Estrogen therapy adverse effects

L E. Quinidine. These are the classic signs of cinchon-ism and are adverse effects of quinidine and quinine, constituents of the cinchona tree. Some of these effects could be seen as toxic effects of phenytoin. However, auditory acuity is associated with cinchonism and not with phenytoin toxicity. Nausea but not the other effects could be associated with ciprofloxacin. Excessive drowsiness would be expected if diazepam were involved. These effects would not be expected with the estrogen replacement therapy. 

When androgen therapy is used in postmenopausal women who complain of poor libido, poor energy, or a feeling of malaise (2), it should be given in association with estrogens, because of its adverse effects on serum lipids. 

Oral contraception and hormone replacement therapy are dealt with specifically in separate monographs. Here the general adverse effects of estrogens for any indication are reviewed. 

Well-designed studies of local, topical, and intradermal forms of estrogen as a means of attaining a general systemic effect have tended to show that when doses are therapeutically equivalent to those used orally the adverse effects are similar (219). However, this is a complex issue, which is discussed more extensively in connection with hormone replacement therapy. 

Estrogen replacement therapy was until recently widely recommended for the prevention of osteoporosis in middle-aged and older women (1). Long-term estrogen therapy also reduces the incidence of ischemic heart disease in such women (2). However, it has always been difficult to know in which women such prophylactic use is likely to be needed, and this dilemma is compounded by the prospect of adverse reactions, which can include any of the acute effects listed in the estrogen monograph, but also in some cases long-term effects such as tumors. 

In 104 women with established postmenopausal osteoporosis, continuous estrogen + progestogen therapy resulted in increases in bone mineral density of the femoral neck and a fall in systolic blood pressure the most common adverse effects were mastalgia (44%) and vaginal bleeding (29%) (2). 

Tibolone is an agonist at estrogen and progestogen receptors, with weak androgenic activity. It is given as an alternative to hormone replacement therapy, without added progestogen, and has been in use for some 30 years to treat bone loss in post-menopausal women. Some long-term studies (for example over 10 years) appear to have confirmed its safety and relative freedom from adverse effects (1). In particular there is little or no increase in thrombotic events and the incidence of breast tenderness is low. 

Despite the still uncertain adverse effects profile of tibolone, it continues to be used in relieving the hot flushes caused by anti-estrogen therapy, and does so in doses that cause no additional problems. In a further double-blind, placebo-controlled study of oral tibolone 2.5 mg/day in 70 postmenopausal women taking tamoxifen after breast cancer surgery tibolone reduced the severity of hot flushes and perhaps also their incidence (3). 

Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7-14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities. 

Some adverse effects associated with estrogen therapy. 

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