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Androgens and Estrogens (Systemic)

This monograph includes information on the following:

1) Estrogens, Esterified, and Methyltestosterone
2) Testosterone and Estradiol

VA CLASSIFICATION
Primary: HS900
Secondary: GU900

{33} Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Androgen-estrogen—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Menopause, vasomotor symptoms of (treatment)——The following are indicated in the treatment of the vasomotor symptoms of menopause: diethylstilbestrol and methyltestosterone, conjugated estrogens and methyltestosterone, esterified estrogens and methyltestosterone, fluoxymesterone and ethinyl estradiol, testosterone cypionate and estradiol cypionate, testosterone enanthate and estradiol valerate and testosterone enanthate benzilic acid hydrazone, estradiol dienanthate, and estradiol benzoate
{15}{09}{119}{10}{21}{20}{17}{18}{19}
[Osteoporosis, estrogen deficiency–induced (treatment)]——testosterone enanthate benzilic acid hydrazone, estradiol dienanthate, and estradiol benzoate is indicated in the treatment of estrogen deficiency induced osteoporosis.{15}

Unaccepted
There is conflicting evidence and opinion as to whether the possible benefits of postmenopausal androgen pharmacologic or replacement therapy outweigh the risks of the frequently occurring virilizing side effects, adverse effects on serum cholesterol profile, or hepatotoxicity. {118} Virilization may be somewhat reduced with the concomitant use of estrogens. {49} However, because further data are needed regarding the efficacy of androgens in combination with estrogen and because side effects are frequent, the routine use of these products for any indication is not recommended.{49} {54}{61}{83}{118}


Pharmacology/Pharmacokinetics

Androgens—See Androgens (Systemic) .

Estrogens—See Estrogens (Systemic) .


Precautions to Consider

Androgens—See Androgens (Systemic). Estrogens—See Estrogens (Systemic) .


Side/Adverse Effects
Androgens—See Androgens (Systemic) .

Estrogens—See Estrogens (Systemic) .



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Androgens and Estrogens (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to anabolic steroids, androgens, or estrogens

Carcinogenicity/tumorigenicity
Hepatocellular carcinoma and neoplasms associated with long-term, high-dose androgen therapy; increased risk of endometrial cancer for patients with intact uteri when progestin is not used with estrogen; risk is decreased when a progestin is used with estrogen; continuous, long-term estrogen use in animal studies increased frequency of cancers of the breast, cervix, and liver

Pregnancy—Androgens are not recommended for use during pregnancy, because of possible masculinization of female fetus; suggestion that use of some estrogens may be associated with congenital abnormalities





Breast-feeding—Use is not recommended, because estrogens are distributed into breast milk and may have unpredictable effects; not known if androgens are distributed into breast milk; androgens could have adverse effects on the infant such as slowing or cessation of growth, precocious sexual development in males, or virilization in females
Other medications, especially anticoagulants (coumarin- or indandione-derivatives), cyclosporine, or hepatotoxic medications
Other medical problems, especially abnormal and undiagnosed vaginal bleeding; breast cancer; cardio-renal disease; cardiac failure; hepatic dysfunction or failure; history of myocardial infarction; nephrosis; nephritis; active thrombophlebitis or thromboembolic disorders

Proper use of this medication
Reading patient package insert carefully

» Compliance with therapy {30}

» Importance of not taking more medication than the amount prescribed {29}

Taking with or immediately after food to reduce nausea {29} {30}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses {29} {30}

» Proper storage

Precautions while using this medication
» Regular visits to physician at least every 6 to 12 months, or more often if so directed, to check progress {11}

Importance of mammography and regular self-breast examinations

Possibility of dental problems, such as tenderness, swelling, or bleeding of gums; brushing and flossing teeth, massaging gums, and having dentist clean teeth regularly; checking with dentist if there are questions about care of teeth or gums or if tenderness, swelling, or bleeding of gums is noticed {11}

Diabetics: May alter blood glucose concentrations {12}

» Stopping medication immediately and checking with physician if pregnancy is suspected {11}

Smoking while taking oral contraceptives containing estrogens can increase risk of cardiovascular side effects; not known whether elevated risk occurs with estrogen therapy

Importance of not giving medication to anyone else {11}


Side/adverse effects
Withdrawal bleeding will occur in many postmenopausal patients placed on cyclic androgen and estrogen therapy with a progestin {46}

Signs of potential side effects, especially anaphylaxis, breast tumors, chorea, peripheral edema, erythrocytosis, gallbladder obstruction, hepatic necrosis, hepatitis, hepatocellular tumor, hepatic dysfunction, leukopenia, menstrual irregularities, peliosis hepatis, polycythemia, virilism


General Dosing Information
For Androgens—See also Androgens (Systemic) .

