Review
This systematic review evaluated the clinical trial evidence base for pharmacological treatments of Hypoactive Sexual Desire Disorder (HSDD) in adult women by systematically searching ClinicalTrials.gov in accordance with PRISMA 2020 guidelines. Nine completed interventional clinical trials met the inclusion criteria, most of which were Phase II or Phase III randomized, double-blind, placebo-controlled studies enrolling primarily premenopausal women with acquired, generalized HSDD. The most extensively studied agents were flibanserin and bremelanotide, both of which target central nervous system pathways involved in sexual desire. Efficacy was most commonly assessed using validated patient-reported outcome tools such as the Female Sexual Function Index desire domain and the Female Sexual Distress Scale. The review found notable heterogeneity across trials in endpoint designation, reporting completeness, and safety data presentation, which limited cross-trial comparisons. Adverse events generally reflected the pharmacological mechanisms of the agents studied. The authors concluded that while progress has been made, significant gaps remain in the pharmacological treatment landscape for HSDD, and called for more standardized trial methodologies and comprehensive outcome reporting to strengthen the overall evidence base. A key limitation is that findings were synthesized descriptively without pooled quantitative (meta-analytic) analysis.
Frontiers in medicine · May 2026DOI ↗ Review
This paper introduces and quantifies the concept of "mercy sex" — defined as sexual activity engaged in by women diagnosed with hypoactive sexual desire disorder (HSDD) despite a documented absence of sexual desire or receptivity. The authors reviewed baseline data on sexually satisfying events (SSEs) drawn from a convenience sample of published, peer-reviewed, prospective, randomized, placebo-controlled clinical trials evaluating HSDD pharmacotherapies (including testosterone, flibanserin, and bremelanotide) conducted over nearly a decade. Baseline SSE data were analyzed across variables including time, age, reproductive status, and geographic region. The study found that women enrolled in these trials reported engaging in sexual activity approximately 2.5 times per month at baseline, despite meeting criteria for HSDD. The authors propose biopsychosocial explanations for this behavior and argue that mercy sex may confound HSDD trial outcomes by inflating baseline SSE rates, potentially skewing assessments of therapeutic efficacy, influencing sample size calculations, and complicating the definition of a clinically meaningful treatment response when SSEs serve as a primary endpoint. Limitations include reliance on secondary analysis of existing trial data and the use of a convenience sample. The paper does not conduct a new primary trial but offers a methodological and conceptual critique of HSDD clinical research design.
Journal of sex & marital therapy · May 2026DOI ↗ Review
This review traces the historical development and clinical adoption of FDA-approved drugs that incorporate d-amino acids — the non-natural mirror-image enantiomers of standard l-amino acids. The authors survey more than 20 FDA-approved drugs spanning therapeutic areas including infectious diseases, endocrine disorders, rare dermatologic conditions, and diagnostic imaging. Key examples discussed include naturally derived compounds such as gramicidin D and synthetic analogs including desmopressin, leuprolide, bremelanotide, and etelcalcetide — the latter highlighted as the first fully d-amino acid peptide to receive FDA approval. The review explains why d-amino acids are pharmacologically attractive: their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them well-suited for long-acting and receptor-selective drug design. The authors also discuss enabling technologies, particularly solid-phase peptide synthesis and mirror-image phage display, that have accelerated the field. As a narrative review, the paper does not present new experimental data, conduct meta-analytic comparisons, or include a systematic literature search, which limits its ability to draw novel evidence-based conclusions. Its primary value lies in synthesizing the historical trajectory and mechanistic rationale of a growing drug class.
Drug development research · May 2026DOI ↗ InsufficientPreprint
This study analyzed a large, publicly available independent testing dataset of 6,441 samples spanning fourteen peptide compounds sold through largely unregulated gray market channels directly to consumers. Compounds examined included BPC-157, semaglutide, tirzepatide, PT-141, TB-500, thymosin beta-4, and others marketed for purposes such as injury recovery, muscle growth, fat loss, and athletic performance. Researchers applied two quality acceptance frameworks — one approximating standards for 503A compounded medications and a stricter model reflecting FDA-approved drug production standards — to assess purity, measured abundance, and endotoxin burden. The study found that between 41.6% and 71.1% of samples failed to meet basic quality criteria depending on the framework applied, and measurable endotoxin contamination was detected in 15% of samples. Gray market peptides were consistently cheaper than FDA-approved alternatives, though cost differentials varied widely (e.g., 72.8% higher for tirzepatide vs. 3,850% higher for PT-141 when comparing FDA-approved options). The authors concluded that consumer-directed third-party testing improves transparency but captures only a fraction of the full safety profile relevant to patients self-administering injectable compounds. Key limitations include reliance on a secondary dataset not collected under controlled research conditions and the inability to assess many other safety dimensions beyond purity and endotoxin levels.
