Pharmacologic treatment options for hypoactive sexual desire disorder

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1 REVIEW Pharmacologic treatment options for hypoactive sexual desire disorder Sheila Y Bolour 1 & Glenn D Braunstein 2 Author for correspondence 1 Cedars-Sinai Medical Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA Tel.: ; Fax: ; bolours@cshs.org 2 Cedars-Sinai Medical Center, David Geffen School of Medicine, UCLA, Los Angeles, California,USA Tel: ; Fax: ; braunstein@cshs.org Keywords: dehydroepiandrosterone, estrogen, female sexual dysfunction, herbal treatments, hypoactive sexual desire disorder, sex therapy, testosterone Hypoactive sexual desire disorder is the most common cause of sexual dysfunction in women. According to a national survey, approximately a third of all women experience low sexual desire. The etiology of the disorder is often multifactorial. Research in treatment options for hypoactive sexual desire disorder is limited. In this article, treatment options including sex therapy, hormone therapy (estrogen, testosterone, dehydroepiandrosterone, tibolone), non-hormonal medical therapies (buproprion, buspirone, phosphodiesterase-5 inhibitors, amantadine and apomorphine) and herbal therapies (Avlimil, Arginmax, Zestra, yohimbine and Ginkgo biloba) are reviewed. According to the National Health and Social Life Survey of over 1700 women between the ages of 18 and 59 years, the feeling of low sexual desire has been associated with poor quality of life, particularly low feelings of physical and emotional satisfaction and low feelings of general happiness [1]. This survey revealed that 32% of women across this age range experienced a lack of interest in sex. rmal sexual function in women involves having adequate interest and motivation to have sex, the ability to become aroused, orgasm and take pleasure in the experience. Sexual problems experienced by women can occur in any of these areas. Each of these components of the sexualresponse cycle are interdependent and thus, impairment of any specific aspect may affect others as well. Traditional models of the sexualresponse cycle, as described by Masters and Johnson, were based on a model more characteristic of male sexual response with inherent linearity and sequential stages. Data from research on female sexuality challenge those assumptions and suggest that sexual dysfunctions in women are often multiple and overlapping [2]. It is common for women with low sexual desire to have concomitant problems with arousal and/or orgasm [3]. In one survey, approximately 25% of women with hypoactive sexual desire disorder (HSDD) also had problems with arousal and orgasm [3]. HSDD (recently also termed women s sexual interest/desire disorder) is the most common type of female sexual dysfunction. It is defined as the lack of, or diminished, feelings of sexual interest or desire; absent sexual thoughts or fantasies; and a lack of responsive desire [2]. Women with HSDD lack the motivation to attempt to become sexually aroused beyond a normative lessening of sexual desire that often accompanies aging and greater relationship duration [2]. The lack of responsive sexual desire must cause personal distress for the diagnosis of HSDD to be made. Possible etiologic factors for the development of HSDD are listed in Box 1, although often the etiology is multifactorial. Patients presenting with complaints of low libido or sexual desire should be assessed for these potential etiologic agents before therapy is initiated. Treatment options Sex therapy There is a very important role for sex therapy in the treatment of HSDD: sex therapy allows women and their partners a means of addressing and modifying dysfunctional beliefs and behaviors in both marital and sexual relationships. Relationship issues often need to be addressed in order to help couples resume a comfortable sexual relationship [4]. Joint marital/couples therapy is an integral part of sex therapy, based on research showing that greater marital satisfaction is associated with a higher frequency of sexual activity and female orgasm [5]. Masters and Johnson developed sex therapy in the late 1960s and demonstrated the effectiveness of behavioral techniques in treating sexual problems. Over the years, sex therapy has evolved such that it is routinely performed within a 1-h session involving both partners. Initially, the goals of sex therapy are to identify the immediate and deeper causes of the sexual problem and to determine the extent to which the problem is related to sexual attitudes versus relationship dynamics. Other goals include addressing whether medical issues are the basis of the / Future Medicine Ltd ISSN Women's Health (2005) 1(2),

2 REVIEW Bolour & Braunstein Box 1. Etiologic factors in hypoactive sexual desire disorder (adapted from [4]). Age Relationship issues Endocrine: Androgen deficiency (androgen insufficiency syndrome) Estrogen deficiency (especially with hot flashes) Hypothyroidism Hyperprolactinemia Systemic illness Insomnia Mood disorders: Depression Anxiety or phobia Drug side effects: Alcohol and drug addiction Antidepressants (selective serotonin reuptake inhibitors, clomipramine etc.) Antiandrogens Oral contraceptives problem, whether the problem is global or situational and whether there are any deeper causes to the problem. Various styles of individual therapy have also been shown to be effective in the treatment of HSDD: individual psychodynamic psychotherapy is beneficial for addressing the relationship between exposure to trauma, relationship problems, unresolved issues from the past and decreased sexual desire. Cognitive behavioral therapy promotes cognitive restructuring and addresses avoidance behaviors. Finally, behavioral desensitization therapy has been shown to be effective for treating sexual aversion disorder [6]. One of the most important goals of sex therapy is to educate patients about normal sexuality and to help reframe their concept of what sexuality is, or can be [4]. Communication training is also important as a means of assisting women in developing a comfortable sexual vocabulary, reducing abusive verbal behavior and encouraging positive verbal exchange. The cornerstone of sex therapy are the sensate focus exercises which use nongenital contact to promote partner comfort and communication [4]. Some studies have shown that women achieve orgasm in only 40 80% of sexual encounters [5], and it has been postulated that low sexual desire may be partially due to the infrequency of orgasms in many women. A study by Hulbert and colleagues demonstrated that orgasm consistency training, in addition to standard couples sex therapy, was