Sexual Dysfunction in Men Bashin and Basson 2015

CHAPTER
20
Sexual Dysfunction in Men
and Women
SHALENDER BHASIN • ROSEMARY BASSON
Human Sexual Response Cycle, 787
Physiologic Mechanisms of Human Sexual Response, 788
The Role of Testosterone in Regulating Sexual Function
in Men, 794
Physiology of Physical Sexual Arousal in Women: Genital
Congestion, 795
Physiology of Orgasm, 796
The Revised Definitions of Sexual Dysfunction in Men, 797
Current Definitions of Sexual Disorders in Women, 799
Sexual Dysfunction in the Context of Endocrine
Disease, 800
Assessment of Sexual Dysfunction, 804
Management of Sexual Dysfunction in Men, 807
Management of Sexual Dysfunction in Women, 816
KEY POINTS
• In contrast to the earlier sexual response model,
depicting a linear progression of discrete phases, current
research conceptualizes sexual response as a motivation/
incentive-based cycle comprising phases of physiologic
response. These phases of the cycle overlap and their
order is variable.
• In middle-aged and older men, sexual dysfunction is
often related to comorbid conditions, such as diabetes,
coronary artery disease, or a hormonal problem.
• Penile erection results from biochemical and hemodynamic events that are associated with activation of
central nervous system sites, cavernosal smooth muscle
relaxation, increased blood flow into cavernosal sinuses,
and venous occlusion.
• Corporal smooth muscle tone is regulated by transmembrane and intracellular calcium flux, which in turn is
regulated by potassium channels, connexin43-derived gap
junctions, and cholinergic, adrenergic, and noradrenergic
noncholinergic mediators, including nitric oxide.
• Testosterone regulates sexual thoughts and desire,
sexual arousal, attentiveness to erotic stimuli, and
sleep-entrained erections. Testosterone deficiency is a
treatable cause of hypoactive sexual desire in men.
• Selective phosphodiesterase 5 inhibitors are safe and
effective and have emerged as first-line therapy for men
with erectile disorder (ED).
• Sexual response is understood to be incentive based:
multiple reasons for sex motivate receptivity to sexual
stimuli that can be appraised as sexually arousing.
• Physical and subjective arousal may diverge. Women
complaining of low sexual arousal usually physically
respond to sexual stimuli in a laboratory setting. In
contrast, men with ED from endothelial or neurologic
deficit—the most common cause of men’s arousal
complaints—typically still experience mental sexual
arousal/excitement.
• Women’s sexual dysfunctions do not link to androgen
deficit.
• Psychological therapies predominate in the treatment of
women’s sexual dysfunctions with emerging evidence of
benefit from mindfulness-based cognitive therapy.
• About 10% to 15% of women have dyspareunia from
provoked vestibulodynia—a chronic pain disorder
associated with central sensitization of the nervous
system and occasionally precipitated by low-dose
combined contraceptives.
Endocrine disease and its treatment can frequently disturb
sexual function in men and women.1 In addition, patients
may believe, often incorrectly, that their sexual dysfunction must necessarily be due to hormonal imbalance and
seek management from endocrinologists.2 Patients consider their sexual lives to be important; recognizing the
importance of sexual function as a determinant of quality
of life, the World Health Organization declared sexual
health a fundamental right of men and women.
For much of human history, the common beliefs about
human sexuality were shaped largely by religious dogma,
whose vehemence was rarely justified by the scientific
evidence. Alfred C. Kinsey’s pioneering epidemiologic
investigations provided the first evidence of the considerable variability in sexual practices of American men and
women.3 Excellent epidemiologic surveys, such as the Massachusetts Male Aging Study (MMAS) by Feldman and associates4 and the National Health and Social Life Survey
(NHSLS) by Laumann and colleagues,5,6 using modern sampling techniques, revealed high prevalence rates of sexual
dysfunction among community-dwelling middle-aged and
older men. Ongoing and distressing sexual dysfunction
affects 10% of people; prevalence rates are even higher in
older men.2,6,7 Temporary or nondistressing dysfunction is
frequently reported by up to 40% of the population.
785
786
SECTION V Reproduction
William Masters and Virginia E. Johnson8 found that
both men and women display predictable physiologic
responses after sexual stimulation. These landmark descriptions of the human sexual response cycle by Masters and
Johnson provided the basis for a rational classification
of human sexual disorders8 (Fig. 20-1A). Sigmund Freud
ascribed sexual problems in adult men and women to
earlier difficulties in maturation of childhood sexuality and
development of parent-child relationships. Recent advances
in our understanding of the physiologic and biochemical
mechanisms of penile erection and the development of
mechanism-specific therapies for ED have largely supplanted Freud’s psychoanalytical theories. The 1980s and
1990s witnessed remarkable progress in our understanding
of the physicochemical mechanisms that lead to penile
tumescence and rigidity. It was recognized that penile erections are the result of cavernosal smooth muscle relaxation
Orgasm
and increased penile blood flow.9-11 The appreciation of
nitric oxide as a key vasodilator in the vascular smooth
muscle was a pivotal discovery, recognized later by awarding of the Nobel Prize in Physiology or Medicine to Robert
F. Furchgott, Louis J. Ignarro, and Ferid Murad. The recognition that nitric oxide caused cavernosal smooth muscle
relaxation by simulating guanylyl cyclase provided the
foundation for the discovery of highly effective oral therapies for the treatment of ED.
Historically, the classification and nomenclature for
sexual disorders were based on the Diagnostic and Statistical
Manual of Mental Disorders (DSM), which is primarily a
psychiatric nomenclature, reflecting the belief that sexual
disorders in men and women are psychogenic in their
origin.12 The DSM and several other expert groups updated
the definitions and classification of sexual disorders in the
early 1990s.12,13 In May 2013, the DSM-5 (5th edition)
Female
Plateau
Male
Excitement
Resolution
A
Multiple incentives for sex
Other rewards—
emotional intimacy,
increased well-being
Deliberate
attention to
stimuli
Sexual satisfaction
and absence of pain
Biologic
factors
Arousal:
Triggers/merges
with desire
B
Arousal:
Subjective
+ ANS response
Appraisal
of stimuli
Psychological
factors
Figure 20-1 A, Four phases of the human sexual response cycle, as postulated by Masters and Johnson. The resolution phase is prolonged considerably in men such that
men may experience refractoriness to further stimulation for varying lengths of time before they can achieve another orgasm. As discussed in the text, our views of the female
response cycle have evolved substantially since then (see B). B, Circular human response cycle of overlapping phases. It is being increasingly recognized that there is a lot
more complexity, circularity, and flexibility in the human sexual response than is reflected in Masters and Johnson’s original model (A). Human sexual response is depicted as
a motivation/incentive-based cycle of overlapping phases of variable order. A sense of desire may or may not be present initially: it can be triggered alongside the sexual arousal
resulting from attending to sexual stimuli. Psychological and biologic factors influence the brain’s appraisal of the sexual stimuli. Sexual arousal comprises subjective (pleasure/
excitement/wanting more of the same) and physical (genital and nongenital) responses. The merged desire and arousal influence the ongoing attention to and appraisal of
further sexual stimulation. The sexual and nonsexual outcomes influence present and future sexual motivation. ANS, autonomic nervous system. (B, Adapted from Basson R.
The female sexual response: the role of drugs in the management of sexual. dysfunction. Obstet Gynecol. 2001;98:350-352.)
CHAPTER 20 Sexual Dysfunction in Men and Women
further refined the classification and definition of sexual
disorders in men and women.14,15
The growing recognition that ED is commonly a manifestation of systemic disease and the availability of easy-touse therapeutic options, including oral and intraurethral
drugs, have duly placed sexual disorders in men within the
purview of the endocrinologist and the primary care provider. In middle-aged and older men, but less so for women,
sexual dysfunction is often related to comorbid medical
conditions.7,9,16-18 Sexual dysfunction can be a manifestation of serious underlying medical disease, such as a pituitary neoplasm, diabetes, or coronary artery disease.10,19 ED
may signal asymptomatic coronary artery disease.19,20 In
women, sexual dysfunction is more strongly linked to
mental health.20-22
The clinical definitions of sexual dysfunction, especially
in women, remain shrouded in debate. In women, there is
poor correlation between a clinician’s diagnosis of sexual
dysfunction and a woman’s perception of the problem.23
For instance, in one study,23 about 20% of middle-aged
women were given a diagnosis of sexual dysfunction even
though they reported no problem, whereas a similar
number did not receive a diagnosis of sexual dysfunction
but reported problematic sex.
This chapter describes the current conceptualization of
sexual response in men and women, the underlying pathophysiologic mechanisms, the sexual sequelae of various
endocrine disorders, and clinical assessment of sexual dysfunction and its management. Management strategies for
sexual dysfunction stemming from hormonal and nonhormonal factors are also outlined.
HUMAN SEXUAL RESPONSE CYCLE
The traditional model of human sexual response stemming
from the research of Masters, Johnson, and Kaplan envisioned a linear progression from desire to arousal to a
plateau of high arousal followed by orgasm/ejaculation,
followed by a phase of resolution (see Fig. 20-1A).8 In
marked contrast to this earlier model depicting a linear
invariable progression of discrete phases, recent research
conceptualizes sexual response as a motivation/incentivebased cycle comprising phases of physiologic response and
subjective experience.24-28 The phases of the cycle overlap
and their order is variable (see Fig. 20-1B). The motivations
and incentives for sex are multiple and varied. A wish
to both demonstrate and enhance emotional intimacy
between the partners is important for both men and
women. Depression is a major cause of reduced sexual
motivation in otherwise healthy persons and in those with
endocrine disease: repeatedly, comorbid depression has
been identified as a factor underlying increased sexual dysfunction in women with diabetes.26,29,30 Even in the absence
of clinical depression, low sexual interest is associated with
having more depressed and more anxious thoughts and
lower sexual self-image than that in control subjects. Endocrine disorders can markedly lessen sexual self-image especially when associated with altered appearances, infertility,
or ability to be gainfully employed.1,26,29,31
Sexual desire, as in lust or drive, is only one of many
reasons people engage in sex and may or may not be sensed
initially: desire can be triggered by the sexual excitement
(i.e., the subjective sexual arousal in response to sexual
stimuli).24,26,32,33 Some researchers posit that arousal and
desire occur exclusively in response to sexually relevant
stimuli and that any internal thoughts or fantasies may
also stem from something external. In both men and
women, the relationship between desire and arousal is vari-
787
able and complex, and both are often unable to separate
the two.34-36 This overlap of phases is in keeping with neuroimaging data of sexual arousal, which have led to the
concept that motivation is one facet of sexual arousal and
desire is one component of motivation.37 Many factors,
psychological and biologic, influence the brain’s appraisal
and processing of the sexual stimuli to allow or disallow
subsequent arousal.22,26,30,32-34,36-45 The sexual and nonsexual
outcomes influence future sexual motivation. The circle
depicted in Figure 20-1B may be partially or completely
repeated a number of times during any given sexual
encounter (i.e., there is true cyclicity).24 Variability is
marked between individuals and within a person’s own
sexual life, influenced by multiple factors, including stage
of life cycle, age, and relationship duration, and robustly
linked to mental health and relationship happiness.36
Even with sufficient sexual motivation and the presence of adequate stimuli, the arousal and pleasure may
not occur if attention is not focused.41 Review of the literature on sexual arousal in 2009 confirmed a central role
for attentional processes in facilitating the subjective and
also the physiologic components of sexual arousal.41
Sexual information is processed in the mind both automatically and consciously.42 The sexual nature of the
stimuli is processed by the limbic system, allowing genital
congestion (observed to be quick and automatic in women
and slower but still involuntary in men).42 Conscious
appraisal of the sexual stimuli and the contextual cues can
lead to subjective arousal.42-45 The latter may be further
increased by awareness of the genital congestion of arousal,
which is more accurately registered and more relevant
to men’s experience than to women’s.24 The subjective
arousal will also be cognitively appraised—for instance, is
this pleasurable and safe or is this shameful or likely to
have a negative consequence?42-45 Cognitions such as these
continually modify both the physiologic and subjective
responses.42,43
Focusing on nonerotic thoughts during sexual stimulation, generated possibly by anxiety as first suggested by
Barlow, is linked to having sexual problems.43 A recent
study of men and women in long-term relationships found
that women tended to report nonerotic thoughts about
their body image and the external consequences of sexual
activity, whereas men were more likely to report nonerotic
thoughts about problematic sexual performance.44 Both
the men and the women in that study had some nonerotic
thoughts about the emotional consequences of the sexual
activity.44 Regardless of content, the more frequent the
nonerotic thoughts, the more sexual dysfunction. Importantly, the more difficult it was to refocus back on an erotic
thought, the more this predicted sexual difficulty. This
research is clearly relevant to patients with endocrine
disease, which frequently has negative impact upon sexual
self-image and sexual functioning.26,29
Thus, the current conceptualization of men’s and
women’s sexual responses is in marked contrast to an
earlier model depicting a linear invariable progression of
discrete phases—from desire, to arousal, to a plateau of
high arousal, followed by orgasm/ejaculation, and finally
a phase of resolution.24,25,46 Women’s sexual dysfunction
typically involves lessened arousal and desire and lessened
frequency of orgasm, now reflected in the recently coined
sexual interest/arousal disorder appearing in the American
Psychiatric Association’s Diagnostic and Statistical Manual,
5th edition (DSM-5) (Table 20-1).14,15 Although the focus in
men has typically been on ED or premature ejaculation,
they too may experience a more generalized sexual distress
disorder affecting desire, erectile function, and ease of
orgasm.18,45
788
SECTION V Reproduction
TABLE 20-1
Current Definitions of Female Sexual Disorders
Female Sexual Interest/Arousal Disorder
Lack of sexual interest/arousal for a minimum duration of 6 months as
manifested by at least three of the following indicators:
1. Absent/reduced frequency or intensity of interest in sexual activity
2. Absent/reduced frequency or intensity of sexual/erotic thoughts or
fantasies
3. Absence or reduced frequency of initiation of sexual activity and
typically unreceptive to a partner’s attempts to initiate
4. Absent/reduced frequency or intensity of sexual excitement/
pleasure during sexual activity on all or almost all (approximately
75%) sexual encounters
5. Sexual interest/arousal is absent or infrequently elicited by any
internal or external sexual/erotic cues (e.g., written, verbal, visual)
6. Absent/reduced frequency or intensity of genital or nongenital
sensations during sexual activity on all or almost all (approximately
75%) sexual encounters
Female Orgasmic Disorder
At least one of the two following symptoms, which must have been
present for a minimum duration of approximately 6 months and be
experienced on all or almost all (approximately 75%) occasions of
sexual activity:
1. Marked delay in, marked infrequency of, or absence of orgasm
2. Markedly reduced intensity of orgasmic sensation
Genitopelvic Pain/Penetration Disorder
Persistent or recurrent difficulties for a minimum duration of
approximately 6 months with one or more of the following:
1. Marked difficulty having vaginal intercourse/penetration
2. Marked vulvovaginal or pelvic pain during vaginal intercourse/
penetration attempts
3. Marked fear or anxiety either about vulvovaginal or pelvic pain on
vaginal penetration
4. Marked tensing or tightening of the pelvic floor muscles during
attempted vaginal penetration
Bancroft and colleagues proposed dual control theories
for sexual appraisal both in men and women.47 Their
control model envisions a balance between sexual activation and sexual inhibition in an individual’s brain, with
this balance determining whether sexual stimulation leads
to arousal. A questionnaire was used to characterize the
specific factors associated with an individual’s sexual excitation and sexual inhibition. The latter items were identified as the threat of performance failure and the threat of
performance consequences (or both) in men, but in women,
relationship importance (reflecting the need for sex to be
within a specific type of relationship), concerns about
sexual function (worries and distractions about sexual
function), and arousal contingency (the potential for
arousal to be inhibited by contextual/situational factors)
were inhibiting factors.47
PHYSIOLOGIC MECHANISMS OF
HUMAN SEXUAL RESPONSE
Physiology of Desire and Arousal
Functional Brain Imaging of Sexual Arousal in Men
and Women
Although mainly focused on male sexual arousal in
response to visual sexual stimuli, functional neuroimaging
techniques have clarified some of the neural correlates of
sexual response.48-54 Review of some 73 published studies,
the majority focused on healthy male heterosexual volunteers, has led to a model that includes multiple facets of
sexual arousal.37 Brain imaging during sexual stimulation
engages complex circuitry with activation of brain regions
related to the different aspects of arousal while other brain
regions inhibitory to sexual arousal are deactivated.48-54
In keeping with the current circular model of sexual
response (depicting sexual incentives/motivations, information processing, overlap of arousal and desire, emphasis
on subjective as well as physiologic arousal, plus importance of reward), the model of sexual arousal emanating
from the neuroimaging data comprises cognitive, motivational, emotional, and autonomic components37 (see Fig.
20-1B). The cognitive component includes appraisal of
potentially sexual stimuli, focused attention on those
stimuli appraised as erotic, and imagery of actual sexual
activity. The activations of the right lateral orbitofrontal
cortex (OFC), of the right and the left inferior temporal
cortices, of the superior parietal lobules, and of areas
belonging to the neural network mediating motor imagery
(inferior parietal lobules, left ventral premotor area, right
and left supplementary motor areas, cerebellum) are considered to be the neural correlates of this cognitive component. The motivational component comprises the processes
that direct behavior to a sexual goal, including the perceived urge to express overt sexual behavior. Thus, the
motivational component is conceptualized as including
the experience of sexual desire. Neural correlates are
thought to involve the anterior cingulate cortex (ACC),
claustrum, posterior parietal cortex, hypothalamus, substantia nigra, and ventral striatum. The emotional component is the brain activity underlying the pleasure from the
mental excitement and the perception of genital and other
physical responses. This pleasure comprises liking and
wanting.55 The left primary and secondary somatosensory
cortices, the amygdalae, and the right posterior insula are
conceived as neural correlates of this emotional component. The autonomic and neuroendocrine component
includes the various responses (e.g., genital, cardiovascular,
respiratory, changes in hormonal plasma levels) that allow
preparedness for sexual activity: activations in the anterior
cingulate cortex, anterior insulae, putamens, and hypothalamus may contribute to this component.
From studying the brain’s deactivations with sexual
arousal, three components of inhibition are suggested37:
1. Inhibition mediated by regions in the temporal lobes
and the gyrus rectus of the OFC in the resting state.
Patients with lesions in the gyrus rectus are noted to
have excessive appetite for sexual and other pleasurable
activities.56 This together with temporal lobe deacti­
vation is exemplified by the marked hypersexuality
of Klüver-Bucy syndrome.57 The deactivated temporal
regions are distinct from those activated in response to
visual sexual stimuli.
2. Inhibition of arousal once it has begun, to limit its
expression because the circumstances are inappropriate,
is mediated in the healthy caudate nucleus and putamen.
This is consistent with reports of hypersexuality associated with lesions in the head of the caudate nuclei.58
3. Activation of the left OFC is thought to undermine
sexual stimuli so as to limit their potential to arouse.
It is of interest that these regions thought to mediate inhibition of sexual arousal have been found to be activated
during tasks that require moral judgments and those that
involve guilt and embarrassment.
Future studies focusing more on women and on nonheterosexual persons are awaited. Of note, men generally
show greater responsiveness to visual sexually arousing
stimuli than do women.46 Moreover, the complexity and
CHAPTER 20 Sexual Dysfunction in Men and Women
variability of these systems was reflected in a study of surgically menopausal women who were sexually active but
were receiving no hormonal therapy.49 When these women
viewed erotica during functional magnetic resonance
imaging (MRI), they failed to display the brain activation
observed in premenopausal women or in themselves when
they were treated with testosterone and estrogen; yet, they
reported sexual arousal from the erotic videos, both without
and with hormonal supplementation.49
Functional imaging during penile or clitoral stimulation
to orgasm indicates that women show more activation in
left frontoparietal regions, notably in the posterior parietal
cortex and the supplementary motor area—regions associated with making a mental representation of another person’s actions.50 It is suggested that these findings may
reflect gender differences in perspective and empathy, and
that men and women use different cerebral strategies to
reach orgasm—the brain responses during the orgasm(s)
themselves being similar in men and women.50
Preliminary research has been published into functional
and structural neural correlates of persons with low sexual
desire. Reduced activation bilaterally in the entorhinal cortices and increased activation in the right medial frontal
gyrus and right inferior frontal gyrus and bilaterally in the
putamen was observed in women with DSM-IV hypoactive
sexual desire disorder (HSDD) as compared to control subjects in response to erotic videos.51 In keeping with the
motivation-based sex response cycle in which processing
of sexual information is crucial to subjective and physiologic response, the authors suggest that encoding of erotic
stimuli and retrieval of past erotic experiences (entorhinal
cortices) differed between the two groups. Additionally, the
increased activation in medial and inferior frontal gyri may
reflect increased monitoring of sexual responses, which is
well documented in women with HSDD. Studying gray
matter volume and white matter fractional anisotropy,
researchers recently identified changes in women with
HSDD as compared to control subjects.52 Whether this is
cause or effect of the sexual dysfunction remains unclear,
but the observed changes suggested HSDD to be linked to
attribution of reduced importance to sexual stimuli (amygdala and occipitotemporal cortex), reduced awareness of
sexual response (insula, anterior temporal cortex), and
altered attention to, and inhibition of, sexual responses
(anterior cingulate cortex, dorsolateral prefrontal cortex).52
Evidence of reversal of these changes with effective treatment is awaited. That structural changes associated with
chronic pain can reverse with therapy is encouraging and
suggests that anatomic as well as functional changes may
reflect rather than control experience.53
Brain imaging in hypogonadal men before and after
treatment suggests that the left OFC might exert a
testosterone-dependent inhibitory tonic control on sexual
arousal and that this control decreases upon visual sexual
stimulation.54 Also the response of the right anterior insula
to visual sexual stimulation was found to depend on the
level of plasma testosterone.54
Neurotransmitters and Hormones Involved in Sexual Desire
and Subjective Arousal
A variety of hormones and peptides are involved in
the sexual response. The interplay among androgens and
neurotransmitters is complex59-69: androgens influence
neurotransmitter release, and neurotransmitters may modulate androgen receptor signaling.46,61,63 The role of testosterone in desire and arousal is better documented in men
than in women.62,63 Serum levels of testosterone do not
correlate with women’s sexual function according to large
789
epidemiologic studies.63-66 The radioimmunoassays used to
measure testosterone concentrations in many epidemiologic studies were designed to measure the substantially
higher levels of testosterone in men and lacked the sensitivity, precision, and accuracy in the low range prevalent
in women. When a more sensitive mass spectrometrybased assay was used in a study of women with low desire
and low subjective arousal and women in a control group,
researchers found no difference in serum testosterone
levels between the groups.66 Additionally, it has been difficult to measure intratissue testosterone levels and activity.
Labrie and associates have proposed the measurements of
androgen metabolites—most notably androsterone glucuronide (ADT-G)—as markers of ovarian plus intracrine
androgen activity. Circulating ADT-G levels decrease with
age.67 Serum ADT-G levels did not differ significantly
between 121 women with low desire and 124 women
without low desire.66 Thus, a link between low desire and
low androgen activity as reflected by serum testosterone
levels or androgen metabolites has not been identified
to date.
Animal Models. In animal models, steroid hormones modulate sexual arousal by directing synthesis of the enzymes
and the receptors for a number of neurotransmitters,
including dopamine, noradrenalin, melanocortin, and oxytocin.59,60,68-71 Systems that act within the hypothalamus
and limbic regions of the brain are involved in the process
of arousal, attention, and sexual behavior. It is thought
that dopamine transmission in the medial preoptic area
(MPOA) and the nucleus accumbens focuses the person’s
attention on sexual stimuli (the incentives or motivations
for sexual activity). It is postulated that the behavioral pattern stimulated by those systems and the subjective feelings
that accompany them constitute the phenomenon commonly referred to as sexual desire or arousal when genital
sensations triggered by these systems are subjectively felt.
The main part of this neural pathway includes the MPOA
and its outputs to the ventral tegmental area. The latter
contains dopamine cell bodies that project to various limbic
and cortical regions, including the prefrontal cortex, the
nucleus accumbens, the anterior cingulate cortex, and the
amygdala.
Brain pathways for sexual inhibition include opioid,
endocannabinoid, and serotonin neural transmissions
feeding back to various levels of the excitatory pathways.60,61 It is thought that the behavioral pattern stimulated by the inhibitory pathways includes both sexual
reward and satiety refractoriness.
Exogenous opiates are sexually inhibiting independent
of their inhibitory effect on luteinizing hormone (LH),
LH-releasing hormone, and testosterone.70 Endogenous
opioids modulate the feedback effects of sex steroids on the
hypothalamus and pituitary.70 β-Endorphin is synthesized
in the anterior pituitary, the hypothalamus, and the
nucleus of the tractus solitarius in the brainstem. The
sexual inhibiting effects of opioids occur mainly through
their action in the MPOA and the amygdala.70 Low doses
of opiates can have facilitatory effects, possibly through
actions in the ventral tegmental area to activate the mesolimbic dopamine system. Exogenous opiates can induce an
intense feeling of pleasure, which has been likened to
orgasm, followed by a state of relaxation and calm.71
Melanocortins are derived from pro-opiomelanocortin
and modulate sexual response through a specific receptor
subtype, the melanocortin-4 receptor. Administration of
melanocortin receptor agonists has been associated with
an increase in spontaneous erections in healthy men and
in men with ED, and with increased desire, but not genital
responses, in women.72,73
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SECTION V Reproduction
Oxytocin levels increase close to orgasm. This hormone
is known to be involved in pair bonding in some animal
species, but its relevance in humans is unclear.
