Treatment for hypoactive sexual desire.

Flibanserin acts at cortical, limbic, hypothalamic, and brainstem nuclei to inhibit serotonin release by binding to 5-HT1A autoreceptors and block postsynaptic action of serotonin at 5-HT2A receptors. This gradually disinhibits the turnover of other monoamines like dopamine and noradrenaline that are critical for sexual desire.

Auditory Cues Alter the Magnitude and Valence of Subjective Sexual Arousal and Desire Induced by an Erotic Video.

Although women and men rate their subjective arousal similarly in response to "female-centric" erotic videos, women rate their subjective arousal lower than men in response to "male-centric" videos, which often end with the male's ejaculation. This study asked whether ratings of subjective sexual arousal and desire using the Sexual Arousal and Desire Inventory (SADI) would be altered if this ending was present or absent, and whether including or excluding the accompanying soundtrack would influence the magnitude and direction of the responses. A total of 119 cis-gendered heterosexual undergraduates (59 women and 60 men) viewed an 11-min sexually explicit heterosexual video that ended with a 15-s ejaculation scene. Two versions of the video were created, one with the ejaculatory ending (E+) and one without (E-). Participants were assigned randomly to view one of the two versions with (S+) or without (S-) the accompanying soundtrack, after which they completed the state version of the SADI. Women and men found both sequences without sound less arousing on the Evaluative, Motivational, and Physiological subscales of the SADI relative to the S+ sequences. However, on the Negative/Aversive subscale, women found the E + S- sequence more negative than did men, whereas this difference was not found with sound. Thus, women and men were sensitive to the auditory content of sexually explicit videos, and scenes of sexual intercourse ending with explicit ejaculation increased the Evaluative and Motivational properties of subjective sexual arousal and desire. However, this occurred in women only when the auditory cues signaled a clear and gratifying sexual interaction.

Participation of the nitric oxide pathway in lordosis induced by apelin-13 in female rats.

The present study investigated the participation of the nitric oxide pathway in facilitating lordosis behavior induced by intrahypothalamic administration of apelin-13 in ovariectomized rats primed with estradiol benzoate (EB). The experiments involved the administration of a nitric oxide synthase inhibitor (L-NAME) or a nitric oxide-dependent, soluble guanylyl cyclase inhibitor (ODQ), and an inhibitor of protein kinase G (KT5823) to the ventromedial hypothalamus (VMH) of EB-primed rats 30 min before infusion of apelin-13 (0.75 µg/µl). This dose of apelin-13 consistently induces lordosis behavior at 30 min, 120 min, and 240 min following infusion. Results showed that injections of either L-NAME or KT5823 significantly reduced the lordosis induced by apelin at 120 and 240 min. However, VMH infusion of ODQ 30 min before apelin-13 infusion reduced but did not significantly inhibit, the lordosis elicited by this peptide at the same time points. We conclude that the nitric oxide pathway in the VMH plays an important role in lordosis induced by apelin-13 in EB-primed rats.

The Cancer of Cancel Culture: Spreading "Correct" Scientific Ideologies Across North American Academia.

The spread of "cancel culture" related to sex and gender controversies in North America is examined as part of a larger movement to politicize sex research findings and certain sex and gender narratives as "correct" and "incorrect" from a so-called social justice standpoint. This binary is then used by academic administrators and empowered individuals or self-interest groups to reward or punish scholars for their viewpoints. The cases described by Meyer-Bahlburg, Lowrey, and Hooven are concrete examples of a growing "sexual McCarthyism" where empirical results are challenged by offended social justice "warriors" and embellished on social media into ad hominem attacks, to the point that it can damage-or even cancel-the careers of productive sexual scientists. This occurs largely out of fear on the part of academic administrators and lawyers charged with protecting the university from "brand damage" that might occur if the offending scholar is not dealt with. Sexual scientists are being vilified for research on sex differences, sex/gender assignment and subsequent causes for transitioning and/or de-transitioning, research that shows few or no untoward social or psychological effects of viewing pornography, research that debunks the notion of porn or sex "addiction," research showing the efficacy of medications to treat sexual desire disorders in women, research on "minor attracted persons" and even animal research that dares to show homologies to human sexual behavior. The silencing of empirical evidence and alternative viewpoints is contrary to the intellectual mission of universities and destructive to academic and political freedoms.