beneficial for the treatment of HSDD [5]. They found that, with both forms of therapy, women experienced improvements in sexual desire and arousal. Those that received orgasm consistency training reported greater sexual arousal, satisfaction and assertiveness than the women in the standard-treatment group [5]. Drug therapy The development of phosphodiesterase (PDE)-5 inhibitors broke new ground in the treatment of sexual dysfunction in men. Unfortunately, there is no equally effective therapy for sexual dysfunction in women, and no medication is currently approved by the US Food and Drug Administration (FDA) for the treatment of HSDD in women. Clinical trials of therapies have mostly studied postmenopausal women and have consisted of trials of: Hormonal treatments nhormonal medical treatments Complementary and herbal treatments Hormonal treatment options Hormonal therapies that have been explored for the treatment of HSDD include estrogen therapy, androgen therapy, dehydroepiandrosterone (DHEA) and tibolone. Estrogen therapy Estrogen deficiency has been clearly documented to result in vaginal atrophy, decreased vaginal secretions, decreased vaginal elasticity, decreased genital sensation and sleep disruption. Atropic vaginitis secondary to estrogen deficiency often leads to dyspareunia and secondary loss of libido. Furthermore, fatigue secondary to insomnia related to night sweats is another cause of HSDD in postmenopausal 264 Women's Health (2005) 1(2)

3 Treatment options for HSDD REVIEW women. Reversal of these effects with estrogen therapy often enhances sexual function and improves sexual desire. In a recent review of double-blind, randomized, controlled trials of estrogen on sexual function among naturally or surgically menopausal women, Alexander and colleagues cite multiple studies supporting the beneficial effects of estrogen therapy for the treatment of sexual dysfunction in naturally postmenopausal women. In their review, they demonstrate that both transdermal and oral estrogen therapy in naturally menopausal women are associated with an increase in sexual desire, fantasy, satisfaction and arousal, and a reduction in dyspareunia (Table 1) [7]. It is clear that estrogen therapy is an important first step in the treatment of HSDD and other types of sexual dysfunction in estrogendeficient women in order to enhance receptivity to sexual activity. Estrogen therapy can have this effect both by improving quality of life (via improved sleep and reduced vasomotor symptoms) and by improvements to vaginal health (via increased secretions and sensation and decreased dryness and dyspareunia). Testosterone therapy There are several lines of evidence that androgens are important for female sexual function. Androgens play an important role in stimulating libido and sexual interest and in maintaining desire [31]. Serum testosterone levels decline with age, antiandrogen therapy reduces libido in women and some studies have correlated changes in testosterone levels with changes in sexual desire and frequency of intercourse [32]. Testosterone therapy has been used for over 40 years in the USA and worldwide for the treatment of sexual desire disorders in women [33,34]. There have been more than 12 trials examining the use of testosterone in women with sexual dysfunction, with most trials in postmenopausal women (Table 1) [35]. However, there are no published studies on the use of testosterone alone in women; in all trials, testosterone therapy was given in conjunction with estrogen therapy. Most of these trials demonstrated that the addition of testosterone to estrogen significantly improved multiple facets of sexual functioning in postmenopausal women including [32]: Libido and sexual desire Arousal Frequency and satisfaction In one trial, testosterone therapy was even effective in improving libido and wellbeing in women who were not seeking treatment for libido problems [19]. One study did not show any significant benefits of the use of oral testosterone on measures of sexual function, possibly because most of the patients enrolled did not consider themselves to have a sexual dysfunction at the start of the study [17]. Testosterone therapy is particularly effective in women who have had bilateral oophorectomy and have subsequently developed HSDD [32,35]. The risks of testosterone therapy that result from physiologic or slightly supraphysiologic blood testosterone levels have been shown to be minimal. There is a dose-dependent increase in facial hair growth, acne and alopecia [35]. Highdensity lipoprotein (HDL) reduction was only observed with oral methyltestosterone, but there was a neutral effect with other forms of testosterone [35]. There have been no reports of liver dysfunction, polycythemia, increased risk of cardiovascular disease or sleep apnea in women given physiologic or slightly supraphysiologic testosterone therapy [35]. Although there are no definitive data on its effect on breast cancer risk, there are epidemiologic and in vitro data to suggest that testosterone may have a protective effect in women [101,36]. At present, only a combination of conjugated equine estrogens and methyltestosterone (Estratest and Estratest -HS, Solvay Pharmacueticals) is approved by the FDA for use in women, and the approval is only for the treatment of menopausal vasomotor symptoms unresponsive to estrogen alone. Therefore, in the USA, women are using this product, as well as those formulated for men or preparations prepared by compounding pharmacies, in an offlabel manner for the treatment of HSDD. An FDA Advisory Panel recently concluded that a transdermal testosterone preparation, which had undergone extensive clinical testing in surgically menopausal women who were receiving concomitant estrogen therapy, was effective and clinically relevant for the treatment of HSDD. However, they concluded that there were insufficient long-term safety data to recommend its approval at the time [101]. Though the FDA did not approve testosterone therapy for the treatment of HSDD in women due to long-term safety concerns, testosterone therapy is the most studied and consistently the most effective treatment for HSDD, particularly in surgically menopausal woman

