JNCI Journal of the National Cancer Institute 2007 99(9):659-661; doi:10.1093/jnci/djk175
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Patricia A. Ganz, Gail A. Greendale
Affiliations of authors: Department of Health Services, School of Public Health (PAG) and Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center (PAG), University of California, Los Angeles, Los Angeles, CA; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA (PAG, GAG)
Correspondence to: Patricia A. Ganz, MD, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 650 Charles Young Dr South, Rm A2-125 CHS, Los Angeles, CA 90095-6900 (e-mail: email@example.com
Sexual dysfunction is common among the US population with a prevalence that is greater for women than men (43% versus 31%) ( 1 ). In this setting, a low level of desire is associated with low levels of arousal and sexual excitement, leading to infrequent orgasms and reduced sexual satisfaction ( 2 ). During the past 10 years, Basson ( 3 ) and Basson et al. ( 4 ) have reconceptualized the female sexual response to account for the complexity of female sexual desire and arousal, which does not follow the linear model of discrete phases of sexual response first proposed by Masters and Johnson ( 5 ) and Kaplan ( 6 ). Instead, a circular intimacy-based sexual response cycle was proposed ( Fig. 1 ), with overlapping phases of variable order. As noted by Basson ( 2 ), women participate in sexual activity for diverse reasons, including a desire for emotional closeness, but sexual desire is an infrequent factor for women in established relationships.
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Fig. 1. Circular model of human sexual response, showing cycle of overlapping phases. The sexual and nonsexual outcomes influence future sexual motivation. Taken from The Lancet 2007; 369: 409–24 ( 11 ) with permission. Original source: Obs Gynecol 2001 ( 3 ).
In a prospective multiethnic cohort study of US premenopausal and early perimenopausal women ( 7, 8 ), about 40% of these middle-aged women reported that they never or infrequently felt sexual desire, but nevertheless, most reported that they were capable of arousal and only 13% reported reduced sexual satisfaction. Variables having the greatest association across all aspects of sexual functioning included relationship factors, the perceived importance of sex, attitudes toward aging, and vaginal dryness ( 8 ). Similar findings have been reported in women with a history of breast cancer ( 9, 10 ). Hypoactive sexual desire disorder is diagnosed when a woman fails to feel desire at any stage of the sexual experience; however, sexual thoughts are generally infrequent in women and the frequency of sexual thoughts has little relationship to sexual satisfaction in women ( 2 ). The factors that influence desire and arousal in women are incompletely understood but are likely the results of a complex interaction among the autonomic nervous system (various neurotransmitters), sex hormones (estrogen, testosterone), and environmental factors (mental health, fatigue, quality of the partner relationship) ( 2, 11 ) ( Fig. 2 ). Thus, when evaluating and planning treatment of reduced sexual desire in women, this broad range of factors should be considered.
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Fig. 2. Model of sexual arousal. ANS = autonomic nervous system. Brain areas activated during arousal to allow sexual feelings, maintain focus on the sexual stimuli, anticipate reward, form a mental image of sexual behavior, limit actual behavior despite arousal, and elicit autonomic nervous system response of physical sexual arousal. Taken from The Lancet 2007; 369: 409-24 ( 11 ) with permission.
Sexual response is a complex and finely tuned process that can easily be disturbed at various time points in the reproductive life cycle (pre- and postpartum, peri- and postmenopause), which likely accounts for the high prevalence of reported sexual dysfunction in the general population of healthy women ( 1, 12 ). With such a high rate of background sexual dysfunction, it is not surprising that a variety of chronic illnesses (diabetes, heart disease, rheumatic conditions) can contribute to an increase in reported problems ( 11 ). Cancer and its treatment cause many potential disruptions to the sexual response cycle in women. These disruptions include, but are not limited to, fatigue, depression, pain, and changes in body image ( 9, 13, 14 ). In addition, premature menopause secondary to chemotherapy, radiation, or oophorectomy can complicate sexual functioning through vaginal atrophy and dyspareunia if estrogen supplementation is not provided ( 15 ). These women may also have low levels of androgens, especially if oophorectomy has been performed.
It is in this context that we should consider the study of Barton et al. ( 16 ) from the North Central Cancer Treatment Group (NCCTG) and Mayo Clinic, who chose to evaluate the efficacy of short-term transdermal testosterone in female cancer survivors with decreased sexual desire. The randomized, double-blind crossover design used in this study, with short-term treatment exposure and targeted symptom evaluation, has been the signature protocol design for NCCTG symptom control studies ( 17 – 19 ). Barton et al. ( 16 ) recruited women with a history of cancer who had a sexual partner and self-reported a decrease in sexual desire to study the efficacy of testosterone in ameliorating the symptom of low sexual desire. Participants also were free of cancer at study entry, were postmenopausal, were not currently on chemotherapy, and had no history of treatment for sexual desire, including androgens. No other inclusion or exclusion factors are described, suggesting that this study included women with a variety of cancer diagnoses and past cancer treatments. Stratification factors for random assignment included age, antidepressant use, tamoxifen or selective estrogen receptor modulator use, and the presence of at least one intact ovary. The women received a physical examination on study entry and had to have normal liver function tests but otherwise had no other specific evaluation of the cause or severity of their diminished sexual desire. No information is provided on whether vaginal dryness and/or dyspareunia occurred among these women. The 150 women entered in this study were randomly assigned to receive either 2% testosterone in Vanicream for a dose of 10 mg daily or placebo Vanicream during the first 4 weeks on study and were then crossed over to the other preparation for the second 4 weeks.
