Estradiol Interactions

Aminocaproic Acid

Antidiabetic Agents
Barbiturates

Bexarotene
Bosentan
Bromocriptine
Calcium Salts
Carbamazepine
Cimetidine
Cyclosporine
Dantrolene
Ethotoin
Exemestane
Felbamate
food
Fosphenytoin
grapefruit juice
Griseofulvin
Hydrocortisone
Isoniazid, INH
Methotrexate
Mineral Oil
Nefazodone

Neuromuscular blockers

Phenytoin
Prednisolone
Raloxifene
Rifabutin
Rifampin
Rifapentine
Somatropin, rh-GH
Soy Isoflavones

Sunscreens

Tamoxifen

Thyroid hormones

Topiramate

Tricyclic antidepressants

Troglitazone
Ursodeoxycholic Acid, Ursodiol
Warfarin

Estradiol Interactions

Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Estrogens can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended.

Estrogens can increase calcium absorption. In general, the interaction between calcium salts and estrogen is beneficial and is used to therapeutic advantage in postmenopausal women who have osteoporosis. However, this interaction may not be advantageous in patients predisposed to hypercalcemia or nephrolithiasis.

There have been reports indicating the estrogens and/or progestins in oral contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to nephrotoxicity and/or hepatotoxicity. If oral contraceptives, estrogens, or progestins are initiated or discontinued in patients receiving cyclosporine, the patient’s cyclosporine concentrations should be monitored closely.

Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone and delayed the clearance of prednisolone. Studies involving other corticosteroids have failed to show an interaction. Estrogens may decrease corticosteroid metabolism secondary to enzyme inhibition, compete at metabolism sites, or alter the protein binding of corticosteroids. Patients should be monitored for increased corticosteroid effects when estrogens are used in patients receiving either hydrocortisone or prednisolone. No interaction was seen between estrogen and dexamethasone, methylprednisolone, or prednisone.

Estrogen use is contraindicated in liver dysfunction and liver disease. Therefore, it may be prudent to avoid estrogen use with medications that are associated with hepatotoxicity (e.g., dantrolene, isoniazid, INH, methotrexate). In the liver, estrogens may alter the chemical and physical properties of hepatocyte membranes, leading to impaired activity of cellular function, and increasing susceptibility to hepatotoxicity due to other agents.

Estrogens interact with growth hormone (somatropin and somatrem) during pre-puberty by accelerating epiphysial maturation.

Estrogens can increase the hepatic synthesis of proteins and vitamin K-dependent clotting factors. The effects of warfarin are generally decreased during concurrent use with estrogens because estrogens increase the production of clotting factors VII, VIII, IX, and X. Furthermore, estrogens promote platelet aggregation. Because of this, patients receiving warfarin should be monitored for loss of anticoagulant effect if an estrogen is added. Dosage adjustment of warfarin should be based on the prothrombin time or INR value.

The administration of estrogens with aminocaproic acid may lead to additive hypercoagulability. The mechanism is pharmacodynamic in nature. Estrogens increase clotting factor production and platelet aggregation; aminocaproic acid inhibits fibrinolysis and the activity of plasminogen.

The use of estrogens, including oral contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.

Raloxifene exerts its effects by blocking estrogen receptors. Since raloxifene and estrogens are pharmacological opposites, it would be illogical to coadminister them.

The oxidative metabolism of tricyclic antidepressants may be decreased by estrogens. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses causing a more significant interaction.

Cimetidine has been reported to reduce the hepatic clearance of estradiol. While the clinical significance of cimetidine’s action on exogenous estrogens is uncertain, this interaction may partially explain the association between cimetidine therapy and gynecomastia.

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs. Estrogens are metabolized by CYP3A4. Rifampin, a potent hepatic enzyme inducer, increases the elimination of estrogen. In addition, free hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Concurrent administration of other hepatic enzyme inducers with estrogens, including barbiturates, carbamazepine, griseofulvin, felbamate, phenytoin or fosphenytoin (and possibly ethotoin), rifabutin, rifapentine, topiramate and troglitazone may produce similar results.

While food does not appear to interfere with conjugated estrogens, grapefruit juice has been reported to decrease estrogen metabolism. Grapefruit juice contains a furano-coumarin compound, 6,7-dihydroxybergamottin that inhibits CYP3A4 in enterocytes. Estrogen levels may increase by up to 30%. The clinical significance of the interaction is unknown. It is possible that estrogen induced side effects could be increased in some individuals. Patients should be advised to not significantly alter their grapefruit juice ingestion.

Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.

Estrogens have caused abnormal thyroid function test results. Estrogens and oral contraceptives containing estrogens increase serum thyroxine binding globulin (TBG). This is not usually a problem for euthyroid patients. However, hypothyroid patients who are on exogenous thyroid hormones for replacement therapy may have decreased response to their dose as a result of decreased free thyroxine levels induced by increased TBG. Dose adjustments may be needed in some hypothyroid patients who initiate estrogen therapy. The incidence of estrogen-thyroid hormone interactions is not well documented.

Estrogens, particularly ethinyl estradiol, have been associated in rare cases with pseudocholinesterase deficiency (i.e., reduced plasma cholinesterase). Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens or combination hormonal oral contraceptives.

While information on this interaction is limited, it appears that the simultaneous administration of estrogens and mineral oil, as a laxative, may decrease the absorption of the estrogens, resulting in lower estrogen plasma concentrations. This interaction may be more likely with the chronic administration of mineral oil, as opposed to a single dose of mineral oil used for occasional constipation. In order to avoid an interaction, it would be prudent to separate administration times, giving estrogens 1 hour before or 2 hours after the administration of mineral oil.

Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole , exemestane, letrozole , testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.

The concurrent use of bisphosphonates, specifically alendronate or risedronate , with hormone replacement therapy (estrogens) has been assessed in several clinical trials. These studies have found that the use of these agents in combination with hormone replacement therapy is safe and effective. The long-term effects of combination therapy on fracture occurrence and fracture healing have not been studied.

Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of ursodeoxycholic acid, ursodiol.

Theoretically, the soy isoflavones may compete with drugs that have estrogenic activity or which selectively modulate estrogen receptors. Soy isoflavones should be used with caution in patients taking estrogens or combination hormonal oral contraceptives.

Based on an interaction with tamoxifen, bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by CYP3A4, including estrogens.

Bosentan is a significant inducer of CYP3A hepatic enzymes. Specific interaction studies have not been performed to evaluate the effect of co-administration of bosentan and estrogens or progestins. Since many of these drugs are metabolized by CYP3A4, there is a possibility of a reduction in efficacy of hormone replacement when bosentan is co-administered.

Nefazodone inhibits the hepatic CYP3A4 isoenzyme. Estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when nefazodone is co-administered with either estrogens or combined hormonal contraceptives, including oral contraceptives. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population.

Application of sunscreen 10 minutes prior to the application of estradiol topical emulsion (i.e., Estrasorb™) increases the exposure to estradiol by approximately 35%. Application of sunscreen 25 minutes after the application of estradiol topical emulsion increases the exposure to estradiol by approximately 15%. Patients should be advised to separate the application of estradiol topical emulsion and sunscreens as long as possible in order to avoid increased estradiol absorption.

Estradiol Interactions

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