4 REVIEW Bolour & Braunstein Table 1. Levels of evidence for hormonal treatment options for hypoactive sexual desire disorder. Type of therapy Estrogen Estrogen Estrogen progestin therapy Estrogen Estrogen vs progesterone progestin therapy Testosterone Testosterone vs estrogen androgen therapy Testosterone Estrogen androgen therapy vs estrogen Testosterone vs estrogen androgen therapy Estrogen androgen therapy Estrogen androgen therapy Sexual parameters evaluated Arousal Satisfaction Sex life Satisfaction with sexual function Activity Enjoyment Fantasy Lubrication Sexual enjoyment Lubrication Orgasm Satisfying sexual activity Decreased distress Fantasy Arousal Overall sexuality Frequency Orgasm Fantasy Arousal Dyspareunia Satisfaction Masturbation Pleasure Did patients meet HSDD criteria? Effect* Level of evidence Comments Ref. Positive 2a [8] Positive 1a Naturally menopausal women Negative 1a Postmenopausal women Those with moderate-tosevere vasomotor symptoms excluded [10] Positive 1a Postmenopausal women [11] Positive with estrogencontaining compounds 2a Double-blind cross-over study of surgically menopausal women only. Yes Positive 1a Randomized controlled trial of surgically menopausal women on estrogen therapy Positive for groups taking testosterone 1a Surgically menopausal women only Yes Positive 1a Surgically menopausal women on estrogen therapy Positive: Dyspareunia and sexual thoughts for both Arousal and satisfaction for testosterone Negative (all therapies) Yes Positive with estrogen androgen therapy Activity Pleasure Orgasm Satisfaction Positive for testosterone 1a 1a 1a 2b Surgically menopausal women only Naturally menopausal women only Surgically and naturally menopausal women Single-blind study of postmenopausal women on estrogen therapy [9] [12] [13] [14] [15] [16] [17] [18] [19] 266 Women's Health (2005) 1(2)

5 Treatment options for HSDD REVIEW Table 1. Levels of evidence for hormonal treatment options for hypoactive sexual desire disorder. (Cont.). Type of therapy DHEA DHEA DHEA DHEA Tibolone progestin therapy Tibolone Tibolone Tibolone progestin therapy Tibolone progestin therapy Sexual parameters evaluated Libido Activity Satisfaction Did patients meet HSDD criteria? Effect* Level of evidence Comments Positive 2b Positive only in women over the age of 70 Arousal Positive 2c Postmenopausal in experimental condition with pharmacologic doses (300 mg) [21] Arousal Negative 2c Premenopausal women [22] in experimental condition with pharmacologic doses (300 mg) Arousal Negative 2b Perimenopausal women [23] Frequency Enjoyment Arousal Orgasm (tibolone only) Dryness and pain Frequency of arousability Lubrication Responsiveness Activity Orgasm Positive with both Those on tibolone had significantly greater improvement of frequency and enjoyment 1a Postmenopausal women [24] Positive 2b Postmenopausal [25] women Positive 2b Single-blind study of postmenopausal women Libido Positive for both Greater improvement for tibolone Activity Dyspareunia Positive for tibolone Estrogen progestin therapy only improved dyspareunia 3 n-blinded study in postmenopausal women 2b Single-blind study of postmenopausal women Ref [20] [26] [27] [28] 267

6 REVIEW Bolour & Braunstein Table 1. Levels of evidence for hormonal treatment options for hypoactive sexual desire disorder. (Cont.). Tibolone vs estrogen androgen therapy Responsiveness Orgasm Dyspareunia Satisfaction Positive: all treatments compared with controls Those on ET or tibolone had greater improvement of interest, orgasm and responsiveness 2b Surgically menopausal women DHEA: Dehydroepiandrosterone; ET: Estrogen therapy; HSDD: Hypoactive sexual desire disorder. *Positive effect was statistically significant Levels of evidence (adapted from [30]): Level 1: High quality individual randomized controlled trial Level 2: Lower quality clinical trial Level 3: Case series, physiologic outcomes study, extrapolation from bench research Strength of Recommendation: a: Recommendation based on consistent and good quality patient-oriented evidence b: Recommendation based on inconsistent or limited quality patient-oriented evidence c: Recommendation based on consensus, usual practice, opinion, disease oriented evidence and case series for studies of diagnosis, treatment, prevention or screening. [29] Dehydroepiandrosterone therapy Another androgen that has been reported to possibly be effective for the treatment of HSDD is dehydroepiandrosterone (DHEA), an androgenic steroid hormone synthesized primarily by the adrenals, that declines with normal aging. Perimenopausal women have only approximately 50% of peak DHEA levels [23]. DHEA and DHEA-sulfate (DHEAS) are precursors to estrogen and testosterone. There have been few clinical trials of DHEA supplementation for the treatment of sexual dysfunction. DHEA therapy in patients with low DHEAS levels due to primary or secondary adrenal insufficiency have been found in some, but not all, studies to increase sexual thoughts, fantasies, interest and satisfaction [38 40]. Data from trials in women without adrenal insufficiency are also conflicting. One trial of elderly women aged years showed a benefit in women over the age of 70 years, with the use of 50 mg DHEA daily increasing libido, sexual activity and sexual satisfaction (after 12 months of treatment), but these benefits were not seen in women younger than 70 years of age [20]. An experimental study using a pharmacologic dose of 300 mg of DHEA was conducted to examine the effects of an acute dose of DHEA on genital and mental arousal, and to examine whether it affected response to an erotic video compared with a nonerotic video [21,22]. This study demonstrated that DHEA administration in postmenopausal women was effective in increasing mental and physical arousal, but not in premenopausal women [21,22]. Lastly, a randomized, controlled trial of 60 perimenopausal women with symptoms of fatigue, lack of energy, anxiety, tension, irritability, depression, insomnia, forgetfulness, concentration difficulties, decreased libido or global reports of a decreased sense of well being failed to show any benefit over placebo with the administration of 50 mg DHEA, although levels of DHEAS did increase [23]. Although DHEA may be beneficial for women over 70 years of age with low libido, the preponderance of clinical data do not support the use of DHEA in younger postmenopausal or premenopausal women. Tibolone Tibolone is a synthetic steroidal agent with tissuespecific estrogenic, androgenic and progestogenic actions [41]. It has been used in Europe for over 20 years for the treatment of vasomotor symptoms and osteoporosis in postmenopausal women, but does not have FDA approval for use in the USA. In postmenopausal women it has favorable effects on the vagina, mood, sexual well being and vasomotor symptoms, but does not stimulate the endometrium. Although it has been reported not to stimulate breast tissue, the Million Women Study demonstrated a relative risk of Women's Health (2005) 1(2)