Unknown journal · Apr 2026DOI ↗ Review
This comprehensive narrative review examines nine therapeutic peptides with proposed applications in healthy aging and age-related conditions: tirzepatide (metabolic dysfunction), epitalon (telomere biology), GHK-Cu (dermal regeneration), BPC-157 and TB-500 (tissue repair), Semax (neuroprotection), CJC-1295 and ipamorelin (growth hormone modulation), and bremelanotide (sexual function). The authors searched PubMed, Scopus, and regulatory databases through January 2026, selecting 20 primary sources based on relevance and methodological quality. The review found that FDA-approved agents such as tirzepatide and bremelanotide have robust safety and efficacy data from large-scale trials, while investigational peptides such as epitalon, BPC-157, and TB-500 show promising signals primarily from preclinical and limited clinical studies. The authors highlight significant knowledge gaps, including the absence of long-term safety data for non-approved peptides, undefined optimal dosing regimens, unknown combination therapy effects, and lack of validated biomarkers for monitoring efficacy. The authors conclude that while therapeutic peptides offer mechanistically diverse approaches to aging hallmarks, investigational agents require rigorous clinical trial validation before clinical adoption. As a narrative review, findings are subject to selection bias and do not represent a quantitative synthesis of evidence.
Frontiers in aging · Apr 2026DOI ↗ Review
This review examines sexual dysfunction as a sequela of breast and gynecologic cancer treatment, with a focus on genitourinary syndrome of menopause (GSM). The authors conducted a comprehensive literature search across PubMed, Google Scholar, and Scopus, covering peer-reviewed studies from the past 30 years. Findings were synthesized thematically, grouping studies by cancer type, treatment modality, and impact on sexual function. The review found that common symptoms—including vaginal dryness, dyspareunia, and diminished sexual desire—are frequently underrecognized. Nonhormonal management strategies identified included minimizing irritants, vaginal moisturizers, lubricants, dilators, and pelvic floor therapy. Local hormonal therapies were noted as potentially appropriate for select patients depending on cancer hormone-sensitivity status. For low sexual desire, pharmacological agents such as bremelanotide and flibanserin were reported to have demonstrated efficacy in the literature reviewed. The authors advise against vaginal laser treatments and compounded hormones in these populations due to safety concerns. A multidisciplinary approach involving gynecologic, psychological, and oncologic expertise was emphasized. Limitations include the absence of a formal quality assessment tool and reliance on narrative thematic synthesis rather than meta-analytic methods.
Journal of minimally invasive gynecology · Dec 2025DOI ↗ Review
This narrative review examines pharmacologic management of vasomotor symptoms (VMS) and decreased libido in breast cancer patients receiving endocrine therapy — a population that commonly experiences new or worsened menopausal symptoms. The authors searched PubMed, Cochrane Library, and Web of Science to summarize established agents (SSRIs, SNRIs, gabapentin, clonidine) and highlight emerging therapies: fezolinetant and elinzanetant (neurokinin 3 receptor antagonists for VMS), and flibanserin and bremelanotide (serotonin/dopaminergic modulator and melanocortin receptor agonist, respectively, for low libido). The review notes that existing options provide inadequate symptom relief, representing a meaningful therapeutic gap. Crucially, the authors emphasize that clinical trials supporting these novel agents explicitly excluded breast cancer patients, meaning their safety and efficacy in this population remain unestablished. The paper aims to equip clinicians with practical considerations for weighing these therapies in breast cancer patients while awaiting dedicated research. Key limitations include the review format, reliance on trials conducted in the general population, and the absence of breast cancer-specific clinical data for the highlighted novel agents.
Expert review of clinical pharmacology · Oct 2025DOI ↗ Animal only
This study developed a biodegradable buccal suction patch designed to improve the systemic delivery of peptide therapeutics by bypassing gastrointestinal degradation. Researchers replaced previously used non-degradable silicone materials with thermally crosslinked, synthesized copolyesters, fabricated via a scalable mold-casting process. Mechanical testing across multiple polymer formulations and patch shapes identified the best-performing biodegradable candidate, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated that the biodegradable patch, when combined with a chemical permeation enhancer, improved permeation of a poorly permeable dye compared to controls. In an in vivo study conducted in beagle dogs, the patch substantially improved the bioavailability of semaglutide (4.11 kDa) relative to a commercially available oral tablet over a 10-minute application window. Additionally, the patch achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) compared to subcutaneous injection. Limitations include the use of an animal model (beagle dogs) rather than human subjects, a small experimental scale, and the need for further clinical translation studies. The work highlights a potential sustainable alternative to silicone-based buccal delivery devices.