Estradiol and progesterone-induced lordosis behavior is modulated by both the Kisspeptin receptor and melanin-concentrating hormone in estradiol benzoate-primed rats.

Intracerebroventricular (ICV) administration of estradiol benzoate (E2B) and progesterone (P) induces intense lordosis behavior in ovariectomized rats primed peripherally with E2B. The present study tested the hypothesis that the Kisspeptin (Kiss) and melanin-concentrating hormone (MCH) pathways regulate female sexual behavior induced by these steroid hormones. In Experiment 1, we tested the relevance of the Kiss pathway by ICV infusion of its inhibitor, kiss-234, before administration of E2B or P in estrogen-primed rats. Lordosis induced by E2B alone or with the addition of P was reduced significantly at 30, 120, and 240 min. In Experiment 2, ICV infusion of MCH 30 min before E2B or P significantly reduced lordosis in rats primed with E2B alone. These data support the hypothesis that the Kiss and MCH pathways, which can release or modulate gonadotropin-releasing hormone (GnRH), are involved in E2B- and P-induced lordosis.

The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Behavioral, Neural, and Molecular Mechanisms of Conditioned Mate Preference: The Role of Opioids and First Experiences of Sexual Reward.

Although mechanisms of mate preference are thought to be relatively hard-wired, experience with appetitive and consummatory sexual reward has been shown to condition preferences for partner related cues and even objects that predict sexual reward. Here, we reviewed evidence from laboratory species and humans on sexually conditioned place, partner, and ejaculatory preferences in males and females, as well as the neurochemical, molecular, and epigenetic mechanisms putatively responsible. From a comprehensive review of the available data, we concluded that opioid transmission at µ opioid receptors forms the basis of sexual pleasure and reward, which then sensitizes dopamine, oxytocin, and vasopressin systems responsible for attention, arousal, and bonding, leading to cortical activation that creates awareness of attraction and desire. First experiences with sexual reward states follow a pattern of sexual imprinting, during which partner- and/or object-related cues become crystallized by conditioning into idiosyncratic "types" that are found sexually attractive and arousing. These mechanisms tie reward and reproduction together, blending proximate and ultimate causality in the maintenance of variability within a species.

Oxytocin induces lordosis behavior in female rats through the prostaglandin E2/GnRH signaling system.

Intracerebroventricular (icv) administration of oxytocin (OT) induces robust lordosis behavior (lordosis quotient and lordosis intensity) in estrogen-primed rats. The present study explored the hypothesis that the OT-Prostaglandin E2-GnRH pathway (a pathway produced in astrocytes) is involved in the facilitation of lordosis behavior by icv infusion of OT (2 µg). In Experiment 1, we tested the involvement of the OT receptor (OTR) by infusion of the OTR antagonist, atosiban (ATO). OT-induced lordosis was significantly reduced at both 30 and 120 min by prior infusion of ATO. In Experiment 2, we studied the effects of aspirin (COX2 inhibitor) and ONO-AE3-208 (ONO; EP4 prostaglandin receptor antagonist) on OT-induced lordosis. Infusions of both compounds diminished OT-induced lordosis at both 120 and 240 min. In Experiment 3, the involvement of the GnRH-1 receptor inhibitor antide on OT-induced lordosis was evaluated. Antide significantly inhibited OT-induced lordosis at all times tested. These data indicate that the OT/PGE2/GnRH pathway is involved in the expression of OT-induced lordosis behavior, an effect that may be occurring directly in hypothalamic astrocytes.

International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD).