For Estrogens—See also Estrogens (Systemic) .

For parenteral dosage forms only
It is recommended that changes in dosage be made in the quantity per injection rather than in the time interval between injections.

Because of the viscosity and high concentration of the double-strength preparation of testosterone enanthate and estradiol valerate, particular care should be taken to administer the full dose.

The side effects of preparations containing testosterone enanthate and testosterone cypionate cannot be quickly reversed by discontinuing medication because of the long durations of action of these medications. {29}

ESTROGENS, ESTERIFIED, AND METHYLTESTOSTERONE


Oral Dosage Forms

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS

Usual adult dose
Menopause, vasomotor symptoms of (treatment)
Oral, 625 mcg (0.625 mg) to 2.5 mg of esterified estrogens and 1.25 to 5 mg of methyltestosterone a day for twenty-one days, the dosage being repeated cyclically following seven days of no medication. {20}


Strength(s) usually available
U.S.—


625 mcg (0.625 mg) of esterified estrogens and 1.25 mg of methyltestosterone (Rx) [Estratest H.S (lactose) ( methylparaben) (propylparaben) ( sodium benzoate) (sucrose){20}]


1.25 mg of esterified estrogens and 2.5 mg of methyltestosterone (Rx) [Estratest (lactose) (methylparaben ) (propylparaben) (sodium benzoate) (sucrose){20}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Note: Include mandatory patient package insert (PPI) if dispensed to patient.



TESTOSTERONE AND ESTRADIOL


Parenteral Dosage Forms

TESTOSTERONE CYPIONATE AND ESTRADIOL CYPIONATE INJECTION

Usual adult dose
Menopause, vasomotor symptoms of (treatment)
Intramuscular, 50 mg of testosterone cypionate and 2 mg of estradiol cypionate every four weeks. {10}


Strength(s) usually available
U.S.—


50 mg of testosterone cypionate and 2 mg of estradiol cypionate per mL (Rx) [Depo-Testadiol (chlorobutanol anhydrous 5.4 mg per mL) (cottonseed oil 874 mg per mL){06}{10}{28}]{06}{28}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Storage at low temperatures may result in separation of crystals, which readily redissolve on warming. {10}

Note: Include mandatory patient package insert (PPI) if dispensed to patient.


Additional information:
Medication should be injected deeply into the upper, outer quadrant of the gluteal muscle.


TESTOSTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION

Usual adult dose
Menopause, vasomotor symptoms of (treatment)
Intramuscular, 90 mg of testosterone enanthate and 4 mg of estradiol valerate every four weeks. {09} {119}


Strength(s) usually available
U.S.—


90 mg of testosterone enanthate and 4 mg of estradiol valerate per mL (Rx) [Valertest No. 1 (chlorobutanol) ( sesame oil){06}{28}]{06}{28}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Storage at low temperatures may result in separation of crystals, which readily redissolve on warming. {09}

Note: Include mandatory patient package insert (PPI) if dispensed to patient.


Additional information:
Medication should be injected deeply into the upper, outer quadrant of the gluteal muscle.


