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Low Sexual Desire - Is it All in Her Head? Pathophysiology, Diagnosis, and
Treatment of Hypoactive Sexual Desire Disorder
Article in Postgraduate Medicine · November 2010
DOI: 10.3810/pgm.2010.11.2230 · Source: PubMed
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© Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN – 0032-5481, e-ISSN – 1941-9260 1
Low Sexual Desire – Is it All in Her Head?
Pathophysiology, Diagnosis, and Treatment
of Hypoactive Sexual Desire Disorder
James A. Simon, MD, CCD,
NCMP, FACOG1,2
1
Department of Obstetrics
and Gynecology, George Washington
University,Washington,DC;2
Women’s
Health and Research Consultants,
Washington, DC
Abstract: Hypoactive sexual desire disorder (HSDD) is thought to be the most prevalent form
of female sexual dysfunction (FSD), affecting up to 1 in 10 US women. Hypoactive sexual desire
disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
Text Revision (DSM-IV-TR) as persistent or recurrent deficiency or absence of sexual fantasies and
thoughts, and/or desire for, or receptivity to, sexual activity, which causes personal distress or
interpersonal difficulties and is not caused by a medical condition or drug. This definition has
recently received criticism and recommendations for changes encompass the inclusion of duration,
intensity, and frequency, and the elimination of distress as a diagnostic criterion. More recently, it
has been suggested that arousal and desire be combined into one disorder for the upcoming DSM-V.
Causes of low desire include chronic medical conditions, medications, surgeries, and psychosocial
factors, but not necessarily increased age; both pre- and postmenopausal women can have HSDD,
although the frequency appears to vary by age. Sexual function requires the complex interaction
of multiple neurotransmitters and hormones, both centrally and peripherally, and sexual desire
is considered the result of a complex balance between inhibitory and excitatory pathways in the
brain. For example, dopamine, estrogen, progesterone, and testosterone play an excitatory role,
whereas serotonin and prolactin are inhibitory. Thus, decreased sexual desire could be due to a
reduced level of excitatory activity, an increased level of inhibitory activity, or both. A number
of validated self-report and clinician-administered instruments are available for assessing female
sexual function; however, most have been used primarily in clinical research trials. The Decreased
Sexual Desire Screener (DSDS) was developed for practicing clinicians who are neither trained
nor specialized in FSD to assist in making an accurate diagnosis of generalized acquired HSDD.
As our understanding of the pathophysiology of HSDD increases, it may become easier for physi-
cians to identify and treat women with low sexual desire.
Keywords: female sexual dysfunction; DSM-IV-TR; testosterone; flibanserin; HSDD
The Female Sexual Response
The female sexual response is thought to be a dynamic process influenced by
physiological,psychological,sociocultural,andinterpersonalfactors.1
Originally,Masters
and Johnson2
proposed the initial linear model of excitement/arousal, plateau, orgasm,
and resolution. In 1979, Kaplan3
added the concept of sexual desire and condensed the
model into 3 stages: desire, arousal, and orgasm. However, in the last decade, debate
around whether this linear model accurately represents the sexual response experience of
all women has grown. Research over the past several years has led to questions regarding
the definitions and diagnostic labels found in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR),4
and evidence to date
shows that many facets of women’s sexual function cannot be explained using the linear
model.5
An intimacy-based model in which women are motivated to seek sexual stimuli
and then experience responsive desire and arousal until satisfaction is reached has been
proposed by Basson in 2005.6
In this model, positive experiences reinforce intimacy
Correspondence: James A. Simon, MD,
CCD, NCMP, FACOG,
Clinical Professor,
Department of Obstetrics
and Gynecology,
George Washington University,
1850 M Street, NW, Suite 450,
Washington, DC 20036.
Tel: 001-202-293-1000
Fax: 001-202-463-6150
E-mail jsimon@jamesasimonmd.com

2 © Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN – 0032-5481, e-ISSN – 1941-9260
James A. Simon
and increase motivation whereas psychological and biological
factors modulate responsive desire and arousal.5,7
It is likely
that women may endorse different models of female sexual
function as representing their own sexual experience and based
on their own personal circumstances. For example, in a study
by Sand and Fisher,6
equal numbers of women endorsed the
Masters and Johnson,2
Kaplan,3
and Basson7
models, which
suggestsheterogeneityinthefemalesexualresponse,andGiles
and McCabe8
reported that women without sexual dysfunction
are more likely to identify with the linear model by Masters
and Johnson while women with sexual dissatisfaction or dys-
function are more likely to endorse Basson’s circular model.
