Leslie R. Schover, Ph.D.
Department of Behavioral Science, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Objective: To contrast the limited evidence that androgen therapy is an effective treatment for low sexual desire in women with the extensive literature suggesting that androgens promote breast cancer.
Received December 13, 2006; revised and accepted May 23, 2007. Reprint requests: Leslie R. Schover, Ph.D., Department of Behavioral Science, Unit 1330, UT M. D. Anderson Cancer Center, P. O. Box 301439, Houston, TX 77230-1439 (FAX: 713-745-4286). E-mail: lschover@mdanderson.org.
Objective: To contrast the limited evidence that androgen therapy is an effective treatment for low sexual desire in women with the extensive literature suggesting that androgens promote breast cancer.
Design: Evidence from population studies of women is reviewed on the association between endogenous androgen levels and sexual function or satisfaction. Recent randomized trials of testosterone therapy for low desire are critiqued in terms of methodology and generalizability. Research on endogenous testosterone levels and breast cancer risk in both premenopausal and postmenopausal women is summarized, as are recent studies of androgenic hormonal therapy and breast cancer risk.
Setting: Literature review.
Intervention(s): Not applicable.
Patient(s): Not applicable.
Main Outcome Measure(s): Not applicable.
Result(s): Endogenous androgen levels are not correlated with sexual desire in population-based studies of aging women. Factors that are strongly associated with low desire include pain with sexual activity, emotional distress, life stress, and relationship conflict. The efficacy of testosterone therapy for women’s desire problems is modest. Expectancy effects were not adequately controlled in randomized trials. Epidemiological findings agree that higher endogenous serum androgen levels confer increased breast cancer risk both before and after menopause. Androgenic hormonal replacement regimens also increase the risk of breast cancer.
Conclusion(s): Testosterone supplementation should not be prescribed to women with low sexual desire unless long-term studies can demonstrate its efficacy and safety. Treatments for low sexual desire in women should address its common correlates: relationship distress, emotional distress, and dyspareunia. (Fertil Steril ©2008;90:129-40. ©2008 by American Society for Reproductive Medicine).
Key Words: Testosterone, androgens, breast cancer, hypoactive sexual desire disorder, hormonal therapy/
Introduction
Recently, reporters and legislators have decried steroid use by amateur and professional athletes. Minimal attention has been given to potential health consequences of steroid use in our own bedrooms, however, as ordinary women turn to androgens to get in the mood for sex. Lack of desire for sex is a major problem for contemporary women. In several recent surveys, about a third of women in the United States (1-3) and 20% globally (4) label themselves as having abnormally low sexual desire.
Less than 20% of these women seek medical help (1, 4); however, with the advent of convenient methods of adminis-tering testosterone in gel or patch form, the pharmaceutical industry has been developing androgen supplements to en-hance women’s sexual desire. This process has been some-what controversial. In December 2004, the Food and Drug Administration (FDA) declined to approve the female testos-terone patch, Intrinsa® (Proctor & Gamble Pharmaceuticals, Cincinnati, OH), requesting more safety studies (5). In October 2006, the Endocrine Society published a guideline advocating further research before prescribing androgens for women in clinical practice (6). However, in July 2006, the European Commission approved Intrinsa® for marketing in the United Kingdom and throughout the European Union (7). Other pharmaceutical companies such as BioSante Pharmaceuticals (Lincolnshire, IL) and Vivus (Mountain View, CA) have testosterone products for women in stage 3 clinical trials (8, 9).
With or without the blessing of the FDA, women in the United States are using testosterone. In their Advisory Committee Briefing Document for the FDA, Proctor and Gamble noted that at least 21% of prescriptions of branded testosterone supplements in 2003 were written for women, contrary to approved usage. In addition, from 2000 to 2003, women filled 1,315,000 prescriptions for generic or compounded testosterone products such as genital creams (10). In a survey completed by 41% of practicing obstetrician/gynecologists in Tucson, Arizona, physicians wrote a mean of four prescrip-tions a week for testosterone. Seventy percent of the scripts were given to premenopausal women (despite minimal data on safety or efficacy in this group); 90% of those given to postmenopausal women were to treat “low libido” (11).
Statistics on testosterone prescriptions do not take into account similar usage of dehydroepiandrosterone (DHEA), a precursor of androgen and estrogen available in health food stores as an unregulated supplement. A political deal exempted DHEA from a bill passed in 2004 regulating other androgens (12). In 2003, the last year that sales figures were available, United States sales of DHEA totaled $47 million (10). Recently, DNA microarray technology has confirmed that DHEA has potent androgenic and anabolic steroid activity (13). In postmenopausal women, it is preferentially transformed into androgens rather than into estrogens (14).
Why are American women reluctant to take estrogens and progesterone after publicity about the Women’s Health Initiative (15) yet eager to use androgens? Neither the public nor the scientific and medical communities involved in reproductive health seem aware of the growing literature in oncology and epidemiology journals documenting a strong association between androgens and risk of breast cancer. The safety concerns in the Intrinsa® hearings at the FDA focused mainly on cardiovascular risk (5). The Endocrine Society Clinical Practice Guideline also only cites one observational study that suggests an antiproliferative impact of androgens on breast tissue (6). The public education pamphlet for Intrinsa® in the United Kingdom mentions unknown risks of breast cancer with long-term use (12), and advises women who have had hormone-sensitive malignancies not to use Intrinsa®. However, the publication states that the only common side effect is a skin reaction to the patch itself.