7 Treatment options for HSDD REVIEW (confidence interval [CI]: ) for the development of breast cancer in women taking tibolone [42]. Potential effects of tibolone on sexual function are believed to be mediated via its metabolite, the 4-isomer, which activates the androgen receptor and via lowering of sex hormone-binding globulin (SHBG) levels, which increases bioavailable testosterone [41]. There have been few trials examining the efficacy of tibolone for sexual dysfunction. Most trials suggest there is a benefit in using tibolone for the treatment of sexual arousal disorder [43,44]. Two of these trials demonstrated that tibolone treatment was associated with an improvement in sexual function with regards to frequency, satisfaction and enjoyment compared with those taking estrogen and progestins, and greater sexual desire compared with placebo [24,25]. Side effects of therapy included weight gain, fluid retention and night sweats [25]. The current data warrant the need for further investigation and larger, controlled trials to investigate the effects of tibolone on sexual function. nhormonal medical therapies A few nonhormonal medical therapies that have been explored for the treatment of female sexual dysfunction. These include PDE-5 inhibitors, bupropion and apomorphine. Phosphodiesterase-5 inhibitor PDE-5 inhibitors are effective in treating male erectile dysfunction. Though case reports have suggested a benefit for the use of PDE-5 inhibitors for the treatment of female sexual dysfunction, randomized, controlled trials of estrogenized and estrogen-deficient women have demonstrated that sildenafil offers no benefit for the treatment of HSDD or of sexual arousal disorder [43,45,46]. Bupropion Sexual dysfunction is one of the most common side effects of all antidepressant therapy [47]. Selective serotonin reuptake inhibitors (SSRIs) can have a negative effect on all three phases of sexual function (libido, arousal and orgasm), with delay in orgasm and anorgasmia being the most common effects [48]. Bupropion, an antidepressant approved for treating depression and smoking cessation, affects both dopamine and norepinephrine reuptake. Most trials of buproprion have been in women with SSRI-induced sexual dysfunction. Only three small studies have examined the effects of bupropion in nondepressed women with HSDD. A total of 29% of women responded to bupropion sustained release (SR) 150 mg twice daily in a single-blind, placebocontrolled trial of 55 nondepressed women (mean age 42 years) with HSDD. These women had a statistically significant increase in sexual desire, arousal and fantasy. Satisfaction with sexual desire did not improve during the first 4 weeks, but did improve after 12 weeks. Side effects included headaches, insomnia, tremor and rash [2]. A further trial of 66 nondepressed premenopausal women randomized patients to buproprion 150 mg (increasing to either 300 or 400 mg) or placebo and demonstrated no statistically significant increase in sexual desire, although there was a slight increase in orgasm and arousal scores in the treatment group [49]. The third trial was an open-label study of 20 women (and ten men) with nonphysiologic orgasm delay or inhibition. In this trial, 150 mg of buproprion-sr was associated with a statistically significant improvement in sexual satisfaction and orgasm [50]. Trials in women with SSRI-induced sexual dysfunction show a stronger effect. In most studies, bupropion has been associated with improvements in sexual functioning when it is substituted for, or added to, other antidepressants [2,48,51,52]. Lack of efficacy in the negative study may have been due to its short duration and insufficient power. Thus far there have been a handful of clinical trials for the treatment of female sexual dysfunction with buproprion. Many of the trials were of short duration and in a small sample of patients with no power calculations. Data obtained thus far suggest a potential role for the addition or substitution of buproprion to standard SSRI therapy when standard therapy leads to sexual dysfunction. In the nondepressed patient, there does not appear to be a role for buproprion in the treatment of desire disorders. There may be potential for its use in the treatment of orgasmic disorder and for the improvement of sexual satisfaction; however, this needs to be explored further before definitive recommendations can be made. Buspirone Buspirone is a partial 5-hydroxytryptamine agonist that is indicated for the treatment of anxiety disorder. There are two trials using buspirone as an antidote to SSRI-induced sexual dysfunction. Although there was a trend towards a lower rate of sexual dysfunction in those patients who received buspirone, there was no statistically significant improvement with the use or addition of buspirone [47,54]

8 REVIEW Bolour & Braunstein Amantadine In a study of patients with fluoxetine-induced sexual dysfunction, some patients were allocated to treatment with amantadine, which is thought to increase dopamine availability; however, treatment did not result in a statistically significant improvement in sexual dysfunction [54]. Apomorphine sublingual Apomorphine is a centrally acting dopamine agonist used for the treatment of erectile dysfunction. In a study of regularly ovulating premenopausal women with normal testosterone levels, daily use of apomorphine (2 or 3 mg) was associated with a statistically significant improvement in libido, arousal, orgasm, enjoyment and frequency of intercourse compared with placebo. The benefit was dose-dependent, with greater improvement observed at the higher dose. Side effects were seen mostly at the 3 mg dose and included nausea, vomiting, headache and dizziness [53]. Studies are currently underway to further explore the use of apomorphine nasal spray for the treatment of sexual dysfunction in women. Complementary and alternative therapies As there is no drug approved by the FDA for the treatment of sexual dysfunction in women, women often turn to over-the-counter remedies that promise to improve sexual functioning. There are many such remedies on the market today, but few have clinical trials to support their claims. Herbs that have been touted as effective for the treatment of sexual dysfunction are listed in Table 2. Herbal products that have been studied in clinical trials are described below. Avlimil Avlimil (Berkeley Premium Nutraceutical) is a popular remedy advertized on cable television channels and lay magazines. It is a proprietary blend of: Salvia officinalis (sage leaf); Rubus idaeus (red raspberry leaf); isoflavones from Pueraria montana (kudzu root extract) and Trifolium pratense (red clover extract); Capsicum annuum (capsicum pepper); Glycyrrhiza glabra (licorice root); Morella cerifera (bayberry fruit); Turnera