Female Sexual Dysfunction (FSD)

Number: 0574

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses Female Sexual Dysfunction (FSD).

1. Medical Necessity

   Note: See Pharmacy Clinical Policy Bulletins for: Vyleesi (bremelanotide injection) for the treatment of pre-menopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), and for Osphena (ospemiphene tablets) for severe vaginal dryness and dysparenuia due to menopause..

2. Experimental and Investigational

   1. Aetna considers biothesiometry experimental and investigational for the diagnosis of FSD.
   2. Aetna considers the following interventions for the treatment of FSD experimental and investigational becasue of insufficient evidence:
      
      
      • Bibliotherapy
      • Biothesiometry
      • Botulinum toxin
      • Female erectile devices (e.g., Eros clitoral stimulation device)
      • Gene therapy
      • Growth factor therapy
      • Hyaluronic acid
      • Laser therapy (e.g., Micro-ablative carbon dioxide laser)
      • Oxytocin
      • Percutaneous tibial nerve stimulation
      • Phosphodiesterase type 5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil)
      • Progesterone
      • Radiofrequency thermal therapy (e.g., the ThermiVa procedure, and the Viveve procedure)
      • Regenerative medicine
      • Sacral neuromodulation
      • Stem cell-based therapies
      • Testosterone therapy (implant or injection - see CPB 0528 - Androgens and Anabolic Steroids)
      • Topical lidocaine
      • Transcranial direct current
      • Vaginal electrical stimulation.

3. Policy Limitations and Exclusions

   Some Aetna plans exclude drugs or supplies for sexual dysfunction or inadequacy. Please check benefit plan descriptions for details.
   
   Aetna does not cover vibrators, which have been used in the treatment of FSD because vibrators do not meet Aetna’s contractual definition of covered durable medical equipment (DME).  Please check benefit plan descriptions. Coverage of DME is limited to devices that are not normally of use in the absence of illness or injury.  Vibrators are not primarily a medical device, and may be of use in the absence of illness and injury.
   

4. Related Policies

   •  CPB 0528 - Androgens and Anabolic Steroids

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes not covered for indications listed in the CPB:
Stem cell based therapies for female erectile devices, biothesiometry, Viveve Procedure, vaginal electrical stimulation, ThermaVi, transcranial direct current, bibliotherapy - no specific code:
0552T	Low-level laser therapy, dynamic photonic and dynamic thermokinetic energies, provided by a physician or other qualified health care professional
0672T	Endovaginal cryogen-cooled, monopolar radiofrequency remodeling of the tissues surrounding the female bladder neck and proximal urethra for urinary incontinence
17110	Destruction (eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; up to 14 lesions [micro-ablative carbon dioxide laser]
17111	15 or more lesions [micro-ablative carbon dioxide laser]
64566	Posterior tibial neurostimulation, percutaneous needle electrode, single treatment, includes programming
Other CPT codes related to the CPB:
11980	Subcutaneous hormone pellet implantation (implantation of estradiol and/or testosterone pellets beneath the skin)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes not covered for indications listed in the CPB:
Topical lidocaine for the treatment of female sexual dysfunction (FSD) - no specific code
J0585	Injection, onabotulinumtoxinA, 1 unit
J0586	Injection, abobotulinumtoxinA, 5 units
J0587	Injection, rimabotulinumtoxinB, 100 units
J0588	Injection, incobotulinumtoxinA, 1 unit
J1071	Injection, testosterone cypionate, 1 mg
J2320	Injection, nandrolone decanoate, up to 50 mg
J2590	Injection, oxytocin, up to 10 units
J2675	Injection, progesterone, per 50 mg
J3121	Injection, testosterone enanthate, 1 mg
J3145	Injection, testosterone undecanoate, 1 mg
J7318	Hyaluronan or derivative, Durolane, for intra-articular injection, 1 mg
J7320	Hyaluronan or derivative, GenVisc 850, for intra-articular injection, 1 mg
J7321	Hyaluronan or derivative, Hyalgan, Supartz or Visco-3, for intra-articular injection, per dose
J7322	Hyaluronan or derivative, Hymovis, for intra-articular injection, 1 mg
J7323	Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose
J7324	Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose
J7325	Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg
J7326	Hyaluronan or derivative, Gel-One, for intra-articular injection, per dose
J7327	Hyaluronan or derivative, Monovisc, for intra-articular injection, per dose
J7328	Hyaluronan or derivative, GELSYN-3, for intra-articular injection, 0.1 mg
J7329	Hyaluronan or derivative, Trivisc, for intra-articular injection, 1 mg
J7331	Hyaluronan or derivative, SYNOJOYNT, for intra-articular injection, 1 mg
J7332	Hyaluronan or derivative, Triluron, for intra-articular injection, 1 mg
S0090	Sildenafil citrate, 25 mg
S0189	Testosterone pellet, 75 mg
ICD-10 codes covered if selection criteria are met:
N90.5	Atrophy of vulva
N94.10 - N94.19	Dyspareunia
N95.2	Postmenopausal atrophic vaginitis
ICD-10 codes not covered for indications listed in the CPB:
F52.0 - F52.1 F52.22 - F52.31 F52.5 - F52.9	Sexual dysfunction not due to a substance or known physiological condition, female
N94.2	Vaginismus
N94.89	Other specified conditions associated with female genital organs and menstrual cycle
R37	Sexual dysfunction, unspecified

---

Background

Female sexual dysfunction (FSD) entails many facets in the sexual process in women including vaginal dryness, arousal disorder, painful intercourse, an inability to achieve orgasm, and lack of clitoral sensation.

Despite significant anatomical and embryological parallels between women and men, the multi-faceted nature of FSD clearly is different from that of the man.  Clinicians can not approach female patients or their sexual function problems in the same fashion as in male patients.  The context in which a woman experiences her sexuality is equally if not more important than the physiological outcome she experiences, and these issues should be determined before beginning medical therapy or determining treatment effectiveness.

Biothesiometry is a technique that can be used for evaluating genital neurological function in women.  It entails the use of a small cylindrical instrument employed to evaluate the sensitivity of the clitoris and labia to pressure and temperature.  However, there is insufficient evidnce regarding its clinical use for the diagnosis of FSD.

Erol et al (2003) evaluated genital and extra-genital somatic sensory system in diabetic women using biothesiometry and investigated the relation with sexual dysfunction.  A total of 30 diabetic women and 20 normal sexually active women as a control group were evaluated with a detailed medical and sexual history including Index of Female Sexual Function (IFSF) questionnaire.  Somatic sensory system of all women enrolled to the study was assessed by biothesiometry and threshold sensory values of 9 genital sites and 14 extra-genital sites were analyzed.  The IFSF score in diabetic women was 23.6 while it was 38.3 in the control group (p < 0.0005).  For each genital as well as extra-genital sites, the mean biothesiometric values were significantly higher in diabetics.  The sensation of introitus vagina, labium minora and clitoris were found to be the most deteriorated genital sites in diabetic women.  The difference between diabetic women with or without FSD was not significant for biothesiometric values.  These findings indicate that, somatic sensory system is affected by diabetes however sexual dysfunction does not always manifest.

If a specific etiology for FSD is discovered on history, physical, and laboratory examination, the suspected etiology may be treated.  If no specific etiology for FSD is discovered, basic treatment strategies are applied.  These include educational interventions, enhancement of stimulation and elimination of routine (e.g., use of erotic books or videos, varying positions, use of vibrators, etc.), provision of distraction techniques (e.g., background music, encourage fantasies, etc.), encouragement of non-coital behaviors (e.g., sensate focus exercises, sensual massage), and techniques to minimize dyspareunia (e.g., change in position, topical lidocaine, lubricants, etc.).

