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Understanding and Treating Female Sexual Dysfunction: An Update on Current Literature

By: Sheryl A. Kingsberg, Ph.D.; James A. Simon, MD, CCD, NCMP, IF, FACOG

This course has expired. You can still review the content but course credit is no longer available.

Supplement Credits: 1

Female sexual dysfunction (FSD) is an overall umbrella disease that may affect as many as 40 million women in the U.S., with prevalence rates cited from 30% to as high as 80%. The etiology of FSD, however, is less well-defined or understood. Comprising both physiological and psychological aspects, FSD can manifest in a variety of ways. This educational activity will include discussions on the definition, prevalence, diagnosis and related guidelines for managing this disease state.

Expiration Date: Thursday, January 31, 2019
Release Date: January 2018

Learning Objectives

Upon completion of this activity, the participant should be able to:

  • Discuss treatment options for women with female sexual dysfunction, including the first-available medication for a specific type of female sexual dysfunction
  • Discuss the prevalence of female sexual dysfunction and counseling programs
  • Evaluate the differences in definitions, severity criteria, and duration of disease for female sexual dysfunction as published in DSM-5

Accreditation and Designation Statement

Accreditation Statement
Evolve Medical Education LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

AMA Credit Designation Statement
Evolve Medical Education LLC designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credit(s)™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Grantor Statement
This continuing medical education activity is supported through an educational grant from Valeant Pharmaceuticals North America LLC.

Faculty and Disclosures

Anita H. Clayton, MD
David C. Wilson Professor and Chair
Department of Psychiatry & Neurobehavioral Sciences
Professor of Clinical Obstetrics & Gynecology
Charlottesville, VA

Sheryl A. Kingsberg, Ph.D.
Chief, Division of Behavioral Medicine
Department of OB/GYN
MacDonald Women’s Hospital
University Hospitals Cleveland Medical Center
Professor, Departments of Reproductive Biology and Psychiatry
Case Western Reserve University School of Medicine
Cleveland, Ohio

James A. Simon, MD, CCD, NCMP, IF, FACOG
Clinical Professor
Department of OB/GYN
George Washington University
Medical Director
Women’s Health & Research Consultants
Washington, DC




The following faculty members have the following financial relationships with commercial interests:

Anita H. Clayton, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board/Speaker’s Bureau: Forest, now Allergan; Palatin Technologies; S1 Biopharma; Sprout Pharmaceuticals, a division of Valeant. Grant/Research Support: Aspex Pharmaceuticals; Axsome; Forest Research Institute, now Allergan; Genomind; Janssen; Palatin Technologies; and Takeda Pharmaceuticals. Stock Shareholder: Euthymics and S1 Biopharma. Royalties/Copyright: Ballantine Books/Random House; Guilford Publications; Changes in Sexual Functioning Questionnaire.

Sheryl A. Kingsberg, PhD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board/Speaker’s Bureau: AMAG Pharmaceuticals, Inc.; Emotional Brain; Endoceuticals Inc; Palatin Technologies; and Valeant Pharmaceuticals North America LLC. Grant/Research Support: Palatin Technologies.

James A. Simon MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board/Speaker’s Bureau: AbbVie, Inc.; Allergan, Plc; AMAG Pharmaceuticals, Inc.; Amgen Inc.; Apotex, Inc.; Ascend Therapeutics; Azure Biotech, Inc.; Eisai, Inc.; JDS Therapeutics, LLC; Merck & Co., Inc;  Millendo Therapeutics, Inc.; Noven Pharmaceuticals, Inc.; Novo Nordisk;  Nuelle, Inc.; Perrigo Company, PLC; Radius Health, Inc.; Regeneron Pharmaceuticals, Inc.; Roivant Sciences, Inc.; Sanofi S.A.; Sebela Pharmaceuticals, Inc.; Sermonix Pharmaceuticals, Inc.; Shionogi Inc.; Sprout Pharmaceuticals; Symbiotec Pharmalab; TherapeuticsMD; and Valeant Pharmaceuticals. Grant/Research Support: AbbVie, Inc.; Actavis, PLC; Agile Therapeutics; Bayer Healthcare LLC.; GlaxoSmithKline’ New England Research Institute, Inc.; Novo Nordisk; Palatin Technologies; Symbio Research, Inc.; and TherapeuticsMD. Patent and Trademark Holder: U.S. Patent: 4,816,257, March 28, 1989: “Method for Producing an In Vivo Environment Suitable for Human Embryo Transplant.”, U.S. Trademark: Reg. No. 3,446,895, Registered June 10, 2008: “You talk…I’ll Listen. We’ll Plan Together”. U.S. Trademark: Reg. No. 3,676,269, Registered September 1, 2009: U.S. Trademark: Reg. No. 3,760,080, Registered March 16, 2010: “Women’s Health & Research Consultants & Design”, U.S. Trademark Serial No.:86-714,153. “DR. SIMON SAYS” Registered February 2, 2016. Stock Shareholder and/or other Financial Support: Sermonix Pharmaceuticals.


