile, lyophilized cake.
[3413,3113] The lyophilized cake also contains lactose, sodium citrate, and simethicone; in addition,
sodium hydroxide and/or hydrochloric acid may be
added during manufacture of the powder for
injection to adjust the pH. A sterile diluent 
containing water for injection and benzyl alcohol
as a preservative is provided for reconstitution.

STBILITY [3333,3323] Conjugated estrogens injection is
physically and chemically compatible with the
following IV solutions: 5% dextrose
0.9% sodium chloride
invert sugar solutions;
the injection is physically and/or chemically
incompatible with ascorbic acid or any solution
with an acid pH. Specialized references should
be consulted for specific compatibility information.

PHARMACOLOGY (PC): 
PRIMARY TEXT: [3205] The principal pharmacologic effects of
conjugated estrogens are similar to those of
other natural and synthetic estrogens. (See
Pharmacology in the Estrogens General Statement 68:16.)
USES (US):
PRIMARY TEXT: [3225,3643] In females, oral conjugated estrogens
is used for the management of moderate to severe
vasomotor symptoms associated with menopause;
however, estrogens do not appear to be effective
for the management of nervous symptoms or depression associated with menopause in patients without
vasomotor symptoms, and the drugs should not be
used in the management of such conditions in
these patients.
[3225] Oral conjugated estrogens is also used
for the management of atrophic vaginitis, kraurosis vulvae, female hypogonadism and castration,
and primary ovarian failure. 
[3225,3003,3900] Oral conjugated estrogens may be used
adjunctively with other therapeutic measures 
(e.g., diet, calcium, physical therapy) to retard
further bone loss and the progression of osteoporosis associated with estrogen deficiency in
postmenopausal women with evidence of bone loss
or deficiency of bone mass. (100,101) (See Uses
in the Estrogens General Statement 68:16.)
[3225,3003] Estrogen replacement therapy has been
shown to reduce bone resorption and retard or
halt bone loss in postmenopausal women; (100)
however, there is no clear method for identifying
those women who will develop osteoporotic fractures, and there is a lack of substantial evidence
that estrogen replacement therapy decreases the
incidence of osteoporotic bone fractures. (101)
Additional study is needed to determine the exact
role and optimum regimen of estrogen and/or other
modalities in the prevention of primary osteoporosis. (100)
[3225] Oral conjugated estrogens is used for
the palliative treatment of advanced, inoperable,
metastatic carcinoma of the breast in postmenopausal women and in men. However, because tamoxifen appears to be at least as effective as 
estrogen therapy in postmenopausal women and 
causes a lower incidence of severe adverse effects,
tamoxifen is preferred by some clinicians. 
[3225,3643] In males, oral conjugated estrogens is 
used for the palliative treatment of advanced, 
inoperable carcinoma of the prostate; however, 
the risk of adverse cardiovascular effects of
estrogens must be considered.
[3225] Conjugated estrogens may be administered
IM or IV for the treatment of abnormal uterine
bleeding caused by hormonal imbalance not 
associated with organic pathology. Conjugated 
estrogens may be administered intravaginally for
the management of atrophic vaginitis or kraurosis
vulvae.
[3225,3643,3653,3900] Conjugated estrogens has not been shown 
to be effective for any purpose during pregnancy,
and use of the drug in pregnant women may cause
severe harm to the fetus. (See Cautions: Pregnancy
and Lactation, in the Estrogens General Statement
68:16.)

ADDITIONAL TEXT: USES [3223] Although oral conjugated estrogens has 
been used for the prevention of postpartum breast
engorgement, data from controlled studies indicate
that the incidence of substantial painful engorgement is low in untreated women, and the condition
usually responds to appropriate analgesic or other 
supportive therapy.
[3223,3643] The benefit derived from estrogen therapy
in the prevention of postpartum breast engorgement
must be carefully weighed against the potential 
increased risk of puerperal thromboembolism 
associated with the use of large doses of estrogens. (See Cautions: Cardiovascular Effects, in
the Estrogens General Statement 68:16.)
[3223,3643] Estrogens are not used in the treatment
of breast cancer in premenopausal women because
the drugs may potentially stimulate tumor growth
rather than inhibit it.
[3223] The specific role of estrogen therapy 
compared with other therapies (e.g., chemo-
therapy, orchiectomy) in the treatment of
prostatic cancer has not been clearly determined,
and patients should generally be referred to
physicians who are actively engaged in the
investigation of the disease and are therefore
familiar with the latest and most advantageous
forms of therapy. Estrogen therapy is currently
considered a therapy of choice for patients with 
inoperable prostatic tumors, for patients who
refuse orchiectomy, and for patients whose disease progresses despite orchiectomy in whom the
benefits of estrogen use are considered to
outweigh the risk of adverse effects.
CAUTIONS (CA):
PRIMARY TEXT: [3605,3643,3900] Conjugated estrogens shares the toxic 
potentials of other estrogens, and the usual 
cautions, precautions, and contraindications 
associated with estrogen therapy should be 
observed. (See Cautions in the Estrogens General
Statement 68:16.)