Journal of Controlled Release · Aug 2025
Moderate · human
This systematic review and meta-analysis examined treatments for female sexual desire, arousal, and orgasmic (DAO) dysfunction, explicitly excluding patients with sexual pain conditions. Researchers searched six major databases through December 2024, screening 8,994 abstracts and ultimately including 36 studies (26 RCTs and 10 single-arm trials). Treatments evaluated included cognitive behavioral therapy (CBT, 10 studies), medications (24 studies), and devices (2 studies). Meta-analyses were feasible for three interventions: mindfulness-based CBT, flibanserin, and bremelanotide, all assessed using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS). The study found that mindfulness-based CBT was associated with significant improvements in total FSFI and DAO subscales; flibanserin was associated with improvements in total FSFI and the desire subscale; and bremelanotide was associated with improvements in total FSFI and both the desire and arousal subscales. All three treatments were associated with reduced sexual distress. Key limitations include the absence of direct head-to-head comparisons between CBT and pharmacotherapy, heterogeneous terminology across studies, varying outcome measures, and insufficient data to draw conclusions about most other treatments reviewed.
Journal of minimally invasive gynecology · Jun 2025DOI ↗ Review
This paper systematically compares four major oncology and gynecology clinical practice guidelines — ASCO (2018), ESO-ESMO (2022), NCCN (2024), and SOGC (2024) — regarding the management of sexual health concerns in female cancer survivors. The authors grouped recommendations across five domains of sexual dysfunction: vaginal dryness, low sex drive, pain, orgasmic dysfunction, and psychological concerns. All four guidelines consistently recommend non-hormonal therapies (lubricants and moisturizers) as first-line treatment for vaginal dryness, with low-dose local estrogen as a second-line option. All guidelines endorse multidisciplinary care including psychosocial counseling, relationship counseling, specialist referral, and cognitive behavioral therapy. Three guidelines (ASCO, NCCN, SOGC) support vaginal dilators and pelvic floor physical therapy for pain. ASCO uniquely recommends any form of stimulation to improve sexual response, while NCCN and SOGC endorse sexual aids for arousal. Pharmacological agents for low libido — including androgens, bupropion, flibanserin, bremelanotide, and buspirone — are mentioned in all guidelines except ESO-ESMO, though the authors note the underlying evidence base is limited. A key limitation is that this is a narrative comparison of guidelines rather than a primary study. The authors conclude that while consensus exists in several areas, further research on pharmacological and counseling interventions is needed.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · Jun 2025DOI ↗ Animal only
This study introduces a biodegradable buccal suction patch designed to improve the systemic delivery of therapeutic peptides by bypassing gastrointestinal degradation. The researchers replaced previously used non-degradable silicone materials with biodegradable copolyesters, which were thermally crosslinked via a scalable mold-casting process. Mechanical testing identified the best-performing polymer formulation, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated enhanced permeation of a poorly permeable dye when a chemical permeation enhancer was co-applied. In a beagle dog in vivo model, the biodegradable patch substantially improved the bioavailability of semaglutide (4.11 kDa) compared to a commercially available oral tablet within a 10-minute application window. The patch also achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) versus subcutaneous injection. Key limitations include the use of an animal model rather than human subjects, a relatively small study scope, and the need for further safety and efficacy validation before clinical translation. The work highlights a promising, more sustainable alternative to silicone-based buccal delivery devices for peptide therapeutics.
Journal of controlled release : official journal of the Controlled Release Society · Jun 2025DOI ↗ Review
This narrative review examines intravenous (IV) peptide and amino acid therapies as potential treatments for erectile dysfunction (ED), a condition involving interrelated vasculogenic, hormonal, and neurological mechanisms in which endothelial dysfunction and oxidative stress are central contributors. The authors conducted a PubMed literature search of English-language publications through October 2024, focusing primarily on studies from the past decade. Four compounds were highlighted: PT-141 (bremelanotide), a melanocortin receptor agonist proposed to act via central nervous system pathways; PnPP-19, a spider venom-derived peptide suggested to work through nitric oxide regulation; and the amino acids L-arginine and L-citrulline, both linked to enhanced endothelial function and nitric oxide synthesis. The review notes that these agents operate through mechanisms distinct from phosphodiesterase type 5 (PDE5) inhibitors, potentially offering alternatives or adjuncts for patients unresponsive to standard therapy. The authors conclude that while early evidence is promising, large-scale clinical trials are needed to establish safety profiles, optimal treatment parameters, and potential synergistic effects with existing ED treatments. As a narrative review, it is subject to selection bias and does not pool quantitative data.