Female erectile devices such as the Eros clitoral stimulation device (UroMetrics, Inc., St. Paul, MN) are used to obtain greater clitoral engorgement, which increases lubrication, and enhances the ability to achieve an orgasm.  However, more studies are needed to ascertain the medical necessity and long-term effects of clitoral stimulation devices as compared with established approaches such as lubricants, manual stimulation, and over-the-counter devices.

In a pilot study, Schroder et al (2005) assessed the effectiveness of Eros therapy in alleviating sexual dysfunction in irradiated cervical cancer patients.  A total of 15 women were enrolled and 13 completed the study.  The median patient age and radiotherapy-enrollment interval was 43.5 years and 2 years, respectively.  These investigators concluded that the clitoral stimulation device may alleviate sexual dysfunction in irradiated cervical cancer patients; and a randomized, controlled study is needed to evaluate the full benefits of this approach.

An UpToDate review on “Sexual dysfunction in women: Management” (Shifren, 2014) states that “A clitoral suction vacuum device, EROS-Clitoral Therapy Device, is approved by the US Food and Drug Association (FDA) for female sexual dysfunction.  Its design is similar to vacuum devices used for male erectile dysfunction.  It may improve local arousal and response by improving clitoral blood flow.  The device is expensive and likely no more effective than less costly devices available without a prescription, such as vibrators”.

Silverstein et al (2011) stated that treatments of FSD have been largely unsuccessful because they do not address the psychological factors that underlie female sexuality.  Negative self-evaluative processes interfere with the ability to attend and register physiological changes (interoceptive awareness).  These researchers examined the effect of mindfulness meditation training on interoceptive awareness and the 3 categories of known barriers to healthy sexual functioning: attention, self-judgment, and clinical symptoms.  A total of 44 college students (30 women) participated in either a 12-week course containing a "meditation laboratory" or an active control course with similar content or laboratory format.  Interoceptive awareness was measured by reaction time in rating physiological response to sexual stimuli.  Psychological barriers were assessed with self-reported measures of mindfulness and psychological well-being.  Women who participated in the meditation training became significantly faster at registering their physiological responses (interoceptive awareness) to sexual stimuli compared with active controls (F(1,28) = 5.45, p = 0.03, η(p)(2) = 0.15).  Female meditators also improved their scores on attention (t = 4.42, df = 11, p = 0.001), self-judgment, (t = 3.1, df = 11, p = 0.01), and symptoms of anxiety (t = -3.17, df = 11, p = 0.009) and depression (t = -2.13, df = 11, p < 0.05).  Improvements in interoceptive awareness were correlated with improvements in the psychological barriers to healthy sexual functioning (r = -0.44 for attention, r = -0.42 for self-judgment, and r = 0.49 for anxiety; all p < 0.05).  The authors concluded that mindfulness-based improvements in interoceptive awareness highlight the potential of mindfulness training as a treatment of FSD.

In a pilot study, Millheiser et al (2010) evaluated the safety and tolerability of non-surgical radiofrequency (RF) thermal therapy for treatment of laxity of the vaginal introitus after vaginal delivery.  They also explored the utility of self-report questionnaires in assessing subjective effectiveness of this device.  A total of 24 women (25 to 44 years) once using reverse gradient RF energy (75 to 90 joules/cm(2) ), delivered through the vaginal mucosa were include in this study.  Post-treatment assessments were at 10 days, 1, 3, and 6 months.  Main outcome measures included pelvic examinations and adverse event reports to assess safety.  The author modified Female Sexual Function Index (mv-FSFI) and Female Sexual Distress Scale-Revised (FSDS-R), Vaginal Laxity and Sexual Satisfaction Questionnaires (designed for this study) to evaluate both safety and effectiveness, and the Global Response Assessment to assess treatment responses.  No adverse events were reported; no topical anesthetics were required.  Self-reported vaginal tightness improved in 67 % of subjects at 1 month post-treatment; in 87 % at 6 months (p < 0.001).  Mean sexual function scores improved: mv-FSFI total score before treatment was 27.6 +/- 3.6, increasing to 32.0 +/- 3.0 at 6 months (p < 0.001); FSDS-R score before treatment was 13.6 +/- 8.7, declining to 4.3 +/- 5.0 at month 6 post-treatment (p < 0.001).  Twelve of 24 women who expressed diminished sexual satisfaction following their delivery; all reported sustained improvements on SSQ at 6 months after treatment (p = 0.002).  The authors concluded that the RF treatment was well-tolerated and showed an excellent 6-month safety profile in this pilot study.  Responses to the questionnaires suggested subjective improvement in self-reported vaginal tightness, sexual function and decreased sexual distress.  They stated that these findings warrant further study.

In a review on “Female sexual disorders: Treatment options in the pipeline”, Krychman (2013) noted that Viveve (Sunnyvale, CA) has developed a monopolar RF thermal therapy to improve laxity of the vaginal introitus and sexual satisfaction in women after vaginal deliveries.  In a pilot study in 24 women aged 25 to 44 years, reverse-gradient RF (energy range of 60 joules [n = 3], 75 joules [n = 3], and 90 joules [n = 18]) was delivered through the vaginal mucosa.  No adverse events were reported, and no topical anesthetics were required.  Self-reported vaginal tightness improved in 67 % of patients at 1 month post-treatment and in 87 % at 6 months (p < 0.001).  Mean sexual function scores improved, and FSDS-R score before treatment was 13.6 +/- 8.7, declining to 4.3 +/- 5.0 at month 6 post-treatment (p < 0.001).  The author concluded that this office-based procedure is well-tolerated and has shown excellent preliminary results.  These findings need to be validated by well-designed studies.

In a prospective single-arm study, Sekiguchi and colleagues (2103) reported the long-term effectiveness of a single non-surgical procedure with RF energy for laxity at the vaginal introitus.  A total of 30 pre-menopausal women (age of 21 to 52 years) with one 30-min office procedure using RF applied to the vaginal introitus; 12-month outcome assessments included the linguistic validated Japanese versions of the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised (FSDS-R) and the Vaginal Laxity and Sexual Satisfaction Questionnaires.  Sexual function improved significantly throughout 6 months (30 subjects); mean FSFI total score was 22.4 ± 6.7 before treatment and then improved to mean 26.0 ± 5.8 at month 6 (p = 0.002), inclusive of improved scores in 5 of 6 FSFI domains except desire (p < 0.001 - <0.01).  In the 22 of 30 subjects remaining evaluable at 12 months, the mean was 26.0 ± 5.2 (p = 0.08).  Distress related to sexual activity decreased significantly; baseline FSDS-R mean score of 15.8 ± 11.7 improved to 9.8 ± 8.0 at 1 month and was sustained throughout 12 months (p <0.001 - 0.002).  Subjects reported decreased vaginal laxity within the 1st month after the procedure (p < 0.001); responses peaked, and effectiveness was sustained through 12 months (p < 0.001).  The authors concluded that a single non-surgical office-based RF procedure for vaginal introital laxity achieved significant and sustainable 12-month effectiveness with respect to improved integrity at the vaginal introitus and improved sexual satisfaction.  Treatment was well-tolerated with no adverse events.  The main drawbacks of this study were the lack of a control group, small sample size and relatively short follow-up.  These preliminary findings need to be validated by well-designed studies.

Ospemifene

Vaginal estrogen products are indicated for vulvovaginal atrophy and have been used for dyspareunia

Ospemifene is an estrogen agonist/antagonist with tissue selective effects. It is thought to bind to estrogen receptors in vaginal tissue with agonist effects and to a lesser degree in breast and endometrium tissue.

