P1: GVG/FZN/GCY P2: GCV Archives of Sexual Behavior pp527-aseb-375624 July 4, 2002 13:29 Style file version July 26, 1999 Archives of Sexual Behavior, Vol. 31, No. 4, August 2002, pp. 323–332 (C 2002) The Effects of Yohimbine Plus L-arginine Glutamate on Sexual Arousal in Postmenopausal Women with Sexual Arousal Disorder1 , Cindy M. Meston, Ph.D.,2 4 and Manuel Worcel, M.D.3 Received August 17, 2001; revision received November 30, 2001; accepted December 31, 2001 This study examined the effects of the nitric oxide-precursor L-arginine combined with the 2-blocker yohimbine on subjective and physiological sexual arousal in postmenopausal women with Female Sex- ual Arousal Disorder. Twenty-four women participated in three treatment sessions in which self-report and physiological (vaginal photoplethysmograph) sexual responses to erotic stimuli were measured following treatment with either L-arginine glutamate (6 g) plus yohimbine HCl (6 mg), yohimbine alone (6 mg), or placebo, using a randomized, double-blind, three-way cross-over design. Sexual responses were measured at approximately 30, 60, and 90 min postdrug administration. The com- bined oral administration of L-arginine glutamate and yohimbine substantially increased vaginal pulse amplitude responses to the erotic film at 60 min postdrug administration compared with placebo. Sub- jective reports of sexual arousal were significantly increased with exposure to the erotic stimuli but did not differ significantly between treatment groups. KEY WORDS: yohimbine; L-arginine; female sexual arousal; photoplethysmography; nitric oxide; adrenergic. INTRODUCTION lubrication-swelling response of sexual excitement” which causes “marked distress or interpersonal difficulty.” Physiological sexual arousal in women involves Prevalence estimates of FSAD vary widely between an increase in pelvic vascular blood flow and resultant studies, likely due to different operational definitions of pelvic vasocongestion, vaginal engorgement, swelling of the disorder. A recent random survey of over 1,600 fe- the external genitalia, and clitoral erection (Levin, 1992). male respondents, ages 18–59 years, found that approx- Vaginal wall engorgement occurs with increased blood imately 19% of women reported difficulties with lubri- flow to the local vascular bed, enabling plasma transuda- cation (Laumann, Gagnon, Michael, & Michaels, 1994). tion and subsequent lubrication of the epithelial surface of Reported risk factors included health and lifestyle fac- the vaginal wall (Levin, 1991; Schiavi & Segraves, 1995). tors (e.g., history of STD, poor health, emotional prob- Female Sexual Arousal Disorder (FSAD) is defined in the lems), social status, and sexual experience (e.g., low sex- Diagnostic and Statistical Manual of Mental Disorders ual frequency, history of sexual abuse; Laumann, Paik, & (DSM-IV; American Psychiatric Association, 2000) as the Rosen, 1999). The incidence of FSAD is higher among “persistent or recurrent inability to attain, or to main- women of peri or postmenopausal years: One study re- tain until completion of the sexual activity, an adequate ported 44% of postmenopausal women experience per- sistent or recurrent lubrication problems (Rosen, Taylor, 1A version of this article was presented at the meeting of the International Leiblum, & Bachmann, 1993). Studies that have used Academy of Sex Research, Paris, France, June 2000. more stringent diagnostic criteria report lower rates. For 2Department of Psychology, University of Texas at Austin, Austin, example, Lindal and Stefansson (1993) reported a lifetime Texas. prevalence of 6% in a large random population sample and 3Nitromed, Inc., Bedford, Massachusetts. 4To whom correspondence should be addressed at Department of Psy- Fugl-Meyer and Sjogren Fugl-Meyer (1999) reported a 1- chology, University of Texas at Austin, 08 E. Dean Keeton, Austin, year prevalence of 8% in a large Swedish sample. Both of Texas 78712; e-mail: [email protected]. these studies used the earlier DSM-III criteria, which did 323 0004-0002/02/0800-0323/0 C 2002 Plenum Publishing Corporation P1: GVG/FZN/GCY P2: GCV Archives of Sexual Behavior pp527-aseb-375624 July 4, 2002 13:29 Style file version July 26, 1999 324 Meston and Worcel not include “marked distress or interpersonal difficulty” effects of DHEA on women specifically diagnosed with (DSM-IV criteria) as part of the diagnostic requirements. FSAD. A device called EROS, which consists of a small To our knowledge, there are no prevalence statistics for suction cup that fits over the clitoral region, was recently FSAD based strictly on DSM-IV diagnostic criteria. approved by the Food and Drug Administration (FDA) as Female sexual arousal disorder is a clinical diagno- a treatment for FSAD. Studies report its success