Neurobiology of Sexual Response
Sexual response in women is thought to involve areas of the
brain stem and the cerebral cortex, including the hypothalamus
and the amygdala.9
Neuroimaging has revealed the involve-
ment of the limbic and paralimbic system, as well as the tem-
poral association area in mediating human sexual arousal.10–13
The temporal association areas process visual and attention
aspectsoferoticstimuli.10
Limbicandparalimbicareas,includ-
ing the amygdala, mediate emotional components of the sexual
response, whereas the hypothalamus and ventral striatum may
mediate physiologic components.11
A study of arousal levels in women with hypoactive
sexual desire disorder (HSDD) by Arnow et al14
is the first to
link HSDD with changes in the central nervous system. This
study used functional magnetic resonance imaging (fMRI)
to compare 16 women with HSDD with 20 women with no
history of sexual dysfunction. Subjective sexual arousal was
assessed, as was peripheral sexual response, using a vaginal
photoplethysmograph. Results showed subjective arousal to
erotic stimuli was significantly greater in women without
sexual dysfunction compared with women with HSDD. Both
groups showed increased brain activation in the precuneus,
fusiform gyrus, inferior temporal gyrus, and inferior occipital
regions. However, there were differences in the way the 2
groups encoded arousing stimuli which suggested that, com-
pared with women without female sexual dysfunction (FSD),
women with HSDD focused significantly more attention on
monitoring or overthinking their reactions, something that may
interfere with their normal sexual response.15
Central and Peripheral Effects
of Neurotransmitters and
Neuroendocrine Hormones
Several neurotransmitters influence sexual function, as evi-
denced by the number of centrally acting agents that cause
adverse sexual side effects. Dopamine appears to mediate
both sexual desire and subjective sense of arousal, and
sustains the drive to continue sexual activity once it begins.
Norepinephrine is the main neurotransmitter regulating
sexual arousal. The effects of both dopamine and norepineph-
rine on sexual functioning can be diminished by increasing
serotonergic neurotransmission (Figure 1A). Centrally acting
hormones include estrogen, which appears to be important in
desire and arousal; testosterone, which may influence desire
and drive initiation of sexual activity; and progesterone,
which mediates receptivity to partner approach. Additionally,
prolactin influences the excitement phase, with increasing
levels inhibiting arousal and sexual functioning, and oxy-
tocin, which may enhance sexual receptivity (Figure 1B).16
Peripherally, vasocongestion of clitoral tissue appears to
be positively mediated by nitric oxide (NO) and vasoactive
intestinal polypeptide (VIP). Adequate levels of estrogen and
testosterone are required for NO to initiate vasocongestion
with sexual stimulation. Serotonin plays a role in the initia-
tion of sexual arousal by effecting vascular tone and blood
flow, and affects orgasm by facilitating uterine contractions;
however, it can also interfere with sexual functioning by
reducing sensation, reducing adrenergic effects, inhibiting
NO synthase, and inhibiting orgasm by stimulating 5-HT2
receptors (Figure 1C; see Clayton 2003 for review).16
Diagnosis of Female Hypoactive
Sexual Desire Disorder
The DSM-IV-TR recognizes 4 distinct disorders of FSD:
female orgasmic disorder, female sexual arousal disorder,
sexual pain disorders, and sexual desire disorders, such
as HSDD.4
Hypoactive sexual desire disorder is defined
as persistent or recurrent deficiency or absence of sexual
fantasies and thoughts, and/or desire for, or receptivity to,
sexual activity, which causes personal distress or interper-
sonal difficulties and is not caused by a medical condition
or drug.4
Hypoactive sexual desire disorder can be classified
as lifelong or acquired, generalized or situational, or due to
psychological or combined factors. Distress is an integral part
of HSDD diagnosis. A diagnosis of HSDD requires a clini-
cal evaluation, taking into account factors that affect sexual
functioning, such as age and the context of the woman’s life.