Osphena (ospemifene) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

Osphena is available in 60 mg tablets. Recommended dosage is one tablet daily with food.

Osphena (ospemifene) carries a black box warning regarding endometrial cancer and cardiovascular disorders. Generally, when a product such as Osphena (ospemifene) with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer.

Osphena has not been studied in women with severe hepatic impairment, therefore it's use in this patient population is not recommended.

Use of Osphena (ospemifene) should be for the shortest duration consistent with treatment goals and risks for the individual woman.

Pregnancy Category X: Teratogenic effects are associated with Osphena (ospemifene).

Ospemiphene should not be used in women with the following concomitant conditions:

• Abnormal genital bleeding
• Known or history of estrogen‐dependent neoplasia
• Active DVT, pulmonary embolism (PE), or a history of these conditions
• Active arterial thromboembolic disease (eg. stroke and myocardial infarction), or a history of these conditions.

Wurz and co-workers (2014) stated that during the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and VVA.  Unlike vasomotor symptoms, vaginal dryness and dyspareunia, the main symptoms of VVA, typically worsen without treatment and can significantly impact the quality of life.  Up to 60 % of post-menopausal women may be affected by VVA, but many women unfortunately do not seek treatment due to embarrassment or other factors.  After 20+ years in development, ospemifene (Osphena) was approved by the FDA in 2013 for treatment of moderate-to-severe dyspareunia associated with VVA due to menopause.  As the first non-hormonal alternative to estrogen-based products for this indication, the approval of ospemifene represents a significant milestone in post-menopausal women's health.  Ospemifene is a non-steroidal estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), from the same chemical class as the breast cancer drugs tamoxifen and toremifene.  Unlike other selective estrogen receptor modulators, ospemifene exerts a strong, nearly full estrogen agonist effect in the vaginal epithelium, making it well suited for the treatment of dyspareunia in post-menopausal women.  Results of phase III clinical trials showed that ospemifene significantly improved the vaginal maturation index (decreased parabasal cells and increased superficial cells), decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) compared to placebo.  Long-term safety studies revealed that 60 mg ospemifene given daily for 52 weeks was well-tolerated and was not associated with any endometrium or breast-related safety concerns.  This review discussed the pre-clinical and clinical data supporting the use of ospemifene for the treatment of dyspareunia associated with VVA due to menopause and provided an overview of its clinical safety.

In a phase-III, randomized, double-blind, 12-week trial (n = 919), Constantine and associates (2015) compared the safety and effectiveness of oral ospemifene 60 mg/day versus placebo in post-menopausal women with VVA in 2 strata based on self-reported, most bothersome symptom of either dyspareunia or dryness.  Primary data were published previously.  These investigators reported herein pre-specified secondary efficacy end-points analyses, including changes from baseline to weeks 4 and 12 for FSFI total and domain scores as well as serum hormone levels.  Ospemifene 60 mg/day demonstrated a significantly greater FSFI total score improvement versus placebo at week 4 (p < 0.001).  Improvement in FSFI scores continued to week 12 (p < 0.001).  At week 4, the FSFI domains of Sexual Pain, Arousal, and Desire were significantly improved with ospemifene versus placebo; at week 12, improvements in all domains were significant (p < 0.05).  Changes in serum hormones were minor and uncorrelated with changes in sexual functioning.  The authors concluded that in a large, randomized, double-blind, placebo-controlled trial, ospemifene 60 mg/day significantly improved FSD in women with VVA; consistent effects across FSFI domains were observed.

Kingsberg and Woodard (2015) stated that low or absent sexual desire is the most common sexual dysfunction in women, and its prevalence peaks during midlife.  Its etiology is complex and may include biological, psychological, and social elements.  Major risk factors for its development include poor health status, depression, certain medications, dissatisfaction with partner relationship, and history of physical abuse, sexual abuse, or both.  Diagnosis is based on criteria set by the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) and requires that a woman experience personal distress.  Clinical evaluation should include medical history, sexual history, and, sometimes, a physical examination.  Laboratory data are of limited value, except when warranted by history or physical examination.  Treatment options include non-pharmacologic interventions such as education, office-based counseling, and psychotherapy.  Although there are no UFDA-approved treatments for low desire, pharmacologic agents have been used off-label for this purpose.  Bupropion is an anti-depressant that has been shown to improve desire in some women with and without depression.  Systemic estrogen therapy is not recommended in the absence of vasomotor symptoms and is not directly associated with desire.  However, vaginal estrogen is useful in patients presenting with concomitant vaginal atrophy and dyspareunia.  Ospemifene is a selective estrogen receptor modulator that can be used as an alternative to vaginal estrogen.  Exogenous testosterone (e.g., gel, implant, injection, patch and oral formulations) has demonstrated efficacy in treating loss of desire in post-menopausal women.  However, patients should be counseled that it is not FDA-approved for this purpose and there are limited published long-term safety data.  Several agents for the treatment of low desire are currently in development.

Testosterone Therapy

Belkin et al (2015) stated that there is growing recognition of FSD as an important women's health concern.  Despite an increased awareness of the pathophysiologic components to FSD, currently, there are no drugs approved for the most common sexual complaint in women-decreased sexual desire.  In response to an overwhelming demand for therapy for FSD, several drugs are undergoing development and testing.  These investigators provided the latest data on pharmacological treatments for FSD currently in phase I and II clinical trials.  These include topical alprostadil, bremelanotide (BMT), intra-nasal testosterone (TBS-2), intra-vaginal dehydroepiandrosterone (DHEA), sublingual testosterone with sildenafil, apomorphine (APO), bupropion and trazodone.  It should be noted that the definitions of FSD have recently been revised in the diagnostic and statistical manual for mental disorders (DSM) 5, with merging of hypoactive sexual desire disorder (HSDD) and female sexual arousal disorder (FSAD) into female sexual interest/arousal disorder (FSIAD).  However, it is noted that the majority of clinical trials discussed in this paper used the DSM IV-R diagnoses of HSDD and FSAD.  The authors concluded that medications in early phase trials showed promise for the treatment of FSD.  These therapies focus on treating many possible causes of FSD.

Jayasena and colleagues (2019) stated that the clinical sequelae of estrogen deficiency during menopause are undoubted.  However, the pathophysiological role of testosterone during the menopause is less clear.  Several randomized, placebo-controlled clinical trials suggested that testosterone therapy improved sexual function in post-menopausal women.  Some studies suggested that testosterone therapy has additional effects, which include increased bone mineral density (BMD) and decreased serum high-density lipoprotein (HDL) cholesterol.  Furthermore, the long-term safety profile of testosterone therapy in post-menopausal women is unclear.

Vaginal Electrical Stimulation

In a randomized study, Aydin and colleagues (2015) evaluated the effectiveness of vaginal electrical stimulation (VES) in women with FSD without a predominant pelvic floor disorder or urinary incontinence.  A total of 42 women with FSD were randomly allocated to VES and placebo groups.  Pelvic floor muscle (PFM) assessment and the FSFI questionnaire were performed at baseline and after the completion of sessions.  Vaginal electrical stimulation treatment was administered using a vaginal probe.  The probe was inserted, and a medium-frequency (50 Hz) alternating current was administered for a duty cycle of 5 seconds on followed by a 5-second rest.  Primary outcome measure was the improvement in FSFI score.  Pelvic floor muscle assessments were performed according to the PERFECT scheme.  Total FSFI scores improved significantly in both the VES group and the control group.  Results showed that in the VES group, there was an improvement in total score and FSFI domains that improved including arousal, desire, orgasm, and satisfaction.  Similarly, control group domains that improved were desire, arousal, and orgasm.  But there was no significant increase in satisfaction scores in the placebo group.  No significant changes in pain or lubrication domains were seen in either group.  Power, endurance, fast contractions, and repetitions were significantly improved in the VES group.  The authors concluded that the lack of significant differences between the placebo and VES groups, except the satisfaction domain, puts into question the effectiveness of electrical stimulation as a monotherapy in treating primary FSD without pelvic floor disorder.