The physiologic role of prolactin in the human sexual
response remains uncertain.74-76 Because a generalized
reduction of dopamine activity in the hypothalamus results
in increased prolactin secretion, it has been difficult to
distinguish between the effects of raised prolactin itself and
the possible effects of the reduced dopamine transmission.
High levels of prolactin are associated with impaired sexual
function in men and women.70,76
The effects of the biologic factors are intertwined with
those of the environmental and social factors. For instance,
dopamine and progesterone, acting on their cognate receptors in the hypothalamus, can increase sexual behavior in
oophorectomized, estrogenized female rats, and the presence of a male animal alongside the cage can cause an
identical stimulation of the sexual behavior without the
administration of either progesterone or dopamine.77 In
rodents, birds, and fish, complex neural networks enable
the animal to assess the context of potential sexual activity
and relate it to past experience and to expectation of
reward.78
Men and women differ substantially with respect to the
correlation between genital congestion and subjective
sexual arousal (excitement). Whereas subjective arousal is
typically concordant with genital congestion in men, there
is a poor correlation between subjective arousal and measures of genital congestion in women.79 There are some
exceptions in men: sleep-related erections are mostly dissociated from erotic dreams or from subjective sexual
arousal.80 Also psychophysiologic studies have found that
men can get erections in response to films of assault or rape
while experiencing no subjective arousal.81 In contrast, a
psychophysiologic study identified some 25% of men in a
community sample with minimal penile response to an
erotic video while their subjective arousal was similar to the
remaining 75% of men with recorded penile congestion.
Devaluing
stimuli
Emotional
Pleasure from subjective
arousal and from
sensations including
genital congestion
Physiologic Mechanisms of Penile Erection
Penile Anatomy and Blood Flow
Genital Sexual Congestion and Arousal
Focused attention
Given the consistent finding of low sexual concordance in
women, a correlation with reduced interoception (awareness of nonsexual physiologic states, e.g., awareness of
heart rate) was suspected but not identified.82
In contrast to men’s typically accurate assessment of
their erections, women’s assessment of their degree of
genital congestion is less accurate. It is thought that genital
congestion in women is a prompt, automatic reflex that
occurs within seconds of an erotic stimulus; it may not be
deemed at all sexually arousing by the woman, or it may
even be deemed emotionally negative.83 Viewing primates
engaging in sexual activity subjectively arouses neither
young men nor young women.79 However, the young
women viewing primate sex display marked genital congestion, as measured by vaginal photoplethysmography
(VPP), whereas no genital response occurs in the men.
Similarly, heterosexual women viewing lesbian women
engaged in sexual activity report mostly low subjective
arousal but show a prompt vasocongestive response; in
contrast, heterosexual men viewing male same-sex activity
show minimal genital or subjective response.79
The erectile tissue of the penis consists of two dorsally
positioned corpora cavernosa and a ventrally placed corpus
spongiosum.10,11,84,85 The erectile tissue of both the corpora
cavernosa and corpus spongiosum is composed of numerous cavernous spaces separated by trabeculae.10,11,84,85 These
trabeculae are composed mainly of smooth muscle cells
that are arranged in a syncytium. Endothelial cells cover
the surfaces of the trabeculae.
The penile arterial blood supply is derived from pudendal arteries, which are branches of the internal iliac arteries
(Fig. 20-2). The pudendal artery divides into cavernosal,
dorsal penile, and bulbourethral arteries. The cavernosal
arteries and their branches, the helicine arteries, provide
blood flow to corpora cavernosa.10,11 Dilatation of the helicine arteries increases blood flow and pressure in the cavernosal sinuses.10,11,84,85
Censoring arousal
to prevent sexual
behavior
Cognitive
Appraisal of
sexual stimuli
Motivational
Expectation of
sexual and nonsexual
rewards
Desire triggered
Imagery of
sexual acts
Autonomic
Unconscious reflex
becomes a conscious
reinforcing stimulus
especially in men
Figure 20-2 Brain areas activated during sexual arousal allow (1) continued focus on sexual stimuli, imaging of sexual behavior, evaluation/censorship, and limitation or
prevention of actual behavior despite arousal (all constituting a cognitive component of arousal), (2) sexual feelings (an emotional component), (3) anticipation of reward (a
motivational component), and (4) an autonomic/neuroendocrine response of physical sexual arousal. (Adapted from Basson R, Weijmar Schultz W. Sexual sequelae of common
medical conditions. Lancet. 2007;369:409-424.)
CHAPTER 20 Sexual Dysfunction in Men and Women
791
TABLE 20-2
Innervation of the Penis
Types of Fibers
Location of
Neurons in the
Spinal Cord
Sympathetic
T10-L2
Parasympathetic
Somatic
S2-S4
S2-S4
Nerves Carrying the Fibers
General Function
Prevertebral outflow through the hypogastric and cavernous nerves;
additionally, paravertebral outflow through the parasympathetic
ganglia, and pudendal or pelvic and cavernous nerves
Cavernosal and pelvic nerves
Pudendal nerve
Generally antierectile; sympathetic
innervation plays an important role
in regulating seminal emission
Proerectile
Penile sensation, contraction of the
striated muscles during ejaculation
Penile Innveration
The neural input to the penis consists of sympathetic (T11L2), parasympathetic (S2-S4), and somatic nerves (Table
20-2).85 Sympathetic and parasympathetic fibers converge
in the inferior hypogastric plexus where the autonomic
input to the penis is integrated and communicated to the
penis through cavernosal nerves. In man, the inferior
hypogastric ganglionic plexus is located retroperitoneally
near the rectum.11,85
Several brain regions, including amygdala, MPOA,
paraventricular nucleus of the hypothalamus, and periaqueductal gray matter act coordinately to affect penile erections.85 The MPOA of the hypothalamus serves as the
integration site for the central nervous system control of
erections; it receives sensory input from the amygdala and
sends impulses to the paraventricular nuclei of the hypothalamus and the periaqueductal gray matter. Neurons in
paraventricular nuclei project onto the thoracolumbar and
sacral nuclei associated with erections.
The parasympathetic input to the penis is proerectile,
and sympathetic input is mainly inhibitory.85 The stimuli
from the perineum and lower urinary tract are carried to
the penis through the sacral reflex arc.85
Hemodynamic Changes During Penile Erection
Penile erection results from a series of biochemical and
hemodynamic events that are associated with activation of
central nervous system sites involved in regulation of erections, relaxation of cavernosal smooth muscle, increased
blood flow into cavernosal sinuses, and venous occlusion
resulting in penile engorgement and rigidity.10,84 Normal
penile erection requires coordinated involvement of intact
central and peripheral nervous systems, corpora cavernosa
and spongiosa, and normal arterial blood supply and
venous drainage.10,84
As cavernosal smooth muscle relaxes and the blood flow
to the penis increases, the increased pooling of blood in
the cavernosal spaces results in penile engorgement10,84
(Fig. 20-3). The expanding corpora cavernosa compress the
venules against the rigid tunica albuginea, restricting the
venous outflow from the cavernosal spaces.10,84 This facilitates entrapment of blood in the cavernosal sinuses,
imparting rigidity to the erect penis.
Biochemical Regulation of Cavernosal Smooth Muscle Tone
The tone of the corporal smooth muscle cells determines
the erectile state of the penis.10,11,84 When the cavernosal
smooth muscle cells are relaxed, the penis is engorged with
blood and erect. When the cavernosal smooth muscle cells
are contracted, there is predominance of sympathetic
neural activity, and the penis is flaccid.85
The smooth muscle tone in the corpora cavernosa is
maintained by the release of stored intracellular calcium
into the cytoplasm and influx of calcium through membrane channels.86-89 The transmembrane influx of calcium
in the cavernosal smooth muscle cells is mediated mostly
by L-type voltage-dependent calcium channels, although
T-type calcium channels are also expressed in cavernosal
smooth muscle cells.86-89 An increase in intracellular calcium
activates myosin light chain kinase resulting in phosphorylation of myosin light chain, actin-myosin interactions,
and smooth muscle contraction.89
The transmembrane and intracellular calcium flux in
the cavernosal smooth muscle cells is regulated by a
number of cellular processes that involve K+ flux through
potassium channels, connexin43-derived gap junctions,
and a number of cholinergic, adrenergic, and noradrenergic noncholinergic mediators (Figs. 20-4 to 20-6).86-94 The
nonadrenergic noncholinegic mediators include vasoactive
intestinal peptide (VIP), calcitonin gene–related peptide
(CGRP), and nitric oxide.94
Prostaglandin E1 (PGE1) binding to its cognate receptor
results in generation of cyclic adenosine monophosphate
(cAMP), which activates protein kinase A. Activated protein
kinase A stimulates K+ channels, resulting in K+ efflux from
the cell (see Fig. 20-4). The protein kinase A–mediated
processes also result in a net decrease in intracellular
calcium, favoring smooth muscle cell relaxation.
Adrenergic pathways, acting through norepinephrine
and α1-adrenergic receptors, activate phospholipase C,
which generates diacyl glycerol and inositol triphosphate
(IP3).89 Diacyl glycerol activates protein kinase C, which
inhibits K+ channels and activates transmembrane calcium
influx by activating L-type calcium channels (see Fig.
20-5).90,91 Inositol triphosphate increases intracellular
calcium by promoting the release of calcium from intracellular calcium stores.90,91 The net increase in intracellular
calcium promotes actin-myosin interactions, resulting in
smooth muscle contraction and a flaccid penis.
Potassium Channels. At least three types of potassium
channels—ATP-sensitive (KATP), voltage-gated (Kv), and
calcium-sensitive K+ channels (referred to as BKCa or maxi-K
channels)—are expressed in the cavernosal smooth muscle
cells.92,93 Of these, the BKCa channels are the most important, as they account for 90% of K+ efflux from the cavernosal smooth muscle cells. BKCa channel openers have been
shown to relax cavernosal smooth muscle cells in vitro.93
Thus, the strategies that increase BKCa channel expression
in vivo improve erectile capacity in diabetic and older
rodents93-95 and are being explored as therapy for ED. A
phase I human gene therapy trial using this approach has
shown the feasibility of this approach.95
Connexin43 Gap Junctions. The smooth muscle cells in the
corpora cavernosa are connected by connexin43 gap junctions that allow the ions and some signaling molecules
792
SECTION V Reproduction
Prostate
Cavernous nerve
(autonomic)
Deep dorsal vein
Dorsal artery
Dorsal nerve
(somatic)
Circumflex
artery
Dorsal
artery
Circumflex
vein
Tunica
albuginea
Dorsal nerve
(somatic)
Deep
dorsal vein
Sinusoidal
spaces
Circumflex
vein
Sinusoidal
spaces
Helicine
arteries
Helicine
arteries
Corpora
cavernosa
Trabecular
smooth muscle
Cavernous
artery
Flaccid
Erect
Subtunical
venular plexus
Figure 20-3 Anatomy and mechanism of penile erection. Corpora cavernosa are made up of trabecular spaces that are surrounded by cavernosal smooth muscle. Helicine
arteries provide the arterial supply to the cavernosal spaces. The dorsal nerve provides the sensory innervation to the penis. During erection, the relaxation of the trabecular
smooth muscle and increased blood flow result in engorgement of the sinusoidal spaces in the corpora cavernosa. The expansion of the sinusoids compresses the venous return
against the tunica albuginea, resulting in entrapment of blood, which imparts rigidity to the tumescent penis. (Adapted from Lue TF. Erectile dysfunction. N Engl J Med.
2000;342(24):1802-1813.)
such as inositol triphosphate to diffuse freely across smooth
muscle cells96 (Fig. 20-7). The ionic changes induced by a
stimulus in one smooth muscle cell are communicated
rapidly across other smooth muscle cells, resulting in
coordinate regulation of the entire corpora cavernosa.96
Thus, corpora cavernosa can be viewed functionally as
a syncytium of interconnected smooth muscle cells (see
Fig. 20-7).96
Nitric Oxide. Nitric oxide, derived from the nerve terminals
innervating the corpora cavernosa, endothelial lining of
penile arteries, and the cavernosal sinuses, is an important
biochemical regulator of cavernosal smooth muscle relaxation. Nitric oxide also induces arterial dilatation.97 The
actions of nitric oxide on the cavernosal smooth muscle
and the arterial blood flow are mediated through the
activation of guanylyl cyclase, the production of cyclic
guanosine monophosphate (cGMP), and the activation of
cGMP-dependent protein kinase (also called protein kinase
G, or PKG) (see Fig. 20-6). cGMP causes smooth muscle
relaxation by lowering intracellular calcium. There is some
evidence that nitric oxide inhibits Rho kinase–induced cavernosal smooth muscle sensitivity to calcium.98
Cyclic Nucleotide Phosphodiesterases. Cyclic nucleotide
phosphodiesterases hydrolyze cAMP and cGMP, thus reducing their concentrations within the cavernosal smooth
muscle. Of the 13 or more isoforms of cyclic nucleotide
phosphodiesterases that have been identified, isoforms 2,
3, 4, and 5 are expressed in the penis.99-106 Only phosphodiesterase 5 (PDE5) is specific to the nitric oxide/cGMP
pathway in the corpora cavernosa.99-106 Hydrolysis of
cGMP by this enzyme results in reversal of the smooth
muscle relaxation and reversal of penile erection (see Fig.
20-6). Sildenafil, vardenafil, and tadalafil are potent and
selective inhibitors of the activity of PDE5 that prevent
breakdown of cGMP and thereby enhance penile erection9,10 (see Fig. 20-6).
Regulation of Sensitivity to Intracellular Calcium by Rho A/Rho
Kinase Signaling. Recently, considerable attention has
focused on the role of Rho kinase in modulating the
sensitivity of cavernosal smooth muscle to intracellular
calcium.107 A growing body of evidence suggests that sensitization to intracellular calcium is regulated by the
balance between phosphorylation of the regulatory light
chain of myosin II by a myosin light chain kinase and its
dephosphorylation by a myosin light chain phosphatase
(Fig. 20-8).107-112 Phosphorylation of regulatory light chain
of myosin II is necessary for activation of myosin II adeno­
sine triphosphatases (ATPases) by actin, and its dephosphorylation prevents activation of myosin II ATPases.107-112
The ratio of the kinase to phosphatase activities is an
CHAPTER 20 Sexual Dysfunction in Men and Women
PGE1
793
NE
G
+
cAMP
+
PKA
+
–
K+
K+
[Ca2+]i
–
+
DAG
+
PKC
IP3
+
[Ca2+]i
K+
Ca2+
K+
Ca2+
+
Ca2+
Figure 20-4 Regulation of cavernosal smooth muscle contractility by prostaglandin
E1 (PGE1). Relaxation of the cavernosal smooth muscle is regulated by intracellular
3′,5′-cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP). These intracellular second messengers, by activating specific protein kinases,
cause sequestration of intracellular calcium (Ca2+) and closure of Ca2+ channels and
opening of potassium K+ channels. This results in a net decrease in intracellular Ca2+,
leading to smooth muscle relaxation. PGE1, by binding to PGE1 receptors, increases
the intracellular concentrations of cAMP, which activates protein kinase A (PKA). PKA
promotes the sequestration of intracellular Ca2+, inhibits Ca2+ influx, and stimulates
K+ channels. The net result is a decrease in intracytoplasmic Ca2+ and smooth muscle
relaxation. PGE1 stimulates cAMP generation. (Adapted from Bhasin S, Benson GS.
Male sexual function. In: De Kretser D, ed. Knobil and Neill’s Physiology of Reproduction, 3rd ed. Boston, MA: Academic Press; 2006:1173-1194; and Lue TF. Erectile
dysfunction. N Engl J Med. 2000;342:1802-1813.)
Ca2+
Figure 20-5 Regulation of cavernosal smooth muscle contractility by norepinephrine (NE), which mediates adrenergic signals, binds to adrenergic receptors, and
stimulates diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG stimulates
protein kinase C (PKC), which, along with IP3, causes an increase in intracytoplasmic
calcium (Ca2+) and inhibition of potassium (K+) channels. Increased intracellular Ca2+
causes cavernosal smooth muscle contraction and loss of penile erection. (Adapted
from Bhasin S, Benson GS. Male sexual function. In: De Kretser D, ed. Knobil and
Neill’s Physiology of Reproduction, 3rd ed. Boston, MA: Academic Press; 2006:11731194; and Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802-1813.)
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Sildenafil
PDE5
Tadalafil
Inhibitors
Vardenafil
NO
K+
–
GTP
5'-GMP
Guanylyl
cyclase
PDE5
cGMP
cGMP-dependent
kinases
Proteins
Phosphoproteins
Sequestration of
intracellular calcium
Smooth muscle
relaxation
Figure 20-6 Regulation of cavernosal smooth muscle relaxation by nitric oxide
(NO). Cyclic guanosine monophosphate (cGMP) regulates cavernosal smooth muscle
relaxation by promoting sequestration of cytoplasmic calcium. NO is released from
noradrenergic norcholinergic nerve endings and possibly from the endothelium. NO
activates guanylyl cyclase, which generates cGMP from guanosine triphosphate
(GTP), which in turn activates cGMP-dependent kinases, resulting in sequestration of
intracellular calcium and smooth muscle relaxation. cGMP is degraded by cyclic
nucleotide phosphodiesterases. Sildenafil, vardenafil, and tadalafil are selective
inhibitors of phosphodiesterase isoform 5 (PDE5), which is present in cavernosal
smooth muscles. (Adapted from Bhasin S, Benson GS. Male sexual function. In: De
Kretser D, ed. Knobil and Neill’s Physiology of Reproduction, 3rd ed. Boston, MA:
Academic Press; 2006:1173-1194; and Lue TF. Erectile dysfunction. N Engl J Med.
2000;342:1802-1813.)
Figure 20-7 The interconnection of cavernosal smooth muscle cells in the penis.
Connexin43-derived gap junctions connect adjacent corporal smooth muscle cells and
allow flow of ions among interconnected smooth muscle cells. Therefore, alterations
in action potential and potassium-channel activity in any myocyte affect the adjacent
myocytes. Ca2+, calcium ions; K+, potassium ions. (Adapted from Melman A, Christ
GJ. Integrative erectile biology: the effects of age and disease on gap junctions and
ion channels and their potential value to the treatment of erectile dysfunction. Urol
Clin North Am. 2001;28:217-230.)
794
SECTION V Reproduction
Myosin II RLC20
MLCK
Ca.CaM
Rho kinase
MLC
phosphatase
Inactive MLC
phosphatase
Myosin II RLC20-P
Cavernosal smooth muscle
contraction and sensitivity
to intracellular Ca2+
Figure 20-8 The role of Rho A/Rho kinase in regulation of cavernosal smooth
muscle sensitivity to intracellular calcium (Ca2+). Sensitivity to calcium and smooth
muscle contractility is regulated by the Rho A/Rho kinase system. The balance
between phosphorylation (P) of myosin regulatory light-chain (myosin II RLC20) kinase
and its dephosphorylation by a myosin light-chain (MLC) phosphatase is a major
determinant of the smooth muscle sensitization to Ca2+. By inhibiting the activity of
MLC phosphatase, Rho kinase, the downstream effector of Rho A, can regulate
smooth muscle responsiveness to calcium. Ca.CaM, calcium calmodulin. (Adapted
from Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle and nonmuscle myosin
II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003;83:
1325-1358.)
important determinant of the contractile sensitivity of the
cavernosal smooth muscle cell to intracellular calcium.109
Rho A is a guanosine triphosphatase (GTPase) of approximately 20 kDa that modulates Rho kinase activity, myosin
light chain phosphorylation, and calcium sensitivity in
smooth muscle cells.107 Rho A–GDP (guanosine diphosphate) complex is associated with a GDP dissociation
inhibitor (RhoGDI) in its inactive state. A number of intracellular signals can promote an exchange of GDP for GTP
on Rho A through the mediation of guanine nucleotide
exchange factors.107-112 The Rho A–GTP interacts with its
downstream effector Rho kinase,107-112 increasing the sensitivity of vascular smooth muscle to intracellular calcium
by inhibiting the myosin light chain phosphatases.
Although the Rho A/Rho kinase expression is not significantly different between young and older rats, the activity
of Rho kinase is higher in older rats than in young rats111;
the age-related increase in Rho kinase activity has been
proposed as one possible mechanism to explain the agerelated decrease in erectile capacity.111 Inhibition of Rho
kinase activity in experimental animals increases cavernosal smooth muscle relaxation and improves intracavernosal pressures and penile erections. Therefore, inhibitors of
Rho A/Rho kinase signaling promise to provide attractive
targets for the development of therapies for ED.111,112
Mechanisms of Ejaculation
The ejaculatory mechanisms consist of three processes:
emission, ejection, and orgasm.113-116 Although orgasm and
seminal fluid ejection often occur contemporaneously,
these two processes are regulated by separate mechanisms.
Emission, the deposition of seminal fluid into the posterior
urethra, is dependent upon the integrity of the vasa deferentia, seminal vesicles, prostate gland, and the bladder
neck.115,116 Ejaculation refers to the ejection of seminal fluid
containing sperm, and the secretions of seminal vesicles,
prostate, and bulbourethral glands from the posterior
urethra out through the urethral meatus, and is regulated
primarily by the central nervous system activation of the
sympathetic nervous system.115 This emission is ejaculated
out of the urethra by the contractions of the bulbospongiosus and levator ani muscles, the closure of the bladder
sphincter due to sympathetic activation, and synchronized
opening of the external urinary sphincter.111 The sensation
associated with the rhythmic contractions of these pelvic
floor muscles is referred to as the orgasm.
The stria terminalis, the posteromedial amygdala, the
subparafascicular thalamus, the MPOA of the hypothalamus, the periaqueductal gray matter in the midbrain
region, and the paragigantocellular nucleus in the pons
integrate seminal fluid emission and ejection during copulatory behavior117,118 (see Table 20-2). The paragigantocellular nucleus in the pons through serotonergic pathways
inhibits the lumbosacral motor nuclei that are involved in
ejaculation118,119; the input from the MPOA to paragigantocellular nucleus causes loss of this inhibition, resulting
in ejaculation.118,119 An ejaculation generator in the spinal
cord integrates the central and peripheral sympathetic and
parasympathetic signals to control ejaculation.113,118 The
parasympatheric fibers from the spinal ejaculation generator feed into the sacral parasympathetic nucleus and are
carried from there through the pelvic nerve and the major
parasympathetic ganglion into the seminal tract.118 Sympathetic fibers are carried from the spinal ejaculation generator into the dorsal gray commissure and intermediolateral
cell column and then through the lumbar sympathetic
chain, pelvic nerve, superior hypogastric plexus, and major
pelvic ganglion onto the seminal tract.118
Neural pathways that utilize serotonin (5-hydroxytryptamine, 5-HT) and dopamine as neurotransmitters play
an important role in regulating ejaculation.115 Thus, administration of selective serotonin reuptake inhibitors
(SSRIs) is being explored for the treatment of premature
ejaculation.117-120 At least 14 different serotonin receptor
subtypes have been identified in different brain regions;
5-HT1A somatodendritic receptors in the mesencephalic
and medullary raphe nuclei reduce ejacu­latory latency.113
A better understanding of the neurochemical mechanisms
that regulate ejaculation may provide mechanism-specific
targets for treatment of ejaculatory disorders.
THE ROLE OF TESTOSTERONE
IN REGULATING SEXUAL
FUNCTION IN MEN
Testosterone regulates many domains of sexual function
in men and women.1 Although androgen-deficient men
can achieve penile erections in response to visual erotic
stimuli, their overall sexual activity is decreased.121 Spontaneous but not stimulus-bound erections are testosteroneresponsive (Table 20-3).121 Testosterone promotes sexual
thoughts and desire54,121-127 and increases sexual arousal
and attentiveness to erotic auditory and other stimuli.122,123
Nocturnal erections, temporally related to peaks of nighttime testosterone secretion, are of lower amplitude and
duration in androgen-deficient men, and testosterone
therapy increases the frequency, fullness, and duration of
nocturnal penile tumescence.127,128 Maximum rigidity may
require a threshold level of androgen activity.129-133 Testosterone regulates nitric oxide synthase (NOS) in the cavernosal smooth muscle,130,131 exerts trophic effects on
cavernosal smooth muscle132 and ischiocavernosus and
bulbospongiosus muscles, and is necessary for the venoocclusive response.129-132 Androgen-deficient men show
delayed orgasm and low ejaculatory volume.1
Testosterone therapy in androgen-deficient men improves overall sexual activity, sexual desire, spontaneous
CHAPTER 20 Sexual Dysfunction in Men and Women
TABLE 20-3
Domains of Sexual Function Regulated by Testosterone*
Domains of Sexual Function That Have Been Shown to Improve in
Response to Testosterone Therapy of Androgen-Deficient Men
1.
2.
3.
4.
5.
6.
7.