Michelle Dalton, Writer, and Cheryl Cavanaugh, MS, Evolve Medical Education LLC, have no real or apparent conflicts of interest to report.

Rishi P. Singh, MD, Peer Reviewer,  has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board/Speaker’s Bureau:  Alcon; Allergan  Inc.; Carl Zeiss Meditec; Genentech, Inc; Optos; Regeneron Pharmaceuticals, Inc; and Shire Plc. Grant/Research Support: Alcon; Apellis Pharmaceuticals; Genentech, Inc; and Regeneron Pharmaceuticals, Inc.


This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Evolve Medical Education LLC or Valeant Pharmaceuticals North America LLC.


Sexuality is important to the quality of life of human beings, and sexual problems are common
in women across all ages. Female sexual dysfunction (FSD) is an umbrella of conditions that may
affect as many as 40 million women in the United States, with a community prevalence ranging
from 30% to 80%.1-5 There are several specific sexual dysfunctions that occur among women including
hypoactive sexual desire disorder (HSDD), female sexual arousal disorder, female orgasmic disorder,
and pain during sex, all of which are persistent, recurrent problems and cause personal distress.6
A woman may have one sexual disorder or one primary dysfunction and other comorbid conditions.

HSDD is the most prevalent sexual dysfunction in women, impacting 1 in 10 women across all ages.7,8
HSDD significantly reduces quality of life and self-worth, leading to profound societal and economic
impact on patients.9

Sexuality is best understood from a biopsychosocial perspective and there can be a variety of
etiologic causes of sexual problems including physiological and psychological causes of sexual
problems, as well as diseases having downstream consequences on sexual function such as multiple
sclerosis, autoimmune disorders, diabetes, and the use of medications such as antidepressants,
anxiolytics, or anti-hypertensives.2,5,10-12 By understanding the overlapping biopsychosocial
etiologies, providers can determine the underlying causes of FSD and select appropriate treatment.13
Treatment is often multidisciplinary, including medical and psychological interventions.

Despite its prevalence, health care providers struggle with asking about sexual concerns and treating
sexual dysfunctions. This is due to several factors, including: lack of awareness of the latest
guidelines; the uncomfortable nature of discussing the topic with patients; and the limited number
of safe, effective therapies approved by the Food and Drug Administration (FDA).7 Flibanserin is
currently the only FDA-approved treatment for premenopausal women with HSDD. Comparatively, there are
more than two dozen medications commercially available for male sexual dysfunction; however, there are
currently more than 70 clinical trials recruiting patients for clinical trials designed to evaluate
treatments or determine prevalence of FSD.



There are a number of models posited to describe a healthy sexual response and most include at least
three phases of sexual functioning: (1) desire; (2) arousal, which can occur in the brain and in the
periphery; and (3) orgasm. These are impacted by excitatory neurotransmitters and hormones and inhibitory neurotransmitters and hormones.14

The primary hormones that have a positive effect on sexual functioning are estrogen, testosterone,
and oxytocin. Estrogen and testosterone levels change throughout the menstrual cycle, peaking
midcycle to improve receptivity and desire at the time when a woman is most fertile. Melanocortins
also have a positive impact on dopamine and norepinephrine function (Figure 1).14



Figure 1. The primary hormones that have a positive effect on sexual functioning are estrogen, testosterone, and oxytocin. 14