DOSAGE AND ADMINISTRATION (DO):
PRIMARY TEXT: RECONSTITUTION AND ADMINISTRATION
[3575] Conjugated estrogens is usually administered orally, but may also be administered intra-
vaginally, topically, or by deep IM or slow IV
injection. When parenteral administration of
conjugated estrogens is required, IV injection is
preferred because of the more rapid response obtained following this route of administration 
compared to IM injection. For direct IV injection,
the drug should be administered slowly to avoid
the occurrence of a flushing reaction. 
[3455] For parenteral administration, conjugated
estrogens powder for injection is reconstituted 
with 5 mL of the diluent provided (sterile water 
for injection containing benzyl alcohol).
DOSAGE [3525] Dosage of conjugated estrogens must be
individualized according to the condition being
treated and the tolerance and therapeutic response
of the patient. To minimize the risk of adverse 
effects, the lowest possible effective dosage 
should be used. When short-term estrogen therapy 
is indicated (e.g., for the management of vasomotor
symptoms associated with menopause; atrophic vaginitis; kraurosis vulvae), therapy should be discontinued as soon as possible; attempts to reduce 
dosage or discontinue the drug should be made at 
3- to 6-month intervals. Estrogen therapy is 
usually administered cyclically. The drugs are 
usually given once daily for 3 weeks, followed by
1 week without the drugs, and then this regimen 
is repeated as necessary.
DOSAGE [3526] Vasomotor Symptoms, Atrophic Vaginitis,
and is Vulvae
[3525] For the management of moderate to severe
vasomotor symptoms associated with menopause or
for the management of atrophic vaginitis or
kraurosis vulvae, the usual oral dosage of
conjugated estrogens is 0.3-1.25 mg daily in a 
cyclic regimen; higher dosages may be required
in some patients. The drug is usually administered once daily for 21 consecutive days, followed
by 7 days without the drug, and then this regimen
is repeated as necessary. If conjugated estrogens
is used in the management of vasomotor symptoms and
the woman is menstruating, administration of the 
drug is started on the fifth day of the menstrual 
cycle; if the woman has not menstruated within the
last 2 or more months prior to initiation of
conjugated estrogens therapy, administration of 
the drug is started arbitrarily. Alternatively,
for the management of atrophic vaginitis or
kraurosis vulvae, 2-4 g of conjugated estrogens
vaginal cream may be administered intravaginally
or topically once daily in the usual cyclic regimen.
DOSAGE [3526] Female Hypogonadism 
[3525] For replacement therapy in female hypogonadism, the usual oral dosage of conjugated
estrogens is 2.5-7.5 mg daily given in divided
doses for 20 consecutive days, followed by 10
days without the drug. If menstruation does
not occur by the end of this period, the same
dosage schedule should be repeated. The number
of courses of estrogen therapy required to
induce menstruation varies, depending on the 
individual responsiveness of the endometrium.
If menstruation occurs before the end of the
10-day drug-free period, a 20-day estrogen-
progestin regimen should be initiated with
conjugated estrogens 2.5-7.5 mg daily given in
divided doses for 20 days; during the last 5
days of estrogen therapy, an oral progestin is 
administered. If menstruation begins before
this estrogen-progestin regimen is completed,
therapy should be discontinued and then
reinstituted on the fifth day of menstruation.
DOSAGE [3526] Female Castration, Primary Ovarian
Failure, and osteoporosis
[3525] For the management of female castration
or primary ovarian failure, or for the
adjunctive treatment of osteoporosis, the usual
initial oral dosage of conjugated estrogens is 
1.25 mg daily in a cyclic regimen. To retard
further bone loss and the progression of osteoporosis associated with estrogen deficiency in
postmenopausal women with evidence of bone loss
or deficiency of bone mass, the usual oral dosage
of conjugated estrogens is 0.625 mg daily in a 
cyclic regimen. (101) The drug is usually ad-
ministered once daily for 21 consecutive days 
followed by 7 days without the drug, and then 
this regimen is repeated as necessary. Subsequent
dosage should be adjusted according to the severity of the symptoms and the patient's therapeutic
response, using the lowest possible effective
maintenance dosage.
DOSAGE [3526] Postpartum Breast Engorgement
[3525] For the prevention of postpartum breast
engorgement, the usual oral dosage of conjugated
estrogens is 3.75 mg every 4 hours for 5 doses,
or 1.25 mg every 4 hours for 5 days.
DOSAGE [3526] Inoperable Carcinoma of the Breast
[3525] For the palliative treatment of in-
operable, advanced, metastatic carcinoma of the
breast in appropriately selected men and postmenopausal women, the usual oral dosage of conjugated estrogens is 10 mg 3 times daily. Estrogen
therapy is usually continued in these patients for
at least 3 months.
DOSAGE [3526] Inoperable Carcinoma of the Prostate
[3525] For the palliative treatment of in-
operable, advanced carcinoma of the prostate,
the usual oral dosage of conjugated estrogens
is 1.25-2.5 mg 3 times daily. Efficacy of
estrogen therapy in these patients can be
evaluated according to the patient's symptomatic
improvement and by serial determinations of
serum acid phosphatase concentration. In general,
if a response to conjugated estrogens therapy is
going to occur, it should be apparent within 3
months following initiation of therapy. If a
response does occur, conjugated estrogens 
therapy should be continued until substantial
progression of the disease occurs.
DOSAGE [3526] Abnormal Uterine Bleeding 
[3525] For the emergency treatment of abnormal
uterine bleeding caused by hormonal imbalance,
the usual IV or IM dose of conjugated estrogens 
is 25 mg. If necessary, the dose may be repeated
in 6-12 hours. The use of conjugated estrogens
for this condition does not preclude the use of
other appropriate measures.
ADDITIONAL TEXT: DOSAGE AND ADMINISTRATION RECONSTITUTION AND
ADMINISTRATION
[3453] To facilitate introduction of the
diluent, at least 5 mL of air should initially
be withdrawn from the vial (Secule) containing
the powder for injection. Using aseptic 
technique, the diluent should then be slowly
added, directing the flow against the inner wall
of the Secule, while gently agitating the
container to facilitate dissolution of the
contents; vigorous shaking of the container
should be avoided.
DOSAGE [3523,3003,3683] Addition of progestin therapy
for 7 or more days of a cycle of estrogen 
administration has been associated with a
decreased incidence of endometrial hyperplasia.
Morphologic and biochemical studies of the 
endometrium suggest that 10-13 days of progestin
are needed to provide maximum maturation of the 
endometrium and to eliminate any hyperplastic
changes.
[3523,3003,3643,3663] It has not been clearly established 
whether addition of progestin therapy will reduce
the risk of developing endometrial carcinoma.
[3003,3643,3523] When a progestin is used in conjunction
with cyclic estrogen administration, the usual
precautions associated with progestin therapy 
should be observed. Clinicians prescribing 
progestins should be aware of the risks associated
with these drugs and the manufacturers' labeling
should be consulted. The choice and dosage of a
progestin may be important factors in minimizing
potential adverse effects.
DOSAGE [3526] Abnormal Uterine Bleeding
[3900] For further information on chemistry,
pharmacology, pharmacokinetics, cautions, acute
toxicity, drug interactions, laboratory test 
interferences, and dosage and administration of
conjugated estrogens, see the Estrogens General
Statement 68:16. 

PREPARATIONS (PR): 
PRIMARY TEXT: CONJUGATED ESTROGENS 
[3474] Oral
[3434] Tablets 
[3436] 0.3 mg* 
[1050,3403] Premarin
[1080,3403] Wyeth-Ayerst
[3436] 0.625 mg* 
[1050,3403] Premarin
[1080,3403] Wyeth-Ayerst
[1050,3403] Premarin Cycle Pack 
[1080,3403] Wyeth-Ayerst
[3436] 0.9 mg 
[1050,3403] Premarin 
[1080,3403] Wyeth-Ayerst
[3436] 1.25 mg* 
[1050,3403] Premarin 
[1080,3403] Wyeth-Ayerst 
[3436] 2.5 mg* 
[1050,3403] Premarin 
[1080,3403] Wyeth-Ayerst 
[3474] Parenteral
[3434] For injection
[3436] 25 mg
[1050,3403] Premarin Intravenous
[3413] (with bacteriostatic water for injection
containing benzyl alcohol 2%)
[1080,3403] Wyeth-Ayerst
[3474] Vaginal
[3434] Cream
[3436] 0.0625% 
[1050,3403] Premarin
[1080,3403] Wyeth-Ayerst
[3403] *available by nonproprietary name

CONJUGATED ESTROGENS COMBINATIONS
[3474] Oral
[3434] Tablets
[3436,3423] 0.45 mg with Meprobamate 200 mg 
[1070,3423] PMB 200]
[1080,3423] Wyeth-Ayerst
[3436,3423] 0.45 mg with Meprobamate 400 mg
[1070,3423] Milprem-400 
[1080,3403] Wallace
[1070,3423] PMB 400
[1080,3423] Wyeth-Ayerst
[3436,3423] 0.625 mg with Methyltestosterone 5 mg
[1070,3423] Premarin with Methyltestosterone
[1080,3423] Wyeth-Ayerst
[3436,3423] 1.25 mg with Methyltestosterone 10 mg
[1070,3423] Premarin with Methyltestosterone
[1080,3423] Wyeth-Ayerst

REFERENCES (RF):
Note: This is a partial list of cited references.
100. National Institutes of Health. Osteoporosis.
JAMA. 1984; 252:799-802.
101. Ayerst Laboratories. Premarin tablets prescribing
information. New York, NY; 1986 Jul. Selected 
Revisions February 1990, (C) Copyright, October
1961, American Society of Hospital Pharmacists,
Inc.

DESCRIPTORS: [3103] Chemistry;
[3113] Chemical description;
[3115] Chemical description;
[3133] Physical description;
[3143] Solubility;
[3303] Stability;
[3323] Drug compatibility; 
[3333] Vehicle compatibility;
[3345] Storage;
[3413] Other chemical ion ingredient;
[3205] Pharmacology;
[3003] Other drug;
[3223] Therapy;
[3225] Therapy;
[3643] Precaution contraindication;
[3653] Fetal toxicity;
[3605] Adverse reaction (side effect);
[3643] Precaution contraindication;
[3003] Other drug;
[3453] Reconstitution; 
[3455] Reconstitution;
[3523] Dosage schedule;
[3525] Dosage schedule;
[3575] Administration route;
[3643] Precaution contraindication;
[3663] Carcinogenicity mutagenicity;
[3683] Treatment toxicity;
[3403] Preparations;
[3413] Other chemicalion ingredient;
[3423] Combination;
[3434] Dosage form;
[3436] Strength concentration
AHFS NO: 68.08
AHFS CLASS: ANDROGENS
SUBFILE: American Hospital Formulary Service
MONOGRAPH TITLE: Methyltestosterone
GENERIC NAME: Methyltestosterone
TRADE NAME(S): Methyltestosterone Powder (micronized) for
Prescription/ Compounding Paddock/
Android-5 Brown/
Metandren Linguets Ciba/
Oreton Methyl Buccal Schering/
Testred ICN/ 
Virilon Star/
Android-10 Brown/
Android-25 Brown/
Metandren Ciba/
Oreton Methyl Schering/
Estratest H.S. Reid-Rowell/ 
Estratest Reid-Rowell/
Premarin with Methyltestosterone Wyeth-Ayerst
CAS REGISTRY NO: 58-18-4

CHEMISTRY AND STABILITY (CH):
PRIMARY TEXT: CHEMISTRY 
[3115] Methyltestosterone is a synthetic androgenic anabolic steroid hormone.
STABILITY
[3345] Commercially available preparations of
methyltestosterone should be protected from
light and stored in well-closed containers at a
temperature less than 40DGC, preferably between
2-30DGC, unless otherwise specified by the
manufacturer.