Sexual desire
Spontaneous sexual thoughts
Attentiveness to erotic auditory stimuli
Frequency of nighttime and daytime erections
Duration, magnitude, and frequency of nocturnal penile erections
Overall sexual activity scores
Volume of ejaculate
Domains of Sexual Function That Have Not Been Shown to Improve in
Response to Testosterone Therapy or for Which There Is Insufficient or
Inconclusive Evidence
1. Erectile response to visual erotic stimulus
2. Erectile function in men who have normal or low-normal
testosterone levels
3. Therapeutic response to selective phosphodiesterase inhibitors
4. Ejaculatory dysfunction
5. Orgasms
*Testosterone administration in androgen-deficient men improves overall
sexual activity scores through its effects on specific domains of sexuality.
From Bhasin S, Enzlin P, Coviello A, et al. Sexual dysfunction in men and
women with endocrine disorders. Lancet. 2007;369:597-611, used with
permission.
sexual thoughts, and attentiveness to erotic auditory
stimuli; frequency of nighttime and daytime erections;
duration, magnitude, and frequency of nocturnal penile
erections; overall sexual activity scores; and the volume of
ejaculate.1,54,121-124,127-129,133-136 However, testosterone does
not improve erectile response to visual erotic stimulus121 or
erectile function in men with ED who have normal testosterone levels.133-136
Brain imaging studies suggest that processing of sexual
stimuli may be altered in androgen-deficient men with
decreased activation in those brain areas that typically are
activated in eugonadal men and in androgen-deficient
men after testosterone replacement in response to erotic
stimuli.54
Acting on dopaminergic receptors in the MPOA of the
hypothalamus, testosterone elicits reward-seeking behavior
in male mammals.60 This may be the basis for testosterone’s
motivational effects on mammalian sexual behavior.60 The
roles of cytochrome P450 (CYP19) aromatase and steroid
5α-reductase systems in mediating androgen effects on
sexual function remain incompletely understood.62 Recent
studies suggest that 5α-reduction of testosterone to
5α-dihydrotestosterone is not essential for mediating testosterone’s effects on desire or erectile function in eugonadal men.137 Recent investigations, including those in
men with mutations of the CYP19A gene suggest that aromatization to estradiol may be important in mediating
testosterone’s effects on sexual desire.138-140 Androgen deficiency and ED are two independently distributed disorders
that may coexist in middle-aged and older men.141-143 Selective phosphodiesterase inhibitors (PDE5Is) are highly effective first-line therapies for ED. However, one third of men
with ED do not respond to PDE5 inhibitors; some of the
men with ED who are PDE5 inhibitor nonresponders have
low testosterone levels. Observations that testosterone
stimulates penile NOS, increases penile blood flow, and has
trophic effects on cavernosal smooth muscle and bulbo­
spongiosus and ischiocavernosus muscles have led to speculation that testosterone therapy might improve erectile
response to PDE5 inhibitors.144-147 Spitzer and associates148
795
evaluated whether the addition of testosterone to sildenafil
improves erectile response in men with ED and low testosterone. In this randomized controlled trial, after optimization of sildenafil dose during an initial run-in period,
subjects were assigned randomly to 14 weeks of daily testosterone or placebo gel. Sildenafil plus testosterone was
not superior to sildenafil plus placebo in improving erectile
function in men with ED and low testosterone.148 In
another placebo-controlled trial (TADTEST) of men with
ED who were deemed tadalafil (Cialis) failures,149 the
primary analysis of all randomized subjects also did not
show a significantly greater improvement in erectile function in the testosterone arm than in the placebo arm.
However, in post hoc analysis, erectile function improved
with the addition of testosterone in a subset of men with
baseline testosterone of 10 nmol/L or less (300 ng/dL).149
Thus, randomized trials have failed to support the hypothesis that addition of testosterone to PDE5 inhibitor
improves erectile function in men with ED. Sildenafil alone
raises testosterone levels presumably because of its direct
effects on Leydig cell steroidogenesis.150
PHYSIOLOGY OF PHYSICAL
SEXUAL AROUSAL IN WOMEN:
GENITAL CONGESTION
A number of physical changes accompany women’s sexual
excitement (i.e., their subjective sexual arousal), including
genital swelling, increased vaginal lubrication, breast
engorgement, and nipple erection; increased skin sensitivity to sexual stimulation; changes in heart rate, blood
pressure, muscle tone, breathing, and temperature; and
mottling of the skin with a sexual flush of vasodilatation
over the chest and face.151 These changes are reflexive,
mediated by the autonomic nervous system. Within
seconds there is increased blood flow to the vagina: vasodilatation of the arterioles in the submucosal plexus that
increases transudation of interstitial fluid from the capillaries across the epithelium and into the vaginal lumen.151
Simultaneously, there is relaxation of smooth muscle cells
around the clitoral sinusoids, which promotes congestion.
MRI studies have confirmed the presence of extensive
clitoral tissue far beyond the visible portion of the clitoris.152 The clitoris comprises the head, the shaft, the rami
that extend along the pubic arch and the periurethral tissue
in front of the anterior vaginal wall, as well as the bulbar
tissue that surrounds the anterior distal vagina and is contiguous with the periurethral tissue.152 As the clitoris
becomes more swollen, it elevates to lie nearer the symphysis pubis. The vagina lengthens and dilates during
arousal, elevating the uterus. The labia become swollen and
darker red, and the lower third of the vagina swells.152
The autonomic nerves subserving the widespread genital
congestion are at risk from gynecologic surgeries that sever
the cardinal ligaments and the uterosacral ligaments to
potentially injure Frankenhauser’s nerve plexus and the
uterovaginal nerve plexus.153,154 Whereas intrafascial abdominal hysterectomy involves an incision and clamping
of the pubocervical fascia to sever the dense attachment of
cardinal and uterosacral ligaments, thereby interrupting a
major support system and nerve plexuses, intrastromal
hysterectomy does not involve cutting or clamping the
cardinal ligament, uterosacral ligament, or fascia. A 2013
study confirmed ongoing sexual satisfaction after this procedure.153 Transvaginal tapes for urinary incontinence may
also compromise the autonomic nerves between anterior
vaginal wall and bladder.154
796
SECTION V Reproduction
When increases in genital congestion in response to
visual erotic stimuli were recorded using vaginal photoplethysmography, the correlation between genital congestion
and subjective arousal are found to be highly variable.50,79
This is true in sexually healthy women and in women
reporting a lack of desire or arousal or sexual pain. Women
reporting chronic lack of arousal show prompt increases in
vaginal congestion, comparable to those in control women,
but report no subjective sexual excitement in response to
the erotic stimulation. Functional MRI studies show that,
unlike in men, activation of the areas organizing genital
vasocongestion in women does not correlate with subjective excitement.50,155
The neurobiology of the genital vasocongestive response
in women is complex and incompletely understood.
Involved is release of nitric oxide and VIP from the parasympathetic nerves.156 Acetylcholine, which blocks noradrenergic vasoconstricting mechanisms and promotes nitric
oxide release from the endothelium, is also released. There
is communication between the nitric oxide–containing
cavernous nerve to the clitoris and the distal portion of the
somatic dorsal nerve of the clitoris from the pudendal
nerve. Pelvic sympathetic nerves release primarily vasoconstrictive noradrenalin, adrenalin, and adenosine triphosphate (ATP), but some release acetylcholine, nitric oxide,
and VIP. The provoked anxiety in the laboratory situation
can increase the vasocongestive response of the genitalia to
erotic stimulation in sexually healthy women.83 The localization of NOS, cAMP, and cGMP-degrading PDE isoenzymes in human vaginal tissue is established, along with
recent identification of cAMP and cGMP-binding proteins.
The latter are co-localized with endothelial NOS (eNOS).
Close proximity to VIP-positive nerves suggests that cAMP
and cGMP work synergistically to control vaginal blood
flow.156 Neuropeptide Y (a vasoconstrictor), CGRP (possibly
influencing capillary permeability and sensation), and substance P (a sensory transmitter) also innervate the vaginal
microcirculation. The melanocortin-4 receptors and oxytocin also may be involved in clitoral and vaginal efferent
pathways.156
Intermittency of the vaginal microcirculation due to
contraction and relaxation of precapillary sphincters in
response to hypoxia and the release of metabolites (PCO2,
lactic acid, ATP), has been termed vasomotion. Vasomotion
is present in the nonaroused state but decreases within
seconds of a sexual stimulus, which increases arterial
supply to thereby recruit more capillaries and diminish
vasomotion: vaginal vasocongestion follows. Slow oscillations in vaginal blood flow, independent of vaginal vasocongestion, have recently been shown to correlate with
subjective arousal in healthy women and to be less marked
in women with arousal disorder.155
Increased blood flow to the submucosal vaginal capillaries results in increased interstitial fluid production, which
diffuses more quickly across the vaginal epithelial cells and
onto the lumen: the lubrication fluid in the aroused state
thereby contains less potassium and more sodium than in
the nonaroused state. How important the contribution of
permeability of the epithelial cells is to the process of lubrication is currently unclear. Relaxation of the vaginal wall
smooth muscle that enables the vagina to move up into
the pelvis is likely mediated by VIP.155
The clitoris is the most sexually sensitive area of the
body. Immunohistologic studies have identified neurotransmitters thought to be associated with sensation
(substance P and CGRP) that are concentrated immediately
under the epithelium of the glans clitoris. Nerve terminals
in the glans clitoris known as corpuscular receptors are
thought to be involved. They are mechanoreceptors, and
their density is variable but can be up to 14 times greater
than the density of similar receptors on the glans penis.157
The physiology of nongenital physical changes and their
correlation with subjective excitement remain poorly
understood.
PHYSIOLOGY OF ORGASM
Orgasm is a brain event, triggered typically by genital stimulation but also by sleep, stimulation of other parts of the
body (including breast and nipple), fantasy, certain medications, and in women with spinal cord injury, vibrostimulation of the cervix. Qualitative differences in orgasm,
depending on type of stimulation, are reported by some
women. Pilot echographic study suggests that vaginal stimulation involves all of the clitoral-urethral complex including the clitoral rami, whereas with clitoral stimulation (i.e.,
to the shaft and glans), anatomic/circulatory involvement
of the clitoral rami is not involved.151 Men report diminished orgasm intensity subsequent to loss of ejaculation
from radical prostatectomy.
Orgasm is a subjective experience in both men and
women, and it has been difficult to determine an objective
marker. In healthy men, there is the associated ejaculation
and, in both genders, involuntary (reflexive) muscular contractions of the striated perineal muscles.158 One objective
and quantitative measure has been established that shows
strong correspondence with the subjective experience of
orgasm. The researchers performed spectral analysis of
rectal pressure data while volunteers imitated orgasm, or
tried to achieve orgasm and failed, or experienced orgasm.158
The most significant and important difference in spectral
power between orgasm in both control tasks was found in
the alpha band. Outbursts of alpha fluctuations in rectal
pressure occurred only during orgasm.158
Positron emission tomography (PET) studies during
orgasm have shown largely similar brain activations and
deactivations in both men and women: activations mainly
in the anterior lobe of the cerebellar vermis and deep cerebellar nuclei and deactivations in the left ventromedial
and OFC. The only major difference between the genders
during orgasm itself was the activation in the periaqueductal gray matter in men.159,160 The lateral OFC is thought to
be involved in urge suppression and behavioral release,
whereas the medial parts encode hedonic experiences,
becoming activated with increasing satiation and subjective pleasantness and deactivated with feelings of satiety.
The medial OFC is part of the neuronal network that
includes the amygdala, whose deactivation during orgasm
is associated with a more carefree state of mind.159 More
recent PET scanning of the brain during orgasm with comparisons to failed attempts to reach orgasm, and also
comparisons to faking an orgasm, has been reported.160
Insertion of a rectal probe measured involuntary pelvic
muscle contractions to identify the occurrence and duration of orgasm. The variations in rectal pressure indicative
of orgasm correlated to widespread blood flow changes in
the prefrontal cortex.160,161 The researchers noted specific
orgasm-related changes in the mid/anterior OFC and
suggest that this fits with the proposed role of the midanterior OFC in the experience of pleasure. Failed orgasm
significantly enhanced left lateral OFC activity: orgasm was
not reached possibly due to excessive behavioral suppression. The researchers suggest that the orgasm-related OFC
dynamics may reflect one of the main features of orgasm
(i.e., the typical sense of loss of control). Prefrontal but not
temporal perfusion was inversely coupled to rectal pressure
fluctuations associated with orgasm. These changes in the
CHAPTER 20 Sexual Dysfunction in Men and Women
OFC (the dorsal and ventral prefrontal divisions) did not
show any clear association with arousal but only with these
indicators of orgasm. The researchers therefore concluded
that the decreased prefrontal cortex activity may be specific
to orgasm. Overall the findings of reduced prefrontal
metabolism during orgasm are in keeping with the critical
role of the prefrontal cortex in behavioral and emotional
control. It may be that successful prefrontal regulation is
key to reaching orgasm in keeping with experimental data
of exaggerated prefrontal activity with associated sexual
dysfunction.
Pontine control of female orgasm appears to center on
a localized region on the left side of the dorsolateral pontine
tegmentum recently termed the pelvic organ–stimulating
center.161 Another pontine area, the ventrolateral pontine
area, recently termed the pelvic floor–stimulating center, is
involved in organizing the pelvic floor–contractions during
orgasm and has direct projections to pelvic floor motor
neurons.
The role of oxytocin and prolactin in orgasm is unclear.
Both hormone levels increase at the time of orgasm: PET
scanning has confirmed increased pituitary blood flow in
women, but not in men, at the moment of orgasm.162 Both
hormones can cause uterine and vaginal smooth muscle
contraction, which may contribute to the sensations of
orgasm.
THE REVISED DEFINITIONS OF SEXUAL
DYSFUNCTION IN MEN
In May 2013, the DSM-5 provided an updated classification
and definitions of male sexual disorders.14 The salient differences of the new DSM-5 classification and definitions
from the DSM-IV are the following15:
1. DSM-5 includes only four male sexual disorders, as
opposed to six in the DSM-IV.15 The four sexual disorders are the following:
a. Male hypoactive sexual desire disorder
b. ED
c. Premature ejaculation
d. Delayed ejaculation
2. DSM-5 lists male HSDD as a separate entry.14,15 Male
orgasmic disorder has been renamed delayed ejaculation,
male ED has been changed to ED, and male orgasmic
disorder has been changed to delayed ejaculation. Premature ejaculation remains unchanged.
3. Male dyspareunia, male sexual pain, sexual aversion
disorder, and sexual dysfunction have been removed in
the DSM-5.14,15
4. Unlike DSM-IV, the DSM-5 includes the requirement
of experiencing the disorder 75% to 100% of the time
to make a diagnosis of sexual disorder. DSM-5 also
requires a minimum duration of approximately 6
months.14,15
5. DSM-5 requires that the sexual disorder must have
caused significant distress. The DSM-IV requirement of
“interpersonal difficulty” has been removed.14,15
6. DSM-5 added one new exclusion criterion: the disorder
should not be better explained by a “nonsexual mental
disorder or a consequence of severe relationship distress
or other significant stressors.”14,15
Male Hypoactive Sexual Desire Disorder
HSDD is the persistent or recurrent deficiency (or absence)
of sexual fantasies and desire for sexual activity that causes
marked distress and that is not better explained by another
797
disorder, direct physiologic effects of a substance (medication), or general medical condition.163-166 A diagnosis of
HSDD is appropriate only if the person reports distress
due to low sexual desire.163-166 Low sexual desire is not
necessarily pathologic, as low sexual desire may be an
appropriate adaptation to relationship and health-related
issues.163-166
HSDD is a multifactorial disorder that can result from
androgen deficiency, use of medications (SSRIs, antiandrogens, gonadotropin-releasing hormone [GnRH] analogues,
antihypertensives, cancer chemotherapeutic agents, anticonvulsants), systemic illness, depression and other psychological problems, other causes of sexual dysfunction,
or relationship and differentiation problems. Androgen
deficiency is an important, treatable cause of HSDD and
should be excluded by measuring serum total testosterone
levels.163-166
The incidence and prevalence of HSDD in the general
population are unknown. In studies of referred patient
populations, the prevalence has been estimated at 5% in
men and 22% in women.5-7,165-167 Prevalence increases with
age.165-167 HSDD often coexists with other sexual disorders,
such as ED, and may develop as a consequence of other
preexisting sexual disorders.165-167
Appropriate evaluation and treatment of HSDD are
important because evaluation may lead to detection of
treatable androgen deficiency. Also, hypoactive sexual
desire in one partner can strain the relationship between
sexual partners168 and lead to ED. Low sexual desire may
impede or reduce effectiveness of treatments for other
sexual dysfunctions.
Erectile Disorder
ED, previously referred to as impotence or male ED, is the
inability to attain or maintain an erection or to achieve
penile rigidity sufficient for satisfactory sexual intercourse.10,11,14,15 DSM-5 requires that the inability to attain
or maintain an erection should occur in 75% to 100% of
encounters over a period of at least 6 months.14,15 Sexual
dysfunction is a more general term that also includes libidinal, orgasmic, and ejaculatory dysfunction, in addition to
the inability to attain or maintain penile erection. The
epidemiologic surveys,4-6,167-175 including the MMAS4 and
the NHSLS,5,6 revealed a surprisingly high prevalence of ED
in men (see later). ED significantly affects quality of life of
both the affected individual and his partner. In one study,
ED had a negative impact on the sexual life of female partners, specifically on their sexual satisfaction and sexual
drive.168
Prevalence and Incidence
The best data on the prevalence of ED in men have
emerged from two cross-sectional studies that have
used population-based sampling techniques, namely the
MMAS4,169,172,173 and the NHSLS.6,7 The MMAS is a crosssectional as well as longitudinal, community-based epidemiologic survey in which 1709 men, 40 to 70 years of age,
residing in the greater Boston area, were surveyed between
1987 and 1989.4 This survey revealed that 52% of men
between the ages of 40 and 70 were affected by ED of
some degree; 17.2% of surveyed men reported minimal
ED, 25.2% moderate ED, and 9.6% complete ED.4,172,173
The NHSLS was a national probability survey of Englishspeaking Americans, 18 to 59 years of age, living in the
United States.6,7 This survey also revealed a high prevalence of ED in men; the prevalence of ED increased with
increasing age.6,7
798
SECTION V Reproduction
These two landmark studies and data from several other
studies are in agreement that ED is a common problem
worldwide.4,6,7,167-174 In the U.S. civilian population, the
prevalence of ED in men aged 20 to 39 years has been
estimated to be 5.1%, whereas prevalence in men aged 40
to 59 years was almost three times as high (14.8%). In the
MMAS, crude incidence of ED was reported at 25.9 cases
per 1000 person-years, although that study included only
men over the age of 40. ED has been estimated to affect 20
million to 30 million men in the United States alone and
150 million to 200 million men worldwide.172,173 The prevalence of ED increases with age; it affects fewer than 10%
of men younger than 45 years of age but 75% of men over
80 years of age.4 Men suffering from other medical problems, such as hypertension, diabetes, cardiovascular disease
(CVD), and end-stage renal disease, have a significantly
higher prevalence of ED than healthy men.4
There is a paucity of longitudinal data on the incidence
rates of ED in men. In the MMAS, the crude incidence rate
of ED in white men in the Boston area was found to be
25.9 cases per 1000 person-years.169 The incidence rates
increased from 12.4 cases per 1000 person-years for men
40 to 49 years of age to 29.8 cases per 1000 person-years
for men 50 to 59 years of age and 46.4 per 1000 person-years
for men 60 to 69 years of age.169 In another study, incidence
rates were derived from a survey of men seen at a preventive medicine clinic.7 This study found the incidence rates
of ED to be less than 3 cases per 1000 person-years among
men less than 45 years of age and 52 cases per 1000
person-years among men 65 years of age or older. These
studies suggest that there were 152 million cases of ED in
the world in 1995 and that 600,000 to 700,000 men in the
United States develop ED each year.172,173
Risk Factors for Erectile Disorder
The risk factors for ED include age, diabetes mellitus,
hypertension, smoking, medication use, depression, dyslipidemia, and CVD.4,9-11,175-185 Advancing age is an important risk factor for ED in men4,6,9-11: less than 10% of men
below the age of 40 and over 50% of men over the age of
70 have ED. In both the MMAS and the NHSLS, the prevalence of ED increased with each decade of life.4,6
Among the chronic diseases associated with ED, diabetes
mellitus is the most important risk factor. In the MMAS,
the age-adjusted risk of complete ED was three times higher
in men with history of treated diabetes mellitus than
in those without a history of diabetes mellitus.4,175 Fifty
percent of men with diabetes mellitus will experience ED
sometime during the course of their illness. In the MMAS,
treated heart disease, treated hypertension, and hyperlipidemia were associated with a significantly increased risk
of ED. Among men with treated heart disease and hypertension, the probability of ED was more than two times
greater for smokers than for nonsmokers.4-6,9-11 Smoking
also increases the risk of ED in men taking medications for
CVDs. Cardiovascular disorders, including hypertension,
stroke, coronary artery disease, and peripheral vascular
disease, are all associated with increased risk of ED. Physical
activity is associated with reduced risk of ED.184
Several reviews have emphasized the relationship of prescription medications and the occurrence of ED. In the
MMAS, the use of antihypertensives, cardiac medication,
and oral hypoglycemic drugs was associated with an
increased risk of ED.4 Thiazide diuretics and psychotropic
drugs used in the treatment of depression may be the most
common drugs associated with ED, simply because of the
high prevalence of their use. However, a variety of drugs,
including almost all antihypertensives, digoxin, histamine-2
receptor antagonists, anticholinergics, cytotoxic agents,
and androgen antagonists, have been implicated in the
pathophysiology of ED.4
Erectile Disorder as a Marker of Cardiovascular Disease
CVD and ED share common risk factors, such as diabetes
mellitus, obesity, hypertension, smoking, and dyslipidemia.176-184 ED precedes the symptoms of coronary artery
disease by 2 to 3 years and cardiovascular events such as
myocardial infarction or stroke by 3 to 5 years.176-184 ED in
men is associated with increased risk of death, particularly
fatality due to CVD.178 The presence of ED is a good predictor of subsequent coronary artery disease, especially in
younger men, independent of traditional coronary risk
factors, although it does not enhance the predictive ability
of models that include traditional risk factors, likely reflecting the common pathophysiologic mechanisms of ED and
coronary artery disease.179 Men reporting ED are 1.3 to 1.6
times more likely to experience a cardiovascular event
within 10 years than men without ED.176-184
Lower Urinary Tract Symptoms and
Erectile Disorder
Recent surveys have revealed an association of lower
urinary tract symptoms (LUTS) with ED185-191 even after
adjusting for age and other risk factors. The Cologne Male
Study and the Multinational Study of Aging Male revealed
that the presence and severity of LUTS is an independent
predictor of ED independent of age.186 LUTS and age are
stronger predictors of ED than all other risk factors, including diabetes, dyslipidemia, and hypertension. As LUTS and
ED are two common conditions in middle-aged and older
men, it is possible that this association reflects the coexistence of two highly prevalent conditions. However, there
is growing evidence that the two conditions may be mechanistically linked, as the biochemical mechanisms that
regulate bladder detrusor and cavernosal smooth muscle
function share many similarities.191,192 K+ channels, especially calcium-sensitive K+ channels (BKCa channels), Rho
A/Rho kinase signaling, L-type calcium channels, and gap
junctions are important mediators of both detrusor and
cavernosal smooth muscle contractility and relaxation.191,192
Increased myocyte contractility that characterizes both
bladder detrusor dysfunction and ED may be mechanistically related to increased Rho kinase activity, impairments
of K+ channel function,192 α-adrenergic receptor imbalance,
and endothelial dysfunction. Additional proposed hypotheses include increased sympathetic activity and autonomic
dysfunction, and alterations in nitric oxide generation or
protein kinase G activity in the detrusor and cavernosal
smooth muscles.191-193 Some therapies for LUTS such as
some types of surgeries and 5α-reductase inhibitors may
worsen sexual dysfunction. PDE5 inhibitors are being
investigated for the treatment of LUTS.192-195
Ejaculatory Disorders
Ejaculatory disorders include premature ejaculation, delayed ejaculation, retrograde ejaculation, anejaculation,
and painful ejaculation.113-116 Recent surveys have highlighted the high prevalence and clinical importance of
ejaculatory disorders.18,113-116,196,197 Although the availability
of oral PDE5 inhibitors has increased awareness of ED,
ejaculatory disorders are at least as prevalent and may be
even more prevalent than ED.18,197 Premature ejaculation,
defined as ejaculation associated with lack of or poor ejaculatory control that causes distress in one or both partners,
CHAPTER 20 Sexual Dysfunction in Men and Women
is the most prevalent sexual disorder in men 18 to 59 years
of age.6,18,197,198 The new DSM-5 definition has now added
a time requirement that the ejaculation must occur within
approximately 1 minute following vaginal penetration to
be deemed premature.14,15 Delayed ejaculation refers to a
man’s inability to ejaculate in a reasonable period that
interferes with sexual or emotional satisfaction and is
associated with distress.