diffusa (damiana leaf); Valeriana officinalis (valeriana root); Zingiber officinale ginger root) and Actaea racemosa (black cohosh root). According to the manufacturer s original website, their claims are based on a randomized trial of 49 women (aged years) who were interested in improving their sexual function [57], although the current website does not list the number of women that participated in these trials [102]. According to the website, sexual desire, arousal, orgasm and overall satisfaction increased significantly at 2 months in the Avlimil-treated group. The validity of this study is highly questionable as there is minimal information concerning the details of the study on the website, and there is no information on the number and baseline features of women involved in the trial. Furthermore, the study was sponsored by the manufacturer and did not undergo a peer-review process, so the effectiveness of this product remains to be proven. Zestra Zestra (QualiLife Pharmaceuticals) is a botanical feminine massage oil formulated to enhance female sexual pleasure, to increase warmth, sensitivity and sensation and to facilitate arousal when applied to the clitoris, labia and vaginal opening. It is a proprietary blend of borage seed oil, evening primrose oil, Angelica extract, Coleus extract, vitamin C and vitamin E. In a double-blind, randomized, controlled trial of 20 women with female sexual arousal disorder, there was a statistically significant improvement in sexual arousal and lubrication, in addition to sexual desire, orgasm and satisfaction [58]. Zestra has been evaluated for the treatment of female sexual arousal disorder but is mentioned in this discussion as it had modest success and showed benefit in improving sexual desire (in normal women, women with arousal disorder and women taking SSRIs) [58]. The only side effect associated with the use of the drug was a mild genital burning sensation that lasted 5 30 mins. Arginmax Arginmax (Daily Wellness Company) is a nutritional supplement containing: Korean ginseng (Panax ginseng: 30% ginsenosides); Ginkgo biloba (24% flavine glycosides and 6% terpene lactones); damiana leaf (Turnera aphrodisiaca) and L- arginine (precursor to nitric oxide); vitamins B6 and B12, folate, niacin, pantothenix acid, riboflavin and thiamin; vitamins A, C and E; calcium; iron; and zinc. A randomized, controlled trial of Arginmax in 77 women (aged years) demonstrated a statistically significant increase in sexual desire, satisfaction with sex life, frequency of intercourse and improved sexual relationship with their partner, increased clitoral sensation 270 Women's Health (2005) 1(2)

9 Treatment options for HSDD REVIEW Table 2. Herbs used for the treatment of sexual dysfunction. Herb Purported benefit Other uses Clinical trials for sexual dysfunction Gingko biloba Yohimbine Damiana leaf Found in Arginmax and Avlimil Korean ginseng (Ginseng panax) Found in Arginmax L-arginine Found in Arginmax Sage leaf (Salvia officinalis) Red raspberry leaf (Rubus idaeus) Kudzu root extract (Pueraria montana) Red clover extract (Trifolium pretense) Licorice root (Glycyrrhiza glabra) Treat sexual dysfunction Reverse sexual dysfunction caused by SSRI antidepressants Aphrodisiac General sexual dysfunction in men and women Sexual dysfunction caused by SSRIs For prophylaxis and treatment of sexual disturbances Aphrodisiac Erectile dysfunction Neurasthenia Topically for the treatment of female sexual dysfunction ne ne ne ne ne Treat and prevent cognitive dysfunction and memory loss Impotence Exhaustion, angina, diabetic neuropathy Syncope and postural hypotension Contraindicated in patients with liver or kidney disease, history of peptic ulcers, psychiatric patients t recommended for long-term use Headache, bedwetting, depression, nervous dyspepsia, atonic constipation, strengthening and stimulation during exertion (overwork) Boosting and maintaining mental and physical capacity By inhalation, damiana is used for a subtle high Vasomotor symptoms of menopause So-called "adaptogen" for increasing resistance to environmental stress, improving well-being and slowing the aging process Impotence and male fertility, fever, hangover and asthma Cardiovascular conditions including congestive heart failure and angina pectoris Erectile dysfunction and male infertility Topically, L-arginine is used as an aid in wound healing, for treating cold hands and feet Dysmenorrhea Loss of appetite, excessive perspiration and saliva Galactorrhea Diarrhea, gastritis; reduction of secretion and digestive problems including flatulence, bloating and dyspepsia Topically used for treatment of inflammation Dysmenorrhea and menorrhagia Topically used for inflammation of the mouth and throat and skin rash Menopause Alcohol hangover and drunkenness kudzu root is consumed as food Menopausal symptoms Cardioprotection Approved by Commission E for: - Cough/bronchitis - Gastritis Yes, in patients with SSRI-induced sexual dysfunction Yes, in patients with SSRI-induced sexual dysfunction Yes for erectile dysfunction 271

10 REVIEW Bolour & Braunstein Table 2. Herbs used for the treatment of sexual dysfunction. (Cont.). Herb Purported benefit Other uses Clinical trials for sexual dysfunction Bayberry fruit (Morella cerifera) ne Coughs and colds Valeriana root (Valeriana officinalis) Ginger root (Zingiber officinale) Black cohosh (Actaea racemosa) Cayenne (Capsicum annuum) Bulgarian chlorella Found in Kyogreen Laminaria Found in Kyogreen Maca* Cotton (Gossypium hirsutum) Walnut (Juglans regia) Pasque flower (Pulsatilla pratensis) Sweet marjoram (Origanum majorana) Oregano (Origanum vulgare) ne ne ne In cream form used as a female orgasm stimulant ne ne Peruvian Andes remedy for inducing sexual desire in women Indian remedy for sexual dysfunction Indian remedy Seeds said to have an aphrodisiac effect Homeopathic remedy for female sexual dysfunction Homeopathic remedy for increasing sexual excitability Homeopathic remedy for increasing sexual excitability Vasomotor symptoms of menopause Approved by Commission E for: - Restless states - Difficulties falling asleep caused by nervousness Approved by Commission E for: - Loss of appetite - Travel sickness - Dyspepsic complaints Approved by Commission E for: - Vasomotor symptoms of menopause - Prementrual syndrome External use approved by Commission E for: - Muscular tension - Rheumatism Use should be limited to 2 days and should only be used again after 2 weeks Longer use can cause dermatitis and ulcering Cancer prevention and stimulation of the immune system Treatment and prevention of GI problems Prementrual syndrome Weight loss Preventing cancer As a bulk laxative for constipation Boosting fertility Also used for sexual dysfunction in men Amenorrhea, dysmenorrhea, irregular, painful or profuse menstrual bleeding Vasomotor symptoms of menopause Anti-fertility drug in males as well as in topical, vaginal contraceptive preparations External use approved by Commission E for: - Inflammation of the skin - Excessive perspiration Orally used for: - Inflammation - Menstrual complaints - Disease and functional disorders of the GI tract Folk medicine used for: - Cramps, depression, GI disorders, migraines In early Greek mythology, the goddess of love, Aphrodite, was believed to have grown marjoram and marjoram has since been used in various love potions Colds, fever, dysentery and jaundice Intestinal parasitic infections 272 Women's Health (2005) 1(2)