This review compares the evidence that testosterone ther-apy is an effective treatment for women’s lack of sexual desire versus the findings that such treatment could promote the risk of breast cancer either as a first malignancy or as a recurrence or second primary.
Low sexual desire in women: when is it a sexual dysfunction?
In Western societies, a sexually healthy woman is expected to experience frequent, spontaneous desire for sex (16). Re-searchers have tried to define “hypoactive sexual desire disorder” (HSDD) in women in a manner that would transcend cultural values. A consensus committee convened by the American Urological Association recommended that any di-agnosis of female sexual dysfunction include the criterion that a woman has “personal distress” about her sexual problem (17). Hypoactive sexual desire disorder is only diagnosed when a woman reports absent desire before sexual activity, states that desire is not triggered during sexual experiences, and rates herself as distressed about the problem. This leads to the paradox that with aging the percentage of women reporting lack of desire increases greatly, but because older women are less distressed about their desire for sex, the prevalence of HSDD as a diagnosis remains constant with age (18). Few women are aware of these complexities, however. Many label themselves as abnormal because they, or their partners, do not believe their desire for sex meets standards portrayed in popular media, even if such “norms” are unrealistic according to population studies.
When is low desire a medical syndrome?
Although HSDD is officially a psychiatric diagnosis, it also is frequently assumed to be a medical problem caused by abnormally low serum androgen levels. In 1995, Sands and Studd (19) coined the term “female androgen insufficiency” (FAI) to describe this syndrome. In 2002, after transdermal testosterone patches and gels had been approved for men, the phar-maceutical industry funded a consensus conference on female androgen insufficiency syndrome (FAIS) (20). This condition was characterized by low values of free serum testosterone along with complaints of low desire, loss of wellbeing, and depressed mood. Researchers acknowledged a lack of normative data on levels of free serum testosterone in women as well as a problem finding reliable, lowcost assays to measure it. Nevertheless, they maintained that FAIS existed because women with the diagnosis improved on testosterone (21).
A fundamental problem with FAIS is that studies of endogenous testosterone do not show a correlation of hormonal levels with women’s sexual function or satisfaction. Conventional wisdom is that testosterone acts in the brain to promote women’s desire for sex, so women in a “deficient” state will have no interest in initiating sex, will have difficulty feeling excitement or pleasure, and also will have trouble reaching orgasm (20, 21).
Table 1 lists six population-based surveys (one represented by two publications) on hormone levels and sexual function in women. Despite differences in methodology, they largely agree that mean levels of endogenous androgens are not correlated with women’s sexual desire or with sexual pleasure and function (3, 22-27), although two studies found that very low levels of DHEAS were associated with sexual dysfunction in some women (3, 26). Changes in androgen levels during transition to menopause or after menopause were not associated with loss of sexual desire (2, 22-25, 27). Rather, vaginal dryness and dyspareunia from vaginal atrophy (28, 29), relationship conflict, life stress, and depression are strongly associated with low desire for sex in women.
Table 1. Population-based studies relating androgen levels to female sexual function.
Table 1. Continued.
Although women’s endogenous androgen levels vary widely across the adult lifespan, perhaps FAIS only exists in extremely deficient states. Table 2 summarizes several recent studies comparing women undergoing surgical menopause versus hysterectomy alone or surgical versus natural menopause. A survey of 1345 European women aged 20 to 70 years, all in sexual relationships, found that women who reached menopause due to surgery had twice the rates of hypoactive sexual desire disorder as premenopausal women or women who had natural menopause (30). A parallel study conducted in the United States reported the same finding (31). The researchers concluded that the hormone impact of oophorectomy caused the HSDD.
Table 2. Studies of oophorectomy, hormones, and sexual function.
Table 2. Continued.
In contrast to these two cross-sectional studies, prospective studies of women undergoing surgical menopause suggest a different etiology. The impact of bilateral oophorectomy was investigated by Aziz et al. (32), who followed 217 Swedish women choosing to have hysterectomy alone for benign indications such as heavy bleeding, compared with 106 opting to have a bilateral prophylactic oophorectomy at the time of hysterectomy. Hormones and sexual function were assessed before surgery and at 1-year follow-up. Women were prescribed estrogen replacement if they were menopausal after surgery so that vaginal atrophy was not a factor in sexual function. Androgen levels did decrease after bilateral oophorectomy, but sexual function and satisfaction remained stable. Psychological well-being improved in both groups.
One caveat is that the women who chose prophylactic oo-phorectomy were significantly more anxious at baseline, and their sexual function/satisfaction, though still within the nor-mative range for Swedish women, was significantly lower than that of the hysterectomy-alone group (33). A similar pattern was observed in a 3-year prospective study in New Zealand comparing 257 women who had hysterectomy alone with 57 who also had bilateral oophorectomy (34). At baseline, the oophorectomy group was less sexually active, more depressed, and reported more pelvic pain. Both groups of women had significant improvements in mood and pain after hysterectomy and neither noted a decline in sexual activity or problems with vaginal dryness (as in the Swedish study, women were offered estrogen replacement after surgery). Baseline differences in sexual interest and emotional distress, rather than hormone changes, may be responsible for postsurgical differences in sexual satisfaction or function between women who choose ovarian conservation versus oophorectomy.
