What Women Want? The State of the Art regarding the Treatment of Young Women with Hypoactive Sexual Desire Disorder

During the European Society for Sexual Medicine meeting in Rotterdam, a round table with leading experts on hypoactive sexual desire disorder (HSDD) was organized titled What women want? The main goal of the event was to discuss the state of the art regarding HSDD in premenopausal women from the biological, psychological, and social perspectives. Presenters were Linda Vignozzi and Annamaria Giraldi, an endocrinologist and a psychiatrist, respectively, and Shelly Varod, a clinical psychologist. The round table was presided by Giovanni Corona, an endocrinologist, and moderated by Yacov Reisman, a urologist. This report reflects partially the information discussed during the presentations on February 17, 2023.

Despite sexual health being more than the mere absence of disease and comprising dimensions of sexual pleasure and sexual rights [1], definitions of health are in close dialogue with those of dysfunction. The concept of sexual desire has been the subject of refinement throughout the years but can be understood as a subjective feeling triggered by either external or internal stimuli [2] that might lean individuals toward or away from sexual behavior [3] either with oneself or with a partner [4]. Sexual desire is also defined as having a responsive dimension, one that does not occur spontaneously in the body but as a response to a partner’s sexual initiative [5‒8]. Finally, sexual desire is thought to be multidetermined and biopsychosocial [9], but to be particularly bound by relational and contextual aspects in women [5, 10], as it might not only be used for sexual pleasure but also for closeness, power, or relaxation only [11‒15].

The sexual health conditions that result from the lack of sexual desire are classified in the International Classification of Diseases and Statistics (ICD) and in the Diagnostic and Statistical Manual of Mental Disorders (DSM). To these correspond the HSDD and the female sexual interest/arousal disorder, respectively. Research indicates that, when compared to men, women experience more sexual desire difficulties [7, 16]. These are characterized by the lack of, or significantly reduced, sexual interest/arousal in almost all sexual encounters and the unreceptiveness to partner’s attempts to initiate sexual activity according to the DSM-5 [17]. While the DSM-5 provides two different diagnostic categories of sexual desire disorders for men and women, the ICD-11 provides one diagnosis only – the HSDD – for both. This is characterized by the absence or marked reduction in desire or motivation to engage in sexual activity as manifested by any reduced or absent spontaneous and responsive desire [18]. Moreover, in the consensus meeting of the International Society for the Study of Women’s Sexual Health (ISSWSH), HSDD was broadly defined in the presence of any of the following [19]: (1) lack of motivation for sexual activity as manifested by either reduced or absent spontaneous desire (sexual thoughts or fantasies) or reduced or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity or (2) loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders, and is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry.

In addition, HSDD can be primary or secondary, lifelong or acquired, and generalized or situational. The prevalence of HSDD varies across studies, depending on how it is defined and measured [20], but it is considerably high, with some studies finding that 50–70% of women might experience low sexual desire [21, 22]. When controlling for sexual distress and menopausal status, these rates drop, but they are still high. This is demonstrated in a systematic review and meta-analysis finding that HSDD was the most prevalent female-estimated sexual disorder reported by 28% of the 40% premenopausal women with sexual dysfunction [23].

Due to the high rates of HSDD in women, the lack of a universally accepted definition, and the limited medical treatment options, leading experts on the topic were present at a round table at the last ESSM meeting to summarize and discuss the latest research insights and revisit contemporary controversies. The aim of this paper was to report the highlights of that event and review the state of the art on the treatment of HSDD.