ADDITIONAL TEXT: CHEMISTRY AND STABILITY
CHEMISTRY 
[3113] The drug is structurally similar to
testosterone, but is methylated at the 17 position
of the steroid nucleus.
[3183] Methylation at the 17 position is associated
with less hepatic metabolism and enhanced pharmacologic activity following oral administration
compared with testosterone. 
[3133,3143] Methyltestosterone occurs as white or
creamy white, odorless, slightly hygroscopic crystals
or a crystalline powder and is practically insoluble
in water and soluble in alcohol.
STABILITY
[3303] One manufacturer states that fading of
the color of the tablets will not affect potency or
efficacy. 

PHARMACOLOGY (PC):
PRIMARY TEXT: [3205] Endogenous androgens are essential hormones
that are responsible for the normal growth and
development of the male sex organs and for maintenance of secondary sex characteristics, including
the growth and maturation of the prostate, seminal
vesicles, penis, and scrotum; development of male
hair distribution, such as beard, pubic, chest,
and axillary hair; laryngeal enlargement and
thickening of the vocal cords; and alterations in
body musculature and fat distribution.
ADDITIONAL TEXT: PHARMACOLOGY
[3203] Like testosterone and other androgenic
anabolic hormones, methyltestosterone also produces 
retention of nitrogen, potassium, sodium, and phosphorus; increases protein anabolism; and decreases
amino acid catabolism and urinary calcium concentrations. Nitrogen balance is improved only when there
is sufficient intake of calories and protein.
[3203,3253] Androgens are responsible for the growth
spurt that occurs during adolescence and for the 
eventual termination of linear growth that results
from fusion of the epiphyseal growth centers.
Although exogenous androgens accelerate linear
growth rates in children, the drugs may cause a
disproportionate advancement in bone maturation,
and long-term administration of the drugs in prepubertal children may result in fusion of the epiphyseal
growth centers and premature termination of the
growth process.
[3243] Exogenous administration of androgens
inhibits the release of endogenous testosterone 
via feedback inhibition of pituitary luteinizing 
hormone (LH). Following administration of large
doses of exogenous androgens, spermatogenesis may
also be suppressed as a result of feedback inhibition of pituitary follicle-stimulating hormone
(FSH). Androgens reportedly stimulate the production of erythrkP?]Y>kP apparently by enhancing the
production of erythropoietic stimulating factor.
USES (US):
PRIMARY TEXT: [3225] Methyltestosterone is used mainly for
replacement or substitution of diminished or absent
endogenous testicular hormone.
USES IN MALES [3525] In males, methyltestosterone is used for
the management of congenital or acquired primary 
hypogonadism such as that resulting from orchidectomy or from testicular failure caused by cryptorchidism, bilateral torsion, orchitis, or vanishing
testis syndrome. Methyltestosterone is also used in
males for the management of congenital or acquired
hypogonadotropic hypogonadism such as that resulting
from idiopathic gonadotropin or gonadotropin releasing
hormone (luteinizing hormone releasing hormone) 
deficiency or from pituitary-hypothalamic injury 
caused by tumors, trauma, or radiation. 
[3225] When the diagnosis is well established,
methyltestosterone may be used to stimulate puberty
in carefully selected males with delayed puberty.

OTHER USES [3225] In females, methyltestosterone is used
for the palliative treatment of androgen-responsive,
advanced, inoperable, metastatic (skeletal) carcinoma
of the breast in women who are 1-5 years postmenopausal.
[3225] Androgen therapy has also been used in pre-
menopausal women with carcinoma of the breast who
have benefited from oophorectomy and are considered
to have a hormone-responsive tumor.
[3225,3640] The decision to use androgen therapy in
women with carcinoma of the breast should be made
by an oncologist with expertise in the treatment of
this carcinoma. 
[3225] Methyltestosterone has also been used for
the prevention of postpartum breast pain and engorgement; however the drug does not appear to prevent or
suppress lactation.
[3225,3003] In females, methyltestosterone is used in
combination with estrogens for the management of
moderate to severe vasomotor symptoms associated
with menopause in patients who do not respond 
adequately to estrogens alone.

MISUSE AND ABUSE
[3213,3645] Because of their anabolic and androgenic
effects on performance (ergogenic potential) and 
physique, androgens have been misused and abused by
athletes, bodybuilders, weight lifters, and others,
including high school- and college-aged individuals
engaged in sports. However, such use is associated
with the potential for serious adverse effects and
generally is considered inappropriate and unacceptable. (See Uses: Misuse and Abuse, in Testosterone
68:08.)

ADDITIONAL TEXT: USES

USES IN MALES [3223] If any of these conditions occur before
puberty, androgen replacement therapy will be 
necessary during adolescence for the development
of secondary sexual characteristics and prolonged
therapy will be required to maintain these characteristics. Prolonged androgen therapy is also 
required to maintain sexual characteristics in other
males who develop testosterone deficiency after
puberty.
[3223] These males usually have a family history
of delayed puberty that is not caused by a pathologic
disorder. Brief treatment with conservative doses of
an androgen may occasionally be justified in these
males if they do not respond to psychologic support.
[3640,3223,3253] Because androgens may adversely affect bone
maturation in these prepubertal males, this potential
risk should be fully discussed with the patient and
his parents prior to initiation of androgen therapy.
(See Cautions: Pediatric Precautions.) If androgen 
therapy is initiated in these prepubertal males,
radiographs of the hand and wrist should be obtained
at 6-month intervals to determine the effect of 
therapy on the epiphyseal centers.

OTHER USES [3223] Primary goals of therapy in these women
include ablation of the ovaries. Other methods of
counteracting estrogen activity include adrenalectomy,
hypophysectomy, and/or antiestrogen therapy (e.g.,
tamoxifen). 
[3223,3003,3643] Estrogens do not appear to be effective for
the management of nervous symptoms or depression
associated with menopause, and the drugs should not
be used in the management of such conditions in these
patients. 
[3223] Although methyltestosterone has been used in
other conditions (e.g., fractures, surgery, convalescence, functional uterine bleeding), there is a lack
of substantial evidence that androgens are effective
in these conditions. In addition, the US FDA states
that there currently is no evidence to support the
safety and efficacy of methyltestosterone as an
aphrodisiac (i.e., to arouse or increase sexual desire
or to improve sexual performance).
CAUTIONS (CA):
PRIMARY TEXT: ADVERSE EFFECTS
[3605] Adverse effects associated with methyltestosterone are similar to those of other synthetic or 
natural androgens and include acne, gynecomastia,
and edema. 
[3605] Oligospermia and decreased ejaculatory
volume may occur in males receiving excessive dosage
or prolonged administration of the drug.
[3605,3250] Priapism or excessive sexual stimulation in
males, especially geriatric patients, may also occur.
[3645,3520] If priapism or excessive sexual stimulation
develops during methyltestosterone therapy, the drug
should be discontinued temporarily, since these are
signs of excessive dosage; if therapy with methyl-
testosterone is reinstituted, a lower dosage should
be used.
[3605] Male pattern of baldness may also occur. 
Amenorrhea and other menstrual irregularities and
inhibition of gonadotropin secretion occur commonly
in females.
[3605,3643] Virilization, including deepening of the
voice, hirsutism, and clitoral enlargement, also
occur commonly in females; these changes may not be
reversible following discontinuance of the drug.
[3605,3623] Hypersensitivity reactions, including skin
manifestations and anaphylactoid reactions, have
occurred rarely with methyltestosterone. 
[3605,3240] Hypercalcemia resulting from osteolysis, 
especially in immobile patients and those with 
metastatic carcinoma of the breast, has been reported
in patients receiving methyltestosterone.
[3645,3603] The drug should be discontinued if hypercalcemia occurs in patients with cancer since this may
indicate progression of metastases to the bone. 
[3605] Retention of water, sodium, chloride,
potassium, and inorganic phosphates has also occurred
in patients receiving the drug. Cholestatic hepatitis
and jaundice and abnormal liver function test results
may occur in patients receiving 17-alpha-alkylandrogens such as methyltestosterone. 
[3645,3603] Methyltestosterone should be discontinued if
cholestatic jaundice or hepatitis occurs, or if liver
function test results become abnormal during therapy
with the drug, and the etiology of these disorders
should be determined.
[3605] Peliosis of the liver and hepatic neoplasms,
including hepatocellular carcinoma, have been 
reported rarely in patients receiving long-term administration of androgenic anabolic steroids.
[3645,3603] Peliosis of the liver can be a lifethreatening
or fatal complication of androgen therapy.
[3605] Other adverse effects associated with
methyltestosterone therapy include nausea, polycythemia, stomatitis in patients using buccal preparations, headache, anxiety, mental depression, 
generalized paresthesia, and suppression of clotting
factors II, V, VII, and X. Serum cholesterol con-
centration may increase during androgen therapy.