Inhibiting neurohormonal effects on sexual function primarily come from prolactin and from the
neurotransmitter, serotonin. Excessive prolactin production, known as hyperprolactinemia, has a
negative impact on desire. This is found commonly in women who are breastfeeding or on antipsychotic medications.
In the periphery, adequate hormonal function is necessary for functional anatomy, but some neuro-
transmitters also have an effect in the periphery. Nitric oxide has a positive effect, as does
norepinephrine, but they tend to be negatively impacted by serotoninergic activity. This may involve
negative effects on sensation, including hyperalgesia, and diminished sensation in the genitalia (Figure 2).14


Figure 2. In the periphery, adequate hormonal function is necessary for functional anatomy, but some neurotransmitters also have an effect

Sexual function means being responsive to excitation and inhibition elements, and there are psychological,
social, and cultural factors that can turn sexual desire on and off. The physiology of sexual function is a
balance between excitatory and inhibitory chemicals. Physiologic and organic factors that contribute to
excitation include: neurotransmitters such as dopamine, norepinephrine, and nitric oxide; hormonal neural
modulators, such as oxytocin, vasopressin, and melanocortins; and sex steroids, such as estrogen and
testosterone. These work in tandem to allow a sexual tipping point, ie, to become excited.15

These cellular components and the communication between cells also interact in a network, known as
a sexual reward system. It has some specific circuitry, mostly involving glutamatergic projections
and GABAergic neurons. Most of this activity involves the medial preoptic area and the nucleus accumbens.

The physiology of sexual function includes excitatory chemicals, which are balanced against and
blunted by inhibitory systems. These account for periods of sexual refractoriness, primary aversion,
or secondary avoidance. Dysfunction occurs with hyperactive inhibition, hypoactive excitation, or both.
Dynamic alterations in this balance also may be modulated or reinforced by experience and behavior,
which represents neuroplasticity.


The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 reduces FSD classification into
three dysfunctions: sexual interest/arousal disorder (which now includes HSDD); genito-pelvic pain/penetration disorder; and female orgasmic disorder (now differs from male sexual dysfunctions). Sexual aversion
disorder sexual dysfunction due to a medical condition, and “not otherwise specified” are not included
in FSD classification.16 Patients must experience symptoms of the disorder a minimum of 75% of the time
before a diagnosis of FSD can be made (excluding substance-or medication induced disorders). Finally,
and importantly, the condition must result in significant distress to the patient in order to qualify
as FSD.16

With a new exclusion criterion and a new group of criteria that includes partner factors, relationship
factors, individual vulnerability factors, cultural or religious factors, and medical factors, the
DSM-5 has completely changed the sexual dysfunction categorization and,therefore, the subsequent
diagnostic guidelines.16

There are those who disagree with the DSM-5 revisions, and suggest they will inadvertently exclude
large numbers of patients with either low desire or arousal issues, but not both.17,18 Clayton et al
further argued some patients would be excluded under the new criteria because they present with an
incomplete loss of receptivity.19 Under the new guidelines, sexual aversion disorder was removed
altogether as a sexual dysfunction, in that the similarities between it and other phobias and anxiety
disorders were more persuasive.


A more appropriate nomenclature for FSD was posited by the International Society for the Study of
Women’s Sexual Health.20 Criteria require that an individual with HSDD has any of the following
symptoms for at least 6 months: (1) a lack of motivation for sexual activity as manifested by reduced
or absent spontaneous desire; (2) reduced or absent responsive desire to erotic cues and to stimulation;
or (3) a loss of the desire to initiate or participate in sexual activity.

Other symptoms include a lack of sexual thoughts or fantasies, the inability to maintain desire or
interest through sexual activity, and avoidance of situations that could lead to sexual activity.
These symptoms, and the loss of desire, are not secondary to a sexual pain disorder and must be
combined with clinically significant personal distress including frustration, aggravation, grief,
incompetence, a sense of loss and/or feelings of anger, sadness, sorrow, dissatisfaction, or worry.21


Researchers have been studying FSDs for many years. The National Health and Social Life Survey included
interviews with 1,749 women between the ages of 18 and 59 years. Approximately 43% of the women
interviewed had a sexual complaint; among those, 33% lacked sexual interest, 25% had difficulty achieving
orgasm, and 1 in 5 experienced pain during sex. Distress was not evaluated.22

