New management approaches for female sexual dysfunction.

PURPOSE OF REVIEW: The goal of this paper is to review the most recent studies evaluating treatments for female sexual dysfunction (FSD), including distressing symptoms of desire, arousal, and orgasm disorder. We divide the sections into psychological and pharmacological. RECENT FINDINGS: There is excellent evidence in favour of mindfulness, cognitive behavioural therapy, and psychoeducation for improving low sexual desire in women, and less evidence in support of these approaches to address other sexual dysfunctions in women. There are two US Food and Drug Administration (FDA) approved pharmacological treatments for low desire in premenopausal women that have modest benefits above placebo, and a significant proportion of users will experience side effects. Evidence also supports the use of transdermal testosterone for low desire in postmenopausal women. SUMMARY: Sexual dysfunction in women is common and distressing, and there are a variety of psychological and pharmacological treatments. More research is needed to better understand the predictors of a positive treatment response in order to deliver more personalized care.

Comparisons and correlations of 1-month recall vs 24-hour recall in patient-reported outcomes of an exploratory, phase 2b, randomized, double-blind, placebo-controlled clinical trial of sildenafil cream, 3.6% for the treatment of female sexual arousal disorder.

BACKGROUND: Efficacy assessments in clinical trials of treatments for female sexual arousal disorder (FSAD) and other female sexual dysfunction (FSD) diagnoses rely on various patient-reported outcomes (PROs). AIMS: We sought to compare 1-month recall PRO measures among participants enrolled in a clinical trial who provided these data without (test population) vs with (control population) use of an at-home, 24-hour recall electronic diary (eDiary), capturing similar data. METHODS: Preplanned subset analysis as performed during a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD. Preliminary product efficacy was assessed via 1-month recall and 24-hour recall questionnaires. A subset of the participants, the Evaluation of Recall Subset [ERS] provided PROs via the 1-month recall instruments but did not provide data via the 24-hour recall eDiary. OUTCOMES: Responses to the 1-month recall instruments were compared among ERS (test) vs non-ERS (control) participants. Among the non-ERS population, correlations between 1-month and 24-hour recall endpoints were calculated. RESULTS: There were no significant differences in the study co-primary 1-month recall efficacy endpoints, the Arousal Sensation (AS) domain of the 28-item Sexual Function Questionnaire (SFQ28) and the Female Sexual Distress Scale - Desire, Arousal, Orgasm question 14, among ERS vs non-ERS participants during the initial 1-month no-drug run-in period or the 1-month single-blind placebo run-in period (P values > .47). Scores on these 1-month recall PROs continued to be similar after randomization for sildenafil cream (P values > .30) and placebo cream (P values > .20) assigned ERS and non-ERS participants during the 3-month double-blind dosing period. There were strong correlations between the SFQ28 AS and eDiary AS scores during the no-drug run-in (R = 0.79, P < .01) and the single-blind run-in (R = 0.73 P < .001). During the double-blind dosing period, the SFQ28 AS score continued to be highly correlated with the eDiary AS score among sildenafil cream users (R = 0.83; P < .001) and placebo cream users (R = 0.8; 2 P < .001). CLINICAL IMPLICATIONS: There was no evidence that 1-month recall PRO instruments introduce recall bias; assessing arousal sensations with 24-hour vs 1-month PRO instruments is similar and either method could be used to assess efficacy depending on study objectives. STRENGTHS AND LIMITATIONS: This preplanned subset analysis compared efficacy of PROs based on recall duration. While the subset was preplanned, the study was powered to detect significant differences in the primary efficacy objectives, not among this subset analyses. CONCLUSION: These data will be used in planning future efficacy assessments of sildenafil cream for FSAD. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with ClinicalTrials.gov, NCT04948151.

Safety of topical sildenafil cream, 3.6% in a randomized, placebo-controlled trial for the treatment of female sexual arousal disorder.

BACKGROUND: There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. AIMS: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. METHODS: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. OUTCOMES: The frequency and incidence of TEAEs among participants and their sexual partners. RESULTS: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54). CLINICAL IMPLICATIONS: These data support further clinical development of topical sildenafil cream for the treatment of FSAD. STRENGTHS AND LIMITATIONS: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. CONCLUSION: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners.

Role of flibanserin in managing hypoactive sexual desire disorder in women: A systematic review and meta-analysis.