PRECAUTIONS AND CONTRAINDICATIONS
[3645] Methyltestosterone shares the toxic potentials
of other androgens, and the usual precautions of
androgen therapy should be observed.
[3645,3003] When methyltestosterone is used in combination
with estrogens, the usual precautions associated with
estrogen therapy should also be observed. 
[3645,3003,3900] (See Cautions in Conjugated Estrogens 68:16.)
Clinicians prescribing estrogens should be aware of
the risks associated with these drugs, and the manufacturers' labeling should be consulted for further 
discussion of these risks and associated precautions.
Patients receiving methyltestosterone in combination
with an estrogen should be given a copy of the
patient labeling for the combination. Methyltestosterone should be used with caution in patients with
cardiac, renal, or hepatic dysfunction, since edema,
with or without congestive heart failure, may occur
as a result of sodium and water retention.
[3645,3683] If edema occurs during methyltestosterone
therapy and it is considered a serious complication,
the drug should be discontinued; diuretic therapy
may also be necessary.
[3645] Liver function should be evaluated periodically during use of methyltestosterone. Females should
be carefully monitored for signs of virilization 
(e.g., deepening of the voice, hirsutism, clitoromegaly, menstrual irregularities) during methyltestosterone therapy. 
[3645] Males should be carefully monitored for the
development of priapism or excessive sexual stimulation since these are signs of excessive dosage.
[3645,3253,3663] Geriatric males may be at increased risk of
developing prostatic hypertrophy and carcinoma during
androgen therapy.
[3645] Adult or adolescent males should be advised
to report too frequent or persistent penile erections
to their physician. Females should be advised to
report hoarseness, acne, menstrual changes, or the
growth of facial hair to their physician. All
patients should be advised to report nausea, vomiting,
changes in skin color, or ankle swelling to their
physician. Patients receiving high dosages of methyl-
testosterone should have periodic hemoglobin and 
hematocrit determinations, since polycythemia may
occur.
[3645,3623,3053,3410] Metandren 10-mg Linguets and 25-mg tablets 
contain the dye tartrazine (FD&C yellow No. 5), which
may cause allergic reactions including bronchial 
asthma in susceptible individuals. 
[3645] Methyltestosterone is contraindicated in
males with carcinoma of the breast or known or 
suspected carcinoma of the prostate. Some manufacturers state that the drug is also contraindicated
in patients with cardiac, renal, or hepatic decompen
sation; hypercalcemia; impaired liver function; and
in patients who are easily sexually stimulated.

PEDIATRIC PRECAUTIONS
[3645,3250] Androgens should be used with extreme
caution in children and only by specialists who are
aware of the adverse effects of these drugs on bone 
maturation. Methyltestosterone should be used 
cautiously to stimulate puberty, and only in care-
fully selected males with delayed puberty. (See Uses:
Uses in Males.)
[3605,3250] In children, methyltestosterone may accelerate
bone maturation without producing compensatory gain in
linear growth. This adverse effect may result in
compromised adult stature. The younger the child,
the greater the risk of methyltestosterone
compromising final mature stature.
[3645,3250] If methyltestosterone is administered to
prepubertal children (e.g., to stimulate puberty in
males), the drug should be used with extreme caution,
and radiographic examination of the hand and wrist
should be performed every 6 months to determine the
rate of bone maturation and to assess the effect of
treatment on the epiphyseal centers. If methyltestosterone is to be used to stimulate puberty in a male
with delayed puberty, the potential risk of therapy 
should be fully discussed with the patient and his
parents prior to initiation of the drug. 

MUTAGENICITY AND CARCINOGENICITY
[3665,3643] Hepatocellular carcinoma has reportedly
occurred in patients receiving long-term therapy with
high dosages of androgens.
[3665,3643,3250] Geriatric patients may be at increased risk
of developing prostatic hypertrophy and carcinoma 
during androgen therapy.

PREGNANCY, FERTILITY, AND LACTATION
[3643,3655] Methyltestosterone may cause fetal harm
when administered to pregnant women.
[3655,3643] Since the risks clearly outweigh the possible
benefits in women who are or may become pregnant,
methyltestosterone is contraindicated in such women.
Women who become pregnant while receiving the drug
should be informed of the potential hazard to the
fetus.
[3615] Increased or decreased libido has also been
reported.
[3875] It is not known whether methyltestosterone
is distributed into milk.
[3645,3870] Because of the potential for serious adverse
reactions to androgens in nursing infants, a decision
should be made whether to discontinue nursing or to
not use methyltestosterone, taking into account the
importance of the drug to the woman.

ADDITIONAL TEXT: CAUTIONS ADVERSE EFFECTS
[3683] If edema is present before or develops
during therapy, administration of diuretics may be
required.
[3603] Gynecomastia frequently develops and
occasionally persists in patients being treated for
hypogonadism.
[3603] These adverse hepatic effects may occur at
relatively low doses of the drug. Drug-induced 
jaundice is usually reversible following discontinuance of the drug.

PRECAUTIONS AND CONTRAINDICATIONS
[3643] The drug should generally be discontinued
when mild virilization is evident, since some adverse
androgenic effects (e.g., voice changes) may not
subside followingdiscontinuance of the drug. The
woman and physician may decide that some virilization is acceptable during treatment for carcinoma of
the breast.
[3643,3250] Males, especially geriatric patients, may
become overly stimulated. Stimulation to the point
of increasing the nervous, mental, and physical 
activities beyond the patient's cardiovascular
capacity should be avoided when methyltestosterone
is used to treat climacteric in males. (See also 
Cautions: Adverse Effects.)
[3643,3623,3053,3410] Although the incidence of tartrazine
sensitivity is low, it frequently occurs in patients
who are sensitive to aspirin.

MUTAGENICITY AND CARCINOGENICITY
[3663] Regression of the tumor does not always occur
following discontinuance of androgen therapy. 
[3663] Following implantation of testosterone in
mice, cervical-uterine tumors developed which
occasionally metastasized. There is some evidence to
suggest that injection of testosterone into some
strains of female mice increases their susceptibility
to hepatomas. Testosterone has also been shown to
increase the number of tumors and decrease the degree
of differentiation of chemically induced tumors in
rats. It is not known whether androgens, including
methyltestosterone, are mutagenic. 

PREGNANCY, FERTILITY, AND LACTATION
[3653] Androgenic effects including clitoral 
hypertrophy, labial fusion of the external genital
fold to form a scrotal-like structure, abnormal
vaginal develop nt, and persistence of a urogenital
sinus have occurred in the female off-spring of
women who were given androgens during pregnancy. The
degree of masculinization is related to the amount of
drug given to the woman and the age of the fetus;
masculinization is most likely to occur in a female
fetus when exposure to androgens occurs during the
first trimester.
[3613] Although the effect of methyltestosterone
on fertility in humans has not been conclusively
determined, the drug produces oligospermia and
decreased ejaculatory volume in males. Priapism and
excessive sexual stimulation have also occurred in
males receiving the drug. (See Cautions: Adverse
Effects and Precautions and Contraindications.)
DRUG INTERACTIONS (DI):
PRIMARY TEXT: 
[3775] Methyltestosterone may potentiate the action
of oral anticoagulants, causing bleeding in some
patients. 
[3775,3640] When methyltestosterone therapy is initiated
in patients receiving oral anticoagulants, dosage
reduction of the anticoagulant may be required to
prevent an excessive hypoprothrombinemic response.
Patients receiving oral anticoagulants should also be
closely monitored when androgen therapy is discontinued. The metabolic effects of androgens may 
decrease blood glucose concentrations and insulin
requirements in patients with diabetes.

LAB TEST INTERFERENCES (LI):
[3763] Protein bound iodine (PBI) concentrations may
be decreased in some patients during methyltestosterone
therapy; however, this does not appear to be clinically
important.
[3763,3713] Androgens may decrease thyroxine-binding
globulin concentrations, resulting in decreased total
serum thyroxine (T4) concentrations and increased
resin uptake of triiodothyronine (T3) and T4. 
[3763] Free thyroid hormone concentrations remain
unchanged, and there is no clinical evidence of
thyroid dysfunction.

DOSAGE AND ADMINISTRATION (DO):
PRIMARY TEXT: ADMINISTRATION
[3575] Methyltestosterone is administered orally or
intrabuccally; the drug is usually given in divided 
daily doses. Buccal tablets (e.g., Linguets) should
be placed in the upper or lower buccal pouch between
the cheek and gum, and allowed to dissolve completely;
buccal tablets should not be swallowed.
[3575,3640] Patients should be advised to avoid eating,
drinking, chewing, or smoking while the buccal tablet
is in place. Proper oral hygiene (e.g., rinsing the
mouth with water) is particularly important following
the use of buccal tablets.