Furthermore, an UpToDate review on “Sexual dysfunction in women: Management” (Shifren, 2015) does not mention electrical stimulation as a therapeutic option.

Botulinum Toxin Therapy

In a prospective, open-label, pilot study, Morrissey and colleagues (2015) examined the effectiveness of electromyography (EMG)-guided onabotulinumtoxinA (Botox; Allergan, Irvine, CA) injections in treating patient's perception of pelvic pain and improving quality of life (QoL) measurement scores.  Women with chronic pelvic pain and high-tone pelvic floor dysfunction (HTPFD) who have failed conventional therapy between January 2011 and August 2013 were enrolled in this study.  Botox injections (up to 300 U) were done using needle EMG guidance, from a trans-perineal approach, to localize spastic pelvic floor muscles (PFMs).  Data were collected at baseline, 4, 8, 12, and 24 weeks after injections.  This included demographics; visual analog scale (VAS) scores for pain and dyspareunia; validated questionnaires for symptoms, QoL, and sexual function; Global Response Assessment scale for pelvic pain; digital examination of PFM for tone and tenderness; and vaginal manometry.  Side effects were also recorded.  Out of 28 women who enrolled in the study, 21 completed the 6-month follow-up and qualified for analysis.  The mean (SD) age was 35.1 (9.4) years (range of 22 to 50 years), and the mean (SD) body mass index was 25 (4.4).  Co-morbidities included interstitial cystitis/bladder pain syndrome (42.9 %) and vulvodynia (66.7 %).  Overall, 61.9 % of subjects reported improvement on Global Response Assessment at 4 weeks and 80.9 % at 8, 12, and 24 weeks post-injection, compared with baseline.  Of the subjects who were sexually active at baseline, 58.8 % (10/17), 68.8 % (11/16), 80 % (12/15), and 83.3 % (15/18) reported less dyspareunia at 4, 8, 12, and 24 weeks, respectively.  Dyspareunia VAS score significantly improved at weeks 12 (5.6, p = 0.011) and 24 (5.4, p = 0.004) compared with baseline (7.8).  Two of the 4 patients who avoided sexual activity at baseline secondary to dyspareunia resumed and tolerated intercourse after Botox.  Sexual dysfunction as measured by the Female Sexual Distress Scale significantly improved at 8 weeks (27.6, p = 0.005), 12 weeks (27.9, p = 0.006), and 24 weeks (22.6, p < 0.001) compared with baseline (34.5).  The Short-Form 12 Health Survey (SF-12) showed improved QoL in the physical composite score at all post-injections visits (42.9, 44, 43.1, and 45.5 versus 40 at baseline; p < 0.05), and in the mental composite score at both 12 and 24 weeks (44.3 and 47.8 versus 38.5, p = 0.012).  Vaginal manometry demonstrated significant decrease in resting pressures and in maximum contraction pressures at all follow-up visits (p < 0.05).  Digital assessment of PFM (on a scale from 0 to 4) showed decreased tenderness on all visits (mean of 1.9, 1.7, 1.8, 1.9; p < 0.001) compared with baseline (2.8).  Reported post-injection adverse effects included worsening of the following pre-existing conditions: constipation (28.6 %), stress urinary incontinence (4.8 %), fecal incontinence (4.8 %), and new onset stress urinary incontinence (4.8 %).  The authors concluded that EMG-guided Botox injection into PFM could be beneficial for women with refractory HTPFD who have failed conservative therapy.  This was a small (n = 21) pilot study with short-term follow-up (24 weeks).  The role of botulinum toxin in the treatment of FSD associated with pelvic floor dysfunction need to be ascertained in well-designed studies.

Phosphodiesterase Type 5 Inhibitors

Gao and colleagues (2016) systematically reviewed evidence from studies comparing phosphodiesterase type 5 inhibitors (PDE5is) with placebo in the treatment of FSD. Searches of PubMed, the Cochrane Library, and Embase databases were performed using the MeSH terms "females/female/women", "sexual", and "sildenafil/tadalafil/vardenafil/PDE5/PDE5i".  All randomized controlled trials (RCTs), available in English, published no later than January 28, 2015 comparing the effectiveness of PDE5is, or PDE5is in combination with other agents, with placebo in improving FSD were included.  The inclusion criteria were met by 14 studies, which were analyzed by 2 reviewers.  The RCTs included in the present study adopted different questionnaires for measuring sexual function; consequently, most of the data had to be considered separately rather than pooled.  In general, the use of PDE5is resulted in significant improvements in sexual function compared with placebo, with some studies demonstrating negative results.  Pooled data regarding adverse events (AEs) demonstrated significantly higher rates of headache, flushing, and changes in vision in PDE5i-treated patients.  The authors concluded that PDE5is could be an effective treatment modality for FSD; although there were significant increases in AEs in comparison with placebo, PDE5is were still relatively safe.

An UpToDate review on “Sexual dysfunction in women: Management” (Shifren, 2016) states that “Phosphodiesterase (PDE-5) inhibitors effectively treat male erectile dysfunction, but generally have not proven successful in women. Studies of sildenafil for treatment of women with sexual dysfunction have reported inconsistent results.  The best available evidence is a randomized trial of nearly 800 pre- and post-menopausal women with disorders of desire, arousal, orgasm, and/or dyspareunia treated with 10 to 100 mg sildenafil for 12 weeks.  Sildenafil was no more effective than placebo in increasing the frequency of enjoyable sexual events or improving any aspect of sexual function”.

Alcantara Montero and Sanchez Carnerero (2016) stated that FSD is a broad term used to describe 3 categories of disorders of a multi-factorial nature. Effective, but limited pharmacotherapies exist to address FSD.  The FDA recently approved the first agent for treatment of hypoactive sexual desire disorder in pre-menopausal women.  Off-label use of hormonal therapies, particularly estrogen and testosterone, are the most widely employed for FSD, especially in post-menopausal women.  The authors noted that other drugs currently under investigation include PDEis and agents that modulate dopamine or melanocortin receptors.

Gene/Growth Factor/Stem Cell-Based Therapies and Regnerative Medicine

Farmer and colleagues (2016) developed an evidence-based state-of-the-art consensus report that critically integrates current knowledge of the therapeutic potential for known molecular and cellular targets to facilitate the physiologic processes underlying female sexual function.  Expert opinion was established by grading the evidence-based medical literature, intensive internal committee discussion, public presentation, and debate.  Scientific investigation is urgently needed to expand knowledge and foster development of future treatments that maintain genital tissue integrity, enhance genital physiologic responsiveness, and optimize positive subjective appraisal of internal and external sexual cues.  The authors concluded that future treatment targets include pharmacologic modulation of emotional learning circuits, restoration of normal tactile sensation, growth factor therapy, gene therapy, stem cell-based therapies, and regenerative medicine. Concurrent use of centrally and peripherally acting therapies could optimize treatment response.