Although HSDD is thought to be highly prevalent, many
women are reluctant to discuss sexual problems with their
physicians and other health care professionals, and many
physicians and other health care professionals are reluctant
to ask.17
Primary care providers, in particular, have little
experience with diagnosing and treating HSDD. As a result,

Hypoactive Sexual Desire Disorder
this condition remains under-recognized, underdiagnosed,
and undertreated.18
The acronym HSDD is poorly understood and even dis-
liked among clinicians, and the current DSM-IV-TR definition
of HSDD has been criticized.19–21
Recently there has been a
call for combining arousal and desire into one disorder.19–21
Recommendations for changes to the definition of HSDD
encompass inclusion of duration, intensity, and frequency, and
elimination of distress as a diagnostic criterion.19
The highly
contextual nature of women’s sexuality, the different models
of female sexual function, and the poor correlation between
subjective sexual arousal and objective measures, such as gen-
Figure 1. Central (A, B) and peripheral effects (C) of neurotransmitters and hormones on female sexual function.
Adapted from Psychiatr Clin North Am. 2003. Vol 26 (3), Clayton AH, Sexual function and dysfunction in women, 673–682. Copyright (2003), with permission from
Elsevier.

James A. Simon
ital vasocongestion,5
also need to be acknowledged. Finally,
there is disagreement about what constitutes low desire. For
instance, a woman may have a normal level of desire, but at
a lower level than her partner (desire discrepancy).
Furthermore, the concept of “distress” is not popular with
women, as it implies a state of fear/anxiety and a degree of
severity not reflected by their feelings. Many women describe
their key feelings in terms of low self-esteem, frustration,
confusion, dissatisfaction, concern, anger, embarrassment,
stress, depression, and a sense of being incomplete. Choos-
ing a more patient-friendly, nonpsychiatric term for HSDD
and its associated symptoms may improve patient–physician
communication.22
Epidemiology
Prevalence studies, such as the Women’s International Study
of Health and Sexuality (WISHeS)23
and Prevalence of Female
Sexual Problems Associated With Distress and Determinants
of Treatment Seeking (PRESIDE)24
studies described below,
are cross-sectional, population-based surveys and do not
include a clinical assessment, which is required for the diag-
nosis of HSDD.4
The prevalence rates obtained are thus not
representative of HSDD, but rather of low desire with distress.
Low sexual desire is believed to be the most prevalent
form of FSD,25,26
and appears to increase with surgical
menopause. Prevalence of distressing low sexual desire in
European (France, Italy, Germany, the UK) and US women
was investigated in the WISHeS study, a cross-sectional
study conducted in 1999 to 2000 involving . 4500 partici-
pants aged 20 to 70 years.23
Women were grouped into 4
arms: younger, surgically menopausal (20–49 years); older,
surgically menopausal (50–70 years); naturally menopausal
(50–70 years); and premenopausal (20–49 years). In the
European cohort, the prevalence of distressing low sexual
desire ranged from 7% in younger, premenopausal women to
16% in younger, surgically menopausal women.27
In the US
cohort, the prevalence of distressing low sexual desire was
14% in premenopausal women; 26% in younger, surgically
postmenopausal women; 9% in naturally postmenopausal
women; and 14% in older, surgically postmenopausal
women.23
In another cross-sectional study, 2207 women aged 30 to
70 years were stratified based on oophorectomy status and
age. Low sexual desire with distress was defined using the
Profile of Female Sexual Function (PFSF) and the Personal
Distress Scale (PDS). Prevalence of HSDD ranged from
6.6% in naturally menopausal women to 19.8% in younger,
surgically postmenopausal women.28
The largest population-based survey to date in the United
States, PRESIDE,24
included 31 581 women and assessed
decreased sexual desire using the Changes in Sexual Function
Questionnaire (CSFQ-14) and personal distress using the
Female Sexual Distress Scale (FSDS). The prevalence of
distressing low sexual desire was estimated to be 10% overall,
with the highest rate in women aged 45 to 64 years (12.3%).
The odds for distressing low sexual desire were approxi-
mately 20% higher in post- versus premenopausal women.
Decreased Sexual Desire and Age
The association between decreased sexual desire and aging
was assessed in a community-based, cross-sectional study
involving 3589 women in Europe and the United States.29
Women (aged 20–70 years) in sexual relationships completed
questionnaires that included 2 validated instruments (PFSF
and PDS) to assess decreased sexual desire and associated
distress. Among European women there was an age-related
increase in low desire, from 11% in the 20- to 29-year-old
group to 53% for those aged 60 to 70 years. In US women,
there was a nonsignificant trend toward an age-related
increase in low desire. In both European and US popula-
tions, the proportion of women who were distressed by low
desire decreased significantly with age. Despite reports that
a higher proportion of older women experience low desire,
distress over loss of desire does not appear to increase with
age and, therefore, the prevalence of distressing low sexual
desire does not change with increasing age.29
Such changes
with aging await confirmation, including a more compre-
hensive assessment of partner changes with aging and other
“external” factors.