TESTOSTERONE ENANTHATE BENZILIC ACID HYDRAZONE, ESTRADIOL DIENANTHATE, AND ESTRADIOL BENZOATE INJECTION

Usual adult dose
Menopause, vasomotor symptoms of (treatment) or
Osteoporosis, estrogen deficiency–induced (treatment)
Intramuscular, 150 mg of testosterone enanthate benzilic acid hydrazone, 7.5 mg of estradiol dienanthate, and 1 mg of estradiol benzoate every four to eight weeks or less frequently. {15}


Usual adult prescribing limits
Intramuscular, 150 mg testosterone enanthate benzilic acid hydrazone, 7.5 mg of estradiol dienanthate, and 1 mg of estradiol benzoate every four weeks {15}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


150 mg of testosterone enanthate benzilic acid hydrazone (69 mg base), 7.5 mg of estradiol dienanthate, and 1 mg of estradiol benzoate per mL (Rx) [Climacteron (benzoate alcohol 7.5%) ( benzyl benzoate){15}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Additional information:
Medication should be injected deeply into gluteus maximus muscle. {15}



Revised: 01/14/2003



References
  1. Package insert, Depo-Testadiol, Upjohn, Rev 2/85, Rec 4/86.
  1. Indications Index 11/86.
  1. Writer's comments.
  1. Writer's comments.
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  1. Facts and Comparisons. ”Estrogen and Androgen Combinations.” 1988 Ed. Rev. 2/87.
  1. Redbook 1988.
  1. Blue Book 1987–1988.
  1. Deladumone (Squibb) Package Insert. Rev 5/86. Rec 7/87.
  1. Depo-Testadiol (Upjohn) Package Insert. Revised 3/86. Rec. 4/25/89.
  1. USP-DI. 1988 Estrogens (Systemic) monograph.
  1. USP-DI 1988. Androgens (Systemic) monograph.
  1. Deladumone OB (Squibb) package insert. Revised 1/86. Received 7/87.
  1. U.S.F.D.A. Labeling guidance for combination oral contraceptives: physician labeling. Contraception May 1988, Vol. 37(5): 433–455.
  1. Climacteron product monograph (Merck-Frosst, Canada) Rec 8-19-88. Rev 5-87.
  1. Canadian Pharmaceutical Association. The Compendium of Pharmaceuticals and Specialties, 23rd ed. Ottawa, Ontario: Author, 1988. Estrand (Taro) product information: 322
  1. Premarin with methyltestosterone product monograph (Ayerst) CPS 1988: 739.
  1. Premarin with methyltestosterone package insert (Ayerst, US.) Rec 4-25-88. Rev 9-87.
  1. Tylosterone package insert (Lilly, US) Rec 1/89. Rev 8-7-85.
  1. Estratest/HS package insert (Reid-Rowell, US) Rec 4-19-89. Rev 1–89.
  1. Halodrin package insert (Upjohn, US) Rec 8-5-88. Rev 4-86.
  1. Deladumone package insert (Squibb, US) Rec 3-14-89. Rev 7-87.
  1. Deladumone OB package insert (Squibb, US) Rec 3-14-89. Rev 6-87.
  1. Androgyn LA package insert (Forest, US) Rec 9-15-88. Rev 4-86.
  1. Andrest 90-4 package insert (Seatreace, US) Rec 9-12-88. Rev 1-87.
  1. Duogex LA product monograph (Stickley) CPS 1988: 288.
  1. Neo-Pause product monograph (Neolab) CPS 1988: 598.
  1. Redbook 1989.
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  1. USP-DI 1989. Estrogens (Systemic) monograph.
  1. USP/NF 1985 and supplements 1-8, 1988.
  1. USAN and USP dictionary of drug names, 1989.
  1. USP-DI 1989, Appendix III VA Classification Listing.
  1. Writer's comments.
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  1. FDA Fertility and Maternal Drugs Advisory Committee meeting. 1989 June 1-2, Bethesda, MD.
  1. Briggs GG, et al. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Baltimore: Williams & Wilkins, 1983.
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  1. Duratestin package insert (Hauck, US) Rec 6-1-89. Rev 7-87.
  1. Dura-Dumone 90/4 package insert (Hauck, US) Rec 6-1-89. Rev 7-87.
  1. Tes Est Cyp package insert (Mfr.-Steris; Dist-Ortega) Rec 5-26-89. Rev 7-87.
  1. OB package insert(Mfr.-Steris; Dist-Ortega) Rec 5-26-89. Rev 1-87.
  1. Reynolds, JEF(ed.) Martindale: the extra pharmacopeia, 29th ed. London: The Pharmaceutical Press, 1989: 1383–1415.
  1. Pernoll ML and Benson RC (editors). Current obstetric & gynecologic diagnosis & treatment, 6th ed. Norwalk, CT: Appleton & Lange, 1987: 947–8.
  1. P.T. Debate over postmenopausal androgens continues. Med World News 27 June 1988: 27.
  1. Writer's comments.
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  1. Alden JC. Osteoporosis—a review. Clin Ther 1989; 11(1): 3–14.