BACKGROUND: Flibanserin, approved for the treatment of hypoactive sexual desire disorder (HSDD) in females, has demonstrated diverse therapeutic and adverse effect (AE) prospects in the extant randomized controlled trials (RCTs). This meta-analysis aimed to characterize the outcomes of flibanserin use in these patients comprehensively. METHODS: RCTs involving women with HSDD receiving flibanserin in the intervention arm and placebo in the control arm were sought after throughout the electronic databases. The primary outcomes were the changes from baseline in satisfying sexual events (SSE) per month and sexual desire score per month measured using an electronic diary (eDiary). RESULTS: From 478 initially screened articles, data from 8 RCTs involving 7906 women with HSDD were analyzed. In premenopausal women, flibanserin 100 mg was superior to placebo in improving the number of SSE per month (mean difference, MD 0.69, 95% CI [0.39, 0.99]), eDiary sexual desire score (MD 1.71, 95% CI [0.43, 2.98]), Female Sexual Function Index (FSFI) desire domain (FSFI-d) score (MD 0.30, 95% CI [0.29, 0.31]), FSFI total score (MD 2.51, 95% CI [1.47, 3.55]), Female Sexual Distress Scale-Revised (FSDS-R) Item 13 score (MD -0.30, 95% CI [-0.31, -0.29]), and FSDS-R total score (MD -3.30, 95% CI [-3.37, -3.23]). Compared to placebo, a higher number of premenopausal women using flibanserin 100 mg achieved improvements in the Patient's Global Impression of Improvement score (OR 1.93, 95% CI [1.58, 2.36], P < .00001) and responded positively at Patient Benefit Evaluation (PBE) (odds ratio, OR 1.76, 95% CI [1.34, 2.31], P < .0001). Postmenopausal women receiving flibanserin 100 mg also benefited in terms of the number of SSE per month, FSFI-d and total scores, FSDS-R Item 13 and total scores, and PBE response. Although flibanserin use was associated with higher risks of dizziness, fatigue, nausea, somnolence, and insomnia, these adverse events were mild in nature; the serious AEs and severe AEs were comparable between the flibanserin and placebo groups. CONCLUSION: While flibanserin has demonstrated efficacy in the treatment of HSDD in both pre- and postmenopausal women, its therapeutic advantages may be overshadowed by the higher likelihood of AEs.

Systemic testosterone for the treatment of female sexual interest and arousal disorder (FSIAD) in the postmenopause.

INTRODUCTION: Female sexual interest and arousal disorder (FSIAD) is the most prevalent female sexual dysfunction in the postmenopause. OBJECTIVE: The aim of this review is to provide a summary of the currently available evidence on the use of testosterone in the treatment of FSIAD in postmenopausal women. METHODS: A narrative review on the topic was performed. Only randomized controlled trials (RCTs) and systematic reviews and meta-analysis were considered. 123 articles were screened, 105 of them assessed for eligibility, and finally 9 were included in qualitative synthesis following the PRISMA declaration. RESULTS: Current evidence recommends, with moderate therapeutic benefit, the use of systemic transdermal testosterone within the premenopausal physiological range in postmenopausal women with Hypoactive Sexual Desire Disorder (HSDD), the previous entity for low desire dysfunction, not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. The available evidence is based on studies with heterogeneity on their design (different testosterone doses, routes of administration, testosterone use in combination and alone, sexual instruments of measurement). There is no data indicating severe short-term adverse effects, although long-term safety data is lacking. CONCLUSIONS: Despite having testosterone as a valuable tool, therapeutic strategies are lacking in the pharmacological field of HSDD/FSIAD. Neuroimaging studies could provide valuable information regarding the sexual desire substrate and suggest the potential application of already approved drugs for women with a good safety profile. The use of validated instruments for HSDD in postmenopausal women, considering the level of distress, is necessary to be able to draw robust conclusions on the evaluated treatments.