The PRESIDE study did evaluate sexual complaints using the Changes in Sexual Functioning Questionnaire
(CSFQ), and the Female Sexual Distress Scale (FSDS-R) to evaluate for sexually associated distress.8
The 31,581 female respondents (response rate of 63%), aged 18 years and older were from 50,002 households
sampled from a national research panel representative of US women. Greater than 80% of respondents
were white, more than half had a high school education, about 75% had a current partner, and 60% were

Similar to the Laumann et al study,22 many of the same sexual complaints and problems were reported
in the PRESIDE study.8 About 33% of respondents had complaints of desire, 25% had challenges with
arousal, and 1 in 5 had issues with orgasm. However, when distress was added to the sexual complaint,
the numbers dropped significantly: about 10% of women reported distressing low sexual desire and about
5% of women reported distressing low arousal or problems with orgasm function. Pain with sexual activity
was not assessed.

Extrapolated, this means nearly 50% of female patients will have sexual function concerns. This is
not an insignificant problem. It affects many patients, even if they aren’t expressing it during regular
office visits. Patients are often uncomfortable discussing sexuality because they are embarrassed and
don’t realize it is an appropriate discussion to have with a health care professional. Providers
cannot treat a problem if they don’t know it exists, so they must bring up the subject with patients.


There are a number of modifiable factors impacting sexual functioning that should be addressed prior
to a sexual disorder diagnosis. Various illnesses impact sexual functioning, such as psychiatric
conditions, cardiovascular disease, neurological disorders, urological problems, and endocrine dysfunction,
such as diabetes and thyroid disease.23-38

The most common comorbid condition with FSD is depression, which was evaluated in the PRESIDE study.
About 40% of the women with complaints of sexual function and distress also said they were depressed
or were being treated with antidepressant medications.8 After adjusting for prevalence, about 6% of
women with distress reported low desire without any comorbid depression, and about 3% of women reported
distress plus low levels of arousal or distress with orgasmic dysfunction (Figure 3).39



Figure 3. After adjusting for prevalence, about 6% of women with distress reported low desire without any comorbid depression, and about 3% of women reported distress plus low levels of arousal or distress with orgasmic dysfunction.

Depression and sexual dysfunction have a bidirectional relationship, meaning having one puts the person
at increased risk for the other. One meta-analysis looked at more than 1,000 citations but ultimately
included only eight; six of which had studies on depression looking at the risk for sexual dysfunction,
and six involved sexual dysfunction and the risk for developing major depressive disorder.40

Depression was associated with a 50% to 70% increased risk of developing sexual dysfunction, whereas
having a sexual dysfunction was associated with a 130% to 210% increased risk of developing major
depression.40 The take-home message from this 2012 metaanalysis is that patients with depression should
be assessed for FSD, and patients with FSD should be assessed for depression.

A number of medications also contribute to an increased risk for developing sexual dysfunction,
including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine
reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).41-49 Cardiovascular medications,
such as beta blockers, alpha blockers, diuretics, lipid-lowering agents, and digoxin also contribute
to sexual dysfunction. Oral contraceptives can also be associated with sexual dysfunction because of
increasing levels of sex hormone-binding globulin, which lowers testosterone, and subsequently, sexual
desire. The other medications that are often unrecognized as contributing to sexual dysfunction include
chronic use of H2 blockers, opioids, and nonsteroidal anti-inflammatory drugs.50-52


There is no “right” time to screen for FSD; it can occur anytime a health care provider feels it
appropriate53—no matter the primary reason the patient presented for an exam. It’s important that
clinicians normalize FSD and not shy away from the topic out of fear of embarrassing patients.
Informing patients that questions about sexual behavior are routine because it’s important to overall
health and quality of life is a way of legitimizing the topic.53

Practitioners should be aware when they see a patient who is peri- or postmenopausal that there are
many vulvar and vaginal changes associated with menopause and the lack of estrogen to the genitourinary
system. These can cause dryness with sexual activity or pain, either with vaginal penetration or touching.
Even gentle caressing can be painful for some women. Many women are reluctant to admit to themselves or
to their partners that this is an issue. They oftentimes don’t even tell their practitioners, which is
why clinicians must broach the issue.

It’s important to be mindful of body language and be comfortable with the terminology. Some experts
have suggested sitting down rather than standing during these discussions with patients. This helps
to convey the message that this is an issue worth making time for. Patients are more likely to answer
honestly if the treating physician is comfortable talking about sex. Ask open-ended questions (for
example, “What sexual concerns do you have?”), and give the patient time to respond. A moment of silence
is normal.