Expert opinion on pharmacotherapy · Mar 2025DOI ↗ Insufficient
This entry reviews the available information on bremelanotide, a cyclic peptide (molecular weight ~1025 Da), specifically in the context of breastfeeding safety. The review notes a complete absence of published clinical data on bremelanotide use during lactation. The authors reason that, based on its physicochemical properties as a large cyclic peptide, transfer into breast milk is theoretically expected to be minimal. Furthermore, even if trace amounts were present in milk, oral absorption by a nursing infant would likely be negligible, as the peptide would probably be degraded by proteolytic enzymes in the infant's gastrointestinal tract. Despite this theoretical reassurance, the review concludes that caution is warranted during breastfeeding due to the lack of empirical data, with particular emphasis on vulnerability in newborn and preterm infants, whose gastrointestinal and hepatic systems are less mature. The primary limitation of this entry is that it is entirely inference-based, drawing on pharmacokinetic principles rather than any direct human or animal lactation studies. No measured milk concentration data, infant outcome data, or controlled observations are cited.
Unknown journal · Feb 2025Source ↗ Review
This review paper evaluates pharmacologic treatments for female sexual dysfunction (FSD), with a primary focus on hypoactive sexual desire disorder (HSDD). The authors examine the two FDA-approved medications for FSD — flibanserin (a daily oral serotonin/dopamine modulator) and bremelanotide (an on-demand injectable melanocortin receptor agonist) — alongside investigational therapies such as Lorexys (a bupropion/trazodone combination) and various testosterone-based treatments. The review synthesizes study outcomes and safety profiles for each agent, and offers clinical guidance on patient selection, diagnosis, expectation setting, side effect management, and patient education. The authors note that while FDA-approved options exist, their clinical uptake has been limited by modest effect sizes, side effect burdens, and barriers to access. Investigational therapies show early promise but require further clinical validation. A key limitation of this paper is its nature as a narrative review, meaning it does not pool data systematically and may be subject to selection bias in the studies included. It does not introduce new primary data.
Clinical obstetrics and gynecology · Jan 2025DOI ↗ Animal only
This study used female Syrian hamsters as an animal model to investigate how bremelanotide (Vyleesi), an FDA-approved drug for hypoactive sexual desire disorder (HSDD), affects the brain's reward system. Researchers examined melanocortin receptor (MC3R and MC4R) expression in the mesolimbic dopamine system — specifically the ventral tegmental area (VTA) and nucleus accumbens (NAc) — and assessed whether the drug enhanced sexual reward using a conditioned place preference (CPP) paradigm. Key findings attributed to the study include: MC4R mRNA was predominantly expressed in dopamine neurons in the VTA, while in the NAc and dorsal striatum, MC4R was rarely co-expressed with dopamine D1 or D2 receptor neurons, appearing instead in interneurons. Neither dose of bremelanotide tested altered melanocortin receptor mRNA expression in the mesolimbic system. Although sexual experience itself produced a CPP in female hamsters, bremelanotide did not enhance this sexual reward response. The authors conclude that bremelanotide does not appear to act through the VTA-NAc reward circuit in this model. A key limitation is that findings are derived entirely from an animal model and may not directly translate to human neurobiology or clinical outcomes.
Neuropharmacology · Jan 2025DOI ↗ Review
This review article summarizes discussions from a round table held at the European Society for Sexual Medicine (ESSM) meeting in Rotterdam (February 2023), where leading experts addressed the diagnosis and treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The authors note that HSDD is the most prevalent female sexual disorder, reported by approximately 28% of the estimated 40% of premenopausal women experiencing sexual dysfunction. The review covers the multifactorial nature of HSDD, encompassing biological, psychological, and sociocultural dimensions—including depression, sexual abuse history, gender-based "pleasure gaps," and structural inequalities. Regarding pharmacotherapy, the authors note that flibanserin and bremelanotide are the only FDA-approved treatments in the USA, while no medications are approved in Europe; compounds such as Lybrido, Lybridos, and Lorexys remain under development. The review reports that evidence supports combining pharmacological and psychosocial approaches, though clinician opinion remains divided. It also highlights that some women express a clear desire for access to drug-based options. A key limitation is that this article is expert opinion and narrative review rather than a systematic review or primary study, limiting the strength of its evidence base.