Preliminary Efficacy of Topical Sildenafil Cream for the Treatment of Female Sexual Arousal Disorder: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of topical sildenafil cream, 3.6% among healthy premenopausal women with female sexual arousal disorder. METHODS: We conducted a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream. Coprimary efficacy endpoints were the change from baseline to week 12 in the Arousal Sensation domain of the SFQ28 (Sexual Function Questionnaire) and question 14 of the FSDS-DAO (Female Sexual Distress Scale-Desire, Arousal, Orgasm). RESULTS: Two hundred women with female sexual arousal disorder were randomized to sildenafil cream (n=101) or placebo cream (n=99). A total of 174 participants completed the study (sildenafil 90, placebo 84). Among the intention-to-treat (ITT) population, which included women with only female sexual arousal disorder and those with female sexual arousal disorder with concomitant sexual dysfunction diagnoses or genital pain, although the sildenafil cream group demonstrated greater improvement in the SFQ28 Arousal Sensation domain scores, there were no statistically significant differences between sildenafil and placebo cream users in the coprimary and secondary efficacy endpoints. An exploratory post hoc subset of the ITT population with an enrollment diagnosis of female sexual arousal disorder with or without concomitant decreased desire randomized to sildenafil cream reported significant increases in their SFQ28 Arousal Sensation domain score (least squares mean 2.03 [SE 0.62]) compared with placebo cream (least squares mean 0.08 [SE 0.71], P =.04). This subset achieved a larger mean improvement in the SFQ28 Desire and Orgasm domain scores. This subset population also had significantly reduced sexual distress and interpersonal difficulties with sildenafil cream use as measured by FSDS-DAO questions 3, 5, and 10 (all P ≤.04). CONCLUSION: Topical sildenafil cream improved outcomes among women with female sexual arousal disorder, most significantly in those who did not have concomitant orgasmic dysfunction. In particular, in an exploratory analysis of a subset of women with female sexual arousal disorder with or without concomitant decreased desire, topical sildenafil cream increased sexual arousal sensation, desire, and orgasm and reduced sexual distress. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04948151.

Sexual Desire and Pharmacologic Management.

Female sexual desire is a complex interplay of neurotransmitters and hormones. Diagnosis is based on clinical features and sexual distress. Treatments that affect neurotransmitters and hormones that may be out of balance can help improve sexual desire in women with hypoactive sexual desire disorder.

Effect of l-arginine compared to placebo on sexual function in women with major depressive disorder: a randomized controlled trial.

BACKGROUND: While some evidence suggests that l-arginine may improve sexual function and alleviate depression, it has not been investigated in women with depression to assess both its effects on the depression and sexual function concurrently. METHODS: Patients who had received a diagnosis of major depressive disorder, as determined by predetermined inclusion and exclusion criteria, were enrolled in this triple-blind clinical trial. Patients were divided into two groups: group A, received L-arginine 1 gram twice daily, and group B, received a placebo for four weeks. They were evaluated at baseline, after four and eight weeks with the Hamilton Depression Rating Scale (HDRS), and Rosen's questionnaire or Female Sexual Function Index (FSFI). RESULTS: A decrease in the severity of depression was observed in all patients, which was determined due to Hamilton's questionnaire (P-value < 0.001). During the time in group A, FSFI increased. Based on the FSFI questionnaire, they had improvement in some domains, including the lubrication index and orgasm index, which significantly changed in the eighth week compared to the baseline (P-value < 0.05). However, these two indicators did not change statistically significantly compared to the placebo group. CONCLUSION: L-arginine supplementation can improve sexual function, particularly lubrication and orgasm, and mood in women with depression, with minimal side effects observed. Additional research is necessary to validate these results by examining the effects of higher dosages, extended durations, and larger populations of depressed patients. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT20100127003210N26.

"One a Day Keeps the Prison Away": Understanding the Experiences of Individuals Convicted of Sexual Offences Receiving Anti-Androgens for the Treatment of Problematic Sexual Arousal.

Problematic sexual arousal (PSA) is an umbrella term to describe a range of clinical presentations related to excessive sexual thinking (e.g., sexual preoccupation) and sexual behavior (e.g., hypersexuality). Although such concepts are known to affect sexual recidivism among individuals convicted of sexual offences, PSA is not routinely or directly targeted in offending behavior programs in England and Wales. However, in recent years, there have been moves to incorporate pharmacological interventions for addressing this among people with sexual offence histories. Although some work to understand the experiences of those taking SSRI medication for this purpose has emerged, little is known about the experiences of service users taking anti-androgen medication. In this study, we interviewed all individuals in prison taking anti-androgens for the treatment of problematic sexual arousal following convictions for sexual offences in England at the time of data collection (N = 10). Using a phenomenologically oriented thematic analysis, we established themes pertaining to "Differing needs: Motivations for treatment," "Medication as a risk management strategy," and how the medication helped the men in their pursuit of "Discovering a 'new me'." This work contributes important knowledge to inform the development of ethical and effective prescribing of anti-androgen medication with this population and offer recommendations for both future research and the development of clinical practice.

Characteristics of systemic testosterone therapy for female hypoactive sexual desire disorder-a claims database analysis.