11 Treatment options for HSDD REVIEW Table 2. Herbs used for the treatment of sexual dysfunction. (Cont.). Herb Purported benefit Other uses Clinical trials for sexual dysfunction Chaste tree (Vitex agnuscastus) Cubeb (Piper cubeba) Iporuru (Alchornea floribunda) Matico (Piper elongatum) Muira-puama (Ptychopetalum olacoides) ne Folk medicine remedy for increasing libido Herb used in Africa as an aphrodisiac Herb used in Peru as an aphrodisiac Herb used in Amazon to treat low libido and anorgasmia in women Homeopathic remedy for male sexual problems Approved by Commission E for: - Premenstrual syndrome - Mastalgia - Menstrual cycle irregularities and infertility Expectorant Used for respiratory and urinary tract infections High doses are highly toxic and hallucinogenic Used externally to stop bleeding and treatment of ulcers Used internally for diarrhea, loss of appetite GI: Gastrointestinal; SSRI: Specific serotonin reuptake inhibitor *List derived from herbs referenced in [56], herbs used in combination pills described in this paper, and herbs listed under the category of sexual dysfunction in the Natural Medicine Comprehensive Database [103] and PDR for Herbal Medicine [56]. and reduced vaginal dryness with the use of Arginmax compared with placebo. There were no adverse side effects reported [59]. Kyo-green Kyo-green (Wakunaga of America Company) is a green, powdered nutritional supplement containing young barley leaves and wheat grass (from the Nasu Highlands of Japan); laminaria (rth Pacific kelp) and brown rice. Clinicians from the Center for Healthful Living at Loma Linda University, (CA, USA), found that women who consumed only a little fruit and vegetables daily reported improved orgasms when given Kyo-green as a nutritional supplement. In a 3- month open-label, nonplacebo-controlled study (medications provided by manufacturer) of 15 women with lack of libido or anorgasmia, or who were sexually inactive, there was a statistically significant improvement in sexual desire, satisfaction and energy among the women starting at 1 month following initiation of treatment and continuing for the duration of the trial [60]. The number of women in this study and the tools used to determine efficacy were insufficient to draw any firm conclusion concerning efficacy. Ginkgo biloba Another common herbal remedy used for the treatment of sexual dysfunction is Ginkgo biloba. Most commonly used to prevent memory loss, there have been reports of the use of Ginkgo biloba for the treatment of female sexual dysfunction. Case reports suggest that Ginkgo biloba is beneficial for the treatment of SSRI-induced arousal disorder [61], but clinical trials on the whole do not support that finding. One small, prospective trial of 22 consecutive patients with SSRI-induced sexual dysfunction demonstrated some benefit for 23% of the women, but no benefit for the men [62]. Another trial of 37 patients (ten females) demonstrated no difference in sexual desire, lubrication/erectile function or orgasm frequency between the groups at any time period [63]. The only trial that demonstrated efficacy was an open-label trial of 63 patients treated with 40 mg Ginkgo biloba twice daily (titrated up to 120 mg twice daily) for 4 weeks. This trial demonstrated that the use of Ginkgo biloba in women was 91% effective in alleviating antidepressantinduced sexual dysfunction. According to the authors, Ginkgo biloba has positive effects on all four phases of the sexual-response cycle, although the raw data were not presented in the article [64]. Yohimbine Classically used for male sexual dysfunction, there is one small pilot study of the use of yohimbine for the treatment of SSRI-induced sexual dysfunction, which included a small percentage of women. In this trial of nine patients (two women and seven men) with fluoxetine-induced 273

12 REVIEW Bolour & Braunstein sexual dysfunction treated with 5.4 mg of yohimbine three times daily, 89% had complete or partial response. Side effects were common, with 56% of participants complaining of adverse effects (most commonly nausea, anxiety, insomnia and increased urinary frequency). Response was seen within the first week and did not fatigue over time [65]. There are no other published studies on the use of yohimbine in women. Other products There are many other products, such as Libidol (Alpine Pharmacueticals) marketed for the treatment of female sexual dysfunction and HSDD specifically, but there are no clinical trials or reports in the medical literature to support their effectiveness. There are also multiple herbal creams containing damiana leaf that are applied to the genitals and advertized to increase sensation and arousal, such as Vigorelle (Leading Edge Herbals), Climatique (Climatique International) and V-gel (Higher Nature Ltd.). The only one which has been clinically shown to increase arousal and desire in a published clinical trial is Zestra. Whether the other herbal creams are effective or not is pure conjecture. Conclusion Although HSDD is a common disorder among women, there are very few trials of treatments specifically for this disorder, with most trials addressing female sexual function as a whole or addressing multiple areas of dysfunction. Most trials have had general end points since many women have overlapping areas of dysfunction, as described by Basson [3], and definitions and standardized tools for assessment of dysfunction were not yet developed at the time the trials were conducted. The most extensive studies have investigated the use of testosterone supplementation in postmenopausal women. This therapy, in well-estrogenized postmenopausal women, is beneficial for the treatment of low libido and has a low risk of side effects. In addition, estrogen therapy alone appears to be an important means of improving sexual desire in postmenopausal women, especially in those with dyspareunia due