Side Effects of Estratest (esterified estrogens and methyltestosterone)

Estratest (esterified estrogens and methyltestosterone) is a combination of female sex hormones and a form of the male hormone testosterone used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. 

Estrogens, when taken alone or in combination with a progestin, have been shown to reduce the risk for hip fracture due to osteoporosis as well as the risk of heart attack and stroke. 

Esterified estrogens are used for numerous medical situations. Estrogens cause growth and development of female sex organs and the maintain sex characteristics, including growth of underarm and pubic hair and shaping of body contours and skeleton. Estrogens also increase secretions from the cervix and growth of the inner lining of the uterus (endometrium). Estrogens reduce LDL-cholesterol ("bad" cholesterol) and increase HDL-cholesterol ("good" cholesterol) concentrations. 

Testosterone is the major male sex hormone responsible for many male sexual characteristics, but women also produce small amounts of testosterone. Following menopause, a woman's production of testosterone decreases. 

When testosterone in the form of methyltestosterone is added to estrogens, there may be a further alleviation of the hot flashes seen after menopause, and there also may be an improvement in a woman's sexual function. The brand name Estratest is discontinued.

Common side effects of Estratest include

• breakthrough bleeding or spotting,
• loss of periods,
• excessively prolonged periods,
• breast pain,
• breast enlargement,
• changes in sex drive,
• acne, and
• the growth of facial hair.

Serious side effects of Estratest include

• gallstones,
• hepatitis,
• migraine headaches, and
• fluid retention (swelling of the lower legs),
• enlargement of the clitoris,
• reduction in breast size, and
• deepening of the voice. 

Melasma (tan or brown patches) may develop on the forehead, cheeks, or temples. 

Esterified estrogens may cause an increase in the curvature of the cornea, and patients with contact lenses may develop intolerance to their lenses.

Drug interactions of Estratest include warfarin, because esterified estrogens increase the liver's ability to manufacture proteins that are required for blood to clot.

• Patients receiving warfarin, which reduces clotting by inhibiting the production of proteins required for clotting, should receive clotting tests if an estrogen is added to their treatment.
• Rifampin, barbiturates, carbamazepine, griseofulvin, phenytoin, and primidone can increase the elimination of esterified estrogens by enhancing the liver's ability to metabolize it.
• Use of these drugs may result in a reduction of the beneficial effects of esterified estrogens.
• Conversely, drugs such as erythromycin, ketoconazole, itraconazole, and ritonavir may reduce the elimination of esterified estrogens by the liver and lead to increased levels of estrogens in the blood.
• Grapefruit juice also may increase levels of esterified estrogens by increasing the absorption of estrogens from the intestine. Increased levels of estrogens in the blood may result in more estrogen-related side effects.
• Methyltestosterone can increase the effects of warfarin, increasing the risk of bleeding.
• Taking methyltestosterone and imipramine together has led to paranoia in a few patients.
• Methyltestosterone can increase blood concentrations of cyclosporine, which can increase the risk of kidney damage. 

Both methyltestosterone and estrogens should not be used during pregnancy due to an increased risk of fetal abnormalities. 

Estrogens are secreted in milk and cause unpredictable effects in the infant. They should not be used during breastfeeding.

For side effects, please read the esterified estrogens article.

Important side effects of methyltestosterone can have masculinizing effects in women, including:

• the development of acne,
• growth of facial hair,
• enlargement of the clitoris,
• reduction in breast size, and
• deepening of the voice.

If treatment is discontinued when these symptoms first appear, they usually diminish or disappear; however, prolonged treatment can cause irreversible masculinizing effects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Associated with Estrogens

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

• Genitourinary System: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; cystitis-like syndrome.
• Breasts: Tenderness; enlargement; pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
• Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
• Gastrointestinal: Nausea; vomiting; abdominal cramps; bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
• Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
• Eyes: Retinal vascular thrombosis, steepening of corneal curvature, intolerance to contact lenses.
• Central Nervous System: Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
• Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

Associated with Methyltestosterone

Endocrine and Urogenital

• Female: The most common side effects of androgen therapy are amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman, androgens cause virilization of external genitalia of the female fetus.
• Skin and Appendages: Hirsutism, male pattern of baldness, and acne.
• Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
• Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis.
• Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
• Central Nervous System: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
• Metabolic: Increased serum cholesterol.
• Miscellaneous: Inflammation and pain at the site of intramuscular injection or subcutaneous implantation of testosterone containing pellets, stomatitis with buccal preparations, and rarely anaphylactoid reactions.

Drug/Laboratory Test Interactions (Estrogens)

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.

Drug Interactions (Androgens)

• Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped.
• Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
• Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements.

Drug/Laboratory Test Interferences (Androgens)

• Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4.
• Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Carcinogenesis, Mutagenesis, Impairment of Fertility (Estrogens)

• Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of
  • endometrial cancer,
  • breast cancer, and
  • ovarian cancer.
• Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the
  • breast,
  • uterus,
  • cervix,
  • vagina,
  • testis, and
  • liver.