Pharmacological Effects of Supportive Care Medications on Sexual Function
Effect of Opioids on Sexual Function
Selective Serotonin-Reuptake Inhibitors
The following sections describe the effects of various commonly used
medications on sexual function in people with cancer. People undergoing cancer
treatment are often treated with multiple medications that can cause diminished
desire or other difficulties in sexual functioning, which can add to the impact
of surgery, radiation, and chemotherapy on sexuality. Medications may
adversely affect one or more of the physiologic mechanisms (i.e., vascular, hormonal,
neurologic) that underlie normal sexual function. Drug therapy may also affect
sexual functioning indirectly through concomitant effects on mental alertness,
mood state, and/or social interactions. The evaluation of sexual problems in
people with cancer must, therefore, be comprehensive and attuned to the
multiple etiologies of these difficulties. The following sections may be
helpful in identifying some of the possible medication side effects, though
more than one may play a role in an individual.
Effect of Opioids on Sexual Function
Reduced libido is a well-known phenomenon for those using heroin or participating in a
methadone maintenance program. Unfortunately, this effect is poorly understood
by clinicians prescribing opioids for pain. Animal studies confirm that
opioids lower testosterone levels and suppress sexual function in males.[1]
Early case studies of persons using heroin or methadone described diminished
libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea
in women.[2-7] Two mechanisms are thought to be responsible for the reported
reduction in libido associated with opioid use. Opioids inhibit the production
of gonadotropin-releasing hormone, subsequently decreasing the release of
luteinizing hormone (LH), thus decreasing the production of testosterone.
Opioids also produce hyperprolactinemia, which causes negative feedback on the
release of LH and decreases the production of testosterone.[8] Opioids are
known to alter the normal function of the hypothalamic-pituitary-gonadal
axis.[9] These effects resolve after the opioid has been discontinued. Other case reports of patients receiving opioids for relief of chronic pain
suggest these same findings.[10-12] Another case-control study examined the effects of chronic oral opioid administration in survivors of cancer and, consistent with the research on intrathecal administration, found marked central hypogonadism among the opioid users with significant symptoms of sexual dysfunction, depression, and fatigue.[12] Although the limited research that has
examined the relationships among sexual functioning, chronic pain, opioid
therapy, and testosterone levels has been predominantly evaluated in men,
anecdotal clinical experience supports similar relationships in women. Empirical support has been documented for women in a study that examined the
endocrine consequences of long-term intrathecal administration of opioids.
Reduced libido was reported in 95% of the men and 68% of the women, with
significant reduction in serum LH for both groups and in serum testosterone for
the men. All of the premenopausal women (n = 21) developed either amenorrhea or
an irregular menstrual cycle, with ovulation in only one woman.[13]
The long-term effects of reduced testosterone and amenorrhea are not well
known. Sexuality is an important component of one’s quality of life,
especially for cancer survivors, but also for some people with advanced
disease. Patients may report a history of changes in libido and sexual
dysfunction. If these changes are distressing to the patient, serum total- and
free-testosterone levels and prolactin levels may be obtained.[14] Should the
patient seek improvement in libido and performance, treatment is often
empirical, keeping in mind that there are many potential causes of changes in
sexual function. Treatment options may include using nonopioids for pain,
adding adjuvant analgesics in the hope that the opioid dose may be reduced, or
replacing testosterone through injections, a patch, or gel if not
contraindicated.[15] More research is needed to understand the relationship
between opioids and sexual function, as well as the most effective treatment
strategies.
Selective Serotonin-Reuptake Inhibitors
Decreased sexual desire is a frequent symptom of depression, and sexual
impairment in depressed patients has been consistently confirmed in controlled
studies.[16,17] Continued recognition of the difficulty in
discerning the subjective complaints that are a part of the depressive
syndrome, the consequences of treatment, a pre-existing sexual dysfunction, or
a combination of these factors is needed. Approximately one-third of depressed patients
without medication treatment report reduced sexual desire, anorgasmia, delayed
ejaculation, or erectile dysfunction.[18] Selective serotonin-reuptake inhibitors (SSRIs), tricyclics, monoamine oxidase inhibitors, and lithium have all been associated with sexual dysfunction.[19,20]
Sexual desire is mediated through the central nervous system by the
reception of sensory stimuli and the subsequent interpretation through the
limbic system and prefrontal cortex.[21] Additionally, the hypothalamic and
preoptic nuclei contribute to the mediation of this process. Serotonin
inhibits hypothalamic arousal postsynaptic receptors resulting in the release
of excitatory neurotransmitters. These neurotransmitters are responsible
for the activation of the erectile centers of the spinal column. Upon
activation of the erectile centers, subsequent erection, orgasm, and
detumescence occur in males, whereas genital vasocongestion, vaginal lubrication,
and clitoral enlargement occur in females.[22] Physiologically, serotonin is
stored in synaptosomal vesicles awaiting another impulse for release. SSRIs
inhibit this uptake mechanism, which results in the pooling of serotonin in the
synaptic space.[21,23] The excess serotonin causes the postsynaptic
receptors to down-regulate, resulting in decreased stimulation of the lower
erectile centers. It is this action that is thought to be the principal
mechanism for SSRI-induced sexual dysfunction.