In general, women who have hysterectomies are more psy-chologically distressed before surgery than women who go through a natural menopause transition (35, 36). Unlike erectile dysfunction, sexual dysfunction in women is not closely linked to aging or poor health status. Rather, it is associated with lower educational attainment, relationship conflict, emotional distress, and living in societies that do not value egalitarian gender roles in dyadic relationships (1, 2, 28, 37, 38). The Endocrine Society’s Clinical Practice Guideline recently recognized the limited evidence for FAIS as a medical cause of low sexual desire and recommended against using it as a diagnosis (6).
Establishing norms for androgens in women.
One chronic problem with measuring androgens is that assays designed for male values lack the sensitivity to measure the low levels of free and total testosterone that are normal in women (6, 39-41). Advocates of the FAIS typically use the Free Androgen Index, a calculated ratio of total testosterone to sex-hormone&binding globulin (SHBG), to diagnose androgen deficiency (42). This ratio is clinically meaningless, however. Less than 3% of testosterone in women is unbound and free to act in target cells, although 30% or 40% is loosely bound to albumin and thus bioavailable, as opposed to the fraction bound to SHBG. However, bioavailability depends on the target tissue (6). The best studies not only sample blood at a standard time of day and point in the menstrual cycle for younger women but also measure free testosterone directly using experimental and expensive methods based on chromatography followed by tandem mass spectrometry (40, 41). Samples should be batched and analyzed in one run per hormone to avoid interassay variability.
Three recent cohort studies provide normative data for total and free androgen levels in healthy premenopausal and postmenopausal women (42-44). They agree that testosterone levels are highest in women in their 20s, falling sharply during the years from 30 to 39. Testosterone does not automatically decline with menopause (6,43, 44). These findings cast even more doubt on the importance of androgens in women’s desire for sex because it is precisely women in their 20s who have the highest rates of sexual dysfunction in population surveys (1). Their difficulty in enjoying sex is statistically significantly correlated with lack of knowledge about sexuality and with having unstable, unsatisfying intimate relationships.
Another thorny issue is whether serum levels of androgens reflect hormonal action in the brain, where sexual desire and pleasure presumably originate, or inside target cells in general. Labrie et al. (45) have suggested that serum levels of androgens are not reflective of their intracellular activity. In human females, peripheral tissues synthesize large amounts of androgens from DHEA, never releasing these hormones into the circulation. However, because all androgens are metabolized to androgen glucuronides, measuring serum levels of androsterone glucuronide (ADT-G) may give a more accurate assessment of androgenic activity in women. Although Labrie et al. (45) found that ADT-G levels did not correlate with serum androgens in a large sample of women, a relationship between the metabolite and supposed symptoms of FAIS has yet to be demonstrated. Two recent large surveys of postmenopausal women have found that DHEAS was the only hormone that correlated with sexual function (3, 26).
Androgens, obesity, and fitness in women.
A gender difference in the relationship of androgens to health also may be relevant to their role in sexual function. In men, testosterone not only declines with aging, but obesity, smok-ing, and a sedentary lifestyle are clearly associated with lower hormonal levels (46). In women, conversely, total and free testosterone are elevated with obesity and SHBG levels are decreased, especially in women who have the abdominal fat distribution associated with cardiac risk or who meet criteria for the metabolic syndrome (27, 47, 48). Estrogens and some androgens, including free testosterone and an- drostenedione, were elevated in the most obese and sedentary women in a sample of 300 randomly chosen from the Woman’s Health Initiative (49). Women who exercise and lose weight actually decrease their androgen levels (50). The potential negative impact on cardiac health of chronic testosterone supplementation was a major concern for the FDA panel evaluating Intrinsa® (5).
Does testosterone improve women’s desire for sex.
Five large randomized, double-blinded trials of a transdermal testosterone patch for women have been published (51-55). Four included only women who had bilateral oophorectomy for benign indications and were already taking stable dosages of unopposed estrogen after surgery (51-53,55). In one study (55), the estrogen was transdermal. The most recent trial recruited naturally menopausal women who were on stable doses of estrogen or estrogen plus progesterone (if they still had a uterus) and complained of loss of desire for sex (54). Abnormal baseline total or free testosterone was not an entry criterion for any of the trials, although oophorectomized women were presumed to have abnormally low testosterone because the ovaries produce about 50% of serum levels. Dosage levels included 150-μg/day, 300-μg/day, and 450-μg/day, but only the 300-μg/day dose improved sexual function significantly more than placebo. The failure of the highest dose is puzzling. It cannot be explained by increased side effects because the 450-μg/day group did not have more adverse events or dropouts from the study (53). Testosterone may influence sexual desire and pleasure on a "threshold model." Once the level of bioavailable hormone is adequate, giving more has no incremental effect (56). However, one would not expect a higher dose to be less effective than an adequate dose.
The results of these trials also raise other questions. Women attained median levels of total testosterone by 24 weeks at the 300-μg/day dosage that exceeded the normal range for premenopausal women in all five trials (51-55). The researchers discount the importance of these findings, however, because free or bioavailable testosterone remained within the premenopausal reference range. These ranges are based on values in premenopausal women, however, and may not be ‘‘physiologic’’ for women over the normal age of menopause.