BACKGROUND: Persistent genital arousal disorder (PGAD), a condition of unwanted, unremitting sensations of genital arousal, is associated with a significant, negative psychosocial impact that may include emotional lability, catastrophization, and suicidal ideation. Despite being first reported in 2001, PGAD remains poorly understood. AIM: To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management. METHODS: A panel of experts reviewed pertinent literature, discussed research and clinical experience, and used a modified Delphi method to reach consensus concerning nomenclature, etiology, and associated factors. Levels of evidence and grades of recommendation were assigned for diagnosis and treatment. OUTCOMES: The nomenclature of PGAD was broadened to include genito-pelvic dysesthesia (GPD), and a new biopsychosocial diagnostic and treatment algorithm for PGAD/GPD was developed. RESULTS: The panel recognized that the term PGAD does not fully characterize the constellation of GPD symptoms experienced by patients. Therefore, the more inclusive term PGAD/GPD was adopted, which maintains the primacy of the distressing arousal symptoms and acknowledges associated bothersome GPD. While there are diverse biopsychosocial contributors, there is a common underlying neurologic basis attributable to spontaneous intense activity of the genito-pelvic region represented in the somatosensory cortex and its projections. A process of care diagnostic and treatment strategy was developed to guide the clinician, whenever possible, by localizing the symptoms as originating in any of five regions: (i) end organ, (ii) pelvis/perineum, (iii) cauda equina, (iv) spinal cord, and (v) brain. Psychological treatment strategies were considered critical and should be performed in conjunction with medical strategies. Pharmaceutical interventions may be used based on their site and mechanism of action to reduce patients' symptoms and the associated bother and distress. CLINICAL IMPLICATIONS: The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment. STRENGTHS AND LIMITATIONS: Strengths and Limitations: Strengths include characterization of the condition by consensus, analysis, and recommendation of a new nomenclature and a rational basis for diagnosis and treatment. Future investigations into etiology and treatment outcomes are recommended. The main limitations are the dearth of knowledge concerning this condition and that the current literature consists primarily of case reports and expert opinion. CONCLUSION: We provide, for the first time, an expert consensus review of the epidemiology and pathophysiology and the development of a new nomenclature and rational algorithm for management of this extremely distressing sexual health condition that may be more prevalent than previously recognized. Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med 2021;18:665-697.

Sexual Attentional Bias in Young Adult Heterosexual Men: Attention Allocation Following Self-Regulation.

Being sexually aroused can lead to a stronger propensity to engage in sexual risk-taking and sexually coercive behaviors possibly by narrowing attentional focus toward immediate gratification rather than long-term consequences. The goal of this paper was to investigate the attentional processes implicated in sexual self-regulation failure and its moderating factors, namely having a stronger sensitivity to sexual cues (dual control model) or being less able to implement behavioral intentions (action control theory) following a first effortful task. A total of 82 young adult heterosexual men completed a Dot Probe task to assess their attentional bias toward sexual stimuli. Effortful control was manipulated using a Stroop task. Regardless of conditions, higher sexual excitability was predictive of a stronger attentional bias toward sexual cues, while higher inhibition due to threat of performance failure was predictive of a lower bias for such cues. In the experimental condition, action-oriented individuals were able to negate this attentional bias by staying more focused on the task, while state-oriented participants showed higher orientation toward the sexual cues and thus a higher bias. These results suggest that both higher-order processes, like intention implementation, and lower-order processes, like sexual inhibition and excitation systems, are the key to regulation failure.

Enhanced D2 Agonism Induces Conditioned Appetitive Sexual Responses Toward Non-reproductive Conspecifics.

Brain mechanisms of sexual attraction toward reproductive partners develop from a systematic interrelationship between biology (nature) and learning (nurture). However, the causes of attraction toward non-reproductive partners are poorly understood. Here, we explored the role of Pavlovian learning under dopaminergic agonism on the development of sexual preference and brain activation for young male rats. During conditioning, adult sexually naïve males received either Saline (Saline-Paired) or the D2-receptor agonist quinpirole (QNP-Paired) and cohabited in contingency, or out of contingency (QNP-Unpaired) during 24 h with an almond-scented prepubertal juvenile male (PD25). Conditioning occurred every 4 days for three trials. Social and sexual responses were assessed four days after the last conditioning trial in a drug-free test, and males chose freely between a scented young male (PD37) and a novel receptive female. Four days later, males were exposed to the conditioned odor only and brain Fos-IR and serum testosterone were analyzed. Saline-Paired and QNP-Unpaired males displayed more non-contact erections (NCEs) and genital investigations for females, whereas QNP-Paired males expressed more NCEs and genital investigations for young males. In the QNP-Paired group, exposure to the young male-paired odor evoked more Fos-IR in limbic, hypothalamic and cortical areas, but no differences in serum testosterone were observed. Cohabitation with juvenile males during enhanced D2 agonism results in atypical appetitive sexual responses and a higher pattern of brain response for the young male-paired odor, with no changes in serum testosterone. We discuss the potential implications for the development of pedophilic disorder and perhaps other paraphilias.

Fos expression is increased in oxytocin neurons of female rats with a sexually conditioned mate preference for an individual male rat.