BACKGROUND: Testosterone therapy (TTh) is recommended for postmenopausal women with hypoactive sexual desire disorder (HSDD); however, there remain insufficient data to support use of TTh in premenopausal women with sexual dysfunction. AIM: In this study, we used a large national database to evaluate prescribing trends of TTh for women with HSDD. METHODS: We conducted a cohort analysis of information from electronic health records acquired from the data network TriNetX Diamond. The study cohort consisted of women 18-70 years of age with a diagnosis of HSDD. We analyzed trends of testosterone prescriptions, routes of testosterone administration, and coadministration of testosterone with estrogen. OUTCOMES: Despite an increase in rates of testosterone prescriptions for HSDD, there remains a high degree of variability in the duration of treatment, route of administration, and coadministration of estrogen with significant underprescription of testosterone. RESULTS: Our query of the TriNetX database led to the identification of 33 418 women diagnosed with HSDD at a mean age of 44.2 ± 10.8 years, among whom 850 (2.54%) women received a testosterone prescription. The testosterone prescriptions were highly variable with regard to duration and route of administration and coadministration with estrogen. For all patients until 2015, the prevalence of testosterone prescriptions for HSDD showed a positive quadratic relation was observed. Since 2015 a linear increase in prevalence was observed, with the highest rate of increase for patients aged 41-55 years. CLINICAL IMPLICATIONS: The findings of this study reveal a significant need for further research investigating the optimal use of TTh to enhance the sexual health of women with HSDD, and further studies on the long-term effects of testosterone use must be undertaken to ensure that patients have access to safe and effective treatment. STRENGTHS AND LIMITATIONS: Limitations to this study include patient de-identification and lack of availability of testosterone dosage data. However, this study also has many strengths, including being the first, to our knowledge, to characterize the prescribing trends of testosterone for women with HSDD. CONCLUSION: Testosterone therapy should be considered as a potential therapy for premenopausal female patients with HSDD. Further studies on the long-term effects of testosterone use must be undertaken to address disparities in the management of HSDD and to ensure patients can access treatment.

Efficacy and safety of visnadine in the treatment of symptoms of sexual dysfunction in heterosexual women: a systematic review of randomized clinical trials.

OBJECTIVE: To synthesize the primary evidence on the efficacy and safety of visnadine on symptoms of sexual dysfunction (SD) in heterosexual women. METHODS: We conducted a systematic review of randomized clinical trials (RCTs) with a primary search without language restriction in PubMed/Medline, Scopus, Embase, Web of Science, Cochrane Library, and international clinical trial registries. Trials reporting the use of visnadine by any route in women with SD were eligible. We performed screening, data extraction, and risk of bias assessment in a double-blind approach. The primary outcomes were the Female Sexual Function Index (FSFI) and its domains. Secondary outcomes were safety, arousal, lubrication, pleasure, orgasm, negative sensations, duration, and overall satisfaction. RESULTS: Initially, 242 records were retrieved. We selected nine papers for full-text reading and finally included two RCTs: one with a parallel design and one with a crossover design with a total of 96 patients. One study compared visnadine aerosol with a placebo, while the other compared different frequencies of visnadine aerosol use. Visnadine use showed a statistically significant improvement (p < 0.05) in overall FSFI scores, regardless of the frequency of use. A meta-analysis was not possible due to the high clinical and methodological heterogeneity between available studies. CONCLUSION: RCTs regarding the use of visnadine for the Female SD are scarce and methodologically limited. This preliminary evidence shows visnadine as a potentially effective and safe option to alleviate some of the clinical symptoms of SD in heterosexual women. However, future better-designed randomized studies with larger sample numbers are required.

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

BACKGROUND: Hypoactive sexual desire disorder (HSDD) in premenopausal women involves biological, psychological, and social aspects. In the European Society for Sexual Medicine meeting in Rotterdam in February 2023, several leading experts in the field discussed the multifaceted nature of this disorder and the state of the art regarding treatment at a round table. This review reflects the information discussed at this event and further discusses current controversies. SUMMARY: HSDD is the most prevalent female-estimated sexual disorder reported by 28% of the 40% premenopausal women with sexual dysfunction. Flibanserin and bremelanotide are the only approved medications to treat HSDD in the USA, and none are approved in Europe. Lybrido, Lybridos, and Lorexys are under development. There are several psychological factors with impact in sexual desire, including depression and sexual abuse. Feminine sexual scripts, the pleasure gap, and structural inequalities also affect sexual desire. Evidence strongly supports the value of combining medical and psychological approaches in the treatment of HSDD, but there is ongoing controversy regarding the pharmacological treatment of young women with HSDD. However, some women seem open and would like to have access to drug treatment. KEY MESSAGES: The treatment of HSDD in young women requires a mixed treatment approach that addresses the disorder's complexity. Despite clinicians seeming to be divided between using pharmacological and/or psychosocial approaches, 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.