It is also imperative not to make assumptions about relationships and sexual partners. Just because a
person is not in a relationship doesn’t mean they don’t have a sexual concern. In fact, a lack of
involvement in a relationship may be the result of a sexual problem. When talking to patients about
partners, use of gender-neutral pronouns is best whenever possible.

Screening does not take long. When the individual has a sexual complaint, sexual assessments should
include the following:

• What is the nature of the problem, and what is the nature of the complaint?
• Are there multiple complaints?
• Does the complaint involve several phases of the sexual response cycle?
• What is the duration of the problem?
• How did the problem begin? Did it begin at a specific time with a situational
change, with a diagnosis with another medical condition, postpartum, or the
addition of a medication?
• Is that complaint situational? Does it just involve a single partner
in certain situations?
• Is the complainant generalized, impacting all sexual situations?
• What is their level of distress, and what is the nature of the distress?
Did they previously have what they considered an adequate level of function
such that they were satisfied?

The Decreased Sexual Desire Screener (DSDS) is a simple and effective HSDD screening tool consisting
of five questions and takes about 3 minutes to complete (Figure 4).54 The first four questions relate
to the following areas: (1) level of desire and satisfaction; (2) presence of decreased desire;
(3) tolerance of decreased desire; and (4) need for improvement of desire.

The fifth question looks at potentially modifiable variables. Some of these variables may be either
the cause of lost sexual desire or corollary conditions. The answers to question five may help to provide
information that helps address causative factors or conclude that the patient needs psychotherapy or
pharmacologic treatment options. For example, if there’s dissatisfaction with the relationship of the
partner, counseling may be appropriate. Although stress and fatigue are not specific risk factors, they
may require workup.



Figure 4. The Decreased Sexual Desire Screener is a simple and effective screening tool consisting of five questions and takes about 3 minutes to complete

If modifiable factors are present, such as a medical or psychiatric diagnosis, medications or other
substances, these should be addressed prior to making a diagnosis or interventions for the sexual
complaint. A physical exam may be needed if there are complaints of arousal or orgasmic dysfunction
or sexual pain.


The current standard of care for patients suffering with HSDD fall into several different categories,
including nonpharmacological approaches and prescription medications.55 Nonpharmacological treatments
include counseling, psychotherapy, mindfulness training,and cognitive behavioral therapy (CBT).

Many women use over-the-counter treatments for sexual dysfunction. These products are unregulated and
have illustrated little efficacy above and beyond their placebo effect in clinical trials.56 Until
recently, all prescription medications, such as testosterone, bupropion, and buspirone, were used
off-label in the treatment of HSDD. Flibanserin is now an FDA-approved option for HSDD in premenopausal

Sexual dysfunction can be the result of psychological, interpersonal, and/or biological factors. CBT
is a straightforward treatment that may help women alter negative thoughts, beliefs and expectations
that can interfere with sexual desire. It can help overcome negative beliefs about sex, improve
communication with their partners, and resolve other underlying issues.

There are a limited number of studies looking at psychotherapy in the treatment of FSD and HSDD,
none of which utilize an adequate control paradigm. However, CBT and mindfulness-based therapy appear
to have some utility based on open-label treatment studies.57,58

Many women have sexual dysfunction as a result of abuse or negative experiences with past or current
partners. Incorporating couples counseling into treatment can oftentimes bring those issues to the
forefront. Couples who have had long-term sexual problems may have a number of new communication barriers
related to the sexual dysfunction that didn’t exist before the dysfunction. In our cumulative experience,
we have found couples therapy can be extremely helpful in those cases.

If psychotherapy is deemed unnecessary or is ineffective, then it is reasonable to go directly to
pharmacotherapy. Some experts have discussed combining psychotherapy with medication, but there are
no good data to support this approach—yet.

Measuring Sexual Function
The FDA evaluates pharmacologic treatments based on safety and efficacy and requires sponsors of
investigational drugs to use validated measures of sexual function and distress in clinical trials.
The Female Sexual Function Index desire domain (FSFI-D), the Female Sexual Distress Scale-Revised
(FSDSR), and the number of satisfying sexual events (SSEs) are the most commonly used measures and
were measures used in the pivotal trials for flibanserin. The FSFI is a 19-item, self-reported measure
based on the prior 28 days and is validated by total score and subdomains including desire, arousal,
lubrication, orgasm, pain and satisfaction.

