Androgen deficiency may underlie menopausal symptoms such as loss of libido, fatigue and loss of the sense of well-being, but there is concern about the potential for masculinizing effects and hepatic abnormalities with the addition of androgens to hormone replacement therapy. However, most of the reports of androgen-related hepatic dysfunction are derived from studies of men or of androgen dosages higher than the 1.25 mg to 2.5 mg per day of methyltestosterone used in combination with estrogen. To compare the hepatic biochemical changes with estrogen alone versus estrogen-androgen replacement therapy, Gitlin and associates performed a meta-analysis of eight double-blind studies of hormone replacement therapy in 641 women.

The eight randomized, double-blind trials included 511 women who had undergone surgical menopause and 130 women who experienced natural menopause. Oophorectomy was performed in 79.7 percent of the surgical group. Seven different hormone replacement regimens were used in the studies: 1.25 mg of esterified estrogens and 2.5 mg of methyltestosterone; 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone; 0.625 mg of conjugated equine estrogen alone; 1.25 mg of conjugated equine estrogen alone; 0.625 mg of esterified estrogens alone; 1.25 mg of esterified estrogens alone; and placebo. Liver function tests were compared at baseline and after one, three, six, 12, 18 and 24 months of therapy.

No differences were found in hepatic biochemical levels in women who received estrogen alone or the combination of estrogen and methyltestosterone over a period of 24 months. No statistically significant changes were found in albumin, bilirubin, alkaline phosphatase, aminotransferase and gamma glutamyl transpeptidase values. None of the patients exhibited features of drug hepatotoxicity or significant elevation of liver biochemistry.

The authors conclude that, with appropriate dosage and indications, the combination of estrogen and methyltestosterone produces the same liver biochemical changes as estrogen alone or placebo in postmenopausal women. The authors cite a 1998 report by Ettinger and Fireman in which no cases of hepatic dysfunction developed in 3,016 person-years of use of estrogen-methyltestosterone formulations. The findings were the same whether patients were older or younger.

editor's note: This meta-analysis provides reassurance about hepatic biochemical function during estrogen-androgen replacement therapy. However, it does not address the risk of adverse effects such as androgenic hair changes, deepening of the voice and a reduction in the high-density lipoprotein cholesterol level with long-term use. Because serum androgen levels do not always correlate with symptoms, decisions about androgen supplementation are based on clinical assessment. Until specific recommendations about androgen replacement can be made, it is prudent to prescribe methyltestosterone for short-term therapy and then reevaluate the need to continue such therapy. —b.a.