Etiology
Low sexual desire can have a number of causes,5,9
including
1) medical conditions (eg, diabetes mellitus, congestive
heart disease, hypothyroidism, hyperprolactinemia, multiple
sclerosis, depression); 2) medications (eg, serotonergic
antidepressants, chemotherapy, antihypertensives); 3) medi-
cal therapies (eg, pelvic radiation); 4) surgical procedures
(eg, radical hysterectomies for cancer of the cervix involving
damage to the autonomic nerves); and 5) psychosocial fac-
tors (eg, past negative experiences, low sexual self-image,
lack of safety concerning birth control, sexually transmitted
disease, or emotional safety).
One of the most important psychosocial variables that
can affect a woman’s desire may be her relationship with
her partner. Low sexual desire leads to less sexual activity,
greater dissatisfaction with sex life and partner relationships,

and increased negative emotional states than normal desire.30
Women with decreased sexual desire have a negative attitude
toward partner interactions and greater severity of decreased
desire is associated with a worse partner relationship.27,31
Con-
sistent with these findings, results from WISHeS found that
compared with women with normal desire, women with low
sexual desire were 11 times more likely to feel dissatisfied with
their sex lives and 2.5 times more likely to feel dissatisfied with
their marriage or partner relationships.23
More than 80% of
women with decreased sexual desire felt concerned, unhappy,
or that they were letting their partner down, compared with ,
10% of women with normal levels of sexual desire.23,27
Psychometric Instruments
Accurate diagnosis of female sexual desire disorder depends
on the effective use of psychometric instruments, and a
standardization of tools in clinical studies is desperately
needed. A number of well-validated self- and clinician-
administered questionnaires are available, including the
Female Sexual Function Index (FSFI), a 19-item self-report
measure of FSD that scores on 6 domains of sexual function
(desire, arousal, lubrication, orgasm, satisfaction, and pain),
as well as a total score,32
and has been validated in women
with HSDD;33
the PFSF, a 37-item instrument, measures the
loss of sexual desire and related aspects of sexual function
in menopausal women with HSDD;28,34
the Sexual Interest
and Desire Inventory–Female Version (SIDI-F), a clinician-
administered tool to quantify the severity of symptoms in
women with HSDD,35,36
and the validated Women’s Sexual
Interest Diagnostic Interview (WSID), an assessment tool
designed to help clinicians identify HSDD in postmenopausal
women.36–38
Shorter questionnaires have also been developed
and validated for use in busy clinical practice, including the
brief version of the PFSF, developed using items from the
PFSF and the PDS and validated in HSDD,39
a 4-item HSDD
screener which can be paired with a face-to-face interview
by the primary care clinician to reliably screen for HSDD in
postmenopausal women,26
and the Decreased Sexual Desire
Screener (DSDS), a 5-item questionnaire developed for
practicing clinicians who are neither trained or specialized
in managing FSD. These brief diagnostic screening tools are
designed to assist clinicians in making an accurate diagnosis
of generalized acquired HSDD.40
The first 4 questions of
the DSDS, for example, assess components of FSD that are
specific for generalized acquired HSDD, asking:
1. In the past, was your level of sexual desire or interest
good and satisfying to you?
2. Has there been a decrease in your level of sexual
desire or interest?
3. Are you bothered by your decreased level of sexual
desire or interest?
4. Would you like your level of sexual desire or interest
to increase?