[Sexual dysfunction on the background of antidepressant therapy]. / Seksual'nye disfunktsii na fone antidepressivnoi terapii.

The review is devoted to the problem of sexual dysfunction caused by taking antidepressants. Sexual dysfunction is widespread, but it is not reported, and its impact on the quality of life and compliance of patients is underestimated. Partly because of its bidirectional association with depression, sexual dysfunction is difficult to diagnose. Possible mechanisms and risk factors associated with sexual dysfunction in patients with depression are considered. The data on the frequency of sexual dysfunction with the use of various antidepressants are given. Therapeutic strategies for sexual dysfunction associated with taking antidepressants are described. The advantages of agomelatin as an antidepressant associated with a low risk of sexual side effects are emphasized.

Sexual Dysfunction in Schizophrenia: A Systematic Review and Meta-Analysis.

Importance: In individuals with schizophrenia, antipsychotic-induced dysfunctions are frequent but often underexplored in clinical practice. Objective: To synthetize the data of observational studies exploring the prevalence of sexual dysfunction in individuals with schizophrenia-spectrum disorders as well as associated factors. Data Sources: A systematic literature search without language or time restrictions was conducted in Google, Google Scholar, PubMed/MEDLINE, Science Direct, and Université Sorbonne Paris Cité for studies published up to June 8, 2022. Study Selection: All observational studies reporting a prevalence of sexual dysfunction in schizophrenia-spectrum disorder were included. Data Extraction and Synthesis: The MOOSE guidelines with independent extraction by 2 observers and random-effects models were used. Main Outcomes and Measures: The prevalence of sexual dysfunction and each specific dysfunction. Results: A total of 72 of 1119 studies from 33 countries on 6 continents published from inception to June 2022 were included with a total of 21 076 participants with schizophrenia. The pooled global prevalence of sexual dysfunctions was 56.4% (95% CI, 50.5-62.2), with a prevalence of 55.7% (95% CI, 48.1-63.1) for men and 60.0% (95% CI, 48.0-70.8) for women. The most frequent sexual dysfunction was erectile dysfunction in men (44%; 95% CI, 33.5-55.2), followed by loss of libido in men (41%; 95% CI, 30.7-51.4), ejaculation dysfunction in men (39%; 95% CI, 26.8-51.8), orgasm dysfunction in women (28%; 95% CI, 18.4-40.2), and amenorrhea in women (25%; 95% CI, 17.3-35.0). Factors associated with heterogeneity were study design, time and location, sociodemographic data, alcohol use disorder, psychiatric diagnosis, illness severity, and the use of antidepressants and anxiolytics. Sexual dysfunctions were more frequent in schizophrenia vs schizoaffective disorders, and erectile disorders were less frequent in individuals with longer illness duration. Antidepressant and mood stabilizer prescriptions were associated with lower rates of erection disorders (ß, -6.30; 95% CI, -10.82 to -1.78); P = .006 and -13.21; 95% CI, -17.59 to -8.83; P < .001, respectively) and ejaculation disorders (ß, -6.10; 95% CI, -10.68 to -1.53; P = .009 and ß, -11.57; 95% CI, -16.34 to -6.80; P < .001, respectively). No obvious improvements in the rates of sexual dysfunction at other times were found, and there were conflicting results regarding antipsychotic classes. Conclusions and Relevance: This systematic review and meta-analysis found a high prevalence of sexual dysfunction among individuals with schizophrenia, with considerable heterogeneity in associated factors. The findings also suggest that some dysfunctions may be explained by schizophrenia. The association between lower rates of dysfunction and antidepressant use suggests that treating comorbid depression could be an effective strategy to improve sexual health. A lack of data on metabolic parameters and physical health in general was also noted, while these issues are frequent in the care of schizophrenia.

Testosterone use for hypoactive sexual desire disorder in postmenopausal women.

Testosterone is an important evidence-based therapy for hypoactive sexual desire disorder (HSDD) in postmenopausal women. Clinical practice guidelines based on the most comprehensive meta-analysis of benefits and risks of testosterone therapy to date state that the sole evidence-based indication for testosterone therapy is HSDD in postmenopausal women. The guidelines also provide recommendations regarding identification of patients, dosing, monitoring, and follow-up. This Practice Pearl will discuss evidence-based testosterone therapy for management of HSDD in postmenopausal women.

Targeting the central melanocortin system for the treatment of metabolic disorders.

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.