Retrograde ejaculation is the failure of the semen to be
ejected out through the urethral meatus; instead the semen
is propelled backward into the urinary bladder.113-116 Retrograde ejaculation can be the result of autonomic neuropathy associated with diabetes mellitus; sympathectomy;
therapy with adrenergic antagonists, some types of antihypertensives, antipsychotics, or antidepressants; bladder
neck incompetence; or urethral obstruction. Retrograde
ejaculation due to diabetes-associated autonomic neuropathy is the second most prevalent ejaculatory disorder.113-116
Following transurethral resection of the prostate, the
bladder neck closure mechanism may be damaged. Patients
remain continent because of a second, more distal, continence mechanism that is present in the region of the
membranous urethra; however, many patients who have
undergone transurethral resection of the prostate experience retrograde ejaculation. Ejaculatory disorders can lead
to infertility among men.113-116
CURRENT DEFINITIONS OF SEXUAL
DISORDERS IN WOMEN
The currently recommended definitions for female sexual
disorders in the DSM-5 are shown in Table 20-1.14,15 A disorder is diagnosed only if there is clinically significant
distress or impairment. Disorders are identified as early
onset (lifelong) versus late onset (acquired). The sexual
dysfunction should not be more attributable to a nonsexual psychiatric disorder, to the effects of a substance (e.g.,
a drug of abuse, a medication), to a medical condition, or
to relationship distress, partner violence, or other significant stressors.14,15
Sexual Interest/Arousal Disorder
The definition addressing problematic desire merges sexual
interest (motivation) with arousal and focuses away from
initial/anticipatory desire.199,200 Increasing evidence suggests that desire ahead of and at the outset of sexual
engagement, although welcomed probably by both partners, is not mandatory for a woman’s sexual enjoyment
and satisfaction.25,27,28,201 It is the inability to trigger desire
and arousal during sexual engagement (as well as an
absence of desire initially) that constitutes disorder. Empirical support for the concept that arousal may precede
desire and the two then coexist is now strong and includes
data from older and younger women.26-28 Therefore,
merging of sexual and desire difficulties into one disorder
appears logical. However, validated questionnaires used to
assess sexual function are based on models of sexual
response in which desire is assumed necessary at the outset
of engagement. This is now acknowledged as a serious
limitation to research,202 and the prevalence of what is currently understood to be disorder is quite unclear.40,201-209
Studies that simply report “low desire and distress” indicate prevalence rates of about 10%, not increasing with
age.40,207 Risk factors include negative feelings for the
partner and mood disorders.204 Depression, either currently or in the past, and, in the absence of any diagnosed
799
depression, more depressive and anxious thoughts and
low self-esteem are found significantly more commonly
than in control women.40,207
Female Orgasmic Disorder
The prevalence of women’s orgasmic disorder is also
unclear, because many studies include women with low
arousal who rarely reach orgasm.20,40,207 Risk factors include
anxiety about the partner’s presence, fear of being vulnerable, fear of not being in control, and fear of intimacy.20
These factors often stem from childhood (nonsexual)
experiences.
Genitopelvic Pain/Penetration Disorder
The merging of former terms vaginismus and dyspareunia
has some merit. Some women report typical phobic avoidance of penetration such that a penile introital contact has
never been possible, and physical examination has to be
deferred until therapy enables a careful inspection and
ultimately a complete pelvic examination to be done.
When abnormalities other than the reflex muscle tightening are absent, then vaginismus was diagnosed. However,
often the condition is complicated. For example, the
woman gives a history of phobic avoidance and fear, and
subsequent examination confirms vaginistic reaction, but
once therapy allows a careful detailed introital examination, allodynia of the vestibule is confirmed. The diagnosis
then, prior to DSM-5, was vaginismus by history but provoked vestibulodynia (PVD) on examination.
Reported prevalence of sexual pain varies between 20%
and 35%.210-214 The most common form of pain with penetration, PVD, affects some 16% of mostly premenopausal
women, many of whom have had pain consistently from
first attempts at penetration.205 Risk factors for PVD include
some personality traits—perfectionism, reward dependency, fear of negative evaluation—as well as harm avoidance, hypervigilance for pain, higher levels of trait anxiety,
and shyness.205 For a small subset, vaginal candidiasis
appears to precipitate and maintain the condition.
Vaginismus is now included within genitopelvic pain/
penetration disorder.14 The term had described (phobic)
avoidance, involuntary pelvic muscle contraction, and
anticipation of, fear of, or the experience of pain—there
being no structural or other abnormalities on examination,
this having to be deferred until some therapy has begun.
Risk factors include depression, anxiety, social phobia,
somatization, and hostility. Some studies identify increased
catastrophic thinking in women with vaginismus compared with women without pain or women with other
forms of pain: moreover, women with vaginismus show
greater disgust propensity.205 Despite the theories, there is
no scientific evidence that vaginismus is secondary to religious orthodoxy, negative sexual upbringing, or concerns
about sexual orientation. Typically there is extreme fear of
vaginal entry, fear that harm will come from something
the size of a penis entering the vagina, and fear of damage
by vaginal delivery.
Persistent Genital Arousal Disorder
Not included in the DSM-5, but clinically an increasingly
common and poorly understood entity, is persistent genital
arousal disorder: spontaneous, intrusive, and unwanted
genital arousal (e.g., tingling, throbbing, pulsating) in the
absence of sexual interest and desire. Any awareness of
subjective arousal is typically, but not invariably, unpleasant. The arousal is unrelieved by one or more orgasms, and
800
SECTION V Reproduction
the feelings of arousal persist for hours or days.206 Prevalence is unknown and a broad range of symptoms is recognized, from mild (and perhaps pleasant) to intrusive,
highly distressing, and markedly interfering with life.
SEXUAL DYSFUNCTION IN THE
CONTEXT OF ENDOCRINE DISEASE
We will focus on sexual sequelae of endocrine disease and
its treatment, but in any given person nonendocrine factors
may be more important. These factors include psychological, relational, contextual, cultural, and nonendocrine
medical influences—especially depression, hypertension,
neurologic disease, and LUTS.20 For patients with chronic
disease, the disease itself, its treatment, its psychological
effects, plus interpersonal, personal, and contextual issues
affect sexual response.20
In healthy women, factors such as attitudes toward sex,
feelings for the partner, past sexual experiences, duration
of relationship, and mental and emotional health have
been shown to more strongly modulate desire and arousability than do biologic factors.20 Contrary to gender stereotypes, recent analysis of the 1035 sexually active adults
who participated in the NHSLS in 1992 showed that men’s
physical sexual pleasure was more closely linked to relational factors than was the case for women.6,40,168 Similarly,
in a recent international study of midlife and older couples,
men rated the importance of sex for closeness and intimacy
to their partner more highly than did their female partners.40 Qualitative research also suggests that men as well
as women note that positive self-esteem and feeling attractive enhance desire and arousal.40,168 Sexual context is also
important for both men and women.168
Endocrine Disorders and Sexual
Dysfunction in Men
Androgen Deficiency Syndromes
Androgen deficiency in men is a syndrome characterized
by a constellation of signs and symptoms associated with
consistently low testosterone levels due to disorders of
the testes, pituitary, or the hypothalamus.1,62 Androgen
deficiency can occur either because of primary testicular
dysfunction or as a result of disorders affecting the hypothalamus or the pituitary.62 Common causes of primary
testicular dysfunction include Klinefelter syndrome, uncorrected cryptorchidism, human immunodeficiency virus
(HIV) infection, orchitis, trauma, torsion, and radiation
and cancer chemotherapy.62 Secondary testicular dysfunction can result from systemic illness; excessive exercise;
recreational drugs, especially opiates, marijuana, cocaine,
and alcohol; pituitary and suprasellar tumors; hemochromatosis; hyperprolactinemia; and infiltrative disorders.
Exclusion of these secondary causes of hypogonadism
may then justify a diagnosis of idiopathic hypogonadotropic hypogonadism, which is a heterogeneous group of
disorders characterized by disordered GnRH secretion.62
The testosterone levels required to maintain sexual function are close to the lower limit of the normal male
range.64,135,140,215-217 Therefore, some men with pituitary
tumors may remain asymptomatic until their tumor has
grown substantially and testosterone levels have declined
to a level below this threshold.
Androgen deficiency is an important treatable cause of
male HSDD. Therefore, the men diagnosed with HSDD
should be evaluated for androgen deficiency by measurement of testosterone levels using a reliable assay, preferably
in an early morning fasting blood sample.62 Although ED
and androgen deficiency in men are distinct disorders
with separate pathophysiologic mechanisms, the two can
coexist in the same patient. Testosterone levels should be
measured in men presenting with any form of sexual dysfunction because androgen deficiency is treatable, and furthermore, androgen deficiency may be a manifestation of
another underlying disease, such as a pituitary tumor,
which may require additional evaluation and diseasespecific intervention.
Diabetes and Sexual Dysfunction in Men
Men with diabetes mellitus are at increased risk of ED,
retrograde ejaculation, and low testosterone levels. Peyronie disease is an important comorbid condition in older
diabetic men with ED.218-225 The men with diabetes have
significantly lower scores for sexual desire, activity, arousal,
and satisfaction,219-225 in part due to the medical and psychological factors associated with diabetes, such as the
variations in glycemic control, reduced energy, altered selfimage, and interpersonal difficulties regarding dietary compliance, glucose monitoring, and medications. Diabetes
also is associated with increased risk of low testosterone
levels.62,226-231 In population studies, sex hormone–binding
globulin (SHBG) and total testosterone are more strongly
associated with diabetes risk than free testosterone levels;
these data suggest that the observed association of testosterone with diabetes risk may be related to factors, such
as insulin sensitivity and inflammation, that regulate
SHBG.230,231
The prevalence of ED in men with diabetes increases
with age and has been as high as 75% in some studies. ED
in men with type 2 diabetes even without other risk factors
for coronary artery disease may signal silent cardiac
ischemia.231-235 Among men with diabetes, those with ED
are more likely to be older smokers with longer duration
of diabetes, poor metabolic control, untreated hypertension, and presence of neuropathy, microalbuminuria and
macroalbuminuria, retinopathy, CVD, diuretic treatment,
low testosterone levels, and psychological vulnerability.221-224
Increased physical activity and consumption of small
amounts of alcohol have been found to be protective. The
risk of ED generally increases with chronic elevation of
hemoglobin A1c.221
Endothelial and smooth muscle dysfunction, autonomic
neuropathy, and psychological and interpersonal issues
contribute to sexual dysfunction in men with diabetes.234,235
Endothelial dysfunction is evident in penile blood vessels
as well as in nongenital vascular beds.189 eNOS is reduced,
possibly due to overexpression of arginase or lack of nicotinamide adenine dinucleotide phosphate (NADPH), an
essential cofactor for NOS.235-240 Additionally, accumulation
of oxygen free radicals, including those from advanced
glycosylation end products (AGEs), quench nitric oxide
and attenuate the action of K+ channels.239,240 The reduction in NADPH is also associated with increased diacylglycerol and protein kinase C, and consequently, increased
smooth muscle contractility.237 An increased activation of
the Rho A/Rho kinase pathway may increase the sensitivity
of cavernosal smooth muscle to calcium.237 Autonomic
neuropathy affecting the pelvic nerves may lead to ED as
well as ejaculatory dysfunction.238
Retrograde ejaculation and partial ejaculatory incompetence affect up to one third of men with diabetes.241 Autonomic nerve damage in diabetes may be associated with
dysfunction of the internal sphincter so that all or a part
of the seminal fluid is propelled into the bladder.238 Partial
ejaculatory incompetence refers to the condition in which
CHAPTER 20 Sexual Dysfunction in Men and Women
ejaculatory emission remains intact but the expulsion
phase is inhibited; consequently, the semen trickles out of
the penis and the experience of orgasm is altered in quality.
Both ejaculatory problems may be a cause of infertility.
Sexual Dysfunction Associated With Therapies for Benign
Prostatic Hypertrophy
Benign prostatic hypertrophy is frequently associated with
LUTS and sexual dysfunction.185-191 Although treatment
with some α1-adrenergic receptor blockers can improve
erectile function, others, such as tamsulosin, are associated
with ejaculatory dysfunction.242,243 Treatment of men with
LUTS with 5α-reductase inhibitors has been associated with
increased risk of ejaculatory disorder, ED, and decreased
libido.244,245 Several surveys have reported the development
of sexual symptoms, including loss of libido, ED, and difficulty with ejaculation in a subset of young men who have
taken finasteride for alopecia246-249; these symptoms have
been reported to persist even after discontinuation of finasteride. Although the causative role of finasteride and the
pathophysiology of these symptoms remain to be established, it has been speculated that polymorphisms in
androgen receptor or other genes may render these individuals susceptible to off-target actions of finasteride.250
Hyperprolactinemia and Sexual Dysfunction
Hyperprolactinemic men often present with decreased
libido or ED; 75% of men with macroprolactinomas and
50% of men with microprolactinomas report reduced
desire or ED and almost all have subnormal nocturnal
penile erections.251-255 Hyperprolactinemia affects 1% to 5%
of men presenting with ED252; a fraction of these men have
prolactin-secreting pituitary adenomas.
Prolactin lowers testosterone levels through its inhibitory effects on GnRH secretion and on the pituitary
response to GnRH. Most, but not all, men with sexual
dysfunction and hyperprolactinemia have low testosterone
levels.251,252 Whether and how hyperprolactinemia directly
affects erectile function through target organ effects is not
well understood. Erectile function generally improves in
hyperprolactinemic men following treatment with dopamine agonists.254,255
Sexual Dysfunction in Patients With Thyroid Disease
Hypothyroidism has been associated with increased risk of
hypoactive sexual desire and ED.256-260 The exact prevalence
of sexual dysfunction in men with hypothyroidism is
unknown. Free testosterone levels are lower in hypothyroid men than in control subjects and become normal
after thyroxine replacement.256-260 Serum LH and folliclestimulating hormone levels are typically not elevated in
men with primary hypothyroidism.259 Hyperprolactinemia
is noted in a small fraction of hypothyroid men.259
Free testosterone levels are typically normal in men with
hyperthyrodism, but SHBG and estradiol levels are elevated, resulting in a high estradiol-to-testosterone ratio
and gynecomastia in some hyperthyroid men.258 Hyperthyroidism has been observed in a small fraction of men
with ED.260
Sexual Dysfunction in Men With Metabolic Syndrome
The men with metabolic syndrome have a higher prevalence of ED than men without the metabolic syndrome.261-264
The risk of ED is correlated with the number of identified
components of metabolic syndrome.260-264
801
Endocrine Disorders and Sexual Dysfunction
in Women
Thyroid Disease in Women
Both hyper- and hypothyroid states have been found to be
risk factors for sexual dysfunction, which mostly remits
with return to an euthyroid state.265-267 Studies are few and
small, and when mood is also assessed, comorbid depression is found to be associated with sexual dysfunction in
the context of thyroid disease.1,265 There is some evidence
that thyroid autoimmunity lessens sexual desire independent of altered thyroid status: euthyroid women with
Hashimoto thyroiditis may report persistent loss of
desire.265-267 One research group found women with nodular
goiter to have significantly more sexual dysfunction than
control subjects. This group also had the highest body mass
index.267
Hyperprolactinemia in Women
Hyperprolactinemia is associated with increased risk of
sexual dysfunction.76,268 Women with hyperprolactinemia
report greater overall dissatisfaction with sexual function
and lower scores for sexual desire, arousal, lubrication, and
orgasm domains than women with normal prolactin levels.
Prolactin inhibits GnRH pulses, attenuates gonadotropin
response to GnRH, and is associated with reduced ovarian
secretion of estrogen and androgen. Although menstrual
disturbance or infertility is more commonly the presenting
symptom of hyperprolactinemia, lower scores for sexual
function and desire have also been found in women with
hyperprolactinemia who have regular menses.268 However,
normal menstruation, younger age, and smaller prolactinoma size are more likely to be associated with normal
sexual function than the actual level of prolactin or testosterone.20 Sexual outcomes of treatment of hyperprolactinemic women with dopamine agonists have not been
well studied.
Diabetes in Women
Women’s sexual response and satisfaction may be compromised by diabetes-associated changes in their well-being,
mood, and self-image, especially if there is unwanted
weight gain, recurrent vaginitis from candidiasis, or imposed infertility.269-282 In addition, there may be a com­
promised neurovascular genital sexual response from
autonomic neuropathy or endothelial dysfunction and microvascular disease. In women with type 1 diabetes, sexual
dysfunction is mostly correlated to psychological factors
including depression, anxiety, and marital status.270,271,273,281
The results from a large prospective study of 625 women
with type 1 diabetes confirmed depression as the major
predictor of dysfunction.277
Most studies on women with type 2 diabetes are small,
but one larger study of 600 women with type 2 diabetes
confirmed only depression and marital status to be independent risk factors for sexual dysfunction.269 Although
sexual dysfunction has been associated with both type
120,270,274,277 and type 220,271-273,276,278 diabetes, not all studies
confirm an association.273,275,279
A recent meta-analysis280 that included 26 studies, 3168
women with diabetes, and 2823 control subjects confirmed
sexual dysfunction to be more frequent in women with
diabetes. Compared to women without diabetes, the
risk of sexual dysfunction was 2.27 and 2.49 times higher
in women with type 1 and type 2 diabetes, respectively.280
The risk for sexual dysfunction was nearly two times
higher for women with any form of diabetes. However,
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SECTION V Reproduction
postmenopausal women with any form of diabetes did not
demonstrate an increased risk of sexual dysfunction. The
increased prevalence of sexual dysfunction and lower
female sexual function index (FSFI) score in women with
diabetes may be related to body weight. This association
would be in keeping with other studies showing an increased
prevalence of sexual dysfunction in obese women281-283
and in women with metabolic syndrome.284,285 Unlike
the situation in men with diabetes, sexual dysfunction has
not been consistently associated with the presence of diabetic complications in the majority of studies. Type 1
diabetes may be associated with loss of genital sexual
sensitivity.286 Sexual dysfunction in women with diabetes
is complex, and the roles of body mass index, fat distribution, diabetic complications, insulin resistance, inflammation, CVD, relationship satisfaction, and depression remain
poorly understood.20,282,283
Pathogenesis of Sexual Dysfunction in Diabetes. Whereas
depression and obesity are the identified major etiologic
factors, in the individual woman, neurovascular complications of diabetes may be relevant.20,287,288 Autonomic and
somatic neuropathy may contribute to loss of genital
sexual sensitivity. When there is less engorgement of the
vascular sinusoidal tissue comprising the shaft, head, rami,
and bulbs of the clitoris, massaging the structures during
sexual stimulation will fail to elicit typical sexual sensations to compromise arousal and limit the experience of
orgasm.287,288
In animal studies, diabetes has been shown to impair
vaginal smooth muscle relaxation responses to the neurotransmitters, particularly VIP and nitric oxide.287 These
studies also report decreased clitoral and vaginal blood flow
to nerve stimulation, diffuse fibrosis of the clitoral and
vaginal tissues, as well as reduced muscular layer and epithelial thickness in vaginal tissue. Endothelial dysfunction
and reduced clitoral blood flow have been documented in
women with diabetes.288
Most studies have not found increased prevalence of
dyspareunia in women with diabetes. Diabetic women are
at higher risk of recurrent candidiasis, which may contribute to dyspareunia.289
Metabolic Syndrome in Women
Metabolic syndrome has been shown to have a deleterious
effect on women’s sexuality, independent of diabetes
and obesity.1,20,289,290 This negative effect seems to be
more prevalent in premenopausal than postmenopausal
women.1,20,289,290
Polycystic Ovary Syndrome
Limited research has shown that women with polycystic
ovary syndrome may be less sexually satisfied and may
regard themselves as less attractive than control subjects.291-294 The presumption is that obesity and androgenrelated symptoms may contribute to poor body image,
which may increase the risk of sexual dysfunction.1,282
Recent studies show little evidence that polycystic ovary
syndrome (as opposed to obesity) is a risk factor for sexual
dysfunction.294,295
Congenital Adrenal Hyperplasia
Nonclassic forms of congenital adrenal hyperplasia may
present with signs of hyperandrogenism in childhood or
adulthood, depending on the severity of the 21-hydroxylase
enzyme deficiency.296 The presenting features of 21hydroxylase enzyme deficiency may include menstrual
disorders such as amenorrhea, anovulation, hirsutism, or
oligomenorrhea with infertility.297 Limited research suggests that sexual functioning of women with nonclassic
21-hydroxylase deficiency is not different from that of
control subjects. However, women with classic congenital
adrenal hyperplasia may show gender-atypical behavior298;
in one study, male-typical role-playing in childhood correlated with reduced satisfaction with the female gender
role and reduced heterosexual interest in adulthood.299 Disturbed body image, repeated genital examinations, and
genital surgery may also affect sexual function in women
with congenital adrenal hyperplasia.298 Caring for these
women requires careful individualized treatment with
appropriate therapy for signs and symptoms of androgen
excess as well as psychosexual counseling.20
Pituitary Disease in Women
There is limited research on sexual function in women who
have deficiencies of various pituitary hormones. It is known
that most women with pituitary disease often report menstrual irregularity or problems with sexual function, including decreased sexual desire and problems with lubrication
or orgasm.76 Although women with hypopituitarism
have lower testosterone levels than healthy menstruating
women, the short- and long-term effects of testosterone
in women with hypopituitarism have not been well
studied.300,301 In one randomized trial of 51 women, testosterone therapy in women who were receiving estrogen
therapy was associated with some benefit in sexual function and mood, compared with placebo, but with a higher
frequency of androgenic side effects than placebo.302 The
effects of dehydroepiandrosterone (DHEA) on sexual function and mood in women with hypopituitarism are also
poorly understood.301
Adrenal Insufficiency in Women
In addition to the deficiency of cortisol and aldosterone,
women with adrenal insufficiency also have low levels of
testosterone and DHEA.1,303-312 Adrenal insufficiency in
women has been associated with low health-related quality
of life.308 However, a 2010 larger study comparing 174
women with Addison disease to 740 age-matched healthy
control subjects and to 234 women who had received a
risk-reducing bilateral salpingo-oophorectomy (BSO) demonstrated that despite subnormal levels of androgens and
androgen metabolites, the women with Addison disease
reported higher sexual pleasure and less discomfort with
intercourse than the normative control women.309 Clinical
trials of DHEA replacement in women with adrenal insufficiency have been small and mostly negative.1,303-307,310,312
An earlier small trial in women with primary or secondary
adrenal insufficiency reported greater improvements in
sexual interest and satisfaction and in mood for women
receiving DHEA compared with placebo303; however, four
subsequent studies did not find significant improvements
in sexual function.304-307 In 2009, a meta-analysis of 10
studies concluded that DHEA therapy in adrenal insufficiency may result in small improvements in health-related
quality of life and depression, but it had no effects on
anxiety or sexual well-being.312 Thus, there are insufficient
data to support the routine use of DHEA in women with
adrenal insufficiency.
Natural Menopause
A majority of women who discontinue postmenopausal
estrogen supplementation develop signs of vulvovaginal
CHAPTER 20 Sexual Dysfunction in Men and Women
atrophy, which is a risk factor for sexual dysfunction.210-214,313,314 However, symptoms from vulvovaginal
atrophy may remit spontaneously within 1 year; risk factors
for more severe symptoms are diabetes, younger age, and
low body mass index.214,313,314 The traditional notion that
maintaining sexual activity will prevent symptomatic vulvovaginal atrophy has been refuted.314 Subjective symptoms and objective signs of vulvovaginal atrophy correlate
poorly.315 Epidemiologic studies have not shown an increase
in the prevalence of dyspareunia with age.210-212 Clearly not
all postmenopausal women develop sexual symptoms of
estrogen deficiency: of 1525 women followed from age 47
to 54 years, the vast majority were not affected by the
major hormonal shifts.213 It is likely that multiple factors
contribute to sexual symptoms, including variations in the
intracrine production of estrogen from adrenal precursors,
the number and sensitivity of estrogen receptors, and the
degree of sexual arousal or excitement at the time of vulval
stimulation and vaginal entry.316-318 Psychological factors
rather than estrogen levels were shown to moderate symptoms when vulvovaginal atrophy is present.318
Most studies report a decrease in sexual desire with
advancing age319 that is not easily explained by hormonal
deficiency alone. Adaptive changes occur in the brain in
response to the reductions in circulating levels of sex hormones associated with age and menopause.320,321 Sex hormones are produced locally within the brain: in women,
steroidogenic enzymes and sex-steroid receptors in the
brain are upregulated in response to decreased circulating
levels of sex hormones.320,321 We do not know whether
there is biologic adaptation to reduced amounts of sex
hormones. In studies of age, menopausal status, and sexual
function, the postmenopausal state has generally been
negatively associated with desire mainly among women
who experienced low emotional intimacy with their partners. Similarly, the negative association between age and
sexual desire was particularly pronounced in women experiencing little intimacy.322
Surgical Menopause
Surgical menopause is a state of both androgen and estrogen depletion of sudden onset and has often been viewed
as a risk factor for sexual dysfunction. However, most
women undergoing bilateral BSO for benign clinical indications do not develop sexual dysfunction. Three pro­
spective studies found that women choosing BSO plus
hysterectomy for benign indications did not develop sexual
dysfunction over the next 1 to 3 years.323-325
A national survey of 2207 American women confirmed
an increased prevalence of distress about low sexual desire
in women with a recent BSO.319 Thus, in women undergoing nonelective surgery, the thematic context of bilateral
oophorectomy may impair sexual desire and function. For
example, women who are treated for malignant disease or
those who desire to preserve their fertility may experience
greater distress about low sexual desire after BSO than
those who undergo BSO for benign conditions. In the same
survey, both older and younger women with a relatively
recent BSO reported low sexual desire per se, as often as
age-matched subjects with intact ovaries.319 Despite their
continued hormonal deficit, women older than 45 years
who underwent oophorectomy before menopause had
fewer complaints of low desire than women of similar age
with intact ovaries.319
A recent study of 1352 women showed no difference in
the report of sexual ideation, sexual function, or sexual
problems between women who have had and women who
have not had bilateral oophorectomy.326 Having thoughts
803
about sex is less likely to be affected by contextual details
including the sexual relationship than is sexual function
or motivation for partnered sex.