Question 5 asks about possible medical and/or psycho-
social factors that could be contributing to the woman’s cur-
rent decrease in sexual desire or interest, such as operations,
depression,injuries;medications,drugs,oralcohol;pregnancy,
recent childbirth, or menopausal symptoms; pain, decreased
arousal, or orgasm; her partner’s sexual problems; dissatisfac-
tion with her relationship or partner; and stress or fatigue. In
order to qualify for a diagnosis of HSDD using the DSDS,
questions 1 to 4 must all be answered with “yes” and all parts
of question 5 must be answered with “no.” A “yes” answer to
any part of question 5 would alert the clinician to discuss the
answer given with the woman and decide if a primary diagno-
sis other than generalized acquired HSDD was appropriate.40
Several psychometric instruments have been used to
measure sexually related personal distress in women with
HSDD. The validated FSDS, a 12-item self-rating instrument,
distinguishesbetweensexuallydysfunctionalwomenandthose
with no sexual dysfunction and effectively measures sexually
relatedpersonaldistressinwomenwithHSDD.41
Thevalidated
FSDS-R is identical to the FSDS except for the addition of
1 question that asks women to rate their level of distress related
to low sexual desire.25
The FSDS-R has the potential to be used
to assess the impact of drug treatment in patients with HSDD.
Treatment of HSDD
There are currently no approved pharmacotherapies for
HSDD outside of Europe, where the testosterone patch is
licensed only for use in surgically menopausal women who
also receive estrogen. There are also no official treatment
guidelines for HSDD; however, recommendations for the
management of women with desire and arousal disorders
were recently published as a result of the 3rd International
Consultation on Sexual Medicine (ICSM).42
Suggested
treatments include psychological therapy such as cognitive
behavioral therapy. However, randomized controlled trials
supporting the efficacy of this approach are lacking.42
Hormone Therapy
While the involvement of hormones in regulating sexual
function is well established in female rodents,43
the role in
humans has been the subject of much debate, particularly the

James A. Simon
roles of testosterone and estrogen. Peaks in female sexual
desire, fantasies, and activity around the time of ovulation
coincide with rising levels of progesterone and testosterone
as well as other hormones.44
Estrogens have vasodilatory
effects and increase vaginal, clitoral, and urethral blood
flow via NO synthase and VIP pathways, leading to genital
congestion and vaginal lubrication. Estrogens also modulate
sensory thresholds.45
Estrogen and androgens in combination
appear to enhance female sexual function.43,45
Estrogen
Several randomized controlled clinical trials showed a positive
effect of systemic estrogens on sexual function in naturally
menopausal women. A recent review concluded that systemic
estrogen treatments were associated with significant benefits
in some domains of menopausal sexual function, particularly
with transdermal delivery of estradiol, whereas local estrogens
are effective in the prevention of urogenital aging.46
Testosterone
Postmenopausal women have lower levels of testosterone
than premenopausal women, probably due to aging rather
than menopause itself, since testosterone levels in women
in their 40s are approximately half that of women in their
20s.47
However, currently available assays have made
it difficult to accurately measure testosterone levels in
women,48,49
and a large cross-sectional study failed to show
a significant relationship between testosterone levels and
female sexual function.50
Early studies established that
testosterone therapy improved sexual function—primarily
desire, arousal, and orgasmic response—in both naturally
and surgically induced postmenopausal women.48,51
In most
studies, testosterone was used in conjunction with estrogen.
Although testosterone therapy has not been approved in the
United States for the treatment of HSDD, off-label usage
does occur.
Hirsutism and acne are the 2 adverse events (AEs) most
often associated with testosterone therapy, but actual risks
are not well defined.51
Testosterone does not appear to have
adverse cardiovascular effects, with the possible excep-
tion that oral testosterone lowers high-density lipoprotein
cholesterol (HDL-C).52
It is not clear whether testosterone
therapy increases the risk of breast cancer or endometrial or
thromboembolic events.51
Transdermal patches and topical
gels/creams are preferred over oral products because first-pass
hepatic effects, including lower HDL-C and increases in sex
hormone-binding globulin, have been documented in treat-
ments with oral formulations.51,53
Transdermal Testosterone
The efficacy and safety of transdermal testosterone patches
(300 µg/day) in surgically menopausal women were inves-
tigated in 2 phase 3 trials. The Investigation of Natural
Testosterone in Menopausal Women Also Taking Estrogen
in Surgically Menopausal Women (INTIMATE SM1 and
SM2) enrolled 562 and 532 patients, respectively, with
HSDD who received concomitant oral/transdermal estro-
gen.54,55
The profiles of the Sexual Activity Log, PFSF, and
PDS were used to measure sexual function, with frequency
of satisfying sexual events (SSEs) as primary endpoint.
Both trials reported significant improvements in total SSEs
and in sexual desire and distress versus placebo. Safety and
tolerability were similar in the treatment and placebo groups;
however, in INTIMATE SM2, the incidence of androgenic
AEs was slightly higher with treatment versus placebo.
