This variant on the theme of estrogen replacement therapy has been propagated from various centers for different reasons (1,2).
The theoretical starting point is the observation that (particularly after oophorectomy) there are deficiencies of both testosterone and androstenedione (3) and from the observation that estrogens alone do not relieve all menopausal symptoms. While there may well be justification for androgen replacement after oophorectomy, it is not clear that most of the claims made for use of this approach following a natural menopause are sufficiently well founded to justify the risks involved.
Adding an androgen to estrogen replacement therapy in the menopause has been thought to provide supplementary benefit with respect to climacteric symptoms, fatigue, and impaired libido, as well as favorably affecting muscle mass, skin quality, and bone density. It is also stated that androgens improve relief of vasomotor symptoms and relieve depression and anxiety when they occur after the menopause in this group of patients. Some workers have concluded that in women who respond to conjugated estrogens with a rise in blood pressure (not a common response by any means), this effect could be avoided by the addition of an androgen. Yet others have asserted that when the hematocrit falls during estrogen therapy, the effect can be prevented by an androgen.
The main reason for caution with the use of androgens is the susceptibility of menopausal women to their viriliz-ing effects, which can sometimes prove irreversible. Deepening of the voice, hirsutism, and acne can occur in many patients at an early stage of treatment and can prove distressing. There may be enlargement of the clitoris, although not consistently.
However, there are other reasons for caution. Statements with respect to the effect of estrogen + androgen combinations on blood lipids are, for example, contradictory, depending on the combinations used. If androgens are to be used, the effect on lipoproteins should at all events be monitored (1).
It is doubtful whether one can avoid unwanted androgenic effects by cautious dosing. For example, the published data seem to show that a desired effect on libido is only likely to occur at androgen doses sufficient to produce serum testosterone concentrations in the virilizing range (over 2 ng/ml), and that even after withdrawal of such doses virilizing concentrations of testosterone are maintained for many months.
Finally, androgens actually appear in some respects to counter the desired effects of estrogens in this patient group. Doppler flowmetry has been used to study the cardiovascular effects of adding an androgen to an estrogen in an open, randomized study in 40 patients over 8 months, all of whom were using transdermal estradiol (50 micrograms/day) and cyclic medroxyprogesterone acetate (10 mg/day) (4). Half of the subjects then received additional testosterone undecanoate (40 mg/day). The investigators concluded that while the androgen improved sexual desire and satisfaction and had no effect on endometrial thickness, it did in part counteract the beneficial effects of the estrogens on cerebral vascular activity and lipids. The most notable change was a significant increase in the pulsatility index of the middle cerebral artery. The androgen also resulted in a 10% reduction in HDL
cholesterol concentration within 8 months. The authors therefore urged caution in using androgens, at least in the manner used in this study.
There are naturally some groups that have worked together with manufacturers to profile the supposed advantages of particular estrogen + androgen regimens, especially when these are available in the form of fixed combination formulations.
The adverse effects of estrogen + androgen therapy include mild hirsutism and acne (5). One group of workers, who examined the use of "Estratest'' (an esterified combination of estrogen and methyltestosterone), concluded that in their experience under 5% of women developed acne or facial hirsutism, a frequency similar to that experienced when using conjugated estrogens 0.625 mg/day. Women had significantly less nausea with the estrogen + androgen treatment than with conjugated estrogen therapy. Cancers, cardiovascular disease, thromboembolism, and liver disease were stated to be rare among users of the combination. The only adverse events exceeding 4% of total reports were alopecia, acne, weight gain, and hirsutism (6). However, much higher rates of complications with such combinations have been reported from other centres (1).
The evident disadvantage of a fixed combination is that it renders it impossible to carry out any fine adjustment of dosages, such as might be called for in the light of the clinical response and adverse effects in a given individual.
All in all, it seems very doubtful whether any of the supposed benefits of androgen therapy justify the risks involved, except possibly as a transitional measure in those recently oophorectomized women who have acute symptoms of sudden androgen withdrawal.
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