I’m not a native english speaker so sorry in advance if this post contains any grammatical errors. I’m neither a doctor/researcher or a science guy so I’ll try to alway provide some reference but be aware that the information that follows may be misinterpreted or simply not correct.

The aim of this post is to understand what is the consensus and the consolidated evidence on PE, and what information we should expect from a clinician/doctor (so you probably won’t find any new therapy you have never heard of). I’m curious and wanted to know a little bit more about this topic since I think there is a lot of misinformation and common beliefs that are rooted but are not backed up by any scientific evidence and even doctors/clinician sometimes are not educated enough on the topic to provide any actual help.Don’t expect anything super well summarised, this is going to be more of a copy and paste work.

Following the Hierarchy of Evidence in medical research meta-analysis, systematic reviews and practice guidelines provide the highest quality of evidence, I focused on the guidelines because I think that are more practical and have more reach to doctors/clinician that are not expert in the field.
I found the ISSM’s (International Society of Sexual Medicine) guidelines to be the most complete guidelines on the topic. The International Society for Sexual Medicine (ISSM) is a medical society devoted to the study of the medicine of human sexuality. It publishes two journals, The Journal of Sexual Medicine (where the guidelines were published, IF for 2022-2023 is 3.9), and the open-access Sexual Medicine Reviews. The last update of the guidelines I found is from 2013/2014, American Urology Association has its own guidelines updated in 2020, they are not specifically focused on just PE but on Disorders of Ejaculation, mainly PE and DE (Delayed Ejaculation). The AUA’s guidelines focus mainly on the management of the patient and the pharmacotherapy and don’t give many indications about the main theories on PE’s causes.

Definition from ISSM

The panel proposed a unified definition of LPE (Long Term PE) and APE (Acquired PE):

It “is a male sexual dysfunction characterized by:

• ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (LPE), OR a clinically significant reduction in latency time, often to about 3 minutes or less (acquired premature ejaculation);
• the inability to delay ejaculation on all or nearly all vaginal penetrations; and
• negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy.”

It also identify additional subtypes: VPE (Variable PE) that occurs irregularly and inconsistently and SPE (Subjective PE) a subjective perception of PE but with the IELT in the “normal range” (so a IELT >= 3 mins, the median IELTs from 2 studies is 5.4 minutes and 6 minutes respectively).

The estimated prevalence of APE and LPE is around 5%, the prevalence of VPE and SPE is higher but these definitions are relatively new so there isn’t a lot of data.

Etiology (form ISSM’s guidelines)

I start by saying that of all the biological factors that have been proposed to explain PE, none has been confirmed in large scale studies, nonetheless some studies are really interesting.

Hypersensitivity of the Glans -> in a small study was found that patient with PE have hypersensitivity and hyperexcitability of the glans via performing somatosensory evoked potentials (brain responses to sensory stimuli). A similar study not cited in ISSM’s Guidelines is Zhang 2009 that found in a small cohort that patients with PE have on average a higher number of dorsal penile nerve branches. Disturbances in central serotonergic neurotransmission -> We know that Serotonin is the main neurotransmitter involved in the control of ejaculation, but in humans specific subtypes of 5-HT (serotonin) receptors involved in PE have not yet been identified. SSRIs work but SSRIs treatment activates many different postsynaptic subtype receptors so we don’t know specifically how it works. In the spinal cord, specific neurons have been found to be essential to ejaculatory reflex in rats and there is also preliminary evidence that such a neural organisation also exists in humans. Genetics of PE -> Some studies have investigated gene polymorphism of receptors of serotonin and oxytocin. Results of the studies are mixed, men with some genetic variants may be predisposed to develop PE but more studies are needed. Hormones imbalances -> Hyperthyroidism has no role in LPE and has been found to be associated with APW in extremely few patients. Recent studies on large population indicate that the endocrine system is involved in the control of ejaculatory function: prolactin in the lowest quartile levels is associated with APE and anxiety symptoms and higher testosterone levels aìcorrelate with PE, while lower androgenization is related to delayed ejaculation. Anyway the guidelines state that both low PRL and relatively high testosterone levels cannot be considered etiologies of PE. Prostatitis -> Prostatic inflammation and chronic bacterial prostatitis have been reported as common findings in men with APE. For the guidelines though there is insufficient evidence to support routine screening of men with PE for this condition. Erectile dysfunction -> For the guidelines ED is unlikely as a comorbidity or etiological factor for LPE, there is data to support that APE is associated with PE. Psychological factors -> there has been limited research on causality; most studies can only report association. It is plausible that psychological factors may lead to PE or vice versa, it is likely that for many men the relationship is reciprocal with either PE or the other factor causing exacerbation of the other.