A sizable placebo effect was observed in all trials, although it was less marked in the trial of women on transdermal estrogen (55). For example, in the third trial with oophorectomized women, those on placebo had a 48% increase in sexual desire scores compared with a 67% increase in the 300-μg/day dosage group (53). The 300-μg/day dosage group had a 79% increase in the frequency of satisfying sex compared with 43% in the placebo group (53). The improvement from testosterone therapy translated into a rather modest increase from three to five satisfying episodes of sex across a 5-week period, although women’s sexual satisfaction also rose significantly (53, 54). Women in these trials consistently reported at least two satisfying episodes of sex per month, which is quite discrepant from women who come to sex therapy clinics for treatment of HSDD. These women typically have not enjoyed sex in many months (30, 31). The criteria for diagnosing HSDD in the clinical trials were not as strict as those proposed by the consensus committee (4), leaving doubt as to generalizability of the results.
Despite the double-blinded design, expectancies could ac-count for the between-group differences. If women could ac-curately identify whether they were receiving the active drug versus the placebo, those who believed they were taking tes-tosterone may have “expected” it to work and therefore per-ceived more improvement. Assessing whether participants can guess their randomization condition is crucial when subjective, selfreport end points such as ratings of pain or desire for sex are used in clinical trials (57, 58). However, no data of this type were reported for any of the trials. In fact, women could have been alerted to their treatment group by a series of questions they were periodically asked about adverse effects, that is, if they had noticed deeper voice timbre, altered patterns of facial and scalp hair, excess body hair, or skin reactions (53, 55, 56).
In summary, testosterone replacement has a significant im-pact on sexual desire in menopausal women, but the clinical magnitude of the improvement remains questionable. Positive changes only occur at a dose that achieves a supraphysio-logic total testosterone level in most women. Placebo effects cannot be ruled out as the source of the improvement. Because transdermal testosterone has only been studied in combination with estrogen replacement, its applicability is currently limited to women who do not have contraindications to taking estrogen. Nevertheless, many physicians are prescribing testosterone for women who do not use estrogen, creating a hormone environment that is unnatural and entails unknown risks.
Testosterone use by female cancer survivors.
Diminished sexual desire and arousal is the most common sexual problem for women after cancer treatment, reported by at least half of women whose cancer therapy causes sudden ovarian failure (59-62). In the early 1990s, the influential sex therapist Helen Singer Kaplan was diagnosed with breast cancer and became interested in this problem, asserting that loss of desire after chemotherapy was a direct result of androgen deficiency (63, 64). Kaplan suggested that testosterone supplementation was safe for breast cancer sur-vivors because it had been used as a treatment for breast cancer before the advent of selective estrogen receptor modifiers. Of course, the impact of a hormone given in a very high dose is far different from a chronic, low dose. Nevertheless, Kaplan’s legacy has continued long after her tragic and premature death. Many breast cancer survivors are using testosterone without estrogen, convinced it is far safer than other forms of hormone replacement. It is ironic that the only two cohort studies measuring androgen levels and sexual function in breast cancer survivors found no evidence that low testosterone is linked to sexual dysfunction (65, 66).
Endogenous testosterone and the risk of breast cancer.
It is crucial that clinicians and the public become aware of the evidence linking women’s androgen levels with breast cancer risk (67). Epidemiological research demonstrates that higher endogenous androgen levels increase breast cancer risk in postmenopausal women. The only controversy is the mechanism (68): Is the association due to aromatization of androgens to estrogen in peripheral fat tissues? Is testosterone binding to SHBG and leaving more estradiol in circulation? Or does testosterone have a direct proliferative effect on breast cancer cells? Most have androgen receptors (68). Androgens appear to have antiproliferative effects in some tumors but proliferative effects in others (69). Androgen blockade or reduction of circulating DHEAS levels may be therapeutic in some subsets of women (69).
A meta-analysis of nine prospective studies in postmeno-pausal women concluded that endogenous testosterone in-creases breast cancer risk even after adjustment for estradiol levels (70). The odds ratio of breast cancer for women with total testosterone in the top quartile compared with those in the bottom quartile was 1.73 (1.16-2.57). Since that publication, two large prospective studies have confirmed the association. In one, both cases and controls were drawn from the Nurse’s Health Study. Hormone levels were compared in 322 postmenopausal women who developed breast cancer and 644 matched controls (71). Endogenous estrogens and androgens (testosterone, androstenedione, DHEAS) contributed independently and significantly to the risk of breast cancer. Another nested case-control study used the Women’s Health Study registry, comparing 297 women who developed breast cancer with 563 controls (72). Endogenous androgens were significantly higher in women who developed breast cancer, but the association decreased when adjusted for levels of estrone, the estrogen most strongly linked to breast cancer risk. The investigators concluded that androgens contribute to risk mainly by being converted to estrogens. A recent case-control study suggested that an interaction of high circulating levels of both androgens and insulin-like growth factor 1 (IGF-I) could act synergistically to increase the risk of hormone-dependent breast cancer in postmenopausal women (73).
Evidence has also increased for a link between premeno-pausal breast cancer and endogenous androgen levels. Within a cohort participating in a prospective study of hormones and diet in breast cancer, 65 women who developed breast cancer before menopause were compared with 243 matched controls (74). All had a blood sampled on days 20 to 24 of the menstrual cycle. The odds ratio for breast cancer was 2.85 (1.11-7.33) in women whose free testosterone was in the highest tertile compared with the lowest tertile. In contrast, higher levels of progesterone were associated with decreased breast cancer risk.