Pharmacology · Dec 2023DOI ↗ Review
This comprehensive review examines Hypoactive Sexual Desire Disorder (HSDD) in women, covering its etiology, diagnosis, treatment, and societal implications. The authors explore biological contributors — including hormonal fluctuations and neurotransmitter imbalances — alongside psychological factors such as stress, body image, and relationship dynamics, and sociocultural influences including media and cultural norms. Diagnostic criteria from DSM-5 and self-report assessment tools are reviewed to aid accurate identification and differentiation from other sexual disorders. The review surveys a broad spectrum of treatment options: non-pharmacological approaches (cognitive-behavioral therapy, sex therapy, couples therapy), pharmacological interventions (hormone therapy, SSRIs), and novel agents such as flibanserin and bremelanotide, as well as integrative strategies combining psychotherapy with lifestyle modification. The authors also address ongoing controversies, including lack of diagnostic consensus, concerns about medicalizing female sexuality, and ethical questions around pharmaceutical promotion. Future research directions highlighted include advances in neurobiology, personalized medicine, long-term outcome studies, and destigmatization efforts. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and is therefore subject to the limitations of selective source inclusion and potential author bias.
Review
This paper is a narrative review evaluating bremelanotide (Vyleesi), a melanocortin receptor agonist delivered by injection, for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The authors conducted a PubMed literature search of peer-reviewed publications and synthesized available evidence on the drug's proposed mechanism of action, pharmacokinetics, efficacy, and safety profile. The review notes that bremelanotide is thought to work by activating central melanocortin signaling pathways that may enhance sexual desire. Based on clinical trial data, the authors report that bremelanotide produced statistically significant improvements on validated questionnaires measuring sexual desire and distress; however, they characterize the overall clinical benefit as modest. The most commonly reported adverse event across trials was nausea, occurring in approximately 40% of participants. The authors caution that interpreting trial results is complicated by methodological challenges inherent to female sexual dysfunction research, including a pronounced placebo effect, long recall periods, and outcome measures susceptible to expectation bias. This paper does not present original trial data and relies on synthesis of existing literature, limiting its ability to independently confirm efficacy or safety claims.
Expert opinion on pharmacotherapy · Oct 2022DOI ↗ Review
This review paper traces more than a century of melanocortin research, from the initial discovery of melanocortins in 1916 to contemporary therapeutic applications. It describes the five known melanocortin receptors (MC1R–MC5R), with particular attention to the two neural receptors—MC3R and MC4R—which are predominantly expressed in the central nervous system and play key roles in regulating energy homeostasis. The authors systematically categorize ligands for these receptors into three groups: classical ligands (endogenous melanocyte-stimulating hormones and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensins, small molecules, and pharmacoperones), and clinically approved or repurposed agents (ACTH, setmelanotide, bremelanotide, and certain repurposed drugs). The review highlights how early medicinal chemistry efforts modifying endogenous peptides yielded potent and selective tool compounds, and how targeting neural MCRs has emerged as a viable strategy for metabolic conditions such as obesity and cachexia. Limitations inherent to this paper include its review design—it synthesizes existing literature rather than generating new experimental data—and therefore cannot independently establish clinical efficacy or safety for any specific ligand.
Biomolecules · Oct 2022DOI ↗ Review
This paper critically examines the regulatory approval of two FDA-approved drugs for hypoactive sexual desire disorder (HSDD) in women: flibanserin (Addyi, approved 2015) and bremelanotide (Vyleesi, approved 2019). The authors analyze the clinical trial data and outcome measures underpinning each approval. They report that clinical trials for flibanserin showed an average of only approximately one additional enjoyable sexual experience every two months compared to placebo, while bremelanotide trials showed no such numerical gain. The paper also highlights concerns about shifts in primary outcome measures during trials, a contested diagnostic indication, and the influence of a politicized, industry-sponsored patient advocacy campaign on flibanserin's approval—which succeeded on its third regulatory attempt. The authors argue that bremelanotide's approval, despite even weaker efficacy evidence, was facilitated by the regulatory precedent set by flibanserin. The paper calls for reconsideration of these approvals and recommends reforms to better manage conflicts of interest and define clinically meaningful benefit in future regulatory decisions. A key limitation is that this is an opinion/review piece rather than an original clinical study, and does not present new primary data.
Drug and therapeutics bulletin · Oct 2021DOI ↗