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Sex Matters
Emerging Sexual Therapeutics
Michael L. Krychman, MD
While pharmacologic options for treating male
sexual dysfunction continue to proliferate, the development of
such drugs for women has lagged far behind. Now, however, a number of agents
are emerging
that may help to fill this gap.
Female sexual disorders often present complex, multifaceted psychomedical
dilemmas that warrant dynamic evaluation, laboratory assessment, and
treatment. The therapeutic choices for male sexual problems have advanced
rapidly in recent years, and include both hormonal and nonhormonal
options for improving or correcting erectile difficulties. By contrast,
female sexual pharmacology is extremely limited; to date, the FDA has
approved only one therapeutic option (the EROS clitoral stimulator).
Although hormones have been the mainstay for treatment of female sexual
complaints, they are not FDA-approved for this indication.
Testosterone therapy has been linked with improved sexual desire
in androgen-deficient women, but has yet to be officially endorsed as
a therapeutic option by the FDA. Many neurophysiologic/hormonal pathways
have been implicated in sexual function, so it is reasonable that research
in pharmacokinetics has focused on potential medical interventions along
these pathways. Dopamine agonists, nitric oxide delivery systems, and
central melanocyte-stimulating hormone (MSH) analogs are all under investigation
as possible treatments. Hormonal therapy is commonly used in sexual medicine,
but many women forego this therapeutic option due to fears about possible
health consequences (eg, cancer, cardiovascular events). Today, the race
is on to develop nonhormonal pharmacologic medications for female sexual
dysfunction that are safe and effective, with a low side-effect profile.
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BUPROPION
This antidepressant, a norepinephrine reuptake inhibitor and dopamine
agonist, has been recognized for its lack of sexual side effects—in contrast
to other psychoactive drugs such as the selective serotonin reuptake inhibitors.
Bupropion is a weak blocker of serotonin and norepinephrine uptake, and
has also been used for smoking cessation. A typical trial starts at a
dose of 75 mg/d, increasing gradually as needed. Side effects include
insomnia, nervousness, and mild to moderate elevations in blood pressure,
as well as a risk of lowering the seizure threshold.
A landmark study by Segraves and Clayton assessed an escalating
dose of bupropion in women with idiopathic acquired or global hypoactive
sexual desire disorder (HSDD) in a randomized, placebo-controlled
setting.1 All
measures indicated improved sexual responsiveness, and a sexual function
questionnaire demonstrated increased sexual arousal, orgasmic completion,
and sexual satisfaction.
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FLIBANSERIN
Flibanserin, a 5-HT1A agonist/5-HT2 antagonist,
is a promising new drug that may
soon be available to treat HSDD. Under investigation worldwide,
it is now in Phase 3 trials in the United States. It has demonstrated
efficacy with minimal side effects (eg, nausea, dizziness, fatigue, sleeplessness).
Increased bleeding may ensue if flibanserin is used with aspirin or an
NSAID.
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ALPROSTADIL
Alprostadil (prostaglandin [PG]E1) is a potent, naturally occurring
vasodilator that has been used to treat male erectile dysfunction,
and may also have an important role in the regulation of blood flow to
the
female reproductive tract. It potentiates the activity of sensory
afferent nerves, such that local application to the clitoris may increase
vaginal
vasocongestion, leading to increased physical and subjective
sexual arousal. Alprostadil is not currently FDA-approved for the treatment
of female
sexual arousal dysfunction. Possible side effects include application-site
reaction, transient genital pain, lowered blood pressure, and
temporary syncope. Randomized, double-blind studies have demonstrated
mixed results,
and further research is underway.2
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APOMORPHINE
Apomorphine is a dopamine agonist that has been used as a subcutaneous injection
for the treatment of Parkinsonism, and has been researched as an oral agent
for arousal disorder. Findings have been inconclusive, however, and the drug
has been associated with emesis. One small study assessed the effect of apomorphine,
3 mg, on both subjective and objective changes in the response cycle of women
diagnosed with orgasmic dysfunction. It found that clitoral hemodynamic peak
velocities were significantly higher in the medication group, translating into
significantly better arousal and lubrication.3 The
researchers concluded that apomorphine was beneficial in women with orgasmic
problems. Side effects and
adverse events were rare, mild, and transient. Although this study was quite
small, many sexual health care professionals are optimistic about this provocative
drug.