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  1. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988; 13(4): 345–57.
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  1. Snyder PJ. Clinical use of androgens. Ann Rev Med 1984; 35: 207–17.
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  1. Reid DM. Corticosteroid-induced osteoporosis and hormone implants [letter]. Lancet 1989 March 11: 563.
  1. Savvas M, et al. Skeletal effects of oral estrogen compared with subcutaneous oestrogen and testosterone in postmenopausal women. Br Med J 1988; 297: 331–3.
  1. Swyer GIM. Skeletal effects of oestrogen and testosterone in postmenopausal women [letter]. Br Med J 1988; 297: 687.
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  1. Creasman, et al. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 1986; 67(3): 326–30.
  1. Sherwin BB, Gelfand M. Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985a; 10(3): 325–35.
  1. Sherwin BB, Gelfand M. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1985b; 151(2): 153–60.
  1. Sambrook PN, et al. Sex hormone status and osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis Rheum 1988; 31(8): 973–8.
  1. Mortimer CH, Perry W. Skeletal effects of oestrogen and testosterone in postmenopausal women [letter]. Br Med J 1988; 297: 687.
  1. Need, et al. Effects of nandrolone decanoate and antiresorptive therapy on vertebral density in osteoporotic postmenopausal women. Arch Int Med 1989; 149(1): 57–60.
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  1. Sherwin BB, Gelfand MM. The role of androgen in the maintenance of sexual function in oopherectomized women. Psychosom Med 1987; 49(4): 397–409.
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  1. Burger HG, et al. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical lipid and hormonal results. Maturitas 1984; 6: 351–8.
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  1. Bauwens SF, Drinka PJ, and Boh LE. Pathogenesis and management of primary osteoporosis. Clin Pharm 1986; 5: 639–59.
  1. Panel comment. Androgens (Systemic) Panel survey date 7/18/89.
  1. Panel comment. Anabolic Steroids (Systemic) Panel survey date 7/21/89.
  1. Manufacturer comment. Anabolic Steroids (Systemic) Panel survey date 7/21/89.
  1. Panel comment. Anabolic Steroids (Systemic) Panel survey date 7/21/89.
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  1. Sarrel PM. Estrogen replacement therapy. Obstet Gynecol 1988; 72(5): 2S–5S.
  1. Brenner PF. The menopausal syndrome. Obstet Gynecol 1988; 72(5): 6S–11S.
  1. Ettinger B. Prevention of osteoporosis: treatment of estradiol deficiency. Obstet Gynecol 1988; 72(5): 12S–17S.
  1. Fahraeus L. The effects of estradiol on blood lipids and lipoproteins in postmenopausal women. Obstet Gynecol 1988; 72(5): 18S–22S.
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  1. Lam SY et al. Gynaecological disorders and risk factors in premenopausal women predisposing to osteoporosis: a review. Brit J Obstet Gynaecol 1988; 95(10): 963–72.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
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  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Panel comment. Estrogens (Vaginal) panel survey date 9/21/89.
  1. Mfr. comment. Estrogens (Vaginal) panel survey date 9/21/89.
  1. Panel comment. Estrogens (Systemic) panel survey date 9/7/89.
  1. Thom M, et al. Br J Obstet Gynaecol 1977; 84: 776.
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  1. Mfr comment. Estrogens (Systemic) panel survey date 9/7/89.
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  1. Bergkvist L, et al. The risk of breast cancer after estrogen-progestin replacement. N Eng J Med 1989; 321(5): 293–7.
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  1. Gilman, Goodman, Rall, and Murad (editors) The pharmacological basis of therapeutics, 7th ed. New York: Macmillan Publishing Company, 1985.
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  1. Writer's notes.
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  1. Panel meeting.
  1. Deladumone package insert (Squibb, US). Rec 3-14-89. Rev 7-87.
  1. Depandrogyn package insert rev 9/18/89. Rec. 7/87.
  1. Mfr. comment.
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