A similar pattern was seen in a nested case-control study of women in the European Prospective Investigation into Cancer and Nutrition (75). A total of 370 premenopausal women developed breast cancer and were matched to 726 controls. The phase of the menstrual cycle at blood collection was not standardized, but was matched between cases and controls. Levels of testosterone, androstenedione, and DHEAS were statistically significantly higher in women who developed breast cancer. When women under age 40 were followed for 10 years, 2.6% of those with testosterone in the highest quartile developed breast cancer compared with 1.5% of women with hormones in the lowest quartile. Again, higher progesterone was associated with decreased cancer risk. The most likely explanation is that breast cancer risk is elevated among women who have an excess of ovarian androgens and produce reduced amounts of progesterone.
Most recently, in a nested case-control study within the Nurses’ Health Study II, higher endogenous levels of total and free testosterone, androstenedione, and follicular total and free estradiol were all significantly associated with breast cancer risk, particularly for risk of invasive and hormonally positive tumors. Adjustment for estradiol did not decrease the association between androgen levels and breast cancer risk (76).
Higher androgen levels are also associated with risk of breast cancer recurrence in postmenopausal women (8, 77). A group of 115 breast cancer survivors free of disease at study entry were followed for 5.5 years. Serum testosterone, estradiol, and glucose were significantly higher, as was body mass, for the 31 who either had a cancer recurrence or new primary breast tumor. The hazard ratio for recurrence/new breast cancer was 7.2 (2.4-21.4) for women whose testosterone was in the upper tertile compared with those in the lowest tertile.
Testosterone supplementation and the risk of breast cancer.
Does supplementing a woman’s testosterone have the same impact on risk for breast cancer as having high endogenous testosterone? High endogenous testosterone may be a marker for obesity or high-fat diet rather than a direct promoter of breast cancer. However, the convergence of hormonal factors in breast cancer etiology is striking. Early menarche, late menopause, nulliparity, obesity after menopause, and post-menopausal estrogen therapy with a progestin all increase the breast’s lifetime exposure to hormones as well as elevating the risk of breast cancer. It is plausible that hormone therapy regimens producing chronically supraphysiologic levels of free and total testosterone would increase breast cancer risk.
Although estrogen use after breast cancer had not been linked to recurrence in observational studies, two recent ran-domized trials suggest that taking estrogen directly increases recurrence rates with a pooled relative risk of 3.41 (1.597.33) (78). Because androgens are converted in vivo to estrogen, these data should increase women’s caution about any type of hormone replacement (79).
Advocates of testosterone replacement cite an observa-tional, retrospective study reporting lower rates of breast cancer in 508 Australian postmenopausal women who used testosterone in addition to other hormonal replacement ther-apy compared with a group taking hormones without testos-terone (80). However, three prospective, case-control comparisons nested within very large cohort studies recently have found that androgen supplementation increases breast cancer risk. A case-control comparison within the Danish Nurse Cohort Study revealed that the more androgenic the hormone replacement regimen and the more extensive the use, the higher a woman’s risk of breast cancer (81). Current users of tibolone had a fourfold relative risk of breast cancer. Tibolone increased breast cancer rates by 50% in the British Million Women Study (82). In the United States, researchers performed a nested case-control comparison including women from the Nurses’ Health Study who were using a variety of postmenopausal hormone regimens (including estrogen alone or estrogen plus progestins). Free and total estradiol were significantly higher in women over 60 years old who developed breast cancer. A trend was also seen for free testosterone to be associated with breast cancer risk in this group (83).
Most recently, a longer, prospective case-control study evaluated women in the large Nurses’ Health cohort from 1978 to 2002 (84). Results confirmed that among women who reached natural menopause, each year of using estrogen plus testosterone hormone replacement produced a 17.2% increase in breast cancer compared with women who did not use any hormone therapy. Their risk of breast cancer was also significantly higher than women using estrogen alone and tended to be higher than the risk of women on combined estrogen and progesterone therapy (84).
It is worth noting that the endogenous serum testosterone levels associated with elevated breast cancer risk in various studies are in the range of ≥51 to 58 ng/dL (74, 75) in pre-menopausal women or ≥ 20 to 26 ng/dL in postmenopausal women (70, 71). In the Intrinsa® trials, median total serum testosterone ranged from 54 to 102 ng/dL after 24 weeks of treatment (51-55).
Recommendations
We suggest that women offered testosterone supplementation be informed of the probable increased risk of breast cancer. Given that the average woman in the United States has one chance in seven of developing breast cancer in her lifetime (85), a significant increase in relative risk translates into a sub-stantial increase in absolute risk. A conservative estimate is that the odds ratio for breast cancer increases to 1.75 for women with high levels of serum testosterone. Some women under age 40 might be willing to trade a 2.6% versus 1.5% risk of breast cancer in the next 10 years for better sexual desire (75). However, would 40 year olds with a 4.18% chance of breast cancer by age 59 (85) be willing to tolerate increasing that risk to 7.32%?