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MELANOCYTE-STIMULATING HORMONE
The MSH analog PT-141 is a melanocortin receptor agonist under
investigation for the treatment of female sexual complaints. A
small, Phase 2A crossover pilot study examined this medication in premenopausal
women
diagnosed with arousal disorder, and reported encouraging results.
Subjects were treated with placebo or PT-141, 20 mg intranasally, followed
by vaginal
photo-plethysmography to measure blood flow and pulse amplitude
and a treatment satisfaction questionnaire. Although there were no changes
in
blood flow, there were significant changes versus placebo in arousal
and desire in the 24-hour period following PT-141 administration.
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PHENTOLAMINE
Phentolamine has been used in oral form and as a vaginal solution
to increase sexual arousal. Rubio-Aurioles et al studied this α-adrenergic
blocker in postmenopausal women with inconclusive results, and
the drug is still under investigation for possible therapeutic effects.4
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LASOFOXIFENE
Lasofoxifene is a selective estrogen receptor modulator (SERM)
that has been formulated to treat osteoporosis, showing bone-sparing and
cardioprotective effects without uterine stimulation. It may also be used
in breast cancer treatment and adjunctive therapy. It has been shown in
some studies to increase bone mineral density (BMD) and decrease low-density
lipoprotein cholesterol levels—as well as improving sexual function parameters.
However, lasofoxifene has not yet been approved by the FDA.
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TIBOLONE
Exhibiting mild estrogenic, progestagenic, and androgenic activity, tibolone is widely used in Europe, but is not currently available in the United States. It has been shown to reduce hot flashes and increase BMD, and women report that it decreases vaginal dryness and dyspareunia and improves female sexual desire. There are some medical concerns regarding lipid metabolism, hemostasis, and long-term cardiovascular and cancer risks.
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PHOSPHODIESTERASE INHIBITORS
Phosphodiesterase inhibitors (eg, sildenafil, vardenafil, tadalafil)
are FDA-approved for the treatment of male erectile dysfunction.
Randomized controlled trials have examined their efficacy in women, but
most fail to
show any significant benefit. However, Dasgupta et al demonstrated
increased genital response in women with autonomic nerve damage.5 It
is thought that these medications may increase blood flow to the
genitopelvic area and relax the clitoral and vaginal smooth muscle, but
significant data
proving efficacy with arousal latency or intensity are lacking.6 Potential
side effects include headache, uterine contractions, dizziness,
hypotension, myocardial infarction, stroke, and sudden death. Lybrido, a
European product
combining testosterone and a phosphodiesterase inhibitor, claims
to have dual effects on sexual motivation and physical sexual response,
and research
findings should be forthcoming.
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CONCLUSION
A wide variety of oral and topical formulations are under investigation
as possible treatment options for female sexual complaints. Most work is
still preliminary, but it is encouraging that both pharmaceutical researchers
and health care professionals are now addressing these distressing disorders.
More randomized, double-blind clinical trials are needed to examine differing
populations, larger sample sizes, and long-term effects.
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Michael L. Krychman, MD, is Medical Director of Sexual Medicine, Hoag Hospital, Newport Beach, CA; Executive Director, Southern California Center for Sexual Health and Survivorship Medicine; and Certified Sexual Counselor (American Association of Sexuality Educators, Counselors, and Therapists). He is a board member of The
Female Patient.
References
- Segraves RT, Clayton A, Croft H, Wolf A, Warnock
J. Bupropion sustained release for the treatment of hypoactive
sexual desire in premenopausal women. J Clin Psychopharmacol.
2004;24(3): 339-342.
- Kielbasa LA, Daniel KL. Topical alprostadil
treatment of female sexual arousal disorder. Ann Pharmacother.
2006;40(7-8):1369-1376.
- Bechara A, Bertolino MV, Casabe A, Fredotovich
N. A Double-blind randomized placebo control study comparing
the objective and subjective changes in female sexual response
using sub-lingual apomorphine. J Sex Med. 2004;1(2): 209-214.
- Rubio-Aurioles E, Lopez E, Lopez M, et al.
Phentolamine mesylate in postmenopausal women with female sexual
arousal disorder: a psychophysiological study. J Sex Marital
Ther. 2002;(28 Suppl 1):205-215.
- Dasgupta R, Wiseman OJ, Kanabar G, Fowler CJ,
Mikol DD. Efficacy of sildenafil in the treatment of female sexual
dysfunction due to multiple sclerosis. J Urol. 2004;171(3):1189-1193.
- Shields KM, Hrometz SL. Use of sildenafil for female
sexual dysfunction. Ann Pharmacother. 2006;40(5):931-934.
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