Introduction to Bremelanotide and Hypoactive sexual desire disorder

Bremelanotide is a non-selective melanocortin receptor (MCR) agonist. It is also an analogue of the natural peptide alpha-melanocyte stimulating hormone (α-MSH). It received FDA approval in June 2019 for the treatment of acquired, systemic HSDD in premenopausal women. It is a self-administered medication that is administered subcutaneously or intranasally as needed prior to anticipated sexual activity.

Hypoactive sexual desire disorder (HSDD) is defined by the International Association for the Study of Women's Sexual Health as a lack of motivation to engage in sexual activity as evidenced by (1) reduced or absent spontaneous desire (sexual thoughts or fantasies), (2) reduced or lack of responsiveness to erotic cues and stimuli or an inability to maintain desire or interest through sexual activity, or (3) a loss of desire to initiate or engage in sexual activity, including behavioural responses such as avoidance of situations that may lead to sexual activity situations that are not secondary to a sexual pain disorder and are associated with clinically significant personal distress.

Currently, two medications are approved by the FDA for the treatment of HSDD in premenopausal women. Flibanserin, a mixture of a blood-hydroxytryptamine receptor 1A (5-HT1A) agonist and a 5-hydroxytryptamine 2A (5-HT2A) antagonist, is a pill that is taken once daily. another final is Bremelanotide, which is a new, therapeutically promising drug for the treatment of HSDD.

Mechanism of action

Bremelanotide is a melanocortin receptor agonist. It nonselectively activates MC1R, MC2R, MC3R, MC4R, and MC5R receptor subtypes. Neurons expressing MC4R are present in central nervous system and peripheral tissues. Activation of these receptors modulates brain pathways involved in sexual response. Activation of MC1R contributes to a possible side effect of hyperpigmentation. Bremelanotide was initially developed as an intranasal formulation. This route was associated with wide variability in bioavailability, which increased the incidence of adverse effects. Bremelanotide is currently formulated as a subcutaneous injection with 100% bioavailability。

Bremelanotide, an analog of α-MSH, primarily acts on excitatory pathways involved in sexual response to enhance sexual desire and arousal by stimulating DA release in the mPOA, as shown in preclinical studies in female rats. Bremelanotide, with its unique mechanism of action, has the potential to fill an unmet medical need for premenopausal women suffering from HSDD who require increased excitation.

Side effects of Bremelanotide

Bremelanotide affects blood pressure and heart rate, causing a transient increase and decrease, respectively. Clinicians should consider cardiovascular risk. Bremelanotide is contraindicated in those with uncontrolled hypertension or unknown cardiovascular disease and should be avoided in those with a high risk of heart disease. Individuals should be advised to separate doses by at least 24 hours to avoid more pronounced blood pressure effects.

Focal hyperpigmentation was reported in 1% of individuals receiving up to 8 monthly doses of bremelanotide. 7 This mainly affected the face, gingiva, and breasts and was more likely to occur in those with dark skin. Hyperpigmentation was not confirmed to resolve after bremelanotide was discontinued. Based on this risk, bremelanotide should be used 8 times per month maximum and should be discontinued if hyperpigmentation develops, as it can be permanent.

References:

[1] PFAUSJAMES G. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.[J]. CNS Spectrums, 2022, 27 3: 281-289. DOI:10.1017/S109285292100002X.

[2] MAYERDANIELLE; LynchSarah E. Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder.[J]. Annals of Pharmacotherapy, 2020, 54 7: 684-690. DOI:10.1177/1060028019899152.