The women who carry a BRCA mutation and undergo
BSO to lessen the risk of breast, ovarian, or fallopian tube
cancer mostly remain satisfied with their decision for
surgery.327 However, studies on sexual response are conflicting. Less sexual pleasure despite the use of local estrogen
to alleviate dyspareunia has been noted,328 whereas another
study comparing 234 women who had received a riskreducing BSO to 740 age-matched control subjects from
the general population demonstrated that the women with
risk-reducing surgery had greater sexual pleasure and less
dyspareunia than the normative control women.326,329
Aging-Associated Decline in Sex Hormone Precursors
in Women
From the middle 30s to the early 60s, a woman’s adrenal
production of precursor hormones—DHEA, androstenedione, and DHEA sulfate (DHEAS)—declines by 70%.65,67
However, the trajectories of decline in these precursor
steroids vary among women.65-67 The relationship of the
age-related decline in these circulating precursors to sexual
function remains poorly understood. On the population
level, variation in circulating levels of sex steroids and their
precursors is related to variation in the activities of ster­
oidogenic enzymes such as 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, 17,20-lyase, and aromatase and
to the variation in the plasma clearance of these hormones
and precursors. Labrie and associates have proposed that
the androgen metabolites, most notably ADT-G, may serve
as useful markers of ovarian as well as tissue production
and activity of androgens in women.67,316,330 A study of 250
women carefully evaluated for sexual dysfunction found
that ADT-G levels in the 124 control women were comparable to those in the 121 women with sexual dysfunction.66
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are a class
of ligands that bind estrogen receptor subtypes and induce
a unique profile of tissue-specific gene expression. Accordingly, each SERM may also be associated with a unique set
of clinical responses. Ospemifene has estrogen antagonist
action on breast and endometrium. Ospemifene, but not
raloxifene or tamoxifen, can ameliorate the genital sexual
symptoms of lack of estrogen.331 Limited research suggests
raloxifene and tamoxifen are not associated with sexual
adverse effects.
Hormonal Contraceptives
The estrogen in combined systemic contraceptives increases
SHBG and thus decreases available free testosterone. The
decrease in sexual desire and subjective arousability in some
women receiving oral contraceptives has been attributed to
the decrease in free testosterone levels. However, to date
low desire has not been associated with testosterone levels,
even when mass spectrometry methods are used.65,66 Hormonal contraceptives exert multiple psychological and biologic actions, some of which may positively affect sexuality,
for example, by reducing anxiety about unwanted pregnancy and diminishing dysmenorrhea.332
Androgen Insensitivity Syndrome
Research is very limited on sexual function in 46,XY
women with androgen insensitivity syndrome due to
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SECTION V Reproduction
mutations in the androgen receptor. Women with complete androgen insensitivity syndrome have a female phenotype with full breast development but variable shallow
vaginal development, which may require surgical intervention or progressive dilatation. Small cross-sectional studies
indicate healthy sexual response with orgasms and experience of self-stimulation and of intercourse.328,333-336 However,
these women are often confronted with complex psychosocial issues related to the mismatch between their genetic
sex and their gender role, the timing of diagnosis and
timing of disclosure to the woman, and infertility. Reduced
sexual confidence, self-esteem, and depression are noted in
these studies.
ASSESSMENT OF SEXUAL
DYSFUNCTION
Assessment of sexual function is an important part of the
general assessment of patients with endocrine diseases.
Open-ended, nonjudgmental questions such as, “Many
men with diabetes notice changes in their erections
or ejaculation—are you having any difficulties?” can facilitate further discussion of sexual problems. When sexual
problems are identified, sensitive and respectful inquiry
into their nature and the current and past sexual context
is necessary. Evaluating both partners together as well as
individually can often uncover problems that may not be
apparent in individual interviews (Table 20-4).
Evaluation of Men With Sexual Dysfunction
There are four important considerations in the evaluation
of men with HSDDs. First, an important initial step in the
evaluation is an interview of the couple to determine
whether the patient primarily has ED or a sexual desire
problem. Second, ascertain whether the couple has a relationship problem. Establish whether self-stimulation continues despite lack of desire for partnered sex. With the
availability of Internet sites, sex alone, possibly on a frequent basis, may allow sexual expression in spite of relationship difficulties. Third, general health evaluation is
necessary to exclude systemic illness, depression, and medication use. Last, testosterone levels should be measured to
exclude androgen deficiency because androgen deficiency
is an important treatable cause of HSDD.
The diagnostic workup of men with ED should start
with an evaluation of general health (Tables 20-4 and
20-5).10,11,337-342 The presence of diabetes mellitus, coronary
TABLE 20-4
Assessment of a Patient With Sexual Dysfunction
Assessment Questions
Questions Asked of One or Both Partners
Comments
1. Sexual problems and reason for presenting at this time
Ask patients to describe sexual problems in their own words; clarify further
with direct questions, giving options rather than leading questions, support
and encouragement, acknowledgment of embarrassment, and reassurance
that sexual problems are common
Are problems present in all situations? Which problem is most troubling?
2. Duration, consistency, and priority if more than one
problem is present
3. Context of sexual problems
4. Each partner’s sexual response in areas other than the
given problem area
5. Reaction of each partner
6. Previous help
Emotional intimacy between partners, activity or behavior just before sexual
activity, privacy, sexual communication, time of day and fatigue level, birth
control (adequacy, type), risk of STIs, usefulness of sexual stimulation,
sexual knowledge
Both currently and before the onset of the sexual problems
How has each reacted emotionally, sexually, and behaviorally?
Compliance with recommendations and effectiveness
Questions Asked of Each Partner When Seen Alone*
1. Partner’s own assessment of the situation
2. Sexual response with self-stimulation
3. Past sexual experiences
4. Developmental history
5. Past or current sexual, emotional, and physical abuse
6. Physical health, especially conditions leading to debility and
fatigue, difficulty with mobility (e.g., in caressing a partner,
performing self-stimulation), and difficulties with self-image
(e.g., from obesity, Cushing syndrome. hypogonadism)
7. Evaluation of mood
Sometimes it is easier to disclose symptom severity (e.g., total lack of desire)
in the partner’s absence
Also inquire about sexual thoughts and fantasies
Positive and negative aspects
Relationships to others in the home while growing up; losses, traumas, to
whom (if anyone) was the patient close; was he or she shown physical
affection, love, respect?
Explain that abuse questions are routine and do not necessarily imply
causation of the problems; it is helpful to ask whether the patient ever felt
hurt or threatened in the relationship and, if so, whether he or she wishes
to give more information
Specifically, ask about medications with known sexual side effects, including
SSRIs, SNRIs, β-blockers, narcotics, antiandrogens, GnRH agonists
A significant correlation of sexual function and mood (including anxiety and
depression) warrants routine screening for mood disorder using either a
questionnaire (e.g., Beck Inventory) or semistructured series of questions
*Items 3 through 5 of the single-patient interview may sometimes be omitted (e.g., for a recent problem after decades of healthy sexual function).
GnRH, gonadotropin-releasing hormone; SSNIs, selective serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors;
STIs, sexually transmitted infections.
Adapted from Basson R. Sexual dysfunction in women. N Engl J Med. 2006;354:1497-1506. Copyright ©2006 Massachusetts Medical Society. All rights
reserved.
CHAPTER 20 Sexual Dysfunction in Men and Women
TABLE 20-5
Directed Diagnostic Evaluation of Erectile Dysfunction
History
Ascertain Psychosexual History
The nature of sexual dysfunction: whether the primary problem is
decreased desire, erectile dysfunction, premature or delayed
ejaculation, or difficulty in achieving orgasms
The strength of marital relationship and marital discord
Depression
Stress
Sexual performance anxiety
Knowledge and beliefs about sexuality
Ascertain Risk Factors
The presence of diabetes mellitus, hypertension, hyperlipidemia,
coronary artery disease, end-stage renal disease, and peripheral
vascular disease
History of spinal cord injury, stroke, or Alzheimer disease
Prostate or pelvic surgery
Pelvic injury
Medications such as antihypertensives, antidepressants,
antipsychotics, antiandrogens, and inhibitors of androgen
production
The use of recreational drugs such as alcohol, cocaine, opiates, and
tobacco
Ascertain Factors That Might Affect Choice of Therapy and the Patient’s
Response to It
Coexisting coronary artery disease and its symptoms and severity
Exercise tolerance
The use of nitrates or nitrate donors
The use of α-adrenergic blockers
The use of vasodilators for hypertension or congestive heart failure
The use of foods (such as cranberry juice) or drugs (such as
erythromycin, protease inhibitors, ketoconazole, and itraconazole)
that might affect metabolism of PDE5 inhibitors
Physical Examination
Ascertain signs of androgen deficiency, such as loss of secondary sex
characteristics, eunuchoidal proportions, small testicular volume, or
breast enlargement
Genital and perineal sensation to evaluate neurologic deficit from
spinal cord lesion, previous stroke, or peripheral neuropathy
Blood pressure and postural change in blood pressure
Evaluate femoral and pedal pulses and evidence of lower extremity
ischemia
Penile examination to exclude Peyronie disease or other penile
deformities
Basic Laboratory Evaluation That Should Be Performed in All Men
With ED
Fasting blood glucose
Plasma lipids
Serum testosterone level
ED, Erectile dysfunction; PDE5, phosphodiesterase 5.
artery disease, peripheral vascular disease, hypertension,
stroke, spinal cord or back injury, multiple sclerosis, depression, or dementia should be verified. Information about
use of recreational drugs such as alcohol, marijuana,
cocaine, and tobacco; prescription medications, particularly antihypertensives, antiandrogens, antidepressants,
and antipsychotic drugs; and nonprescription over-thecounter supplements is important because almost a quarter
of all cases of impotence can be attributed to medications.
A detailed sexual history including the nature of relationships, partner expectations, situational erectile failure, performance anxiety, and marital discord needs to be elicited.
It is important to distinguish between inability to achieve
erection, changes in sexual desire, failure to achieve orgasm
and ejaculation, and dissatisfaction with the sexual rela-
805
tionship, as the etiologic factors vary with the type of
sexual disorder.
A directed physical examination should focus on secondary sex characteristics, the presence or absence of breast
enlargement and testicular volume; evaluation of femoral
and pedal pulses; neurologic examination to determine
the presence of motor weakness, perineal sensation, anal
sphincter tone, and bulbocavernosus reflex; and examination of the penis to evaluate any unusual curvature, palpable plaques, or superficial lesions.337-342
The laboratory tests in the evaluation of a man with
ED usually include measurements of hemoglobin, blood
glucose, blood urea nitrogen and creatinine, plasma lipid,
and testosterone levels.
Thus, the initial diagnostic workup in most men presenting with ED consists of general health evaluation;
evaluation of cardiovascular risk by the measurements of
blood glucose, plasma lipids, and blood chemistries; and
measurement of serum testosterone levels. Further evaluation using more invasive diagnostic testing is limited to
those men who do not respond to an empiric trial of oral
PDE5 inhibitors; these patients should be referred to a
specialist for detailed urologic evaluation.
Self-reporting questionnaires are useful because many
men with ED do not voluntarily come forward to their
physicians and state their sexual complaints for a variety
of reasons.337-340 The International Index of Erectile Function (IIEF), for example, is a multidimensional scale consisting of 15 questions that address relevant domains of
male sexual function, including sexual desire, intercourse
satisfaction, orgasmic function, and overall satisfaction337;
a short form is also available.340
The diagnosis of androgen deficiency should be made
only in men with consistent symptoms and signs and
unequivocally low early morning serum testosterone levels
that are below the lower limit of the normal range for
healthy young men (e.g., testosterone <300 ng/dL in some
laboratories) on at least two occasions.1,11,64 Initial eval­
uation is directed at excluding systemic illness, eating
disorders, excessive exercise, and use of medicines and
recreational drugs that can suppress testosterone levels.
The measurement of morning total testosterone level by a
reliable assay, such as liquid chromatography tandem mass
spectrometry (LC-MS/MS), using rigorously derived reference ranges, remains the best initial test.343-346 The advent
of LC-MS/MS, the availability of a testosterone calibrator
from the National Institute of Standards and Technologies
(NIST), and the institution of Hormone Standardization
Program for Testosterone (HoST) has greatly improved
the accuracy of testosterone assays and reduced interlaboratory variability among Centers for Disease Control and
Prevention (CDC)-certified laboratories.343-346
The measurement of free testosterone levels is useful in
men with suspected SHBG alteration due to genetic factors,
aging, obesity, diabetes, chronic illness, thyroid and liver
disease, and HIV or hepatitis B or C infection.347 Free testosterone levels should be measured using a reliable assay,
such as the equilibrium dialysis assay, in a laboratory that
has experience in performing this assay.64 Free testosterone
concentrations can also be calculated from total testosterone and SHBG concentrations.347 However, Zakharov and
colleagues348 have shown that the published linear law of
mass action equations based on a linear model of testosterone’s binding to SHBG in which one molecule of SHBG
binds one molecule of testosterone with a single binding
affinity constant are erroneous.348 These studies have
shown that testosterone’s binding to SHBG is a dynamic
multistep process that includes heterogeneity in circulating
isoforms of SHBG dimer, an allosteric interaction between
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SECTION V Reproduction
the two binding sites on SHBG such that the binding affinities of the two binding sites on SHBG are not equivalent,
and convergence to an energetically favored bound state
in which both sites are occupied.348 The free testosterone
levels computed using this dynamic multistep binding
with allosteric match closely the values measured directly
by equilibrium dialysis.348
In men found to be androgen-deficient, measurement
of LH levels helps distinguish between testicular (LH elevated) and hypothalamic-pituitary (LH low or inappro­
priately normal) defects.64 Men with hypogonadotropic
hypogonadism may require measurement of serum prolactin, serum iron, and total iron binding capacity; evaluation
of other pituitary hormones; and a pituitary MRI. The
diagnostic yield of pituitary imaging to exclude pituitary
tumor can be improved by selecting men whose total testosterone level is less than 150 ng/dL or who have panhypopituitarism, persistent hyperprolactinemia, or symptoms
of tumor mass.251,252
There is considerable debate about the usefulness and
cost-effectiveness of hormonal evaluation and the extent
to which androgen deficiency should be investigated in
men presenting with ED. Between 8% and 10% of men
with ED have low testosterone levels; the prevalence of
androgen deficiency increases with advancing age.216,349-351
The prevalence of low testosterone levels is not significantly different among men who present with ED and in
an age-matched population.141 These data are consistent
with the proposal that ED and androgen deficiency are
two common but independently distributed disorders.141
However, it is important to exclude androgen deficiency in
this patient population. Androgen deficiency is a correctable cause of sexual dysfunction, and some men with ED
and low testosterone levels will respond to testosterone
replacement. Androgen deficiency may be a manifestation
of serious systemic disease and may have additional deleterious effects on the individual’s health; for instance,
androgen deficiency might contribute to osteoporosis
and loss of muscle mass and function. In large studies,64
only a small fraction of men with ED and low testosterone
levels have been found to have space-occupying lesions
of the hypothalamic-pituitary region.251,252 In one large
survey, all of the hypothalamic-pituitary lesions were
found in men with serum testosterone levels lower than
150 ng/dL.252 Therefore, the cost-effectiveness of the diagnostic workup to rule out an underlying lesion of the
hypothalamic-pituitary region can be increased by limiting the workup to men with serum testosterone levels less
than 150 ng/dL.64
If the history, physical examination, and laboratory
tests do not identify medical problems needing further
workup, then a cost-effective approach is to prescribe a trial
of oral PDE5 inhibitor provided there are no contraindications (e.g., nitrate use).
Tests that evaluate the integrity of penile vasculature
and blood flow352,353 are not needed in most patients
with ED, are reserved for patients in whom the results of
these tests would alter the management or prognosis, and
should be performed only by those with considerable experience with their use. The penile brachial blood pressure
index is a simple and specific, but not a sensitive, index of
vascular insufficiency. It is rarely used today in the evaluation of ED.
Intracavernosal injection of a vasoactive agent such as
PGE1 can be useful as a diagnostic as well as a potential
therapeutic modality. This procedure can reveal whether
the patient will respond to this therapeutic modality and
can facilitate patient education about the procedure and
its potential side effects. Failure to respond to intracaver-
nosal injection can raise the suspicion of vascular insufficiency or a venous leak that might need further evaluation
and treatment.
Most men with ED do not need duplex color sonography, cavernosography, or pelvic angiography.10,11,341,342,352
For instance, angiography could be useful in a young man
with arterial insufficiency associated with pelvic trauma.
Similarly, suspicion of congenital or traumatic venous leak
in a young men presenting with ED would justify a cavernosography. In each instance, confirmation of the vascular
lesion might lead to consideration of surgery. Duplex ultrasonography can provide a noninvasive evaluation of vascular function.352
Nocturnal penile tumescence testing is not needed for
most patients being evaluated for ED and is recommended
only for a limited number of patients with a high clinical
suspicion of psychogenic ED or situational problems, or
to document preoperatively poor penile rigidity, or for
medical-legal reasons. Although recording of nocturnal
penile tumescence in a sleep laboratory for successive
nights can help differentiate organic from psychogenic
impotence, this test is expensive and labor intensive. The
introduction of portable RigiScan devices in 1985 has provided clinicians with a reliable means of continuously
monitoring penile tumescence and rigidity at home.353 It
is a multicomponent device that the patient wears at
bedtime for 2 to 3 nights. It has two wire gauge loops that
are placed around the base and tip of the penis that record
changes in penile circumference and rigidity. Data are
stored and downloaded via a software program that allows
for interpretation. For most cases, a careful history of
nighttime or early morning erections provides a reasonable
correlation with nocturnal penile tumescence and RigiScan
studies.353
Evaluation of Women With
Sexual Dysfunction
Sexual dysfunction is diagnosed by clinical interview and,
when necessary, physical examination. Sexual function
questionnaires can be used to monitor treatment.354-356
One such instrument is the FSFI.354,355 Despite the original
intention of such questionnaires to monitor treatment
progress, they are frequently (mis)used to diagnose sexual
dysfunction in women who have not been clinically
assessed. Moreover, the FSFI is based on the DSM-IV criteria of sexual disorders, which are grounded in the conceptualization of female sexual response beginning with
conscious desire leading to a phase of arousal, then orgasm,
and then resolution, these phases being in set order, discrete, and necessary for normal function. The limitations
of the FSFI include the lack of recognition of triggered
desire and the normality of beginning an experience initially sexually neutral, the possibility of sexual satisfaction
without orgasm, and a focus on partnered sex, which
interferes with accurate scoring of women who are currently unpartnered.355 Although the FSFI has been used in
most studies of women’s sexual function including those
of women with endocrine disease, more contemporary
instruments such as the National Survey of Sexual Attitudes and Lifestyles (Natsal-3)356 better reflect the importance of sexual satisfaction in contrast to many previous
instruments. This attribute of Natsal-SF instrument is particularly important because patients may report satisfaction despite dysfunction, and dissatisfaction can occur in
the context of a functional response357: women’s satisfaction may or may not include orgasms.200 A recent study
confirms strong links between sexual satisfaction and
sexual motivation.358
CHAPTER 20 Sexual Dysfunction in Men and Women
TABLE 20-6
Directed Physical Examination of the Woman With
Sexual Dysfunction
General Examination
Signs of systemic disease leading to low energy, low desire, or low
arousability, such as anemia, bradycardia, and slow relaxing
reflexes of hypothyroidism
Signs of connective tissue disease, such as scleroderma or Sjögren
syndrome, that are associated with vaginal dryness
Disabilities that might preclude movements involved in caressing a
partner, self-stimulation, or intercourse
Disfigurements or presence of stomas or catheters that may decrease
sexual self-confidence leading to low desire, low arousability
External Genitalia
Sparsity of pubic hair suggesting low adrenal androgens
Vulval skin disorders, including lichen sclerosis, that may cause
soreness with sexual stimulation and reduce sexual sensitivity
Cracks or fissures in the interlabial folds suggestive of chronic
candidiasis
Labial abnormalities that may cause embarrassment or sexual
hesitancy
Past genital mutilation: absent labia minora, minimal or no clitoral
tissue
Introitus
Vulval disease involving introitus, such as pallor, friability, loss of
elasticity and moisture of vulval atrophy; lichen sclerosis; recurrent
splitting of the posterior fourchette manifested as just visible
white lines perpendicular to the fourchette edge; disfigurement,
narrowing from genital mutilation; abnormalities of the hymen,
adhesions of the labia minora, swellings in the area of the major
vestibular glands, allodynia (pain sensation from touch stimulus) of
the crease between the outer hymenal edge and the inner edge of
the labia minora—typical of provoked vestibulodynia
Presence of cystocele, rectocele, prolapse interfering with the
woman’s sexual self-image
Inability to tighten and relax perivaginal muscles often associated with
hypertonicity of pelvic muscles and midvaginal dyspareunia;
abnormal vaginal discharge associated with burning dyspareunia
Internal Examination
Pelvic muscle tone, presence of tenderness, trigger points on
palpation of deep levator ani due to underlying hypertonicity
Full Bimanual Examination
Presence of nodules or tenderness in the cul-de-sac or vaginal fornix
and along uterosacral ligaments, retroverted fixed uterus as causes
of deep dyspareunia
Tenderness on palpation of posterior bladder wall from anterior vaginal
wall suggestive of bladder disease
Adapted from Basson R. Sexual dysfunction in women. N Engl J Med.
2006;354:1497-1506, used with permission.
Physical Examination
Physical examination, including pelvic and genital examination, is part of routine care (Table 20-6) and can be reassuring to the patient by confirming normal anatomy and
tissue health. Unless dyspareunia is involved, it is not often
that physical examination identifies the cause of sexual
dysfunction. For some women with a history of coercive
or abusive sexual experiences, such examination may cause
extreme anxiety. The reason for the examination and an
explanation of what will and will not be done should be
provided before the examination begins. If the woman
would prefer to invite her partner to be present, then the
careful examination can be highly educational for both
partners. In women with genitopelvic penetration pain
disorder with a marked component of vaginismus, the
vaginal examination should be delayed until psychological
807
therapy renders it possible and informative for both the
patient (and partner if present) and the clinician.
Laboratory Testing
Laboratory testing plays a small role in women’s sexual
evaluation. Estrogen activity is best evaluated by history
and examination. The commercially available estradiol
radioimmunoassays lack the sensitivity and precision
required to measure the low concentrations present in the
older woman; also, these assays do not measure estrone,
the major estrogen after menopause. As discussed earlier,
serum testosterone levels do not correlate with sexual function, even when LC-MS/MS assays are used.65,66 The
circulating testosterone levels may not reflect intracrine
production, metabolism, or activity of androgens. Measurement of testosterone metabolites has been proposed as
a marker of intracrine plus gonadal production of testosterone,67 but the circulating levels of these metabolites
have been shown to be similar in women with and without
sexual dysfunction.66 The optimal markers of total androgen activity and the clinical usefulness of these metabolites
remain to be demonstrated. Prolactin or thyrotropin should
be measured if there are other symptoms that suggest
abnormality.
MANAGEMENT OF SEXUAL
DYSFUNCTION IN MEN
Treatment of Hypoactive Sexual Desire
in Men
There is need to focus on the couple when the patient has
a sexual partner. Treating the sexual dysfunction in the
male partner improves the female partner’s sexual function
and satisfaction. Comorbid depression should be treated
and relationship difficulties addressed. The efficacy of cognitive and behavioral therapies has not been evaluated
systematically in men with HSDD.
