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EDITORIALS
Female Sexual Desire—Beyond Testosterone
Patricia A. Ganz, Gail A. Greendale
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.
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.
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
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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
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 protected]).
See “Note” following “References.”
DOI: 10.1093/jnci/djk175
© The Author 2007. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
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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).
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
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.
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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
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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).
References
(1) Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States:
prevalence and predictors. JAMA 1999;281:537–44.
(2) Basson R. Sexual desire and arousal disorders in women. N Engl J Med
2006;354:1497–506.
(3) Basson R. Female sexual response: the role of drugs in the management of
sexual dysfunction. Obstet Gynecol 2001;98:350–3.
(4) Basson R, Brotto LA, Laan E, Redmond G, Utian WH. Assessment and
management of women’s sexual dysfunctions: problematic desire and
arousal. J Sex Med 2005;2:291–300.
(5) Masters WH, Johnson VE. Human sexual response. Boston (MA): Little,
Brown, and Company; 1966.
(6) Kaplan HS. Disorder of sexual desire: the new sex therapy. New York
(NY): Brunner/Mazel; 1979.
(7) Cain VS, Johannes CB, Avis NE, Mohr B, Shocken M, Skurnick J, et al.
Sexual functioning and practices in a multi-ethnic study of midlife women:
baseline results from SWAN. J Sex Res 2003;40:266.
(8) 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;12:385–98.
(9) Ganz PA, Desmond KA, Belin TR, Meyerowitz BE, Rowland JH.
Predictors of sexual health in women after a breast cancer diagnosis. J Clin
Oncol 1999;17:2371–80.
(10) Greendale GA, Petersen L, Zibecchi L, Ganz PA. Factors related to sexual
function in postmenopausal women with a history of breast cancer.
Menopause 2001;8:111–9.
(11) Basson R, Weijmar Schultz W. Sexual sequelae of general medical disorders. Lancet 2007;369:409–24.
(12) Rosen RC, Taylor JF, Leiblum SR, Bachmann GA. Prevalence of
sexual dysfunction in women: results of a survey study of 329 women
in an outpatient gynecological clinic. J Sex Marital Ther 1993;19:
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(13) Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz BE, Belin TR.
Fatigue in breast cancer survivors: occurrence, correlates, and impact on
quality of life. J Clin Oncol 2000;18:743–53.
(14) Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life
after breast cancer: understanding women’s health-related quality of life
and sexual functioning. J Clin Oncol 1998;16:501–14.
(15) Syrjala KL, Roth-Roemer SL, Abrams JR, Scanlan JM, Chapko MK,
Visser S, et al. Prevalence and predictors of sexual dysfunction in
long-term survivors of marrow transplantation. J Clin Oncol 1998;16:
3148–57.
(16) Barton DL, Wender DB, Sloan JA, Dalton RJ, Balcueva EP, Atherton PJ,
et al. Randomized controlled trial to evaluate transdermal testosterone in
female cancer survivors with decreased libido; North Central Cancer
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(17) Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR,
et al. Prospective evaluation of vitamin E for hot flashes in breast cancer
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(18) Goldberg RM, Loprinzi CL, O’Fallon JR, Veeder MH, Miser AW,
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(19) Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL,
et al. Venlafaxine in management of hot flashes in survivors of breast
cancer: a randomised controlled trial. Lancet 2000;356:2059–63.
(20) Ganz PA, Greendale GA, Petersen L, Kahn B, Bower JE. Breast cancer in
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(21) Thase MEM, Clayton AHM, Haight BRP, Thompson AHM, Modell JGM,
Johnston JAP. A double-blind comparison between Bupropion XL and
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Ganz PA. Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst 2000;
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(23) Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP,
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(24) 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 hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med 2005;165:1582–9.
(25) Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, et al.
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(26) Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot C, Rees M,
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(27) Basson R. Biopsychosocial models of women’s sexual response: applications to management of “desire disorders”. Sex Relat Ther 2003;18:
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(28) Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C,
Stefanick ML, et al. Risks and benefits of estrogen plus progestin in
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(29) Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, et al.
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Note
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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