to diminished vaginal secretions. Trials in premenopausal women are limited and there is a need to pursue studies in this age group. A major limitation of most of the trials is that they addressed the treatment of female sexual dysfunction as a whole, without specifying which aspect they aimed to treat. Patients were rarely required to meet rigorous diagnostic criteria for a specific type of sexual dysfunction in order to be enrolled in the studies. Only trials on testosterone therapy addressed women with a clinical diagnosis of HSDD. In addition, no trials have attempted to evaluate therapies in women with comorbid sexual dysfunction (e.g., HSDD and arousal disorder) or whether the treatment of one type of disorder (e.g., arousal disorder) impacts the course of the other (e.g., HSDD). Furthermore, there are very few high-quality studies except those examining testosterone treatment of estrogen-replete surgically menopausal women with HSDD. Most trials were pilot or open-label studies with no placebo control. The inclusion of a control is important since there is a large placebo effect in this area. Many studies included a small sample size and were underpowered to detect a difference. There was also a large drop-out rate in many of the studies and most did not employ intent-to-treat analysis of the results. Another limitation of many of the trials is that different trials used different, often nonvalidated, instruments for assessing levels of dysfunction and clinical response. Often the trials were of short duration, which did not allow long-term benefit to be assessed. Finally, side effects were not documented or followed-up in many of the trials. One of the major limitations of the SSRIinduced sexual-dysfunction trials was that there were no clear demarcations as to whether sexual dysfunction was the result of the SSRI therapy (i.e., it began after the start of treatment) or whether it was a symptom of the depressive disorder (i.e., it preceded the SSRI treatment). In those patients who had sexual dysfunction as a result of their depression, it is important to note how patients sexual dysfunction changed with treatment and with changes to their depressive symptoms, as trials of patients with SSRIinduced sexual dysfunction also demonstrated improvement of depression scores with the addition of buproprion-sr [3,103]. Whether the improvement of sexual dysfunction was a result of the medication or a result of the improvement in depressive symptoms is not clear. HSDD is a widespread disorder affecting more than a third of women of all ages. Most investigators were highly optimistic about the beneficial effects of their therapy for the treatment of female sexual dysfunction and HSDD and reported positive results even when the results were not statistically significant or were of slight benefit. Only estrogen, testosterone 274 Women's Health (2005) 1(2)

13 Treatment options for HSDD REVIEW and sex therapy have been proven to be effective in clinical trials trials for all other therapies are limited and/or conflicting. Thus, the best therapies for this disorder are estrogen and testosterone therapy for postmenopausal women, and sex therapy for women of all ages and their partners. Future perspective Insight into the etiology and biology of female sexual dysfunction is evolving rapidly. In the past 10 years, headway has been made in all aspects of the diagnosis and treatment of HSDD and female sexual dysfunction. Most importantly, the problem has been identified and named, with the specific diagnostic criteria necessary for the diagnosis of each subtype of female sexual dysfunction elucidated. Validated questionnaires have been developed to ensure that patients truly have female sexual dysfunction and, specifically, HSDD, and that the problem is not a reflection of other underlying disorders such as depression. Gender differences in the sexual-response cycle have been identified and the impact of various hormones on the normal female sexual-response cycle are better understood. Finally, an understanding of gender differences in response to pharmaceutical treatments has been developed. With this growing body of knowledge concerning the normal female sexual-response cycle, and the diagnosis of disorders, the ability to include appropriate patients in studies and assess the effects of treatments has improved. In addition, as the molecular basis and impact of hormone and neurotransmitters on the sexual-response cycle are elucidated, more targeted therapies can be developed. This increased understanding should allow for more rational development of therapeutics and improved study designs. Executive Summary Hypoactive sexual desire disorder (HSDD) is a common disorder in women and is often mutifactorial in etiology. Sex therapy, couples therapy and individual therapy are important and effective strategies for treating HSDD. There are no US Food and Drug Administration (FDA)-approved medications for the treatment of HSDD. Multiple randomized, controlled trials demonstrate the effectiveness of estrogen in conjunction with testosterone therapy for the treatment of HSDD. There may be a role for the addition or substitution of buproprion sustained release for the treatment of antidepressant-induced sexual dysfunction, but clinical trials thus far do not support the use of phosphodiesterase (PDE)-5 inhibitors, buspirone, amantadine, yohimbine or Ginkgo biloba. There are no published controlled trials on Avlimil, Libidol, Vigorelle or V-gel to demonstrate the effectiveness of these overthe-counter products. There are individual studies of the proprietary herbal combinations Zestra, Arginmax and Kyo-green for the treatment of arousal disorders in women, but insufficient evidence to recommend these agents for the treatment of HSDD. In evaluating treatment options for the treatment of HSDD, it is important to consider the large placebo effect that is seen in wellconducted randomized, controlled trials and, without an adequate control for this important phenomenon, it would be prudent to withhold judgment of the true effectiveness of a therapy. Bibliography Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Laumann EO, Paik A, Rosen RC: Sexual dysfunction in the United States: prevalence and predictors. JAMA 281, (1999). Landmark study on the prevalence of sexual dysfunction and the determinants and health consequences of these disorders in various age and social groups in the USA. 2. Basson R: Definitions of women s sexual dysfunction reconsidered: advocating expansion and revision. J. Psychosom. Obstet. Gynaecol. 