Evidence suggests an important role of Pavlovian learning in sexual partner selection. Female rats that experience paced copulation with a male scented with a neutral odor selectively solicit and receive ejaculations from the scented male relative to an unscented male. Exposure to the conditioned odor alone induces Fos protein in regions of the brain associated with sexual excitation. Here we tested whether female rats can be conditioned to show a sexual preference for an unscented male rat of the same strain. Female Long-Evans rats were given 10 copulatory trials with either a one-hole pacing divider or a four-hole pacing divider in a unilevel chamber with the same conspecific male (n = 16). Females were then given an open-field partner preference test with the paired male versus a novel male. After two reconditioning trials females were exposed to the partner or a novel male to induce Fos expression. Females that paced with the one-hole divider received the first ejaculation and more ejaculations overall from the paired compared to novel male. Fos immunoreactivity within oxytocin neurons in the PVN, mPOA, and VMH was increased in females with a preference that were exposed to the paired male. These data indicate that female rats can form selective sexual preferences for an individual conspecific and that their formation depends on the type of pacing during conditioning. These findings further suggest the involvement of oxytocin in the display of conditioned preferences. Thus, early copulatory experience appears to determine the mating strategy used by female rats.

Effects of ovarian hormones on the emission of 50-kHz ultrasonic vocalizations during distributed clitoral stimulation in the rat.

Fifty-kHz ultrasonic vocalizations (USVs) are emitted by adult rats during appetitive phases of behavior in response to stimuli thought to be associated with a positive affective state. In particular, 50-kHz USVs with rapid frequency oscillations, known as trills and flat-trills, in which these oscillations are flanked by a monotonic portion, are together positively correlated with appetitive behaviors such as rough and tumble play, drug and natural reward, and mating. Female rats produce 50-kHz USVs during a variety of sexual contexts, yet data are still vague as female sexual behavior is seldom studied on its own. Distributed clitoral stimulation (CLS) offers a unique approach to investigating female 50-kHz USVs as it mimics stimulation received during mating. Although CLS induces a sexual reward state, it is unknown whether CLS elicits trills and flat-trills. We addressed this question using eight ovariectomized rats, we investigated whether ovarian hormones augmented these call subtypes in response to CLS. The combined and separate effects of estradiol benzoate (EB) and progesterone (P), and oil vehicle were assessed through comparison of these call subtypes between CLS and inter-CLS interval. We found that CLS with EB + P significantly increased call duration and rate, lowered peak frequency, and widened the bandwidth of trills. Flat-trills showed a similar pattern except for call duration. Call distribution during the CLS and inter-CLS interval suggest that trill and flat-trills may be indicative of both anticipatory and sexual reward.

Effect of CS preexposure on the conditioned ejaculatory preference of the male rat: behavioral analyses and neural correlates.

Early experiences with sexual reward play a pivotal role in the formation of sexual behavior and partner preference. Associations of salient partner cues, or even neutral cues on a partner, with sexual reward states are a product of Pavlovian learning. However, the extent to which first experiences that associate a neutral stimulus with no immediate consequence, and how that association may affect subsequent associability after being paired with a sexual reward state after copulation to ejaculation, remains unclear. To address this question, sexually naïve males were preexposed over one or five trials to almond scented gauze pads prior to training during which half of the males were trained 10 times with scented receptive females, and the other half with unscented receptive females. A final test of partner preference was conducted in a large open field containing two sexually receptive females, one scented and the other unscented. Males developed a conditioned ejaculatory preference for the type of female they were trained with, except when they were preexposed five times to the odor and then trained with females bearing the same odor, indicating a significant CS preexposure effect. One CS preexposure was not sufficient to inhibit subsequent conditioning. Exposure to the scent before perfusion for inmunohistochemistry, revealed different patterns of brain activation in brain areas previously associated with the development of partner preference, like the medial preoptic area, ventral tegmental area, nucleus accumbens, basolateral amygdala, among others, depending on group membership. Thus, CS preexposure results in a subsequent impairment of the association that links the odor cue to sexual reward and preference. This highlights the impact of the first sexual experiences in future partner preference.

First sexual experiences determine the development of conditioned ejaculatory preference in male rats.