Psychological/Behavioral interventions

There is not much to say on this topic, well designed studies on behavioural interventions are scarce, apart from the squeeze/start-stop technique other interventions are correct breathing and relaxation of the muscles to control excitement (discussed a lot in this community).

Pharmacological Treatment (from ISSM guidelines)

Dapoxetine: it is a rapid acting and short half-life SSRI with a pharmacokinetic profile supporting a role as an on demand treatment for PE. In randomised controlled trials, dapoxetine 30mg or 60mg taken 1-2 hours before intercourse is more effective than placebo from the first dose resulting in a 2.5 and 3.0 fold increase in IELT. Treatment-related side effects were uncommon, dose dependent and included nausea, diarrhoea, headache and dizziness: they were responsible for study discontinuation in 4% (30mg) and 10% (60mg) of subjects.

Off-Label SSRIs and TCAs: Daily treatment with off-label paroxetine 10-40 mg, clomipramine 12.5-50 mg, sertraline 50-200 mg, fluoxetine 20.40 mg and citalopram 20.40 mg is usually effective in delaying ejaculation. A meta-analysis of published data suggests that paroxetine exerts the strongest ejaculation delay, increasing IELT approximately 8.8-fold over baseline. SSRIs should be avoided in men with a history of bipolar depression.

Topical Local Anesthetics: lidocaine and/or prilocaine as a cream, gel, or spray is well established and is moderately effective in delaying ejaculation, data suggest that diminishing the glans sensitivity may inhibit the spinal reflex that are responsible for ejaculation. PSD502 (Fortacin in Europe) , a lidocaine-prilocaine spray applied 5 minutes before intercourse is associated with a 6.3-fold increase in IELT. There were minimal reports of penile hypoanesthesia and transfer to the partner due to the unique formulation of the compound.

PDE5i: SIldenafil, Tadalafil, Vardenafil, are effective treatments for ED, there is some evidence to support the efficacy and safety of off-label on demand or daily dosing of PDE5i in the treatment of LPE in men with normal erectile function but further evidence based research is encouraged to understand conflicting data.

Other pharmacological treatments

Tramadol: Tramadol has been investigated as a potential off.label therapy for PE, with several studies demonstrating efficacy, the mechanism of action is not completely understood. It may be considered when other therapies have failed because of the risk of addiction and side effects.

Oxytocin: Intraventricular administration of oxytocin antagonist inhibits sexual behaviour in animal studies, however in one human study, an oxytocin antagonist failed to clinically or statistically improve IELT, further human studies are necessary.

Alpha1-adrenoceptor antagonists: not mentioned in ISSM’s guidelines but in the AUA’s. There are not good quality studies on these drugs, Silodosin seems the most effective one. From AUA <Existing efficacy data remains very limited. Additional controlled studies are required to determine the true role of alpha1-blocker for management of PE.

Other treatments

Cryoablation and Neuromodulation of the Dorsal Penile Nerve: invasive and irreversible procedure, which is associated with an increase in the IELT. However, safety of this treatment modality needs to be determined before this procedure can be recommended for treating patients.

Intracavernosal Injection for PE: There is limited evidence regarding the efficacy of intracavernosal vasoactive drug injection for the treatment of PE.

Injections with hyaluronic acid in the glans: a study cited by AUA found a 2.6 fold increase vs 1.1 placebo in ELT, AUA recommends that surgical intervention for PE only to be considered in the context of ethical board approved trial for patients who have failed or cannot tolerate alternative management strategies for PE.

Preclinical studies for PE

Several agents have been studied in animal models for treating PE: a potent SSRI (DA-8031) significantly inhibited ejaculation in rat models. There are some human studies after 2013 (so after the publication of the guidelines) but I can’t understand in which phase the drug is and if the possible therapy with this SSRI is on-demand or not and the drug is not mentioned in AUA’s guidelines and I don’t understand why.

Modafinil, used in the treatment of narcolepsy, produced significant delay in ejaculation in rat models. Can’t find a lot of studies after 2013, in the AUA’s guidelines form 2020 it’s reported that in an uncontrolled pilot study of on-demand modafinil it’s reported a modest but significant two-fold increase in IELT.

Injection of botulinum toxin in the bulbospongiosus muscle, from AUA’s guidelines: the toxin that blocks neural transmission when injected into the muscle. But studies for PE were discontinued due to lack of efficacy in interim analysis.

Oxytocin antagonists (from AUA’s guidelines): Cligosoban is a oxytocin receptor antagonist that in a RCT double blind trial showed statistically significant effect of LPE men (3.6 fold increase in ELT vs 1.8 for placebo).

Further study and potentially development of agents with different distribution is required to determine if these therapies will have a role in PE management in the future.