Androgen supplementation is particularly undesirable in women with a history of breast cancer. Other cancer survivors at increased risk for breast cancer as a second malignancy should also be warned not to use androgens. This category in-cludes women treated for Hodgkin disease with mantle irra-diation (86), survivors of chest irradiation for pediatric cancer, or young women with a history of bone or soft tissue sarcoma (87). The risks of hormone therapy for more than a short period may also be exacerbated for women carrying BRCA mutations (88). Because the link between androgens and sexual desire has been so salient, clinicians forget that behavioral therapies may be more effective than hormonal treatment if they target the factors that repeatedly predict HSDD such as dyspareunia, life stress, psychological distress, and relationship conflict (89).
The FDA should reevaluate the over-the-counter status of androgenic steroids such as DHEA (6, 12, 13). Off-label tes-tosterone prescriptions should also be discouraged because their dosage and safety profiles are unknown (90). If products such as Intrinsa® are to gain FDA approval, safety studies should be required with adequate power and duration of follow-up to ascertain breast cancer risk.
Acknowledgments
The author would like to thank Graham A. Colditz, M.D., Dr. P.H., for comments on earlier drafts.
References.
Laumann EO, Paik A, Rosen RD. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44.
Avis NE, Zhao X, Johannes CB, Ory M, Brockwell S, Greendale GA. Correlates of sexual function among multi-ethnic middle-aged women: results from the Study of Women’s Health Across the Nation (SWAN). Menopause 2005;2:385-98.
Gracia CR, Freeman EW, Sammel MD, Lin H, Mogul M. Hormones and sexuality during transition to menopause. Obstet Gynecol 2007;109: 831-40.
Moreira ED, Brock G, Glasser DB, Nicolosi A, Laumann EO, Paik A, et al, for the Global Study of Sexual Attitudes and Behaviors Study Group. Help-seeking behaviour for sexual problems: the Global Study of Sexual Attitudes and Behaviors. Int J Clin Pract 2005;59:6-16.
Spark RF. Intrinsa fails to impress FDA advisory panel. Int J Impot Res 2005;17:283-4.
Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, Santoro N. Androgen therapy in women: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006;91:3697-710.
European Medicines Agency. European Public Assessment Report (EPAR): Intrinsa®. EPAR Summary for the Public. EMEA/H/C/634, June 2006. Available at: http://www.emea.eu.int/humandocs/PDFs/ EPAR/intrinsa/063406en1.pdf. Accessed May 2, 2007.
BioSante Pharmaceuticals Investor Fact Sheet, January 2007. Available at: http://www.biosantepharma.com/pub/factsheet.pdf. Accessed May 15, 2007.
Vivus, Inc. Testosterone metered dose transdermal spray (MDTR®)— for treatment of low sexual desire in women. Available at: http://www. vivus.com/main.taf?p=3,3,3,2. Accessed May 15, 2007.
Advisory Committee Briefing Document. Intrinsa® (testosterone transdermal system), NDA No. 21-769. Procter& Gamble Pharmaceuticals, Inc. Advisory Committee for Reproductive Health Drugs, December 02, 2004, p. 15 Available at: http://www.fda.gov/ohrms/dockets/ac/04/ briefing/2004-4082B1_01_A-P%26G-Intrinsa.pdf. Accessed June 15, 2007.
Freeman MP. Testosterone supplementation in women: prescribing practices in one community. J Womens Health 2004;13:239-40.
Kornblut AE, Wilson D. How one pill escaped place on steroid list. New YorkTimes, April 17, 2005. Available at: http://www.biopsychiatry.com/ dhea/legal.html. Accessed May 2, 2007.
Labrie F, Luu-The V, Martel C, Chernomoretz A, Calvo E, Morissette J, et al. Dehydroepiandrosterone (DHEA) is an anabolic steroid like dihydrotestosterone (DHT), the most potent natural androgen, and tetrahy- drogestrinone (THG). J Steroid Biochem Mol Biol 2006;100:52-8.
Labrie F, Belanger A, Belanger P, Berube R, Martel C, Cusan L, et al. Metabolism of DHEA in postmenopausal women following percutaneous administration. J Steroid Biochem Mol Biol 2007;103:178-88.
Schonberg MA, Davis RB, Wee CC. After the Women’s Health Initiative: decision making and trust of women taking hormone therapy. Womens Health Issues 2005;15:187-95.
Basson R. Rethinking low sexual desire in women. BJOG 2002;109: 357-63.
Basson R, Leiblum S, Brotto L, Derogatis L, Fourcroy J, Fugl-Meyer K, et al. Revised definitions of women’s sexual dysfunction. J Sex Med 2004;1:40-8.
Hayes RD, Dennerstein L, Bennett CM, Koochaki PE, Leiblum SR, Graziottin A. Relationship between hypoactive sexual desire disorder and aging. Fertil Steril 2007;87:107-12.
Sands R, Studd J. Exogenous androgens in postmenopausal women. Am J Med 1995;98:76S-9.
Bachmann G, Bancroft J, Braunstein G, Burger H, Davis S, Dennerstein L, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 2002;77:660-5.
Rivera-Woll LM, Papalia M, Davis SR, Burger HG. Androgen insufficiency in women: diagnostic and therapeutic implications. Hum Reprod Update 2004;10:421-32.
Cawood EH, Bancroft J. Steroid hormones, the menopause, sexuality and well-being of women. Psychol Med 1996;26:925-36.
