Androgens in women: To replace or not?
Androgen therapy can improve sexual desire and response—here’s how
IN THIS ARTICLE
Although women produce only one tenth the amount of androgen that men do, testosterone and related androgen metabolites are as important to women throughout the lifespan as is estrogen. Androgens modulate a feeling of well-being, increase energy, support bone metabolism, and improve sexual function in women.1-3 But too much androgen production, with elevated levels of testosterone and dehydroepiandrosterone (DHEA), can result in hirsutism, acne, and infertility in the setting of polycystic ovary syndrome (PCOS), all of which present clinical problems.
An equally complicated topic is androgen insufficiency in women. Not only is it difficult to diagnose, it is a major clinical issue to decide whether, when, and how to replace androgens in women. In this article, I look at androgen production throughout the female lifespan, particularly the relationship between estrogen and androgen. I also describe the evaluation of androgen insufficiency, which requires understanding of androgen physiology and ovarian function before and after menopause. These issues form the basis of the decision to replace androgen in women.
Androgen over the lifespan
In the premenopausal woman, androgen production is approximately equally divided between the adrenal gland and the ovaries. Androstenedione from both is converted to testosterone and then irreversibly to dihydrotestosterone (DHT). Androstenedione, testosterone, and even DHEA are secreted in equal quantities by the adrenals and ovaries. The only androgen that is predominantly adrenal is DHEAS, which is sulfated in the adrenal gland.
In premenopausal women, androstenedione is the precursor to testosterone, which is then metabolized to DHT, the androgen most active in hair follicles and implicated in hirsutism. It has been clear for many years that DHEA, although a weak androgen, is present in the greatest quantity in the circulation and is secreted during adrenarche, prior to menarche, beginning at ages 8 to 10. DHEAS peaks in young adulthood and begins to decline after age 40.4 The same is true for both total testosterone and free testosterone levels, which also decline in women after about age 25. Thus, peri- and postmenopausal women have approximately half the level of circulating androgens of women in their 20s (FIGURE 1, TABLE 1).5
Testosterone levels in women decline with aging
SOURCE: Davison S, et al5TABLE 1
How menopause affects plasma hormone levels
MEAN PLASMA LEVEL
* Mean value during early follicular phase
† P<.01 for comparison with reproductive age
‡ P<.01 for comparison with naturally menopausal women
§ P<.05 for comparison with naturally menopausal women
It matters how menopause happens
Circulating androgen levels are greatly influenced by menopause—how much depends on whether it occurs naturally with the ovaries intact, or by surgical removal of the ovaries. Not only does estradiol diminish significantly in naturally menopausal women, but all androgens do as well. In young oophorectomized women, estrogen levels are similar to levels in naturally menopausal women, but androgen levels—including testosterone, DHT, and androstenedione—are significantly lower than in naturally menopausal women, demonstrating that the circulating levels of androgen after natural menopause are still significantly greater than those in oophorectomized women.6 Thus, the postmenopausal ovary contributes significantly to circulating levels of androgen.
Both androgens and estrogens circulate in the bloodstream tightly bound to the protein sex hormone-binding globulin (SHBG), and more loosely bound to albumin. The SHBG-bound fraction is unavailable for biologic activity. Therefore, the amount of SHBG a woman produces is a key determinant of her level of androgen bioactivity. For this reason, it is crucial to measure circulating SHBG.
In a feedback mechanism, SHBG production is regulated by androgen and estrogen levels, with estrogen stimulating SHBG production and testosterone decreasing it.7 In the normal woman, about 65% of testosterone is bound to SHBG and 30% is bound to albumin, leaving only 0.5% to 2% free and bioactively available.8 In postmenopausal women taking hormone replacement therapy, SHBG increases, but the addition of methyltestosterone lowers the overall levels of SHBG, even in the presence of estrogen, increasing the amount of bioavailable testosterone simply by lowering SHBG levels. Postmenopausal replacement with estrogen alone decreases the amount of bioavailable testosterone because of higher SHBG levels.
SHBG is synthesized in the liver, whose metabolism is increased by exposure to steroids. Therefore, oral forms of estrogen replacement, which stimulate the liver because of the “first pass” effect, result in a greater increase in SHBG than do transdermal estrogen preparations.
Elevated androgen levels have both ill and good effects
As I stated earlier, an appropriate level of androgen is optimal for women as well as men. Elevated androgen levels are problematic, in that they are the hallmark of PCOS, usually resulting from increased ovarian production of androgen. This elevation can cause anovulation, infertility, hirsutism, and other androgen-mediated physiologic effects. Androgen is also associated with elevated low-density lipoprotein and decreased high-density lipoprotein cholesterol, implying a possible relationship with cardiovascular disease. At the same time, however, elevated testosterone has been correlated with increased bone density in both the hip and the femoral neck.9
It is clear that appropriate androgen secretion, which does not elicit the side effects described above, is best for both the health and well-being of the woman.