There are no well-controlled studies that evaluate the effects of SSRIs on
sexual function within the oncology patient population. There are several
studies, however, that have examined the effects of fluoxetine (Prozac),
fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) on sexual
function in patients being treated for depression or obsessive-compulsive
disorder. There are few data regarding the prevalence of sexual
dysfunction with the use of citalopram (Celexa) in the treatment of depression.
Sexual dysfunction from SSRIs has generally been reported to affect
approximately 1% to 15% of patients in clinical trials of these medications in
physically healthy depressed patients. Other studies, however, report
significantly higher rates of sexual dysfunction that may more accurately
reflect the incidence typical of clinical practice. A large-scale
retrospective nonrandomized comparison trial of 596 psychiatric outpatients
(167 men, 429 women) treated for at least 6 months with sertraline (n = 170),
fluoxetine (n = 298), venlafaxine (n = 36), or paroxetine (n = 265) found that
symptoms of sexual dysfunction were spontaneously reported by approximately 20%
of patients overall and were more common in men (23.4%) and married
individuals of both genders. The rates of sexual dysfunction associated with
each of the SSRIs were the following: sertraline (16%), fluoxetine (20%),
paroxetine (22%), and venlafaxine (38%). For this sample, the most common sexual
symptoms reported were orgasmic delay or anorgasmia, followed by decreased
desire and arousal difficulties.[24] A prospective multicenter study of 344
patients (152 men, 192 women) with mixed psychiatric disorders treated
with SSRIs and systematic inquiry of sexual dysfunction by the physician found
the frequency of sexual side effects was highest for paroxetine (65%), followed
by fluvoxamine (59%), sertraline (56%), and fluoxetine (54%).[25] Paroxetine
produced significantly greater delay of orgasm or ejaculation (48%) and more
frequent erectile dysfunction and vaginal lubrication difficulties than
sertraline (37% and 16%), fluvoxamine (31% and 10%), or fluoxetine (34% and 16%).
Loss of libido and anorgasmia were more severe in women, though men reported
a greater frequency of sexual dysfunction. The effects of SSRIs are dose
related and may vary among the group. The incidence of sexual dysfunction
obtained by patient self-report does not appear to reflect the true incidence
of sexual dysfunction associated with antidepressant therapy, and systematic
inquiry by providers is needed as sexual dysfunction may be an unrecognized
cause of noncompliance.[26] Two critical reviews of the effects of SSRIs on
sexual function are available.[26,27]
For individuals with premature ejaculation, SSRIs provide an effective
treatment. In a recent double-blind placebo-controlled trial of men with
lifelong rapid ejaculation, paroxetine delayed ejaculation the most, and
fluvoxamine delayed ejaculation the least. Daily doses of 20 mg of paroxetine
and 20 mg of fluoxetine may be regarded as effective treatments for lifelong
rapid ejaculation.[28] Cancer patients treated with these medications in
clinical situations may have higher rates of anorgasmia, decreased sexual
desire, and other problems, possibly because these medications
compound the difficulties cancer patients encounter from multiple etiologies.
There are several possible interventions in the management of SSRI-induced
sexual dysfunction. An obvious, though not always appropriate, possibility is
to decrease the dosage of the SSRI. Altering the timing of SSRI
administration, either by delaying doses until after intercourse or dosing
immediately before intercourse,[29] may be an effective intervention. There
are published data to suggest a drug-holiday intervention over the
weekend can improve the sexual dysfunction induced by SSRIs.[30] Another
possibility is the addition of another medication to help in the control of
SSRI-induced sexual dysfunction or consideration of another antidepressant
with less known sexual side effects. In a randomized, double-blind,
multicenter trial comparison of sustained-release bupropion (bupropion SR) and
sertraline, both were found to be similarly efficacious in the treatment of
outpatients with moderate-to-severe depression. There was a significantly
greater percentage of sertraline-induced sexual dysfunction (63% and 41% of men
and women, respectively), however, compared with bupropion SR–induced sexual
dysfunction (15% and 7%, respectively).[31]
A definitive treatment has not been established for SSRI-induced sexual
dysfunction in males or females. The oncology patient population presents with
significantly more obstacles in the management of sexual dysfunction, as
compared with patients whose symptoms are being managed with SSRIs for depression alone. The
etiology of sexual dysfunction in cancer patients is multifactorial and
complex. The above data are intended to provide practitioners and patients
with possible options in the management of SSRI-induced sexual dysfunction.
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