DOSAGE [3525,3830] Since intrabuccal administration of the drug
bypasses metabolism in the GI tract and on first pass
through the liver, dosage of buccal tablets is
approximately one-half the oral dosage.

DOSAGE [3526] Male Hypogonadism
[3525] For replacement of endogenous testicular
hormone in androgen-deficient males, the usual oral
dosage of methyltestosterone is 10-50 mg daily as
conventional tablets. Alternatively, buccal tablets
may be administered in a dosage of 5-25 mg daily.
For the management of postpubertal cryptorchidism in
patients with evidence of hypogonadism, several
manufacturers recommend an oral methyltestosterone
dosage of 30 mg daily as conventional tablets.
Alternatively, buccal tablets may be administered in
a dosage of 15 mg daily. Various dosage regimens have
been used to induce pubertal changes in hypogonadal
males. Some clinicians recommend that lower dosages
be used initially, followed by gradual increases in
dosage as puberty progresses; subsequently, the dosage
may be decreased to maintenance levels. Other clinicians state that higher dosages are required initially
to induce pubertal changes and lower dosages can then
be used for maintenance therapy after puberty. The
chronologic and skeletal ages of the patient must be
considered when determining the initial dosage and
subsequent dosage adjustment.
[3555] In general, short-term administration (e.g.,
4-6 months) of methyltestosterone and dosages in the
lower end of the usual range for replacement (i.e.,
10 mg daily as conventional tablets or 5 mg daily as
buccal tablets) are used for the treatment of delayed
puberty in males.

DOSAGE [3526] Inoperable Carcinoma of the Breast 
[3525] For the palliative treatment of advanced,
inoperable, metastatic carcinoma of the breast in
women, the usual oral dosage of methyltestosterone
is 50-200 mg daily as conventional tablets. Alter-
natively, buccal tablets may be administered in a
dosage of 25-100 mg daily.

DOSAGE [3526] Postpartum Breast Pain and Engorgement
[3525] For the prevention of postpartum breast pain
and engorgement, the usual oral dosage of methyltestosterone is 80 mg daily as conventional tablets for
3-5 days after parturition. Alternatively, buccal
tablets may be administered in a dosage of 40 mg daily
for 3-5 days after parturition.

DOSAGE [3526] Vasomotor Symptoms Associated with Menopause 
[3525,3003,3643] When methyltestosterone is used in combination
with an estrogen (i.e., conjugated estrogens or 
esterified estrogens) for the short-term management
of moderate to severe vasomotor symptoms associated
with menopause, the lowest possible effective dosage
should be used and therapy should be discontinued as
soon as possible. Attempts to reduce dosage or discontinue the drugs should be made at 3- to 6-month
intervals. The combinations are administered for 21
consecutive days, followed by 7 days without the 
drugs, and then this regimen is repeated as necessary.
The manufacturers' labeling should be consulted for 
usual recommended dosages of the combinations.
[3645,3003,3663] Women with an intact uterus receiving a 
combination preparation should be closely monitored
for signs of endometrial carcinoma, and appropriate
diagnostic measures should be employed if persistent
or recurring abnormal vaginal bleeding occurs during
therapy with the drugs. 

ADDITIONAL TEXT: DOSAGE AND ADMINISTRATION
DOSAGE [3523] Dosage of methyltestosterone is variable and
should be individualized according to the condition
being treated, the severity of symptoms, and the
patient's age, gender, and history of prior androgenic therapy.

PREPARATIONS (PR):
PRIMARY TEXT: METHYLTESTOSTERONE 
[3434] Powder*
[1050,3403] Methyltestosterone Powder (micronized) for Prescription Compounding
[1080,3403] Paddock 
[3474] Buccal (Transmucosal)
[3434] Tablets
[3436] 5 mg 
[1050,3403] Android-5
[1080,3403] Brown
[1050,3403] Metandren Linguets
[1080,3403] Ciba
[3436] 10 mg*
[1050,3403] Metandren Linguets
[3413] (with tartrazine)
[1080,3403] Ciba 
[1050,3403] Oreton Methyl Buccal
[1080,3403] Schering
[3474] Oral
[3434] Capsules
[3436] 10 mg
[1050,3403] Testred
[1080,3403] ICN
[1050,3403] Virilon
[1080,3403] Star
[3434] Tablets
[3436] 10 mg*
[1050,3403] Android-10
[1080,3403] Brown
[1050,3403] Metandren
[3403] (scored)
[1080,3403] Ciba
[1050,3403] Oreton Methyl
[1080,3403] Schering
[3436] 25 mg* 
[1050,3403] Android-25
[1080,3403] Brown
[1050,3403] Metandren
[3413] (with tartrazine [3403] scored)
[1080,3403] Ciba
[1050,3403] Oreton Methyl
[1080,3403] Schering
[3403] *available by nonproprietary name

METHYLTESTOSTERONE COMBINATIONS
[3474] Oral
[3434] Tablets
[3436,3423] 1.25 mg with Esterified Estrogens 0.625 mg 
[1070,3423] Estratest H.S.
[3413,3423] (with parabens and povidone)
[1080,3423] Reid-Rowell
[3436,3423] 2.5 mg with Esterified Estrogens 1.25 mg
[1070,3423] Estratest
[3413,3423] (with parabens and povidone)
[1080,3423] Reid-Rowell 
[3436,3423] 5 mg with Conjugated Estrogens 0.625 mg
[1070,3423] Premarin with Methyltestosterone
[1080,3423] Wyeth-Ayerst 
[3436,3423] 10 mg with Conjugated Estrogens 1.25 mg
[1070,3423] Premarin with Methyltestosterone
[1080,3423] Wyeth-Ayerst 

Selected Revisions February 1990, (C) Copyright, 1959, American Society of
Hospital Pharmacists, Inc.

DESCRIPTORS: [3113] Chemical description;
[3115] Chemical description;
[3133] Physical description;
[3143] Solubility;
[3183] Structure activity;
[3303] Stability;
[3345] Storage;
[3203] Pharmacology;
[3205] Pharmacology;
[3243] Mechanism; 
[3253] Age effect;
[3003] Other drug;
[3213] Unlabeled investigational use;
[3223] Therapy;
[3225] Therapy;
[3253] Age effect;
[3525] Dosage schedule;
[3640] Precaution contraindication;
[3643] Precaution contraindication;
[3645] Precaution contraindication;
[3003] Other drug;
[3053] Product specific information;
[3240] Mechanism;
[3250] Age effect;
[3253] Age effect;
[3410] Other chemical ion ingredient;
[3520] Dosage schedule;
[3603] Adverse reaction (side effect);
[3605] Adverse reaction (side effect);
[3613] Toxicity;
[3615] Toxicity;
[3623] Sensitivity photosensitivity allergy;
[3643] Precaution contraindication;
[3645] Precaution contraindication;
[3653] Fetal toxicity;
[3655] Fetal toxicity; 
[3663] Carcinogenicity mutagenicity;
[3665] Carcinogenicity mutagenicity;
[3683] Treatment toxicity;
[3870] Lactation;
[3875] Lactation ;
[3640] Precaution contraindication;
[3775] Drug interaction;
[3713] Interaction mechanism;
[3763] Lab test interference;
[3003] Other drug;
[3523] Dosage schedule;
[3525] Dosage schedule;
[3555] Age dosage relation;
[3575] Administration route;
[3640] Precaution contraindication;
[3643] Precaution contraindication;
[3645] Precaution contraindication;
[3663] Carcinogenicity mutagenicity;
[3830] Elimination;
[3403] Preparations;
[3413] Other chemical ion ingredient;
[3423] Combination;
[3434] Dosage form;
[3436] Strength concentration
AHFS NO: 68.16 

AHFS CLASS: ESTROGENS
SUBFILE: American Hospital Formulary Service
MONOGRAPH TITLE: Estrogens General Statement 
GENERIC NAME: Chlorotrianisene;
Dienestrol; 
Diethylstilbestrol Diphosphate;
Estradiol Cypionate;
Estradiol Valerate;
Estrogens, Conjugated ;
Estrogens, Esterified;
Estrone;
Estropipate;
Ethinyl Estradiol;
Mestranol ;
Polyestradiol Phosphate;
Quinestrol
CAS REGISTRY NO: 569-57-3; 84-17-3; 56-53-1; 522-40-7; 
50-28-2; 313-06-4; 979-32-8; 53-16-7;
7280-37-7; 57-63-6; 72-33-3; 28014-46-2;
152-43-2