Oxytocin and Progesterone

Worsley and colleagues (2016) reviewed the contribution of hormones, other than estrogens and androgens, to female sexual functioning and the evidence that specific endocrinopathies in women are associated with FSD and updated the previously published International Society of Sexual Medicine Consensus on this topic.  The literature was searched using several online databases with an emphasis on studies examining the physiologic role of oxytocin, prolactin, and progesterone in female sexual function and any potential therapeutic effect of these hormones.  The association between common endocrine disorders, such as polycystic ovary syndrome, pituitary disorders, and obesity, and FSD also was examined.  Quality of data published in the literature and recommendations were based on the Grading of Recommendations Assessment, Development and Education system.  There is no evidence to support the use of oxytocin or progesterone for FSD.  Treating hyper-prolactinemia might lessen FSD.  Polycystic ovary syndrome, obesity, and metabolic syndrome could be associated with FSD, but data are limited.  There is a strong association between diabetes mellitus and FSD.  The authors concluded that further research is needed; in particular, high-quality, large-scale studies of women with common endocrinopathies, to determine the impact of these prevalent disorders on female sexual function.

Radiofrequency Thermal Therapy (The ThermiVa Procedure and the Viveve Procedure)

Lalji and Lozanova (2017) evaluated the safety and efficacy of a non-invasive radiofrequency device when used to treat stress urinary incontinence (SUI) and vulvo-vaginal laxity through its heating effect that stimulates collagen and elastin fibers.  A total of 27 women (average age of 44.78 ± 10.04 years) with indications of mild/moderate SUI as well as vulvo-vaginal laxity were treated with a monopolar RF device.  The treatment course consisted of 3 once-weekly sessions.  Each session included intra-vaginal treatment followed by treatment of labia majora and the perineum.  Improvement in the SUI condition was evaluated by applying the International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF).  Data were collected at the baseline, after the last treatment and at 1-month follow-up visit.  Vaginal laxity was assessed by subjective vulvo-vaginal laxity questionnaire (VVLQ).  Data were collected before the 1st treatment and during the 1-month follow-up visit.  Patient's satisfaction was recorded using a satisfaction questionnaire.  Data were collected after the last treatment and at the 1-month follow-up visit.  Any AEs related to the treatments were monitored.  On a scale of 0 to 5, the average frequency of urine leak improved from "2 to 3 times a week" (2.15 ± 1.03 points prior to treatment) to "once a week" (1.00 ± 0.78 points post-treatment), and on to "never" (0.44 ± 0.51 points at the 1-month follow-up visit); 16  subjects (59.3 %) reported decrease in the amount of leakage, with 15 women (55.6 %) becoming completely leak-free at the 1-month follow-up.  At the 1-month follow-up visit, 24 subjects (88.9 %) expressed their condition's interference with everyday life decreased and 17 patients (62.9 %) said the condition did not interfere with their everyday life at all as a result of the treatment.  All results were statistically significant (p < 0.05).  No AEs were recorded.  All subjects reported improvement in vaginal laxity, from average perception of "very loose" (2.19 ± 1.08 points prior to treatment) to "moderately tight" (5.74 ± 0.76 points at the 1-month follow-up visit).  During the follow-up visit, 89 % of the patients "agreed" or "strongly agreed" that their SUI condition improved, and 93 % of the patients "agreed" or "strongly agreed" that their gratification during intercourse improved.  None of the subjects reported dissatisfaction.  The authors concluded that the findings of this study confirmed the monopolar RF method as a safe and effective treatment of SUI and vulvo-vaginal laxity.  The treatments were well-tolerated by all subjects with no AEs.  Moreover, these investigators stated that further controlled study is needed to confirm the data and evaluate the long-term effects in the endo-vaginal treatment.

In a sub-analysis of the VIVEVE I trial, Krychman and colleagues (2018) evaluated the impact of cryogen-cooled monopolar RF (CMRF) therapy for the treatment of vaginal laxity, on the domains of sexual function included in the FSFI.  The VIVEVE I clinical trial was prospective, randomized, single-blind, and sham-controlled; 9 clinical study centers in Canada, Italy, Spain, and Japan were included.  This sub-analysis included pre-menopausal women with self-reported vaginal laxity who had greater than or equal to 1 term vaginal delivery and a baseline FSFI total score less than or equal to 26.5, indicating sexual dysfunction.  Enrolled subjects were randomized (2:1) to receive CMRF therapy [active (90 J/cm2) versus sham (less than or equal to 1 J/cm2)] delivered to the vaginal tissue.  Independent analyses were conducted for each FSFI domain to evaluate both the mean change, as well as the clinically important change for active- versus sham-treated subjects at 6 months post-intervention.  Subjects randomized to active treatment (n = 73) had greater improvement than sham subjects (n = 35) on all FSFI domains of sexual function at 6 months post-intervention.  The analysis of co-variance change from baseline analyses showed statistically significant improvements, in favor of active treatment, for sexual arousal (p = 0.004), lubrication (p = 0.04), and orgasm (p = 0.007).  In addition, active treatment was associated with clinically important and statistically significant improvements in sexual desire (odds ratio [OR] = 3.01 (1.11 to 8.17)), arousal (OR = 2.73 (1.06 to 7.04)), and orgasm (OR = 2.58 (1.08 to 6.18)).  The authors concluded that this sub-analysis of the VIVEVE I trial showed that a single, non-ablative CMRF treatment significantly improved overall sexual function (FSFI total score) in women with FSD and self-reported vaginal laxity.  Of the 6 domains of the FSFI, the improvement achieved using CMRF therapy was primarily being driven by the statistically significant and/or clinically important improvements in sexual desire, arousal, lubrication, and orgasm in women with vaginal laxity and baseline sexual dysfunction.  The findings of sexual function improvement provided evidence for the clinical utility, and direction for further evaluation, of this novel, single treatment, 30-minute, non-surgical outpatient modality for a highly prevalent and undertreated condition.  Furthermore, these results underscored the importance of conducting rigorous research using a randomized sham or placebo comparator arm with adequate follow-up time to permit the estimation of a valid treatment effect.

These investigators stated that this sub-analysis had several drawbacks.  No control for multiplicity was implemented for the post-hoc analyses of the VIVEVE I trial; thus, results should be interpreted as exploratory or hypothesis-generating.  In addition, the generalizability of the findings was restricted to women with self-reported vaginal laxity and FSD as defined by a baseline FSFI total score less than or  equal to 26.5.  Women who were sexually functional (i.e., baseline FSFI total score greater than 26.5) were not analyzed as part of this sub-analysis.  therefore, a substantial proportion of parous women fell into this category.  In the VIVEVE I trial, 66 % of included subjects presented with sexual dysfunction at the screening visit.  Finally, early system characteristics made double-blinding of treatment assignment difficult to achieve.  While all subjects were unaware of their treatment assignment for the entire study duration, the site investigator was aware of treatment assignment.  Despite this limitation, similar baseline characteristics and study drop-out rates for subjects in the active and sham groups empirically suggested that bias was not introduced by investigator channeling or differential study conduct by treatment assignment throughout the entire duration of trial follow-up.  The robust “sham” effect in the first 3 months further indicated that study validity was not compromised by single-blinding.  To mitigate the potential for investigator channeling bias, subjects assigned to the sham group were permitted to receive the active CMRF therapy upon study completion.

The ThermiVa procedure uses heat therapy delivered via RF waves to promote collagen synthesis, shrinkage and tightening of female tissues.  However there is a lack of evidence regading its effectiveness for vaginal rejuvenation, FSD and other gynecological disorders.