Only a limited description of the patient characteristics is provided to the reader. Those that are reported suggest that the majority of participants had a breast cancer history (47% had used tamoxifen and 31% were taking an aromatase inhibitor), and only a minority had received treatment for a pelvic malignancy (7% with a history of pelvic radiation). The vast majority of study participants had received prior chemotherapy (80%), and most had an intact ovary (72%). Because this is a young patient sample (mean age = 52.3 years), it would be helpful to know whether or not these women had had chemotherapy-induced menopause, which is more abrupt than natural menopause and can have more profound physiologic and psychologic manifestations ( 14, 20 ). Although stratification for use of antidepressants was mentioned in the study design, the authors did not report the frequency with which these medications were used by the study participants. This information would be important, given the association of low sexual desire with many of these medications ( 21 ). It would also be useful to know how recently the participants had been diagnosed with and/or treated for cancer, whether they had any past history of low desire or sexual difficulties, and the frequency of mastectomy in the two treatment arms. Mastectomy is strongly associated with poorer body image, which in turn is strongly associated with diminished sexual desire in breast cancer survivors ( 9, 14, 22 ). In addition, the mean scores for the standardized measures used in the study, specifically the Changes in Sexual Functioning Questionnaire, the Vitality Scale of the Medical Outcomes Study Short Form 36 item scale, and the Profile of Mood States scores might provide more information about the women who participated in this trial.
The negative results from this study are clearly stated for the primary endpoint of libido (desire/interest) as well as the secondary endpoints of mood, vitality, sexual pleasure, and total sexual functioning. The authors report no statistically significant improvement with treatment compared with placebo for any of these endpoints. Biologic measures that paralleled the questionnaire data from this study revealed statistically significant increases in bioavailable, free, and total testosterone in the treated group, and no changes in serum estrogen, sex hormone–binding globulin, or serum aspartate aminotransferase. These findings suggest that transdermal treatment with 2% testosterone did lead to measurable changes in testosterone levels and that in this short-term study there were no adverse effects on estrogen levels or liver function tests. However, between baseline and 8 weeks of follow-up, both groups showed improvement in almost all the outcome measures, although not differentially by treatment condition, suggesting that there was a large placebo effect in this study sample. Such an effect is consistent with a developing body of neuroscience research on the placebo response, demonstrating direct actions of the placebo on the brain and then subsequent effects on the body such as alleviation of pain or other symptoms. Some prior studies of topical testosterone for low sexual desire in noncancer survivors ( 23, 24 ) have also reported a strong placebo response, whereas others ( 25, 26 ) have noted a much smaller placebo effect. No obvious explanations exist for this broad range of placebo effects for the outcome of sexual desire, but more careful scrutiny of the variation in placebo responses might yield fruitful insights. Given the complex model of female sexual response described earlier, it should be no surprise that a woman's sexual desire might demonstrate improvement with use of a placebo that was perceived to have potential benefit, specifically testosterone.
The authors have attributed the lack of efficacy of testosterone in this trial to the low estrogen levels of these women, which may indeed be a major factor accounting for the study's null results and highlights the complex relationship of biological, emotional, and cognitive inputs to the perception of desire ( Fig. 2 ). For example, low levels of estrogen can lead to vaginal atrophy ( 15 ), which often causes pain with intercourse and probably also reduces the enjoyable genital sensations that trigger desire ( Fig. 2 ). Thus, there are important interactions between the biologic inputs to sexual desire that must be considered, and we must take a comprehensive approach to the interaction of mind and body as we approach a symptom as complex as low sexual desire, especially in the setting of past cancer treatment. Finally, although the randomized trial focused on mean or group changes in outcomes, a post hoc examination of the study results according to baseline testosterone levels (e.g., low versus normal), with regard to improved sexual desire, might have been useful to inform future study designs.
The NCCTG has conducted pioneering research in the area of symptom control for cancer patients and survivors with studies that are simple in design. This is both a strength and a weakness. Although ovarian hormones play an important role in the maintenance of sexual health in women, a large body of evolving information about sexual functioning (and dysfunction) suggests that these hormones may be necessary but not sufficient to overcome disorders of desire and arousal in women ( 27 ). The long-term safety of estrogen supplementation has been challenged by the results of the Women's Health Initiative hormone studies ( 28 ), and there is limited long-term safety data for androgen supplementation in healthy women ( 29 ). Effective management of diminished sexual desire in women with a cancer history must take a comprehensive approach ( 2 ). Health care providers who wish to assist their female cancer survivors who complain of diminished sexual desire should pay careful attention to the partner relationship and its quality, the woman's body image and mental health, as well as vaginal dryness and dyspareunia, which can provide aversive conditioning for engaging in sexual activity and thus decrease desire. Identification and modification of medications that are known to contribute to low desire can also be very helpful in these situations (e.g., opiates, selective serotonin reuptake inhibitors). Although not all clinicians will be prepared to provide counseling for all of the issues associated with sexual functioning, at a minimum they can identify the patient's needs and provide appropriate referrals. Management of vaginal dryness with nonestrogen or low-dose vaginal estrogen preparations may be an important first step that all clinicians can institute in their symptomatic patients ( 30 ).
Supported in part by The Breast Cancer Research Foundation and an American Cancer Society Clinical Research Professorship (to P. A. Ganz).
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