Gracia CR, Sammel MD, Freeman EW, Liu L, Hollander L, Nelson DB. Predictors of decreased libido in women during the late reproductive years. Menopause 2004;1:144-50.
Dennerstein L, Randolph J, Taffe J, Dudley E, Burger H. Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 2002;77(Suppl 4):S42-8.
Dennerstein L, Lehert P, Burger H. The relative effects of hormones and relationship factors on sexual function of women though the natural menopausal transition. Fertil Steril 2005;84:174-80.
Davis SR, Davison SL, Donath S, Bell RJ. Circulating androgen levels and self-reported sexual function in women. JAMA 2005;294: 91-6.
Santoro N, Torrens J, CrawfordS, Allsworth JE, Finkelstein JS, Gold EB, et al. Correlates of circulating androgens in mid-life women: the Study of Women’s Health Across the Nation. J Clin Endocrin Metab 2005;90:4836-45.
Mishra G, Kuh D. Sexual functioning throughout menopause: the perceptions of women in a British cohort. Menopause 2006;13:880-90.
ModelskaK, LitwackS, Ewing SK, Yaffe K. Endogenous estrogen levels affect sexual function in elderly post-menopausal women. Maturitas 2004;49:124-33.
Dennerstein L, Koochaki P, Barton I, Graziottin A. Hypoactive sexual desire disorder in menopausal women: a survey of western European women. J Sex Med 2006;3:212-22.
Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC. Hypo- active sexual desire disorder in postmenopausal women: US results from the Women’s International Study of Health and Sexuality (WISHeS). Menopause 2006;13:46-56.
Aziz A, Brannstrom M, Bergquist C, Silfverstolpe G. Perimenopausal androgen decline after oophorectomy does not influence sexuality or psychological well-being. Fertil Steril 2005;83:1021-8.
Aziz A, Bergquist C, Brannstrom M, Nordholm L, Silfverstolpe G. Differences in aspects of personality and sexuality between perimeno- pausal women making different choices regarding prophylactic oophorectomy at elective hysterectomy. Act Obstet Gynecol Scand 2005;85: 854-9.
Farquhar CM, Harvey SA, Yu Y, Sadler L, Stewart AW. A prospective study of 3 years of outcomes after hysterectomy with and without oophorectomy. Am J Obstet Gynecol 2006;194:711-7.
McKinlay JB, McKinlay SM, Brambilla DJ. Health status and utilization behavior associated with menopause. Am J Epidemiol 1987;125:110-21.
Shifren JL, Avis NE. Surgical menopause: effects on psychological wellbeing and sexuality. Menopause 2007;14:586-91.
Nicolosi A, Laumann EO, Glasser DB, Moreira ED Jr, Paik A, Gingell C, for the Global Study of Sexual Attitudes and Behaviors Investigators’ Group. Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. Urology 2004;64:991-7.
Laumann EO, Paik A, Glasser DB, Kang J-H, Wang T, Levinson B, et al. A cross-national study of subjective sexual well-being among older women and men: finding from the Global Study of Sexual Attitudes and Behaviors. Arch Sex Behav 2006;35:145-61.
Fears TR, Ziegler RG, Donaldson JL, Falk RT, Hoover RN, Stanczyk FZ, et al. Reproducibility studies and interlaboratory concordance for androgen assays in female plasma. Cancer Epid Biomarkers Prev 2000;9: 403-12.
Gruschke A, Kuhl H. Validity of radioimmunological methods for determining free testosterone in serum. Fertil Steril 2001;76:576-82.
Sinha-Hikiml, ArverS, BeallG, ShenR, GuerreroM, SattlerF, etal.The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and human immunodeficiency virus-infected women. J Clin Endocrin Metab 1998;83: 1312-8.
Guay A, Munarriz R, Jacobson J, Talakoub L, Traish A, Quirk F, et al. Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: Part A. Serum androgen levels in women aged 20-49 years with no complaints of sexual dysfunction. Int J Impot Res 2004;16:112-20.
Davison S, Bell R, Donath S, Montalto J, Davis S. Androgen levels in adult females: changes with age, menopause and oophorectomy. J Clin Endocrinol Metab 2005;90:3847-53.
Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrin Metab 2000;85:2832-8.
Labrie F, Belanger A, Belanger P, Berube R, Martel C, Cusan L, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006;99: 182-8.
Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002;87:587-98.
Sowers MF, Beebe JL, McConnell JR, Jannausch M. Testosterone concentrations in women aged 25-50 years: associations with lifestyle, body composition, and ovarian status. Am J Epidemiol 2001;153: 256-64.
Tufano A, Marzo P, Enrini R, Morricone L, Caviezel F, Ambrosi B. An-thropometric, hormonal and biochemical differences in lean and obese women before and after menopause. J Endocrin Invest 2004;27:648-53.
McTiernan A, Wu L, Chen C, Chlebowski R, Mossavar-Rahmani Y, Modugno F, et al. Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity 2006;14:1662-77.
McTiernan A, Tworoger SS, Rajan KB, Yasui Y, Sorenson B, Ulrich CM, et al. Effect of exercise on serum androgens in postmenopausal women: a 12-month randomized clinical trial. Cancer Epidemiol Biomarkers Prev 2004;13:1099-105.
Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA, et al. Safety and efficacy of a testosterone patch for the treatment of hy- poactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005;165:1582-9.
Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343: 682-8.
Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944-52.