Data derived from animal models and clinical research have identified two pathways involved in the regulation of women’s sexual desire: one excitatory and one inhibitory [24]. The excitatory pathway is based on the activation of neurotransmitters such as dopamine, noradrenaline, oxytocin, vasopressin, and melanocortins [24]. Conversely, the inhibitory pathway involves opioids and serotonin. While the first system works toward sexual arousal, desire, and partner preference, the second works against these, yet playing an important role in sexual reward and satiety. Additional evidence of these mechanisms is corroborated by research targeting the medical treatment of HSDD [20, 25]. Moreover, some women with HSDD seem to benefit with testosterone treatment, suggesting that low androgens may play a role in this sexual disorder. In this regard, a recent systemic review and meta-analysis by Maseroli and Vignozzi [26] showed a moderate positive association between testosterone circulating levels and sexual desire/global sexual function, despite arguing that more research is needed.

There are few medical treatments available for the treatment of HSDD in women. Flibanserin and bremelanotide are the only Food and Drug Administration-approved medications to treat premenopausal women with generalized acquired HSDD in the USA, but these medications have never been approved in Europe. Other medications, such as Lybrido, Lybridos, and Lorexys, are still in the early phase of development.

Flibanserin (Addyi^®) is a serotonin 1A receptor agonist (5-hydroxytryptamine [5-HT]1A) and a 5-HT2A serotonin receptor antagonist. In animals, it has shown to reduce 5-HT2A and increase noradrenaline and dopamine in the prefrontal cortex [27‒29]. In women with HSDD, flibanserin taken daily works to rebalance excitatory activity driven by desire and arousal and inhibitory activity driven by 5-HT (satiety) – both necessary for a healthy sexual response [30]. Flibanserin was reported to be well tolerated, to improve sexual desire, and to reduce sexual distress in premenopausal women [31, 32]. Flibanserin-related adverse events were found to be similar to those pertaining serotonergic antidepressants [33] and presented safe and well tolerated by premenopausal women with mild or remitted depression taking serotonergic antidepressants in a small clinical trial [34].

Bremelanotide (Vyleesi^®) is a melanocortin type 4 receptor dopaminergic agonist working in the hypothalamic center to stimulate sexual desire and arousal on demand [35‒37]. It consists of a 1.75 mg subcutaneous injection applied 45 min before sexual activity for premenopausal women with acquired, generalized HSDD [36, 38]. Its most common adverse effect is nausea, experienced by 40% of patients, representing a crucial limitation despite its positive effects reported in some clinical trials [39, 40].

Lybrido^® and Lybridos^® aim to increase excitation and decrease inhibition to sexual cues, respectively, and have been studied to the treatment of HSDD [41‒44]. Lybrido consists of sublingual testosterone (0.5 mg) and the phosphodiesterase type 5 inhibitor sildenafil citrate (50 mg) used on demand to increase sensitivity to external and internal sexual cues and to the physiological genital sexual response. In the same respect, Lybridos consists of a combination of testosterone and buspirone (5-HT1A receptor agonist) to increase the brain’s response to sexual cues and reduce the inhibitory response to such cues. Although these medications are not currently available, some studies suggest that they might improve sexual satisfaction and sexual desire in women with low sensitivity for sexual cues.

Lorexys^® is a combination of the antidepressants bupropion (a dopamine/norepinephrine reuptake inhibitor) and trazodone (a serotonergic agonist-antagonist), which are implicated in neurotransmission regulating sexual inhibition and exhibition [44, 45]. Initial trials with premenopausal women find a decrease in sexual distress and some adverse effects such as dry mouth, somnolence, headache, and dizziness [46].

Much evidence supports that psychological factors can interfere with sexual desire in women, including depression/anxiety; poor self/body image; stress/distraction; history of abuse (physical, sexual, emotional); substance abuse; self-imposed pressure for sex; and internalized religious, personal, cultural, or family values, beliefs, and taboos [20]. In this report, we will not address these in detail, yet wish to highlight the bidirectional relationship between depression and sexual desire – as antidepressant medication can contribute to low sexual desire [47] as well as to increase sexual desire by alleviating overall depressive symptoms [48, 49]. Further, research suggests that the impact of unwanted sexual experiences in women varies according to their timing of occurrence, with adolescence being the period that presented more deleterious effects on sexuality, compared to childhood and adult life, possibly because adolescence represents a critical period for building sexuality [50].