The FSDS-R was revised in 2008 to address low desire with the question, “How bothered are you by your
low desire, and rate that as zero, one, two, three or four as never, rarely, occasionally, frequently,
or always.”

An SSE is defined as sexual intercourse, oral sex, masturbation,or genital stimulation by the partner
with determination by the woman as to whether the event was gratifying, fulfilling, satisfactory, or
successful; orgasm is not a requirement to meet this definition. Therefore, SSEs are not necessarily
a reflection of desire, despite the FDA’s classification. SSEs were derived for this use from an erectile
dysfunction model of successful sexual eventswhen drugs such as sildenafil citrate, vardenafil hydrochloride,
and tadalafil were developed. It was easy to count whether a man had an adequate erection because his
penis either was or was not rigid enough for intercourse.

Desire is difficult to measure and is not necessarily a reflection of the number of SSEs that occur,
in that SSEs may be removed from desire. For example, a woman may be very desirous but may not have
a sexual event because her husband is out of town or she’s upset with him. Women may experience significantly
improved desire or even arousal, but not choose to engage in sexual behaviors for a variety of different
reasons, whether they are practical, behavioral, or interactional.59

Flibanserin is a multimodal agent of 5-hydroxytyptamin (5-HT)serotonin type 1A receptors and an
antagonist of 5-HT type 2A receptors. Originally in development as an antidepressant, the compound
was not more effective than placebo in treating major depression, but was found to improve scores
on sexual desire endpoints. The mechanism by which the drug improves sexual desire and related distress
is not known but is hypothesized to increase dopamine and norepinephrine (excitatory systems) and
decrease serotonin (inhibitory neurotransmitter) in the prefrontal cortex.60,61

The BEGONIA study62 compared flibanserin 100 mg once daily (n = 542) to placebo (n = 545) for 24 weeks.
The average patient in the trial was 36 years old with generalized, acquired HSSD who had reduced or
absent interest in sexual activity for about 5 years. The lack of desire couldn’t be explained by a
drug, device, fatigue, recent birth, breastfeeding, or a hormonal imbalance. All patients in the trial
were in a stable, monogamous relationship for at least 1 year, with an available sexually functional
partner willing to try sexual activity one or more times a month.

According to the study findings, the lack of desire didn’t prevent them from having some SSEs.62
Patients were having sex about five times a month whether or not they had interest, with 2.5 SSEs
per month at baseline. Patients with female sexual arousal disorder (FSAD) and female orgasmic dysfunction
(FOD) as their primary dysfunction were excluded. However, these patients were included in the study if
FSAD and FOD were found to be secondary to their low desire.

Flibanserin 100 mg at bedtime significantly increased the number of SSEs compared with placebo
beginning at week 4, and continued to endpoint at 24 weeks. In addition, the desire score on the FSFI
also increased by the fourth week of treatment.62

Flibanserin is currently the only FDA approved treatment for HSDD in premenopausal women.63

The most common adverse events, somnolence, nausea, and fatigue, which occurred in about 10% of
patients (Figure 5). Most of the adverse events were transient or episodic, mild to moderate in
severity, and decreased over time. Flibanserin is also associated with weight loss, although the
exact mechanism for why remains unknown. Flibanserin should not be mixed with alcohol due to hypotension
or syncope-related adverse events.62 Clinically significant adverse events of hypotension and syncope
were observed in three phase 1 studies of flibanserin that involved daytime dosing and either high
exposure due to coadministration of a CYP3A4 inhibitor, direct administration of a supra-therapeutic
dose of flibanserin,or concomitant significant alcohol use.63




Figure 5. The most common adverse events in the phase 3 flibanserin trials included dizziness, somnolence and nausea. Most were mild to moderate in intensity and most began within the first 14 days of treatment.

The FDA has required a Risk Evaluation and Mitigation Strategy(REMS) to ensure the benefits of
flibanserin outweigh the increased risk of hypotension and syncope due to an interaction with alcohol.64

The side-effect profile has added to the debate about the drug,65 but literature confirms the role the
medication may play in women’s health.63,66 Although increasing effects continue beyond 12 weeks of dosing,
if no response is seen by week 8 of treatment, continued administration is not likely to be effective,
according to the clinical data.