Furthermore, on July 30, 2018, FDA Commissioner Scott Gottlieb stated that “We’ve recently become aware of a growing number of manufacturers marketing “vaginal rejuvenation” devices to women and claiming these procedures will treat conditions and symptoms related to menopause, urinary incontinence or sexual function.  The procedures use lasers and other energy-based devices to destroy or reshape vaginal tissue.  These products have serious risks and don’t have adequate evidence to support their use for these purposes.  We are deeply concerned women are being harmed.  As part of our efforts to promote women’s health, the FDA has cleared or approved laser and energy-based devices for the treatment of serious conditions like the destruction of abnormal or pre-cancerous cervical or vaginal tissue, as well as condylomas (genital warts).  But the safety and effectiveness of these devices hasn’t been evaluated or confirmed by the FDA for “vaginal rejuvenation”.  In addition to the deceptive health claims being made with respect to these uses, the “vaginal rejuvenation” procedures have serious risks.  In some cases, these devices are being marketed for this use to women who have completed treatment for breast cancer and are experiencing symptoms caused by early menopause.  The deceptive marketing of a dangerous procedure with no proven benefit, including to women who’ve been treated for cancer, is egregious.  In reviewing adverse event reports and published literature, we have found numerous cases of vaginal burns, scarring, pain during sexual intercourse, and recurring or chronic pain.  We haven’t reviewed or approved these devices for use in such procedures.  Thus, the full extent of the risks is unknown.  But these reports indicate these procedures can cause serious harm.  Today, we’re warning women and their healthcare providers that the FDA has serious concerns about the use of these devices to treat gynecological conditions beyond those for which the devices have been approved or cleared.  We recently notified seven device manufacturers of our concerns about inappropriate marketing of their devices for “vaginal rejuvenation” procedures.  They are: Alma Lasers, BTL Industries, Cynosure, InMode, Sciton, Thermigen and  Venus Concept.  We requested that the manufacturers address our concerns within 30 days.  If our concerns are not addressed, then the FDA will consider what next actions, including potential enforcement actions, are appropriate.  This matter has the full attention of our professional staff”.

Bupropion and Tricyclic Anti-Depressants

In a review on “The evaluation and management of female sexual dysfunction”, Dawson and colleagues (2017) stated that “Buproprion, a mild dopamine and norepinephrine reuptake inhibitor and acetylcholine receptor antagonist, has been shown to improve desire in women with and without depression.  Although it is FDA-approved for major depressive disorder, it is not approved for FSD and is still under investigation … Tricyclic anti-depressants such as nortriptyline and amitriptyline may be effective in treating neuropathic pain.  Starting doses of both amitriptyline and nortriptyline are 10 mg/day and can be increased to a maximum of 100 mg/day.  Tricyclic anti-depressants are still under investigation for the treatment of FSD”.

Micro-Ablative Carbon Dioxide Laser

In a retrospective, case-control study, Pitsouni and associates (2017) compared 30 versus 40 W power of carbon dioxide (CO2) laser for the therapy of genitourinary syndrome of menopause (GSM).  Post-menopausal women with severe intensity of dyspareunia and dryness were eligible to be included in this study.  Primary outcomes were dyspareunia and dryness; secondary outcomes were itching/burning, dysuria, frequency and urgency, FSFI, vaginal maturation value (VMV), and vaginal health index score (VHIS).  One laser therapy was applied every month for 3 months.  Outcomes were evaluated at baseline and 1 month following the 3rd therapy.  A total of 50 (25 per group) women were included in this study.  In the 30-W group, mean improvement of dyspareunia, dryness, itching/burning, FSFI, VMV, and VHIS was 6.1 ± 1.7, 6.0 ± 1.9, 5.9 ± 2.0, 16.6 ± 6.7, 29.9 ± 13.0, and 11.0 ± 2.9, respectively (within group comparisons all p < 0.001).  In the 40-W group, mean improvement of dyspareunia, dryness, itching/burning, FSFI, VMV, and VHIS was 6.1 ± 1.7, 6.5 ± 2.0, 5.2 ± 2.5, 14.8 ± 7.1, 25.0 ± 13.4, and 10.5 ± 4.1, respectively (within-group comparisons, all p ≤ 0.001).  Comparison between 30 and 40 W revealed that mean improvement or presence of all GSM symptoms and clinical signs was not statistically significant different.  The authors concluded that CO2 laser therapy may improve GSM symptoms and clinical signs; and this improvement did not appear to be associated to power of 30 or 40 W.

In a systematic review, Weinberger and colleagues (2019) examined what treatments are effective across the various symptom complexes of FSD.  Utilizing Meta-analysis of Observational Studies in Epidemiology guidelines, these researchers conducted a systematic review of PubMed, Embase, clinicaltrials.gov, and the Cochrane Review databases.  A total of 11 search strings, encompassing the terms "female sexual dysfunction" and "treatment" in combination with "vulvovaginal atrophy", "vaginismus", "vaginal atrophy", "vulvodynia", "vestibulitis", "hypoactive sexual desire", "arousal disorder", "sexual pain disorder", "genitourinary syndrome of menopause" and "orgasmic disorder" were utilized.  A total of 605 relevant articles were retrieved; and 103 original studies met inclusion criteria.  A total of 42 treatment modalities were utilized, including 26 different classes of medications.  Although outcome measures varied, the most substantial improvement across multiple studies was noted with various hormonal regimens.  The most common treatments included hormonal therapy (25 studies), phosphodiesterase type-5 inhibitors (9 studies), botulinum toxin A (5 studies), and flibanserin (5 studies).  The psychotherapeutic approach was detailed in 36 articles while 3 studies utilized homeopathic treatments.  Numerous treatments showed efficacy in a single case series, including the promising results associated with the micro-ablative carbon dioxide laser.  Despite the marked improvement in specific FSD domains, neither pharmacologic treatments nor psychotherapeutic interventions demonstrated consistent disease resolution.  The authors concluded that treatment of FSD is multi-factorial; medications alone do not resolve FSD.  The wide variability of treatment and outcome measures across the literature attests to the complexity of FSD and the need for a treatment algorithm that addresses all 4 domains of FSD.

Febrina et al (2022) noted that cancer and its treatment negatively affect female sexual health and function.  The prevalence of FSD after cancer is between 33 % and 43 %.  Numerous studies have addressed therapeutic options for sexual dysfunction in women with cancer; however, it still remains a challenge to select the most effective option for patients.  These investigators compiled and appraised recent evidence of any interventions for managing sexual dysfunction in female cancer survivors.  They carried out a literature search of the electronic databases Medline, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials (January 2011 to February 2021) using general search terms of "women", "cancer", "intervention", and "sexual dysfunction".  They included RCTs and uncontrolled before-after studies that examined the effectiveness of intervention for FSD in women with history of cancer.  Methodological quality of studies was assessed using Risk of Bias (RoB) 2.0 for RCTs and National Institutes of Health (NIH) assessment tools for uncontrolled before-after studies.  A total of 36 studies were included for qualitative synthesis (14 RCTs (n = 1,284), 17 uncontrolled trials (n = 589), and 5 cohort studies (n = 497).  Only 4 studies were at low risk of bias.  Topical interventions (vaginal gels or creams) were able to alleviate vaginal dryness and dyspareunia, with intra-vaginal DHEA (6.5 mg) gel showing evidence of improved sexual function.  Evidence for estriol-lactobacilli vaginal tablets was unreliable due to a small-scale study.  Psychoeducational therapy (internet-based cognitive behavioral therapy [CBT]) studies typically were at high risk of bias, but all displayed significant improvements of sexual function.  Both laser therapy (fractional CO2 and erbium) and multi-modal approach studies were at concerning risk of bias, although suggesting beneficial effects on sexual function.  The authors concluded that the most reliable evidence for improvement was from a study of DHEA vaginal gel, but in general, gels or creams were useful in reducing dyspareunia.  Pharmacological, psychoeducational, laser therapy, and multi-modal approaches demonstrated potential in managing cancer-related sexual issues, but most were small in size (10 to 70 participants), with moderate-to-high risk of bias.  Moreover, these researchers stated that large-scale, double-blind, RCTs with long-term follow-up, and at low risk of bias are needed to demonstrate the clinical effectiveness of these interventions.