Some of the aspects affecting young women’s sexual desire reported above, as well as factors pertaining sexual relationships and lifestyle, including relationship satisfaction [20], are affected by the wider social context. This includes the socially prescribed sexual scripts that shape what is culturally accepted by defining gendered norms of sexual behavior [51‒53] and teach girls to be desirable but not to desiring sex [54, 55]. Nonetheless, the feminine sexual scripts appear to fall short in capturing women’s sexual needs and agency, which encompass consensual, mutually gratifying, loving, and liberating sex [56].

The pleasure gap between men and women [57] is likely a consequence of differences in incentive, sexual context, and (lack of) sex quality [58], which in turn is probably explaining women’s overall lower levels of sexual desire [59]. In addition, structural inequalities related to domestic work, child rearing, and emotional labor are possibly contributing to low sexual desire in women partnered with men according to the heteronormative theory of sexual desire [60]. Beyond, research indicates that being in a relationship with a partner is the strongest correlate of sexual distress in women with low desire [61] and that the sexual desire discrepancy within a couple is a strong predictor of sexual distress [62], highlighting the dyadic dimension of sexual desire.

Regardless of HSDD being the most prevalent sexual disorder in young women, there are seemingly few long-term effective solutions to mitigate it [63, 64]. This is related, at least partially, to the structural inequalities jeopardizing women’s sexual rights and sexual pleasure. Therefore, approaches to addressing sexual desire issues through medicalization, which fail to address the underlying social factors, are unlikely to succeed. This is the thesis of the New View of Women’s Sexual Problems [65], which criticizes the medicalization of sexuality because it entails compartmentalizing mind and body, focusing on sexual function and on the individual, and privileging the biological over the political. But the feminist critique to the current medical approaches does not stand alone. In a recent commentary, Spielmans [66] posits that the positive findings related to flibanserin [67] are underwhelming and disappointing and questions their markers of clinical success as the author considers that there was only minimal improvement and no assessment of relationship satisfaction.

Regarding bremelanotide, it shows promise due to its impact on dopamine release in the hypothalamus [35]. However, it requires a subcutaneous injection, and a significant number of women encounter adverse effects, leading to treatment discontinuation in 18% of cases, as reported by the FDA [68].

Medical findings and historical controversy have left the clinical and research communities divided, with some endorsing positive views of current and future drug treatments of HSDD and others disputing and criticizing them. This raises the question of why medical treatments for HSDD such as testosterone, flibanserin, and bremelanotide are considered effective by some and weak by others. Excluding matters of belief or political opinion, health professionals also seem concerned about the safety of these medications and put forward their concerns following the round table. This fear and marketing difficulties might have contributed to these therapies having been held back [69]. However, available data do not identify important long-term effects associated with the use of these substances and consider them safe [34, 70, 71]. Yet, many clinicians are still doubtful and resisting the efficacy of these medications. Others might not even investigate sexual problems or downplay these when mentioned by patients [72], possibly due to the physicians’ own inhibitions and lack of sexual education.

The pressing demand for sexual education in the general population could also be explaining the low referrals to drug and hormonal therapy for HSDD in young women. Truth is, giving permission, information and specific suggestions are common and effective ways of addressing sexual problems in sexual counseling and therapy [73, 74]. Many clinicians, medical and otherwise, agree that informing and managing patients’ expectations is critical to the success of any pharmacotherapy. Furthermore, an emerging body of evidence strongly supports the value of combining medical and psychological approaches in the treatment of HSDD [75]. The ISSWSH recommends that the care process for HSDD emphasizes the assessment and intervention of modifiable biopsychosocial factors [20]. This may be a transdiagnostic factor applicable to all sexual disorders, but it could play a crucial role in the experience of HSDD in young women. Research finds consistently that women experience arousal non-concordance, that is, their assessment of their genital arousal does not match their subjective arousal [76]. These women might benefit from a combination of sexual education with enhanced attention to sexual cues. A recent randomized trial comparing treatments for sexual desire from Brotto and Zdaniuk [77] concluded that both group mindfulness and group-supportive sex education improved sexual desire over a 12-month period. Mindfulness increases attention to genital and arousing bodily sensations [78]. Lybrido, meant to increase sensitivity to external and internal sexual cues and to the physiological genital sexual response, might also be used with the same effect. The question of when to potentially use or combine each approach is not set in stone, but there are diagnostic tools that might be used to determine which women would benefit from which on-demand drug [79]. Also, there is a matter of choice. What do women want? In a recent survey with women with low desire, 48% reported to be interested in or willing to use drug treatment for HSDD that has undergone extensive testing [80].

