Stoking Sexual Arousal and Desire: GLP-1s, Nerve Stimulation, ‘Scream Cream’

WASHINGTON — Interest in GLP-1 receptor agonists as a potential aid to sexual desire and arousal disorders took off in the field of sexual medicine — and landed with a thud.

“GLP-1s are not what I would call treatments for low desire or arousal because we’ve actually been seeing that they may negatively impact sexual function,” said Jessica Yih, MD, of the University of California Irvine, during the Society of Sexual Medicine of North America session at the American Urological Association meeting.

Yih cited several recent examples:

• A case report linked initiation of GLP-1 treatment to new-onset anorgasmia in a woman.
• A retrospective cohort analysis showed a significantly increased risk of erectile dysfunction and testosterone deficiency in nondiabetic men taking GLP-1 agonists.
• A review of the FDA Adverse Events Reporting System turned up 182 cases of sexual dysfunction in men, including orgasmic dysfunction, erectile dysfunction, and decreased libido.
• A preclinical study showing reduced sexual interest and activity in sexually experienced female animals exposed to GLP-1 drugs.

GLP-1 receptor agonists may adversely affect sexual arousal and desire by two mechanisms, said Yih. Rapid weight loss induced by the drugs may increase levels of sex hormone-binding globulin and reduce levels of free testosterone, both of which can diminish libido and sexual arousal. Additionally, GLP-1 agonists can activate the serotonergic pathway, leading to increased serotonin load, which has been implicated in sexual dysfunction among users of selective serotonin reuptake inhibitors, a class of antidepressants.

“We really need to screen for these drugs,” said Yih. “A lot of patients don’t necessarily have GLP-1s on their medication list, so you don’t know that they have them. They’re getting them from an online pharmacy somewhere. Some patients still have a lot of judgement or negative feelings about taking these medications, so they aren’t willing to disclose that. We really need to ask patients specifically if they are on these drugs, especially if they present with concerns like low libido or low desire.”

“We need to check their testosterone and their free testosterone to see whether low libido is related to the hormonal pathway or whether it’s more related to the serotonergic pathway.”

The effects of GLP-1 drugs on sexual function might be population dependent, Yih added. Improvement in obesity or diabetes related to weight loss can reduce erectile dysfunction in some men. However, GLP-1 agonists can decrease desire and arousal in women and nondiabetic men, wherein the metabolic benefit is not the primary driver.

In contrast to GLP-1 receptor agonists, a number of other treatments have more established potential to improve sexual arousal and desire disorders.

‘Scream Cream’

This colloquial term refers to several types of compounded topical formulations that are applied to the clitoris and genital area before sexual activity, said Yih. Common ingredients include sildenafil (Viagra), L-arginine, pentoxifylline, aminophylline, and testosterone.

“Basically, these are all things that may potentially cause vasodilation,” she said. “The limitation here is that these are all compounded medications. There are no FDA-approved medications, so they have nonstandardized formulations. Every provider may have their own preferred formulation.”

Results of randomized clinical trials are mixed, Yih continued. Some trials have shown significant benefits whereas others failed to improve the primary endpoint. One consistent finding from the trials has been a large placebo effect. For example, one randomized trial from China showed that more than half of women achieved “arousal success” with topical alprostadil, but a third of patients randomized to a placebo formulation also met criteria for success.

Understanding criteria for grading compounding pharmacies’ safety and reliability can help clinicians evaluate products and counsel patients about their use. In general, the highest rated compounding pharmacies are 503B Outsourcing Facilities, said Yih. They are FDA registered, compliant with Current Good Manufacturing Practices, and batch tested.

From the 503B facilities, the standards for compounding pharmacies include various forms of state regulation, inspection by the Pharmacy Compounding Accreditation Board, and voluntary compliance with standards criteria. The least reliable are direct-to-consumer compounding pharmacies, which are found primarily online and have no verifiable oversight of standards.

“If you’re prescribing these for patients, and some of the products can be quite effective, you want to be sure that you’re sending your prescriptions to a very reliable compounding pharmacy,” said Yih.

Vaginal Androgens

These products typically consist of some combination of DHEA and testosterone. The products are FDA approved for moderate-to-severe dyspareunia related to genitourinary syndrome of menopause. Benefits likely result from local-tissue effects rather than central neuromodulation.

One of the larger clinical trials of vaginal DHEA showed significant improvement in all six domains of the Female Sexual Function Index (FSFI). A comparison of vaginal estradiol and vaginal DHEA showed that the former was superior for markers of vaginal atrophy and vaginal pH, whereas DHEA provided greater relief of dyspareunia. In a recent review of compounded vaginal testosterone plus DHEA, the American College of Obstetricians and Gynecologists found evidence of significant improvement in arousal, lubrication, satisfaction, pain, and total FSFI score but no improvement in desire or orgasm.

“We want to treat the local tissue with vaginal DHEA, vaginal estrogen, and testosterone, but we also want to make sure that we’re treating any central deficiency, because using vaginal therapies is probably just improving libido and desire through improvement in vaginal tissue,” said Yih.

Central-acting therapies that have proven useful for treating desire and arousal disorders include transdermal testosterone, bremelanotide (Vyleesi), flibanserin (Addyi), and bupropion.

Sacral Neuromodulation

The benefits of sacral neuromodulation on sexual function come with the caveat that all the evidence is from studies involving women with overactive bladder, urinary retention, or fecal incontinence, said Yih. Effects on sexual function were assessed as secondary outcomes. No trial has specifically assessed the treatment for sexual dysfunction. That being said, the sexual function results have generally been favorable.

A meta-analysis of 17 studies involving women with pelvic floor/bladder dysfunction showed improvement in sexual function in eight studies. A recent systematic review of 30 studies showed improvement in desire, arousal, orgasm, lubrication, and dyspareunia in a pooled analysis of the data.

“Is this an improvement in their local tissue versus a central issue?” Yih asked. “Is their improvement in libido and desire related to leaking less, less incontinence and that is putting them in more of a mindset to be sexually active because they’re not worried about being incontinent during sexual activity? Is this actually improving their sexual function independent of that? That question is still unanswered, but I think it would be a great ‘next thing’ to take a look at.”

Bremelanotide for Men

Already an FDA-approved treatment for hypoactive sexual desire disorder in women, a growing number of men ask about off-label use for erectile dysfunction, said Yih. A central acting melanocortin-4 receptor agonist, the drug has shown potential to improve erectile dysfunction. Intranasal bremelanotide was evaluated in a placebo-controlled trial in men with erectile dysfunction that had not responded to sildenafil. The results showed a positive response rate of 33.5% versus 8.5%, and men randomized to bremelanotide reported greater satisfaction with intercourse.

“The medication increases dopamine and norepinephrine in the areas of the brain that increase sexual desire and arousal,” said Yih. “We all have brains, men and women, so it’s going to work in the brain for everybody.

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