Miscellaneous Investigational Therapies

Kershaw and co-workers (2019) stated that percutaneous tibial nerve stimulation (PTNS) is now an established treatment of pelvic floor dysfunction such as overactive bladder, fecal incontinence or voiding dysfunction.  Prevalence of female sexual dysfunction is high in this group.  These researchers examined the effect of PTNS on sexual function in this patient group by systematically reviewing the literature and pooling the data in a meta-analysis.  The literature search was conducted using the Medline, Embase and CINAHL databases.  Initial results yielded 74 citations.  From these, 9 articles met the inclusion criteria; 2 articles were doubly reported, leaving 7 studies in the systematic review.  Only 4 studies reported sufficient information to be included in the meta-analysis.  A total of 3 studies were RCTs, and 5 were before-after studies.  The number of subjects in each study ranged from 11 to 220.; 4 of 7 studies reported a positive effect of PTNS on sexual function.  In the meta-analysis of 4 studies there was a significant improvement in general sexual function with PTNS (p = 0.04, standardized mean difference [SMD] -0.41, confidence intervals [CI]: -0.79 to -0.03], I2 = 0 %).  In a subgroup analysis of the bowel domain of sexual function, there was a significant improvement with PTNS (p = 0.03, MD 17.7, CI: 1.92 to 33.47, I2 = 0 %).  The authors concluded that although the studies were of small size, the results were promising in terms of a positive effect of PTNS on sexual function, and these researchers recommended further research in this area.

Khunda and associates (2019) noted that sexual function is being increasingly recognized as an important patient-reported outcome.  Sacral neuromodulation (SNM) is a treatment with an expanding list of indications.  The effect of SNM on sexual function has been examined in a number of studies with variable results.  In a systematic review and meta-analysis, these investigators evaluated the literature and pooled the data if appropriate.  The literature search was carried out primarily on the Healthcare Databases Advanced Search (HDAS) platform using the Medline, Embase and CINHAL search engines.  Of 196 initial citations, 17 articles met the pre-defined inclusion criteria; 13 studies reported enough information to be included in the meta-analysis.  RevMan5 software was used for analysis; 8 of 17 studies reported a positive effect of SNM on sexual function.  Pooled analysis of data from 11 studies involving 573 patients before SNM and 438 patients after SNM showed significant improvement in sexual function (SMD = -0.39; 95 % CI: -0.58 to -0.19; p = 0.0001).  The results remained significant in most subgroup analyses except in patients suffering from fecal incontinence.  The authors concluded that SNM in women with pelvic floor disorders, especially bladder dysfunction, appeared to have a positive effect on sexual function.  These researchers stated that these findings need to be verified in adequately powered primary research using sexual function as the primary outcome.

In a systematic review, Perez-Lopez and colleagues (2019) examined the effects of available treatments of vestibulodynia.  Using 6 search engines, these investigators searched for RCTs that compared any intervention versus placebo or sham in women with vestibulodynia until December 2018.  Primary outcome was dyspareunia assessed with VAS or numeric rating scales (NRS).  Secondary outcomes were daily vestibular symptoms (DVS), the McGill Pain Questionnaire (MPQ) and the Female Sexual Function Index (FISS).  Effects were described as MDs with their 95 % CIs.  Traditional and frequentist network meta-analyses (NMA) were performed using random effect models.  A total of 4 RCTs (n = 275) were included evaluating vaginal cream of conjugated estrogens, oral desipramine with or without topical lidocaine, topical lidocaine, laser therapy and transcranial direct current.  In traditional MA, interventions did not reduce dyspareunia (MD = 0.08; 95 % CI: -0.49 to 0.64), DVS (MD = -0.04; 95 % CI: -0.31 to 0.24; 4 interventions), or MPQ (MD = -0.17; 95 % CI: -2.16 to 1.81; 4 interventions).  ISS was significantly improved (MD = -5.14; 95 % CI: -9.52 to -0.75).  In NMA, oral desipramine with or without lidocaine significantly improved ISS versus other treatments.  The authors concluded that several existing interventions were not associated with improvements in vestibulodynia  There only was improvement of sexual function with oral desipramine with or without lidocaine.

Vyleesi (Bremelanotide Injection) for the Treatment of Hypoactive Sexual Desire Disorder

Kingsberg and colleagues (2019) examined the safety and efficacy of bremelanotide for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD).  Two identical phase-III, randomized, double-blind, placebo-controlled, multi-center clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in pre-menopausal women with HSDD.  Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo.  Sample size was estimated based on simulations from key endpoints in patients with HSDD from a prior trial.  Co-primary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.  Study 301 began on January 7, 2015; and concluded on July 26, 2016.  Study 302 began on January 28, 2015; and concluded on August 4, 2016.  Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively.  Most subjects were white (85.6 %), from U.S. sites (96.6 %), and had a mean age of 39 years.  From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, p < 0.001; study 302: 0.42, p < 0.001; integrated studies 0.35, p < 0.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, p < 0.001; study 302: -0.29, p = 0.005; integrated studies -0.33, p < 0.001) compared with placebo.  Patients taking bremelanotide experienced more nausea, flushing, and headache (10 % or more in both studies) compared with placebo.  The authors concluded that both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in pre-menopausal women with HSDD; the safety profile was favorable.  Most treatment-emergent AEs were related to tolerability and the majority were mild or moderate in intensity.

Simon and associates (2019) examined the long-term safety and efficacy of bremelanotide for the treatment of HSDD in pre-menopausal women.  Women who completed the 24-week double-blind core phase of RECONNECT, composed of 2 parallel phase-III clinical trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in pre-menopausal women with HSDD, could enroll in the 52-week open-label extension, provided they had not experienced serious AEs during the core phase.  Efficacy was evaluated using the co-primary endpoints from the core phase, and all AEs were collected during the open-label extension.  All statistical analyses were descriptive.  The study 301 open-label extension began on July 17, 2015; and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015; and concluded on June 29, 2017.  Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it.  The most common treatment-emergent AEs considered related to study drug were nausea (40.4 %), flushing (20.6 %), and headache (12.0 %), and the only severe treatment-emergent AE experienced by more than 1 subject in both studies was nausea during the open-label extension.  The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70 to 0.77 and -0.9, respectively, for patients who received placebo during the core phase.  The authors concluded that during the 52-week open-label extension of RECONNECT, no new safety signals were observed, and pre-menopausal women with HSDD who were treated with bremelanotide exhibited sustained improvements in symptoms.

Mayer and Lynch (2020) reviewed data regarding bremelanotide, a recently FDA-approved therapy for the treatment of HSDD in pre-menopausal women.  These researchers carried out a literature search of Medline, SCOPUS, and Embase using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019.  Reference lists from included articles were also reviewed for pertinent citations.  These investigators included phase-II and phase-III clinical trials of bremelanotide.  There were 2 reports of phase-III clinical trials and 2 reports of phase-II clinical trials.  Additional information from supplementary analyses was also referenced.  Bremelanotide showed significant improvement in desire and a significant decrease in distress related to lack of desire.  The most common adverse effects include nausea (39.9 %), facial flushing (20.4 %), and headache (11 %).  Bremelanotide was the 2nd FDA-approved medication for the treatment of HSDD.  Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest.  The authors concluded that bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 mins prior to sexual activity.  Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol.