How androgen affects female sexual function
We have known for years that androgen—not estrogen—is associated with satisfactory sexual function. Although estrogen replacement increases vaginal lubrication, it is androgen, most commonly in the form of oral methyltestosterone or injectable testosterone, that increases frequency of intercourse, desire, and sexual sensation (FIGURE 2).10 The definition of androgen insufficiency has been hotly debated, and is currently “a pattern of clinical symptoms in the presence of decreased bioavailable testosterone and normal estrogen.”11
How estrogen plus androgen affects sexual function
EE=esterified estrogens; MT=methyltestosterone
SOURCE: Sarrel PM, et al19
Assessing androgen levels
Clinical signs and symptoms of androgen insufficiency are important in establishing the diagnosis. They include a diminished sense of well-being, unexplained fatigue, decreased sexual desire, and thinning and loss of pubic hair.11 Although it is possible to assess testosterone production and availability in women by measuring serum testosterone levels, a lack of consensus about the best measurement technique and interpretation of results makes it difficult to base the diagnosis of androgen insufficiency solely on serum levels.12 Therefore, the diagnosis of androgen insufficiency is primarily a clinical diagnosis of symptoms.11
Obtain serum samples between 8 and 10 AM after day 8 and before day 20 of the normal menstrual cycle because testosterone is subject to diurnal variation, peaking in the early morning, as well as cyclic variation, peaking around midcycle.
Because free testosterone is the only bioavailable steroid, total testosterone and either free testosterone or SHBG must be measured to assess how much androgen is actually available. From total testosterone and SHBG, one can assess the free testosterone index as a measure of bioavailable androgen (the free testosterone index is a ratio of the amount of total testosterone divided by the SHBG level).11 In fact, using the free testosterone index is preferable to the actual measurement of free testosterone because commercial assays lack the sensitivity and reliability to accurately measure the low levels of androgen found in women.
Several different testosterone assays exist, and the immunoassay for total testosterone is reasonably accurate. However, measurements of free testosterone are relatively inaccurate and poorly reproducible. Equilibrium dialysis is thought to be the gold standard for measuring free testosterone, but it is a difficult and time-consuming assay.12
Causes of low testosterone
In women, low testosterone secretion is usually the result of normal aging. Other conditions that alter testosterone production include oophorectomy, ovarian failure, adrenal insufficiency, hypopituitarism, and other forms of chronic illness.
Treatment with corticosteroids and estrogen therapy lowers active androgen levels in women.
What levels are cause for concern?
If androgen levels are at or below the 25th percentile of the normal range for reproductive-aged women, consider the possibility of androgen insufficiency and determine whether androgen replacement is in order.11
When the signs and symptoms of testosterone insufficiency are present, one must first assess estrogen levels by measuring serum estradiol, obtaining vaginal cytology, or both, and by determining whether symptoms of estrogen insufficiency are present, such as hot flashes, night sweats, and vaginal dryness. If the patient is estrogen-insufficient, the first step in resolving her symptoms is estrogen replacement. If estrogen levels are adequate and there is no other reason for the patient’s symptoms of fatigue, lack of sexual desire, or low energy, a trial of testosterone is reasonable.
Treating androgen insufficiency
Current therapies include oral methyltestosterone combined with estrogen, and intramuscular testosterone propionate, testosterone cypionate, and testosterone enanthate. Subcutaneous implants of testosterone propionate are also available, as are transdermal preparations (TABLE 2). However, the transdermal formulations are designed for androgen insufficiency in men, and therefore deliver approximately 10 times as much androgen as women normally produce. Testosterone gel preparations are available that can be applied in lower levels to achieve normal female androgen levels.
Testosterone therapies available now—or in the pipeline
How long until relief?
It is clear from a number of studies13,14 that estrogen plus methyltestosterone oral replacement improves sexual desire in women after 12 to 16 weeks, and that this improvement is based on an increase in bioavailable testosterone. A testosterone patch under development delivers 300 μg per day. When used with conjugated equine estrogens, this patch has been shown to increase bioavailable testosterone in women without ovaries who have very low androgen levels.3
In a 2005 study,15 more than 500 women with hypoactive sexual desire who had undergone a total abdominal hysterectomy–bilateral salpingo-oophorectomy were randomized to placebo or a testosterone patch that delivered 300 μg per day for 24 weeks. Not only did serum testosterone levels increase, but satisfying sexual activity and the numbers of sexual interactions and orgasms increased (FIGURE 3). Side effects of therapy included increased facial hair and acne, but there was no increase in serious adverse effects, and no increase in withdrawal from the study because of side effects. Unfortunately, this patch is in development and unavailable commercially in the United States.
Watch for side effects, and follow closely
Testosterone therapy is most appropriate for women who have undergone surgical menopause and for postmenopausal women who are dissatisfied with estrogen therapy because of symptoms such as decreased libido and a diminished sense of well-being, including headaches and fatigue. Side effects of testosterone therapy include hirsutism, acne, alopecia, worsening lipoproteins, and, in the case of methyltestosterone, the possibility of liver toxicity, so women receiving testosterone should be followed frequently and carefully to detect any of these effects.
Androgen insufficiency in a nutshell
Androgens in women engender a general sense of well-being, which includes elevated energy and mood and increased libido. It is appropriate to consider androgen replacement using oral methyltestosterone, androgen implants, or transdermal androgen gels in women with a clinical diagnosis of androgen insufficiency.
Before initiating androgen therapy, however, it is important to measure total androgen level and assess clinical symptoms. Also, monitor the incidence of side effects to ensure that the patient does not exceed normal female androgen levels. It is hoped that additional forms of androgen replacement for women will become available in the near future.