CHEMISTRY AND STABILITY (CH):
PRIMARY TEXT: [3115] Estrogens are naturally occurring hormones
or synthetic steroidal and nonsteroidal compounds
with estrogenic activity. The estrogens can be
divided into 2 groups based on their chemical structures: steroidal and nonsteroidal compounds.
[3115] The natural steroidal estrogens (estradiol,
estrone, estriol, equilin, and equilenin) and their
conjugates are usually obtained from pregnant mares'
urine or prepared synthetically.
[3115] Synthetic derivatives of the natural 
steroidal estrogens are also available. The non-
steroidal estrogens include diethylstilbestrol (DES),
dienestrol, and chlorotrianisene.
ADDITIONAL TEXT: CHEMISTRY steroidal estrogen nucleus 
[3183] All naturally occurring estrogens are steroids
which contain a cyclopentanoperhydrophenanthrene ring
structure with an unsaturated A ring, a methyl group
at the C 13 position, a phenolic hydroxyl group at the
C 3 position, and a ketone or hydroxyl group at the
C 17 position. Only a limited number of changes can be
made in this basic steroid structure without losing 
estrogenic activity. These changes are limited to an
inter conversion of the hydroxyl and ketone groups or
the addition of various side chains at the C 3 and C
17 positions.
[3143] The natural estrogens are insoluble in water
but when conjugated as the sulfates or glucuronides,
these hormones become water soluble.

PHARMACOLOGY (PC): PRIMARY TEXT:
[3205] Estrogens are hormones secreted principally
by the ovarian follicles and also by the adrenals,
corpus luteum, placenta, and testes, or are synthetic
steroidal and nonsteroidal compounds. Estrogenic
hormones are secreted at varying rates during the
menstrual cycle throughout the period of activity of
the ovaries. During pregnancy, the placenta becomes
the main source of estrogens. At the menopause,
ovarian secretion of estrogens declines at varying
rates. The gonadotropins of the anterior pituitary
regulate secretion of the ovarian hormones, estradiol
and progesterone; hypothalamic control of pituitary
gonadotropin production is in turn regulated by plasma
concentrations of the estrogens and progesterone. This
complex feedback system results in the cyclic phenomenon of ovulation and menstruation. Exogenous estrogens elicit,to varying degrees, all the pharmacologic
responses usually produced by endogenous estrogens. 
Endogenous estrogens are essential hormones that are
responsible for the normal growth and development of
the female sex organs and for maintenance of secondary
sex characteristics, including the growth and maturation of the vagina, uterus, and fallopian tubes; 
enlargement of the breasts; maintenance of tone and
elasticity of urogenital structures; growth of
auxiliary and pubic hair; and pigmentation of the
nipples and genitals. Although the mechanisms has
not been elucidated, estrogens contribute to the
shaping of body contours and the skeleton, to the
growth spurt that occurs during adolescence, and to
the eventual termination of linear growth that results
from fusion of the epiphyseal centers. Estrogens cause
an increase in cell height and secretions of the
cervical mucosa, thickening and cornification of the 
vaginal mucosa, proliferation of the endometrium, and
an increase in uterine tone.
[3245] Although the precise actions of estrogens on
secretory activity of the pituitary have not been
fully characterized, estrogens affect the release of
gonadotropins (e.g., follicle-stimulating hormone 
(FSH)) from the pituitary, apparently as a result of
feedback inhibition; the effect of estrogens on
luteinizing hormone (LH) is complex and biphasic. The
effects of estrogens on pituitary secretion of gonadotropins result in inhibition of lactation, inhibition
of ovulation, development of a proliferative endometrium and, by inhibiting androgen secretion, a reduction of sebaceous secretions.

ADDITIONAL TEXT: PHARMACOLOGY
[3203] The estrogen-stimulated endometrium may
bleed within 48-72 hours after discontinuance of
estrogen therapy. Paradoxically, prolonged estrogen
therapy may cause shrinkage of the endometrium and
an increase in size of the myometrium. Estrogens
have a weak anabolic effect and may cause sodium
retention with associated fluid retention and edema.
Estrogens may also decrease elevated blood cholesterol
and phospholipid concentrations. Estrogens affect bone
by increasing calcium deposition and accelerating
epiphyseal closure, following initial growth stimulation. During the preovulatory or nonovulatory phase
of the menstrual cycle, estrogen is the principal
determinant in the onset of menstruation. A decline
of estrogenic activity at the end of the menstrual
cycle also may induce menstruation; however, the
cessation of progesterone secretion is the most
important factor during the mature ovulatory phase of
the menstrual cycle.
[3243] Intracellular cytosol-binding proteins for
estrogens have been identified in estrogen-responsive
tissues including the female genital organs, breasts, 
pituitary, and hypothalamus. The exact role of
cytosol-binding proteins in mediating the actions of
estrogens is not fully understood, but the estrogen-
binding protein complex (i.e., cytosol-binding
protein and estrogen) distributes into the cell
nucleus where it stimulates DNA, RNA, and protein
synthesis. The presence of these receptor proteins
is responsible for the palliative response to estrogen
therapy in women with metastatic carcinomaof the 
breast.
PHARMACOKINETICS (PK): 
PRIMARY TEXT: ABSORPTION 
[3835,3573] Following oral administration, the natural,
unconjugated estrogens are inactivated in the GI
tract and liver; therefore, these estrogens are
usually administered parenterally.
[3573,3813,3835] Conjugated estrogens, some synthetic derivatives of the natural estrogens, and the nonsteroidal
estrogens may be administered orally.
[3813,3835] Absorption and metabolism following oral
administration of these drugs is rapid and daily doses
are usually required. 
[3815] Estrogens are readily absorbed through the
skin and mucous membranes.

DISTRIBUTION [3825] Estrogens are distributed throughout most
body tissues.
[3825,3833] Studies utilizing radioisotopes have indicated
that the greatest concentrations of estrogens may
occur in the fat deposits of the body; obese patients
have demonstrated slower and more prolonged estrogen
excretion.
[3865] Estrogens are 50-80% bound to plasma proteins.
Estriol is bound less to plasma proteins than is
estrone or estradiol but all 3 estrogens are bound 
to approximately the same extent by erythrocytes.
[3885] Studies using radioisotopes have demonstrated
a rapid transfer of free estrone and estradiol between
mother and fetus. Fetal estrogens appear to originate
principally from the placenta and mother.

ELIMINATION [3835] The steroidal estrogens are metabolized
principally in the liver, although the kidneys,
gonads, and muscle tissues may be involved to some
extent.
[3835] Large amounts of free estrogens are also
distributed into the bile, reabsorbed from the GI
tract, and recirculated through the liver where
further degradation occurs. Estrogens and their
metabolites are excreted mainly in urine; however,
small amounts are also present in feces. The
metabolic fate of the synthetic estrogens has not
been fully elucidated. Diethylstilbestrol metabolism,
however, appears to be similar to that of the natural
estrogens with the drug being excreted mainly as the
glucuronide in urine.
ADDITIONAL TEXT: PHARMACOKINETICS
ABSORPTION [3823,3203] Chlorotrianisene, however, has a prolonged
duration of action which may result from the storage
in and slow release of estrogenically active substance
from adipose tissue. Similarly, quinestrol has a pro-
longed duration of action as a result of its extensive
storage in and slow release from adipose tissue. 
[3813,3573] Following IM administration of crystalline
estrogen aqueous suspensions or oil solutions, absorption begins promptly and continues for several days.
[3813,3843] Esterification or polymerization of the 
estrogens delays the absorption of these drugs 
following IM administration.
[3823,3203] Depending on the amount of estrogen applied,
systemic as well as local effects may occur following
topical application.