Shifren JL, Davis SR, Moreau M, Waldbaum A, Bouchard C, Derogatis L, et al. Testosterone patch for the treatment ofhypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study. Menopause 2006;13:770-9.
Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot J, Rees M, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause 2006;13:387-96.
Bancroft J. Androgens and sexual function in men and women. In: Bagatell C, Bremner WJ, eds. Contemporary endocrinology: androgens in health and disease. Totowa, NJ: Humana Press, 2003:259-90.
Gaudiano BA, Herbert JD. Methodological issues in clinical trials of antidepressant medications: perspectives from psychotherapy outcome research. Psychother Psychosom 2005;74:17-25.
Bausell RB, Lao L, Bergman S, Lee WL, Berman BM. Is acupuncture analgesia an expectancy effect? Preliminary evidence based on participants’ perceived assignments in two placebo-controlled trials. Eval Health Prof 2005;28:9-26.
Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE, Belin TR. Quality of life in long-term, disease-free survivors of breast cancer: a follow-up study. J Natl Cancer Inst 2002;94:39-49.
Andersen BL, Anderson B, deProsse C. Controlled prospective longitudinal study of women with cancer: I. sexual functioning outcomes. J Consult Clin Psychol 1989;57:683-91.
Hendren SK, O’Connor BL, Liu M, Asano T, Cohen Z, Swallow CH, et al. Prevalence of male and female sexual dysfunction is high following surgery for rectal cancer. Ann Surg 2005;242:212-23.
Syrjala KL, Schroeder TC, Abrams JR, Atkins TZ, Brown WS, Sanders JE, et al. Sexual function measurement and outcomes in cancer survivors and matched controls. J Sex Res 2000;37:213-25.
Kaplan HS. A neglected issue: the sexual side effects of current treatments for breast cancer. J Sex Marital Ther 1992;18:3-19.
Kaplan HS, Owett T. The female androgen deficiency syndrome. J Sex Marital Ther 1993;19:3-24.
Greendale GA, Peterson L, Zibecchi L, Ganz PA. Factors related to sexual function in postmenopausal women with a history of breast cancer. Menopause 2001;8:111-9.
Speer JJ, Hillenberg B, Sugrue DP, Blacker C, Kresge CL, Decker VB, et al. Study of sexual functioning determinants in breast cancer survivors. Breast J 2005;11:440-7.
Franco B. Androgens and breast cancer. Int J Gynecol Cancer 2006;16(Suppl 2):493.
Lillie EO, Bernstein L, Ursin G. Review: The role of androgens and poly-morphisms in the androgen receptor in the epidemiology of breast cancer. Breast Cancer Res 2003;5:164-73.
Moe RE, Anderson BO. Guest editorial. Androgens and androgen receptors: a clinically neglected sector in breast cancer biology. J Surg Oncol 2007;95:437-9.
Key T, Appleby P, Barnes I, Reeves, G. Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606-16.
Missmer SA, Eliaasen H, Baribieri RL, et al. Endogenous estrogen, androgen and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 2004;96:1856-65.
Zeleniuch-Jacquotte A, Shore RE, Akhmedkhanov A, Afanasyeva Y, Kim MY, et al. Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study. Br J Cancer 2004;90:153-9.
Kahan Z, Gardi J, Nyari T, Foldesi I, Hajnal-Papp R, Ormandi K, et al. Elevated levels of circulating insulin-like growth factor-1, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: acase control study. IntJOncol 2006;29:193-200.
Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, et al. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer 2004;112:312-8.
Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2005;97:755-65.
Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 2006;98:1406-15.
Berrino F, Pasanisi P, Bellati C, Venturelli E, Krogh V, Mastroianni A, et al. Serum testosterone levels and breast cancer recurrence. Int J Cancer 2005;113:499-502.
Col NF, Kim JA, Chlebowski RT. Menopausal hormone therapy after breast cancer: a meta-analysis and critical appraisal of the evidence. Breast Cancer Res 2005;7:R535-40.
Colditz GA. Menopausal hormone therapy after breast cancer. Breast Cancer Res 2005;7:168-70.
Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause 2004;11:531-5.
Stahlberg C, Pedersen AT, Lynge E, Andersen ZJ, Keiding N, Hundrup YA, et al. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer 2004;109:721-7.
Tibolone: cancers of the breast and endometrium. Prescrire Int 2006;15: 107.
Tworoger SS, Missmer SA, Barbieri RL, Willett WC, Colditz GA, Hankinson SE. Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones. J Natl Cancer Inst 2005;97:595-602.
Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 2006;166:1483-9.
American Cancer Society. Cancer facts and figures, 2005. Atlanta: American Cancer Society, 2005:14.
Horwich A, Swerdlow AJ. Second primary breast cancer after Hodgkin’s disease. Br J Cancer 2004;90:294-8.
Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, et al. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med 2004;141:590-7.
Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al. Effect of short-term hormone replacement therapy on breast cancer riskre- duction after bilateral prophylactic oophorectomy in brca1 and brca2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005;23:7804-10.
Hartmann U, Heiser K, Ruffer-Hesse C, Kloth G. Female sexual desire disorders: subtypes, classification, personality factors and new directions for treatment. World J Urol 2002;20:79-88.
North American Menopause Society. The role of testosterone therapy in postmenopausal women: position statement of the North American Menopause Society. Menopause 2005;12:496-511.