Several other studies were used as pivotal studies for the FDA approval, such as SUNFLOWER, VIOLET,
and DAISY.67-69 All studies showed that flibanserin increased desire in 46% to 60% of patients (Figure 6).
About 46% reported an increase in SSEs, 50% had an increase in their FSFI desire score, and about 60% had
a decrease in sexually related distress.


Figure 6. The results were highly significant. By 24 weeks, 46% to 60% of patients had significant benefit from flibanserin when applying this responder analysis.

There were three significant study endpoints, according to the FDA: the number of SSEs, the impact of
the treatment on desire, and the impact of the treatment on lowering distress. In each of these trials,
the flibanserin group (100 mg at bedtime) was superior to placebo in the rise in number of SSEs,
increased sexual desire, and decreased sexual distress. These were reproducible finding across all three
of clinical trials (Figure 7).62, 67, 68 

Testosterone is commonly used as an off-label treatment for low sexual desire in postmenopausal women,
and it has been shown to increase and improve sexual activity. 70 Prior to the availability of
flibanserin, trials were conducted for a testosterone patch with a 300-μg dose of transdermal
testosterone for the treatment of HSDD in naturally and surgically postmenopausal women. Transdermal
testosterone was studied in a number of placebo-controlled, randomized clinical trials.71-73

Clinical trials of the testosterone patch showed a statistically significant increase in the number of
SSEs and sexual desire, and a decrease in sexual distress. Although transdermal testosterone was never
approved in the United States due to unrealized concerns regarding long-term safety, it was made
available in Europe, and a number of additional studies were performed there. One such study was the
APHRODITE trial.74 Results showed that testosterone use in postmenopausal women with HSDD not only
increased desire, but also statistically and significantly increased arousal, orgasm, and pleasure.
It also reduced sexual concerns and increased sexual responsiveness and the woman’s self-image.
Testosterone safety was assessed over 48 months. There were no clinically relevant changes in lipids,
liver function tests, hematology, or carbohydrate metabolism. There was a small increase in blood pressure
(< 2 mm Hg). There was also an increase in the rate of breast cancer, which was expected given the
Surveillance, Epidemiology, and End Results database and the increase in the frequency of breast cancer
with age.74


Figure 7. In each of the three pivotal trials, the flibanserin group (100 mg at bedtime) was superior to placebo in the rise in number of SSEs, increased sexual desire, and decreased sexual distress.

Bupropion and Buspirone
Bupropion and buspirone are two off-label mediations that have historically been used for treating HSDD.

Bupropion is a norepinephrine-dopamine reuptake inhibitor that results in increased norepinephrine
and dopamine function, and has been shown in small clinical trials to improve sexual function.75-77
Bupropion sustained release 400 mg/day demonstrated an increase in arousal and orgasm scores in women
with HSDD that were statistically significantly better than placebo over the course of a few months
of treatment.77

Buspirone is a unique partial agonist at the 5-HT1A receptor, which is associated with increased sexual
desire. Buspirone has been shown to improve sexual function when added to SSRIs for treatment of depression, specifically for patients whose sexual dysfunction persisted despite improvement in their depression.78
Landén et al showed that 58% of subjects treated with 30 to 60 mg/day of buspirone reported an
improvement in sexual function, compared with 30% treated with placebo.79

One important consideration is that dopamine receptor agonist drugs have a strong signal associated
with impulse control disorders (n = 710; PRR = 277.6, P < .001).80 The association was strongest for
the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5,
P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole,
an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001).
Increases in dopamine and have been associated with hypersexuality, in pathological gambling, and
compulsive shopping.80

There are many more studies under way with additional treatment options with unique mechanisms of
action being investigated for future FDA approval.


Once a patient has been identified as a candidate for treatment, it’s important to manage expectations
through education that under promises and over delivers. Most patients will see some benefit in
6 to 8 weeks on medication. Focusing on when the patient is likely to see a benefit is more effective
than discussing how beneficial the treatment may be. This approach sets low expectations for what
a treatment is going to do, but gives patients a time frame for any anticipated changes.


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