24, (2003). Another landmark paper from an international panel of experts in this field that discusses the evidence for gender differences in sexual response and presents a revised definition of subtypes of female sexual dysfunction based on the new model of the female sexual-response cycle. 3. Segraves RT, Croft H, Kavoussi R et al.: Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women. J. Sex Marital Ther. 27(3), (2001). 4. Plaut SM, Graziottin A, Heaton JP: Fast Facts: Sexual Dysfunction. Health Press Limited, Oxford, UK (2004). Excellent pocket handbook discussing female and male sexual function and dysfunction and treatment options. 5. Hurlbert DF: A comparative study using orgasm consistency training in the treatment of women reporting hypoactive sexual desire. J. Sex Marital Ther. 19(1), (1993). 6. Finch S: Sexual aversion disorder treated with behavioural desensitization. Can. J. Psychiatry 46(6), (2001). 7. Alexander JL, Kotz K, Dennerstein L, Kutner SJ, Wallen K, telovitz M: The effects of postmenopausal hormone therapies on female sexual functioning: a review of double-blind, randomized controlled trials. Menopause 11(Suppl.6), (2004)

14 REVIEW Bolour & Braunstein Recent review of randomized, controlled trials of hormonal therapies for the treatment of female sexual dysfunction. 8. Sherwin BB: The impact of different doses of oestrogen and oestrogen-androgens on mood and sexual behavior in postmenopausal women. J. Clin. Endocrin. Metab. 72(2), (1991). 9. Wiklund I, Karlberg J, Mattsson L: Quality of life of postmenopausal women on a regimen of transdermal estadiol therapy: a double-blind placebo-controlled study. Am.J.Obstet. Gynecol. 168(3), (1993). 10. Hays J, Ockene JK, Brunner RL et al.: Effects of oestrogen plus progestin on health related quality of life. N. Engl. J. Med. 348(10), (2003). 11. Nathorst-Boos J, Wiklund I, Mattsson LA et al.: Is sexual life influenced by transdermal oestrogen therapy? A doubleblind placebo-controlled study. Acta Obstet. Gynecol. Scand. 72, (1993). 12. Dennerstein L, Burrows GD, Wood C et al.: Hormones and sexuality: effects of oestrogen and progestogen. Obstet. Gynecol. 56, (1980). 13. Buster JE, Kingsberg SA, Aguirre O et al.: Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet. Gynecol. 105, (2005). 14. Sherwin BB, Gelfand M: Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom. Med. 47(4), (1985). 15. Shifren, JL, Braunstein GD, Simon JA et al.: Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N. Engl. J. Med. 343(10), (2000). 16. Floter A, Nathorst-Boos K, Carlstrom K et al.: Addition of testosterone to oestrogen replacement in oophorectomized women: effects on sexuality and well being. Climacteric 5, (2002). 17. Myers LS, Dixen J, Morrissette D, Carmichael M, Davidson JM: Effects of oestrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J. Clin. Endocrin. Metab. 70(4), (1990). 18. Lobo RA: Comparative effects of oral esterified oestrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive desire disorder. Fertil. Steril. 79, (2003). 19. Davis SR, McCloud P, Strauss BJ, Burger H: Testosterone enhances estradiol s effects on postmenopausal bone density and sexuality. Maturitas 21, (1995). 20. Baulieu EE, Thomas G, Legrain S et al.: Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc. Natl Acad. Sci. USA 97(8), (2000). 21. Hackbert L, Heiman JR: Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women. J. Womens Health Gend. Based Med. 11(2), (2002). 22. Meston CM, Heiman JR: Acute dehydroepiandrosterone effects on sexual arousal in premenopausal women. J. Sex Marital Ther. 28(1), (2002). 23. Barnhart KT, Freeman E, Grisso JA et al.: The effect of deydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J. Clin. Endocrinal Metab. 84, (1999). 24. Nathorst-Boos J, Hammar M: Effect on sexual life a comparison between tibolone and a continuous estradiol-northisterone acetate regimen. Maturitas 26, (1997). 25. Laan E, van Lunsen RH, Everaerd W: The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric 4, (2001). 26. Palacios S, Menendez C, Jurado AR, Castano R, Vargas JC: Changes in sex behavior after menopause: effects of tibolone. Maturitas 22, (1995). 27. Egarter C, Huber J, Leikermoser R et al.: Tibolone versus conjugated oestrogens and sequential progestogen in the treatment of climacteric complaints. Maturitas 23, (1996). 28. Kokcu A, Cetinkaya MB, Yanik F, Alper T, Malatyalioglu E: The comparison of effects of tibolone and conjugated oestrogenmedroxyprogesterone acetate therapy on sexual performance in postmenopausal women. Maturitas 36, (2000). 29. Castelo-Branco C, Vicente JJ, Figueras F et al.: Comparitive effects of oestrogen plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas 36, (2000). 30. Siwek J, Gourlay M, Slawson DC, Shaughnessy AF: How to write an evidencebased clinical review article. Am. Fam. Physician 65, (2001). 31. Davis SR, Tran J: Testosterone influences libido and well being in women. Trends Endocrinol. Metab. 12, (2001). 32. Cameron DR, Braunstein GD: Androgen replacement therapy in women. Fertil. Steril. 82(2), (2004). 33. Geist SH: Androgen therapy in gynecology. JAMA 117, (1940). 34. Greenblatt RB: Evaluation of an androgen, oestrogen, oestrogen-androgen combination, and a placebo in the treatment of menopause. J. Clin. Endocrinol. Metab. 10(12), (1950). 35. Bolour SY, Braunstein G: Testosterone therapy in women: a review. Int. J. Impot. Res. (2005) (In press). Recent review of testosterone therapy for the treatment of female sexual dysfunction. 36. Dimitrakakis C, Jones RA, Liu A, Bondy CA: Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause 11, (2004). 37. Somboonporn W, Davis SR: Testosterone effects on breast: implications for testosterone therapy for women. Endocr. Rev. 25, (2004). 38. Arlt W, Callies F, van Vlijmen JC et al.: Dehydroepiandrosterone replacement in women with adrenal insufficiency. N. Engl. J. Med. 341, (1999). 39. Hunt PJ, Gurnell EM, Huppert FA et al.: Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison s Disease in a randomized doubleblind trial. J. Clin. Endocrinol. Metab. 85(12), (2000). 40. Lovas K, Gebre-Medhim G, Trovik TS et al.: Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J. Clin. Endocrinal Metab. 88(3), (2003). 41. Modelska K, Cummings S: Tibolone for postmenopausal women: systematic review of randomized trials. J. Clin. Endocrinal Metab. 87(1), (2002). 42. Million Women Study Collaborators: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, (2003). 43. Lae TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F: Sexual Medicine: Sexual Dysfunction in Men and Women. Health Publications, Paris, France (2004). 44. Davis SR: The effects of tibolone on mood and libido. Menopause 9(3), (2002). 276 Women's Health (2005) 1(2)