Testosterone therapy should be considered in men with
HSDD who have androgen deficiency, even though there
are no randomized trials of testosterone in men with
HSDD. Much of the information about the effects of testosterone on sexual desire has emerged from open-label
trials of testosterone in hypogonadal men.64,124,359-362 These
trials recruited men based on the presence of low testosterone levels alone.124,359-362 Testosterone therapy in these trials
has been associated with significant improvements in
overall sexual activity, sexual desire, attention to erotic
cues, and the duration and frequency of nocturnal penile
erections.64,124,359-362 Meta-analyses of randomized testosterone trials mostly in middle-aged and older men reported
greater improvements in nocturnal erections, sexual
thoughts and motivation, number of successful intercourses, scores of erectile function, and overall sexual satisfaction in men receiving testosterone than in those
receiving placebo.64,134,136,142,362 A large placebo-controlled
randomized trial of testosterone in older men with
decreased sexual desire and unequivocally low testosterone
levels, funded by the National Institutes of Health, is currently in progress and should provide novel information
about the efficacy of testosterone.363
Treatment of Erectile Disorder
The current practice employs a stepwise approach that first
utilizes minimally invasive therapies that are easy to use
808
SECTION V Reproduction
Psychosexual counseling
of the couple
Optimize medical management
of comorbid conditions
Evaluate cardiovascular risk and potential
contraindications to PDE5I use
No contraindications
to PDE5I use
PDE5I use
contraindicated
Initiate PDE5I therapy
Satisfactory
clinical
response
Unsatisfactory
clinical
response
Recommend second-line therapies:
vacuum constriction device, intraurethral
alprostadil, or intracavernosal alprostadil
• Evaluate: appropriate use,
compliance, couple relationship,
AEs, or fear of AEs
• Escalate dose to maximal allowed
or maximal tolerable dose
Satisfactory
clinical
response
Unsatisfactory
clinical
response
Unsatisfactory response
Periodic medical follow-up
Penile implant
Figure 20-9 An algorithmic approach to the treatment of erectile dysfunction in men. AE, adverse effects; PDE5I, phosphodiesterase 5 inhibitor.
and have fewer adverse effects and progresses to more
invasive therapies that may require injections or surgical
intervention after the first-line choices have been exhausted
(Fig. 20-9). The physician should discuss the risks, benefits,
and alternatives of all therapies with the couple. The selection of the therapeutic modality should be based on the
underlying cause, patient preference, the nature and
strength of the relationship with his sexual partner, and
the absence or presence of underlying CVD and other
comorbid conditions.10,11,341,342 All patients with ED can
benefit from psychosexual counseling.10,11,341,342,364-368
In the execution of good medical practice, treatment of
all associated medical disorders should be optimized. In
men with diabetes mellitus, efforts to optimize glycemic
control should be instituted, although improving glycemic
control may not improve sexual function. In men with
hypertension, control of blood pressure should be optimized and, if possible, the therapeutic regimen may be
modified to remove antihypertensive drugs that impair
sexual function. This strategy is not always feasible because
almost all antihypertensive agents have been associated
with sexual dysfunction; the frequency of this adverse
event is less with converting enzyme inhibitors and angiotensin receptor blockers than with other agents.
First-Line Therapies
Psychosexual Counseling. The major goals of psychosexual
therapy are to reduce performance anxiety, develop the
patient’s sexual skills and knowledge, modify negative
sexual attitudes, and improve communication between
partners.364 Counseling can be of benefit in both psy­
TABLE 20-7
Goals of Psychosexual Therapy in Men With Sexual
Dysfunction
•
•
•
•
Reduce performance anxiety; train the couple to avoid
“spectatoring” and be “sensate focused”
Identify relationship problems and improve partner communication
and intimacy
Modify sexual attitudes and beliefs
Improve couple’s sexual skills
Adapted from Rosen RC. Psychogenic erectile dysfunction: classification and
management. Urol Clin North Am. 2001;28:269-278.
chogenic and organic causes of sexual dysfunction364-370
(Table 20-7).
An individual’s focus on sexual performance rather than
erotic stimulation is a major factor in the pathophysiology
of psychogenic ED364,365; this behavior is referred to as spectatoring. Many experts recommend a sensate focus treatment approach in which the couple avoids intercourse and
engages in nongenital, nondemanding, pleasure-seeking
exercises in order to reduce performance anxiety.364
Involving the partner in the counseling process helps
dispel misperceptions about the problem, decreases stress,
enhances intimacy and the ability to talk about sex, and
increases the chances of successful outcome.364 Counseling
sessions are also helpful in uncovering conflicts in relationships, psychiatric problems, alcohol and drug abuse, and
significant misperceptions about sex. As many men and
women may harbor misinformation and unrealistic expectations about sexual performance and age-related changes
CHAPTER 20 Sexual Dysfunction in Men and Women
809
TABLE 20-8
Clinical Pharmacology of Selective PDE5 Inhibitors*
Feature
Sildenafil
Vardenafil
Tadalafil
Avanafil
Commercial name
Tmax
T 12
Viagra
0.5-2.0 h
3-4 h
Levitra
0.7-0.9 h
4-5 h
Stendra, Spedra
30-45 min
5h
Onset of erection (min)
Muscle selectivity (ratio of PDE6 IC50/PDE5 IC50)
Retinal selectivity (ratio of PDE11/PDE5 IC50),
higher number indicates greater selectivity
Effect of food and alcohol
Protein binding
Bioavailability
30-60
11 (most selective)
780
15-45
25
1160 (most selective)
Cialis
2h
16.9 h (young)
21.6 (old)
20-30 min
187 (least selective)
5 (least selective)
Cmax decreased
96%
41%
Minimal change
94%
Not available
No change
94%
15%
Absorption delayed
98-99%
Not available
O
CH3CH2O
CH3
N
HN
O
N
N
CH2CH2CH3
O3S
N
N
H
HOOC
CH3
Sildenafil
OH
S
N
N
N
H
N
CO2H
H
15 min
>100-fold
>10,000-fold
O
N
* * X
Z
* N Y
(R0) q
N
O
R3
O
N
N
O
N
H
Cl
N
H
R2 R1
O
CO2H
Vardenafil
OH
Tadalafil
N
N
Avanafil
*Comparative pharmacokinetic data on the three oral selective PDE5 inhibitors. Selectivity refers to the ratio of the IC50 for a PDE isoform other than PDE5 to the
IC50 for PDE5. A higher number implies greater selectivity. Sildenafil is more selective than tadalafil for PDE5 relative to PDE11, but it is less selective than
tadalafil for PDE6 relative to PDE5.
Cmax, maximum plasma concentration; IC50, 50% inhibitory concentration; PDE, phosphodiesterase; T 12 , half-life; Tmax, time to peak concentration.
Adapted from references 99, 101, 373.
in sexual function, cognitive restructuring techniques are
helpful in correcting sexual myths and beliefs.364 There is
a paucity of outcome data on the effectiveness of this psychobehavioral therapy, but meta-analyses have reported
benefit from group psychotherapy administered in conjunction with PDE5 inhibitors.367
Selective Phosphodiesterase 5 Inhibitors (Tables 20-8 and 20-9).
Selective PDE5 inhibitors are safe and effective and have
become widely accepted as first-line therapy for patients
with ED, except in men for whom these drugs are
contraindicated.9-11,99,101,341,342,370-372 Selective PDE5 inhibitors are contraindicated in men using nitrates on a regular
basis, in those with heart disease in whom sexual activity
is not recommended, and in those with nonarteritic anterior ischemic optic neuropathy.10,11,99,101,341,342,371,372
Mechanisms of Action. Three classes of enzymes—adenylyl
cyclase, guanylyl cyclase, and PDEs—play an important
role in regulating the intracavernosal concentrations of
cAMP and cGMP. PDEs hydrolyze cAMP and cGMP, thus
reducing their concentrations within the cavernosal
smooth muscle.100,101,104-106,373-376 Although PDE isoforms 2,
3, 4, and 5 are expressed in the penis, only PDE5 is specific
to the nitric oxide/cGMP pathway in the corpora cavernosa.376 PDE inhibitors sildenafil, vardenafil, tadalafil, avanafil, and udenafil are relatively selective inhibitors of
PDE5.100,101,104-106,373-399 These drugs block the hydrolysis of
cGMP induced by nitric oxide, thus promoting cavernosal
smooth muscle relaxation. The action of these drugs
requires an intact nitric oxide response, as well as constitutive synthesis of cGMP by the smooth muscle cells of the
corpora cavernosa. By selectively inhibiting cGMP catabolism in the cavernosal smooth muscle cells, PDE5 inhibitors restore the natural erectile response to sexual
stimulation but do not produce an erection in the absence
of sexual stimulation.
TABLE 20-9
Common Adverse Effects of Selective Phosphodiesterase
Inhibitors
1.
2.
3.
4.
5.
6.
7.
8.
9.
Headache
Flushing
Dyspepsia
Nasal and sinus congestion
Dizziness
Abnormal vision*
Back pain*
Myalgia*
Hearing problems
*These adverse effects are related to nonselective inhibition of
phosphodiesterase isoforms in other tissues. Headache, flushing, and
nasal congestion are related to the drug’s mechanism of vasodilator action.
Adapted from Wespes E, Rammal A, Garbar C. Sildenafil no-responders:
hemodynamic and morphometric studies. Eur Urol. 2005;48:136-139;
Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil
for the treatment of erectile dysfunction: results of integrated analyses.
J Urol. 2002;168:1332-1336; Morales A, Gingell C, Collins M, et al. Clinical
safety of oral sildenafil citrate (Viagra) in the treatment of erectile
dysfunction. Int J Impot Res. 1998;10:69-73; Katz EG, Tan RB, Rittenberg
D, Hellstrom WJ. Avanafil for erectile dysfunction in elderly and younger
adults: differential pharmacology and clinical utility. Ther Clin Risk Manag.
2014;10:701-711.
Clinical Pharmacology (see Table 20-8). Although the three
currently available PDE inhibitors have some structural
similarities, they differ in their selectivity and pharmacokinetics (see Table 20-8). The common adverse effects of
the available PDE5 inhibitors—headache, visual problems,
flush, and myalgias—are related to nonselective inhibition
of PDE isoforms 6 and 11 in other organ systems101 (see
Table 20-9). The selectivity of PDE5 inhibitor is the ratio
of its inhibitory potency for PDE isoforms other than type
810
SECTION V Reproduction
5 relative to its inhibitory potency for PDE isoform.101 For
PDE6, tadalafil is the most selective and sildenafil is the
least selective; for PDE11, vardenafil is the most selective
and tadalafil is the least selective.101 The retinal side effects
of sildenafil are related to inhibition of PDE6 in the retina,
whereas muscle aches experienced by a small fraction of
men using tadalafil are related to inhibition of PDE11 in
the skeletal muscle.101
Pharmacokinetics (see Table 20-8). After oral administration
of sildenafil, peak plasma concentrations are achieved
within 30 to 120 minutes, after which plasma con­
centrations decline, with a half-life of 4 hours (see Table
20-8).100,373-382 Vardenafil achieves peak concentrations
within 0.7 to 0.9 hour and has a half-life of 4 to 5 hours.
The peak concentrations of tadalafil are achieved at 2
hours, and its half-life of 16.9 hours in young men is significantly longer than the half-lives of sildenafil and vardenafil. The half-life of tadalafil is even longer in older men
(21.6 hours) than in young men (16.9 hours).100,373-376
Because of the relatively short half-lives of vardenafil and
sildenafil, these drugs should be taken 1 to 4 hours before
the planned intercourse; in contrast, tadalafil, because of
its longer half-life, does not have to be taken on demand,
although it can be.100,373-376 The second-generation PDE5
inhibitors avanafil and udenafil have a more rapid onset of
action than the first-generation PDE5 inhibitors sildenafil,
vardenafil, and tadalafil.377-380
Food, particularly a high-fat meal and large amounts of
alcohol, can delay and decrease the absorption of sildenafil.381,382 However, early pharmacokinetic studies have not
reported changes in maximum serum concentrations or
absorption rates of vardenafil or tadalafil due to food or
moderate alcohol ingestion.376
Efficacy. The orally active, selective PDE5 inhibitors—
sildenafil, vardenafil, avanafil, udenafil, and tadalafil—
have been shown to be effective and safe in randomized
clinical trials of men with ED.9-11,379-405 In men treated
with oral, selective PDE5 inhibitors, the rates of successful
intercourse vary from 50% to 65%, and rates of improved
erections vary from 70% to 75%.379-405 The selective
PDE5 inhibitors are effective in men of all ethnic groups
and ages379-405 who have ED due to a multitude of
causes, although response rates vary in different patient
subgroups.379-405
Introduced to the U.S. market in March 1998, sildenafil
citrate (Viagra, Pfizer, New York, NY) was the first effective
oral agent for the treatment of ED.406 The efficacy of sil­
denafil has been demonstrated in men with organic, psychogenic, or mixed ED in multiple randomized controlled
trials (RCTs)383-390,406 and confirmed by meta-analyses of
randomized trials.386-388 In these trials, patients receiving
sildenafil experienced greater increments in the number
of successful attempts per month, penile rigidity, frequency
of vaginal penetration, and maintenance of erection
than those receiving placebo.386-388 Increasing doses of
sildenafil were associated with higher mean scores for the
frequency of penetration and maintenance of erections
after sexual penetration. The mean scores for orgasms,
intercourse satisfaction, and overall satisfaction were also
significantly higher in the sildenafil group than in the
placebo group.386-388 Sildenafil also is an effective treatment
for ED in men with diabetes mellitus.389,390 A meta-analysis
of randomized clinical trials of sildenafil confirmed its efficacy in improving erectile function in men with diabetes
mellitus.390
In the vardenafil efficacy trials, 5-, 10-, and 20-mg doses
of vardenafil were all superior to placebo in improving
erectile function domain scores; the improvements in erectile function scores were dose-related.391-397 Vardenafil
improved rates of vaginal penetration, penile rigidity,
intercourse success, and satisfaction with sexual experience
in men with ED from diverse causes.391-397
Similarly, in randomized, clinical trials, 2.5-, 5-, 10-, and
20-mg doses of tadalafil were each superior to placebo in
improving erectile function scores.398-402 The beneficial
effects of tadalafil were dose-related.398-402
Two new PDE5 inhibitors have been introduced recently
in clinical practice. Avanafil has a very rapid onset of action
because of its rapid absorption, which allows it to reach
maximum circulating concentration in about 30 to 45
minutes.377-379 Therefore, a majority of patients taking
avanafil are able to engage in sexual activity within 15
minutes.377-379 Udenafil also has a relatively rapid onset of
action, with a time to maximum serum concentrations of
1.0 to 1.5 hours. It has been approved in Korea, Russia, and
the Philippines, but not in the United States.380
PDE5 inhibitors are effective in men with ED due to a
variety of causes, including spinal cord injury and radical
prostatectomy.389,390 In general, baseline sexual function
correlates positively with response to PDE5 inhibitors, and
patients with diabetes mellitus or previous prostate surgery
respond less well than patients with psychogenic or vasculogenic ED.389,390 Because there is no baseline characteristic
that predicts the likelihood of failure to respond to silden­
afil therapy, a therapeutic trial of PDE5 inhibitors should
be tried in all patients except in those in whom it is
contraindicated.372
Adverse Effects (see Table 20-9). In clinical trials, the adverse
effects that have been reported with greater frequency in
men treated with PDE5 inhibitors than in those treated
with placebo include headaches, flushing, rhinitis, dyspepsia, muscle aches, and visual disturbances.101,372,403-405 The
occurrence of headache, flushing, and rhinitis, a direct
consequence of nonselective PDE5 inhibition in other
organ systems, is related to the administered dose. These
drugs do not affect semen characteristics.407,408 No cases of
priapism were noted in the pivotal clinical trials.
Several cases of nonarteritic anterior ischemic optic neuropathy have been reported after ingestion of oral PDE5
inhibitor use.409,410 This condition is characterized by the
sudden onset of monocular visual loss due to acute ische­
mia of the anterior portion of the optic nerve in the absence
of demonstrable arteritis. This may progress to partial or
complete infarction of the optic nerve head resulting in
permanent visual loss or visual field cuts.409,410 Although a
cause-and-effect relationship with PDE5 inhibitor use has
not been established, patients with history of sudden visual
loss should not be treated with PDE5 inhibitors without
ophthalmologic evaluation.
Recently the U.S. Food and Drug Administration (FDA)
noted several reports of sudden hearing loss with and
without vestibular symptoms, such as tinnitus, vertigo, or
dizziness, in temporal relationship to administration of
sildenafil, vardenafil, and tadalafil in postmarketing surveillance. Hearing loss was also reported in a few patients
in clinical trials of these drugs.411,412 Hearing loss has been
noted in patients using sildenafil for the treatment of pulmonary arterial hypertension. Although a causal relationship has not been established, the temporal relationship
between the use of PDE5 inhibitors and the onset of sudden
hearing loss prompted the FDA to recommend change in
the product labeling for the drug class. One observational
study has reported an association of PDE5 inhibitor use
with an increased risk of melanoma.413
Cardiovascular and Hemodynamic Effects. In postmarketing
surveillance of adverse events associated with sildenafil
use, several instances of myocardial infarction and sudden
death were reported in men using sildenafil in temporal
CHAPTER 20 Sexual Dysfunction in Men and Women
relation to the ingestion of the drug414; many of these
deaths occurred in individuals who also were taking
nitrates. Because most men presenting with ED also have
high prevalence of cardiovascular risk factors, it is unclear
whether these events were causally related to the ingestion
of sildenafil, underlying heart disease, or both.414 In controlled studies,415-418 oral administration of 100 mg of sil­
denafil to men with severe coronary artery disease produced
only a small decrease in systemic blood pressure and no
significant changes in cardiac output, heart rate, coronary
blood flow, and coronary artery diameter. In a separate
pooled analysis of five randomized, placebo-controlled
trials of vardenafil,417 the overall frequency of cardiovas­
cular events was similar in vardenafil-treated men and
placebo-treated men. However, vardenafil treatment was
associated with a mild reduction in blood pressure (4.6-mm
Hg decrease in systolic blood pressure) and a small increase
in heart rate (2 beats per minute).418 This led the American
Heart Association and other experts to conclude that preexistent coronary artery disease by itself does not constitute a contraindication for the use of PDE5 inhibitors
(Table 20-10).418-424
Drug-Drug Interactions. Sildenafil is metabolized mostly by
the CYP2C9 and the CYP3A4 pathways. Cimetidine and
erythromycin, inhibitors of CYP3A4, increase the plasma
concentrations of sildenafil. HIV protease inhibitors may
also alter the activity of the CYP3A4 pathway and affect
the clearance of sildenafil.425 Conversely, sildenafil is an
inhibitor of the CYP2C9 metabolic pathway, and its
administration could potentially affect the metabolism of
drugs metabolized by this system, such as warfarin and
tolbutamide. Combined administration of sildenafil and
ritonavir results in significantly higher plasma levels of
sildenafil than sildenafil given alone.425 There are similar
TABLE 20-10
Guidelines for the Use of Selective
Phosphodiesterase Inhibitors
1. Do not administer selective PDE5 inhibitors to men taking
long-acting or short-acting nitrate drugs on a regular basis.
2. If the patient has stable coronary artery disease, is not taking
long-acting nitrates, and uses short-acting nitrates only infrequently,
the use of selective PDE5 inhibitor should be guided by careful
consideration of risks.
3. Do not administer selective PDE5 inhibitors within 24 hours of the
ingestion of any form of nitrate.
4. Advise men about the risks of the potential interaction between
selective PDE5 inhibitors and nitrates, nitrate donors, and
α-adrenergic blockers. Concurrent use of nitrates, nitrate donors, or
α-adrenergic blockers could result in hypotension that could be
serious.
5. In men with preexisting coronary artery disease, assess the risk of
inducing cardiac ischemia during sexual activity before prescribing
PDE5 inhibitors. This assessment may include a stress test.
6. In men who are taking vasodilators and diuretics for the treatment
of hypertension or congestive heart failure, consider the potential
risk of inducing hypotension because of potential interaction
between PDE5 inhibitors and vasodilators, especially in patients
with low blood volume.
7. In HIV-infected men, consider potential drug-drug interactions
between selective PDE5 inhibitors and antiretroviral drugs and
antimicrobial agents.
ACC/AHA, American College of Cardiology/American Heart Association; HIV,
human immunodeficiency virus; PDE5, phosphodiesterase isoform 5.
Adapted from Cheitlin MD, Hutter AM Jr, Brindis RG, et al. Use of sildenafil
(Viagra) in patients with cardiovascular disease: Technology and Practice
Executive Committee [published erratum appears in Circulation.
1999;100(23):2389]. Circulation. 1999;99(1):168-177; Lue TF, Giuliano F,
Montorsi F, et al. Summary of recommendations on sexual dysfunctions in
men. J Sex Med. 2004;1:6-23.
811
interactions with other drugs, including saquinavir and
itraconazole. Therefore, the doses of PDE5 inhibitors
should be reduced appropriately in men taking protease
inhibitors or erythromycin.
Grapefruit juice can alter oral drug pharmacokinetics by
different mechanisms. Grapefruit juice given in normal
amounts (e.g., 200-300 mL) or as whole fresh fruit segments can inactivate irreversibly intestinal CYP3A4, thus
reducing presystemic metabolism and increasing oral bioavailability of PDE5 inhibitors.426 Although the magnitude
of this problem in clinical practice is unknown, it seems
prudent to warn men who are contemplating the use of
PDE5 inhibitors not to ingest more than a small amount
of grapefruit juice.
The most serious interactions of PDE5 inhibitors are
with the nitrates. The vasodilator effects of nitrates are
augmented by PDE5 inhibitors; this also applies to inhaled
forms of nitrates such as amyl nitrate or nitrites that are
sold under the street name “poppers.” Concomitant administration of the two vasodilator drugs can cause a potentially fatal decrease in blood pressure.193-195
PDE inhibitors should be used carefully in men taking
α-adrenergic blockers. In men with congestive heart failure
or those receiving vasodilator drugs or those who are using
complex regimens of antihypertensive drugs, blood pressure should be monitored after initial administration of
PDE5 inhibitors.193-195 Several trials have demonstrated
the safety of administering PDE5 inhibitors in combination with α-adrenergic blockers in men with ED and
LUTS.193-195
Therapeutic Regimens. Excellent therapeutic guidelines
have been published by expert panels from several societies.99,371,372,419 To minimize the risk of hypotension and
adverse cardiovascular events in association with the use
of PDE5 inhibitors, the American Heart Association/
American College of Cardiology has published a list of
recommen­dations (see Table 20-10), which should be followed rigorously.419
In most men with ED, sildenafil is started at an initial
dose of 25 or 50 mg. If this dose does not produce any
adverse effects, the dose can be titrated up to 100 mg.99,371,372,427
Further dose adjustment should be guided by the therapeutic response to therapy and occurrence of adverse effects.
Vardenafil should be started at an initial dose of 10 mg; the
dose should be increased to 20 mg or decreased to 5 mg
depending on the clinical response and the occurrence of
adverse effects. Unit doses higher than 20 mg are not recommended. Tadalafil is started at an initial unit dose of
10 mg, with further adjustment of dose based on effectiveness and side effects. Tadalafil need not be taken more
frequently than once every 48 hours.
In men taking protease inhibitors (particularly ritonavir
and indinavir), erythromycin, ketoconazole, itraconazole,
or large amounts of grapefruit, the doses of PDE5 inhibitors
should be reduced, and doses greater than 25 mg of sil­
denafil, 5 mg of vardenafil, or 10 mg of tadalafil are not
recommended.
Sildenafil and vardenafil are taken at least 1 hour before
sexual intercourse and not more than once in any 24-hour
period; because of its longer half-life, tadalafil need not be
taken immediately before intercourse.
Based on the results of the randomized clinical trials,408,428,429 the FDA has approved 2.5 mg or 5 mg tadalafil
once daily for the treatment of ED. In the pivotal trials,
men using 2.5 mg or 5 mg tadalafil once daily experienced
greater improvements in erectile function compared with
those taking a placebo.408,428,429 Subsequent open-label extension studies indicated that once-daily 5 mg tadalafil for
up to 2 years was effective in maintaining improvements
812
SECTION V Reproduction
in erectile function.408,428,429 Thus, tadalafil may be taken at
2.5 mg or increased to 5 mg, as tolerated. The adverse
events associated with once-daily administration of tadalafil included headaches, indigestion, back pain, muscle
aches, nasal congestion, and flushing and were similar to
those observed with on-demand tadalafil ingestion.408,428,429
Once-daily regimen of tadalafil had no significant effect on
semen or reproductive hormone levels.408
The Use of Phosphodiesterase 5 Inhibitors in Men With Coronary
Artery Disease (see Table 20-10).424 Before prescribing PDE5
inhibitors, cardiovascular risk factors should be assessed. If
the patient has hypertension or symptomatic coronary
artery disease, the treatment of those clinical disorders
should be addressed first.424 The use of nitrates must be
ascertained because PDE5 inhibitors are contraindicated in
individuals taking any form of nitrates regularly. PDE5
inhibitors should not be used within 24 hours of the use
of nitrates or nitrate donors.10,11,423,424
Sexual activity can induce coronary ischemia in men
with preexisting coronary artery disease420; therefore, men
contemplating use of ED therapies should undergo assessment of their exercise tolerance. One practical way to assess
exercise tolerance is to have the patient climb one or two
flights of stairs. If the individual can safely climb one or
two flights of stairs without angina or excessive shortness
of breath, he can likely engage in sexual intercourse with
a stable partner without inducing similar symptoms. Exercise testing before prescribing PDE5 inhibitors may be indicated in some men with significant heart disease to assess
the risk of inducing cardiac ischemia during sexual
activity.419-421 Selective PDE inhibitors have been shown not
to impair the ability of patients with stable coronary artery
disease to engage in exercise at levels equivalent to that
attained during sexual intercourse.419-421 Similarly, each of
the three PDE5 inhibitors has been shown not to have
significant adverse effects on hemodynamics and cardiac
events in carefully selected men with ED who did not have
any contraindication for the use of PDE5 inhibitors.417-424
None of the PDE5 inhibitors adversely affects total exercise
time or time to ischemia during exercise testing in men
with stable angina.417-424
Treatment of Patients Who Do Not Respond to Phosphodiesterase 5 Inhibitors. Although oral PDE5 inhibitor therapy has
revolutionized the management of ED, not all men will
respond to this treatment. The cumulative probability of
intercourse success with sildenafil citrate increases with the
number of attempts, reaching a maximum after eight
attempts.430 Based largely on these data,430 the failure to
respond to PDE inhibitor therapy has been defined as the
failure to achieve satisfactory response even after eight
attempts of either the highest approved dose (e.g., 100 mg
sildenafil) or the highest tolerable dose of PDE inhibitor,
whichever is lower. Many factors may contribute to apparent treatment failure, including failure to take the medi­
cation as recommended, suboptimal dose, dose-limiting
adverse effects, psychological issues, partner and relationship issues, incorrect diagnosis, and patient-specific pathophysiologic factors.430-432 In clinical trials of PDE5 inhibitors,
treatment failures were reported predominantly in men
who had diabetes mellitus, non-nerve sparing radical prostatectomy, cavernosal nerve damage, venous leak, and high
disease severity.430-432 In an evaluation of cavernosal smooth
muscle biopsies in sildenafil nonresponders, Wespes and
coworkers432 found severe vascular lesions and cavernosal
smooth muscle atrophy and fibrosis to be the underlying
pathologic processes.