We have shown previously that male rats develop a conditioned ejaculatory preference (CEP) for females scented with a neutral odor like almond or lemon that is paired with the male's post-ejaculatory reward state during their first and subsequent early sexual experiences. However, preexposing males to the neutral odor alone prior to its pairing with sexual reward results in latent inhibition. Here, we examined the phenomenon of unconditioned stimulus (US) preexposure, in which male rats were preexposed to the ejaculatory reward state either one or five times with scented (ScF) versus unscented (UnScF) females prior to multiple ejaculatory trials with females in the opposite condition (e.g., ScF preexposure received 10 subsequent ejaculatory trials with UnScF, whereas UnScF preexposure received 10 subsequent ejaculatory trials with ScF). As before, mate and partner preference was evaluated in an open field where each male had access to two females, one ScF and the other UnScF. Males that underwent five trials of preexposure did not display a CEP for either female. Conversely, males preexposed once to a ScF, and later trained with UnScF developed a preference for the latter, whereas males preexposed once to the UnScF, and then trained with ScF did not show a preference for any of the females. Subsequent exposure to the odor cue alone revealed different patterns of brain activation in areas related to sexual behavior that depended on the animal's group membership. Altogether, these findings demonstrate the pivotal role of first sexual experiences in the establishment of future sexual partner preference in the male rat, and suggest an innate preference for estrous odors over neutral odors that can become conditioned subsequently as predictors of sexual reward.

Central ghrelin receptor stimulation modulates sex motivation in male rats in a site dependent manner.

Ghrelin, a hormone produced primarily by the stomach, has been associated with motivational processes that include reward-seeking behaviors. In male laboratory mice, elevation of ghrelin levels enhances some aspects of sexual motivation and behavior, whereas in other experiments with male mice, rats, and other species, ghrelin treatment or food deprivation decreases sexual motivation and/or behavior. The present tested the hypothesis that stimulation of ghrelin receptors in different brain regions have opposite effects on male sexual motivation and behavior. To do this we examined appetitive and consummatory sex behaviors of male rats with a truncated ghrelin receptor (FHH-GHSRm1/Mcwi), and that of their WT (FHH) littermates. We also examined the effects of ghrelin or the ghrelin antagonist D-Lys-GHRP6 delivered into the VTA or the MPOA on appetitive and consummatory sex behaviors in male Long Evans rats. Results demonstrate that rats with a truncated ghrelin receptor, or rats that are food deprived, show deficits in anticipatory sex. Furthermore, although ghrelin does not further stimulate sex anticipation in rats when infused into the VTA, intra-VTA infusions of D-Lys-GHRP6 into the VTA further decreases in sex anticipation in food deprived rats. In contrast, ghrelin delivery into the mPOA decreased sex anticipation compared to saline or D-Lys-GHRP6 infused rats. Overall, these data suggest that ghrelin receptor signalling is important for full expression of appetitive sex behaviors. Within the VTA, ghrelin may act to enhance sex motivation, while acting on the mPOA to decrease sex motivation and promote foraging.

Brain activation associated to olfactory conditioned same-sex partner preference in male rats.

Sexual preferences can be strongly modified by Pavlovian learning. For instance, olfactory conditioned same-sex partner preference can occur when a sexually naïve male cohabits with an scented male during repeated periods under the effects of enhanced D2-type activity. Preference is observed days later via social and sexual behaviors. Herein we explored brain activity related to learned same-sex preference (Fos-Immunoreactivity, IR) following exposure to a conditioned odor paired with same-sex preference. During conditioning trials males received either saline or the D2-type receptor agonist quinpirole (QNP) and cohabitated during 24 h with a stimulus male that bore almond scent on the back as conditioned stimulus. This was repeated every 4 days, for a total of three trials. In a drug-free final test we assessed socio/sexual partner preference between the scented male and a receptive female. The results indicated that QNP-conditioned males developed a same-sex preference observed via contact, time spent, olfactory investigations, and non-contact erections. By contrast, saline-conditioned and intact (non-exposed to conditioning) males expressed an unconditioned preference for the female. Four days later the males were exposed to almond scent and their brains were processed for Fos-IR. Results indicated that the QNP-conditioned group expressed more Fos-IR in the nucleus accumbens (AcbSh), medial preoptic area (MPA), piriform cortex (Pir) and ventromedial nucleus of the hypothalamus (VMH) as compared to saline-conditioned. Intact males expressed the lowest Fos-IR in AcbSh and VMH, but the highest in MPA and Pir. We discuss the role of these areas in the learning process of same-sex partner preferences and olfactory discrimination.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.