JAMA. 2000;283:2643-2644.

Boston-Androgens, which are vital for proper development and maintenance of the male reproductive system, also play important physiological roles in women, some of which are only beginning to be understood. Because of the importance of these hormones to human health, researchers suspect that a decline in androgen levels, which occurs with age, may have adverse effects on women's health.

Unraveling the impact of androgen deficiency in women is a goal of Susan R. Davis, MBBS, PhD, of the Jean Hailes Foundation, an Australian not-for-profit organization in Clayton, Victoria, involved in education about, research into, and treatment of women's health care issues. Davis and colleagues have been studying why androgens are biologically important for women and how the replacement of testosterone may alleviate some symptoms that seem to be associated with androgen deficiency.

Androgens appear to have an important effect on women's energy and well-being, said Davis at the American Society of Andrology meeting here last month. She shared her results, soon to be published, from an Australian clinical trial of a transdermal testosterone patch developed specifically for women. Davis said postmenopausal women using the active preparation had an improvement in well-being as measured by the Psychological General Well-Being Index, particularly in relation to depression. Improvements in libido also were reported.

Assessment of patient well-being is a sort of touchy-feely aspect of endocrinology, Davis said, but an important one. Lack of energy is one of the factors that most negatively affect the quality of life for many menopausal and postmenopausal women, she said, and women who receive testosterone therapy claim the biggest boost is to their energy level. "They have more energy to do things, and I think that is what ultimately affects libido," she said.

DEFINING A DEFICIENCY

Davis acknowledged that there is no accepted biochemical or clinical definition of androgen deficiency in women. (According to Dorland's Medical Dictionary, the reference range for testosterone plasma levels in women is 0.8-2.6 nmol/L [23-75 ng/dL].) "There are studies showing that replacement shows improvements, but there's been no deficiency state documented or explanation of how this might relate to clinical symptomatology," she noted.

"I would consider treating a woman with a level of free testosterone below the midpoint of the normal range for the available assay," said Davis. "Units differ among countries and assays differ, but that is what I find useful." Davis proposes that a symptom triad of low libido, blunted motivation, and persistent background fatigue be used as a clinical definition of androgen deficiency in randomized trials of testosterone therapy.

Davis said the concept of androgen deficiency has been most readily accepted in the case of women who have had bilateral oophorectomy, since the ovaries are a main source of circulating testosterone. However, because testosterone levels decline with age, women in their later reproductive years also may have lower levels of testosterone than younger premenopausal women and may experience such symptoms as loss of libido, she said.

By the time a woman has gone through menopause, said Davis, her testosterone levels may be further depleted, especially if she is taking estrogen replacement therapy. Because estrogen replacement therapy can significantly reduce bioavailable testosterone in postmenopausal women, "this can add insult to injury." Davis said oral contraceptives also can reduce greatly levels of bioavailable testosterone in younger women, which may be the reason that some women on the pill report a loss of libido.

Because symptoms of androgen deficiency can be caused by a number of factors, Davis said that before making this diagnosis, other possible causes of fatigue and low libido such as depression or iron deficiency should be ruled out. Many of the patients Davis sees are referred by sex therapists and psychiatrists "who feel they have nothing to offer their patients because they aren't clinically depressed or don't seem to have underlying sexual relationship problems," she said.

A "NASTY" HORMONE?

There is a tendency, said Davis, to think of testosterone as a "nasty" steroid in terms of cardiovascular risk. "Common wisdom has it that women are protected [from cardiovascular disease] because they have estradiol and men are at increased risk because they have high levels of testosterone throughout their lives." Yet the picture may not be so simple. Recently, estradiol's cardiovascular protective effect was called into question by results from the Women's Health Initiative study of hormone replacement therapy, in which women on active therapy had a 1% rise in risk of cardiovascular disease and stroke. Davis suggested that as more is learned about testosterone, assumptions about its negative effects may be found to be overstated. "In our studies," she said, "testosterone has some benefits and doesn't appear to have risks."

The increased risk reported in some studies may relate to oral vs parenteral dosing. For example, there have been reports that oral administration of testosterone can reduce levels of high-density lipoprotein cholesterol and apolipoprotein A-I, but Davis said to her knowledge, this has not been seen with parenteral administration.

Another concern about testosterone therapy is the risk of breast cancer. Epidemiological studies have shown both positive and negative associations between endogenous androgen levels and breast cancer risk, she said, and more research is needed to clarify this question, said Davis.

While adverse effects of testosterone in women, such as masculinization and fluid retention, are possible, Davis said these effects are unusual when therapeutic hormone levels are maintained within normal physiological levels.

"This is cutting edge work," said Erol Onel, MD, chief of andrology at Tufts University School of Medicine, commenting on Davis' presentation. The potential risks associated with androgen therapy must be determined, but once these have been identified, and researchers have defined normal testosterone ranges for women and the proper treatment of a woman with androgen deficiency, Onel said, the potential of the research is "phenomenal."