Patients may not take the medication appropriately because of inadequate instructions, failure to understand the
instructions, adverse effects, or fear of adverse effects.430-432
Oral PDE5 inhibitors are taken optimally 1 to 2 hours
before planned intercourse. The medication is unlikely to
be effective if it is taken immediately before intercourse; a
high-fat meal and large amounts of alcohol may further
affect the maximal serum concentrations of sildenafil
citrate. Similarly, patients may not take the appropriate
dose because of side effects or fear of side effects. The men
who have been misdiagnosed as having ED and whose
primary sexual disorder is unresponsive to PDE5 inhibitors
may be incorrectly deemed treatment failures. For instance,
men with HSDD, Peyronie disease, or orgasmic or ejaculatory disorder would not be expected to respond to PDE5
inhibitors. The anxiety associated with resumption of
sexual activity and unresolved relationship and partner
issues can attenuate response to treatment. The sexual partner may not be willing or able to engage in sexual activity
because of relationship issues, sexual disorder, or real or
perceived health issues.
Patients who report lack of satisfactory response to
initial administration of PDE5 inhibitors should be asked
about the time of drug administration, the dose taken, and
adverse effects experienced. Psychological and partner
issues should be evaluated. The dose of PDE5 inhibitor
should be increased gradually as tolerated. Should the
patient not respond to maximal tolerable doses of PDE5
inhibitors, PDE5 inhibitors can be combined with vacuum
devices or intraurethral therapy. Second-line therapies such
as intracavernosal injections should be pursued. The men
who are unresponsive to oral PDE5 inhibitors and secondline therapies may find penile implant an acceptable
alternative.430
Cost-Effectiveness of Phosphodiesterase 5 Inhibitor Use for Erectile Disorder. A number of studies have evaluated the economic cost of treating ED in men in managed care health
plans.433-437 One simulation estimated sildenafil citrate cost
to be approximately $11,000 per quality-adjusted life year
(QALY) that it produces.435 This amount is less than that
for many other accepted treatments for medical disorders
that cost less than $50,000 to $100,000 per QALY; thus, the
cost-effectiveness of PDE5 inhibitor therapy compares
favorably with other accepted medical therapies. Other
analyses have concluded that PDE5 inhibitors and vacuum
constriction devices are the most cost-effective of all the
available therapeutic options.433-437 Several recent analyses
have shown that the financial burden imposed by patients
with ED on managed care plans is surprisingly small.433-437
In one such cost-utility analysis, the monthly cost of providing ED-related treatment services in a health plan with
100,000 members amounted to less than $0.10 per member.435 Thus, the failure of many insurance companies to
cover the cost of PDE5 inhibitor therapy is not informed
by cost-utility analyses.
Second-Line Therapies
Vacuum Devices for Inducing Erection. The vacuum devices
consist of a plastic cylinder, a vacuum pump, and an elastic
constriction band.438-440 The plastic cylinder fits over the
penis and is connected to a vacuum pump. The negative
pressure created by the vacuum within the cylinder draws
blood into the penis, producing an erection. An elastic
band slipped around the base of the penis traps the blood
in the penis, maintaining an erection as long as the rubber
band is retained. The constriction band should not be left
in place for more than 30 minutes. Also, only vacuum
devices with a pressure-limiting mechanism should be recommended to prevent injury due to high vacuum.
Limited data on the efficacy of vacuum devices from
open-label trials indicate that these devices are safe,
CHAPTER 20 Sexual Dysfunction in Men and Women
relatively inexpensive, and moderately effective.438-440 They
can impair ejaculation, resulting in entrapment of semen.
Some couples dislike the lack of spontaneity engendered
by the use of these devices. Partner cooperation is important for successful use of these devices.440
Intraurethral Therapies. An intraurethral system for delivery
of alprostadil called MUSE (medicated urethral system for
erection; VIVUS, Menlo Park, CA) was released in 1997.
Alprostadil is a stable, synthetic form of PGE1, which results
in generation of cAMP and activation of protein kinase A.
Activated protein kinase A stimulates K+ channels, resulting
in K+ efflux from the cell. In addition, protein kinase A–
mediated processes also result in a net decrease in intracellular calcium, favoring smooth muscle cell relaxation.
Alprostadil, when applied into the urethra, is absorbed
through the urethral mucosa into the corpus cavernosum.
In comparison to intracavernosal injection of PGE1, intraurethral PGE1 is easier to administer and has a lower frequency of adverse effects, particularly penile fibrosis.
Alprostadil is available in 125-, 250-, 500-, and 1000-µg
strengths. Typically, the initial alprostadil dose of 250 µg
is applied in the clinician’s office to observe changes in
blood pressure or urethral bleeding secondary to misapplication of the device into the urethra.
Initial randomized, placebo-controlled studies reported
40% to 60% success rates, defined as having at least one
successful sexual intercourse during a 3-month study
period.441-443 In clinical practice, only about a third of men
using intrauretheral alprostadil will respond.444
Common side effects of intraurethral alprostadil are
penile pain and urethral burning in up to 30% of
patients441-444; its use also may cause dizziness, hypotension, and syncope in a small fraction of users. Intraurethral
alprostadil can cause mild burning or itching in the vagina
of the sexual partner. Intraurethral alprostadil should not
be used by men whose partners are pregnant or planning
to get pregnant.
Intracavernosal Injection of Vasoactive Agents (Table 20-11).
The use of intracavernosal injections of vasoactive agents
has been a cornerstone of the medical management of ED
since the early 1980s. Patients can be taught to inject a
TABLE 20-11
Guidelines for Intracavernosal Therapy
1. Do not prescribe intracavernosal therapy to men who have
psychiatric disorders, hypercoagulable states, sickle cell disease;
those who are receiving anticoagulant therapy; or those who are
unable to comprehend the risks or take appropriate action should
complications occur.
2. Designate a physician or a urologist to be available to handle
emergencies related to complications of intracavernosal injections
such as prolonged erection and priapism.
3. Instruct the patient in the injection technique, the risks of
intracavernosal therapy, and the steps to be taken in the event
of prolonged erection or priapism.
4. Administer the first injection in the office and observe the blood
pressure and heart rate response. This provides an excellent
opportunity for educating the patient, observing adverse effects,
and determining whether the patient will respond to
intracavernosal therapy.
5. Start with a low dose of alprostadil and titrate the dose based on
the erectile response and the duration of erection. Adjust the dose
of alprostadil to achieve an erection that is sufficient for sexual
intercourse but that does not last more than 30 minutes.
6. If the erection does not abate in 30 minutes, the patient should be
instructed to take a tablet of pseudoephedrine or brethine or an
intracavernosal injection of phenylephrine. If this is not effective,
the patient should call the designated physician or the urologist,
and come to the emergency room.
813
vasoactive agent into their corpora cavernosa using a 27- or
30-gauge needle prior to the planned intercourse. Erections
occur typically 15 minutes after intracorporal injection and
last 45 to 90 minutes. Although intracavernosal injection
therapy is highly effective,445-452 it is associated with significantly higher complication rates than oral therapy and
should be used only by practitioners who are experienced
in the use of this therapy and who can provide emergency
medical support to their patients in the event of a serious
adverse event, such as priapism.
Although several different agents—PGE1, papaverine,
and phentolamine—have been used alone or in combination,445-453 only intracavernosal PGE1 has been approved for
clinical use. The long-term data on the efficacy and safety
of intracavernosal therapy are sparse.
Several formulations of alprostadil (PGE1) are commercially available (Caverject, Pharmacia; Prostin VR, Pharmacia; Edex, Schwarz Pharma). PGE1 binds to PGE1 receptors
on the cavernosal smooth muscle cells, stimulates adenylyl
cyclase, increases the concentrations of cAMP, and is a
powerful smooth muscle relaxant. The usual dose is 5 to
20 µg, and response to therapy is dose-related and should
be titrated.445-451
In one placebo-controlled efficacy trial, the intracavernosal alprostadil injection resulted in satisfactory sexual
performance after more than 90% of administrations, and
approximately 85% of men and their partners reported
satisfactory sexual activity.445 Intracavernosal alprostadil is
more effective than intraurethral alprostadil.449
The common adverse effects of intracavernosal therapy
include penile pain, occurrence of hematoma, formation
of corporal nodules, penile fibrosis, and prolonged erections.445-452 Despite the effectiveness of this approach in
producing rigid erections, many patients do not relish
injecting a needle into their penis; therefore, it is not surprising that long-term dropout rates are high.
Intracavernosal injections of papaverine, phentolamine,
forskolin, and VIP have also been used, although these
agents are not approved by the FDA.453 Papaverine, derived
originally from the poppy seed, is a nonspecific PDE inhibitor, which increases both intracellular cAMP and cGMP. It
has a greater propensity to induce priapism and fibrosis
with long-term use, and efficacy and long-term safety data
from randomized, placebo-controlled trials are lacking.
Therefore, there is insufficient information to evaluate its
efficacy and safety.
Phentolamine is a competitive α1- and α2-adrenergic
antagonist that contributes to smooth muscle relaxation.
As a single agent it is minimally efficacious, but it has been
used to potentiate the effects of papaverine, VIP, and
PGE1.453 Randomized clinical trial data on its efficacy and
safety are lacking. Therefore, there is insufficient information to evaluate its efficacy and safety.
A serious concern with the use of intracavernosal injection therapy is priapism. In patients who develop a prolonged or painful erection with PGE1, either brethane 5 mg
or pseudoephedrine 60 mg, administered orally, may be of
benefit. If priapism persists longer than 4 hours, patients
should be instructed to seek medical care in which aspiration alone or with the injection of an α-adrenergic agent
is used to induce detumescence. If this fails, surgical therapy
may be indicated to reverse a prolonged erection; otherwise, anoxic damage to the cavernosal smooth muscle cells
and fibrosis can occur.
Third-Line Therapies
Penile Prosthesis. The penile prostheses are invasive and
costly, but they can be an effective method for restoring
814
SECTION V Reproduction
erectile function for patients with advanced organic disease
who are unresponsive to other medical therapies, have
significant structural disorders of the penis (e.g., Peyronie
disease), or have suffered corporal loss from cancer or traumatic injury.454-456
Penile implants are paired supports that are placed in
each of the two erectile bodies. There are two basic types
of penile implants: hydraulic (fluid filled), referred to as
inflatable prostheses; and malleable, semirigid rods, which
are bendable but always remain firm in the penis.454-456
Penile prostheses come in a variety of lengths and girths.
Implantation surgery usually takes less than an hour and
in most cases can be done as an outpatient procedure
under general or regional anesthesia.
Infection and mechanical malfunction are the most
common problems with penile prostheses. With recent
improvements in materials and design, the chance of
mechanical malfunction has decreased to 5% to 10% in the
first 10 years.454-456 Infection occurs in 1% to 3% of cases,
but infection rates can be higher in revision surgery, especially in men with diabetes mellitus.
The total cost of penile prosthesis implantation varies
from $3,000 to $20,000, depending on the type of device
used and the community in which the procedure is performed. There are no randomized efficacy trials, but retrospective analyses have reported that greater than 80%
of patients and 70% of partners are pleased with their
prosthesis and the togetherness that it brings to their
relationship.454-457
Testosterone Replacement in Androgen-Deficient Men Presenting With Erectile Disorder. Testosterone treatment does not
improve sexual function in men with ED who have normal
testosterone levels.1,64,134,135,142 It is not known whether testosterone replacement improves sexual function in impotent men with borderline serum testosterone levels. Many,
but not all, of the impotent men with low testosterone
levels experience improvements in their libido and overall
sexual activity with androgen replacement therapy.1,64,134,135
The response to testosterone therapy even in this group of
men is variable, because of the coexistence of other disorders such as diabetes mellitus, hypertension, CVD, and
psychogenic factors.1,134,135,142
ED in middle-aged and older men is a multifactorial
disorder, often associated with other comorbid conditions
such as diabetes mellitus, hypertension, medications,
peripheral vascular disease, psychogenic factors, and endstage renal disease. Therefore, it is not surprising that testosterone treatment alone may not improve sexual function
in all men with androgen deficiency. Testosterone induces
NOS activity,130,131 has trophic effects on cavernosal smooth
muscle and ischiocavernosus and bulbospongiosus muscles,132 increases penile blood flow,145 and is essential for
achieving venous occlusion in animal models.129 These
observations have led to speculation that testosterone
might improve response to PDE5 inhibitors; however, as
discussed earlier, data from randomized trials have not
shown the superiority of testosterone over placebo in
improving erectile function in men with ED who have low
testosterone levels and in whom the PDE5 inhibitor dose
has been optimized.148
Therapies With Either Unproven Efficacy or Limited Efficacy
Data. There are insufficient efficacy data to support the use
of trazodone458 or yohimbine459 in men with ED. The literature on the effectiveness of herbal therapies is difficult to
interpret because of lack of consistency in product formulations and potencies, contamination of herbal products
with PDE5 inhibitors, poor trial design, and paucity of
randomized clinical trial data.460-464 One randomized trial
of Korean red ginseng reported this product to be effective
in the treatment of ED461; these data need further confirmation. Icariin is a flavonoid, derived from several species of
plants, whose extracts have been known in herbal medicine to produce aphrodisiac effects and enhance erectile
function.464 Dipyridamole also inhibits PDE5 and can
augment the effects of nitric oxide. 4-Methylpiperazine
and pyrazolopyrimidine, components of the lichen Xanthoparmelia scabrosa, have also been claimed to inhibit
PDE5.463 The use of these or other herbal therapies is not
recommended.463 Apomorphine also functions as a dopamine agonist and acts centrally to initiate erection; its
main adverse effect is nausea.
Gene Therapy and Erectile Disorder. The goal of gene therapy
for ED is to introduce novel genetic material into the cavernosal smooth muscle cells to restore normal cellular
function and produce a therapeutic effect.465-467 Gene
therapy has been proposed as a treatment option for diseases that have a vascular origin, such as arteriosclerosis,
congestive heart failure, and pulmonary hypertension.465-467
ED may be particularly amenable to gene therapy because
of the easily accessible external location of the penis,465-467
which permits direct injection into the corpora cavernosa.
A tourniquet placed around the base of the penis limits
entry of the injected material into the systemic circulation.
This is a distinct advantage of the gene therapy of penile
diseases over gene therapy for other systemic diseases
because introduction of the genetic material into the systemic circulation can potentially induce adverse systemic
effects due to insertion of the material into an incorrect
organ or vascular bed. Additionally, in the penis, only a
small number of cells need to be transfected because the
interconnection of smooth muscle cells in the corpus cavernosum by gap junctions allows second messenger molecules and ions to be transferred to other interconnected
smooth muscle cells.465-467 The low turnover rate of the
vascular smooth muscle cells of the penis allows the desired
gene to be expressed for long periods of time.
The current strategies of gene therapy for ED treatment
have focused on the molecules that regulate corporal
smooth muscle relaxation or neovascularization (Table
20-12).465-467 A number of candidate genes have been
explored, including the penile-inducible NOS, eNOS, VIP,
calcitonin-related peptide, maxi-K+ channel, vascular endothelial growth factor (VEGF), the brain neurotrophic
factor, angiopoietin-1, neurturin (a member of the glial
cell line–derived neurotrophic factor family), superoxide
dismutase, IGF-1, protein kinase G (PKG-1α), and Rho A/
Rho kinase465-475 (see Table 20-12). A number of vectors
have been used to transfer exogenous genes, including
adenoviruses, adeno-associated viruses, retroviruses, sinbis
viruses, replication-deficient retroviruses, liposomes, naked
DNA, and gold nanoparticles.465-481
Garban and associates468 first demonstrated that gene
therapy can be performed in the penis by utilizing naked
cDNA (complementary DNA) encoding the penile-inducible
NOS gene leading to physiologic benefit in the aging rat.
Christ and colleagues469 injected hSlo cDNA (which encodes
the human smooth muscle maxi-K+ channel) into the rat
corpora cavernosa and demonstrated increased gap junction formation and enhanced erectile responses to nerve
stimulation in the aged rat. Adenoviral constructs encoding the eNOS and CGRP genes were shown to reverse agerelated ED in rats.470,471 In these studies, both eNOS and
CGRP expression were sustained for at least 1 month in the
corpora cavernosa of the rat penis. Five days after transfection with the AdCMVeNOS or AdRSVeNOS viruses, aged
rats had significant increases in erectile function as determined by cavernosal nerve stimulation and pharmacologic
injection with the endothelium-dependent vasodilator
CHAPTER 20 Sexual Dysfunction in Men and Women
815
TABLE 20-12
Physiologic Targets for Gene Therapy
Gene Target
Vector and Mechanism
Reference
Nitric oxide isoforms
Increase eNOS, nNOS, and iNOS activity in the cavernosal smooth
muscle
Protein inhibitor of NOS
(PIN)
Maxi-K+ channel
Antisense and short hairpin RNA (shRNA) constructs targeting PIN
(protein inhibitor of NOS)
Transfer of maxi-K+ channels using a plasmid vector that carries the hSlo
gene encoding the α-subunit of the maxi K+ channel; first human trial
demonstrates the safety and feasibility of gene therapy in humans
Replication-deficient recombinant adenoviruses carrying the PKG-1α
Transfer of VEGF cDNA into rat corpora cavernosa to promote
neovascularization
Adenovirus-mediated transfer of human angiopoietin-1
Transfer of brain-derived neurotrophic factor using adeno-associated virus
Transfer of neurotrophin 3 gene using HSV vector
Neurturin (NTN), a member of glial cell line–derived neurotrophic factor
(GDNF) family
Transfection of corpora cavernosa of streptozotocin-treated diabetic rats
using pcDNA3 carrying VIP cDNA
Adenoviral transfer of CGRP in aged rats
Adenoviral-mediated gene transfer of extracellular superoxide dismutase
injected into the corpora cavernosa
Adenoviral-mediated gene transfer of IGF-1
Champion 1999; Bivalacqua 2000,
2003, 2005; Gonzalez-Cadavid 2004;
Kendirci 2005; Wessels 2006
Magee et al 2007
PKG-1α
VEGF
Angiopoietin-1
BDNF
Neurotrophin 3 gene
Neurturin
VIP
CGRP
Superoxide dismutase
Insulin-like growth factor-1
Christ et al 2002, 2004, 2004; Melman
2003, 2005, 2006, 2007, 2008; So
et al 2007
Bivalacqua et al 2007
Rogers et al 2003; Buchardt et al 2005;
Dall’Era et al 2008
Ryu et al 2006; Jin et al 2010
Rogers et al 2005; Gholani et al 2003
Bennett et al 2005
Kato et al 2009
Shen et al 2005
Bivalacqua et al 2001; Deng 2004
Bivalacqua 2003; Brown 2006; Lund
2007
Pu et al 2007
BDNF, brain-derived neurotrophic factor; cDNA, complementary DNA; CGRP, calcitonin gene–related peptide; HSV, human syncytial virus; IGF-1, insulin-like
growth factor 1; NOS, nitric oxide synthase (epithelial [e], inducible [i], or neuronal [n] isoforms); PIN, protein inhibitor of NOS; PKG, protein kinase G; VEGF,
vascular endothelial growth factor; VIP, vasoactive intestinal protein.
Adapted from Melman and Davies481; Condorelli et al, 2010; Harraz et al465; Strong et al466; Deng et al.467
acetylcholine and the type PDE5 inhibitors.470,471 In one
study, intracavernous injection of adeno-associated virus
construct carrying the brain-derived neurotrophic factor
gene improved erectile function after cavernosal nerve
injury.475 This neurotrophic factor purportedly restored
neuronal NOS in the major pelvic ganglion, thus enhancing the recovery of erectile function after bilateral cavernous nerve injury.475 In other studies, intracavernosal VEGF
injection and adeno-associated virus-mediated VEGF gene
therapy were each shown to reverse venogenic ED in
rats.472,473 These preclinical studies and others using additional targets for gene therapy such as CGRP, superoxide
dismutase, and Rho A/Rho kinase provide evidence that in
vivo gene transfer can be accomplished technically. The
translation of these preclinical data into human trials has
been slow and unsuccessful so far.
Ion Channel Innovations, Inc. has completed a phase I
trial of slow K+ channel in men with ED.95,477,478 In this trial,
hmaxi-K, a “naked” DNA plasmid carrying the human
cDNA encoding for the gene for the α-subunit of the
human smooth muscle maxi-K channel, was injected
directly into the penises of 11 men with ED. Patients who
received the highest dose of hmaxi-K experienced significant improvements in their erectile function that was sustained for the 24-week duration of the trial. This trial
demonstrated the feasibility and safety of injecting naked
DNA into the human penis.477,478 A trial of hmaxi-K in
patients with overactive bladders is ongoing. Phase I gene
therapy trials using VEGF and hepatocyte growth factor
have been conducted in patients with peripheral vascular
disease and chronic limb ischemia and to prevent the
development of stent restenosis; these trials have reported
low frequency of serious adverse effects. However, phase II
studies have not confirmed efficacy. Thus, the early therapeutic promise of gene therapy has yet to be realized.
Successful gene therapy may require introduction of multiple gene products using vectors with higher efficiency of
transfection of a larger number of target cells and more
prolonged action than can be realized with the current
generation of vectors.
The Potential of Stem Cell Therapy for Erectile Disorder. The
past decade has seen considerable interest in the transplantation of stem cells derived from bone marrow, adipose
tissue, or skeletal muscle into the corpora cavernosa.482-490
However, it has become apparent that the stem cells, even
when injected within the corpora cavernosa, escape rapidly
from the penis and hone into the bone marrow.482-490 The
mechanism of the reported improvements in intracavernosal pressure after stem cell injection into the corpora cavernosa remains unclear.485 The safety and efficacy of stem
cell therapy in humans has yet to be demonstrated. We do
not know whether transplanted human mesenchymal
stem cells (hMSCs) can differentiate into functional cavernosal smooth muscle cells and restore erectile capacity in
men with ED. Also, the long-term outcomes including the
tumorigenic potential of these transplanted progenitor
cells are unknown.
hMSCs may also be attractive gene delivery vehicles
because these cells can replicate in vitro as well as in vivo,
thus potentially providing a large pool of cells.486,487 Initial
studies have demonstrated that rat mesenchymal stem
cells, expanded and transfected ex vivo and implanted into
the corpora cavernosa, are capable of expressing the gene
product of interest.482-487 Stem cell therapy using stem cells
carrying angiogenic or neurotrophic genes or proteins is
also being explored. Although several animal studies have
reported improved erectile function with hMSC transplantation, few studies have shown evidence of long-term stem
cell survival in the cavernosal smooth muscle or evidence
of differentiation of the transplanted stem cells into endothelial cells or cavernosal smooth muscle cells.482-490
Management of Retrograde Ejaculation
Case reports have shown benefit from methoxamine, imipramine, midodrine, and ephedrine, although randomized
816
SECTION V Reproduction
clinical trial data are lacking.491-493 Induction of fertility
in men with retrograde ejaculation may require retrieval
of sperm from the urinary bladder after sexual stimulation
or electrostimulation of the prostatic nerve plexus per
rectum plus assisted reproductive techniques, such as intrauterine insemination or in vitro fertilization with or without intracytoplasmic sperm injection using the retrieved
sperm.494-497
MANAGEMENT OF SEXUAL
DYSFUNCTION IN WOMEN
Psychotherapeutic methods are the mainstay of management of the female sexual dysfunction; Frühauf and
coworkers498 provided a systematic review and metaanalysis of these interventions in 2013.
On an investigational basis a small number of medications have received limited study (see Table 20-13).
Management of Low Desire and Arousal
in Women
Management of sexual interest/arousal disorder (SIAD)
begins with explaining the circular model of sexual response
(see Fig. 20-1B) as a basis for discussing which areas are
problematic with one or preferably both partners. When
insufficient emotional intimacy is identified, the normality
of low interest to be sexual can be clarified; referral for
couple counseling may be indicated. When the lack of
sexual context and stimuli are contributing factors, simply
emphasizing the requirement of appropriate environment
and sufficiently erotic stimuli is usually sufficient, but referral to a sex therapist may be appropriate. Nonsexual distractions, fears about sexual outcome, self-monitoring
of sexual response, anxiety, low self-image, and depression
all interrupt the mental appraisal of stimuli. These issues
can be explained and addressed. The main modalities
of treatment are cognitive therapy, sex therapy, and
psychoeducation.
Psychoeducation
Psychoeducation includes giving information while simultaneously soliciting the woman’s input to share thoughts
and feelings that emerge in session, which are then
addressed and processed. It includes teaching cognitive
techniques and can help dispel widespread myths about
sexuality in women (e.g., that the absence of desire preceding sexual activity denotes sexual dysfunction). Bibliotherapy with self-help reading material or videos can be helpful.