In a study of naturally menopausal women (INTIMATE
NM1), transdermal testosterone was investigated in 549
patients with HSDD who also received a stable dose of oral
estrogen with/without progestin.53
Women were randomly
assigned to 300 µg/day transdermal testosterone or placebo
patches twice weekly for 24 weeks. Significant improve-
ments were observed with testosterone versus placebo in
total SSEs and in sexual desire and distress. Significant
improvements were also seen in the testosterone group for
all secondary efficacy measures, including arousal, orgasm,
pleasure, reduced concerns, responsiveness, and body image.
Incidence of androgenic AEs was higher with testosterone
treatment, but the majority was of mild severity. Benefit
from testosterone therapy was found to be meaningful to
patients.56
In a study in premenopausal women, Goldstat et al47
investigated the efficacy of transdermal testosterone in 34
patients aged 30 to 45 years who reported low libido. In this
randomized, placebo-controlled, crossover study, testoster-
one cream 10 mg/day (or placebo) was applied for 12-week
periods separated by a 4-week washout period. Compared
with placebo, testosterone therapy resulted in significant
improvements in the composite scores of the Psychological
General Well-being Index (PGWB) and the Sabbatsberg
Sexual Self-Rating Scale. A mean decrease in the Beck
Depression Inventory score approached significance and
no adverse effects were reported.
Significant improvements were also seen in sexuality
and psychological well-being in postmenopausal women
treated with testosterone gels.48
The European Agency for
the Evaluation of Medical Products has approved the testos-
terone patch (300 µg/day) as a therapy for HSDD.

Testosterone Without Estrogen
A prospective, crossover study examined the effects of intra-
muscular testosterone on sexual function in 53 surgically
menopausal women randomized to testosterone alone, estro-
gen alone, testosterone plus estrogen, placebo, or control.
Results showed that testosterone significantly increased
intensity of sexual desire, arousal, and fantasy compared
with estrogen alone or placebo.57
A Phase III Research Study of Female Sexual Dysfunc-
tion in Women on Testosterone Patch Without Estrogen
(APHRODITE) investigated efficacy and safety of testos-
terone in 814 postmenopausal women with HSDD not on
concomitant estrogen therapy. Women were randomized to
receive a testosterone patch (150 or 300 µg/day) or placebo
for 52 weeks.58
The primary endpoint was the frequency of
SSEs. Secondary endpoints included sexual function using
the PFSF and distress assessed using the PDS. At 24 weeks,
there was a significantly greater increase in the frequency
of SSEs in the 300-µg/day group versus placebo (2.1 vs
0.7 episodes; P , 0.001).58
By week 24, 78% of sexual
episodes were satisfying in those women who received
300 µg testosterone compared with 65% in women receiv-
ing placebo. Both doses of testosterone were associated
with significant increase in desire and decreases in distress
versus placebo. Significant improvements were seen with
300 µg testosterone for all other secondary efficacy mea-
sures (eg, arousal, orgasm, pleasure, reduced concerns,
responsiveness, and self-image). The overall incidence
of AEs was similar among groups and most events were
mild and unrelated to treatment. Although an increase in
mild hair growth was seen in the testosterone 300-µg/day
group, these women were not more likely to discontinue
therapy. Breast cancer was diagnosed in 3 women in the
testosterone groups, although 1 woman reported the pres-
ence of symptoms before randomization. In the 300-µg/day
group, more women who had not undergone hysterectomy
(10.6%) reported vaginal bleeding than in the other groups,
but no cases of endometrial hyperplasia or carcinoma were
diagnosed.