According to the Prescribing Information, Vyleesi (bremelanotide) is a melanocortin receptor agonist indicated for the treatment of pre-menopausal women with acquired, generalized HSDD as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.   Vyleesi is not indicated for treatment of HSDD in post-menopausal women or in men; and it is also not indicated to enhance sexual performance.  Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month.  Individuals should discontinue use after 8 weeks without benefit.

Cocchetti and co-workers (2020) noted that HSDD represents a common condition among transgender women; however, to-date no specific guidelines for the management of HSDD in transgender persons are available.  These researchers examined evidence-based treatment for HSDD and suggested therapeutic options for HSDD in transgender women.  Clinically relevant publications on the management of HSDD (from 1985 to 2020) were searched in PubMed and Medline databases, using the following terms: "sexual desire", "sexual health", "HSDD", "transgender", "gender-affirming treatment", "sexual therapy", "testosterone treatment", "central nervous system-active medications", and variants.  Since sexual desire could be affected by several factors, a comprehensive assessment of HSDD -- exploring biological, psychological, and social domains -- was recommended, in order to identify possible predisposing, precipitating and maintaining factors.  Among therapeutic options, transgender women may benefit from different sex therapy strategies and/or central nervous system-active medications (e.g., flibanserin, bremelanotide, bupropion and buspirone; and transdermal testosterone, bearing in mind that this option could be poorly accepted by patients due to the risk of virilizing effects.  The authors concluded that the lack of data regarding the efficacy of HSDD therapeutic options in transgender women emphasized the need for literature to focus more on this topic in the future.

Bibliotherapy for the Treatment of Female Sexual Dysfunction

van Lankveld and colleagues (2021) examined the efficacy of bibliotherapy for sexual dysfunctions, when compared with no treatment and compared with other interventions.  Medline, Embase, and PsycINFO were searched from 1970 to January 2020.  Selection criteria were RCTs examining assisted or unassisted bibliotherapy for all types of sexual dysfunctions compared with no treatment (waitlist or placebo) or with other psychological interventions.  Bibliotherapy is defined as psychological treatment using printed instruction to be used by the individual or couple suffering from sexual dysfunction.  Primary outcome measures were male and female sexual functioning level and continuation/remission of sexual dysfunction.  Secondary outcomes were sexual satisfaction and drop-out rate.  Sexual functioning and sexual satisfaction were self-reported by subjects using validated questionnaires.  A total of 15 RCTs (1,113 subjects -- 781 women; 332 men) met inclusion criteria.  Compared with no treatment, unassisted bibliotherapy resulted in larger proportions of female subjects reporting remission of sexual dysfunction, and sexual satisfaction was higher in treated subjects, both female and male participants.  Compared with no treatment, assisted bibliotherapy had significant positive effects on female sexual functioning; no effects on male sexual functioning were found.  Results of unassisted and assisted bibliotherapy did not differ from those of other intervention types on any outcome.  Overall, no differences between study conditions were found regarding drop-out rates.  The certainty of the evidence for all outcomes was rated as very low.  The authors found indications of positive effects of bibliotherapy for sexual dysfunctions.  Across studies, more significant effects were found for women than for men.  However, owing to drawbacks in the study designs as well as imprecision of the findings, these investigators were unable to draw firm conclusions regarding the use of bibliotherapy for the treatment of sexual dysfunction.  These researchers stated that more high quality and larger trials are needed.  Relevant outcome measures for future studies should be defined as well as unified grading systems to measure these endpoints.  Furthermore, future studies should report on treatment acceptability and adherence.

Hyaluronic Acid for the Treatment of Female Sexual Dysfunction

Dos Santos and colleagues (2021) stated that the decline in post-menopausal serum estrogen concentration results in several changes in the vulvovaginal and vesicourethral areas, resulting in the genitourinary syndrome of menopause, including symptoms such as vaginal atrophy.  In a systematic review, these investigators examined the effects of hyaluronic acid (HA) in the treatment of vaginal atrophy.  The search strategy was developed using the following terms: "hyaluronic acid vaginal gel", "vaginal estrogens", "vaginitis, atrophic", and "post-menopause".  This strategy was used in major databases such as Medline, Embase, Scopus, Cochrane library, Web of Science, Virtual Health Library (BVS), Congress Abstracts, and Gray Literature (Google Scholar and British Library) for studies published until June 2020.  The systematic review was performed to evaluate the results of atrophic vaginitis/vaginal dryness, dyspareunia, vaginal pH, and cell maturation of the studies found by the search strategy.  A total of 833 studies were identified; 528 studies were directed for reading titles and abstracts; and 515 were excluded for not meeting the selection criteria.  A total of 13 studies were selected for reading the full text; 5 primary studies involving 335 women met the criteria and were included.  The studies were published between the years 2011 and 2017.  It was not possible to perform meta-analysis due to the substantial heterogeneity present in the studies.  The findings suggested that treatment with HA, when compared with the use of estrogens, did not present a significant difference in the results obtained for the outcomes: epithelial atrophy, vaginal pH, dyspareunia, and cell maturation.  The authors concluded that the findings suggested that HA has a profile of efficacy, safety, and tolerability comparable with vaginal estrogens for the treatment of symptoms of vaginal atrophy; it was a possible alternative for women who could not use hormonal treatment.  These researchers stated that the analysis of the studies in this systemic review suggested that HA exhibited efficacy similar to vaginal estrogens for the treatment of the signs of vaginal atrophy and dyspareunia; however, the included studies measured the data in different ways, causing the performance of meta-analysis to be impaired.

In a systematic review, Wierzbicka and associates (2021) examined the available treatments that reduce symptoms of vaginitis and vaginal atrophy by improving dyspareunia, mucosal inflammation, vaginal pH and vaginal dryness in women who have undergone brachytherapy or radiotherapy due to uterine or cervical malignancies.  These investigators carried out a comprehensive literature search following PRISMA guidelines.  The systematic search was performed using electronic databases, namely Scopus, Web of Science and PubMed, between October and November 2020 to identify RCTs and prospective randomized studies (PRS).  The analyzed population consisted of 376 patients with uterine or cervical cancer, treated with HA, vitamin A, vitamin E, alpha-tocopherol acetate and dienestrol.  Treatment with HA along with vitamin A and vitamin E revealed advantage in endpoints such as reduced dyspareunia, vaginal mucosal inflammation, vaginal dryness, bleeding, fibrosis and cellular atypia.  Administration of alpha-tocopherol acetate reduced vaginal mucosal inflammation and improved vaginal acanthosis, whereas dienestrol resulted in reduced dyspareunia, vaginal caliber and bleeding.  The authors concluded that vaginal suppositories were found to be clinically effective at the management of late-onset vulvovaginal side effects following radiotherapy.

These researchers noted that the use of HA, vitamin A, vitamin E or dienestrol can be considered a positive supplement to gynecological cancer survivors; therefore, a significant improvement in sexual function, vaginal health and self-pleasure could be observed.  The afore-mentioned suppositories reduced the symptoms of long-term vulvovaginal lesions such as dyspareunia, mucosal inflammation, dryness and fibrosis.  Moreover, research has established a positive correlation between the vaginal suppositories and decreased vaginal bleeding, fibrosis and cellular atypia.  As such, it appeared that enhancing the cancer survivors’ QoL as well as their sexual activity provided them with a heightened sense of identity along with enhanced femininity, value, self-perception and purpose.  Unfortunately, the data available in the literature are not sufficient, and large, randomized, placebo-controlled trials are needed to prove their effect before introducing these treatments as a standard therapy.

---

References