TABLE 20-13
Investigational Pharmacotherapy for Women’s Sexual Dysfunctions
Sexual Dysfunction
Sexual interest
arousal disorder
Mechanisms of
Dysfunction
Loss of brain’s
sexual
arousability to
sexual stimuli
Drug Type
Drugs with specific
serotonin receptor
subtype of agonist/
antagonist profile
Melanocortin agonists
Dopamine agonists
Genital arousal
disorder:
estrogen deplete
Genital arousal
disorder despite
estrogen replete
Serotonergic
antidepressant–
associated
orgasmic disorder
Off Label/Investigational
Drug
Comments
Flibanserin: 5HT1A agonist
and 5HT2A antagonist,
weak partial agonist D4
Recent FDA approval despite marginal
benefit and potentially serious side
effects521a
Bremelanotide–synthetic
peptide: α-melanocytestimulating hormone
analogue-agonist at
MCR1, MC3R, and
MC4R receptors
Bupropion
Small RCT showed benefit for women’s
arousal disorder with in home use
of nasal drug 45 min before sex.73
Sponsor has discontinued trials
Loss of genital
vasocongestion
in response to
sexual
stimulation
Loss of genital
vasocongestion
in response
to sexual
stimulation
Loss of genital
vasocongestion
in response
to sexual
stimulation
To provide local substrate
for estrogen and
testosterone intracrine
synthesis
Local vaginal DHEA
Selective tissue estrogenic
activity regulator with
androgenic and
progestogenic
properties
To enhance the action of
NO-PDEIs
Tibolone
Former orgasmic
response absent
or extremely
delayed
PDEIs
Sildenafil
Sildenafil, tadalafil,
vardenafil
One small 4-month study, in
nondepressed premenopausal
women showed increased
arousability and sexual response,
no increase in initial desire.110
Recent phase III RCT showing increased
maturation of vaginal epithelium,
lower pH and sexual benefit in all
domains of response from local
vaginal DHEA for 12 weeks558
RCT of dysfunctional women showed
tibolone marginally superior to 50
µg/140 µg combined transdermal
estradiol/norethisterone.112
Major problem is distinguishing the
subgroup of women with genital
arousal disorder who have reduced
genital vasocongestion. Small RCTs
in diabetes146 and MS116 showed only
modest benefit from sildenafil.
Recent 8-week RCT with very strict
entry criteria showed benefit from
50-100 mg.510
Superscript numbers indicate references at the end of the chapter.
D4, dopamine 4 receptor; DHEA, dehydroepiandrosterone; 5-HT, serotonin; ISSWSH, International Society for the Study of Women’s Sexual Health; MC1R,
melanocortin-1 receptor; MS, multiple sclerosis; MSH, melanocyte-stimulating hormone; NO, nitric oxide; PDEIs, phosphodiesterase inhibitors; RCTs,
randomized controlled trials.
CHAPTER 20 Sexual Dysfunction in Men and Women
For some women, information on anatomy and physiology
is necessary.
Cognitive Behavioral Therapy
Cognitive behavioral therapy (CBT) can assist the woman
to recognize, challenge, and in time, change her negative
and often catastrophic self-view imposed by underlying
illness, including endocrine conditions or their imposed
infertility. Some of the exaggerated or catastrophic thoughts
amenable to cognitive therapy include “sex is only for well
women,” “I am no longer fertile, so I am no longer sexually
attractive,” and “if intercourse is too painful to include,
then no one will want me.” Identifying these biased/
maladaptive thoughts is the first step: changing such
thoughts to be more evidenced-based is then practiced.
Empiric support for benefit from targeting cognitions and
emotions during sex in order to increase physical and subjective arousal is emerging.42,499
Mindfulness-Based Cognitive Therapy
New to Western medicine is the addition of mindfulness,
which is of benefit for medically well women with sexual
dysfunction,500,501 those with pelvic cancer,502 and those
with PVD.503 Mindfulness is an Eastern practice of medi­
tation: the learned skill is to be fully present and accepting of all that is sensed in that moment. Attention is
enhanced by the gradual ability to identify thoughts
arising in that moment, be they future- or past-oriented,
but not to engage in them but ultimately to view these
negative or positive thoughts more distantly as if they are
just sensations not dissimilar to physical sensations. The
practice of mindfulness focuses the attention on sexual
sensations rather than on self-monitoring. Functional
brain imaging performed before and after mindfulness
training supports the clinical finding that such training
lessens self-referencing of sensations and emotions, including pain and anxiety.504-506 Resources in the community and through the Internet for mindfulness practice
can be given.
Recently, an adapted form of CBT blended with mindfulness was defined—the treatment is called mindfulnessbased cognitive therapy (MBCT). Regular mindfulness practice
is an integral component. As with CBT, the skill of detecting maladaptive thoughts including those critical or evaluative is learned but with simple observation of their
presence and an acknowledgment that they are just mental
events, not necessarily the truth; there is no focus here
to change thoughts. MBCT is used to treat or prevent
anxiety disorder and depression and has been adapted to
treat arousal and desire disorders and chronic pain of
PVD.500,501,503,507
Current clinical research includes the use of detailed
treatment manuals for clinicians with separate versions for
patients. The aim is to provide sufficiently detailed manuals
for non–mental health professionals and non–sexual medicine specialists to provide CBT and MBCT to small groups
of women. This small group format is consistently rated as
a major benefit.508
Sex Therapy
Sex therapy usually focuses on sensate focus exercises
whereby each partner takes turns giving and receiving
sensual and, later on, sexual touches, caresses, and kisses.
Initially, genital areas and breasts are off-limits. The idea
of any goal or expectation is put aside. The couple together
with the clinician decides as to when breasts and genital
817
areas are on-limits. Ultimately, the act of intercourse (or
vaginal penetration with dildo), may be included—but not
as the focus.
Outcome of Psychological Treatments for Women’s
Sexual Dysfunctions
Data are limited regarding the long-term effects of psychological treatments for women’s sexual dysfunction. A systematic review and a meta-analysis of controlled clinical
trials for female and male sexual dysfunction published
before 2009 was recently conducted.498 None of these studies targeted patients with endocrine disease. The overall
conclusion was that psychosocial interventions for sexual
dysfunction were efficacious. For women with sexual dysfunction associated with the hormonal changes arising
from breast cancer treatment, a systematic review suggests
that the most effective interventions are couple-based psychoeducational interventions that include an element of
sex therapy.509
Management of Women’s Orgasmic Disorder
Although in clinical practice CBT methods and mindfulness training have been used in women with orgasmic
disorder, outcome research is sparse. The 2013 metaanalysis found clear evidence of benefit in both symptom
severity and sexual satisfaction for women with orgasmic
dysfunction, but only three trials were identified.498 To date
there is no pharmacologic treatment for orgasmic disorder.
In one trial with highly selective inclusion criteria, sil­
denafil was reported to improve orgasm dysfunction associated with SSRI use,510 whereas a recent small trial of
transdermal testosterone did not improve sexual function
beyond placebo as measured by the Sabbatsberg Sexual
Self-Rating Scale as the primary outcome.511 However, testosterone therapy was associated with statistically significant increase in the number of sexually satisfying events
(SSEs) per month. Confirmation of these findings and their
clinical relevance is awaited (Table 20-13).
Management of Genitopelvic
Pain/Penetration Disorder (Dyspareunia
and Vaginismus)
The most common type of dyspareunia is PVD, which
affects about 12% to 18% of women.512 PVD and the other
common type of dyspareunia—that stemming from vul­
vovaginal atrophy—are typically associated with pelvic
muscle hypertonicity and reflexive involuntary contractions when penetration is anticipated. DSM-5 therefore
merged the previous terms of dyspareunia and vaginismus.
The use of pain-free transperineal four-dimensional ultrasound on pelvic floor muscle morphometry in women
with PVD confirmed abnormalities both at rest (e.g., small
levator hiatus area, small anorectal angle suggesting
increased tone) and with maximal contraction. These findings are thought to be consistent with weakness and poor
control of pelvic muscle.513 Pelvic floor physiotherapy is
frequently part of sexual pain management.
Management of Provoked Vestibulodynia
There is no definite association between PVD and endocrine status, but recent investigation of the presence of
polymorphism in the guanine triphosphate cyclohydrolase
gene (GCH1) is of interest. Specific single nucleotide polymorphisms (SNPs) in the GCHI gene are associated with
818
SECTION V Reproduction
reduced pain sensitivity. Although no correlation between
PVD and the pain-protective GCH1 SNP combination was
found, patients with PVD using oral contraceptives and
carrying the specified SNP combination had higher pain
sensitivity.514 This finding is in keeping with the documented clinical experience that some women with PVD
benefit from discontinuing oral contraceptives.515
Randomized trials of oral and topical medications for
PVD including tricyclics, anticonvulsants, lidocaine, flu­
conazole, cromolyn, and nifedipine gave similar results in
analgesic benefit compared to placebo.516 Investigational
botulinum toxin was statistically inferior to placebo in
reduction of sexual distress.516 Because medical treatments
for PVD have been unsatisfactory, an interdisciplinary biopsychosexual approach is currently encouraged.517,518
Although rarely chosen by women, surgical vestibulectomy can be of benefit; however, exclusion factors are
numerous519 and benefit is obtained mostly in women with
acquired as opposed to lifelong histories. Other common
negative prognostic factors for successful vestibulectomy
include comorbid muscle tightening, widespread allodynia
of the introital margin, involvement of the Skene duct
openings, unwillingness to have sex therapy if offered, and
comorbid depression and anxiety. Negative prognostic
factors for all treatment modalities include disgust and
contamination sensitivity, erotophobia (the tendency to
respond with negative effects to sexual cues), and coexistence of depression and anxiety.520
Recent research suggests an expanded stress model of
chronic pain,520,521 focusing on allostasis, which is the
physiologic stability maintained by various mechanisms
within the body that promote adaptation to stress in the
longer term. Allostatic load/overload522 depicts the wear
and tear of body systems, including the brain, from excessive stress. Given the debility and negative consequences
of recurrent pain, the stress produced by the pain disorder
maintains a vicious cycle. This cycle may be especially
applicable to the sexual pain of PVD: a stress-induced and
maintenance model for the pain of PVD was recently
described,516 similar to the vicious cycle depicted for
migraine.521 Personality traits of women with PVD, including negative self-evaluation and fear of negative evaluation
by others, predisposes to self-labeling as sexually substandard or even sexually inadequate. The stress model of pain
posits that sexual stress not only contributes to the chronic
pelvic muscle hypertonicity but also maintains a heightened reactivity of the pain circuitry from top-down modulation afforded by neuroplasticity. The cause of the
sensitization within the nervous system has not been
established with certainty, but internal stress appears to be
a likely cause. Women with PVD report higher levels of
premorbid depression and anxiety, as well as perfectionism, reward dependency, fear of negative evaluation,
increased prevalence of type D personality, self-dislike,
harm avoidance, hypervigilance for pain, and shyness
compared to women without PVD.523-527
Given that mood disorder is so commonly comorbid
with PVD, management needs to address both pain and
the depression/anxiety. There is evidence of benefit from
CBT, which was sustained over the 2 years of follow-up.528
Catastrophic thinking, amenable to CBT approaches, is
par­ticularly common in women with PVD.529 The lack of
self-acceptance apparent in women with PVD, considered
to be a pain-maintaining stress, is potentially amenable to
MBCT given that a key component of MBCT is acceptance.
Significant beneficial effects beyond waitlist control were
confirmed from a brief mindfulness-based group intervention on both cotton swab–induced vestibular pain and
psychological measures of pain.503,508
Management of Phobic Reflex Pelvic Muscle
Contractions (Vaginismus)
Heightened pelvic muscle tone, often along with muscle
tension elsewhere, may be the only physical findings in
women reporting dyspareunia or painful but unsuccessful
attempts at penetration. Often guided by pelvic floor physiotherapists, management involves progressive desensiti­
zation and progressive vaginal accommodation using a
variety of relaxation techniques and vaginal inserts.530 The
term dilators is preferably avoided, because women fear
that their therapy is going to (painfully) stretch the vagina.
Psychotherapies including mindfulness and CBT are often
used to reduce anxiety.531 A 2013 waitlist controlled study
of in-clinic physical therapy suggests better outcomes than
traditional guidance for insert therapy at home.532
Testosterone Therapy for Women With
Sexual Dysfunction
As discussed earlier in this chapter, testosterone deficiency
has not been demonstrated in women diagnosed with
sexual dysfunction, either by measurement of blood levels
or by measurement of androgen metabolites. Several
randomized trials of testosterone therapy have been conducted, mostly in postmenopausal women. These testos­
terone trials were conducted largely in women distressed
by reduced sexual desire since their menopause. The eligibility criteria for these trials did not meet the diagnostic
criteria for DSM-IV, HSDD, or for the newly coined SIAD
of DSM-5.
The first series of randomized trials showed a statistically
significant improvement in the numbers of SSEs in women
receiving testosterone: on average SSEs increased from 2 to
3 per month to 5 per month in women on active drug and
to 4 per month in women receiving placebo. Testosterone
was given transdermally in the form of a patch with a
nominal testosterone delivery of 300 µg/day. Doses of
either 150 or 450 µg/day were not effective.533 Serum testosterone and dihydrotestosterone concentrations exceeded
the target high-normal serum concentrations of these
hormones in a significant number of women receiving
testosterone.534 Women on active drug reported further
improvements in arousal, pleasure, orgasm, self-image, and
responsiveness to a statistically significantly greater extent
than did women receiving placebo.
These testosterone trials focused mostly on surgically
menopausal women, but one testosterone patch study
included naturally menopausal women535 with comparable
results. Two testosterone studies recruited naturally and
surgically menopausal women who were not receiving
estrogen therapy. One of these studies reported a significant increase in SSEs in the naturally menopausal women
from the active drug but not in the smaller subgroup of
surgically menopausal women.536 Only 464 of the 814 participants completed treatment, with similar distribution of
high discontinuation rates in all three arms. A second
study of 272 naturally menopausal women, of whom a
total of 73% of the participants were not receiving systemic estrogen therapy, showed a significant increase
in SSEs.537
On the basis of these studies, all by the same sponsor,
the transdermal testosterone patch was approved in Europe,
but not in North America or elsewhere, for the treatment
of surgically menopausal women with persistently distressing low sexual desire despite adequate systemic estrogen
therapy that did not include conjugated equine estrogens.
Although approved, the patch is no longer available in
Europe because of low sales.
CHAPTER 20 Sexual Dysfunction in Men and Women
Negative Trials of Testosterone Therapy
In contrast to the previous studies, two large phase III RCTs
by a different sponsor of 1172 postmenopausal women,
approximately half of whom received systemic estrogen,
showed no benefit of transdermal testosterone in the form
of a gel over placebo.538 Full study details are not available
as these two studies have not been published. The entry
criterion of distressingly reduced sexual desire after menopause was similar to the previous randomized trials; end
points were numbers of SSEs per month and the level of
sexual desire as assessed from a daily diary.
There is very little information available on the effects
of testosterone in premenopausal women. One study of
261 women who experienced loss of their former sexual
satisfaction reported minimal benefit from testosterone.539
Testosterone Plus a Phosphodiesterase Inhibitor
One small study evaluated the efficacy of a pharmacologic
dose of testosterone (0.5 mg sublingually) to improve
attentiveness for erotic cues in women with low desire.540
The testosterone was combined with sildenafil, a PDE
inhibitor, to facilitate genital congestion. In those women
who at baseline already showed high levels of subconscious
attention bias for erotic cues (as measured by a masked
version of the emotional Stroop task), this drug combination had no effect, and in fact, testosterone alone reduced
attention to erotic cues. However, the women with lower
arousability or sensitivity to erotic cues at baseline showed
increased physiologic genital congestion and increased
awareness of the genital sensations and of sexual desire
when they subsequently viewed an erotic video. The safety
of intermittent use of markedly supraphysiologic testosterone therapy is unknown.
Limitations of Trials of Testosterone Therapy in Women
A major limitation of testosterone trials to date is the targeted population. Studies have recruited women with
decreased desire since menopause, most of whom retained
the ability to be aroused and sexually satisfied on at least
some (on average 50%) occasions. Thus, an absence of
sexual desire between sexual encounters has been the
focus. However, research confirms this to be well within
the range of normal female sexual experience. The majority of 3250 multiethnic middle-aged women in the SWAN
cohort indicated that although moderately or extremely
sexually satisfied, they never or very infrequently felt
desire.541 In an online survey of 3687 younger women,
1865 were assessed to be without evidence of sexual dysfunction, specifically confirming their easy sexual arousal—
close to one third of this group rarely or never began a
sexual experience with a sense of sexual desire.542 As noted
earlier in this chapter, an incentives/motivations model of
human sexual response is now considered to more accurately reflect sexual experience, desire for sex per se being
just one of many reasons or incentives for sex. When
absent at the beginning of a sexual encounter, desire can
be triggered along with arousal after effective stimulation.
Clinical trials have been conducted largely in women
who were able to have satisfactory sexual experiences 50%
of the time, leading to the criticism that these women
probably did not have a biologic cause or consistent sexual
dysfunction to merit any hormonal therapy.543-545 The
studies of postmenopausal women showed improvements
in desire and response domains using validated sexual
questionnaires; however, increasing the degree and frequency of pleasure and arousal currently experienced by
819
study subjects does not necessarily imply that improvements would be observed in women with consistent
absence of pleasure and arousal.543
There has been criticism of the use of statistical significance alone to evaluate the difference between the powerful placebo effects and active drug treatments in the area
of women’s sexual dysfunction—especially that of low
desire.546,547 It is suggested that effects might be better
reported in terms of percentage of participants no longer
meeting criteria for sexual dysfunction.546 As noted, the
women in the testosterone trials were not recruited on the
basis of a clinical diagnosis of sexual dysfunction but based
on confirmation of low desire after menopause that caused
distress.
Risks of Testosterone Therapy
Long-term safety data are lacking; published safety data
from trials of up to 12 months’ duration are reassuring.547
There are theoretical reasons to consider exogenous testosterone as either a risk factor or a protective factor for breast
cancer; high endogenous testosterone may be associated
with an increased risk.545,548 A high endogenous testosteroneto-estrogen ratio can increase the risk of metabolic syndrome and CVD.549 However, some data suggest that low
SHBG may be related to the risk of diabetes, metabolic
syndrome, and CVD.550 In the Melbourne Women’s Midlife
Health Project, weight gain and free androgen index, but
not total testosterone, were strong predictors of CVD
risk.551 Similar results were observed in 9-year follow-up of
the SWAN cohort.552 In this study, free androgen index was
positively and SHBG was negatively associated with the
development of obesity. Weight gain preceded changes in
the free androgen index and SHBG. The expert panel of the
American Endocrine Society noted that the association
between the free androgen index, CVD risk factors, and the
metabolic syndrome phenotype appears to be more driven
by obesity and low SHBG rather than testosterone.548
In most randomized trials, testosterone therapy has
been administered in the background of concurrent estrogen therapy.548 However, the present advice, especially in
North America, is to limit the duration of estrogen therapy.
The Endocrine Society Task Force noted the limited safety
data (median follow-up 4 months, range 6 weeks to 2
years). Furthermore, the efficacy data are focused on sexually responsive women without the common comorbid
conditions including depression or antidepressant treatment. The task force requested a meta-analysis of transdermal testosterone RCTs; the gel studies, however, were
excluded as they are only published in abstract form.
Across all trials testosterone, used mostly in sexually
responsive women, was associated with a statistically significant improvement in satisfaction, pleasure, orgasm,
and libido.553 The Endocrine Society’s recommendations
include the following548:
1. Most studies of testosterone therapy have targeted
women with low desire but with the ability to be aroused
and sexually satisfied on at least some (on average 50%)
occasions. An incentives/motivations model of human
sexual response is now considered to more accurately
reflect sexual experience, desire for sex per se being just
one of many reasons or incentives for sex. Studies are
needed in women with low sexual interest/incentives
and low arousal (and typically few orgasms) to reflect
the prevalent clinical situation.
2. The expert panel recommended against the generalized
use of testosterone by women for infertility or sexual
dysfunction (but with the previous caveat in mind,
except for a specific diagnosis of DSM-IV HSDD).
820
SECTION V Reproduction
3. The expert panel recommended against the routine
treatment of women with low androgen levels due to
hypopituitarism, adrenal insufficiency, bilateral oophorectomy, or other conditions associated with low androgen levels because of the lack of adequate data supporting
efficacy and long-term safety of therapy.
4. The expert panel suggested consideration of a 3- to
6-month trial of a dose of testosterone resulting in a
midnormal premenopausal value of plasma testosterone
for postmenopausal women who request therapy for
properly diagnosed HSDD and in whom therapy is not
contraindicated.
Needed Research in the Area of
Testosterone Supplementation
Further research is needed in women with low sexual
interest/incentives and low arousal (and typically few
orgasms) to reflect the prevalent clinical situation and to
merit a diagnosis of SIAD. It is of note, however, that in
the study of 125 women with and 125 women without
HSDD when no group differences in androgen activity
were found, 55% of the women with HSDD also met criteria for SIAD.554
Women diagnosed with SIAD and in remission from
depression but taking antidepressants and women who,
despite treatment, still score in the depressive range again
reflect the clinical situation. Given that depression typically blunts sexual response, it has been an exclusion factor in clinical trials, as has the use of antidepressant
therapy, but the reality is that mood disorder and its treatment commonly accompany complaints of low sexual
desire.554-556 Not only is depression the factor most robustly
linked to low desire in otherwise healthy women but also
depression frequently determines the presence of sexual
dysfunction even when other medical conditions including diabetes are comorbid.20
Oral Dehydroepiandrosterone for Sexual
Dysfunction in Healthy Women
Small trials of DHEA have been conducted in older healthy
women. A recent systematic review and meta-analysis to
evaluate the benefits and risks of systemic DHEA therapy
for postmenopausal women557 included 15 randomized
trials that were in general considered at high risk of bias
and were of short duration. Statistically, DHEA use was
marginally significant for desire, and there were no other
significant improvements to outcome. The quality of evidence was considered low to moderate for benefit and very
low for long-term harm. The recent Endocrine Society Task
Force recommended against using DHEA in this setting.548
Local DHEA Therapy for Sexual Dysfunction in
Healthy Women
A recent phase III randomized trial of local vaginal DHEA
therapy in postmenopausal women with vulvovaginal
atrophy reported benefit of such therapy in improving
vaginal symptoms of dryness and dyspareunia and all
domains of sexual function.558 Moreover, all steroids, measured by mass spectrometry methods, remained in the
postmenopausal range. Specifically, ADT-G remained constant. This delivery of precursor hormones to the target
tissue may allow strictly local estrogen and androgen
actions and may be a preferable choice for women in
whom any systemic estrogen therapy is undesirable, such
as those receiving aromatase inhibitors for breast cancer
who can develop severe vulvovaginal atrophy. Rodent
work suggests that local DHEA’s beneficial effect on genital
sexual sensitivity might stem from its potent stimulatory
effect on vaginal nerve fiber density.559
Estrogen Therapy for Women With
Sexual Dysfunction
Local vaginal therapy is recommended for dyspareunia
associated with vulvovaginal atrophy. Low doses of estrogen can be supplied by a Silastic vaginal ring, vaginal
cream, or a mucoadhesive vaginal tablet with similar
benefit and low systemic absorption. Use of estradiol, 10
µg twice weekly and the estring (a Silastic ring containing
estradiol, placed high in the vaginal vault), results in serum
levels of 4.6 and 8.0 pg/mL, respectively. Progesterone is
usually considered unnecessary for endometrial protection.
Smaller doses of these formulations of estrogen are being
investigated (e.g., 10 µg rather than 100 µg estradiol cream,
0.03 mg rather than 0.2 mg estriol vaginal pessaries) or
have already been approved (e.g., 10-µg rather than 25µg estradiol vaginal tablets). When local estrogen does
not ameliorate postmenopausal vulvovaginal atrophyassociated dyspareunia, comorbid PVD may be present.560
Of concern is that women using aromatase inhibitors
and vaginal estrogen may show a small increase in serum
estradiol levels561: a prospective trial of aromatase inhibition plus vaginal estrogen is under way. Investigational
vaginal DHEA that appears not to increase serum levels of
testosterone or estrogen has not been studied in breast
cancer patients but appears promising.558 Intravaginal testosterone may alleviate symptoms,562 but any systemic
absorption could increase serum estrogen through aromatization. Of particular relevance to women with past breast
cancer is a 2013 report of a hyaluronic acid vaginal gel
improving dyspareunia in 85% of women, comparable to
women receiving vaginal estriol.563
When systemic estrogen is needed for other menopausal
symptoms, it is sometimes necessary to give additional
local estrogen for dyspareunia. In contrast, for some
women, ultra-low-dose (0.014 mg/day) systemic transdermal estradiol may be sufficient for all menopausal symptoms including dyspareunia.564 If systemic supplementation
improves insomnia and dyspareunia, sexual motivation
would logically be expected to increase, but this has not
been vigorously studied. No significant differences were
found between estrogen and placebo groups in reported
sexual satisfaction in the Women’s Health Initiative Trial.565
However, sexual dysfunction was not a primary focus of
that trial; women with marked menopausal symptoms
were excluded; and the instruments used to assess sexual
function were substandard.
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