Finally, HSDD does not happen in a social vacuum. Social inequalities and difficulties seem to impact women’s sexual desire [60] as they result in higher stress, fatigue, and mental health issues which have been established to dampen sexual desire [81‒83]. However, in many situations, clinicians will not be able to change these women’s circumstances. This might be especially true when considering culturally sensitive interventions. Furthermore, in some women, medication might enhance the effect of sexual therapy or vice versa, but other women might accept only medication or only sexual therapy. This need not discourage clinicians from fostering pleasure-focused sex education and gender equality, but equality in this field might also be prompted by improving access to comprehensive healthcare and research. Only by devoting time and resources for alternative and conjoint treatments for HSDD will women be allowed to choose what best fits their needs. On the other hand, only informed choices can be truly empowering, and these cannot take place if clinicians are not well versed in non-pharmacological approaches nor if systemic and structural inequalities overturn women’s freedom of choice.

Sexual desire is multifaceted and comprises biological, psychological, and social aspects. From a biological perspective, it seems to involve excitatory and inhibitory central mechanisms as well as androgens. HSDD is the most common sexual disorder in women and can be rooted to depression and to prior sexual abuse in some women. In addition, gendered social scripts and inequalities, lack of sex quality/pleasure, and sexual desire discrepancies also contribute to low sexual desire and associated distress. In the clinical field, experts seem divided between using pharmacological approaches privileging the biological aspects and psychosocial approaches. The complexity of HSDD and the diverse presentations of low sexual desire in women suggest the need for combined therapy and a mix of these approaches. Nevertheless, some women might respond better to one type of intervention over the others. This calls for the development of tools that assess the best approach for each person, including their will and informed choice. Some women seem open and would like to have access to drug treatment.

This review refers to information presented at a conference symposium supported with an unrestricted grant to the European Society for Sexual Medicine by Freya Pharmaceuticals. Leonor de Oliveira, Shelly Varod, and Giovanni Corona have no conflict of interest to declare. Annamaria Giraldi declares the following: Eli Lilly – lecturer, consultant; Boehringer and Pfizer/Viatris – lecturer, advisory board; Palatin Technologies, Sandoz, Emotional Brain, Futura Medical, OvacoBio, and Freya – advisory board; Astellas – lecturer; Novo Nordic – stockholder, lecturer. Linda Vignozzi declares to have received funding from the following companies for scientific research, advisory board attendance, and speaker honoraria: Therascience, Theramex, Bayer-Schering Pharma, Intercept Pharmaceutics, Lipocine Incorporated, Bruno Pharmaceutics, Penta, Ibsa Farmaceutici Italia, Galecto Inc., and Freya. Yacov Reisman declares the following: Freya, Ohhmed, and Viatris – advisory board; Besins Healthcare – advisory board, speaker; Coloplast, Boston Scientific, Berlin-Chemie, and Lundback – speaker.

No funding was received.

Leonor de Oliveira contributed to conception and draft of the manuscript. The manuscript was reviewed and approved by Leonor de Oliveira, Linda Vignozzi, Annamaria Giraldi, Shelly Varod, Giovanni Corona, and Yacov Reisman. All the authors are accountable for the final work presented.