in draw- sis that rarely presents alone. In fact, several theorists have ing blood into the genital tissue, but anecdotal reports in- suggested that the majority of female sexual difficulties re- dicate that some women find the external aid decreases flect disruptions in sexual arousal. Orgasm is impossible sexual spontaneity. without arousal and a lack of arousal commonly leads to To date, there are no FDA-approved pharmacolo- a lack of desire simply because sexual activity is not en- gical agents for the treatment of FSAD. Sildenafil joyable or reinforcing. Even sexual pain disorders may be (Viagra) has been highly effective in alleviating erectile intricately linked to a lack of sufficient sexual arousal. In- dysfunction resulting from organic, psychogenic, and tercourse without lubrication can be painful, and repeated mixed causes (Derry et al., 1998; Dinsmore et al., 1999; intercourse without arousal may cause vulvar infections, Giuliano et al., 1999; Goldstein et al., 1998; Marks, Duda, chronic irritation, and may even lead to secondary vagin- Dorey, Macairan, & Santos, 1999; Montorsi et al., 1999; ismus, fear of sex, or the avoidance of sexual activity al- Padma-Nathan, Steers, & Wicker, 1998) and might also be together (for review, see Everaerd & Laan, 2000). effective for treating FSAD. Sildenafil acts on nitric oxide Most commonly, the treatment of FSAD involves ad- (NO) systems by prolonging the action of cGMP (thus ministering topical lubricants (e.g., K-Y Jelly, Astroglide), inhibiting the metabolism of cGMP by cyclic nucleotide vitamin E, or mineral oils that help to mask the impair- phosphodiesterase isozymes [PDE5]; Boolell et al., 1996). ment in vaginal lubrication associated with FSAD. These In men, sexual stimulation leads to the production of treatments are, however, ineffective in enhancing genital/ NO and the subsequent release of guanylate cyclase. clitoral blood flow or in alleviating the decrease in gen- Guanylate cyclase converts guanosine triphosphate to ital sensations that often accompanies FSAD. In post- cyclic guanosine monophosphate (cGMP) and cGMP pro- menopausal women, estrogen creams, tablets, or rings are duces relaxation of the smooth muscles of the penile arter- sometimes recommended to alleviate vasomotor symp- ies and corpus cavernosum, resulting in increased blood toms and vaginal atrophy. The impact of testosterone flow into the penis (Burnett, 1995, 1997). Recent evidence administration on sexual arousal is unclear. Supraphys- suggests that this may also occur in the clitoris. Immuno- iologic doses of testosterone have been shown to increase histochemical evaluation of the human clitoris revealed sexual arousal more than placebo or estrogen alone in that NO is produced in this tissue (Burnett, Calvin, Silver, surgically menopausal women (Sherwin, Gelfand, & Peppas, & Docimo, 1997) and, with the exception that the Brender, 1985). However, recently, in a study of 75 sur- clitoris does not contain a subalbugineal layer (which con- gically menopausal women treated with estrogen, nei- tributes to the rigidity of the penis), the clitoris may be con- ther 50 gor300g of testosterone/day transdermally sidered the homologue of the male penis (Toesca, Stolfi, & for 12 weeks showed a significant improvement in sex- Cocchia, 1996). Arterial blood inflow is delivered via the ual arousal beyond placebo (Shiffrin et al., 2000). In a clitoral cavernosal arteries and is regulated by helicine ar- group of women with androgen insufficiency and sex- teriolar smooth muscle tone (Park, Moreland, Goldstein, ual dysfunction, 50 mg/day of dehydroepiandrosterone Anthony, & Traish, 1998). Thus, impaired smooth mus- (DHEA; a precursor for testosterone) was shown to signif- cle function may adversely impact the process of clitoral icantly improve ratings of sexual arousal and lubrication erection and vaginal engorgement and lubrication. (Munarriz et al., 2001). However, among sexually func- Some studies have found Sildenafil reverses tional, premenopausal women, 300 mg DHEA had no sig- antidepressant-induced sexual dysfunction in women nificant effect on vaginal pulse amplitude (VPA; a mea- (e.g., Ashton, 1999; Ashton & Bennett, 1999; Nurnberg, sure of moment to moment changes in vasocongestion) Hensley, Lauriello, Parker, & Keith, 1999). However, the or subjective sexual arousal responses to erotic stimuli lack of a placebo control in these studies severely lim- at 30 min postdrug administration compared to placebo its the interpretation of findings. Preliminary results from (Meston & Heiman, 2002). In a comparable study among a double-blind, placebo controlled study showed a sig- postmenopausal women, 300 mg DHEA also had no sig- nificant increase in VPA with a single dose of Sildenafil nificant effect on VPA