ELIMINATION [3833] The steroids and their metabolites are
conjugated at the hydroxyl group of the C 3 position
with sulfuric or glucuronic acid; these conjugates
may undergo further metabolic change. Conjugation
increases water solubility and facilitates excretion
in urine.
USES (US):
PRIMARY TEXT: [3225] Estrogens are used in the treatment of a
variety of conditions associated with a deficiency
of estrogenic hormones, including moderate to severe
vasomotor symptoms associated with menopause,
atrophic vaginitis, kraurosis vulvae, female hypogonadism and castration, and primary ovarian failure.
Estrogens may also be used in the treatment of abnormal uterine bleeding caused by hormonal imbalance not
associated with organic pathology; however, progestins
are usually preferred.
[3225,3643] Estrogens do not appear to be effective for
the management of nervous symptoms or depression
associated with menopause in patients without vasomotor symptoms, and the drugs should not be used in
the management of such conditions. Although estrogens
have been used for the prevention of postpartum breast
engorgement, data from controlled studies indicate
that the incidence of substantial painful engorgement
is low in untreated women, and the condition usually
responds to appropriate analgesic or other supportive
therapy. The benefit derived from estrogen therapy
in the prevention of postpartum breast engorgement
must be carefully weighed against the potential
increased risk of puerperal thromboembolism associated
with the use of large doses of estrogens.
[3225,3900] Short-acting, oral estrogens (e.g., conjugated
estrogens) may be used adjunctively with other
therapeutic measures (e.g., diet, calcium, physical
therapy) to retard further bone loss and the progression of osteoporosis associated with estrogen
deficiency in postmenopausal women with evidence of
bone loss or deficiency of bone mass. (100,101)
Estrogen replacement therapy has been shown to reduce
bone resorption and retard or halt bone loss in post-
menopausal women; (100) however, there is no clear
method for identifying those women who will develop
osteoporotic fractures, and there is a lack of sub-
stantial evidence that estrogen replacement therapy
decreases the incidence of osteoporotic bone fractures.
(101)In case-controlled studies in white women, 
estrogen replacement therapy has been associated with
a reduction in the incidence of hip and wrist fractures in those in whom estrogen therapy was initiated
within a few years of menopause; some studies suggest
that estrogens may also reduce the incidence of vertebral fracture. (100) Estrogen replacement therapy
has also reportedly prevented further estrogen
deficiency-induced bone loss in postmenopausal women
when started up to 6 years after menopause, but did 
not restore bone mass to premenopausal levels;
however, there is no convincing evidence that 
initiating estrogen therapy in elderly women will
prevent osteoporosis. (100) Some clinicians suggest
that cyclic, low-dose estrogen replacement therapy
be considered in white women whose ovaries have been
removed before the age of 50 years in whom there are
no contraindications to estrogen therapy and in white
women who have had a natural menopause and have no
contraindications to estrogen therapy but fully
understand the risks associated with estrogen use and
agree to regular medical examinations. (100) However,
until more data are available concerning the risks
and benefits of estrogen therapy in these women, other
clinicians suggest that estrogen therapy be reserved
for patients with conditions associated with a high
risk of osteoporosis, such as the occurrence of pre-
mature menopause. (100) Women who have had a hysterectomy have a more favorable benefit-to-risk ratio than
those who have an intact uterus because of the lack
of risk of endometrial carcinoma. (101) Other forms
of therapy, such as calcium supplementation, should
also be considered in the prevention and/or management
of primary osteoporosis. (100) (See Uses: Oral Pre-
parations, in Calcium Salts 40:12.) The efficacy of 
estrogen replacement therapy in non-white women has
not been determined to date. (100) 
[3225,3643] Additional study is needed to determine the
exact role and optimum regimen of estrogen and/or
other modalities in the prevention of primary osteoporosis. (100) Estrogens are used in the palliative
treatment of advanced, inoperable, metastatic 
carcinoma of the breast in postmenopausal women and
in men; however, because tamoxifen appears to be at
least as effective as estrogen therapy in postmenopausal women and causes a lower incidence of severe
adverse effects, tamoxifen is preferred by some 
clinicians. Estrogens are not used in the treatment
of breast cancer in premenopausal women because the
drugs may potentially stimulate tumor growth rather
than inhibit it. In males, estrogens are used for
the palliative treatment of advanced, inoperable 
carcinoma of the prostate; however, the risk of
adverse cardiovascular effects of the drugs must be
considered.
[3225,3643,3900] Estrogens have not been shown to be effective for any
purpose during pregnancy, and use of the drugs in
pregnant women may cause severe harm to the fetus.
(See Cautions: Pregnancy and Lactation.) 
[3225,3003,3900,3643,3653] Estrogens are also used in combination with
progestins for ovulation control in the prevention of
conception. (See Uses in Estrogen-Progestin 
Combinations 68:12.)
[3225,3900] For information on the uses of specific
estrogens, see the individual monographs in 68:16. 

ADDITIONAL TEXT: USES
[3223] The specific role of estrogen therapy 
compared with other therapies (e.g., chemotherapy,
orchiectomy) in the treatment of prostatic cancer 
has not been clearly determined, and patients should
generally be referred to physicians who are actively
engaged in the investigation of the disease and are 
therefore familiar with the latest and most advantageous forms of therapy. Estrogen therapy is currently
considered a therapy of choice for patients with in-
operable prostatic tumors, for patients who refuse
orchiectomy, and for patients whose disease progresses
despite orchiectomy in whom the benefits of estrogen
use are considered to outweigh the risk of adverse 
effects.
CAUTIONS (CA): 
PRIMARY TEXT: [3605] Numerous adverse effects have been reported
in patients receiving estrogens and these may be 
similar to the adverse effects associated with
estrogen-progestin oral contraceptives.
[3605,3643,3503] Although most of the serious adverse effects
of estrogen-progestin oral contraceptives (e.g.,
thromboembolic disorders, hepatocellular adenoma) 
generally have not been associated with postmenopausal estrogen therapy, this may reflect the comparatively low dosages of estrogens used in postmenopausal
women. When larger dosages of estrogen are used
(e.g., for the palliative treatment of carcinoma of 
the breast or prostate, for the prevention of postpartum breast engorgement), an increased risk of the
serious adverse effects may occur.
[3605,3643,3900] For additional information on the adverse
effects, precautions, and contraindications associated with estrogens, see Cautions in Estrogen-Progestin Combinations 68:12.
GI EFFECTS [3605] Nausea has been frequently associated with
estrogen therapy. Other adverse GI effects include 
vomiting, abdominal cramps, bloating, and diarrhea.
Changes in appetite and changes in weight may also
occur.
DERMATOLOGIC EFFECTS [3605] The most frequent adverse dermatologic 
reaction associated with estrogen therapy is chloasma
or melasma.
[3605] Other dermatologic reactions include erythema
multiforme, erythema nodosum, and hemorrhagic 
eruption. Hirsutism and alopecia have also occurred.
Porphyria cutanea has reportedly been adversely
affected in some women receiving estrogen therapy.
CARDIOVASCULAR EFFECTS [3606] Elevated Blood Pressure
[3605] Increases in blood pressure may occur in 
women receiving estrogens. Blood pressure elevations
are usually minor, but clinically important hyper-
tension may occur in some women.
[3645] Women receiving high dosages of estrogens or
those with a history of hypertension, preexisting
renal disease, a history of toxemia or elevated blood
pressure during pregnancy, a familial tendency toward
hypertension or its consequences, or a history of 
excessive weight gain or fluid retention during the
menstrual cycle may be at increased risk of developing
elevated blood pressure during estrogen therapy and,
therefore, should be monitored closely. Even though
elevated blood pressure may remain within the normal
range, the clinical implications of elevations should
be considered in all patients. All women, but particularly those with other risk factors for cardio-
vascular disease or stroke and those receiving high
dosages of estrogens, should have blood pressure
measurements before an estrogen is prescribed and at
regular intervals during therapy. Estrogens should
be discontinued if the patient becomes hypertensive
during therapy.
CARDIOVASCULAR EFFECTS [3606] Thromboembolic Disorders 
[3605,3643] Although an increased rate of thromboembolic
and thrombotic disorders has not been found in post-
menopausal women receiving estrogens, the possibility
that such an increase may occur or that subgroups of
women who have underlying risk factors or who are 
receiving relatively large dosages of estrogens may 
have an increased risk should be considered.
[3605] In addition, in a study in men, large dosages
(i.e., 5 mg daily) of conjugated estrogens have been
shown to increase the risk of nonfatal myocardial
infarction, pulmonary embolism, and thrombophlebitis.
[3645] The clinician and the patient using estrogens
should be alert to the earliest signs and symptoms
of thromboembolic and thrombotic disorders (e.g.,
thrombophlebitis, pulmonary embolism, cerebrovascular
insufficiency, coronary occlusion, retinal thrombosis,
mesenteric thrombosis). Estrogen therapy should be 
discontinued immediately when any of these disorders
occurs or is suspected. (See Cautions: Precautions
and Contraindications.) 