Other Pharmacologic Approaches
Dehydroepiandrosterone (DHEA) is an androgen that is
classified as a prohormone, as it can be converted into a
number of biologically active steroids (eg, testosterone and
estrogen) via the traditional androgen/estrogen synthetic
and metabolic pathways. DHEA production declines with
age; however, evidence for its efficacy in sexual function-
ing is conflicting.59
Drugs Affecting Peripheral Vasocongestion
Drugs that facilitate erection in men have been investigated
in women with HSDD, with the rationale that sexual arousal
in women involves peripheral vasocongestion similar to
penile erection. In general, trials of α-adrenergic blockers,
alprostadil, and phosphodiesterase inhibitors (PDEs) have
been unsuccessful in women.60
Failure of vasoactive drugs
to increase subjective sexual responsiveness in women is not
unexpected since numerous studies have failed to demon-
strate a consistent relationship between measures of genital
arousal and subjective sexual arousal in women.61
Agents with Serotoninergic or Dopaminergic Effects
Dopamine, norepinephrine, melanocortin, and oxytocin are
thought to have excitatory effects on sexual function, whereas
serotonin and prolactin may be inhibitory.62
Serotonin is
thought to be involved in the control of sexual drive.62
Anti-
depressant drugs with serotonergic effects are associated
with treatment-emergent decreases in sexual desire in up to
85% of men and 72% of women. These effects appear to be
mediated by 5HT2
-receptor activation, as drugs that have
antagonistic effects at 5HT2
receptors are not associated
with sexual desire dysfunction.63
In comparison, drugs that
act as 5HT1A
agonists appear to reverse treatment-emergent
sexual dysfunction. Flibanserin, a novel postsynaptic 5HT1A
agonist/5HT2A
antagonist, is currently under investigation
as a potential treatment for HSDD. Flibanserin was also
found to lower serotonin levels and increase dopamine and
norepinephrine levels in rat prefrontal cortex.64
Flibanserin
may, therefore, attenuate inhibitory serotoninergic function
and restore a more normal level of dopamine and norepi-
nephrine function.65
Two randomized, placebo-controlled trials (VIOLET and
DAISY) assessed the efficacy of flibanserin 100 mg/day in
women with generalized acquired HSDD.66
Efficacy data
from these 24-week trials were pooled and included 1378
women (flibanserin, n = 685; placebo, n = 693). Co-primary
endpoints were the change from baseline to study end (week
24) in the number of SSEs and the eDiary desire score. After
24 weeks, the number of SSEs increased by 1.7 from a
baseline mean of 2.8, compared with an increase of 1.0 with
placebo (P , 0.0001). Significant improvements with fliban-
serin were also observed in the eDiary desire score, which
increased by 9.0 from a baseline score of 11.6, compared with
an increase of 7.1 with placebo (P , 0.05). Flibanserin was
also associated with significant improvements in secondary
endpoints, such as the FSFI total score (increase with fliban-
serin vs placebo, 4.4 vs 2.5), the FSFI desire domain (0.9 vs

James A. Simon
0.5), the FSDS-R total score (–8.0 vs –4.8), and the FSDS-R
item 13 (–0.8 vs –0.5; all secondary endpoints P , 0.0001).66
Mirtazapine, an α-2 adrenergic, 5HT2
and 5HT3
recep-
tor antagonist, improves desire in women with depression
and existing sexual problems, although it may be associated
with new-onset desire problems in 20% of patients soon
after starting treatment.63
Bupropion, a dual norepinephrine/
dopamine reuptake inhibitor, appears to improve libido,
arousal, orgasm, and satisfaction in women with HSDD.67
Bremelanotide, a synthetic agonist at melanocortin receptors,
appears to have a positive effect on desire and arousal in pre-
menopausal women with female sexual arousal disorder.68
All
of these studies are exploratory or proof-of-concept studies
and further research is needed to establish the peripheral and
central roles of hormones and neurotransmitters, and their
interactive effects, in the female sexual response.
Conclusion
Despite the considerable prevalence of distressing low
desire in young women and its impact on their lives, this
condition remains under-recognized, underdiagnosed, and
undertreated. There are currently no approved pharmaco-
logical treatments in the United States, although a number
of promising agents—hormonal and nonhormonal—have
been studied. There is a need for better screening methods,
improved patient–provider dialog, and more available treat-
ment options. Improved understanding of the pathophysiol-
ogy of HSDD will enable physicians to better identify and
treat women for whom low sexual desire is a problem.
Acknowledgments
This work was supported by Boehringer-Ingelheim Pharma-
ceuticals, Inc (BIPI). Editorial assistance was provided by
Sue Cooper, PhD, and Linda Merkel, PhD, from Envision
Scientific Solutions, Inc., which was contracted by BIPI for
these services. The author meets criteria for authorship as
recommended by the International Committee of Medical
Journal Editors (ICMJE) and was fully responsible for all
content and editorial decisions, and was involved at all stages
of article development. The author received no compensation
related to the development of the article.
Conflict of Interest Statement
James A. Simon, MD, CCD, NCMP, FACOG discloses . . .
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