CARDIOVASCULAR EFFECTS
[3606] Other Cardiovascular Effects 
[3605] Estrogens may cause some degree of fluid
retention and edema.
ENDOCRINE AND METABOLIC EFFECTS
[3605] Endocrine function test results (e.g.,
glucose tolerance, thyroid function) may be altered
in patients receiving large dosages of estrogens.
(See Laboratory Test Interferences.) Decreased
glucose tolerance has occurred in women receiving
estrogen-containing oral contraceptives and may occur
in patients receiving large dosages of estrogens.
[3645] Prediabetic and diabetic patients should be
carefully monitored during estrogen therapy.
[3605] Increased serum triglyceride concentrations
have occurred in some women receiving estrogen-
containing oral contraceptives and may occur during
therapy with estrogens, especially when large dosages
are used.
[3645,3603] The clinical importance of these alterations
in lipid and lipoprotein concentrations has not been
established; however, it may be advisable to avoid 
use of estrogens in women with elevated serum lipid
concentrations. 
[3605] Estrogens have reportedly caused severe
hypercalcemia in patients with metastatic carcinoma
of the breast.
[3645] If severe hypercalcemia occurs, estrogen
therapy should be discontinued and appropriate therapy
to decrease serum calcium concentration should be
instituted.
[3605,3643] Estrogen-containing oral contraceptives have
reportedly caused folate deficiency possibly by 
interfering with polyglutamate (dietary folate) 
absorption, and supplementary folic acid therapy may
be required; the possibility that folate deficiency
may occur in patients receiving estrogens should be
considered.
HEPATIC EFFECTS [3605,3643] Liver function test results may be altered in
patients receiving estrogen therapy; if results of
these tests are abnormal, they should be repeated 2
months after discontinuance of the drug.
[3605,3643] Cholestatic jaundice has been reported in
women receiving estrogen-containing oral contraceptives, and the possibility that this effect may
occur during estrogen therapy should be considered.
[3645] If jaundice occurs during estrogen therapy,
the drug should be discontinued.
[3605,3643] Estrogens may precipitate hepatic forms of
porphyria, and the drugs probably should not be used
by women who have a familial history history of
hepatic porphyrias, since the occurrence of these
conditions appears to be genetically determined.
[3645] Steroid hormones (including estrogens) may
be poorly metabolized in patients with hepatic dysfunction; therefore, estrogens should be administered
with caution to these individuals. 
[3605] Liver tumors have been associated with use of
estrogen-containing oral contraceptives.
[3645] Although benign hepatocellular adenomas have
not been reported to date with estrogens, the
possibility of a liver tumor should be considered in
any patient receiving an estrogen who develops sudden
severe abdominal pain or shock.
GENITOURINARY EFFECTS [3605] Breakthrough bleeding, spotting, changes in
menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving 
estrogen therapy. Dysmenorrhea and a premenstrual-
like syndrome may also occur.
[3645] In patients with breakthrough bleeding or
irregular vaginal bleeding, nonfunctional causes 
should be considered. Appropriate diagnostic 
procedures should be performed in patients with 
undiagnosed persistent or recurrent vaginal bleeding.
[3605] Changes in cervical erosion and secretions
may occur during estrogen therapy. In addition,
preexisting uterine leiomyoma may increase in size in
women receiving estrogens. A cystitis-like syndrome
has been reported but has not been definitely 
attributed to estrogens. An increased incidence of 
Candida vaginitis has been associated with estrogen
therapy.
NERVOUS SYSTEM EFFECTS [3605] Mental depression may occur in patients
receiving estrogens.
[3645] Patients with a history of mental depression
should be observed carefully and estrogens discontinued if severe depression recurs during use.
[3605] Dizziness, changes in libido, and chorea have
been reported in patients receiving estrogens. Head-
ache, especially migraine headache, may occur during
estrogen therapy.
[3645] Estrogens should be discontinued and the
cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that
is recurrent, persistent, and/or severe.
OCULAR EFFECTS [3605] Estrogens have been reported to produce keratoconus (steepening or corneal curvature) and
intolerance to contact lenses.
[3645] Contact lens wearers who develop visual
disturbances or changes in lens tolerance during
estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact
lens wear should be considered.
[3645] If unexplained, sudden or gradual, partial or
complete loss of vision; proptosis or diplopia; 
papilledema; or retinal vascular lesions occur
during therapy with an estrogen, the drug should be
discontinued and appropriate diagnostic and therapeutic measures instituted.
HEMATOLOGIC EFFECTS [3605] Changes in various blood factors and blood
components have been observed in women receiving
estrogen-containing oral contraceptives and may occur
in patients receiving estrogens; however, further
studies are required before the clinical importance
of these changes can be established.
OTHER ADVERSE EFFECTS [3605] Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen 
therapy. Estrogen use and oral contraceptive use
appear to be associated with an increased risk of
gallbladder disease. 

PRECAUTIONS AND CONTRAINDICATIONS
[3645] Use of estrogens, especially in large dosages,
may be associated with anincreased risk of several
serious conditions including thromboembolism, stroke,
myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, 
malignancy, and hypertension. Clinicians prescribing
estrogens should be aware of the risks associated 
with the use of estrogens; the manufacturers' labeling
also should be consulted for further discussion of
these risks and associated precautions.
[3645,3003] When estrogens are used in combination with
other drugs (e.g., androgens, meprobamate, progestins),
the usual precautions associated with the other drugs
should also be observed. If a progestin is administered concomitantly with estrogen therapy, potential
risks may include adverse effects on carbohydrate and
lipid metabolism. (101)
[3645] Patients receiving estrogens should be under
the supervision of a physician who should inform them
of the possible risks involved. Patients receiving
estrogens should also be given a copy of the patient
labeling for the drugs. A complete medical and family
history should be taken prior to initiation of
estrogen therapy and periodically thereafter. 
Estrogens should generally not be prescribed for
longer than 1 year without a repeat physical examination being performed. Physical examination should
include special attention to blood pressure, breasts,
abdomen, and pelvic organs and should include a
Papanicolaou test (Pap smear) and relevant laboratory
tests. Patients receiving estrogens should be
informed to notify their physician if signs or symptoms of thromboembolic or thrombotic disorders (e.g.,
thrombophlebitis, pulmonary embolism, cerebrovascular
insufficiency, coronary occlusion, retinal thrombosis,
mesenteric thrombosis) occur, including sudden severe
headache or vomiting, disturbance of vision or speech,
sudden partial or complete loss of vision, dizziness
or faintness, weakness or numbness in an extremity, 
sharp or crushing chest pain, unexplained cough, 
hemoptysis, sudden shortness of breath, calf pain, or
heaviness in the chest. Patients receiving large 
dosages of an estrogen (e.g., 5 mg of conjugated 
estrogens daily) may be at increased risk of nonfatal
myocardial infarction, pulmonary embolism, and thrombophlebitis, since males being treated with such dosages
for prostatic and breast cancer have been shown to
have an increased risk for developing these conditions. Patients receiving estrogens should also be
advised to inform their physician if severe abdominal
pain or an abdominal mass (indicating a possible liver
tumor), jaundice, severe mental depression, or unusual
bleeding occurs. Women receiving estrogens should be
instructed in self-examination of their breasts and
should report lumps in the breast to their physician. 
Estrogens should be used with caution, and only with
careful monitoring, in patients with conditions that
might be aggravated by fluid retention (e.g., asthma;
seizure disorders; migraine; or cardiac, renal, or
hepatic insufficiency); in patients with cerebrovascular or coronary artery disease (including
myocardial infarction); and in women with a strong
family history of breast cancer or who have breast
nodules, fibrocystic disease, or abnormal mammographic
findings (see Cautions: Carcinogenicity). Because an
increased risk of postsurgery thromboembolic complications may occur during estrogen therapy, estrogens
should be discontinued, whenever feasible, at least
4 weeks prior to surgery that is associated with an
increased risk of thromboembolism or prolonged
immobilization. The decision as to when to resume
estrogen therapy following major surgery or immobilization should be based on the risks of postsurgery
thromboembolic complications and the need for such
therapy. Because estrogens influence the metabolism
of calcium and phosphorus, the drugs should be used
with caution in patients with renal insufficiency
and in patients with metabolic bone diseases that
are associated with hypercalcemia.
[3645,3653] Estrogens are contraindicated in patients
with known or suspected pregnancy, undiagnosed
abnormal genital bleeding, thrombophlebitis or 
thromboembolic disorders, or known or suspected
estrogen-dependent neoplasia.
[3645] Estrogens are also contraindicated in patients
with a history of thrombophlebitis, thrombosis, or
thromboembolic disorders associated with previous
estrogen use (except when used for the palliative
treatment of carcinoma of the breast), and in patients
with known or suspe